FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Weinberg, OK Gibson, CJ Pozdnyakova, O Kuo, FC Ebert, B Hasserjian, RP AF Weinberg, Olga K. Gibson, Christopher J. Pozdnyakova, Olga Kuo, Frank C. Ebert, Benjamin Hasserjian, Robert P. TI Both Mutations and Morphology Independently Predict Prognosis in De Novo AML with Intermediate-Risk Karyotype SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 Boston Childrens Hosp, Boston, MA USA. Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 1543 BP 385A EP 385A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724402027 ER PT J AU Weinberg, OK Gibson, CJ Pozdnyakova, O Kuo, FC Ebert, B Hasserjian, RP AF Weinberg, Olga K. Gibson, Christopher J. Pozdnyakova, Olga Kuo, Frank C. Ebert, Benjamin Hasserjian, Robert P. TI Specific Dysplastic Findings Correlate with Gene Mutations in De Novo AML SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 Boston Childrens Hosp, Boston, MA USA. Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 1542 BP 385A EP 385A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724402026 ER PT J AU Wong, WJ Baltay, MT Kuo, FC Fuhrman, K Hasserjian, RP Pozdnyakova, O AF Wong, Waihay J. Baltay, Michele T. Kuo, Frank C. Fuhrman, Kit Hasserjian, Robert P. Pozdnyakova, Olga TI Integrated Molecular and Histologic Analysis Identifies Distinctive Gene Expression Patterns in Primary Myelofibrosis SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Nanostring Technol Inc, Seattle, WA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 1546 BP 386A EP 386A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724402030 ER PT J AU Xia, D Sayed, S Moloo, Z Gakinya, S Mutuiri, A Courville, EL Hasserjian, RP Sohani, A AF Xia, Daniel Sayed, Shahin Moloo, Zahir Gakinya, Samuel Mutuiri, Anderson Courville, Elizabeth L. Hasserjian, Robert P. Sohani, Aliyah TI Clinicopathologic Characterization of Nodular Lymphocyte Predominant Hodgkin Lymphoma from Kenya SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Aga Khan Univ Hosp, Nairobi, Kenya. Univ Minnesota, Minneapolils, MN USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 1547 BP 386A EP 386A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724402031 ER PT J AU Fu, XJ Bautista, P Lennerz, JK Onozato, M Iafrate, A Yagi, Y AF Fu, Xiujun Bautista, Pinky Lennerz, Jochen K. Onozato, Maristela Iafrate, Anthony Yagi, Yitkako TI Apply a Confocal WSI Scanner for FISH Slides Imaging, 3D Reconstruction, and Semi-Automated Diagnosis SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 1585 BP 396A EP 396A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724402069 ER PT J AU Faulkner-Jones, BE Law, C Rosen, M Rosen, D Luffman, CI Rosen, S AF Faulkner-Jones, Beverly E. Law, Charles Rosen, Milan Rosen, Devin Luffman, Christina I. Rosen, Seymour TI Renal Biopsy Data Analysis from Whole Slide Imaging: A Novel "Holistic" Approach SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 BIDMC, Boston, MA USA. Kitware Inc, Clifton Pk, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 1624 BP 406A EP 406A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724402107 ER PT J AU Xu, J Rosen, M Luffman, CI Faulkner-Jones, BE Rosen, S AF Xu, Jia Rosen, Milan Luffman, Christina I. Faulkner-Jones, Beverly E. Rosen, Seymour TI Convergence of Vasculopathy and Vasculitis: Digital Profiling as a Novel Approach for the Study of the Renal Biopsy SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 [Xu, Jia; Rosen, Milan; Luffman, Christina I.; Faulkner-Jones, Beverly E.; Rosen, Seymour] BIDMC, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 1649 BP 411A EP 411A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724402129 ER PT J AU Lee, M de Gonzalez, AK Remotti, HE Gandhi, M Levinson, S Deshpande, V Lagana, SM AF Lee, Michael de Gonzalez, Anne Koehne Remotti, Helen E. Gandhi, Manoj Levinson, Shauna Deshpande, Vikram Lagana, Stephen M. TI In-Situ Hybridization for Glypican-3 RNA Is More Sensitive Than Immunohistochemistry in Hepatocellular Carcinoma SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 Columbia Univ, New York, NY USA. Affymetrix, Santa Clara, CA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 1679 BP 419A EP 419A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724402159 ER PT J AU Solomon, D Goode, B Hyun, MD Joseph, NM Van Ziffle, J Butowski, N Brat, DJ Kleinschmidt-DeMasters, B Rodriguez, F Louis, DN Yong, W Lopes, B Rosenblum, M Tihan, T Bollen, A Perry, A AF Solomon, David Goode, Benjamin Hyun, Michael D. Joseph, Nancy M. Van Ziffle, Jessica Butowski, Nicholas Brat, Daniel J. Kleinschmidt-DeMasters, Bette Rodriguez, Fausto Louis, David N. Yong, William Lopes, Beatriz Rosenblum, Marc Tihan, Tarik Bollen, Andrew Perry, Arie TI A Recurrent Kinase Domain Mutation p.D463H in PRKCA Defines Chordoid Glioma of the Third Ventricle SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. Emory Univ, Atlanta, GA 30322 USA. Univ Colorado, Denver, CO 80202 USA. Johns Hopkins Univ, Baltimore, MD USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Calif Los Angeles, Los Angeles, CA USA. Univ Virginia, Charlottesville, VA USA. Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 1753 BP 437A EP 437A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724402234 ER PT J AU Williams, E Kim, J Muzikansky, A Shaw, M Iafrate, J Plotkin, S Suva, M Stemmer-Rachamimov, A AF Williams, Erik Kim, James Muzikansky, Alona Shaw, McKenzie Iafrate, John Plotkin, Scott Suva, Mario Stemmer-Rachamimov, Anat TI Molecular and Histologic Features of a Series of Sporadic and Familial Schwannomas SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Broad Inst MIT & Harvard, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 1763 BP 439A EP 439A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724402244 ER PT J AU Nowak, JA Wu, YR Qian, ZR Rubinson, DA Morales-Oyarvide, V Dunne, RF Findeis-Hosey, JJ Hornick, JL Brais, L Da Silva, A Welch, M Yuan, C Kozak, M Ducar, M Thorner, A Wollison, B Fuchs, C Ogino, S Hezel, A Koong, A Wolpin, B AF Nowak, Jonathan A. Wu, Yiru Qian, Zhirong Rubinson, Douglas A. Morales-Oyarvide, Vicente Dunne, Richard F. Findeis-Hosey, Jennifer J. Hornick, Jason L. Brais, Lauren Da Silva, Annacarolina Welch, Marisa Yuan, Chen Kozak, Margaret Ducar, Matthew Thorner, Aaron Wollison, Bruce Fuchs, Charles Ogino, Shuji Hezel, Aram Koong, Albert Wolpin, Brian TI Molecular Correlates of Major Morphologic Subtypes of Pancreatic Ductal Adenocarcinoma SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Rochester, Rochester, NY USA. Stanford Univ, Stanford, CA 94305 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 1803 BP 449A EP 449A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724402284 ER PT J AU Marino-Enriquez, A Kuo, FC Baltay, M Demetri, G Lindeman, NI Fletcher, J Sholl, LM AF Marino-Enriquez, Adrian Kuo, Frank C. Baltay, Michele Demetri, George Lindeman, Neal I. Fletcher, Jonathan Sholl, Lynette M. TI Identification of Sarcoma Fusion Genes by Multiplex Detection of Aberrant 3 ' to 5 ' Expression Ratios SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 1847 BP 459A EP 460A PG 2 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724402328 ER PT J AU Glass, CH Redig, AJ Hung, YP French, C Sholl, LM AF Glass, Carolyn H. Redig, Amanda J. Hung, Yin P. French, Christopher Sholl, Lynette M. TI SMARCA4 Loss in Lung Cancer Is Associated with Distinct Clinicopathologic Features SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 1926 BP 479A EP 479A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724402407 ER PT J AU Hung, YR Dong, F Nardi, V Watkins, JC Godleski, J Dal Cin, P Crum, CP Chirieac, LR AF Hung, Yin (Rex) Dong, Fei Nardi, Valentina Watkins, Jaclyn C. Godleski, John Dal Cin, Paola Crum, Christopher P. Chirieac, Lucian R. TI A Subset of Diffuse Malignant Peritoneal Mesothelioma Have Novel ALK Rearrangements and Distinct Clinicopathologic Features SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 1931 BP 480A EP 480A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724402412 ER PT J AU Hwang, DH Mentzer, SJ Johnson, BE Sholl, LM AF Hwang, David H. Mentzer, Steven J. Johnson, Bruce E. Sholl, Lynette M. TI Next Generation Sequencing Frequently Contradicts Surgical Pathology Impression of Relatedness of Multiple Tumors in the Lung SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 1932 BP 480A EP 480A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724402413 ER PT J AU Jin, Y Matsubara, O Yamanaka, K Mark, E AF Jin, Yasuto Matsubara, Osamu Yamanaka, Kazuki Mark, Eugene TI Intratumoral Programmed Cell Death-Ligand 1 (PD-L1) and Intratumoral CD8(+) T Cell Expression in Lung Cancer SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 Hiratsuka Kyosai Hosp, Hiratsuka, Kanagawa, Japan. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 1935 BP 481A EP 481A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724402416 ER PT J AU Ordulu, Z Kem, M Huynh, T Dias-Santagata, D Iafrate, J Mino-Kenudson, M AF Ordulu, Zehra Kem, Marina Huynh, Tiffany Dias-Santagata, Dora Iafrate, John Mino-Kenudson, Mari TI PDL-1 Expression in Synchronous Lung Nodules: Association with Driver Mutations and CD8+Cytotoxic T Lymphocytes SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 [Ordulu, Zehra; Kem, Marina; Huynh, Tiffany; Dias-Santagata, Dora; Iafrate, John; Mino-Kenudson, Mari] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 1963 BP 487A EP 487A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724402444 ER PT J AU Ritterhouse, L Vivero, M Mino-Kenudson, M Sholl, LM Iafrate, J Nardi, V Dong, F AF Ritterhouse, Lauren Vivero, Marina Mino-Kenudson, Mari Sholl, Lynette M. Iafrate, John Nardi, Valentina Dong, Fei TI GNAS Mutations in Mucinous and Non-Mucinous Lung Carcinomas SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 1977 BP 491A EP 491A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724402458 ER PT J AU Rosen, LE Ananthanarayanan, V Gallan, A Tjota, MY Attanoos, R Alchami, FS Brcic, L Butnor, K Hiroshima, K Klampatsa, A Litzky, L Marchevsky, AM Medeiros, F Montero-Fernandez, MA Moore, DA Nabeshima, K Pavlisko, EN Sharma, A Sheaf, M Walls, AE Galateau, F Le Stang, N Krausz, T Husain, AN AF Rosen, Lauren E. Ananthanarayanan, Vijayalakshmi Gallan, Alexander Tjota, Melissa Yuwono Attanoos, Richard Alchami, Fouad S. Brcic, Luka Butnor, Kelly Hiroshima, Kenzo Klampatsa, Astero Litzky, Leslie Marchevsky, Alberto M. Medeiros, Filomena Montero-Fernandez, M. Angeles Moore, David A. Nabeshima, Kazuki Pavlisko, Elizabeth N. Sharma, Anupama Sheaf, Michael Walls, Ann E. Galateau, Francoise Le Stang, Nolwenn Krausz, Thomas Husain, Aliya N. TI Nuclear Grade, Necrosis and Solid Growth Pattern Predict Survival in Epithelioid Malignant Mesothelioma: An International, Multi Institutional Study SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 Univ Chicago, Chicago, IL 60637 USA. Loyola, Maywood, IL USA. Univ Wales Coll Cardiff, Cardiff, S Glam, Wales. Med Univ Graz, Graz, Austria. Univ Vermont, Burlington, VT USA. Tokyo Womens Med Ctr, Kawadacho, Japan. Univ Penn, Philadelphia, PA 19104 USA. Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. Basildon & Thurrock Univ Hosp, Basildon, England. Royal Brompton & Harefield Hosp, London, England. Univ Leicester, Leicester, Leics, England. Fukuoka Univ, Fukuoka, Japan. Duke Univ, Durham, NH USA. Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA USA. Barts Hlth NHS Trust, London, England. Ctr Leon Berard, Lyon, France. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 1980 BP 492A EP 492A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724402461 ER PT J AU Shih, A Uruga, H Muzikansky, A Bozkurtlar, E Chung, JH Hariri, L Minami, Y Moreira, AL Wang, H Yoshizawa, A Mino-Kenudson, M AF Shih, Angela Uruga, Hironori Muzikansky, Alona Bozkurtlar, Emine Chung, Jin-Haeng Hariri, Lida Minami, Yuko Moreira, Andre L. Wang, He Yoshizawa, Akihiko Mino-Kenudson, Mari TI Reproducibility in Classification of Small Lung Adenocarcinomas: An International Interobserver Study SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Marmara Univ, Istanbul, Turkey. Seoul Natl Univ, Bundang Hosp, Seongnam, South Korea. Ibarakihigashi Natl Hosp, Natl Hosp Org, Naka, Ibaraki, Japan. NYU, Langone Med Ctr, New York, NY USA. Temple Univ, Sch Med, Philadelphia, PA 19122 USA. Kyoto Univ Hosp, Kyoto, Japan. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 1993 BP 495A EP 495A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724402474 ER PT J AU Shih, A Fu, XJ Hariri, L Huynh, T Mark, E Yagi, Y Mino-Kenudson, M AF Shih, Angela Fu, Xiujun Hariri, Lida Huynh, Tiffany Mark, Eugene Yagi, Yukako Mino-Kenudson, Mari TI Alveolar Framework Alterations in Fibrosing Interstitial Lung Disease: A Three-Dimensional Reconstruction Study SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 [Shih, Angela; Fu, Xiujun; Hariri, Lida; Huynh, Tiffany; Mark, Eugene; Yagi, Yukako; Mino-Kenudson, Mari] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 1992 BP 495A EP 495A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724402473 ER PT J AU Zhang, ML Kem, M Campo, MJ Huynh, T Gainor, JF Mino-Kenudson, M AF Zhang, Mingjuan L. Kem, Marina Campo, Meghan J. Huynh, Tiffany Gainor, Justin F. Mino-Kenudson, Mari TI Differential Expression of Immune Inhibitory Markers in Association with the Immune Microenvironment in Resected Lung Adenocarcinomas SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 [Zhang, Mingjuan L.; Kem, Marina; Campo, Meghan J.; Huynh, Tiffany; Gainor, Justin F.; Mino-Kenudson, Mari] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 2012 BP 500A EP 500A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724402493 ER PT J AU Crotty, R Prasad, S Brachtel, E Deshpande, V AF Crotty, Rory Prasad, Shilpa Brachtel, Elena Deshpande, Vikram TI XIST as a Tool for Resolving Specimen Contamination Events SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Boston Univ, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 2028 BP 504A EP 504A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724402509 ER PT J AU Maglantay, RJ Cunningham, VL Goodwin, MT Feeney, M Keefe, J Sohani, A Tambouret, RH AF Maglantay, Remegio J. Cunningham, Vickie L. Goodwin, Michele T. Feeney, Margaret Keefe, Joan Sohani, Aliyah Tambouret, Rosemary H. TI Evaluation of Body Fluids: Detection of Malignancy in Specimens Submitted for Cell Count and Differential in the Hematology Laboratory SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 [Maglantay, Remegio J.; Cunningham, Vickie L.; Goodwin, Michele T.; Feeney, Margaret; Keefe, Joan; Sohani, Aliyah; Tambouret, Rosemary H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 2059 BP 511A EP 511A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724402540 ER PT J AU Maglantay, RJ Wang, JL Pozdnyakova, O Ly, A AF Maglantay, Remegio J. Wang, Jessica L. Pozdnyakova, Olga Ly, Amy TI Comparison of Two Methods for Cytologic Evaluation of Cerebrospinal Fluids SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. Atrius Hlth, Needham, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 2060 BP 512A EP 512A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724402541 ER PT J AU Qin, J Tambouret, RH AF Qin, Jia Tambouret, Rosemary H. TI Rapid FNA Diagnosis of Lymphadenopathy SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 [Qin, Jia; Tambouret, Rosemary H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 2078 BP 516A EP 516A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724402559 ER PT J AU Wong, A Bhan, A Lennerz, JK Brachtel, E AF Wong, Adele Bhan, Atul Lennerz, Jochen K. Brachtel, Elena TI HER2/ERBB2 Testing in Breast Carcinoma by Next Generation Sequencing SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 Massachusetts Gen Hosp, Boston, MA USA. Harvard Med Sch, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 2101 BP 522A EP 522A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724402582 ER PT J AU Ahmed, R Yetisen, AK Yun, SH Butt, H AF Ahmed, Rajib Yetisen, Ali K. Yun, Seok Hyun Butt, Haider TI Color-selective holographic retroreflector array for sensing applications SO LIGHT-SCIENCE & APPLICATIONS LA English DT Article DE Bragg gratings; corner cube retroreflectors; diffraction optics; holography; sensors ID NANOPARTICLES; GRAPHENE; SENSORS AB Corner cube retroreflectors (CCRs) have applications in sensors, image processing, free space communication and wireless networks. The ability to construct low-loss wavelength filters embedded in CCRs can enable the development of wavelength multiplexing, tunable lasers and photonic integrated circuits. Here we created an similar to 10-mu m-thick holographic corner cube retroreflector (HCCR) array that acted as a color-selective wavelength filter and diffracted light at broad angles. Angle-resolved spectral measurements showed that the Bragg peak of the diffracted light from the HCCR array could be tuned from 460 to 545 nm by varying the incident angle. The HCCR array also exhibited a wavelength-selective tuning capability based on the rotation angle in the visible spectrum. HCCRs projected holographic images with the rotational property in the far field. The utility of the HCCR was demonstrated as optical temperature and relative humidity sensors that produced a visible colorimetric response for rapid diagnostics. C1 [Ahmed, Rajib; Butt, Haider] Univ Birmingham, Sch Engn, Microengn & Nanotechnol Lab, Birmingham B15 2TT, W Midlands, England. [Yetisen, Ali K.; Yun, Seok Hyun] Harvard Med Sch, Cambridge, MA 02139 USA. [Yetisen, Ali K.; Yun, Seok Hyun] Massachusetts Gen Hosp, Wellman Ctr Photomed, Cambridge, MA 02139 USA. [Yetisen, Ali K.; Yun, Seok Hyun] MIT, Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Butt, H (reprint author), Univ Birmingham, Sch Engn, Microengn & Nanotechnol Lab, Birmingham B15 2TT, W Midlands, England. EM h.butt@bham.ac.uk FU Leverhulme Trust; Wellcome Trust FX HB thanks the Leverhulme Trust and Wellcome Trust for research funding. We thank Jeff Blyth for discussions. NR 38 TC 3 Z9 3 U1 0 U2 0 PU CHINESE ACAD SCIENCES, CHANGCHUN INST OPTICS FINE MECHANICS AND PHYSICS PI CHANGCHUN PA 3888, DONGNANHU ROAD, CHANGCHUN, 130033, PEOPLES R CHINA SN 2047-7538 J9 LIGHT-SCI APPL JI Light-Sci. Appl. PD FEB PY 2017 VL 6 AR e16214 DI 10.1038/lsa.2016.214 PG 9 WC Optics SC Optics GA EN2IW UT WOS:000395834200004 ER PT J AU Katon, J Cypel, Y Raza, M Zephyrin, L Reiber, G Yano, EM Barth, S Schneiderman, A AF Katon, Jodie Cypel, Yasmin Raza, Mubashra Zephyrin, Laurie Reiber, Gayle Yano, Elizabeth M. Barth, Shannon Schneiderman, Aaron TI Deployment and Adverse Pregnancy Outcomes: Primary Findings and Methodological Considerations SO MATERNAL AND CHILD HEALTH JOURNAL LA English DT Article DE Deployment; Preterm birth; Low birth weight; Women Veterans; OEF/OIF ID GULF-WAR VETERANS; POSTTRAUMATIC-STRESS-DISORDER; LOW-BIRTH-WEIGHT; PRETERM BIRTH; UNITED-STATES; VIETNAM VETERANS; GESTATIONAL-AGE; MATERNAL RECALL; WOMEN VETERANS; RISK AB Objective To characterize the pregnancy outcomes of women Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) Veterans including prevalence of preterm delivery, low birth weight, and macrosomia, and to highlight methodological limitations that can impact findings. Methods A retrospective cohort study was conducted starting in 2014 analyzing data from the 2009 to 2011 National Health Study for a New Generation of US Veterans, which sampled Veterans deployed and not deployed to OIF/OEF. All pregnancies resulting in a live birth were included, and categorized as occurring among non-deployers, before deployment, during deployment, or after deployment. Outcomes included preterm birth, low birth weight, and macrosomia. The association of deployment with selected outcomes was estimated using separate general estimating equations to account for lack of outcome independence among women contributing multiple pregnancies. Adjustment variables included maternal age at outcome, and race/ethnicity. Results There were 2276 live births (191 preterm births, 153 low birth weight infants, and 272 macrosomic infants). Compared with pregnancies before deployment, pregnancies among non-deployers and those after deployment appeared to have greater risk of preterm birth [non-deployers: odds ratio (OR) = 2.16, 95 % confidence interval (CI) 1.25, 3.72; after deployment: OR = 1.90, 95 % CI 0.90, 4.02]. A similar pattern was observed for low birth weight. No association of deployment with macrosomia was detected. Discussion Compared with non-deployers, those who eventually deploy appear to have better pregnancy outcomes prior to deployment, but this advantage is no longer apparent after deployment. Non-deployers may not be an appropriate reference group to study the putative health impacts of deployment on pregnancy outcomes. C1 [Katon, Jodie; Zephyrin, Laurie] US Dept Vet Affairs VA, Off Patient Care Serv, Womens Hlth Serv, Washington, DC 20420 USA. [Katon, Jodie; Reiber, Gayle] VA Puget Sound Hlth Care Syst, Sch Med, Ctr Innovat Vet Ctr & Value Driven Care, VA Hlth Serv Res & Dev HSR&D, 1660 South Columbia Way S-152, Seattle, WA 98108 USA. [Katon, Jodie; Reiber, Gayle] Univ Washington, Dept Hlth Serv, Sch Publ Hlth, Seattle, WA 98195 USA. [Cypel, Yasmin; Raza, Mubashra; Barth, Shannon; Schneiderman, Aaron] VA Off Publ Hlth, Post Deployment Hlth Strateg Healthcare Grp, Washington, DC USA. [Reiber, Gayle] Univ Washington, Dept Epidemiol, Sch Publ Hlth, Seattle, WA 98195 USA. [Zephyrin, Laurie] New York Harbor VA Healthcare Syst, New York, NY USA. [Yano, Elizabeth M.] VA Greater Los Angeles Healthcare Syst, VA HSR&D Ctr Study Healthcare Innovat Implementat, Los Angeles, CA USA. [Yano, Elizabeth M.] Univ Calif Los Angeles, Jonathan & Karin Fielding Sch Publ Hlth, Dept Hlth Policy & Management, Los Angeles, CA USA. RP Katon, J (reprint author), US Dept Vet Affairs VA, Off Patient Care Serv, Womens Hlth Serv, Washington, DC 20420 USA.; Katon, J (reprint author), VA Puget Sound Hlth Care Syst, Sch Med, Ctr Innovat Vet Ctr & Value Driven Care, VA Hlth Serv Res & Dev HSR&D, 1660 South Columbia Way S-152, Seattle, WA 98108 USA.; Katon, J (reprint author), Univ Washington, Dept Hlth Serv, Sch Publ Hlth, Seattle, WA 98195 USA. EM jodie.katon@va.gov FU US Department of Veterans Affairs (VA), Office of Public Health; Office of Academic Affiliations' Associated Health Postdoctoral Fellowship [TTP 61-026]; VA Office of Patient Care, Women's Health Services; VA Puget Sound Center of Innovation in Patient-Centered and Value-Driven Care; VA HSR&D Senior Research Career Scientist awards [RCS-98-353, RCS-05-195] FX This study was funded by the US Department of Veterans Affairs (VA), Office of Public Health. Dr. Katon was supported by an Office of Academic Affiliations' Associated Health Postdoctoral Fellowship (#TTP 61-026), by the VA Office of Patient Care, Women's Health Services, and by the VA Puget Sound Center of Innovation in Patient-Centered and Value-Driven Care. Drs. Reiber (#RCS-98-353) and Yano (#RCS-05-195) are supported by VA HSR&D Senior Research Career Scientist awards. The views expressed within are solely those of the authors, and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government. The authors would like to acknowledge Katherine Hoggatt, PhD and Kristen Gray, PhD for providing a critical review of the manuscript. NR 40 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1092-7875 EI 1573-6628 J9 MATERN CHILD HLTH J JI Matern. Child Health J. PD FEB PY 2017 VL 21 IS 2 BP 376 EP 386 DI 10.1007/s10995-016-2122-x PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EK9VQ UT WOS:000394272400019 PM 27449782 ER PT J AU Chen, QS Ayer, T Chhatwal, J AF Chen, Qiushi Ayer, Turgay Chhatwal, Jagpreet TI Sensitivity Analysis in Sequential Decision Models: A Probabilistic Approach SO MEDICAL DECISION MAKING LA English DT Article DE Markov models; operations research; optimal control theory; probabilistic sensitivity analysis; mathematical models and decision analysis ID COST-EFFECTIVENESS; HEALTH STATES; UNCERTAINTY; THERAPY AB Background: Sequential decision problems are frequently encountered in medical decision making, which are commonly solved using Markov decision processes (MDPs). Modeling guidelines recommend conducting sensitivity analyses in decision-analytic models to assess the robustness of the model results against the uncertainty in model parameters. However, standard methods of conducting sensitivity analyses cannot be directly applied to sequential decision problems because this would require evaluating all possible decision sequences, typically in the order of trillions, which is not practically feasible. As a result, most MDP-based modeling studies do not examine confidence in their recommended policies. Method: In this study, we provide an approach to estimate uncertainty and confidence in the results of sequential decision models. Results: First, we provide a probabilistic univariate method to identify the most sensitive parameters in MDPs. Second, we present a probabilistic multivariate approach to estimate the overall confidence in the recommended optimal policy considering joint uncertainty in the model parameters. We provide a graphical representation, which we call a policy acceptability curve, to summarize the confidence in the optimal policy by incorporating stakeholders' willingness to accept the base case policy. For a cost-effectiveness analysis, we provide an approach to construct a cost-effectiveness acceptability frontier, which shows the most cost-effective policy as well as the confidence in that for a given willingness to pay threshold. We demonstrate our approach using a simple MDP case study. Conclusions: We developed a method to conduct sensitivity analysis in sequential decision models, which could increase the credibility of these models among stakeholders. C1 [Chen, Qiushi; Ayer, Turgay] Georgia Inst Technol, H Milton Stewart Sch Ind & Syst Engn, Atlanta, GA 30332 USA. [Chhatwal, Jagpreet] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Chhatwal, Jagpreet] Harvard Med Sch, Boston, MA 02114 USA. RP Chhatwal, J (reprint author), Harvard Med Sch, MGH Inst Technol Assessment, 101 Merrimac St,Floor 10th, Boston, MA 02114 USA. EM JagChhatwal@mgh.harvard.edu NR 18 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0272-989X EI 1552-681X J9 MED DECIS MAKING JI Med. Decis. Mak. PD FEB PY 2017 VL 37 IS 2 BP 243 EP 252 DI 10.1177/0272989X16670605 PG 10 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA EL1DP UT WOS:000394361000010 PM 27681992 ER PT J AU Sellgren, CM Sheridan, SD Gracias, J Xuan, D Fu, T Perlis, RH AF Sellgren, C. M. Sheridan, S. D. Gracias, J. Xuan, D. Fu, T. Perlis, R. H. TI Patient-specific models of microglia-mediated engulfment of synapses and neural progenitors SO MOLECULAR PSYCHIATRY LA English DT Article ID CELLS; PHAGOCYTOSIS; SCHIZOPHRENIA; ELIMINATION; INDUCTION; PATHOLOGY AB Engulfment of synapses and neural progenitor cells (NPCs) by microglia is critical for the development and maintenance of proper brain circuitry, and has been implicated in neurodevelopmental as well as neurodegenerative disease etiology. We have developed and validated models of these mechanisms by reprogramming microglia-like cells from peripheral blood mononuclear cells, and combining them with NPCs and neurons derived from induced pluripotent stem cells to create patient-specific cellular models of complement-dependent synaptic pruning and elimination of NPCs. The resulting microglia-like cells express appropriate markers and function as primary human microglia, while patient-matched macrophages differ markedly. As a demonstration of diseaserelevant application, we studied the role of C4, recently implicated in schizophrenia, in engulfment of synaptic structures by human microglia. The ability to create complete patient-specific cellular models of critical microglial functions utilizing samples taken during a single clinical visit will extend the ability to model central nervous system disease while facilitating high-throughput screening. C1 [Sellgren, C. M.; Sheridan, S. D.; Gracias, J.; Xuan, D.; Fu, T.; Perlis, R. H.] Massachusetts Gen Hosp, Ctr Human Genet Res, Ctr Expt Drugs & Diagnost, Boston, MA 02114 USA. [Sellgren, C. M.; Sheridan, S. D.; Gracias, J.; Xuan, D.; Fu, T.; Perlis, R. H.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Sellgren, C. M.; Sheridan, S. D.; Gracias, J.; Xuan, D.; Fu, T.; Perlis, R. H.] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Sellgren, C. M.] Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden. RP Perlis, RH (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Simches Res Bldg,185 Cambridge St,6th Floor, Boston, MA 02114 USA. EM RPERLIS@mgh.harvard.edu FU NIMH and NHGRI [P50-MH106933]; NCCIH [R01AT009144]; Knut och Alice Wallenbergs Stiftelse FX We are grateful to Jayla Ruiliera for technical assistance with isolating buffy coats. This work was supported by P50-MH106933 (NIMH and NHGRI), R01AT009144 (NCCIH) and Knut och Alice Wallenbergs Stiftelse. NR 26 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD FEB PY 2017 VL 22 IS 2 BP 170 EP 177 DI 10.1038/mp.2016.220 PG 8 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA EK7JR UT WOS:000394102600004 PM 27956744 ER PT J AU Jensen, KP Smith, AH Herman, AI Farrer, LA Kranzler, HR Sofuoglu, M Gelernter, J AF Jensen, K. P. Smith, A. H. Herman, A. I. Farrer, L. A. Kranzler, H. R. Sofuoglu, M. Gelernter, J. TI A protocadherin gene cluster regulatory variant is associated with nicotine withdrawal and the urge to smoke SO MOLECULAR PSYCHIATRY LA English DT Article ID GENOME-WIDE ASSOCIATION; STATE FUNCTIONAL CONNECTIVITY; INTRAVENOUS NICOTINE; QUIT SMOKING; ACETYLCHOLINE-RECEPTOR; ANXIETY SENSITIVITY; EUROPEAN-AMERICANS; DISTRESS TOLERANCE; PREFRONTAL CORTEX; NUCLEUS-ACCUMBENS AB Nicotine withdrawal symptoms contribute to relapse in smokers, thereby prolonging the harm caused by smoking. To investigate the molecular basis for this phenomenon, we conducted a genome-wide association study of DSM-IV nicotine withdrawal in a sample of African American (AA) and European American (EA) smokers. A combined AA and EA meta-analysis (n = 8021) identified three highly correlated single nucleotide polymorphisms (SNPs) in the protocadherin (PCDH)-alpha, -beta and -gamma gene cluster on chromosome 5 that were associated with nicotine withdrawal (P<5x10(-8)). We then studied one of the SNPs, rs31746, in an independent sample of smokers who participated in an intravenous nicotine infusion study that followed overnight smoking abstinence. After nicotine infusion, abstinent smokers with the withdrawal risk allele experienced greater alleviation of their urges to smoke, as assessed by the Brief Questionnaire on Smoking Urges (BQSU). Prior work has shown that the PCDH-alpha, -beta and -gamma genes are expressed in neurons in a highly organized manner. We found that rs31746 mapped to a long-range neuron-specific enhancer element shown previously to regulate PCDH-alpha, -beta and -gamma gene expression. Using Braincloud mRNA expression data, we identified a robust and specific association between rs31746 and PCDH-beta 8 mRNA expression in frontal cortex tissue (P<1x10(-5)). We conclude that PCDH-alpha, -beta and -gamma gene cluster regulatory variation influences the severity of nicotine withdrawal. Further studies on the PCDH-alpha, -beta and -gamma genes and their role in nicotine withdrawal may inform the development of novel smoking cessation treatments and reduce the harm caused by tobacco smoking. C1 [Jensen, K. P.; Smith, A. H.; Herman, A. I.; Sofuoglu, M.; Gelernter, J.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Jensen, K. P.; Smith, A. H.; Herman, A. I.; Sofuoglu, M.; Gelernter, J.] VA Connecticut Healthcare Syst, 950 Campbell Ave, West Haven, CT 06516 USA. [Smith, A. H.] Yale Univ, Sch Med, Interdept Neurosci Program, New Haven, CT USA. [Smith, A. H.] Yale Univ, Sch Med, Med Scientist Training Program, New Haven, CT USA. [Farrer, L. A.] Boston Univ, Sch Med & Publ Hlth, Dept Med Biomed Genet, Boston, MA 02215 USA. [Farrer, L. A.] Boston Univ, Dept Neurol, Sch Med & Publ Hlth, Boston, MA 02215 USA. [Farrer, L. A.] Boston Univ, Dept Ophthalmol, Sch Med & Publ Hlth, Boston, MA 02215 USA. [Farrer, L. A.] Boston Univ, Dept Epidemiol, Sch Med & Publ Hlth, Boston, MA 02215 USA. [Farrer, L. A.] Boston Univ, Dept Biostat, Sch Med & Publ Hlth, Boston, MA 02215 USA. [Kranzler, H. R.] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Kranzler, H. R.] Philadelphia VA Med Ctr, MIRECC VISN4, Philadelphia, PA 19104 USA. [Gelernter, J.] Yale Univ, Sch Med, Dept Neurobiol, New Haven, CT USA. [Gelernter, J.] Yale Univ, Sch Med, Dept Genet, New Haven, CT USA. RP Gelernter, J (reprint author), VA Connecticut Healthcare Syst, 950 Campbell Ave, West Haven, CT 06516 USA.; Gelernter, J (reprint author), Yale Univ, Dept Psychiat, Sch Med, 950 Campbell Ave, West Haven, CT 06516 USA. EM joel.gelernter@yale.edu FU Veterans Administration (VA) Mental Illness Research, Education and Clinical Center (MIRECC); VA VISN1 Career Development Award; NIH [R03 DA027474, R01 AA017535, R01 DA030976, R01 DA12690, MSTP 5T32GM007205-38, CTSA 8UL1TR000142 TL1, F30 DA037665]; Army STARRS; Department of the Army; US Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health (NIH/NIMH) [U01MH087981]; NIH/NCRR [1 S10 RR19895-01]; NIH Genes, Environment and Health Initiative (GEI) [U01 HG004422, U01HG004438]; Gene Environment Association Studies (GENEVA) under GEI; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; NIH contract 'High throughput genotyping for studying the genetic contributions to human disease' [HHSN268200782096C] FX This research was supported by the Veterans Administration (VA) Mental Illness Research, Education and Clinical Center (MIRECC) and a VA VISN1 Career Development Award; NIH grants R03 DA027474, R01 AA017535, R01 DA030976, R01 DA12690, MSTP 5T32GM007205-38, CTSA 8UL1TR000142 TL1, F30 DA037665; and Army STARRS, which is sponsored by the Department of the Army and funded under cooperative agreement number U01MH087981 with the US Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health (NIH/NIMH). The Yale Biomedical Supercomputer, funded by NIH/NCRR (1 S10 RR19895-01), was used for some analyses. The publically available datasets used for the analyses described in this manuscript were obtained from dbGaP (accession number phs000092.v1.p and phs000417.v2.p1). Funding support for the Study of Addiction: Genetics and Environment (SAGE) was provided through the NIH Genes, Environment and Health Initiative (GEI) (U01 HG004422). SAGE is one of the genome-wide association studies funded as part of the Gene Environment Association Studies (GENEVA) under GEI. Assistance with phenotype harmonization and genotype cleaning and with general study coordination was provided by the GENEVA Coordinating Center (U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for collection of datasets and samples was provided by the Collaborative Study on the Genetics of Alcoholism (COGA; U10 AA008401), the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392) and the Family Study of Cocaine Dependence (FSCD; R01 DA013423). Funding for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (U01HG004438), the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse and the NIH contract 'High throughput genotyping for studying the genetic contributions to human disease' (HHSN268200782096C). NR 80 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD FEB PY 2017 VL 22 IS 2 BP 242 EP 249 DI 10.1038/mp.2016.43 PG 8 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA EK7JR UT WOS:000394102600013 PM 27067016 ER PT J AU Cristofaro, V Carew, JA Carey, SD Goyal, RK Sullivan, MP AF Cristofaro, Vivian Carew, Josephine A. Carey, Sean D. Goyal, Raj K. Sullivan, Maryrose P. TI MOLECULAR AND FUNCTIONAL EVIDENCE OF P2 x 4 RECEPTOR IN DETRUSOR SMOOTH MUSCLE SO NEUROUROLOGY AND URODYNAMICS LA English DT Meeting Abstract CT Winter Meeting of the Society-of-Urodynamics-Female-Pelvic-Medicine-and-Urogenital-Reconstruct ion CY FEB 28-MAR 04, 2017 CL Scottsdale, AZ SP Soc Urodynam Female Pelv Med & Urogenital Reconstruct C1 [Cristofaro, Vivian; Carew, Josephine A.; Carey, Sean D.; Goyal, Raj K.; Sullivan, Maryrose P.] Harvard Med Sch, VA Boston Healthcare Syst, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0733-2467 EI 1520-6777 J9 NEUROUROL URODYNAM JI Neurourol. Urodyn. PD FEB PY 2017 VL 36 SU S1 BP S128 EP S129 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA EL5MJ UT WOS:000394664900242 ER PT J AU Cristofaro, V Carew, JA Carey, SD Goyal, RK Sullivan, MP AF Cristofaro, Vivian Carew, Josephine A. Carey, Sean D. Goyal, Raj K. Sullivan, Maryrose P. TI MOLECULAR AND FUNCTIONAL EVIDENCE OF P2 x 4 RECEPTOR IN DETRUSOR SMOOTH MUSCLE SO NEUROUROLOGY AND URODYNAMICS LA English DT Meeting Abstract CT Winter Meeting of the Society-of-Urodynamics-Female-Pelvic-Medicine-and-Urogenital-Reconstruct ion CY FEB 28-MAR 04, 2017 CL Scottsdale, AZ SP Soc Urodynam Female Pelv Med & Urogenital Reconstruct C1 [Cristofaro, Vivian; Carew, Josephine A.; Carey, Sean D.; Goyal, Raj K.; Sullivan, Maryrose P.] Harvard Med Sch, VA Boston Healthcare Syst, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0733-2467 EI 1520-6777 J9 NEUROUROL URODYNAM JI Neurourol. Urodyn. PD FEB PY 2017 VL 36 SU S1 MA BS10 BP S11 EP S12 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA EL5MJ UT WOS:000394664900012 ER PT J AU Cristofaro, V Carew, JA Dasari, SP Goyal, RK Sullivan, MP AF Cristofaro, Vivian Carew, Josephine A. Dasari, Suhas P. Goyal, Raj K. Sullivan, Maryrose P. TI HYPERGLYCEMIA INCREASES DETRUSOR SMOOTH MUSCLE ACTIVITY THROUGH A CAVEOLAE DEPENDENT REGULATION OF RHO SIGNALING SO NEUROUROLOGY AND URODYNAMICS LA English DT Meeting Abstract CT Winter Meeting of the Society-of-Urodynamics-Female-Pelvic-Medicine-and-Urogenital-Reconstruct ion CY FEB 28-MAR 04, 2017 CL Scottsdale, AZ SP Soc Urodynam Female Pelv Med & Urogenital Reconstruct C1 [Cristofaro, Vivian; Carew, Josephine A.; Dasari, Suhas P.; Goyal, Raj K.; Sullivan, Maryrose P.] Harvard Med Sch, VA Boston Healthcare Syst, Boston, MA USA. FU Department of Veterans Affairs, Research Service [BX001790, BX002806] FX Department of Veterans Affairs, Research Service BX001790); BX002806 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 0733-2467 EI 1520-6777 J9 NEUROUROL URODYNAM JI Neurourol. Urodyn. PD FEB PY 2017 VL 36 SU S1 MA BS1 BP S12 EP S12 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA EL5MJ UT WOS:000394664900013 ER PT J AU Doyle, C Sack, B Costa, K Cristofaro, V Sullivan, MP Adam, RM AF Doyle, Claire Sack, Bryan Costa, Kyle Cristofaro, Vivian Sullivan, Maryrose P. Adam, Rosalyn M. TI THE ROLE OF THE MUCOSA IN MODULATION OF EVOKED RESPONSES IN THE SPINAL CORD INJURED RAT BLADDER SO NEUROUROLOGY AND URODYNAMICS LA English DT Meeting Abstract CT Winter Meeting of the Society-of-Urodynamics-Female-Pelvic-Medicine-and-Urogenital-Reconstruct ion CY FEB 28-MAR 04, 2017 CL Scottsdale, AZ SP Soc Urodynam Female Pelv Med & Urogenital Reconstruct C1 [Doyle, Claire; Sack, Bryan; Costa, Kyle; Adam, Rosalyn M.] Boston Childrens Hosp, Boston, MA USA. [Doyle, Claire; Sack, Bryan; Cristofaro, Vivian; Sullivan, Maryrose P.; Adam, Rosalyn M.] Harvard Med Sch, Boston, MA USA. [Cristofaro, Vivian; Sullivan, Maryrose P.] VA Boston Healthcare Syst, W Roxbury, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0733-2467 EI 1520-6777 J9 NEUROUROL URODYNAM JI Neurourol. Urodyn. PD FEB PY 2017 VL 36 SU S1 MA 2 BP S124 EP S125 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA EL5MJ UT WOS:000394664900234 ER PT J AU Doyle, C Sack, B Costa, K Cristofaro, V Sullivan, M Adam, R AF Doyle, Claire Sack, Bryan Costa, Kyle Cristofaro, Vivian Sullivan, Maryrose Adam, Rosalyn TI THE ROLE OF THE MUCOSA IN MODULATION OF EVOKED RESPONSES IN THE SPINAL CORD INJURED RAT BLADDER SO NEUROUROLOGY AND URODYNAMICS LA English DT Meeting Abstract CT Winter Meeting of the Society-of-Urodynamics-Female-Pelvic-Medicine-and-Urogenital-Reconstruct ion CY FEB 28-MAR 04, 2017 CL Scottsdale, AZ SP Soc Urodynam Female Pelv Med & Urogenital Reconstruct C1 [Doyle, Claire; Sack, Bryan; Costa, Kyle; Adam, Rosalyn] Boston Childrens Hosp, Boston, MA USA. [Doyle, Claire; Sack, Bryan] Harvard Med Sch, Boston, MA USA. [Cristofaro, Vivian; Sullivan, Maryrose] West Roxbury & Harvad Med Sch, VA Boston Healthcare Syst, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0733-2467 EI 1520-6777 J9 NEUROUROL URODYNAM JI Neurourol. Urodyn. PD FEB PY 2017 VL 36 SU S1 MA BS2 BP S7 EP S8 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA EL5MJ UT WOS:000394664900004 ER PT J AU Banks, CA Jowett, N Azizzadeh, B Beurskens, C Bhama, P Borschel, G Coombs, C Coulson, S Croxon, G Diels, J Fattah, A Frey, M Gavilan, J Henstrom, D Hohman, M Kim, J Marres, H Redett, R Snyder-Warwick, A Hadlock, T AF Banks, Caroline A. Jowett, Nathan Azizzadeh, Babak Beurskens, Carien Bhama, Prabhat Borschel, Gregory Coombs, Christopher Coulson, Susan Croxon, Glen Diels, Jaqueline Fattah, Adel Frey, Manfred Gavilan, Javier Henstrom, Douglas Hohman, Marc Kim, Jennifer Marres, Henri Redett, Richard Snyder-Warwick, Alison Hadlock, Tessa TI Worldwide Testing of the eFACE Facial Nerve Clinician-Graded Scale SO PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Article ID GRADING SYSTEMS; BELLS-PALSY; PARALYSIS; SUNNYBROOK AB Background: The electronic, clinician-graded facial function scale (eFACE) is a potentially useful tool for assessing facial function. Beneficial features include its digital nature, use of visual analogue scales, and provision of graphic outputs and scores. The authors introduced the instrument to experienced facial nerve clinicians for feedback, and examined the effect of viewing a video tutorial on score agreement. Methods: Videos of 30 patients with facial palsy were embedded in an Apple eFACE application. Facial nerve clinicians were invited to perform eFACE video rating and tutorial observation. Participants downloaded the application, viewed the clips, and applied the scoring. They then viewed the tutorial and rescored the clips. Analysis of mean, standard deviation, and confidence interval were performed. Values were compared before and after tutorial viewing, and against scores obtained by an experienced eFACE user. Results: eFACE feedback was positive; participants reported eagerness to apply the instrument in clinical practice. Standard deviation decreased significantly in only two of the 16 categories after tutorial viewing. Subscores for static, dynamic, and synkinesis all demonstrated stable standard deviations, suggesting that the instrument is intuitive. Participants achieved posttutorial scores closer to the experienced eFACE user in 14 of 16 scores, although only a single score, nasolabial fold orientation with smiling, achieved statistically significant improvement. Conclusions: The eFACE may be a suitable, cross-platform, digital instrument for facial function assessment, and was well received by facial nerve experts. Tutorial viewing does not appear to be necessary to achieve agreement, although it does mildly improve agreement between occasional and frequent eFACE users. C1 [Banks, Caroline A.] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Dept Otolaryngol Head & Neck Surg, Div Facial Plast & Reconstruct Surg, 243 Charles St, Boston, MA 02114 USA. Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. Radboud Univ Nijmegen, Med Ctr, Dept Orthoped Phys Therapy, Nijmegen, Netherlands. Radboud Univ Nijmegen, Med Ctr, Dept Otolaryngol Head & Neck Surg, Nijmegen, Netherlands. Alaska Native Tribal Hlth Consortium, Alaska Native Med Ctr, Dept Otolaryngol Head & Neck Surg, Anchorage, AK USA. Hosp Sick Children, Div Plast & Reconstruct Surg, Toronto, ON, Canada. Royal Childrens Hosp, Dept Plast & Maxillofacial Surg, Parkville, Vic, Australia. Univ Sydney, Sydney, NSW 2006, Australia. Royal Prince Alfred Hosp, Camperdown, NSW, Australia. Royal Prince Alfred Hosp, Dept Otolaryngol, Camperdown, NSW, Australia. Univ Wisconsin Hosp & Clin, Dept Orthoped & Rehabil, Madison, WI 53792 USA. Facial Nerve Programme, Reg Paediat Burns & Plast Surg, Liverpool, Merseyside, England. Med Univ Vienna, Div Plast & Reconstruct Surg, Vienna, Austria. La Paz Univ Hosp, Idipaz Res Inst, Dept Otolaryngol Head & Neck Surg, Madrid, Spain. Univ Iowa Hosp & Clin, Div Plast Surg & Cosmet Serv, Dept Otolaryngol Head & Neck Surg, Iowa City, IA 52242 USA. Madigan Army Med Ctr, Tacoma, WA 98431 USA. Univ Michigan, Div Facial Plast & Reconstruct Surg, Dept Otolaryngol Head & Neck Surg, Ann Arbor, MI 48109 USA. Johns Hopkins Sch Med, Dept Plast & Reconstruct Surg, Baltimore, MD USA. Washington Univ St Louis, Dept Surg, Div Plast & Reconstruct Surg, St Louis, MO USA. RP Banks, CA (reprint author), Harvard Med Sch, Massachusetts Eye & Ear Infirm, Dept Otolaryngol Head & Neck Surg, Div Facial Plast & Reconstruct Surg, 243 Charles St, Boston, MA 02114 USA. EM caroline_banks@meei.harvard.edu NR 18 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0032-1052 EI 1529-4242 J9 PLAST RECONSTR SURG JI Plast. Reconstr. Surg. PD FEB PY 2017 VL 139 IS 2 BP 491E EP 498E DI 10.1097/PRS.0000000000002954 PG 8 WC Surgery SC Surgery GA EK6UI UT WOS:000394059300047 PM 28121888 ER PT J AU Hixon, AM Yu, GX Leser, JS Yagi, S Clarke, P Chiu, CY Tyler, KL AF Hixon, Alison M. Yu, Guixia Leser, J. Smith Yagi, Shigeo Clarke, Penny Chiu, Charles Y. Tyler, Kenneth L. TI A mouse model of paralytic myelitis caused by enterovirus D68 SO PLOS PATHOGENS LA English DT Article ID ACUTE FLACCID MYELITIS; UNKNOWN ETIOLOGY; IDENTIFICATION; INFECTION; CHILDREN; FEATURES; SEROTYPE; ILLNESS AB In 2014, the United States experienced an epidemic of acute flaccid myelitis (AFM) cases in children coincident with a nationwide outbreak of enterovirus D68 (EV-D68) respiratory disease. Up to half of the 2014 AFM patients had EV-D68 RNA detected by RT-PCR in their respiratory secretions, although EV-D68 was only detected in cerebrospinal fluid (CSF) from one 2014 AFM patient. Given previously described molecular and epidemiologic associations between EV-D68 and AFM, we sought to develop an animal model by screening seven EV-D68 strains for the ability to induce neurological disease in neonatal mice. We found that four EV-D68 strains from the 2014 outbreak (out of five tested) produced a paralytic disease in mice resembling human AFM. The remaining 2014 strain, as well as 1962 prototype EV-D68 strains Fermon and Rhyne, did not produce, or rarely produced, paralysis in mice. In-depth examination of the paralysis caused by a representative 2014 strain, MO/14-18947, revealed infectious virus, virion particles, and viral genome in the spinal cords of paralyzed mice. Paralysis was elicited in mice following intramuscular, intracerebral, intraperitoneal, and intranasal infection, in descending frequency, and was associated with infection and loss of motor neurons in the anterior horns of spinal cord segments corresponding to paralyzed limbs. Virus isolated from spinal cords of infected mice transmitted disease when injected into naive mice, fulfilling Koch's postulates in this model. Finally, we found that EV-D68 immune sera, but not normal mouse sera, protected mice from development of paralysis and death when administered prior to viral challenge. These studies establish an experimental model to study EV-D68-induced myelitis and to better understand disease pathogenesis and develop potential therapies. C1 [Hixon, Alison M.] Univ Colorado, Sch Med, Med Sci Training Program, Boulder, CO 80309 USA. [Hixon, Alison M.] Univ Colorado, Sch Med, Aurora, CO 80309 USA. [Yu, Guixia; Chiu, Charles Y.] Univ Calif San Francisco, Dept Lab Med & Med, Div Infect Dis, San Francisco, CA USA. [Yu, Guixia; Chiu, Charles Y.] Univ Calif San Francisco, UCSF Abbott Viral Diagnost & Discovery Ctr, San Francisco, CA 94143 USA. [Leser, J. Smith; Clarke, Penny; Tyler, Kenneth L.] Univ Colorado, Sch Med, Dept Neurol, Aurora, CO 80309 USA. [Yagi, Shigeo] Calif Dept Publ Hlth, Richmond, CA USA. [Tyler, Kenneth L.] Denver VA Med Ctr, Denver, CO USA. [Tyler, Kenneth L.] Univ Colorado, Sch Med, Dept Immunol & Microbiol, Boulder, CO 80309 USA. [Tyler, Kenneth L.] Univ Colorado, Sch Med, Dept Med, Boulder, CO 80309 USA. RP Tyler, KL (reprint author), Univ Colorado, Sch Med, Dept Neurol, Aurora, CO 80309 USA.; Tyler, KL (reprint author), Denver VA Med Ctr, Denver, CO USA.; Tyler, KL (reprint author), Univ Colorado, Sch Med, Dept Immunol & Microbiol, Boulder, CO 80309 USA.; Tyler, KL (reprint author), Univ Colorado, Sch Med, Dept Med, Boulder, CO 80309 USA. EM ken.tyler@ucdenver.edu OI Chiu, Charles/0000-0003-2915-2094 FU United States National Institutes of Health [RO1-NS076512, R33-AI101064, R01-HL105704]; United States Department of Veterans Affairs [101BX000963]; University of California San Francisco (UCSF)-Abbott Pathogen Discovery Award FX We would like to acknowledge support by grants (to KLT) from the United States National Institutes of Health (https://www.nih.gov/) (RO1-NS076512, R33-AI101064) and United States Department of Veterans Affairs (http://www.va.gov/) merit grant support (101BX000963). This study was also supported in part by grants (to CYC) from the United States National Institutes of Health (R01-HL105704) and a University of California San Francisco (UCSF)-Abbott Pathogen Discovery Award. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 0 Z9 0 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD FEB PY 2017 VL 13 IS 2 AR e1006199 DI 10.1371/journal.ppat.1006199 PG 19 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA EN1BH UT WOS:000395744700023 ER PT J AU Maurovich-Horvat, P Suhai, FI Czimbalmos, C Toth, A Becker, D Kiss, E Ferencik, M Hoffmann, U Vago, H Merkely, B AF Maurovich-Horvat, Pal Suhai, Ferenc Imre Czimbalmos, Csilla Toth, Attila Becker, David Kiss, Emese Ferencik, Maros Hoffmann, Udo Vago, Hajnalka Merkely, Bela TI Coronary Artery Manifestation of Ormond Disease: The "Mistletoe Sign" SO RADIOLOGY LA English DT Article ID RETROPERITONEAL FIBROSIS AB A 69-year-old woman presented with symptoms of presumed cardiac involvement of idiopathic retroperitoneal fibrosis, otherwise known as Ormond disease. Distinct pericoronary tissue proliferations were depicted at cardiac magnetic resonance (MR) imaging and coronary computed tomographic (CT) angiography. On images, the coronary manifestation was termed the "mistletoe sign." The presence of the mistletoe sign on cardiac MR and coronary CT angiographic images is probably rare, but it might be a characteristic manifestation of retroperitoneal fibrosis. With the increasing number of noninvasive cardiac imaging tests performed worldwide, the recognition of the mistletoe sign could be helpful in diagnosing retroperitoneal fibrosis. (C) RSNA, 2016 C1 [Maurovich-Horvat, Pal; Suhai, Ferenc Imre; Czimbalmos, Csilla; Toth, Attila; Becker, David; Vago, Hajnalka; Merkely, Bela] Semmelweis Univ, Heart & Vasc Ctr, MTA SE Cardiovasc Imaging Res Grp, Varosmajor St 68, H-1122 Budapest, Hungary. [Kiss, Emese] Natl Inst Rheumatism & Physiotherapy, Budapest, Hungary. [Ferencik, Maros; Hoffmann, Udo] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Cardiac MR PET CT Program, Boston, MA USA. RP Maurovich-Horvat, P (reprint author), Semmelweis Univ, Heart & Vasc Ctr, MTA SE Cardiovasc Imaging Res Grp, Varosmajor St 68, H-1122 Budapest, Hungary. EM p.maurovich.horvat@mail.harvard.edu NR 6 TC 0 Z9 0 U1 0 U2 0 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 FEB PY 2017 VL 282 IS 2 BP 356 EP 360 DI 10.1148/radiol.2016160644 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EM7VY UT WOS:000395521600008 PM 27548369 ER PT J AU Shinagare, AB Ramaiya, NH AF Shinagare, Atul B. Ramaiya, Nikhil H. TI When Imaging Becomes Clinically Relevant: Multikinase Inhibitor-related Pancreatic Insufficiency and Pancreatic Atrophy Response SO RADIOLOGY LA English DT Letter ID SUNITINIB C1 [Shinagare, Atul B.] Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Imaging, Boston, MA 02115 USA. RP Shinagare, AB (reprint author), Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. EM ashinagare@partners.org FU Shore Fellowship Program for Scholars in Medicine FX A.B.S. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: received a research grant from the Shore Fellowship Program for Scholars in Medicine. Other relationships: disclosed no relevant relationships. N.H.R. disclosed no relevant relationships. NR 2 TC 0 Z9 0 U1 0 U2 0 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 FEB PY 2017 VL 282 IS 2 BP 610 EP 610 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EM7VY UT WOS:000395521600037 ER PT J AU Raj, MS Schwab, JH AF Raj, Mamtha S. Schwab, Joseph H. TI An unusual cause of cervical kyphosis SO SPINE JOURNAL LA English DT Article DE Chin-to-chest deformity; Dystonic reaction; Fixed cervical kyphosis; Haloperidol; Osteophyte formation; Severe neck pain ID MOVEMENT-DISORDERS; DYSTONIC REACTIONS; HALOPERIDOL; PROPHYLAXIS; MYELOPATHY; FUSION; SPINE AB BACKGROUND CONTEXT: Acute fixed cervical kyphosis may be a rare presentation of conversion disorder, psychogenic dystonia, and potentially as a side effect from typical antipsychotic drugs. Haldol has been associated with acute dystonic reactions. In some cases, rigid deformities ensue. We are reporting a case of a fixed cervical kyphosis after the use of Haldol. PURPOSE: To present a case of a potential acute dystonic reaction temporally associated with Haldol ingestion leading to fixed cervical kyphosis. STUDY DESIGN: This is a case report. METHODS: A patient diagnosed with bipolar disorder presented to the emergency room several times with severe neck pain and stiffness. The neck appeared fixed in flexion with extensive osteophyte formation over a 3-month period. RESULTS: The patient's condition was resolved by a posterior-anterior-posterior surgical approach. It corrected the patient's cervical curvature from 88 degrees to 5 degrees. CONCLUSIONS: Acute dystonic reactions have the potential to apply enough pressure on bone to cause rapid osteophyte formation. (C) 2016 Elsevier Inc. All rights reserved. C1 [Raj, Mamtha S.; Schwab, Joseph H.] Massachusetts Gen Hosp, Dept Spine Orthopaed, Boston, MA 02114 USA. RP Raj, MS (reprint author), Orthopaed Spine Ctr, 55 Fruit St,Yawkey Ctr Outpatient Care,Suite 3A, Boston, MA 02114 USA. EM mamtharajMD@gmail.com NR 15 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 1529-9430 EI 1878-1632 J9 SPINE J JI Spine Journal PD FEB PY 2017 VL 17 IS 2 BP E7 EP E9 DI 10.1016/j.spinee.2016.09.008 PG 3 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA EO1IP UT WOS:000396452300001 PM 27664338 ER PT J AU Lubitz, CC De Gregorio, L Fingeret, AL Economopoulos, KP Termezawi, D Hassan, M Parangi, S Stephen, AE Halpern, EF Donelan, K Swan, JS AF Lubitz, Carrie C. De Gregorio, Lucia Fingeret, Abbey L. Economopoulos, Konstantinos P. Termezawi, Diana Hassan, Mursal Parangi, Sareh Stephen, Antonia E. Halpern, Elkan F. Donelan, Karen Swan, J. Shannon TI Measurement and Variation in Estimation of Quality of Life Effects of Patients Undergoing Treatment for Papillary Thyroid Carcinoma SO THYROID LA English DT Article DE thyroid cancer; clinical research; surgery; quality of life ID HEALTH UTILITIES INDEX; CANCER SURVIVORS; RADIOIODINE ABLATION; ACTIVE SURVEILLANCE; INSTRUMENTS; MICROCARCINOMA; MULTIATTRIBUTE; VALIDITY; THERAPY; SURGERY AB Background: Thyroid cancer incidence is increasing. The effect of diagnosis and treatment on health-related quality of life (HRQoL) is an essential variable in the absence of a change in life span for the majority of patients. HRQoL instruments, with data useful for between-disease comparisons, are being increasingly used for health policy and outcomes evaluation. Variation exits among the instruments based on the impact of a specific disease. We assessed which of four well-validated, preference-based surveys detect changes in health and clinical intervention in patients diagnosed with papillary thyroid cancer (PTC). Methods: Four commonly used HRQoL questionnaires (Short Form-12v2 (R) [SF6D], EuroQol-5D [EQ5D], and Health Utilities Index Mark 2 and 3 [HUI2, HUI3]) were administered to patients with the diagnosis of PTC at three perioperative time points during the first year of treatment. Clinicopathological and treatment course data were assessed for HRQoL impact including complications from surgery, re-operation for persistence/early recurrence, and adjuvant radioactive iodine treatment. We compared standard metrics, including ceiling effect, intraclass correlation coefficient, effect sizes, and quality-adjusted life-years between the four instruments. Results: Of 117 patients, 27% had a preoperative diagnosis of anxiety or depression, 41% had regional lymph node metastases, three had distant metastases and 49% underwent adjuvant radioactive iodine treatment. The ceiling effect (i.e., proportion with a perfect score) was greatest with EQ5D and least with SF6D. Index scores ranged from 0.77 (SF6D) to 0.90 (EQ5D). All scores declined at two weeks postoperatively and returned to pretreatment levels at six months. The SF6D was the only instrument to exceed the conventional minimally important difference between all three time points. Quality-adjusted life-years were as follows: SF6D, 0.79; EQ5D, 0.90; HUI2, 0.88; and HUI3, 0.86. Conclusions: Our results reflect the general good health of PTC patients. The effect on quality of life is primarily related to emotional and social impacts of treatment. The results support the measurement of a similar underlying construct, although variation in detecting changes in health exists between the instruments. Of the instruments assessed, the SF6D is the most responsive to treatment effects and should be utilized in future economic analyses in this patient population. C1 [Lubitz, Carrie C.; De Gregorio, Lucia; Fingeret, Abbey L.; Economopoulos, Konstantinos P.; Termezawi, Diana; Hassan, Mursal; Parangi, Sareh; Stephen, Antonia E.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Boston, MA USA. [Halpern, Elkan F.; Swan, J. Shannon] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Lubitz, Carrie C.; Economopoulos, Konstantinos P.; Halpern, Elkan F.; Donelan, Karen; Swan, J. Shannon] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Donelan, Karen] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Lubitz, CC (reprint author), Massachusetts Gen Hosp, Dept Surg, 55 Fruit St,Yawkey 7B, Boston, MA 02114 USA. EM clubitz@partners.org FU National Institutes of Health/National Cancer Institute; Claflin Foundation at Massachusetts General; Hospital and Alfonso Martin Escudero Foundation Research Grant FX This study was funded by the following research grants and agencies: National Institutes of Health/National Cancer Institute (C.C.L.), The Claflin Foundation at Massachusetts General (C.C.L.) Hospital and Alfonso Martin Escudero Foundation Research Grant (L.D.G.). NR 51 TC 0 Z9 0 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 EI 1557-9077 J9 THYROID JI Thyroid PD FEB PY 2017 VL 27 IS 2 BP 197 EP 206 DI 10.1089/thy.2016.0260 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EK6RK UT WOS:000394051600010 PM 27824301 ER PT J AU Ma, RS Morshed, SA Latif, R Davies, TF AF Ma, Risheng Morshed, Syed A. Latif, Rauf Davies, Terry F. TI TAZ Induction Directs Differentiation of Thyroid Follicular Cells from Human Embryonic Stem Cells SO THYROID LA English DT Article DE thyroid follicular cells; human embryonic stem cells; NK2 homeobox 1 (NKX2-1); Paired box gene 8 (PAX8); transcriptional co-activator with PDZ-binding motif (TAZ); ethacridine ID SYNERGISTICALLY ACTIVATE; TRANSCRIPTION FACTOR-1; COACTIVATOR; PAX8; ENDODERM; MORPHOGENESIS; ENHANCER; PROTEIN; TTF-1; GLAND AB Objective: The differentiation program for human thyroid follicular cells (TFCs) relies on the interplay between sequence-specific transcription factors and transcriptional co-regulators. Transcriptional co-activator with PDZbinding motif (TAZ) is a co-activator that regulates several transcription factors, including PAX8 and NKX2-1, which play a central role in thyroid-specific gene transcription. TAZ and PAX8/ NKX2-1 are co-expressed in the nuclei of thyroid cells, and TAZ interacts directly with both PAX8 and NKX2-1, leading to their enhanced transcriptional activity on the thyroglobulin (TG) promoter and additional genes. Methods: The use of a small molecule, ethacridine, recently identified as a TAZ activator, in the differentiation of thyroid cells from human embryonic stem (hES) cells was studied. First, endodermal cells were derived from hES cells using Activin A, followed by induction of differentiation into thyroid cells directed by ethacridine and thyrotropin (TSH). Results: The expression of TAZ was increased in the Activin A-derived endodermal cells by ethacridine in a dose-dependent manner and followed by increases in PAX8 and NKX2-1 when assessed by both quantitative polymerase chain reaction and immunostaining. Following further differentiation with the combination of ethacridine and TSH, the thyroid-specific genes TG, TPO, TSHR, and NIS were all induced in the differentiated hES cells. When these cells were cultured with extracellular matrix-coated dishes, thyroid follicle formation and abundant TG protein expression were observed. Furthermore, such hES cell-derived thyroid follicles showed a marked TSH-induced and dose-dependent increase in radioiodine uptake and protein-bound iodine accumulation. Conclusion: These data show that fully functional human thyroid cells can be derived from hES cells using ethacridine, a TAZ activator, which induces thyroid-specific gene expression and promotes thyroid cell differentiation from the hES cells. These studies again demonstrate the importance of transcriptional regulation in thyroid cell development. This approach also yields functional human thyrocytes, without any gene transfection or complex culture conditions, by directly manipulating the transcriptional machinery without interfering with intermediate signaling events. C1 Mt Sinai Beth Israel Med Ctr, Icahn Sch Med Mt Sinai, Dept Med, Thyroid Res Unit, New York, NY USA. James J Peters VA Med Ctr, New York, NY USA. RP Ma, RS (reprint author), Icahn Sch Med Mt Sinai, 1 Gustave L Levy Pl BOX 1055, New York, NY 10029 USA. EM risheng.ma@mssm.edu FU National Institutes of Health [DK069713]; David Owen Segal Endowment; VA Merit Review Program FX Supported in part by DK069713 from the National Institutes of Health, the David Owen Segal Endowment, and the VA Merit Review Program (to T.F.D.). NR 27 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 EI 1557-9077 J9 THYROID JI Thyroid PD FEB PY 2017 VL 27 IS 2 BP 292 EP 299 DI 10.1089/thy.2016.0264 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EK6RK UT WOS:000394051600019 PM 27829313 ER PT J AU Seger, CD He, XM Braverman, LE Yeh, MW Bernet, VJ Singh, RJ Rhee, CM Leung, AM AF Seger, Christian D. He, Xuemei Braverman, Lewis E. Yeh, Michael W. Bernet, Victor J. Singh, Ravinder J. Rhee, Connie M. Leung, Angela M. TI Negligible Thyroid Hormone Content Present in Nonprescription U. S. Weight Loss Products SO THYROID LA English DT Letter C1 [Yeh, Michael W.] Sect Endocrine Surg, Los Angeles, CA USA. [Leung, Angela M.] Div Endocrinol, Los Angeles, CA USA. [Seger, Christian D.; Yeh, Michael W.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [He, Xuemei; Braverman, Lewis E.] Boston Univ, Sch Med, Sect Endocrinol Diabet & Nutr, Boston, MA 02118 USA. [Bernet, Victor J.] Mayo Clin Florida, Div Endocrinol, Jacksonville, FL USA. [Singh, Ravinder J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Rhee, Connie M.] Univ Calif Irvine, Div Nephrol & Hypertens, Irvine, CA USA. [Leung, Angela M.] VA Greater Los Angeles Healthcare Syst, Div Endocrinol, 111D,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. RP Leung, AM (reprint author), VA Greater Los Angeles Healthcare Syst, Div Endocrinol, 111D,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM amleung@mednet.ucla.edu FU NIH [K23HD068552] FX Supported by NIH K23HD068552 (A.M.L.). NR 3 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 EI 1557-9077 J9 THYROID JI Thyroid PD FEB PY 2017 VL 27 IS 2 BP 300 EP 301 DI 10.1089/thy.2016.0534 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EK6RK UT WOS:000394051600020 PM 27897088 ER PT J AU Teng, KY Han, JF Zhang, XL Hsu, SH He, S Wani, NA Barajas, JM Snyder, LA Frankel, WL Caligiuri, MA Jacob, ST Yu, JH Ghoshal, K AF Teng, Kun-Yu Han, Jianfeng Zhang, Xiaoli Hsu, Shu-Hao He, Shun Wani, Nissar A. Barajas, Juan M. Snyder, Linda A. Frankel, Wendy L. Caligiuri, Michael A. Jacob, Samson T. Yu, Jianhua Ghoshal, Kalpana TI Blocking the CCL2-CCR2 Axis Using CCL2-Neutralizing Antibody Is an Effective Therapy for Hepatocellular Cancer in a Mouse Model SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID NK CELLS; MACROPHAGE INFILTRATION; LIVER-DISEASE; IN-VIVO; CARCINOMA; CCL2; GENES; INHIBITION; CHEMOKINE; BLOCKADE AB Hepatocellular carcinoma, a deadly disease, commonly arises in the setting of chronic inflammation. C-C motif chemokine ligand 2 (CCL2/MCP1), a chemokine that recruits CCR2positive immune cells to promote inflammation, is highly upregulated in hepatocellular carcinoma patients. Here, we examined the therapeutic efficacy of CCL2-CCR2 axis inhibitors against hepatitis and hepatocellular carcinoma in the miR122 knockout (a.k.a. KO) mouse model. This mouse model displays upregulation of hepatic CCL2 expression, which correlates with hepatitis that progress to hepatocellular carcinoma with age. Therapeutic potential of CCL2-CCR2 axis blockade was determined by treating KO mice with a CCL2-neutralizing antibody (nAb). This immunotherapy suppressed chronic liver inflammation in these mice by reducing the population of CD11(high)Gr(1) inflammatory myeloid cells and inhibiting expression of IL6 and TNF alpha inKOlivers. Furthermore, treatment of tumor-bearing KO mice with CCL2 nAb for 8 weeks significantly reduced liver damage, hepatocellular carcinoma incidence, and tumor burden. Phospho-STAT3 (Y705) and c-MYC, the downstream targets of IL6, as well as NF-kB, the downstream target of TNFa, were downregulated upon CCL2 inhibition, which correlated with suppression of tumor growth. In addition, CCL2 nAb enhanced hepatic NK-cell cytotoxicity and IFNg production, which is likely to contribute to the inhibition of tumorigenesis. Collectively, these results demonstrate that CCL2 immunotherapy could be an effective therapeutic approach against inflammatory liver disease and hepatocellular carcinoma. C1 [Teng, Kun-Yu] Ohio State Univ, Mol Cellular & Dev Biol Program, Columbus, OH 43210 USA. [Teng, Kun-Yu; Hsu, Shu-Hao; Wani, Nissar A.; Barajas, Juan M.; Frankel, Wendy L.; Ghoshal, Kalpana] Ohio State Univ, Dept Pathol, 420 West 12th Ave,646C TMRF Bldg, Columbus, OH 43210 USA. [Teng, Kun-Yu; Han, Jianfeng; Hsu, Shu-Hao; He, Shun; Wani, Nissar A.; Barajas, Juan M.; Frankel, Wendy L.; Caligiuri, Michael A.; Jacob, Samson T.; Yu, Jianhua; Ghoshal, Kalpana] Ohio State Univ, Wexner Med Ctr, Comprehens Canc Ctr, Columbus, OH 43210 USA. [Zhang, Xiaoli] Ohio State Univ, Ctr Biostat, Columbus, OH 43210 USA. [He, Shun; Caligiuri, Michael A.; Jacob, Samson T.; Yu, Jianhua] Ohio State Univ, Virol Immunol & Med Genet, Columbus, OH 43210 USA. [He, Shun] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA USA. [Snyder, Linda A.] Janssen Res & Dev LLC, Spring House, PA USA. [Wani, Nissar A.; Jacob, Samson T.; Ghoshal, Kalpana] Ohio State Univ, Dept Mol & Cellular Biochem, Columbus, OH 43210 USA. [He, Shun] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA USA. RP Ghoshal, K (reprint author), Ohio State Univ, Dept Pathol, 420 West 12th Ave,646C TMRF Bldg, Columbus, OH 43210 USA.; Yu, JH (reprint author), Ohio State Univ, Wexner Med Ctr, Comprehens Canc Ctr, Columbus, OH 43210 USA.; Yu, JH (reprint author), Ohio State Univ, Virol Immunol & Med Genet, Columbus, OH 43210 USA. EM Jianhua.Yu@osumc.edu; kalpana.ghoshal@osumc.edu FU NIH [R01CA193244, R01CA086978]; Pelotonia IDEA grants; Pelotonia Graduate Fellowship FX This work was supported, in part, by NIH grants R01CA193244 (to K. Ghoshal) and R01CA086978 (to S.T. Jacob and K. Ghoshal) as well as by Pelotonia IDEA grants (to J. Yu and K. Ghoshal) and Pelotonia Graduate Fellowship (to K.-Y. Teng). NR 45 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 EI 1538-8514 J9 MOL CANCER THER JI Mol. Cancer Ther. PD FEB PY 2017 VL 16 IS 2 BP 312 EP 322 DI 10.1158/1535-7163.MCT-16-0124 PG 11 WC Oncology SC Oncology GA EM8LV UT WOS:000395563700006 PM 27980102 ER PT J AU Barak-Corren, Y Castro, VM Javitt, S Hoffnagle, AG Dai, Y Perlis, RH Nock, MK Smoller, JW Reis, B AF Barak-Corren, Yuval Castro, Victor M. Javitt, Solomon Hoffnagle, Alison G. Dai, Yael Perlis, Roy H. Nock, Matthew K. Smoller, Jordan W. Reis, Ben Y. TI Predicting Suicidal Behavior From Longitudinal Electronic Health Records SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID CLAIMS DATA; E-CODES; RISK; HOSPITALIZATION; IDEATION AB Objective: The purpose of this article was to determine whether longitudinal historical data, commonly available in electronic health record (EHR) systems, can be used to predict patients' future risk of suicidal behavior. Method: Bayesian models were developed using a retrospective cohort approach. EHR data from a large health care database spanning 15 years (1998-2012) of inpatient and outpatient visits were used to predict future documented suicidal behavior (i.e., suicide attempt or death). Patients with three or more visits (N= 1,728,549) were included. ICD-9-based case definition for suicidal behavior was derived by expert clinician consensus review of 2,700 narrative EHR notes (from 520 patients), supplemented by state death certificates. Model performance was evaluated retrospectively using an independent testing set. Results: Among the study population, 1.2% (N= 20,246) met the case definition for suicidal behavior. The model achieved sensitive (33%-45% sensitivity), specific (90%-295% specificity), and early (3-4 years in advance on average) prediction of patients' future suicidal behavior. The strongest predictors identified by the model included both well-known (e.g., substance abuse and psychiatric disorders) and less conventional (e.g., certain injuries and chronic conditions) risk factors, indicating that a data-driven approach can yield more comprehensive risk profiles. Conclusions: Longitudinal EHR data, commonly available in clinical settings, can be useful for predicting future risk of suicidal behavior. This modeling approach could serve as an early warning system to help clinicians identify high-risk patients for further screening. By analyzing the full pheno-typic breadth of the EHR, computerized risk screening approaches may enhance prediction beyond what is feasible for individual clinicians. C1 [Barak-Corren, Yuval] Boston Childrens Hosp, Informat Program, Predict Med Grp, Boston, MA 02115 USA. Technion Israel Inst Technol, Haifa, Israel. Partners Res Informat Syst & Comp, Boston, MA USA. Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. Harvard Univ, Dept Psychol, Boston, MA 02115 USA. Harvard Med Sch, Boston, MA USA. RP Barak-Corren, Y (reprint author), Boston Childrens Hosp, Informat Program, Predict Med Grp, Boston, MA 02115 USA. EM jsmoller@hms.harvard.edu FU Healthrageous; Massachusetts General Hospital; Pfizer FX Dr. Perlis has served on scientific advisory boards for or as a consultant to Genomind, Perfect Health, Proteus Biomedical, PsyBrain, and RID Ventures; and he has also received support from Healthrageous, Massachusetts General Hospital, and Pfizer. All other authors report no financial relationships with commercial interests. NR 30 TC 1 Z9 1 U1 0 U2 0 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD FEB 1 PY 2017 VL 174 IS 2 BP 154 EP 162 DI 10.1176/appi.ajp.2016.16010077 PG 9 WC Psychiatry SC Psychiatry GA EO4JW UT WOS:000396662200013 PM 27609239 ER PT J AU O'Malley, BW Crowley, WF AF O'Malley, Bert W. Crowley, William F. TI In Memoriam, P. Michael Conn, PhD (1949-2016) SO ENDOCRINE REVIEWS LA English DT Biographical-Item C1 [O'Malley, Bert W.] Baylor Coll Med, Mol & Cellular Biol, Houston, TX 77030 USA. [Crowley, William F.] Harvard Med Sch, Massachusetts Gen Hosp, Reprod Endocrine Unit, Harvard Reprod Endocrine Sci Ctr,Dept Med, Boston, MA 02114 USA. RP O'Malley, BW (reprint author), Baylor Coll Med, Dept Mol & Cellular Biol, 1 Baylor Plaza, Houston, TX 77030 USA. EM berto@bcm.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0163-769X EI 1945-7189 J9 ENDOCR REV JI Endocr. Rev. PD FEB PY 2017 VL 38 IS 1 BP 1 EP 2 DI 10.1210/er.2016-1145 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EO4FT UT WOS:000396651500001 ER PT J AU Altice, CK Banegas, MP Tucker-Seeley, RD Yabroff, KR AF Altice, Cheryl K. Banegas, Matthew P. Tucker-Seeley, Reginald D. Yabroff, K. Robin TI Financial Hardships Experienced by Cancer Survivors: A Systematic Review SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Review ID OUT-OF-POCKET; CARE EXPENDITURE BURDEN; UNITED-STATES; BREAST-CANCER; HEALTH-CARE; ECONOMIC BURDEN; COLORECTAL-CANCER; PROSTATE-CANCER; MULTIPLE-MYELOMA; INDIRECT COSTS AB Background: With rising cancer care costs, including high-priced cancer drugs, financial hardship is increasingly documented among cancer survivors in the United States; research findings have not been synthesized. Methods: We conducted a systematic review of articles published between 1990 and 2015 describing the financial hardship experienced by cancer survivors using PubMed, Embase, Scopus, and CINAHL databases. We categorized measures of financial hardship into: material conditions (eg, out-of-pocket costs, productivity loss, medical debt, or bankruptcy), psychological responses (eg, distress or worry), and coping behaviors (eg, skipped medications). We abstracted findings and conducted a qualitative synthesis. Results: Among 676 studies identified, 45 met the inclusion criteria and were incorporated in the review. The majority of the studies (82%, n = 37) reported financial hardship as a material condition measure; others reported psychological (7%, n = 3) and behavioral measures (16%, n = 7). Financial hardship measures were heterogeneous within each broad category, and the prevalence of financial hardship varied by the measure used and population studied. Mean annual productivity loss ranged from $ 380 to $ 8236, 12% to 62% of survivors reported being in debt because of their treatment, 47% to 49% of survivors reported experiencing some form of financial distress, and 4% to 45% of survivors did not adhere to recommended prescription medication because of cost. Conclusions: Financial hardship is common among cancer survivors, although we found substantial heterogeneity in its prevalence. Our findings highlight the need for consistent use of definitions, terms, and measures to determine the best intervention targets and inform intervention development in order to prevent and minimize the impact of financial hardship experienced by cancer survivors. C1 [Altice, Cheryl K.; Yabroff, K. Robin] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. [Banegas, Matthew P.] Kaiser Permanente, Ctr Hlth Res, Portland, OR USA. [Tucker-Seeley, Reginald D.] Harvard Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA USA. [Tucker-Seeley, Reginald D.] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. RP Yabroff, KR (reprint author), US Dept HHS, Div Hlth Care Financing Policy, Off Hlth Policy, Planning & Evaluat, 200 Independence Ave SW, Washington, DC 20201 USA. EM robin.yabroff@hhs.gov FU National Cancer Institute K01 Career Development Grant [K01 CA169041] FX Dr. Tucker-Seeley was supported by a National Cancer Institute K01 Career Development Grant (K01 CA169041). NR 82 TC 1 Z9 1 U1 2 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 FEB PY 2017 VL 109 IS 2 AR djw205 DI 10.1093/jnci/djw205 PG 17 WC Oncology SC Oncology GA EO6AM UT WOS:000396774100004 ER PT J AU Harvey, HB Weinstein, DF AF Harvey, H. Benjamin Weinstein, Debra F. TI Predatory Publishing: An Emerging Threat to the Medical Literature SO ACADEMIC MEDICINE LA English DT Editorial Material AB The quality of medical literature is increasingly threatened by irresponsible publishing, leading to rising retraction rates, irreproducible results, and a flood of inconsequential publications that distract readers from more meaningful scholarship. "Predatory publishers" offer rapid publication with loose peer review, exploiting a system in which faculty seek longer bibliographies to achieve academic promotion. In this Commentary, the authors highlight some of the evidence that this problem exists and suggest actions to address it. Recommendations for protecting the medical literature include preventing predatory journals from being indexed by the National Library of Medicine; encouraging academic promotions committees to ensure that they prioritize value over volume of publications and that faculty understand that priority; excluding publications from predatory journals on curricula vitae and requiring that retractions are included; developing sanctions for repeated retractions or duplicate publications; and convening an expert panel to better elucidate this problem and determine strategies to combat it. C1 [Harvey, H. Benjamin] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Harvey, H. Benjamin] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Harvey, H. Benjamin] Harvard Med Sch, Boston, MA USA. [Weinstein, Debra F.] Partners Healthcare Syst, Grad Med Educ, Boston, MA USA. [Weinstein, Debra F.] Harvard Med Sch, Med, Boston, MA USA. RP Harvey, HB (reprint author), 101 Merrimac St,10th Floor, Boston, MA 02114 USA. EM HBHarvey@partners.org NR 7 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-2446 EI 1938-808X J9 ACAD MED JI Acad. Med. PD FEB PY 2017 VL 92 IS 2 BP 150 EP 151 DI 10.1097/ACM.0000000000001521 PG 2 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA EK1IA UT WOS:000393677800013 PM 28121685 ER PT J AU Dorsey, ER Chan, YF McConnell, MV Shaw, SY Trister, AD Friend, SH AF Dorsey, E. Ray Chan, Yu-Feng Yvonne McConnell, Michael V. Shaw, Stanley Y. Trister, Andrew D. Friend, Stephen H. TI The Use of Smartphones for Health Research SO ACADEMIC MEDICINE LA English DT Article ID TRIAL AB Because of their growing popularity and functionality, smartphones are increasingly valuable potential tools for health and medical research. Using ResearchKit, Apple's open-source platform to build applications ("apps") for smartphone research, collaborators have developed apps for researching asthma, breast cancer, cardiovascular disease, type 2 diabetes, and Parkinson disease. These research apps enhance widespread participation by removing geographical barriers to participation, provide novel ways to motivate healthy behaviors, facilitate high-frequency assessments, and enable more objective data collection. Although the studies have great potential, they also have notable limitations. These include selection bias, identity uncertainty, design limitations, retention, and privacy. As smartphone technology becomes increasingly available, researchers must recognize these factors to ensure that medical research is conducted appropriately. Despite these limitations, the future of smartphones in health research is bright. Their convenience grants unprecedented geographic freedom to researchers and participants alike and transforms the way clinical research can be conducted. C1 [Dorsey, E. Ray] Univ Rochester, Med Ctr, Dept Neurol, Rochester, NY 14642 USA. [Dorsey, E. Ray] Univ Rochester, Med Ctr, CHET, Rochester, NY 14642 USA. [Chan, Yu-Feng Yvonne] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Chan, Yu-Feng Yvonne] Icahn Sch Med Mt Sinai, Dept Emergency Med, New York, NY 10029 USA. [Chan, Yu-Feng Yvonne] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Digital Hlth, New York, NY 10029 USA. [McConnell, Michael V.] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. [McConnell, Michael V.] Stanford Univ, Sch Med, Cardiovasc Hlth Innovat, Stanford, CA 94305 USA. [Shaw, Stanley Y.] Harvard Med Sch, Dept Med, Boston, MA USA. [Shaw, Stanley Y.] Harvard Med Sch, CATCH, Massachusetts Gen Hosp, Boston, MA USA. [Trister, Andrew D.; Friend, Stephen H.] Sage Bionetworks, Seattle, WA USA. RP Dorsey, ER (reprint author), Univ Rochester, Med Ctr, 265 Crittenden Blvd,CU 420694, Rochester, NY 14642 USA. EM ray.dorsey@chet.rochester.edu FU National Institute of Neurological Disorders and Stroke [P20 NS092529] FX Apple provided in-kind technical support for the development of each of the research apps. The preparation of this report was supported in part by the National Institute of Neurological Disorders and Stroke (P20 NS092529). NR 19 TC 1 Z9 1 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-2446 EI 1938-808X J9 ACAD MED JI Acad. Med. PD FEB PY 2017 VL 92 IS 2 BP 157 EP 160 DI 10.1097/ACM.0000000000001205 PG 4 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA EK1IA UT WOS:000393677800015 PM 27119325 ER PT J AU Carnes, M Johnson, P Klein, W Jenkins, M Merz, CNB AF Carnes, Molly Johnson, Paula Klein, Wendy Jenkins, Marjorie Merz, C. Noel Bairey TI Advancing Women's Health and Women's Leadership With Endowed Chairs in Women's Health SO ACADEMIC MEDICINE LA English DT Article ID INSTITUTES-OF-HEALTH; GENDER BIAS; ACADEMIC MEDICINE; PHYSICIAN-RESEARCHERS; CAREER-DEVELOPMENT; CLINICAL-TRIALS; PAY GAP; SEX; ARTHROPLASTY; SPECIALTIES AB Gender-based bias and conflation of gender and status are root causes of disparities in women's health care and the slow advancement of women to leadership in academic medicine. More than a quarter of women physicians train in internal medicine and its subspecialties, and women physicians almost exclusively constitute the women's health focus within internal medicine. Thus, internal medicine has considerable opportunity to develop women leaders in academic medicine and promote women's health equity. To probe whether holding an endowed chair-which confers status-in women's health may be an effective way to advance women leaders in academic medicine and women's health, the authors explored the current status of endowed chairs in women's health in internal medicine. They found that the number of these endowed chairs in North America increased from 7 in 2013 to 19 in 2015, and all were held by women. The perceptions of incumbents and other women's health leaders supported the premise that an endowed chair in women's health would increase women's leadership, the institutional stature of women's health, and activities in women's health research, education, and clinical care. Going forward, it will be important to explore why not all recipients perceived that the endowed chair enhanced their own academic leadership, whether providing women's health leaders with fundraising expertise fosters future success in increasing the number of women's health endowed chairs, and how the conflation of gender and status play out (e.g., salary differences between endowed chairs) as the number of endowed chairs in women's health increases. C1 [Carnes, Molly] Univ Wisconsin, Ctr Womens Hlth Res, Sch Med & Publ Hlth, Madison, WI USA. [Carnes, Molly] Univ Wisconsin, Dept Med, Sch Med & Publ Hlth, Madison, WI USA. [Carnes, Molly] Univ Wisconsin, Dept Psychiat, Sch Med & Publ Hlth, Madison, WI 53706 USA. [Carnes, Molly] Univ Wisconsin, Dept Ind & Syst Engn, Sch Med & Publ Hlth, Madison, WI USA. [Carnes, Molly] William S Middleton Mem Vet Adm Med Ctr, Womens Hlth, Madison, WI USA. [Johnson, Paula] Brigham & Womens Hosp, Connors Ctr Womens Hlth & Gender Biol, 75 Francis St, Boston, MA 02115 USA. [Johnson, Paula] Brigham & Womens Hosp, Dept Med, Div Womens Hlth, 75 Francis St, Boston, MA 02115 USA. [Johnson, Paula] Harvard Med Sch, Epidemiol, Boston, MA USA. [Johnson, Paula] Wellesley Coll, Wellesley, MA 02181 USA. [Klein, Wendy] Inst Womens Hlth, Richmond, VA USA. [Klein, Wendy] Virginia Commonwealth Univ, Richmond, VA USA. [Jenkins, Marjorie] Laura W Bush Inst Womens Hlth, Amarillo, TX USA. [Jenkins, Marjorie] Texas Tech Univ, Hlth Sci Ctr, Med, Amarillo, TX USA. [Merz, C. Noel Bairey] Barbra Streisand Womens Heart Ctr, Los Angeles, CA USA. [Merz, C. Noel Bairey] Cedars Sinai Heart Inst, Med, Los Angeles, CA USA. RP Carnes, M (reprint author), Ctr Womens Hlth Res, 700 Regent St,Suite 301, Madison, WI 53715 USA. EM mlcarnes@wisc.edu NR 60 TC 1 Z9 1 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-2446 EI 1938-808X J9 ACAD MED JI Acad. Med. PD FEB PY 2017 VL 92 IS 2 BP 167 EP 174 DI 10.1097/ACM.0000000000001423 PG 8 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA EK1IA UT WOS:000393677800017 PM 27759706 ER PT J AU Rao, SK Kimball, AB Lehrhoff, SR Hidrue, MK Colton, DG Ferris, TG Torchiana, DF AF Rao, Sandhya K. Kimball, Alexa B. Lehrhoff, Sara R. Hidrue, Michael K. Colton, Deborah G. Ferris, Timothy G. Torchiana, David F. TI The Impact of Administrative Burden on Academic Physicians: Results of a Hospital-Wide Physician Survey SO ACADEMIC MEDICINE LA English DT Article ID MEDICAL-SCHOOL; SATISFACTION; CARE; PATIENT; BURNOUT AB Purpose To determine the characteristics of clinically active academic physicians most affected by administrative burden; the correlation between administrative burden, burnout, and career satisfaction among academic physicians; and the relative value and burden of specific administrative tasks. Method The authors analyzed data from the 2014 Massachusetts General Physicians Organization Survey. Respondents reported the percentage of time they spent on patient-related administrative duties and rated the value and burden associated with specific administrative tasks. A five-point Likert scale and multivariate regression identified predictors of administrative burden and assessed the impact of administrative burden on perceived quality of care, career satisfaction, and burnout. Results Of the eligible workforce, 1,774 physicians (96%) responded to the survey. On average, 24% of working hours were spent on administrative duties. Primary care physicians and women reported spending more time on administrative duties compared with other physicians. Two-thirds of respondents reported that administrative duties negatively affect their ability to deliver high-quality care. Physicians who reported higher percentages of time spent on administrative duties had lower levels of career satisfaction, higher levels of burnout, and were more likely to be considering seeing fewer patients in the future. Prior authorizations, clinical documentation, and medication reconciliation were rated the most burdensome tasks. Conclusions Administrative duties required substantial physician time and affected physicians' perceptions of being able to deliver high-quality care, career satisfaction, burnout, and likelihood to continue clinical practice. There is variation in administrative burden across specialties, and multiple areas of work contribute to overall administrative workload. C1 [Rao, Sandhya K.] Massachusetts Gen Phys Org, Qual Improvement, Boston, MA USA. [Rao, Sandhya K.; Ferris, Timothy G.] Harvard Med Sch, Med, Boston, MA USA. [Kimball, Alexa B.] Harvard Med Fac Phys, Boston, MA USA. [Kimball, Alexa B.] Harvard Med Sch, Dermatol, Boston, MA USA. [Lehrhoff, Sara R.] Massachusetts Gen Phys Org, Phys Programs, Strateg Commun & Phys Programs Dept, Boston, MA USA. [Hidrue, Michael K.] Massachusetts Gen Phys Org, Performance Analyt & Improvement Dept, Boston, MA USA. [Colton, Deborah G.; Torchiana, David F.] Partners Healthcare, Boston, MA USA. [Ferris, Timothy G.] Massachusetts Gen Phys Org, Populat Hlth, Boston, MA USA. [Torchiana, David F.] Harvard Med Sch, Surg, Boston, MA USA. RP Rao, SK (reprint author), Massachusetts Gen Hosp, 55 Fruit St,Bulfinch 205, Boston, MA 02114 USA. EM skrao@partners.org NR 19 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-2446 EI 1938-808X J9 ACAD MED JI Acad. Med. PD FEB PY 2017 VL 92 IS 2 BP 237 EP 243 DI 10.1097/ACM.0000000000001461 PG 7 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA EK1IA UT WOS:000393677800030 PM 28121687 ER PT J AU Chen, H Coseno, M Ficarro, SB Mansueto, MS Komazin-Meredith, G Boissel, S Filman, DJ Marto, JA Hogle, JM Coen, DM AF Chen, Han Coseno, Molly Ficarro, Scott B. Mansueto, My Sam Komazin-Meredith, Gloria Boissel, Sandrine Filman, David J. Marto, Jarrod A. Hogle, James M. Coen, Donald M. TI A Small Covalent Allosteric Inhibitor of Human Cytomegalovirus DNA Polymerase Subunit Interactions SO ACS INFECTIOUS DISEASES LA English DT Article DE human cytomegalovirus; DNA polymerase; protein-protein interaction; covalent inhibitor; SGM8 ID PROTEIN-PROTEIN INTERACTION; ACCESSORY PROTEIN; CATALYTIC SUBUNIT; SMALL-MOLECULE; CRYSTAL-STRUCTURE; C-TERMINUS; UL44; REPLICATION; UL54; IDENTIFICATION AB Human cytomegalovirus DNA polymerase comprises a catalytic subunit, UL54, and an accessory subunit, UL44, the interaction of which may serve as a target for the development of new antiviral drugs. Using a high-throughput screen, we identified a small molecule, (5-((dimethylamino)methylene-3-(methylthio)-6,7-dihydrobenzo[c]thiophen- 4(5H)-one), that selectively inhibits the interaction of UL44 with a UL54-derived peptide in a time-dependent manner, fulllength UL54, and UL44-dependent long-chain DNA synthesis. A crystal structure of the compound bound to UL44 revealed a covalent reaction with lysine residue 60 and additional noncovalent interactions that cause steric conflicts that would prevent the UL44 connector loop from interacting with UL54. Analyses of the reaction of the compound with model substrates supported a resonance-stabilized conjugation mechanism, and substitution of the lysine reduced the ability of the compound to inhibit UL44-ULS4 peptide interactions. This novel covalent inhibitor of polymerase subunit interactions may serve as a starting point for new, needed drugs to treat human cytomegalovirus infections. C1 [Chen, Han; Coseno, Molly; Mansueto, My Sam; Komazin-Meredith, Gloria; Boissel, Sandrine; Filman, David J.; Marto, Jarrod A.; Hogle, James M.; Coen, Donald M.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, 250 Longwood Ave, Boston, MA 02115 USA. [Ficarro, Scott B.; Marto, Jarrod A.] Dana Farber Canc Inst, Dept Canc Biol, 450 Brookline Ave, Boston, MA 02215 USA. [Ficarro, Scott B.; Marto, Jarrod A.] Dana Farber Canc Inst, Blais Prote Ctr, 450 Brookline Ave, Boston, MA 02215 USA. [Coseno, Molly] Univ Vermont, Burlington, VT 05405 USA. [Mansueto, My Sam] Merck, Boston, MA 02115 USA. [Komazin-Meredith, Gloria] Penn State Univ, University Pk, PA 16802 USA. [Boissel, Sandrine] Greenlight Biosci, Medford, MA 02155 USA. RP Coen, DM (reprint author), Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, 250 Longwood Ave, Boston, MA 02115 USA. EM don_coen@hms.harvard.edu FU NIH [AI019838]; Biota Holdings Limited; Dana-Farber Strategic Resources Initiative FX We thank Walt Massefski of the Dana-Farber Cancer Institute NMR core, Tom Wyche of the Harvard Medical School analytical chemistry core, and Jinhua Wang of Nathanael Gray's laboratory for help in analysis of SGM8; Michael J. Eck for kindly providing a robotic system for high-throughput screening of initial crystallization conditions; Cai-Hong Yun for assistance in crystallization and refinement; Nathanael Gray for advice, assistance, and a critical reading of the manuscript; and James Marvel-Coen for editorial help. We are especially grateful to personnel at ICCB-L for assistance with high-throughput screening, Robin Ross of the Biomolecule Production Core of NERCE (U54 AI057158) for production of UL44 and UL42, and Kelly Arnett at the Harvard Medical School Center for Molecular Interactions for help with BLItz. This work was supported by NIH Grant AI019838 to D.M.C. and J.M.H., a sponsored research agreement from Biota Holdings Limited to D.M.C., and the Dana-Farber Strategic Resources Initiative to J.A.M. NR 31 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 2373-8227 J9 ACS INFECT DIS JI ACS Infect. Dis. PD FEB PY 2017 VL 3 IS 2 BP 112 EP 118 DI 10.1021/acsinfecdis.6b00079 PG 7 WC Chemistry, Medicinal; Infectious Diseases SC Pharmacology & Pharmacy; Infectious Diseases GA EK7AR UT WOS:000394078400002 PM 28183184 ER PT J AU Uchida, M Fitzgerald, M Lin, K Carrellas, N Woodworth, H Biederman, J AF Uchida, M. Fitzgerald, M. Lin, K. Carrellas, N. Woodworth, H. Biederman, J. TI Can subsyndromal manifestations of major depression be identified in children at risk? SO ACTA PSYCHIATRICA SCANDINAVICA LA English DT Article DE subsyndromal; depression; children; pediatric ID ATTENTION-DEFICIT HYPERACTIVITY; DEFICIT/HYPERACTIVITY DISORDER; BIPOLAR DISORDER; YOUNG ADULTHOOD; ADOLESCENTS; 10-YEAR; YOUTH; GIRLS; ADHD; ESCALATION AB Objective: Children of parents with major depression are at significantly increased risk for developing major depression themselves; however, not all children at genetic risk will develop major depressive disorder (MDD). We investigated the utility of subsyndromal scores on the Child Behavior Checklist (CBCL) Anxiety/Depression scale in identifying children at the highest risk for pediatric MDD from among the pool of children of parents with MDD or bipolar disorder. Method: The sample was derived from two previously conducted longitudinal case-control family studies of psychiatrically and pediatrically referred youth and their families. For this study, probands were stratified based on the presence or absence of a parental mood disorder. Results: Subsyndromal scores on the CBCL Anxiety/Depression scale significantly separated the children at high risk for pediatric MDD from those at low risk in a variety of functional areas, including social and academic functioning. Additionally, children at genetic risk without elevated CBCL Anxiety/Depression scale scores were largely indistinguishable from controls. Conclusion: These results suggest that the CBCL Anxiety/Depression scale can help identify children at highest risk for pediatric MDD. If implemented clinically, this scale would cost-effectively screen children and identify those most in need of early intervention resources to impede the progression of depression. C1 [Uchida, M.; Fitzgerald, M.; Carrellas, N.; Woodworth, H.; Biederman, J.] Massachusetts Gen Hosp, Div Child Psychiat, Pediat Psychopharmacol & Adult ADHD Program, Warren Bldg 624, Boston, MA 02114 USA. [Uchida, M.; Lin, K.; Biederman, J.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA USA. RP Uchida, M (reprint author), Massachusetts Gen Hosp, Div Child Psychiat, Pediat Psychopharmacol & Adult ADHD Program, Warren Bldg 624, Boston, MA 02114 USA. EM muchida@partners.org FU MGH Pediatric Psychopharmacology Council Fund FX This study was supported by the MGH Pediatric Psychopharmacology Council Fund. NR 37 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0001-690X EI 1600-0447 J9 ACTA PSYCHIAT SCAND JI Acta Psychiatr. Scand. PD FEB PY 2017 VL 135 IS 2 BP 127 EP 137 DI 10.1111/acps.12660 PG 11 WC Psychiatry SC Psychiatry GA EN9JJ UT WOS:000396316200005 PM 27805260 ER PT J AU Piper, ME Vasilenko, SA Cook, JW Lanza, ST AF Piper, Megan E. Vasilenko, Sara A. Cook, Jessica W. Lanza, Stephanie T. TI What a difference a day makes: differences in initial abstinence response during a smoking cessation attempt SO ADDICTION LA English DT Article DE Anhedonia; craving; latent class analysis; person-centered analysis; relapse; smoking cessation; withdrawal ID ECOLOGICAL MOMENTARY ASSESSMENT; NICOTINE WITHDRAWAL SYMPTOMS; TOBACCO WITHDRAWAL; NEGATIVE AFFECT; QUIT ATTEMPT; TIME-COURSE; IMMEDIATE ANTECEDENTS; ANXIETY SENSITIVITY; WISCONSIN INVENTORY; DEPENDENCE MOTIVES AB Aims To (1) identify distinct classes of smokers based on quit day withdrawal symptoms and (2) explore the relations between withdrawal classes and demographics, tobacco dependence, treatment and smoking outcomes. Design Secondary data analysis of participants (n = 1504) in a randomized double-blind placebo-controlled multi-site smoking cessation trial who provided ecological momentary assessments of withdrawal symptoms on their quit day. Participants received smoking cessation counseling and were randomized to receive placebo or one of five active pharmacotherapies. Setting Research offices in Madison and Milwaukee, Wisconsin, USA. Participants Adult smokers (n = 1236; 58% female, 86% white), recruited from the community via advertisements, who abstained on their quit day. Measurements Demographics and tobacco dependence were assessed at baseline and participants carried palmtop computers to record withdrawal symptoms (craving, negative affect, difficulty concentrating, hunger and anhedonia) on their quit day. Point-prevalence abstinence and latency to relapse were assessed at 8 weeks and 6 months post-quit. Findings Latent class analysis identified four withdrawal classes [Akaike information criterion (AIC) = 70.09]: Moderate withdrawal (64% of sample), high craving-anhedonia (8% of sample), affective withdrawal (13% of sample) and hunger (15% of sample). The high craving-anhedonia class reported significantly higher dependence (P < 0.01), were less likely to have received combination nicotine replacement, reported lower week 8 abstinence rates and relapsed sooner than those in the moderate withdrawal class (P < 0.05). The affective withdrawal class reported higher levels of baseline negative affect and life-time psychopathology (P < 0.05) and relapsed more quickly than the moderate withdrawal class (P < 0.01). Conclusions While the majority of smokers report typical levels of withdrawal symptoms on their quit day, more than one-third report extreme craving or extreme negative affective or extreme hunger responses to initial abstinence. These distinct quit-day withdrawal symptom patterns are related to baseline characteristics, treatment and cessation success. C1 [Piper, Megan E.; Cook, Jessica W.] Univ Wisconsin, Sch Med & Publ Hlth, Ctr Tobacco Res & Intervent, 1930 Monroe St,Suite 200, Madison, WI 53711 USA. [Piper, Megan E.; Cook, Jessica W.] Univ Wisconsin, Dept Med, Madison, WI USA. [Vasilenko, Sara A.; Lanza, Stephanie T.] Penn State Univ, Methodol Ctr, University Pk, PA 16802 USA. [Cook, Jessica W.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. [Lanza, Stephanie T.] Penn State Univ, Dept Biobehav Hlth & Human Dev, University Pk, PA 16802 USA. RP Piper, ME (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, Ctr Tobacco Res & Intervent, 1930 Monroe St,Suite 200, Madison, WI 53711 USA. EM mep@ctri.wisc.edu FU NIH [P50DA0197, P50 DA039838, R01 CA168676]; US Department of Veterans Affairs [101CX00056]; Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Clinical Science Research and Development; [1KL2RR025012] FX This research was funded by NIH Grant P50DA0197 to the University of Wisconsin Center for Tobacco Research and Intervention and NIH grants P50 DA039838 and R01 CA168676 to the Pennsylvania State University. M.E.P. was funded in part by 1KL2RR025012. J.W.C. was funded in part by a VA Merit Review Award 101CX00056 from the US Department of Veterans Affairs, and by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Clinical Science Research and Development. Medication was provided to patients at no cost under a research agreement with GlaxoSmithKline. NR 63 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0965-2140 EI 1360-0443 J9 ADDICTION JI Addiction PD FEB PY 2017 VL 112 IS 2 BP 330 EP 339 DI 10.1111/add.13613 PG 10 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA EK5RP UT WOS:000393983800029 PM 27633341 ER PT J AU Atukunda, EC Musiimenta, A Musinguzi, N Wyatt, MA Ashaba, J Ware, NC Haberer, JE AF Atukunda, Esther C. Musiimenta, Angella Musinguzi, Nicholas Wyatt, Monique A. Ashaba, Justus Ware, Norma C. Haberer, Jessica E. TI Understanding Patterns of Social Support and Their Relationship to an ART Adherence Intervention Among Adults in Rural Southwestern Uganda SO AIDS AND BEHAVIOR LA English DT Article DE Social support; Adherence; Relation dynamics; ART; Uganda ID MEDICATION ADHERENCE; SOUTH-AFRICA; ANTIRETROVIRAL THERAPY; HIV; HIV/AIDS; DEPRESSION; WOMEN; AIDS; MEN AB SMS is a widely used technology globally and may also improve ART adherence, yet SMS notifications to social supporters following real-time detection of missed doses showed no clear benefit in a recent pilot trial. We examine the demographic and social-cultural dynamics that may explain this finding. In the trial, 63 HIV-positive individuals initiating ART received a real-time adherence monitor and were randomized to two types of SMS reminder interventions versus a control (no SMS). SMS notifications were also sent to 45 patient-identified social supporters for sustained adherence lapses. Like participants, social supporters were interviewed at enrollment, following their matched participant's adherence lapse and at exit. Social supporters with regular income (RR = 0.27, P = 0.001) were significantly associated with fewer adherence lapses. Instrumental support was associated with fewer adherence lapses only among social supporters who were food secure (RR = 0.58, P = 0.003). Qualitative interview data revealed diverse and complex economic and relationship dynamics, affecting social support. Resource availability in emotionally positive relationships seemingly facilitated helpful support, while limited resources prevented active provision of support for many. Effective social support appeared subject to social supporters' food security, economic stability and a well-functioning social network dependent on trust and supportive disclosure. C1 [Atukunda, Esther C.; Musiimenta, Angella; Musinguzi, Nicholas; Ashaba, Justus] Mbarara Univ Sci & Technol, Global Hlth Collaborat, Mbarara, Uganda. [Wyatt, Monique A.; Ware, Norma C.] Harvard Med Sch, Global Hlth & Social Med, Boston, MA USA. [Haberer, Jessica E.] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. RP Atukunda, EC (reprint author), Mbarara Univ Sci & Technol, Global Hlth Collaborat, Mbarara, Uganda. EM estheratukunda@gmail.com FU NIH [R34MH100940, NCT01957865] FX The study was funded by NIH (Grant Nos. R34MH100940 and NCT01957865). Jessicca E Haberer was the recipient. NR 24 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD FEB PY 2017 VL 21 IS 2 BP 428 EP 440 DI 10.1007/s10461-016-1559-7 PG 13 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA EK8CF UT WOS:000394150800010 PM 27671479 ER PT J AU Bogart, LM Wagner, GJ Musoke, W Naigino, R Linnemayr, S Maistrellis, E Klein, DJ Jumamil, RB Mukasa, B Bassett, IV Giordano, TP Wanyenze, RK AF Bogart, Laura M. Wagner, Glenn J. Musoke, William Naigino, Rose Linnemayr, Sebastian Maistrellis, Emily Klein, David J. Jumamil, Riana B. Mukasa, Barbara Bassett, Ingrid V. Giordano, Thomas P. Wanyenze, Rhoda K. TI A Comparison of Home-Based Versus Outreach Event-Based Community HIV Testing in Ugandan Fisherfolk Communities SO AIDS AND BEHAVIOR LA English DT Article DE Community-based HIV testing and counseling; Fisherfolk; Linkage to HIV care; Uganda ID SUB-SAHARAN AFRICA; ANTIRETROVIRAL THERAPY; SOUTH-AFRICA; COST-EFFECTIVENESS; WESTERN UGANDA; LAKE VICTORIA; FISHING COMMUNITIES; STIGMA SCALE; RISK-FACTORS; CARE AB We compared two community-based HIV testing models among fisherfolk in Lake Victoria, Uganda. From May to July 2015, 1364 fisherfolk residents of one island were offered (and 822 received) home-based testing, and 344 fisherfolk on another island were offered testing during eight community mobilization events (outreach event-based testing). Of 207 home-based testing clients identified as HIV-positive (15% of residents), 82 were newly diagnosed, of whom 31 (38%) linked to care within 3 months. Of 41 who screened positive during event-based testing (12% of those tested), 33 were newly diagnosed, of whom 24 (75%) linked to care within 3 months. Testing costs per capita were similar for home-based ($45.09) and event-based testing ($46.99). Compared to event-based testing, home-based testing uncovered a higher number of new HIV cases but was associated with lower linkage to care. Novel community-based test-and-treat programs are needed to ensure timely linkage to care for newly diagnosed fisherfolk. C1 [Bogart, Laura M.; Wagner, Glenn J.; Linnemayr, Sebastian; Klein, David J.] RAND Corp, Hlth Unit, 1776 Main St,POB 2138, Santa Monica, CA 90407 USA. [Bogart, Laura M.; Maistrellis, Emily; Klein, David J.; Jumamil, Riana B.] Boston Childrens Hosp, Dept Med, Div Gen Pediat, Boston, MA 02115 USA. [Bogart, Laura M.] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA. [Musoke, William; Mukasa, Barbara] Mildmay Uganda, Kampala, Uganda. [Naigino, Rose; Wanyenze, Rhoda K.] Makerere Univ, Sch Publ Hlth, Dept Dis Control & Environm Hlth, Kampala, Uganda. [Bassett, Ingrid V.] Harvard Med Sch, Massachusetts Gen Hosp, Div Gen Med, Boston, MA USA. [Bassett, Ingrid V.] Harvard Med Sch, Div Infect Dis, Boston, MA USA. [Giordano, Thomas P.] Baylor Coll Med, Houston, TX USA. [Giordano, Thomas P.] Michael E DeBakey Dept Vet Affairs Med Ctr, Houston, TX USA. RP Bogart, LM (reprint author), RAND Corp, Hlth Unit, 1776 Main St,POB 2138, Santa Monica, CA 90407 USA.; Bogart, LM (reprint author), Boston Childrens Hosp, Dept Med, Div Gen Pediat, Boston, MA 02115 USA.; Bogart, LM (reprint author), Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA. EM lbogart@rand.org FU National Institute of Mental Health [R21MH098657, R21MH098657-02S1] FX This study was funded by R21MH098657 and R21MH098657-02S1 from the National Institute of Mental Health (LM Bogart, Principal Investigator). NR 60 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD FEB PY 2017 VL 21 IS 2 BP 547 EP 560 DI 10.1007/s10461-016-1629-x PG 14 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA EK8CF UT WOS:000394150800022 PM 27900501 ER PT J AU Petrakis, IL Simpson, TL AF Petrakis, Ismene L. Simpson, Tracy L. TI Posttraumatic Stress Disorder and Alcohol Use Disorder: A Critical Review of Pharmacologic Treatments SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Review DE PTSD; Alcohol Use Disorder; Critical Review; Pharmacotherapy ID RANDOMIZED CONTROLLED-TRIAL; SUBSTANCE USE DISORDERS; NATIONAL EPIDEMIOLOGIC SURVEY; CLINICAL-TRIAL; PILOT TRIAL; ALPHA-1-ADRENERGIC ANTAGONIST; SERTRALINE TREATMENT; COMORBIDITY SURVEY; EXPOSURE THERAPY; HEALTH-CARE AB Treatment of alcohol use disorder (AUD) is complicated by the presence of psychiatric comorbidity including posttraumatic stress disorder (PTSD). This is a critical review of the literature to date on pharmacotherapy treatments of AUD and PTSD. A systematic literature search using PubMed MESH terms for alcohol and substance use disorders, PTSD, and treatment was undertaken to identify relevant randomized controlled trials (RCTs). The studies were independently evaluated (ILP and TLS) and those that evaluated the efficacy of a pharmacotherapy for individuals diagnosed with AUD and PTSD and were RCTs were selected. Studies were grouped in 3 categories: (i) those that evaluated first-line treatments for PTSD, (ii) those that evaluated medications to target AUD, and (iii) those that evaluated medications hypothesized to be effective in targeting alcohol consumption as well as PTSD symptoms. Nine RCTs were identified; 3 focused on medications to treat PTSD, 4 focused on AUD, and 3 to target both. One study included both a medication to treat PTSD and 1 to treat AUD so was discussed twice. All but 1 of the studies found that PTSD symptoms and drinking outcomes improved significantly over time. There is not 1 agent with clear evidence of efficacy in this comorbid group. The results for medications to treat PTSD are inconclusive because of contradictory results. There was weak evidence to support the use of medications to treat AUD among those with comorbidity with PTSD. Findings for medications that were hypothesized to treat both disorders were also contradictory. Most studies provided a combination of interventions to treat both disorders. Despite the contradictory results, this review suggests that individuals with AUD and comorbid PTSD can safely be prescribed medications used in noncomorbid populations and patients improve with treatment. C1 [Petrakis, Ismene L.] VA CT Healthcare Syst, Mental Illness Res & Clin Ctr MIRECC, West Haven, CT USA. [Petrakis, Ismene L.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Simpson, Tracy L.] VA Puget Sound Hlth Care, CESATE, Seattle, WA USA. [Simpson, Tracy L.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. RP Petrakis, IL (reprint author), VA Connecticut Healthcare Syst, 116-A,950 Campbell Ave, West Haven, CT 06516 USA. EM ismene.petrakis@yale.edu FU NIH/NIAAA [R01AA020252-01-Simpson] FX We gratefully acknowledge the contributions of Jessica Dascher, Erin Gandleman, and Diana Limoncelli. This work was funded in part by a grant from NIH/NIAAA (R01AA020252-01-Simpson). NR 66 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD FEB PY 2017 VL 41 IS 2 BP 226 EP 237 DI 10.1111/acer.13297 PG 12 WC Substance Abuse SC Substance Abuse GA EK4IV UT WOS:000393891200001 PM 28102573 ER PT J AU Lee, JJ Kroshinsky, D Hoang, MP AF Lee, Jonathan J. Kroshinsky, Daniela Hoang, Mai P. TI Cutaneous Reactions to Targeted Therapy SO AMERICAN JOURNAL OF DERMATOPATHOLOGY LA English DT Article DE cutaneous; drug eruption; targeted therapy ID CHRONIC LYMPHOCYTIC-LEUKEMIA; CHRONIC MYELOID-LEUKEMIA; OF-THE-LITERATURE; BRAF INHIBITOR THERAPY; CELL LUNG-CANCER; FACTOR RECEPTOR INHIBITORS; INDUCED LEUKOCYTOCLASTIC VASCULITIS; RITUXIMAB-INDUCED VASCULITIS; ERUPTIVE MELANOCYTIC NEVI; METASTATIC MELANOMA AB Over the past decade, numerous targeted therapeutic agents have become available for clinical use in the oncologic setting with the hopes of realizing personalized cancer treatment. These agents have achieved great improvements in clinical outcomes for patients suffering from solid and hematologic malignancies. However, adverse cutaneous reactions are among the most common toxicities observed in patients undergoing treatment with a targeted agent and can alter the overall clinical management strategy. For these reasons, the practicing dermatopathologist should be mindful of the breadth and depth of adverse cutaneous reaction patterns associated with this mechanistically diverse array of targeted agents. C1 [Lee, Jonathan J.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Kroshinsky, Daniela] Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,Warren 820, Boston, MA 02114 USA. [Hoang, Mai P.] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Kroshinsky, Daniela; Hoang, Mai P.] Harvard Med Sch, Boston, MA USA. RP Hoang, MP (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,Warren 820, Boston, MA 02114 USA. EM mhoang@mgh.harvard.edu NR 170 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0193-1091 EI 1533-0311 J9 AM J DERMATOPATH JI Am. J. Dermatopathol. PD FEB PY 2017 VL 39 IS 2 BP 67 EP 82 PG 16 WC Dermatology SC Dermatology GA EK3HS UT WOS:000393817900002 PM 28134724 ER PT J AU Weisz, JR Kuppens, S Ng, MY Eckshtain, D Ugueto, AM Vaughn-Coaxum, R Jensen-Doss, A Hawley, KM Marchette, LSK Chu, BC Weersing, VR Fordwood, SR AF Weisz, John R. Kuppens, Sofie Ng, Mei Yi Eckshtain, Dikla Ugueto, Ana M. Vaughn-Coaxum, Rachel Jensen-Doss, Amanda Hawley, Kristin M. Marchette, Lauren S. Krumholz Chu, Brian C. Weersing, V. Robin Fordwood, Samantha R. TI What Five Decades of Research Tells Us About the Effects of Youth Psychological Therapy: A Multilevel Meta-Analysis and Implications for Science and Practice SO AMERICAN PSYCHOLOGIST LA English DT Article DE children; youth; psychological therapy; treatment outcome; meta-analysis ID RANDOMIZED CONTROLLED-TRIAL; COGNITIVE-BEHAVIORAL-THERAPY; DEFICIT-HYPERACTIVITY-DISORDER; CHILD INTERACTION THERAPY; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; TREATMENT FOSTER-CARE; OBSESSIVE-COMPULSIVE DISORDER; CONDUCT-PROBLEM CHILDREN; 1-YEAR FOLLOW-UP; DEPRESSION PREVENTION PROGRAM AB Across 5 decades, hundreds of randomized trials have tested psychological therapies for youth internalizing (anxiety, depression) and externalizing (misconduct, attention deficit and hyperactivity disorder) disorders and problems. Since the last broad-based youth meta-analysis in 1995, the number of trials has almost tripled and data-analytic methods have been refined. We applied these methods to the expanded study pool (447 studies; 30,431 youths), synthesizing 50 years of findings and identifying implications for research and practice. We assessed overall effect size (ES) and moderator effects using multilevel modeling to address ES dependency that is common, but typically not modeled, in meta-analyses. Mean post-treatment ES was 0.46; the probability that a youth in the treatment condition would fare better than a youth in the control condition was 63%. Effects varied according to multiple moderators, including the problem targeted in treatment: Mean ES at posttreatment was strongest for anxiety (0.61), weakest for depression (0.29), and nonsignificant for multiproblem treatment (0.15). ESs differed across control conditions, with "usual care" emerging as a potent comparison condition, and across informants, highlighting the need to obtain and integrate multiple perspectives on outcome. Effects of therapy type varied by informant; only youth-focused behavioral therapies (including cognitive-behavioral therapy) showed similar and robust effects across youth, parent, and teacher reports. Effects did not differ for Caucasian versus minority samples, but more diverse samples are needed. The findings underscore the benefits of psychological treatments as well as the need for improved therapies and more representative, informative, and rigorous intervention science. C1 [Weisz, John R.; Ng, Mei Yi; Vaughn-Coaxum, Rachel] Harvard Univ, Dept Psychol, William James Hall,33 Kirkland St, Cambridge, MA 02138 USA. [Kuppens, Sofie] Katholieke Univ Leuven, HIVA Res Inst Work & Soc, Leuven, Belgium. [Eckshtain, Dikla] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA USA. [Ugueto, Ana M.] Harvard Med Sch, Judge Baker Childrens Ctr, Boston, MA USA. [Jensen-Doss, Amanda] Univ Miami, Dept Psychol, Coral Gables, FL 33124 USA. [Hawley, Kristin M.] Univ Missouri, Dept Psychol Sci, Columbia, MO 65211 USA. [Marchette, Lauren S. Krumholz] Harvard Med Sch, Cambridge Hlth Alliance, Dept Psychiat, Boston, MA USA. [Chu, Brian C.] Rutgers State Univ, Grad Sch Appl & Profess Psychol, Dept Clin Psychol, New Brunswick, NJ USA. [Weersing, V. Robin] San Diego State Univ, Joint Doctoral Program Clin Psychol, San Diego, CA 92182 USA. [Weersing, V. Robin] Univ Calif San Diego, La Jolla, CA 92093 USA. [Fordwood, Samantha R.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. RP Weisz, JR (reprint author), Harvard Univ, Dept Psychol, William James Hall,33 Kirkland St, Cambridge, MA 02138 USA. EM john_weisz@harvard.edu FU Norlien Foundation; National Institute of Mental Health [MH068806, MH085963, MH093511] FX We acknowledge with thanks the funding provided by the Norlien Foundation and the National Institute of Mental Health (MH068806, MH085963, MH093511) to the first author. We are grateful to Katherine Corteselli, Margaret Crane, Katherine DiVasto, Rayna Edels, Natalia Gil, Melanie Hill, David Langer, Elizabeth Lewis, Nicole Long, Aliya Moreira, Angie Morssal, Louisa Michl, Katherine Nolan, Anushka Patel, Lea Petrovic, Aaron Rosales, Selma Sehovic, Saliha Selman, Esther Tung, and colleagues from the Harvard University Institute for Quantitative Social Sciences Research for their help in multiple aspects of this work. NR 638 TC 0 Z9 0 U1 3 U2 3 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0003-066X EI 1935-990X J9 AM PSYCHOL JI Am. Psychol. PD FEB-MAR PY 2017 VL 72 IS 2 BP 79 EP 117 DI 10.1037/a0040360 PG 39 WC Psychology, Multidisciplinary SC Psychology GA EN0RY UT WOS:000395718500001 PM 28221063 ER PT J AU Siddiqi, OK Brown, M Cooper, C Atadzhanov, M Lakhi, S Koralnik, IJ AF Siddiqi, Omar K. Brown, Merritt Cooper, Christine Atadzhanov, Masharip Lakhi, Shabir Koralnik, Igor J. TI Developing a successful global neurology program SO ANNALS OF NEUROLOGY LA English DT Editorial Material C1 [Siddiqi, Omar K.; Koralnik, Igor J.] Harvard Med Sch, Beth Deaconess Med Ctr, Div Neuroimmunol,Dept Neurol, Ctr Virol & Vaccine Res,Global Neurol Program, Boston, MA USA. [Siddiqi, Omar K.; Atadzhanov, Masharip; Lakhi, Shabir] Univ Zambia, Dept Internal Med, Sch Med, Lusaka, Zambia. [Brown, Merritt] Univ Penn Hlth Syst, Div Neurocrit Care, Dept Neurol, Philadelphia, PA USA. [Cooper, Christine] Med Univ South Carolina, Movement Disorders Div, Dept Neurol, Columbia, SC USA. [Koralnik, Igor J.] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. RP Siddiqi, OK (reprint author), Beth Israel Deaconess Med Ctr, 330 Brookline Ave, Boston, MA 02215 USA. EM osiddiqi@bidmc.harvard.edu 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 0364-5134 EI 1531-8249 J9 ANN NEUROL JI Ann. Neurol. PD FEB PY 2017 VL 81 IS 2 BP 167 EP 170 DI 10.1002/ana.24863 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EM0GM UT WOS:000394996800001 PM 28019673 ER PT J AU Herranz, E Hooker, JM Izquierdo-Garcia, D Loggia, ML Mainero, C AF Herranz, Elena Hooker, Jacob M. Izquierdo-Garcia, David Loggia, Marco L. Mainero, Caterina TI [C-11]PBR-28 Positron Emission Tomography in Multiple Sclerosis: Neuroinflammation or Otherwise? Reply SO ANNALS OF NEUROLOGY LA English DT Letter ID GRAY-MATTER; INFLAMMATION C1 [Herranz, Elena; Hooker, Jacob M.; Izquierdo-Garcia, David; Loggia, Marco L.; Mainero, Caterina] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Herranz, Elena; Hooker, Jacob M.; Izquierdo-Garcia, David; Loggia, Marco L.; Mainero, Caterina] Harvard Med Sch, Boston, MA 02115 USA. RP Herranz, E (reprint author), Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA.; Herranz, E (reprint author), Harvard Med Sch, Boston, MA 02115 USA. NR 10 TC 0 Z9 0 U1 1 U2 1 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 FEB PY 2017 VL 81 IS 2 BP 324 EP 325 DI 10.1002/ana.24865 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EM0GM UT WOS:000394996800020 PM 28032651 ER PT J AU Lo, GH Driban, JB Kriska, AM McAlindon, TE Souza, RB Petersen, NJ Storti, KL Eaton, CB Hochberg, MC Jackson, RD Kwoh, CK Nevitt, MC Suarez-Almazor, ME AF Lo, Grace H. Driban, Jeffrey B. Kriska, Andrea M. McAlindon, Timothy E. Souza, Richard B. Petersen, Nancy J. Storti, Kristi L. Eaton, Charles B. Hochberg, Marc C. Jackson, Rebecca D. Kwoh, C. Kent Nevitt, Michael C. Suarez-Almazor, Maria E. TI Is There an Association Between a History of Running and Symptomatic Knee Osteoarthritis? A Cross-Sectional Study From the Osteoarthritis Initiative SO ARTHRITIS CARE & RESEARCH LA English DT Article ID ALL-CAUSE MORTALITY; PHYSICAL-ACTIVITY; MEN; QUESTIONNAIRE; RUNNERS; DENSITY; RISK AB ObjectiveRegular physical activity, including running, is recommended based on known cardiovascular and mortality benefits. However, controversy exists regarding whether running can be harmful to knees. The purpose of this study is to evaluate the relationship of running with knee pain, radiographic osteoarthritis (OA), and symptomatic OA. MethodsThis was a retrospective cross-sectional study of Osteoarthritis Initiative participants (2004-2014) with knee radiograph readings, symptom assessments, and completed lifetime physical activity surveys. Using logistic regression, we evaluated the association of history of leisure running with the outcomes of frequent knee pain, radiographic OA, and symptomatic OA. Symptomatic OA required at least 1 knee with both radiographic OA and pain. ResultsOf 2,637 participants, 55.8% were female, the meanSD age was 64.3 +/- 8.9 years, and the mean +/- SD body mass index was 28.5 +/- 4.9 kg/m(2); 29.5% of these participants ran at some time in their lives. Unadjusted odds ratios of pain, radiographic OA, and symptomatic OA for those prior runners and current runners compared to those who never ran were 0.83 and 0.71 (P for trend=0.002), 0.83 and 0.78 (P for trend=0.01), and 0.81 and 0.64 (P for trend=0.0006), respectively. Adjusted models were similar, except radiographic OA results were attenuated. ConclusionThere is no increased risk of symptomatic knee OA among self-selected runners compared with nonrunners in a cohort recruited from the community. In those without OA, running does not appear to be detrimental to the knees. C1 [Lo, Grace H.; Petersen, Nancy J.] Baylor Coll Med, 1 Baylor Plaza,BCM 285, Houston, TX 77030 USA. [Lo, Grace H.] Michael E DeBakey Med Ctr, Houston, TX USA. [Driban, Jeffrey B.; McAlindon, Timothy E.] Tufts Med Ctr, Boston, MA USA. [Kriska, Andrea M.] Univ Pittsburgh, Pittsburgh, PA USA. [Souza, Richard B.; Nevitt, Michael C.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Storti, Kristi L.] Indiana Univ Penn, Indiana, PA USA. [Eaton, Charles B.] Mem Hosp Rhode Isl, Pawtucket, RI USA. [Eaton, Charles B.] Brown Univ, Alpert Med Sch, Pawtucket, RI USA. [Hochberg, Marc C.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Jackson, Rebecca D.] Ohio State Univ, Columbus, OH 43210 USA. [Kwoh, C. Kent] Univ Arizona, Tucson, AZ USA. [Suarez-Almazor, Maria E.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Lo, GH (reprint author), Baylor Coll Med, 1 Baylor Plaza,BCM 285, Houston, TX 77030 USA. EM ghlo@bcm.edu OI Driban, Jeffrey/0000-0001-6098-4273 FU NIH [N01-AR-2-2258, N01-AR-2-2259, N01-AR-2-2260, N01-AR-2-2261, N01-AR-2-2262]; Merck Research Laboratories; Novartis Pharmaceuticals; GlaxoSmithKline; Pfizer; Foundation for the NIH; VA Health Services Research and Development [CIN-13-413]; NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases [K23-AR062127, K24-AR053593] FX This article was prepared using an Osteoarthritis Initiative (OAI) public-use data set, and its contents do not necessarily reflect the opinions or views of the OAI Study Investigators, the NIH, or the private funding partners of the OAI. The OAI is a public-private partnership between the NIH (contracts N01-AR-2-2258, N01-AR-2-2259, N01-AR-2-2260, N01-AR-2-2261, and N01-AR-2-2262) and private funding partners (Merck Research Laboratories, Novartis Pharmaceuticals, GlaxoSmithKline, and Pfizer) and is conducted by the OAI Study Investigators. Private-sector funding for the OAI is managed by the Foundation for the NIH.; Supported in part by the VA Health Services Research and Development service that funds the Center for Innovations in Quality, Effectiveness and Safety, at the Michael E. DeBakey VA Medical Center in Houston, Texas (CIN-13-413). Drs. Lo and Suarez-Almazor's work is supported by the NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases (grants K23-AR062127 and K24-AR053593, respectively). NR 25 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2151-464X EI 2151-4658 J9 ARTHRIT CARE RES JI Arthritis Care Res. PD FEB PY 2017 VL 69 IS 2 BP 183 EP 191 DI 10.1002/acr.22939 PG 9 WC Rheumatology SC Rheumatology GA EK4CU UT WOS:000393875500004 PM 27333572 ER PT J AU Furie, R Khamashta, M Merrill, JT Werth, VP Kalunian, K Brohawn, P Illei, GG Drappa, J Wang, LW Yoo, S AF Furie, Richard Khamashta, Munther Merrill, Joan T. Werth, Victoria P. Kalunian, Kenneth Brohawn, Philip Illei, Gabor G. Drappa, Jorn Wang, Liangwei Yoo, Stephen CA CD1013 Study Investigators TI Anifrolumab, an Anti-Interferon-alpha Receptor Monoclonal Antibody, in Moderate-to-Severe Systemic Lupus Erythematosus SO ARTHRITIS & RHEUMATOLOGY LA English DT Article ID DISEASE-ACTIVITY INDEX; I INTERFERON; REVISED CRITERIA; CLASSIFICATION; THERAPY; CLASI AB Objective. To assess the efficacy and safety of anifrolumab, a type I interferon (IFN) receptor antagonist, in a phase IIb, randomized, double-blind, placebo-controlled study of adults with moderate-to-severe systemic lupus erythematosus (SLE). Methods. Patients (n=305) were randomized to receive intravenous anifrolumab (300 mg or 1,000 mg) or placebo, in addition to standard therapy, every 4 weeks for 48 weeks. Randomization was stratified by SLE Disease Activity Index 2000 score (<10 or >= 10), oral corticosteroid dosage (<10 or >= 10 mg/day), and type I IFN gene signature test status (high or low) based on a 4-gene expression assay. The primary end point was the percentage of patients achieving an SLE Responder Index (SRI[4]) response at week 24 with sustained reduction of oral corticosteroids (<10 mg/day and less than or equal to the dose at week 1 from week 12 through 24). Other end points (including SRI[4], British Isles Lupus Assessment Group [BILAG]-based Composite Lupus Assessment [BICLA], modified SRI[6], and major clinical response) were assessed at week 52. The primary end point was analyzed in the modified intent-to-treat (ITT) population and type I IFN-high subpopulation. The study result was considered positive if the primary end point was met in either of the 2 study populations. The Type I error rate was controlled at 0.10 (2-sided), within each of the 2 study populations for the primary end point analysis. Results. The primary end point was met by more patients treated with anifrolumab (34.3% of 99 for 300 mg and 28.8% of 104 for 1,000 mg) than placebo (17.6% of 102) (P=0.014 for 300 mg and P=0.063 for 1,000 mg, versus placebo), with greater effect size in patients with a high IFN signature at baseline (13.2% in placebo-treated patients versus 36.0% [P=0.004] and 28.2% [P=0.029]) in patients treated with anifrolumab 300 mg and 1,000 mg, respectively. At week 52, patients treated with anifrolumab achieved greater responses in SRI(4) (40.2% versus 62.6% [P<0.001] and 53.8% [P=0.043] with placebo, anifrolumab 300 mg, and anifrolumab 1,000 mg, respectively), BICLA (25.7% versus 53.5% [P<0.001] and 41.2% [P=0.018], respectively), modified SRI(6) (28.4% versus 49.5% [P=0.002] and 44.7% [P=0.015], respectively), major clinical response (BILAG 2004 C or better in all organ domains from week 24 through week 52) (6.9% versus 19.2% [P=0.012] and 17.3% [P=0.025], respectively), and several other global and organ-specific end points. Herpes zoster was more frequent in the anifrolumab-treated patients (2.0% with placebo treatment versus 5.1% and 9.5% with anifrolumab 300 mg and 1,000 mg, respectively), as were cases reported as influenza (2.0% versus 6.1% and 7.6%, respectively), in the anifrolumab treatment groups. Incidence of serious adverse events was similar between groups (18.8% versus 16.2% and 17.1%, respectively). Conclusion. Anifrolumab substantially reduced disease activity compared with placebo across multiple clinical end points in the patients with moderate-to-severe SLE. C1 [Furie, Richard] Northwell Hlth, Hofstra Northwell Sch Med, New York, NY USA. [Khamashta, Munther] Kings Coll London, London WC2R 2LS, England. [Khamashta, Munther] St Thomas Hosp, London, England. [Merrill, Joan T.] Oklahoma Med Res Fdn, Oklahoma City, OK USA. [Werth, Victoria P.] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Werth, Victoria P.] Univ Penn, Philadelphia, PA 19104 USA. [Kalunian, Kenneth] Univ Calif San Diego, Sch Med, La Jolla, CA 92093 USA. [Brohawn, Philip; Illei, Gabor G.; Drappa, Jorn; Wang, Liangwei] MedImmune, Gaithersburg, MD USA. [Yoo, Stephen] Regenxbio, Rockville, MD USA. RP Furie, R (reprint author), Northwell Hlth, Div Rheumatol, 865 Northern Blvd, Great Neck, NY 11021 USA. EM RFurie@northwell.edu FU MedImmune FX The study was funded by MedImmune. All authors interpreted the data, critically reviewed the manuscript for important intellectual content, approved the final draft, and agreed to its submission. Publication of the article was contingent upon approval by MedImmune. Writing assistance was provided by Katie Alexander, PhD (QXV Communications, an Ashfield business, part of UDG Healthcare, Macclesfield, UK) and fully funded by MedImmune. NR 32 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD FEB PY 2017 VL 69 IS 2 BP 376 EP 386 DI 10.1002/art.39962 PG 11 WC Rheumatology SC Rheumatology GA EK4FK UT WOS:000393882300015 PM 28130918 ER PT J AU Paik, JM Kim, SC Feskanich, D Choi, HK Solomon, DH Curhan, GC AF Paik, Julie M. Kim, Seoyoung C. Feskanich, Diane Choi, Hyon K. Solomon, Daniel H. Curhan, Gary C. TI Gout and Risk of Fracture in Women: A Prospective Cohort Study SO ARTHRITIS & RHEUMATOLOGY LA English DT Article ID SERUM URIC-ACID; BONE-MINERAL DENSITY; CORONARY-HEART-DISEASE; US GENERAL-POPULATION; HIP FRACTURE; POSTMENOPAUSAL WOMEN; ATHEROSCLEROSIS RISK; DISTAL FOREARM; INCIDENT GOUT; URATE LEVELS AB Objective. Uric acid may be linked to bone health through its antioxidant or prooxidant effects, thereby affecting bone resorption and formation, or through its dual inhibition of vitamin D activation and parathyroid hormone production. Results of prior studies on the relationship between uric acid and bone mineral density have been conflicting. This prospective study was undertaken to examine the relationship between gout, a disease characterized by hyperuricemia and inflammation, and risk of hip or wrist fracture in women. Methods. We conducted a prospective observational study of gout and risk of incident wrist and hip fracture in women participating in the Nurses' Health Study (n=103,799 at baseline, with 14 years of follow-up for the wrist fracture analysis and 22 years of follow-up for the hip fracture analysis). Gout history and incident cases of wrist and hip fracture were assessed by biennial questionnaire. Cox proportional hazards models were used to simultaneously adjust for potential confounders. Results. In this cohort, there were 3,769 incident wrist fractures (1990-2004) and 2,147 incident hip fractures (1990-2012), with 107 wrist fractures and 117 hip fractures occurring in participants with gout. In those women with a history of gout compared with women without gout, the multivariable-adjusted relative risk of wrist fracture was 1.12 (95% confidence interval [95% CI] 0.92-1.36) and the multivariable-adjusted relative risk of hip fracture was 1.38 (95% CI 1.14-1.68). Conclusion. In women, a history of gout is associated with a modestly increased risk of hip fracture, but not significantly associated with a risk of wrist fracture. C1 [Paik, Julie M.; Curhan, Gary C.] Brigham & Womens Hosp, Harvard Med Sch, Boston, MA 02115 USA. [Paik, Julie M.; Feskanich, Diane; Curhan, Gary C.] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Kim, Seoyoung C.; Feskanich, Diane; Solomon, Daniel H.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Kim, Seoyoung C.; Choi, Hyon K.; Solomon, Daniel H.] Harvard Med Sch, Boston, MA USA. [Choi, Hyon K.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Paik, JM (reprint author), Channing Div Network Med, 181 Longwood Ave,Room 432, Boston, MA 02115 USA. EM jmpaik@partners.org OI Kim, Seoyoung/0000-0002-2517-3579 FU NIH (National Institute of Diabetes and Digestive and Kidney Diseases) [DK-100447, DK-091417]; NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases) [AR-055989]; NIH (National Cancer Institute) [CA-186107] FX Supported by the NIH (National Institute of Diabetes and Digestive and Kidney Diseases grants DK-100447 and DK-091417, National Institute of Arthritis and Musculoskeletal and Skin Diseases grant AR-055989, and National Cancer Institute grant CA-186107). NR 66 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD FEB PY 2017 VL 69 IS 2 BP 422 EP 428 DI 10.1002/art.39852 PG 7 WC Rheumatology SC Rheumatology GA EK4FK UT WOS:000393882300019 PM 27589491 ER PT J AU Han, C Shen, JK Hornicek, FJ Kan, QC Duan, ZF AF Han, Chao Shen, Jacson K. Hornicek, Francis J. Kan, Quancheng Duan, Zhenfeng TI Regulation of microRNA-1 (miR-1) expression in human cancer SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS LA English DT Review DE miRNA; miR-1; Cancer; Regulatory mechanisms ID ACUTE MYELOID-LEUKEMIA; LONG NONCODING RNA; COLORECTAL-CANCER; DNA METHYLATION; DOWN-REGULATION; NASOPHARYNGEAL CARCINOMA; MULTIPLE-MYELOMA; TUMOR-SUPPRESSOR; PROSTATE-CANCER; GENE-EXPRESSION AB MicroRNAs (miRs) have been found to play important roles in tumorigenesis, apoptosis, metastasis, and drug resistance in cancer. Among a number of miRs, miR-1 was shown to be predominantly downregulated in almost all examined human cancers. As a tumor suppressor miR involved in post-transcriptional regulation of crucial tumor associated gene expression, miR-1 represents a promising target for anticancer therapy. Re-expression of miR-1 can suppress cancer cell proliferation, promote apoptosis, and reverse drug resistance in cancers both in vitro and in vivo. Recently, the regulatory mechanisms of miR-1 expression have been studied in various cancers in different model systems. In this review, we summarize the mechanisms of miR-1 expression through epigenetic, transcriptional, and post-transcriptional regulation. These regulatory mechanisms of miR-1 expression could help us to understand the functions of altered miR-1 expression and provide valuable insights for further investigations into miR-1 based cancer therapy. Published by Elsevier B.V. C1 [Han, Chao; Kan, Quancheng; Duan, Zhenfeng] Zhengzhou Univ, Affiliated Hosp 1, Dept Pharm, 1 Jianshe East Rd, Zhengzhou 450052, Peoples R China. [Han, Chao; Shen, Jacson K.; Hornicek, Francis J.; Duan, Zhenfeng] Massachusetts Gen Hosp, Ctr Sarcoma & Connect Tasue Oncol, Sarcoma Biol Lab, 100 Blossom St,Jackson 1115, Boston, MA 02114 USA. RP Kan, QC; Duan, ZF (reprint author), Zhengzhou Univ, Affiliated Hosp 1, Dept Pharm, 1 Jianshe East Rd, Zhengzhou 450052, Peoples R China.; Duan, ZF (reprint author), Massachusetts Gen Hosp, Ctr Sarcoma & Connect Tasue Oncol, Sarcoma Biol Lab, 100 Blossom St,Jackson 1115, Boston, MA 02114 USA. EM quanchengkan@yeah.net; zduan@mgh.harvard.edu FU Joint Research Fund [228282]; National Natural Science Foundation of China [81402266, 81372875]; Henan Scholarship Council; Gattegno and Wechsler funds [226303] FX This work was supported by a Joint Research Fund (228282) devoted to clinical pharmacy and precision medicine (Z.D and Q.K). Support has also been provided by the National Natural Science Foundation of China (No.: 81402266 and 81372875), the Gattegno and Wechsler funds (226303). Dr. Han is supported by a scholarship from the Henan Scholarship Council. The authors thank Carol A. Trahan for assistance with editing the manuscript. NR 69 TC 1 Z9 1 U1 3 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1874-9399 EI 0006-3002 J9 BBA-GENE REGUL MECH JI Biochim. Biophys. Acta-Gene Regul. Mech. PD FEB PY 2017 VL 1860 IS 2 BP 227 EP 232 DI 10.1016/j.bbagrm.2016.12.004 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA EK6YT UT WOS:000394072900006 PM 27923712 ER PT J AU Mattson, JM Turcotte, R Zhang, YH AF Mattson, Jeffrey M. Turcotte, Raphael Zhang, Yanhang TI Glycosaminoglycans contribute to extracellular matrix fiber recruitment and arterial wall mechanics SO BIOMECHANICS AND MODELING IN MECHANOBIOLOGY LA English DT Article DE Glycosaminoglycan; Proteoglycan; Collagen; Elastin; Multiphoton microscopy; Biaxial tensile testing; Fiber recruitment; Extracellular matrix ID ARTICULAR-CARTILAGE; STRESS-RELAXATION; TENDON FASCICLES; IN-VITRO; COLLAGEN; AORTA; PROTEOGLYCANS; ELASTIN; STABILITY; BEHAVIOR AB Elastic and collagen fibers are well known to be the major load-bearing extracellular matrix (ECM) components of the arterial wall. Studies of the structural components and mechanics of arterial ECM generally focus on elastin and collagen fibers, and glycosaminoglycans (GAGs) are often neglected. Although GAGs represent only a small component of the vessel wall ECM, they are considerably important because of their diverse functionality and their role in pathological processes. The goal of this study was to study the mechanical and structural contributions of GAGs to the arterial wall. Biaxial tensile testing was paired with multiphoton microscopic imaging of elastic and collagen fibers in order to establish the structure-function relationships of porcine thoracic aorta before and after enzymatic GAG removal. Removal of GAGs results in an earlier transition point of the nonlinear stress-strain curves . However, stiffness was not significantly different after GAG removal treatment, indicating earlier but not absolute stiffening. Multiphoton microscopy showed that when GAGs are removed, the adventitial collagen fibers are straighter, and both elastin and collagen fibers are recruited at lower levels of strain, in agreement with the mechanical change. The amount of stress relaxation also decreased in GAG-depleted arteries . These findings suggest that the interaction between GAGs and other ECM constituents plays an important role in the mechanics of the arterial wall, and GAGs should be considered in addition to elastic and collagen fibers when studying arterial function. C1 [Mattson, Jeffrey M.; Zhang, Yanhang] Boston Univ, Dept Mech Engn, Boston, MA 02215 USA. [Turcotte, Raphael; Zhang, Yanhang] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [Turcotte, Raphael] Harvard Med Sch, Massachusetts Gen Hosp, Adv Microscopy Program, Ctr Syst Biol,Wellman Ctr Photomed, Boston, MA USA. RP Zhang, YH (reprint author), Boston Univ, Dept Mech Engn, Boston, MA 02215 USA.; Zhang, YH (reprint author), Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. EM yanhang@bu.edu FU National Science Foundation [CMMI 1463390]; National Institutes of Health [2T32HL007969] FX This work was supported, in part, by a Grant from National Science Foundation (CMMI 1463390) and a predoctoral training grant from National Institutes of Health (2T32HL007969). NR 52 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1617-7959 EI 1617-7940 J9 BIOMECH MODEL MECHAN JI Biomech. Model. Mechanobiol. PD FEB PY 2017 VL 16 IS 1 BP 213 EP 225 DI 10.1007/s10237-016-0811-4 PG 13 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA EK8DF UT WOS:000394153400015 PM 27491312 ER PT J AU Sarantopoulos, J Mita, AC He, AW Wade, JL Hsueh, CT Morris, JC Lockhart, AC Quinn, DI Hwang, J Mier, J Zhang, WP Wack, C Yin, J Clot, PF Rixe, O AF Sarantopoulos, John Mita, Alain C. He, Aiwu Wade, James L. Hsueh, Chung-Tsen Morris, John C. Lockhart, A. Craig Quinn, David I. Hwang, Jimmy Mier, James Zhang, Wenping Wack, Claudine Yin, Jian Clot, Pierre-Francois Rixe, Olivier TI Safety and pharmacokinetics of cabazitaxel in patients with hepatic impairment: a phase I dose-escalation study SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Cabazitaxel; Hepatic impairment; Maximum tolerated dose; Pharmacokinetics; Phase I ID ADVANCED SOLID TUMORS; EVERY 3 WEEKS; CANCER-PATIENTS; OPEN-LABEL; DYSFUNCTION; TAXANE; TRIAL AB Cabazitaxel has not been studied in patients with hepatic impairment (HI). This phase I study assessed cabazitaxel safety and pharmacokinetics in patients with HI. Patients with advanced, non-hematologic cancer, and normal hepatic function (Cohort 1: C-1), or mild (C-2), moderate (C-3), severe (C-4) HI received cabazitaxel starting doses of 25, 20, 10, and 10 mg/m(2), respectively. Doses were escalated in patients with HI based on Cycle 1 dose-limiting toxicities (DLTs). Adverse events and the cabazitaxel pharmacokinetic profile were assessed. In C-2, three patients receiving cabazitaxel 25 mg/m(2) experienced DLTs; maximum tolerated dose (MTD) was 20 mg/m(2). In C-3, two patients receiving 20 mg/m(2) experienced DLTs; MTD was 15 mg/m(2). C-4 was discontinued early due to DLTs. The most frequent cabazitaxel-related, grade 3-4 toxicity was neutropenia (42%). Cabazitaxel clearance normalized to body surface area (CL/BSA) was lower in C-1 (geometric mean [GM] 13.4 L/h/m(2)) than expected (26.4 L/h/m(2)), but similar in C-2 (23.5 L/h/m(2)) and C-3 (27.9 L/h/m(2)). CL/BSA in C-4 was 18.1 L/h/m(2). Compared with C-2, CL/BSA increased 19% in C-3 (GM ratio 1.19; 90% CI 0.74-1.91), but decreased 23% in C-4 (0.77; 0.39-1.53). Cabazitaxel free fraction was unaltered. No significant correlation was found between grade 3-4 toxicities and pharmacokinetic parameters. Mild-moderate HI did not cause substantial decline in cabazitaxel clearance. Cabazitaxel dose reductions in patients with mild-moderate HI, and a contraindication in patients with severe HI, are justified based on safety data. C1 [Sarantopoulos, John] Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, Inst Drug Dev, San Antonio, TX 78229 USA. [Mita, Alain C.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. [He, Aiwu; Hwang, Jimmy] Georgetown Univ, Lombardi Comprehens Canc Ctr, Dept Med & Oncol, Washington, DC USA. [He, Aiwu; Hwang, Jimmy] Georgetown Univ, Lombardi Comprehens Canc Ctr, Innovat Ctr Biomed Informat, Washington, DC USA. [Wade, James L.] Canc Care Ctr Decatur, Div Med Oncol Hematol, Decatur, IL USA. [Hsueh, Chung-Tsen] Loma Linda Univ, Div Med Oncol Hematol, Loma Linda, CA 92350 USA. [Morris, John C.] Univ Cincinnati, Dept Med, Inst Canc, Div Hematol Oncol, Cincinnati, OH USA. [Lockhart, A. Craig] Washington Univ, Sch Med, Siteman Canc Ctr, St Louis, MO USA. [Quinn, David I.] Univ Southern Calif, Norris Comprehens Canc Ctr, Los Angeles, CA USA. [Mier, James] Beth Israel Deaconess Med Ctr, Dana Farber Harvard Canc Ctr, Dept Med, Boston, MA 02215 USA. [Zhang, Wenping; Yin, Jian] Sanofi, Bridgewater, NJ USA. [Wack, Claudine; Clot, Pierre-Francois] Sanofi, Chilly Mazarin, France. [Rixe, Olivier] Univ New Mexico, Ctr Comprehens Canc, Div Hematol Oncol, Albuquerque, NM 87131 USA. RP Rixe, O (reprint author), Univ New Mexico, Ctr Comprehens Canc, Div Hematol Oncol, Albuquerque, NM 87131 USA. EM ORixe@salud.unm.edu FU Sanofi; Institute for Drug Development at the Cancer Therapy and Research Center, University of Texas Health Science Centre, San Antonio, Texas [P30CA054174] FX The authors would like to thank participating patients and their families, in addition to the staff at participating sites. This study was supported by Sanofi. The authors received editorial support in the form of medical writing services provided by Danielle Lindley of MediTech Media, funded by Sanofi. The authors were responsible for all content and editorial decisions and received no honoraria related to the development of this manuscript. The authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The authors would like to thank the Institute for Drug Development at the Cancer Therapy and Research Center, University of Texas Health Science Centre, San Antonio, Texas, for the Cancer Center Support Grant (P30CA054174). NR 21 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 EI 1432-0843 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD FEB PY 2017 VL 79 IS 2 BP 339 EP 351 DI 10.1007/s00280-016-3210-8 PG 13 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA EK9OD UT WOS:000394252900012 PM 28058445 ER PT J AU Li, ZJ Lan, L Zeng, F Makris, N Hwang, JW Guo, TP Wu, F Gao, YJ Dong, MK Liu, ML Yang, J Li, Y Gong, QY Sun, SR Liang, FR Kong, J AF Li, Zhengjie Lan, Lei Zeng, Fang Makris, Nikos Hwang, Jiwon Guo, Taipin Wu, Feng Gao, Yujie Dong, Mingkai Liu, Mailan Yang, Jie Li, Ying Gong, Qiyong Sun, Sharon Liang, Fanrong Kong, Jian TI The altered right frontoparietal network functional connectivity in migraine and the modulation effect of treatment SO CEPHALALGIA LA English DT Article DE Acupuncture; migraine without aura; fMRI; independent component analysis; frontoparietal network; resting-state functional connectivity ID CHRONIC PAIN; HUMAN BRAIN; PERIAQUEDUCTAL GRAY; DEFAULT NETWORK; ACUPUNCTURE; FMRI; ACTIVATION; PLACEBO; CORTEX; PATHOPHYSIOLOGY AB Aims: This study aims to investigate the resting-state functional connectivity (rs-fc) of the right frontoparietal network (rFPN) between migraineurs and healthy controls (HCs) in order to determine how the rFPN rs-fc can be modulated by effective treatment. Methods: One hundred patients and 46 matched HCs were recruited. Migraineurs were randomized to verum acupuncture, sham acupuncture, and waiting list groups. Resting-state functional magnetic resonance imaging data were collected before and after longitudinal treatments. Independent component analysis was applied in the data analysis. Results: We found that migraineurs showed decreased rs-fc between the rFPN and bilateral precuneus compared with HCs. After treatments (real and sham), rFPN rs-fc with the precuneus was significantly reduced. This reduction was associated with headache intensity relief. In order to explore the role of the precuneus in acupuncture modulation, we performed a seed-based rs-fc analysis using the precuneus as a seed and found that the precuneus rs-fc with the bilateral rostral anterior cingulate cortex/medial prefrontal cortex, ventral striatum, and dorsolateral prefrontal cortex was significantly enhanced after treatment. Conclusion: Our results suggest that migraineurs are associated with abnormal rFPN rs-fc. An effective treatment, such as acupuncture, may relieve symptoms by strengthening the cognitive adaptation/coping process. Elucidation of the adaptation/coping mechanisms may open up a new window for migraine management. C1 [Li, Zhengjie; Lan, Lei; Zeng, Fang; Guo, Taipin; Wu, Feng; Gao, Yujie; Dong, Mingkai; Yang, Jie; Li, Ying; Liang, Fanrong] Chengdu Univ Tradit Chinese Med, Teaching Hosp 3, Chengdu, Sichuan, Peoples R China. [Li, Zhengjie] Xiamen Univ, Dept Tradit Chinese Med, Coll Med, Xiamen, Fujian, Peoples R China. [Makris, Nikos; Sun, Sharon; Kong, Jian] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Makris, Nikos; Sun, Sharon; Kong, Jian] Harvard Med Sch, Boston, MA USA. [Makris, Nikos; Sun, Sharon; Kong, Jian] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Hwang, Jiwon] Beijing Univ Tradit Chinese, Sch Acupuncture Moxibust & Tuina, Beijing, Peoples R China. [Liu, Mailan] Hunan Univ Chinese Med, Acupuncture & Tuina Sch, Changsha, Hunan, Peoples R China. [Gong, Qiyong] Sichuan Univ, Huaxi MR Res Ctr, West China Hosp, Chengdu, Sichuan, Peoples R China. RP Liang, FR (reprint author), Chengdu Univ Tradit Chinese Med, Teaching Hosp 3, Chengdu, Sichuan, Peoples R China. EM acuresearch@126.com FU State Key Program for Basic Research of China [2012CB518501]; National Natural Science Foundation of China [81590950, 81273154, 81473602]; Program for New Century Talents in the University of Ministry of Education of China; Youth Foundation of Sichuan Province [2012JQ0052]; NCCIH/NIH [R01AT006364, R01AT008563, R21AT008707, P01 AT006663] FX The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: grants from the State Key Program for Basic Research of China (2012CB518501), the National Natural Science Foundation of China (No. 81590950, No. 81273154, and No. 81473602), the Program for New Century Talents in the University of Ministry of Education of China (2013) and the Youth Foundation of Sichuan Province (No. 2012JQ0052); JK is supported by R01AT006364 (NCCIH/NIH), R01AT008563 (NCCIH/NIH), R21AT008707 (NCCIH/NIH), and P01 AT006663 (NCCIH/NIH). NR 62 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0333-1024 EI 1468-2982 J9 CEPHALALGIA JI Cephalalgia PD FEB PY 2017 VL 37 IS 2 BP 161 EP 176 DI 10.1177/0333102416641665 PG 16 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EK4KO UT WOS:000393895700008 PM 27053062 ER PT J AU Taylor, SW Psaros, C Pantalone, DW Tinsley, J Elsesser, SA Mayer, KH Safren, SA AF Taylor, S. Wade Psaros, Christina Pantalone, David W. Tinsley, Jake Elsesser, Steven A. Mayer, Kenneth H. Safren, Steven A. TI "Life-Steps" for PrEP Adherence: Demonstration of a CBT-Based Intervention to Increase Adherence to Preexposure Prophylaxis (PrEP) Medication Among Sexual-Minority Men at High Risk for HIV Acquisition SO COGNITIVE AND BEHAVIORAL PRACTICE LA English DT Article DE CBT; HIV; MSM; medication adherence; PrEP ID RANDOMIZED CONTROLLED-TRIAL; COGNITIVE-BEHAVIORAL THERAPY; INFECTED INDIVIDUALS; HEALTH-PROBLEMS; ANTIRETROVIRAL MEDICATION; UNITED-STATES; PREVENTION; DEPRESSION; NONADHERENCE; FACILITATORS AB One dramatic advance in human immunodeficiency virus (HIV) prevention efforts has been the prescription of medications typically used for HIV treatment as prophylaxis against acquiring HIV. As a preventative agent, this practice is referred to as "preexposure prophylaxis" (PrEP). The U.S. Federal Drug Administration approved daily PrEP for adults at risk for HIV who do not consistently Use condoms during sex with HIV-infected or unknown-status partners. In this paper, we describe a cognitive-behavioral therapy (CBT) PrEP adherence intervention developed for use in high-risk sexual-minority men in the United States, adapted from "Life-Steps," an evidence-based CBT intervention to promote adherence to HIV treatment. Modules include creating a PrEP dosing schedule, adhering to daily PrEP, problem solving barriers to adherence, and sexual risk-reduction. techniques. Supplemented with practical video vignettes, this novel intervention may help to enhance the clinical practice of health care providers in outpatient settings to increase PrEP adherence in sexual-minority men. C1 [Taylor, S. Wade] Wheelock Coll, Boston, MA 02215 USA. [Taylor, S. Wade; Pantalone, David W.; Elsesser, Steven A.; Mayer, Kenneth H.; Safren, Steven A.] Fenway Hlth, Boston, MA 02215 USA. [Psaros, Christina; Mayer, Kenneth H.; Safren, Steven A.] Harvard Med Sch, Boston, MA USA. [Psaros, Christina; Mayer, Kenneth H.; Safren, Steven A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Pantalone, David W.] Univ Massachusetts Boston, Boston, MA USA. [Elsesser, Steven A.] Thomas Jefferson Univ, Sidney Kimmel Med Coll, Philadelphia, PA 19107 USA. [Safren, Steven A.] Univ Miami, Coral Gables, FL 33124 USA. RP Taylor, SW (reprint author), Wheelock Coll, Boston, MA 02215 USA.; Taylor, SW (reprint author), Fenway Hlth, Boston, MA 02215 USA. EM wtaylor@fenwayhealth.org FU NIMH [R34MH095584]; [5K23MH096651] FX This publication was made possible with the help from NIMH grant R34MH095584 awarded to Drs. Kenneth H. Mayer and Steven A. Safren. Some additional author time and support is from 5K23MH096651 (Dr. Christina Psaros). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 55 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 1077-7229 EI 1878-187X J9 COGN BEHAV PRACT JI Cogn. Behav. Pract. PD FEB PY 2017 VL 24 IS 1 BP 38 EP 49 PG 12 WC Psychology, Clinical SC Psychology GA EK2AI UT WOS:000393729100004 ER PT J AU Jalal, B Samir, SW Hinton, DE AF Jalal, Baland Samir, Sherine W. Hinton, Devon E. TI Adaptation of CBT for Traumatized Egyptians: Examples from Culturally Adapted CBT (CA-CBT) SO COGNITIVE AND BEHAVIORAL PRACTICE LA English DT Article DE cognitive behavioral therapy; cultural adaptation; PTSD ID POSTTRAUMATIC-STRESS-DISORDER; RANDOMIZED CONTROLLED-TRIAL; TREATMENT-RESISTANT PTSD; CAMBODIAN REFUGEES; BEHAVIOR-THERAPY; LOVING-KINDNESS; SLEEP PARALYSIS; PANIC-ATTACKS; MINDFULNESS; ACCEPTANCE AB In this article we illustrate how CBT can be adapted to a traumatized Egyptian population with Islamic beliefs, giving examples from our adaptation of Culturally Adapted CBT (CA-CBT) for this cultural group. We discuss a culturally sensitive assessment measure of local somatic complaints and cultural syndromes that was devised based on clinical experience with traumatized Egyptians. We also demonstrate how to normalize symptoms, create positive expectancy about the treatment, and educate about trauma. We give examples of how mindfulness can be adapted for an Egyptian Islamic population, and we describe local religious strategies, such as dhikr (religious chanting), salah (ritualistic prayer), and dua (supplication), that may be used to promote attentional shiftfrom rumination topics and to teach attentional control. We describe how "loving kindness" can be adapted for this group. We outline how to modify culturally generated catastrophic cognitions and how to conduct interoceptive exposure and to create positive re-associations in a culturally sensitive manner. We describe how worry themes are explored and addressed based on a heuristic panic attack PTSD model; how to teach anger management in a culturally sensitive way; and how to address sleep-related problems in this population. We suggest using cultural transitional "rituals" at the end of the treatment to give patients a sense of closure and a positive feeling of transformation. A case example is presented to illustrate cultural challenges associated with delivering CA-CBT to an Egyptian population. We introduce certain concepts such as cultural grounding and explanatory model bridging, both therapeutic techniques that increase adherence, positive expectancy, and cultural consonance. C1 [Jalal, Baland] Univ Cambridge, Cambridge CB2 1TN, England. [Samir, Sherine W.] Schweizer Gesell Therapeut Hypnose & Hypnoseforsc, Mannedorf, Switzerland. [Hinton, Devon E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hinton, Devon E.] Harvard Med Sch, Boston, MA USA. RP Jalal, B (reprint author), Univ Cambridge, Cambridge CB2 1TN, England.; Jalal, B (reprint author), Trinity Coll Cambridge, Cambridge CB2 1TQ, England. EM bj272@medschl.cam.ac.uk NR 58 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1077-7229 EI 1878-187X J9 COGN BEHAV PRACT JI Cogn. Behav. Pract. PD FEB PY 2017 VL 24 IS 1 BP 58 EP 71 PG 14 WC Psychology, Clinical SC Psychology GA EK2AI UT WOS:000393729100006 ER PT J AU Walker-Sperling, VE Pohlmeyer, CW Veenhuis, RT May, M Luna, KA Kirkpatrick, AR Laeyendecker, O Cox, AL Carrington, M Bailey, JR Arduino, RC Blankson, JN AF Walker-Sperling, Victoria E. Pohlmeyer, Christopher W. Veenhuis, Rebecca T. May, Megan Luna, Krystle A. Kirkpatrick, Allison R. Laeyendecker, Oliver Cox, Andrea L. Carrington, Mary Bailey, Justin R. Arduino, Roberto C. Blankson, Joel N. TI Factors Associated With the Control of Viral Replication and Virologic Breakthrough in a Recently Infected HIV-1 Controller SO EBIOMEDICINE LA English DT Article DE HIV-1; HIV controllers; NK cells; CD8+ T cells; Transmission pair ID IMMUNODEFICIENCY-VIRUS TYPE-1; CD8(+) T-CELLS; NATURAL-KILLER-CELLS; ELITE SUPPRESSORS; ANTIRETROVIRAL THERAPY; IMMUNE CONTROL; LOW-FREQUENCY; HLA-B; CAPACITY; VIREMIA AB HIV-1 controllers are patients who control HIV-1 viral replication without antiretroviral therapy. Control is achieved very early in the course of infection, but the mechanisms through which viral replication is restricted are not fully understood. We describe a patient who presented with acute HIV-1 infection and was found to have an HIV-1 RNA level of <100 copies/mL. She did not have any known protective HLA alleles, but significant immune activation of CD8 + T cells and natural killer (NK) cells was present, and both cell types inhibited viral replication. Virus cultured from this patient replicated as well in vitro as virus isolated from her partner, a patient with AIDS who was the source of transmission. Virologic breakthrough occurred 9 months after her initial presentation and was associated with an increase in CD4 + T cell activation levels and a significant decrease in NK cell inhibitory capacity. Remarkably, CD8 + T cell inhibitory capacity was preserved and there were no new escape mutations in targeted Gag epitopes. These findings suggest that fully replication-competent virus can be controlled in acute HIV-1 infection in some patients without protective HLA alleles and that NK cell responses may contribute to this early control of viral replication. (C) 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). C1 [Walker-Sperling, Victoria E.; Pohlmeyer, Christopher W.; Veenhuis, Rebecca T.; May, Megan; Laeyendecker, Oliver; Cox, Andrea L.; Bailey, Justin R.; Blankson, Joel N.] Johns Hopkins Univ, Sch Med, Ctr AIDS Res, Dept Med, Baltimore, MD 21218 USA. [Luna, Krystle A.] Univ Texas MD Anderson Canc Ctr, Dept Med, Austin, TX USA. [Kirkpatrick, Allison R.; Laeyendecker, Oliver] NIAID, Immunoregulat Lab, Div Intramural Res, NIH, Baltimore, MD USA. [Carrington, Mary] Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Arduino, Roberto C.] Univ Texas Hlth Sci Ctr Houston, Dept Internal Med, Div Infect Dis, Houston, TX 77030 USA. [Carrington, Mary] MIT, Ragon Inst, Massachusetts Gen Hosp, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Carrington, Mary] Harvard Univ, Cambridge, MA 02138 USA. RP Blankson, JN (reprint author), Johns Hopkins Univ, Sch Med, Ctr AIDS Res, Dept Med, Baltimore, MD 21218 USA.; Arduino, RC (reprint author), Univ Texas Hlth Sci Ctr Houston, Dept Internal Med, Div Infect Dis, Houston, TX 77030 USA. EM jblanks@jhmi.edu FU Johns Hopkins University Center for AIDS Research [P30AI094189, 2R56AI080328-05A1, 1R01AI120024-01]; Frederick National Laboratory for Cancer Research [HHSN261200800001E]; NIH, Frederick National Lab, Center for Cancer Research FX Funded by the Johns Hopkins University Center for AIDS Research (P30AI094189) and 2R56AI080328-05A1 and 1R01AI120024-01 (JNB) and with federal funds from the Frederick National Laboratory for Cancer Research, under Contract No. HHSN261200800001E and in part by the Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research. The funding sources had no role in the writing of the manuscript or the decision to submit it for publication. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government NR 50 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2352-3964 J9 EBIOMEDICINE JI EBioMedicine PD FEB PY 2017 VL 16 BP 141 EP 149 DI 10.1016/j.ebiom.2017.01.034 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA EM4DB UT WOS:000395262400027 PM 28159573 ER PT J AU Huang, CF Huang, CY Yeh, ML Wang, SC Chen, KY Ko, YM Lin, CC Tsai, YS Tsai, PC Lin, ZY Chen, SC Dai, CY Huang, JF Chuang, WL Yu, ML AF Huang, Chung-Feng Huang, Cing-Yi Yeh, Ming-Lun Wang, Shu-Chi Chen, Kuan-Yu Ko, Yu-Min Lin, Ching-Chih Tsai, Yi-Shan Tsai, Pei-Chien Lin, Zu-Yau Chen, Shinn-Cherng Dai, Chia-Yen Huang, Jee-Fu Chuang, Wan-Long Yu, Ming-Lung TI Genetics Variants and Serum Levels of MHC Class I Chain-related A in Predicting Hepatocellular Carcinoma Development in Chronic Hepatitis C Patients Post Antiviral Treatment SO EBIOMEDICINE LA English DT Article DE HCC; SVR; SNP; MICA; PNPLA3; IL-28; EGF; sMICA; Treatment ID GENOME-WIDE ASSOCIATION; GROWTH-FACTOR GENE; VIRUS GENOTYPE 1; FUNCTIONAL POLYMORPHISM; PEGYLATED INTERFERON; ASIAN PATIENTS; RISK; INFECTION; CIRRHOSIS; THERAPY AB Background/aims: The genome-wide association study has shown that MHC class I chain-related A (MICA) genetic variants were associated with hepatitis C virus (HCC) related hepatocellular carcinoma. The impact of the genetic variants and its serum levels on post-treatment cohort is elusive. Methods: MICA rs2596542 genotype and serum MICA (sMICA) levels were evaluated in 705 patients receiving antiviral therapy. Results: Fifty-eight (8.2%) patients developed HCC, with a median follow-up period of 48.2 months (range: 6-129 months). The MICA A allele was associated with a significantly increased risk of HCC development in cirrhotic non-SVR patients but not in patients of non-cirrhotic and/or with SVR. For cirrhotic non-SVR patients, high sMICA levels (HR/CI: 5.93/1.86-26.38.1, P = 0.002) and the MICA rs2596542 A allele (HR/CI: 4.37/1.52-12.07, P = 0.002) were independently associated with HCC development. The risk A allele or GG genotype with sMICA >175 ng/mL provided the best accuracy (79%) and a negative predictive value of 100% in predicting HCC. Conclusions: Cirrhotic patients who carry MICA risk alleles and those without risk alleles but with high sMICA levels possessed the highest risk of HCC development once they failed antiviral therapy. (C) 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). C1 [Huang, Chung-Feng; Huang, Cing-Yi; Yeh, Ming-Lun; Wang, Shu-Chi; Chen, Kuan-Yu; Ko, Yu-Min; Lin, Ching-Chih; Tsai, Yi-Shan; Tsai, Pei-Chien; Lin, Zu-Yau; Chen, Shinn-Cherng; Dai, Chia-Yen; Huang, Jee-Fu; Chuang, Wan-Long; Yu, Ming-Lung] Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Dept Internal Med, Hepatobiliary Div, Kaohsiung, Taiwan. [Huang, Chung-Feng; Yeh, Ming-Lun; Lin, Zu-Yau; Chen, Shinn-Cherng; Dai, Chia-Yen; Huang, Jee-Fu; Chuang, Wan-Long; Yu, Ming-Lung] Kaohsiung Med Univ, Sch Med, Fac Internal Med, Coll Med, Kaohsiung, Taiwan. [Huang, Chung-Feng; Dai, Chia-Yen] Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Dept Occupat Med, Kaohsiung, Taiwan. [Dai, Chia-Yen] Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Dept Prevent Med, Kaohsiung, Taiwan. [Yu, Ming-Lung] Natl Sun Yat Sen Univ, Inst Biomed Sci, Kaohsiung 80424, Taiwan. [Yu, Ming-Lung] Harvard Med Sch, Massachusetts Gen Hosp, Div Gastroenterol, Ctr Liver, Boston, MA USA. RP Yu, ML (reprint author), Kaohsiung Med Univ Hosp, Hepatobiliary Div, Dept Internal Med, Kaohsiung, Taiwan. EM fish6069@gmail.com FU Kaohsiung Medical University [103-CCH-KMU-006]; Kaohsiung Medical University Hospital [KMUH104-4R04, KMUH104-4R06] FX This study was supported by grants from Kaohsiung Medical University (103-CCH-KMU-006) and Kaohsiung Medical University Hospital (KMUH104-4R04 and KMUH104-4R06). The funders had no role in study design, data collection, data analysis, interpretation, writing of the report. NR 32 TC 2 Z9 2 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2352-3964 J9 EBIOMEDICINE JI EBioMedicine PD FEB PY 2017 VL 15 BP 81 EP 89 DI 10.1016/j.ebiom.2016.11.031 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA EM4BL UT WOS:000395258200013 PM 27998720 ER PT J AU Wasfy, JH Rao, SK Essien, UR Richardson, CA Jeune, T Goldstein, SA Laikhter, E Chittle, MD Weil, M Wein, M Ferris, TG AF Wasfy, Jason H. Rao, Sandhya K. Essien, Utibe R. Richardson, Calvin A. Jeune, Tamika Goldstein, Susan A. Laikhter, Elizabeth Chittle, Melissa D. Weil, Michelle Wein, Marc Ferris, Timothy G. TI Initial experience with endocrinology e-consults SO ENDOCRINE LA English DT Article ID CARE C1 [Wasfy, Jason H.; Laikhter, Elizabeth] Harvard Med Sch, Massachusetts Gen Hosp, Div Cardiol, Dept Med, Boston, MA 02115 USA. [Wasfy, Jason H.; Rao, Sandhya K.; Jeune, Tamika; Goldstein, Susan A.; Ferris, Timothy G.] Harvard Med Sch, Massachusetts Gen Hosp, Massachusetts Gen Phys Org, Boston, MA 02115 USA. [Rao, Sandhya K.; Essien, Utibe R.; Ferris, Timothy G.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Boston, MA USA. [Richardson, Calvin A.] Athena Hlth, Watertown, MA USA. [Chittle, Melissa D.] Harvard Med Sch, Massachusetts Gen Hosp, Div Intervent Radiol, Boston, MA USA. [Weil, Michelle; Wein, Marc] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Endocrine Unit, Boston, MA USA. RP Wasfy, JH (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Div Cardiol, Dept Med, Boston, MA 02115 USA.; Wasfy, JH (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Massachusetts Gen Phys Org, Boston, MA 02115 USA. EM jwasfy@mgh.harvard.edu NR 13 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-008X EI 1559-0100 J9 ENDOCRINE JI Endocrine PD FEB PY 2017 VL 55 IS 2 BP 640 EP 642 DI 10.1007/s12020-016-1053-z PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EK9RS UT WOS:000394262200037 PM 27507674 ER PT J AU Micali, N Horton, NJ Crosby, RD Swanson, SA Sonneville, KR Solmi, F Calzo, JP Eddy, KT Field, AE AF Micali, Nadia Horton, N. J. Crosby, R. D. Swanson, S. A. Sonneville, K. R. Solmi, F. Calzo, J. P. Eddy, K. T. Field, A. E. TI Eating disorder behaviours amongst adolescents: investigating classification, persistence and prospective associations with adverse outcomes using latent class models SO EUROPEAN CHILD & ADOLESCENT PSYCHIATRY LA English DT Article DE ALSPAC; Adolescent; Eating disorders; Latent class ID FEELINGS QUESTIONNAIRE; ANOREXIA-NERVOSA; SELF-REPORT; SHORT MOOD; SAMPLE; VALIDATION; CHILDREN; GIRLS; IDENTIFICATION; TRANSITION AB Diagnostic criteria for eating disorders (ED) remain largely based on clinical presentations, but do not capture the full range of behaviours in the population. We aimed to derive an empirically based ED behaviour classification using behavioural and body mass index (BMI) indicators at three time-points in adolescence, and to validate classes investigating prospective associations with adverse outcomes. Adolescents from the Avon Longitudinal Study of Parents and Children (ALSPAC) provided data on ED at age 14 (n = 6615), 16 (n = 5888), and 18 years (n = 5100), and had weight and height measured. Psychological and behavioural outcomes were assessed at 15.5/16 and 17.5/18 years. We fit gender- and age-stratified latent class models, and employed logistic regression to investigate associations between classes and later outcomes. One asymptomatic and two symptomatic (largely representing higher and lower frequency ED behaviours) classes were observed at each time-point, although their relative prevalence varied by age and gender. The majority of girls in symptomatic classes remained symptomatic at subsequent assessments. Girls in symptomatic classes had higher odds of subsequent anxiety and depressive disorders, binge drinking, drug use, and deliberate self-harm. Data analyses were underpowered amongst boys. The presence of two symptomatic classes (characterised by different ED behaviour frequency) and their prospective association with adverse outcomes suggest a need to refine diagnostic thresholds based on empirical data. Despite some instability of classes, particularly in mid-adolescence, evidence that half of girls in symptomatic classes remained symptomatic suggests persistence of ED behaviours in adolescence, and highlights a need for early identification to reduce chronicity. C1 [Micali, Nadia] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Micali, Nadia] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. [Micali, Nadia] UCL, Inst Child Hlth, London, England. [Horton, N. J.] Amherst Coll, Dept Math & Stat, Amherst, MA 01002 USA. [Crosby, R. D.] Neuropsychiat Res Inst, Dept Biomed Stat, Fargo, ND USA. [Crosby, R. D.] Univ North Dakota, Sch Med & Hlth Sci, Dept Psychiat & Behav Sci, Fargo, ND USA. [Swanson, S. A.] Harvard TH ChanSch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Swanson, S. A.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Sonneville, K. R.] Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Human Nutr Program, Ann Arbor, MI 48109 USA. [Solmi, F.] UCL, Div Psychiat, London, England. [Calzo, J. P.] Boston Childrens Hosp, Dept Med, Div Adolescent Med, Boston, MA USA. [Calzo, J. P.] Harvard Med Sch, Boston, MA USA. [Eddy, K. T.] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Eddy, K. T.] Massachusetts Gen Hosp, Eating Disorders Clin & Res Program, Boston, MA 02114 USA. [Field, A. E.] Brown Univ, Sch Publ Heath, Dept Epidemiol, Providence, RI 02912 USA. RP Micali, N (reprint author), Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA.; Micali, N (reprint author), Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA.; Micali, N (reprint author), UCL, Inst Child Hlth, London, England. EM n.micali@ucl.ac.uk OI Solmi, Francesca/0000-0003-0219-9503 FU UK Medical Research Council; Wellcome Trust [092731]; University of Bristol; National Institute of Health Research (NIHR); NIMH [R01 MH087786] FX The UK Medical Research Council and the Wellcome Trust (Grant Ref: 092731) and the University of Bristol provide core support for ALSPAC.This research was funded by a National Institute of Health Research (NIHR) clinician scientist award to Dr N Micali and by a grant from NIMH to Drs Field and Micah (R01 MH087786). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. NR 38 TC 1 Z9 1 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1018-8827 EI 1435-165X J9 EUR CHILD ADOLES PSY JI Eur. Child Adolesc. Psych. PD FEB PY 2017 VL 26 IS 2 BP 231 EP 240 DI 10.1007/s00787-016-0877-7 PG 10 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA EL2PV UT WOS:000394462800010 PM 27341841 ER PT J AU Singh, A Laribi, S Teerlink, JR Mebazaa, A AF Singh, Abhishek Laribi, Said Teerlink, John R. Mebazaa, Alexandre TI Agents with vasodilator properties in acute heart failure SO EUROPEAN HEART JOURNAL LA English DT Review DE Acute heart failure; Vasodilators; Clinical trials; Outcomes; Haemodynamics ID SOLUBLE GUANYLATE-CYCLASE; CHIMERIC NATRIURETIC PEPTIDE; 1ST CLINICAL-EXPERIENCE; ARRESTIN-BIASED LIGAND; CINACIGUAT BAY 58-2667; PRE-RELAX-AHF; BETA-ARRESTIN; RENAL-FUNCTION; CD-NP; CONTROLLED TRIAL AB Millions of patients worldwide are admitted for acute heart failure (AHF) each year and physicians caring for these patients are confronted with the short-term challenges of reducing symptoms while preventing end organ dysfunction without causing additional harm, and the intermediate- term challenges of improving clinical outcomes such as hospital readmission and survival. There are limited data demonstrating the efficacy of any currently available therapies for AHF to meet these goals. After diuretics, vasodilators are the most common intravenous therapy for AHF, but neither nitrates, nitroprusside, nor nesiritide have robust evidence supporting their ability to provide meaningful effects on clinical outcomes, except perhaps early symptom improvement. Recently, a number of novel agents with vasodilating properties have been developed for the treatment of AHF. These agents include serelaxin, natriuretic peptides (ularitide, cenderitide), beta-arrestin-biased angiotensin II type 1 receptor ligands (TRV120027), nitroxyl donors (CXL-1020, CXL-1427), soluble guanylate cyclase modulators (cinaciguat, vericiguat), shortacting calcium channel blockers (clevidipine), and potassium channel activators (nicorandil). These development programmes range from the stage of early dose-finding studies (e. g. TRV120027, CXL-1427) to large, multicentre mortality trials (e. g. serelaxin, ularitide). There is an urgent need for agents with vasodilating properties that will improve both in-hospital and post-discharge clinical outcomes, and these novel approaches may provide opportunities to address this need. C1 [Singh, Abhishek; Teerlink, John R.] San Francisco VA Med Ctr, Cardiol Sect, San Francisco, CA 94121 USA. [Singh, Abhishek; Teerlink, John R.] Univ Calif San Francisco, Sch Med, San Francisco, CA 94143 USA. [Laribi, Said; Mebazaa, Alexandre] INSERM, UMRS 942, Biomarkers & Cardiac Dis, F-75010 Paris, France. [Laribi, Said] St Louis Lariboisiere Hosp, AP HP, Emergency Dept, F-75010 Paris, France. [Mebazaa, Alexandre] Univ Paris Diderot, Sorbonne Paris Cite, F-75010 Paris, France. [Mebazaa, Alexandre] St Louis Lariboisiere Hosp, AP HP, Dept Anesthesiol & Crit Care, F-75010 Paris, France. RP Teerlink, JR (reprint author), San Francisco VA Med Ctr, Cardiol Sect, San Francisco, CA 94121 USA.; Teerlink, JR (reprint author), Univ Calif San Francisco, Sch Med, San Francisco, CA 94143 USA. EM john.teerlink@ucsf.edu FU Servier; Actelion; Amgen; Bayer; Cytokinetics; Novartis; Sevier; Trevena FX S.L. received fees as a member of advisory board from Servier. J.T. has received research grants and consulting fees from Actelion, Amgen, Bayer, Cytokinetics, Novartis, Sevier and Trevena. A.M. received speaker's honoraria from Abbott, Novartis, Orion, Roche et Servier. A.M. received fee as member of advisory board and/or Steering Committee from Cardiorentis, Adrenomed, MyCartis, ZS Pharma and Critical Diagnostics. NR 88 TC 1 Z9 1 U1 1 U2 1 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 FEB 1 PY 2017 VL 38 IS 5 BP 317 EP + DI 10.1093/eurheartj/ehv755 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EK6DH UT WOS:000394014700007 PM 28201723 ER PT J AU Applebaum, MA Vaksman, Z Lee, SM Hungate, EA Henderson, TO London, WB Pinto, N Volchenboum, SL Park, JR Naranjo, A Hero, B Pearson, AD Stranger, BE Cohn, SL Diskin, SJ AF Applebaum, Mark A. Vaksman, Zalman Lee, Sang Mee Hungate, Eric A. Henderson, Tara O. London, Wendy B. Pinto, Navin Volchenboum, Samuel L. Park, Julie R. Naranjo, Arlene Hero, Barbara Pearson, Andrew D. Stranger, Barbara E. Cohn, Susan L. Diskin, Sharon J. TI Neuroblastoma survivors are at increased risk for second malignancies: A report from the International Neuroblastoma Risk Group Project SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE Neuroblastoma; Second malignant; neoplasms; INRG; Genetic association study ID THERAPY-RELATED LEUKEMIA; ACUTE MYELOID-LEUKEMIA; LONG-TERM RISK; COMPETING RISK; NEOPLASMS; CHEMOTHERAPY; SUSCEPTIBILITY; POLYMORPHISMS; I-131-METAIODOBENZYLGUANIDINE; CLASSIFICATION AB Background: The incidence of second malignant neoplasm (SMN) within the first ten years of diagnosis in high-risk neuroblastoma patients treated with modern, intensive therapy is unknown. Further, the underlying germline genetics that contribute to SMN in these survivors are not known. Methods: The International Neuroblastoma Risk Group (INRG) database of patients diagnosed from 1990 to 2010 was analysed. SMN risk was accessed by cumulative incidence, standardised incidence ratios (SIRs) and absolute excess risk. A candidate gene-based association study evaluated genetic susceptibility to SMN in neuroblastoma survivors. Results: Of the 5987 patients in the INRG database with SMN data enrolled in a clinical trial, 43 (0.72%) developed a SMN. The 10-year cumulative incidence of SMN for high-risk patients was 1.8% (95% confidence interval [CI] 1.0-2.6%) compared with 0.38% (95% CI: 0.22 -0.94%) for low-risk patients (P = 0.01). High-risk patients had an almost 18-fold higher incidence of SMN compared to age- and sex-matched controls (SIR = 17.5 (95% CI: 11.4-25.3), absolute excess risk = 27.6). For patients treated on high- and intermediate-risk clinical trials, the SIR of acute myelogenous leukaemia was 106.8 (95% CI: 28.7-273.4) and 127.7 (95%CI: 25.7-373.3), respectively. Variants implicating DNA repair genes XRCC3 (rs861539: P = 0.006; odds ratio: 2.04, 95%CI: 1.19-3.46) and MSH2 (rs17036651: P = 0.009; odds ratio: 0.26, 95% CI: 0.08-0.81) were associated with SMN. Conclusion: The intensive multi-modality treatment strategy currently used to treat high-risk neuroblastoma is associated with a significantly increased risk of secondary acute myelogenous leukaemia. Defining the interactions of treatment exposures and genetic factors that promote the development of SMN is critical for optimising survivorship care. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Applebaum, Mark A.; Hungate, Eric A.; Henderson, Tara O.; Volchenboum, Samuel L.; Cohn, Susan L.] Univ Chicago, Dept Pediat, Chicago, IL 60637 USA. [Vaksman, Zalman; Diskin, Sharon J.] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Vaksman, Zalman; Diskin, Sharon J.] Childrens Hosp Philadelphia, Ctr Childhood Canc Res, Philadelphia, PA 19104 USA. [Vaksman, Zalman; Diskin, Sharon J.] Childrens Hosp Philadelphia, Dept Biomed & Hlth Informat, Philadelphia, PA 19104 USA. [Lee, Sang Mee] Univ Chicago, Dept Publ Hlth Sci, Chicago, IL 60637 USA. [London, Wendy B.] Boston Childrens Hosp, Boston, MA USA. [London, Wendy B.] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA USA. [Pinto, Navin; Park, Julie R.] Univ Washington, Dept Pediat, Seattle Childrens Hosp, Seattle, WA 98195 USA. [Naranjo, Arlene] Univ Florida, Dept Biostat, Stat & Data Ctr, Childrens Oncol Grp, Gainseville, FL USA. [Hero, Barbara] Univ Cologne, Childrens Hosp, Dept Pediat Oncol & Hematol, Cologne, Germany. [Pearson, Andrew D.] Royal Marsden NHS Fdn Trust, Inst Canc Res, Div Canc Therapeut, Sutton, Surrey, England. [Pearson, Andrew D.] Royal Marsden NHS Fdn Trust, Inst Canc Res, Div Clin Studies, Sutton, Surrey, England. [Pearson, Andrew D.] Royal Marsden NHS Fdn Trust, Children & Young Peoples Unit, Sutton, Surrey, England. [Stranger, Barbara E.] Univ Chicago, Dept Med, Med Genet Sect, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Stranger, Barbara E.] Univ Chicago, Ctr Data Intens Sci, Inst Genom & Syst Biol, Chicago, IL 60637 USA. [Diskin, Sharon J.] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Diskin, Sharon J.] Abramson Family Canc Res Inst, Philadelphia, PA USA. RP Diskin, SJ (reprint author), Univ Penn, Dept Pediat, CTRB, 3501 Civ Ctr Blvd,Room 3026, Philadelphia, PA 19104 USA. EM diskin@email.chop.edu OI Applebaum, Mark/0000-0001-9766-8477 FU William Guy Forbeck Research Foundation; St. Baldrick's Foundation; Little Heroes Cancer Research Fund; Children's Neuroblastoma Cancer Foundation; Neuroblastoma Children's Cancer Foundation; Super Jake Foundation; Matthew Bittker Foundation; Alex's Lemonade Stand Foundation; National Institutes of Health [R01CA124709, R00 CA151869, K12CA139160, T32GM007019] FX The INRG database is supported in part by the William Guy Forbeck Research Foundation, the St. Baldrick's Foundation, the Little Heroes Cancer Research Fund, Children's Neuroblastoma Cancer Foundation, Neuroblastoma Children's Cancer Foundation, the Super Jake Foundation, Matthew Bittker Foundation and the Alex's Lemonade Stand Foundation. Data included in the INRG database were provided by Children's Oncology Group [COG], Pediatric Oncology Group [POG], Children's Cancer Study Group [CCSG], German Gesellschaft fiir Padiatrische Onkologie and Hamatologie [GPOH], European Neuroblastoma Study Group [ENSG], International Society of Paediatric Oncology Europe Neuroblastomp. Group [SIOPEN], Japanese Neuroblastoma Study Group [JNBSG], Japanese Infantile Neuroblastoma Cooperative Study Group [JINCS], Spanish Neuroblastoma Group and the Italian Neuroblastoma Group. This work was supported by the National Institutes of Health (R01CA124709, R00 CA151869 to S.J.D, and K12CA139160 and T32GM007019 to M.A.A.). The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. NR 38 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD FEB PY 2017 VL 72 BP 177 EP 185 DI 10.1016/j.ejca.2016.11.022 PG 9 WC Oncology SC Oncology GA EK6YK UT WOS:000394072000020 PM 28033528 ER PT J AU Ceglia, L Nelson, J Ware, J Alysandratos, KD Bray, GA Garganta, C Nathan, DM Hu, FB Dawson-Hughes, B Pittas, AG AF Ceglia, Lisa Nelson, Jason Ware, James Alysandratos, Konstantinos-Dionysios Bray, George A. Garganta, Cheryl Nathan, David M. Hu, Frank B. Dawson-Hughes, Bess Pittas, Anastassios G. CA Diabet Prevention Program Res Grp TI Association between body weight and composition and plasma 25-hydroxyvitamin D level in the Diabetes Prevention Program SO EUROPEAN JOURNAL OF NUTRITION LA English DT Article DE Body composition; Diabetes Prevention Program; Body weight; Obesity; Vitamin D; Adipose tissue ID IMPAIRED GLUCOSE-TOLERANCE; VITAMIN-D CONCENTRATIONS; PARATHYROID-HORMONE; VISCERAL ADIPOSITY; JAPANESE-AMERICANS; AFRICAN-AMERICANS; OBESE CHILDREN; MASS INDEX; SERUM; WOMEN AB We examined associations between body weight and plasma 25-hydroxyvitamin D concentration (25OHD) in prediabetes and sought to estimate the impact of adiposity on these associations. The study was conducted in the placebo (n = 1082) and intensive lifestyle (n = 1079) groups of the Diabetes Prevention Program (DPP), a multicenter trial to prevent type 2 diabetes in adults with prediabetes. Weight and 25OHD were measured at baseline, month 6, years 1 and 2. In a subset (n = 584), visceral (VAT) and subcutaneous (SAT) adiposity were assessed by computed tomography at baseline and year 1. In cross-sectional analyses, baseline body weight, total fat, VAT, and SAT were inversely associated with plasma 25OHD concentration after multivariable adjustment. VAT accounted for 40 % [95 % CI 11, 69] of the association of body weight with plasma 25OHD concentration. There was no significant contribution by total fat or SAT. Two-year changes in plasma 25OHD concentration varied inversely with changes in body weight (p < 0.0001). One-year changes in total fat, VAT, or SAT were not significant mediators of the association between change in plasma 25OHD concentration and body weight. Our study found an inverse association between body weight and plasma 25OHD concentration at baseline and over a 2-year period in adults with prediabetes. These findings in the DPP, a weight loss intervention study, raise the possibility that weight loss increases plasma 25OHD concentration. Whether adiposity mediates this association remains inconclusive. C1 [Ceglia, Lisa; Dawson-Hughes, Bess; Pittas, Anastassios G.] Tufts Med Ctr, Div Endocrinol Diabet & Metab, Box 268,800,Washington St,268, Boston, MA 02111 USA. [Nelson, Jason] Tufts Med Ctr, Inst Clin Res & Hlth Policy Studies, Boston, MA USA. [Ware, James] Harvard Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Bray, George A.] Louisiana State Univ, Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. [Garganta, Cheryl] Univ Florida, Dept Pathol Immunol & Lab Med, Gainesville, FL USA. [Nathan, David M.] Massachusetts Gen Hosp, Ctr Diabet, Boston, MA 02114 USA. [Nathan, David M.] Harvard Med Sch, Boston, MA USA. [Hu, Frank B.] Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Hu, Frank B.] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Hu, Frank B.] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. [Ceglia, Lisa; Dawson-Hughes, Bess] Tufts Univ, Jean Mayer US Dept Agr, Human Nutr Res Ctr Aging, Bone Metab Lab, Boston, MA 02111 USA. [Alysandratos, Konstantinos-Dionysios] Boston Univ, Med Ctr, Div Neurol, Boston, MA USA. RP Ceglia, L (reprint author), Tufts Med Ctr, Div Endocrinol Diabet & Metab, Box 268,800,Washington St,268, Boston, MA 02111 USA.; Ceglia, L (reprint author), Tufts Univ, Jean Mayer US Dept Agr, Human Nutr Res Ctr Aging, Bone Metab Lab, Boston, MA 02111 USA. EM lisa.ceglia@tufts.edu FU National Institute of Diabetes and Digestive and Kidney Disease [R01DK79003]; National Center for Research Resources [UL1RR025752]; National Center for Advancing Translational Sciences, National Institutes of Health; Gerald J. and Dorothy R. Friedman Foundation; US Department of Agriculture [58-1950-9001]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health [UO1DK48489]; NIDDK, Intramural Research Program; Indian Health Service; National Institute of Child Health and Human Development; National Institute on Aging; National Eye Institute; National Heart Lung and Blood Institute; Office of Research on Women's Health; National Center for Minority Health and Human Disease; Centers for Disease Control and Prevention; American Diabetes Association FX The present ancillary study was supported by research Grant R01DK79003 (to AGP) from the National Institute of Diabetes and Digestive and Kidney Disease; UL1RR025752 (to Tufts University) from the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health; a research grant by the Gerald J. and Dorothy R. Friedman Foundation (to LC); the US Department of Agriculture Agreement 58-1950-9001 (to BDH). The parent DPP study was supported by research Grant UO1DK48489 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health to the DPP clinical centers and the Coordinating Center for the design and conduct of the DPP study. The Southwestern American Indian Centers were supported directly by the NIDDK, including its Intramural Research Program, and the Indian Health Service. The General Clinical Research Center Program, National Center for Research Resources, supported data collection at many of the clinical centers. Funding was also provided by the National Institute of Child Health and Human Development, the National Institute on Aging, the National Eye Institute, the National Heart Lung and Blood Institute, the Office of Research on Women's Health, the National Center for Minority Health and Human Disease, the Centers for Disease Control and Prevention, the Indian Health Service, and the American Diabetes Association. Lipha (Merck-Sante) provided medication. LifeScan Inc., Merck-Medco Managed Care, Inc., and Merck and Co. donated materials, equipment, or medicines for concomitant conditions. NR 41 TC 3 Z9 3 U1 2 U2 2 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1436-6207 EI 1436-6215 J9 EUR J NUTR JI Eur. J. Nutr. PD FEB PY 2017 VL 56 IS 1 BP 161 EP 170 DI 10.1007/s00394-015-1066-z PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA EK8IW UT WOS:000394168100014 PM 26525562 ER PT J AU von Frankenberg, AD Marina, A Song, XL Callahan, HS Kratz, M Utzschneider, KM AF von Frankenberg, Anize D. Marina, Anna Song, Xiaoling Callahan, Holly S. Kratz, Mario Utzschneider, Kristina M. TI A high-fat, high-saturated fat diet decreases insulin sensitivity without changing intra-abdominal fat in weight-stable overweight and obese adults SO EUROPEAN JOURNAL OF NUTRITION LA English DT Article DE Dietary fat; Saturated fat; High-fat diet; Insulin sensitivity ID LIFE-STYLE INTERVENTION; ADIPOSE-TISSUE; LIVER FAT; POLYUNSATURATED FAT; CARBOHYDRATE DIET; GLYCEMIC CONTROL; ACID SYNTHESIS; HEALTHY-MEN; DE-NOVO; RESISTANCE AB We sought to determine the effects of dietary fat on insulin sensitivity and whether changes in insulin sensitivity were explained by changes in abdominal fat distribution or very low-density lipoprotein (VLDL) fatty acid composition. Overweight/obese adults with normal glucose tolerance consumed a control diet (35 % fat/12 % saturated fat/47 % carbohydrate) for 10 days, followed by a 4-week low-fat diet (LFD, n = 10: 20 % fat/8 % saturated fat/62 % carbohydrate) or high-fat diet (HFD, n = 10: 55 % fat/25 % saturated fat/27 % carbohydrate). All foods and their eucaloric energy content were provided. Insulin sensitivity was measured by labeled hyperinsulinemic-euglycemic clamps, abdominal fat distribution by MRI, and fasting VLDL fatty acids by gas chromatography. The rate of glucose disposal (Rd) during low- and high-dose insulin decreased on the HFD but remained unchanged on the LFD (Rd-low: LFD: 0.12 +/- 0.11 vs. HFD: -0.37 +/- 0.15 mmol/min, mean +/- SE, p < 0.01; Rd-high: LFD: 0.11 +/- 0.37 vs. HFD: -0.71 +/- 0.26 mmol/min, p = 0.08). Hepatic insulin sensitivity did not change. Changes in subcutaneous fat were positively associated with changes in insulin sensitivity on the LFD (r = 0.78, p < 0.01) with a trend on the HFD (r = 0.60, p = 0.07), whereas there was no association with intra-abdominal fat. The LFD led to an increase in VLDL palmitic (16:0), stearic (18:0), and palmitoleic (16:1n7c) acids, while no changes were observed on the HFD. Changes in VLDL n-6 docosapentaenoic acid (22:5n6) were strongly associated with changes in insulin sensitivity on both diets (LFD: r = -0.77; p < 0.01; HFD: r = -0.71; p = 0.02). A diet very high in fat and saturated fat adversely affects insulin sensitivity and thereby might contribute to the development of type 2 diabetes. NCT00930371. C1 [von Frankenberg, Anize D.; Marina, Anna; Kratz, Mario; Utzschneider, Kristina M.] Univ Washington, Dept Med, Div Metab Endocrinol & Nutr, 1959 NE Pacific St, Seattle, WA 98195 USA. [von Frankenberg, Anize D.] Univ Fed Rio Grande do Sul, Sch Med, Postgrad Endocrinol Program, Porto Alegre, RS, Brazil. [Song, Xiaoling; Kratz, Mario] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1100 Fairview Ave N, Seattle, WA 98109 USA. [Song, Xiaoling; Kratz, Mario] Univ Washington, Dept Epidemiol, 1959 NE Pacific St, Seattle, WA 98195 USA. [Callahan, Holly S.] Univ Washington, Sch Med, 1959 NE Pacific St, Seattle, WA 98195 USA. [von Frankenberg, Anize D.; Utzschneider, Kristina M.] VA Puget Sound Hlth Care Syst, Endocrinol, 1660 S Columbian Way 151, Seattle, WA 98108 USA. RP von Frankenberg, AD (reprint author), Univ Washington, Dept Med, Div Metab Endocrinol & Nutr, 1959 NE Pacific St, Seattle, WA 98195 USA.; von Frankenberg, AD (reprint author), Univ Fed Rio Grande do Sul, Sch Med, Postgrad Endocrinol Program, Porto Alegre, RS, Brazil.; von Frankenberg, AD (reprint author), VA Puget Sound Hlth Care Syst, Endocrinol, 1660 S Columbian Way 151, Seattle, WA 98108 USA. EM anize.frankenberg@gmail.com; annam45@hotmail.com; hcal@uw.edu; mkratz@fhcrc.org; kutzschn@u.washington.edu FU Department of Veteran Affairs, Diabetes Research Center [P30DK017047]; Institute for Translational Health Sciences [UL1TR000423]; Nutrition Obesity Research Center [P30 DK035816]; Diagnostic Imaging Sciences Center at the University of Washington; Brazilian Federal Agency for Support and Evaluation of Graduate Education (CAPES) FX We are grateful to the study participants for their contribution and time. This study was supported by funding and resources from the Department of Veteran Affairs, Diabetes Research Center (P30DK017047), the Institute for Translational Health Sciences (UL1TR000423), the Nutrition Obesity Research Center (P30 DK035816), the Diagnostic Imaging Sciences Center at the University of Washington, and the Brazilian Federal Agency for Support and Evaluation of Graduate Education (CAPES) (AF). NR 50 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1436-6207 EI 1436-6215 J9 EUR J NUTR JI Eur. J. Nutr. PD FEB PY 2017 VL 56 IS 1 BP 431 EP 443 DI 10.1007/s00394-015-1108-6 PG 13 WC Nutrition & Dietetics SC Nutrition & Dietetics GA EK8IW UT WOS:000394168100038 PM 26615402 ER PT J AU Peponis, T Cropano, MC Larentzakis, A van der Wilden, MG Mejaddam, YA Sideris, CA Michailidou, M Fikry, K Bramos, A Janjua, S Chang, Y King, DR AF Peponis, T. Cropano, M. C. Larentzakis, A. van der Wilden, M. G. Mejaddam, Y. A. Sideris, C. A. Michailidou, M. Fikry, K. Bramos, A. Janjua, S. Chang, Y. King, D. R. TI Trauma team utilization of universal precautions: if you see something, say something SO EUROPEAN JOURNAL OF TRAUMA AND EMERGENCY SURGERY LA English DT Article DE Universal safety precautions; Occupational safety; Compliance; Hand washing; Prophylactic measures ID HEALTH-CARE WORKERS; BARRIER PRECAUTIONS; RESUSCITATION; NONCOMPLIANCE; KNOWLEDGE; EDUCATION; STANDARD AB The risks deriving from the lack of compliance with universal safety precautions (USPs) are unequivocal. However, the adoption of these prophylactic precautions by healthcare providers remains unacceptably low. We hypothesized that trauma teams are not routinely adhering to USPs and that a brief educational intervention, followed by real-time peer feedback, would substantially improve compliance rates. This before-and-after interventional study took place in the resuscitation bay of a Level I Trauma Center during trauma team activations. Six USPs were examined: hand washing (before and after patient contact), use of gloves, gowns, eye protection, and masks. Surgery and Emergency Medicine attending physicians, residents, and nurses, who had direct patient contact, were included. Following 162 baseline observations, an educational intervention in the form of brief lectures was conducted, emphasizing the danger to self from dereliction of USPs. Subsequently, 167 post-intervention observations were made after a one-month period of knowledge decay. Finally, real-time feedback was provided by trauma team leaders and study staff. Adherence to prophylactic measures was recorded again. Baseline compliance rates were dismal. Only hand washing prior to patient interaction, the use of eye protection, and the use of masks improved significantly (p < 0.05) after the educational initiative. However, compliance rates remained suboptimal. No difference was noted regarding the three other USPs. Impressively, following real-time behavioral corrections, compliance improved to nearly 90 % for all USPs (p < 0.05). Compliance with OSHA-required USPs during trauma team activations is unacceptably low, but can be dramatically improved through simple educational interventions, combined with real-time peer feedback. C1 [Peponis, T.; Cropano, M. C.; Larentzakis, A.; van der Wilden, M. G.; Mejaddam, Y. A.; Sideris, C. A.; Michailidou, M.; Fikry, K.; Bramos, A.; Janjua, S.; Chang, Y.; King, D. R.] Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, 165 Cambridge St,Suite 810, Boston, MA 02114 USA. [Peponis, T.; Cropano, M. C.; Larentzakis, A.; van der Wilden, M. G.; Mejaddam, Y. A.; Sideris, C. A.; Michailidou, M.; Fikry, K.; Bramos, A.; Janjua, S.; Chang, Y.; King, D. R.] Harvard Med Sch, 165 Cambridge St,Suite 810, Boston, MA 02114 USA. RP King, DR (reprint author), Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, 165 Cambridge St,Suite 810, Boston, MA 02114 USA.; King, DR (reprint author), Harvard Med Sch, 165 Cambridge St,Suite 810, Boston, MA 02114 USA. EM DKING3@PARTNERS.ORG NR 13 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1863-9933 EI 1863-9941 J9 EUR J TRAUMA EMERG S JI Eur. J. Trauma Emerg. Surg. PD FEB PY 2017 VL 43 IS 1 BP 145 EP 150 DI 10.1007/s00068-016-0663-8 PG 6 WC Emergency Medicine SC Emergency Medicine GA EL0MG UT WOS:000394315900020 PM 27084540 ER PT J AU Peponis, T Cropano, MC Larentzakis, A van der Wilden, GM Mejaddam, YA Sideris, CA Michailidou, M Fikry, K Bramos, A Janjua, S Chang, Y King, DR AF Peponis, T. Cropano, M. C. Larentzakis, A. van der Wilden, G. M. Mejaddam, Y. A. Sideris, C. A. Michailidou, M. Fikry, K. Bramos, A. Janjua, S. Chang, Y. King, D. R. TI Trauma team utilization of universal precautions: if you see something, say something (vol 43, pg 145, 2017) SO EUROPEAN JOURNAL OF TRAUMA AND EMERGENCY SURGERY LA English DT Correction C1 [Peponis, T.; Cropano, M. C.; Larentzakis, A.; van der Wilden, G. M.; Mejaddam, Y. A.; Sideris, C. A.; Michailidou, M.; Fikry, K.; Bramos, A.; Janjua, S.; Chang, Y.; King, D. R.] Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, 165 Cambridge St,Suite 810, Boston, MA 02114 USA. [Peponis, T.; Cropano, M. C.; Larentzakis, A.; van der Wilden, G. M.; Mejaddam, Y. A.; Sideris, C. A.; Michailidou, M.; Fikry, K.; Bramos, A.; Janjua, S.; Chang, Y.; King, D. R.] Harvard Med Sch, 165 Cambridge St,Suite 810, Boston, MA 02114 USA. RP King, DR (reprint author), Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, 165 Cambridge St,Suite 810, Boston, MA 02114 USA.; King, DR (reprint author), Harvard Med Sch, 165 Cambridge St,Suite 810, Boston, MA 02114 USA. EM DKING3@PARTNERS.ORG NR 1 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1863-9933 EI 1863-9941 J9 EUR J TRAUMA EMERG S JI Eur. J. Trauma Emerg. Surg. PD FEB PY 2017 VL 43 IS 1 BP 151 EP 151 DI 10.1007/s00068-016-0746-6 PG 1 WC Emergency Medicine SC Emergency Medicine GA EL0MG UT WOS:000394315900021 PM 27915401 ER PT J AU Thorlacius, L Ingram, J Garg, A Villumsen, B Esmann, S Kirby, J Gottlieb, AB Merola, J Dellavalle, R Christensen, R Jemec, GBE AF Thorlacius, L. Ingram, J. Garg, A. Villumsen, B. Esmann, S. Kirby, J. Gottlieb, A. B. Merola, J. Dellavalle, R. Christensen, R. Jemec, G. B. E. TI Development of a core domain set for managing hidradenitis suppurativa: Protocol for identification using an international patient and provider combined Delphi survey SO EXPERIMENTAL DERMATOLOGY LA English DT Meeting Abstract CT 6th Conference of the European-Hidradenitis-Suppurativa-Foundatation-e-V (EHSF) CY FEB 08-10, 2017 CL Copenhagen, DENMARK SP European Hidradenitis Suppurativa Fdn C1 [Thorlacius, L.] Univ Copenhagen, Fac Hlth Sci, Roskilde, Denmark. [Thorlacius, L.; Christensen, R.] Capital Reg Denmark, Parker Inst, Bispebjerg & Frederiksberg Hosp, Musculoskeletal Stat Unit, Copenhagen, Denmark. [Thorlacius, L.; Esmann, S.; Jemec, G. B. E.] Zealand Univ Hosp, Dept Dermatol, Roskilde, Denmark. [Ingram, J.] Univ Wales Hosp, Inst Infect & Immun, Hlth Pk, Cardiff, S Glam, Wales. [Garg, A.] Hofstra Northwell Sch Med, Dept Dermatol, New Hyde Pk, NY USA. [Villumsen, B.] Patients Assoc HS Denmark, Copenhagen, Denmark. [Kirby, J.] Penn State Hershey Med Ctr, Dept Dermatol, Hershey, PA USA. [Gottlieb, A. B.] New York Med Coll, Dept Dermatol, Valhalla, NY 10595 USA. [Merola, J.] Brigham & Womens Hosp, Div Rheumatol, Dept Dermatol, 75 Francis St, Boston, MA 02115 USA. [Merola, J.] Brigham & Womens Hosp, Dept Med, Div Rheumatol, 75 Francis St, Boston, MA 02115 USA. [Merola, J.] Harvard Med Sch, Boston, MA USA. [Dellavalle, R.] US Dept Vet Affairs, Med Ctr, Dermatol Serv, Denver, CO 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 0906-6705 EI 1600-0625 J9 EXP DERMATOL JI Exp. Dermatol. PD FEB PY 2017 VL 26 SU 1 SI SI MA P015 BP 34 EP 35 PG 2 WC Dermatology SC Dermatology GA EK4PE UT WOS:000393908300070 ER PT J AU Erstad, DJ Krowsoski, LS Kaafarani, HMA AF Erstad, Derek J. Krowsoski, Leandra S. Kaafarani, Haytham M. A. TI Abdominal Pain After Colonoscopy SO GASTROENTEROLOGY LA English DT Editorial Material ID CECAL VOLVULUS C1 [Erstad, Derek J.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Krowsoski, Leandra S.; Kaafarani, Haytham M. A.] Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. RP Erstad, DJ (reprint author), Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD FEB PY 2017 VL 152 IS 3 BP 486 EP 487 DI 10.1053/j.gastro.2016.08.060 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EO1BC UT WOS:000396431600014 PM 28056353 ER PT J AU Yazinski, SA Comaills, V Buisson, R Genois, MM Nguyen, HD Ho, CK Kwan, TT Morris, R Lauffer, S Nussenzweig, A Ramaswamy, S Benes, CH Haber, DA Maheswaran, S Birrer, MJ Zou, L AF Yazinski, Stephanie A. Comaills, Valentine Buisson, Remi Genois, Marie-Michelle Nguyen, Hai Dang Ho, Chu Kwen Kwan, Tanya Todorova Morris, Robert Lauffer, Sam Nussenzweig, Andre Ramaswamy, Sridhar Benes, Cyril H. Haber, Daniel A. Maheswaran, Shyamala Birrer, Michael J. Zou, Lee TI ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cells SO GENES & DEVELOPMENT LA English DT Article DE ATR; BRCA-deficient cancer; PARP inhibitor ID DNA-DAMAGE RESPONSE; 5' END RESECTION; POLY(ADP-RIBOSE) POLYMERASE; REPLICATION FORKS; MEDIATED PHOSPHORYLATION; PLATINUM RESISTANCE; PANCREATIC-CANCER; MAMMARY-TUMORS; PROTEIN-KINASE; MUTANT-CELLS AB Poly-(ADP-ribose) polymerase (PARP) inhibitors (PARPis) selectively kill BRCA1/2-deficient cells, but their efficacy in BRCA-deficient patients is limited by drug resistance. Here, we used derived cell lines and cells from patients to investigate how to overcome PARPi resistance. We found that the functions of BRCA1 in homologous recombination (HR) and replication fork protection are sequentially bypassed during the acquisition of PARPi resistance. Despite the lack of BRCA1, PARPi-resistant cells regain RAD51 loading to DNA double-stranded breaks (DSBs) and stalled replication forks, enabling two distinct mechanisms of PARPi resistance. Compared with BRCA1-proficient cells, PARPi-resistant BRCA1-deficient cells are increasingly dependent on ATR for survival. ATR inhibitors (ATRis) disrupt BRCA1-independent RAD51 loading to DSBs and stalled forks in PARPi-resistant BRCA1-deficient cells, overcoming both resistance mechanisms. In tumor cells derived from patients, ATRis also overcome the bypass of BRCA1/ 2 in fork protection. Thus, ATR inhibition is a unique strategy to overcome the PARPi resistance of BRCA-deficient cancers. C1 [Yazinski, Stephanie A.; Comaills, Valentine; Buisson, Remi; Genois, Marie-Michelle; Nguyen, Hai Dang; Ho, Chu Kwen; Kwan, Tanya Todorova; Morris, Robert; Lauffer, Sam; Ramaswamy, Sridhar; Benes, Cyril H.; Haber, Daniel A.; Maheswaran, Shyamala; Birrer, Michael J.; Zou, Lee] Harvard Med Sch, Ctr Canc, Massachusetts Gen Hosp, Charlestown, MA 02129 USA. [Kwan, Tanya Todorova] Massachusetts Gen Hosp, Howard Hughes Med Inst, Charlestown, MA 02129 USA. [Lauffer, Sam; Birrer, Michael J.] Massachusetts Gen Hosp, Gillette Ctr, Boston, MA 02115 USA. [Nussenzweig, Andre] NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA. [Zou, Lee] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02115 USA. RP Zou, L (reprint author), Harvard Med Sch, Ctr Canc, Massachusetts Gen Hosp, Charlestown, MA 02129 USA.; Zou, L (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02115 USA. EM zou.lee@mgh.harvard.edu FU National Institutes of Health [GM076388, CA197779, CA129933]; National Cancer Institute Federal Share of Program Income; Jim and Ann Orr MGH Research Scholar Award; Susan Komen for the Cure [KG09042]; Wellcome Trust [102696]; National Institutes of Health instrumentation [1S10RR023440-01A1]; Department of Defense [W81XWH-13-1-0027]; Philippe Foundation FX We thank S. Cantor, J. Chen, D. Durocher, N. Dyson, L. Ellisen, S. Orsulic, and B. Xia for reagents and discussions. This work was supported by grants from the National Institutes of Health (GM076388 and CA197779 to L.Z., and CA129933 to D.A.H.), National Cancer Institute Federal Share of Program Income (to L.Z.), Jim and Ann Orr MGH Research Scholar Award (to L.Z.), Susan Komen for the Cure (KG09042 to S.M.), and the Wellcome Trust (102696 to C.H.B.). The Flow Cytometry Core is supported by National Institutes of Health instrumentation grant 1S10RR023440-01A1. S.A.Y. was supported by a fellowship from the Department of Defense (W81XWH-13-1-0027). V.C. and R.B. have received support from the Philippe Foundation. M.-M.G. is a fellow of Fonds de recherche du Quebec-Sante. H.D.N. was a Medical Discovery Post-doctoral Fellow. R.B. was a Marsha Rivkin Scholar. L.Z. is the James and Patricia Poitras Endowed Chair in Cancer Research. NR 79 TC 0 Z9 0 U1 2 U2 2 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 EI 1549-5477 J9 GENE DEV JI Genes Dev. PD FEB 1 PY 2017 VL 31 IS 3 BP 318 EP 332 DI 10.1101/gad.290957.116 PG 15 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA EN1UQ UT WOS:000395796100010 PM 28242626 ER PT J AU Balter, ML Chen, AI Maguire, TJ Yarmush, ML AF Balter, Max L. Chen, Alvin I. Maguire, Timothy J. Yarmush, Martin L. TI Adaptive Kinematic Control of a Robotic Venipuncture Device Based on Stereo Vision, Ultrasound, and Force Guidance SO IEEE TRANSACTIONS ON INDUSTRIAL ELECTRONICS LA English DT Article DE Medical robots; motion control; robot vision systems ID SURGERY; SYSTEMS; DESIGN AB Robotic systems have slowly entered the realm of modern medicine; however, outside the operating room, medical robotics has yet to be translated to more routine interventions such as blood sampling or intravenous fluid delivery. In this paper, we present a medical robot that safely and rapidly cannulates peripheral blood vessels-a procedure commonly known as venipuncture. The device uses near-infrared and ultrasound imaging to scan and select suitable injection sites, and a 9-DOF robot to insert the needle into the center of the vessel based on image and force guidance. We first present the system design and visual-servoing scheme of the latest generation robot, and then evaluate the performance of the device through workspace simulations and free-space positioning tests. Finally, we perform a series of motion tracking experiments using stereo vision, ultrasound, and force sensing to guide the position and orientation of the needle tip. Positioning experiments indicate sub-millimeter accuracy and repeatability over the operating workspace of the system, while tracking studies demonstrate real-time needle servoing in response to moving targets. Finally, robotic phantom cannulations demonstrate the use of multiple system states to confirm that the needle has reached the center of the vessel. C1 [Balter, Max L.; Chen, Alvin I.; Yarmush, Martin L.] Rutgers State Univ, Dept Biomed Engn, Piscataway, NJ 08854 USA. [Maguire, Timothy J.] VascuLogic LLC, Piscataway, NJ 08854 USA. [Yarmush, Martin L.] Massachusetts Gen Hosp, Boston, MA 02108 USA. RP Balter, ML (reprint author), Rutgers State Univ, Dept Biomed Engn, Piscataway, NJ 08854 USA. EM balterm53@gmail.com; alv6688@gmail.com; tim.maguire@vasculogic.com; yarmush@rci.rutgers.edu FU National Science Foundation [1448550]; National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health [R01EB020036]; NSF Graduate Research Fellowship [DGE-0937373]; NIH/National Institute of General Medical Science Rutgers Biotechnology Training Program [T32 GM008339]; NIH F31 Predoctoral Fellowship [EB018191] FX This work was supported in part by the National Science Foundation under Award Number 1448550, and in part by the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, under Award Number R01EB020036. The work of M. L. Balter was supported by an NSF Graduate Research Fellowship (DGE-0937373). The work of A. I. Chen was supported by the NIH/National Institute of General Medical Science Rutgers Biotechnology Training Program (T32 GM008339), and an NIH F31 Predoctoral Fellowship (EB018191). (Max L. Balter and Alvin I. Chen contributed equally to this work.) NR 30 TC 1 Z9 1 U1 9 U2 9 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0278-0046 EI 1557-9948 J9 IEEE T IND ELECTRON JI IEEE Trans. Ind. Electron. PD FEB PY 2017 VL 64 IS 2 BP 1626 EP 1635 DI 10.1109/TIE.2016.2557306 PG 10 WC Automation & Control Systems; Engineering, Electrical & Electronic; Instruments & Instrumentation SC Automation & Control Systems; Engineering; Instruments & Instrumentation GA EN2FU UT WOS:000395826100079 PM 28111492 ER PT J AU Chen, YX Furuya-Kanamori, L Doi, SA Ananthakrishnan, AN Kirk, M AF Chen, Yingxi Furuya-Kanamori, Luis Doi, Suhail A. Ananthakrishnan, Ashwin N. Kirk, Martyn TI Clostridium difficile Infection and Risk of Colectomy in Patients with Inflammatory Bowel Disease: A Bias-adjusted Meta-analysis SO INFLAMMATORY BOWEL DISEASES LA English DT Review DE inflammatory bowel disease; Clostridium difficile infection; colectomy; meta-analysis ID ULCERATIVE-COLITIS PATIENTS; QUALITY-EFFECTS MODEL; POSTOPERATIVE COMPLICATIONS; NATURAL-HISTORY; CLINICAL-TRIALS; IMPACT; BURDEN; EPIDEMIOLOGY; PREVALENCE; RECURRENCE AB Background: Clostridium difficile infection (CDI) is a common complication of inflammatory bowel diseases (IBDs) and is associated with worse outcome. Variable rates of colectomy have been reported among IBD complicated by CDI. We conducted a systematic review and meta-analysis of studies to assess the association between CDI and colectomy among patients with IBD. Methods: The literature was systematically searched using PubMed from inception through April 2016. Studies were limited to cohort, case-control, and cross-sectional studies reporting colectomy risk stratified by CDI in patients with IBD. We estimated summary ORs and 95% CIs using the quality-effects model. Study quality was assessed using an adaptation of the Newcastle-Ottawa scale. Results: Six studies were included in the meta-analysis, comprising 8 data sets. Results from meta-analysis showed that CDI was a significant risk factor for colectomy among patients with IBD, mainly patients with ulcerative colitis, almost doubling the odds (OR 1.90; 95% CI, 1.23-2.93). There was significant heterogeneity across studies (Q = 22.02, P < 0.001; I-2 = 68%). Funnel plots were grossly asymmetrical. Results of sensitivity analysis restricting studies to those reporting ulcerative colitis only and studies using laboratory tests to confirm CDI were consistent with the result from the main analysis. Conclusions: CDI is a significant risk factor for colectomy in patients with IBD. Further research is needed to investigate the attributable risks of surgery due to CDI among patients with Crohn's disease. C1 [Chen, Yingxi; Furuya-Kanamori, Luis; Doi, Suhail A.; Kirk, Martyn] Australian Natl Univ, Res Sch Populat Hlth, Canberra, ACT, Australia. [Doi, Suhail A.] Qatar Univ, Coll Med, Doha, Qatar. [Doi, Suhail A.] Univ Southern Queensland, Sch Agr Computat & Environm Sci, Toowoomba, Qld, Australia. [Ananthakrishnan, Ashwin N.] Massachusetts Gen Hosp, Harvard Med Sch, Div Gastroenterol, Boston, MA 02114 USA. RP Chen, YX (reprint author), Australian Natl Univ, Canberra, ACT 0200, Australia. EM yingxi.chen@anu.edu.au FU Australian Government Department of Education and Training [3929_2014]; Australian National University; Endeavour Postgraduate Scholarship [3781_2014]; Australian National University Higher Degree Scholarship; Fondo para la Innovacion, Cienciay Tecnologia Scholarship [095-FINCyT-BDE-2014] FX Y. Chen received the 2014 Prime Minister's Australia Asia Postgraduate Scholarship from the Australian Government Department of Education and Training (#3929_2014) and a Higher Degree Research Scholarship from the Australian National University. L. Furuya-Kanamori is funded by an Endeavour Postgraduate Scholarship (#3781_2014), an Australian National University Higher Degree Scholarship, and a Fondo para la Innovacion, Cienciay Tecnologia Scholarship (#095-FINCyT-BDE-2014). NR 43 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1078-0998 EI 1536-4844 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD FEB PY 2017 VL 23 IS 2 BP 200 EP 207 DI 10.1097/MIB.0000000000000998 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EK4LF UT WOS:000393897500008 PM 28079620 ER PT J AU Velonias, G Conway, G Andrews, E Garber, JJ Khalili, H Yajnik, V Ananthakrishnan, AN AF Velonias, Gabriella Conway, Grace Andrews, Elizabeth Garber, John J. Khalili, Hamed Yajnik, Vijay Ananthakrishnan, Ashwin N. TI Older Age- and Health-related Quality of Life in Inflammatory Bowel Diseases SO INFLAMMATORY BOWEL DISEASES LA English DT Article DE quality of life; elderly; older age; inflammatory bowel disease ID CROHNS-DISEASE; ULCERATIVE-COLITIS; SURGERY; IMPACT; ONSET; HOSPITALIZATIONS; RESILIENCE; PHENOTYPES; ADVERSITY; OUTCOMES AB Background: The burden of inflammatory bowel disease (IBD) in the older population is increasing. Older-onset disease is associated with reduced use of immunosuppressive medications. In addition, older patients may be more vulnerable to the effect of disease-related symptoms and consequently may experience worse health-related quality of life (HRQoL) compared with younger patients. Methods: This prospective study included a cohort of patients with Crohn's disease and ulcerative colitis recruited from a single center. All patients completed the Short Inflammatory Bowel Disease Questionnaire (SIBDQ) and the short form-12 (SF-12) questionnaire yielding general physical health (PCS) and mental health component scale subscores (MCS). Patients older than 60 years were compared with those younger than 60 years using multivariable regression analysis. Results: Our study included 1607 patients, among whom 186 were older than 60 at the time of assessment. Older patients were more likely to have isolated colonic disease and less likely to use immunosuppressive therapy. On multivariable analysis, older patients with IBD had higher SIBDQ (2.34, 95% confidence interval, 0.82-3.87) and SF-12 mental subscores (3.78, 95% confidence interval, 2.26-5.30), but lower physical HRQoL (21.80, 95% confidence interval, 23.21 to 20.38). There was no difference in the SIBDQ and PCS scores between older patients and newly diagnosed IBD or with established disease. Conclusions: Older age was associated with modestly higher SIBDQ and mental HRQoL scores, but lower physical HRQoL. Comprehensive care of the older patient with IBD should include assessment of factors impairing physical quality of life to ensure appropriate C1 [Velonias, Gabriella; Conway, Grace; Andrews, Elizabeth; Garber, John J.; Khalili, Hamed; Yajnik, Vijay; Ananthakrishnan, Ashwin N.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Garber, John J.; Khalili, Hamed; Yajnik, Vijay] Harvard Med Sch, Boston, MA 02215 USA. RP Ananthakrishnan, AN (reprint author), Massachusetts Gen Hosp, Crohns & Colitis Ctr, 165 Cambridge St 9th Floor, Boston, MA 02114 USA. EM aananthakrishnan@mgh.harvard.edu FU National Institutes of Health (NIH) [P30 DK043351]; National Institutes of Health [K23 DK097142] FX Supported by the National Institutes of Health (NIH) (P30 DK043351) to the Center for Study of Inflammatory Bowel Diseases. A.N. Ananthakrishnan is supported in part by a grant from the National Institutes of Health (K23 DK097142). NR 47 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1078-0998 EI 1536-4844 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD FEB PY 2017 VL 23 IS 2 BP 283 EP 288 DI 10.1097/MIB.0000000000001008 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EK4LF UT WOS:000393897500017 PM 28079625 ER PT J AU Shen, BJ Xu, Y Eisenberg, S AF Shen, Biing-Jiun Xu, Yue Eisenberg, Stacy TI Psychosocial and Physiological Predictors of Mortality in Patients of Heart Failure: Independent Effects of Marital Status and C-Reactive Protein SO INTERNATIONAL JOURNAL OF BEHAVIORAL MEDICINE LA English DT Article DE Heart failure; Mortality; Marital status; C-reactive protein; Depression; Social support ID EVENT-FREE SURVIVAL; QUALITY-OF-LIFE; DEPRESSIVE SYMPTOMS; CLINICAL-OUTCOMES; SELF-EFFICACY; RISK-FACTOR; DISEASE; INFLAMMATION; READMISSION; PREVALENCE AB Few studies have examined the interplay between psychosocial and physiological variables in prediction of mortality in heart failure (HF) patients. This study investigated the prospective influence of marital status, social support, depression, and C-reactive protein (CRP) on the mortality of patients with chronic HF. In addition, it examined whether there was a mediating relationship between social support and marital status and whether depression and inflammation influenced one another to predict mortality of HF patients. The participants were 220 HF patients, among whom 48 were deceased over an average of 4.60 years. A number of psychosocial and biomedical variables were examined for their associations with mortality and their relationships between each other in hierarchical logistic regression analyses. After adjusting for New York Heart Association (NYHA) class, age, and gender, being unmarried predicted mortality (OR = 2.80, p = 0.004), whereas perceived social support did not. Higher CRP was not associated with depression, and it independently predicted mortality (OR = 1.92, p = 0.030). Depression predicted mortality only in the univariate analysis (OR = 1.02, p = 0.030), but the association was no longer significant either after removing somatic items or after adjusting for covariates. In the combined multivariate model, marital status (OR = 2.20, p = 0.047), CRP (OR = 1.91, p = 0.035), and NYHA class (OR = 2.41, p = 0.001) independently predicted mortality. Monitoring chronic HF patients who are unmarried, with elevated inflammation, or in higher NYHA class may help identify those at greater mortality risk to implement targeted intervention. C1 [Shen, Biing-Jiun; Xu, Yue] Nanyang Technol Univ, Div Psychol, 14 Nanyang Dr,HSS04-02, Singapore 637332, Singapore. [Shen, Biing-Jiun] Univ Delaware, Dept Psychol & Brain Sci, Newark, DE 19716 USA. [Eisenberg, Stacy] VA Greater Los Angeles Healthcare Ctr, Los Angeles, CA USA. RP Shen, BJ (reprint author), Nanyang Technol Univ, Div Psychol, 14 Nanyang Dr,HSS04-02, Singapore 637332, Singapore.; Shen, BJ (reprint author), Univ Delaware, Dept Psychol & Brain Sci, Newark, DE 19716 USA. EM bshen@alumni.uchicago.edu FU American Heart Association [0530052N] FX The study was funded by the American Heart Association (Grant no. 0530052N). NR 59 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1070-5503 EI 1532-7558 J9 INT J BEHAV MED JI Int. J. Behav. Med. PD FEB PY 2017 VL 24 IS 1 BP 83 EP 91 DI 10.1007/s12529-016-9579-2 PG 9 WC Psychology, Clinical SC Psychology GA EK8CP UT WOS:000394151800013 PM 27384414 ER PT J AU Chaudhry, S Kumar, N Behbahani, H Bagai, A Singh, BK Menasco, N Lewis, GD Sperling, L Myers, J AF Chaudhry, Sundeep Kumar, Naresh Behbahani, Hushyar Bagai, Akshay Singh, Binoy K. Menasco, Nick Lewis, Gregory D. Sperling, Laurence Myers, Jonathan TI Abnormal heart-rate response during cardiopulmonary exercise testing identifies cardiac dysfunction in symptomatic patients with non-obstructive coronary artery disease SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Angina; Ischemic heart disease; Exercise testing; Women ID ISCHEMIA SYNDROME EVALUATION; SYNDROME EVALUATION WISE; MYOCARDIAL-ISCHEMIA; MICROVASCULAR DYSFUNCTION; CARDIOVASCULAR EVENTS; NATIONAL-HEART; ANGINA-PECTORIS; WOMEN TRIAL; CHEST-PAIN; RISK AB Background: Symptomatic non-obstructive coronary artery disease is a growing clinical dilemma for which contemporary testing is proving to be of limited clinical utility. New methods are needed to identify cardiac dysfunction. Methods and results: This is a prospective observational cohort study conducted from December 2013 to August 2015 in two outpatient cardiology clinics (symptomatic cohort) and 24 outpatient practices throughout the US (healthy cohort) with centralized methodology and monitoring to compare heart-rate responses during cardiopulmonary exercise testing (CPET). Participants were 208 consecutive patients (median age, 61; range, 32-86 years) with exercise intolerance and without prior heart or lung disease in whom coronary anatomy was defined and 116 healthy subjects (median age, 45; range, 26-66 years). Compared to stress ECG, the novel change in heart-rate as a function of work-rate parameter (Delta HR-WR Slope) demonstrated significantly higher sensitivity to detect under-treated atherosclerosis with similar specificity. In men, area under the ROC curve increased from 60% to 94% for non-obstructive CAD and from 64% to 80% for obstructive CAD. In women, AUC increased from 64% to 85% for non-obstructive CAD and from 66% to 90% for obstructive CAD. Delta HR-WR Slope correctly reclassified abnormal studies in the non-obstructive CADgroup from 22% to 81%; in the obstructive CAD group from 18% to 84% and in the revascularization group from 35% to 78%. Conclusion: Abnormal heart-rate response during CPET is more effective than stress ECG for identifying under-treated atherosclerosis and may be of utility to identify cardiac dysfunction in symptomatic patients with normal routine cardiac testing. (C) 2016 The Authors. Published by Elsevier Ireland Ltd. C1 [Chaudhry, Sundeep; Menasco, Nick] MET TEST Inc, Res & Dev, 1117 Perimeter Ctr West,Suite W-211, Atlanta, GA 30338 USA. [Kumar, Naresh; Behbahani, Hushyar] Whitby Cardiovasc Inst, Div Res, Whitby, ON, Canada. [Bagai, Akshay] Univ Toronto, St Michaels Hosp, Div Cardiol, Toronto, ON, Canada. [Singh, Binoy K.] Hofstra Univ, Hofstra Northwell Sch Med, Div Cardiovasc Med, New York, NY 11549 USA. [Lewis, Gregory D.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Sperling, Laurence] Emory Univ, Div Prevent Cardiol, Atlanta, GA 30322 USA. [Myers, Jonathan] Stanford Univ & Vet Affairs, Palo Alto Hlth Care Syst, Div Cardiovasc Med, Palo Alto, CA USA. RP Chaudhry, S (reprint author), MET TEST Inc, Res & Dev, 1117 Perimeter Ctr West,Suite W-211, Atlanta, GA 30338 USA. EM schaudhry@mettest.net NR 40 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD FEB 1 PY 2017 VL 228 BP 114 EP 121 DI 10.1016/j.ijcard.2016.11.235 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EJ7NJ UT WOS:000393408600017 PM 27863351 ER PT J AU Aldiss, P Davies, G Woods, R Budge, H Sacks, HS Symonds, ME AF Aldiss, Peter Davies, Graeme Woods, Rachel Budge, Helen Sacks, Harold S. Symonds, Michael E. TI 'Browning' the cardiac and peri-vascular adipose tissues to modulate cardiovascular risk SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Review DE Epicardial adipose tissue; Perivascular adipose tissue; Brown adipose tissue; CVD ID CONJUGATED LINOLEIC-ACID; CORONARY-ARTERY-DISEASE; REDUCES BODY-FAT; BETA(3)-ADRENERGIC RECEPTOR AGONIST; DIET-INDUCED THERMOGENESIS; ENERGY-EXPENDITURE; EPICARDIAL FAT; INSULIN SENSITIVITY; METABOLIC SYNDROME; GENE-EXPRESSION AB Excess visceral adiposity, in particular that located adjacent to the heart and coronary arteries is associated with increased cardiovascular risk. In the pathophysiological state, dysfunctional adipose tissue secretes an array of factors modulating vascular function and driving atherogenesis. Conversely, brown and beige adipose tissues utilise glucose and lipids to generate heat and are associated with improved cardiometabolic health. The cardiac and thoracic perivascular adipose tissues are now understood to be composed of brown adipose tissue in the healthy state and undergo a brown-to-white transition i.e. during obesity which may be a driving factor of cardiovascular disease. In this review we discuss the risks of excess cardiac and vascular adiposity and potential mechanisms by which restoring the brown phenotype i.e. "re-browning" could potentially be achieved in clinically relevant populations. (C) 2016 The Authors. Published by Elsevier Ireland Ltd. C1 [Aldiss, Peter; Davies, Graeme; Woods, Rachel; Budge, Helen; Symonds, Michael E.] Univ Nottingham, Univ Hosp, Sch Med, Div Child Hlth Obstet & Gynaecol,Early Life Res U, Nottingham NG7 2UH, England. [Sacks, Harold S.] VA Greater Los Angeles Healthcare Syst, Endocrinol & Diabet Div, Los Angeles, CA 90073 USA. [Sacks, Harold S.] David Geffen Sch Med, Dept Med, Los Angeles, CA 90073 USA. RP Symonds, ME (reprint author), Univ Nottingham, Univ Hosp, Div Child Hlth Obstet & Gynaecol, Sch Med, Nottingham NG7 2UH, England. EM michael.symonds@nottingham.ac.uk OI Aldiss, Peter/0000-0002-1809-2092 FU British Heart Foundation [FS/15/4/31184]; University of Nottingham and Cardio-metabolic Research Foundation, Los Angeles; BBSRC [BBSRCBB/I016015/1] FX P. Aldiss is funded by the British Heart Foundation (FS/15/4/31184), G. Davies is funded by University of Nottingham and Cardio-metabolic Research Foundation, Los Angeles (CRFLAPhD2012) and R. Woods is funded by the BBSRC (BBSRCBB/I016015/1). NR 171 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD FEB 1 PY 2017 VL 228 BP 265 EP 274 DI 10.1016/j.ijcard.2016.11.074 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EJ7NJ UT WOS:000393408600044 PM 27865196 ER PT J AU Tsugawa, Y Jena, AB Figueroa, JF Orav, EJ Blumenthal, DM Jha, AK AF Tsugawa, Yusuke Jena, Anupam B. Figueroa, Jose F. Orav, E. John Blumenthal, Daniel M. Jha, Ashish K. TI Comparison of Hospital Mortality and Readmission Rates for Medicare Patients Treated by Male vs Female Physicians SO JAMA INTERNAL MEDICINE LA English DT Article ID GENDER-DIFFERENCES; PRIMARY-CARE; DECISION-MAKING; SEX-DIFFERENCES; DIABETES CARE; UNITED-STATES; RISK; QUALITY; WOMEN; COMMUNICATION AB IMPORTANCE Studies have found differences in practice patterns between male and female physicians, with female physicians more likely to adhere to clinical guidelines and evidence-based practice. However, whether patient outcomes differ between male and female physicians is largely unknown. OBJECTIVE To determine whether mortality and readmission rates differ between patients treated by male or female physicians. DESIGN, SETTING, AND PARTICIPANTS We analyzed a 20% random sample of Medicare fee-for-service beneficiaries 65 years or older hospitalized with a medical condition and treated by general internists from January 1, 2011, to December 31, 2014. We examined the association between physician sex and 30-day mortality and readmission rates, adjusted for patient and physician characteristics and hospital fixed effects (effectively comparing female and male physicians within the same hospital). As a sensitivity analysis, we examined only physicians focusing on hospital care (hospitalists), among whom patients are plausibly quasi-randomized to physicians based on the physician's specific work schedules. We also investigated whether differences in patient outcomes varied by specific condition or by underlying severity of illness. MAIN OUTCOMES AND MEASURES Patients' 30-day mortality and readmission rates. RESULTS A total of 1 583 028 hospitalizations were used for analyses of 30-day mortality (mean [SD] patient age, 80.2 [8.5] years; 621 412 men and 961 616 women) and 1 540 797 were used for analyses of readmission (mean [SD] patient age, 80.1 [8.5] years; 602 115 men and 938 682 women). Patients treated by female physicians had lower 30-day mortality (adjusted mortality, 11.07% vs 11.49%; adjusted risk difference, -0.43%; 95% CI, -0.57% to -0.28%; P < .001; number needed to treat to prevent 1 death, 233) and lower 30-day readmissions (adjusted readmissions, 15.02% vs 15.57%; adjusted risk difference, -0.55%; 95% CI, -0.71% to -0.39%; P < .001; number needed to treat to prevent 1 readmission, 182) than patients cared for by male physicians, after accounting for potential confounders. Our findings were unaffected when restricting analyses to patients treated by hospitalists. Differences persisted across 8 common medical conditions and across patients' severity of illness. CONCLUSIONS AND RELEVANCE Elderly hospitalized patients treated by female internists have lower mortality and readmissions compared with those cared for by male internists. These findings suggest that the differences in practice patterns between male and female physicians, as suggested in previous studies, may have important clinical implications for patient outcomes. C1 [Tsugawa, Yusuke; Figueroa, Jose F.; Jha, Ashish K.] Harvard TH Chan Sch Publ Hlth, Dept Hlth Policy & Management, 42 Church St, Cambridge, MA 02138 USA. [Tsugawa, Yusuke; Figueroa, Jose F.; Orav, E. John; Jha, Ashish K.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Tsugawa, Yusuke; Figueroa, Jose F.; Orav, E. John; Jha, Ashish K.] Harvard Med Sch, Boston, MA USA. [Jena, Anupam B.] Harvard Med Sch, Dept Hlth Care Policy, Boston, MA USA. [Jena, Anupam B.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Jena, Anupam B.] Natl Bur Econ Res, Cambridge, MA 02138 USA. [Orav, E. John] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Blumenthal, Daniel M.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Jha, Ashish K.] Vet Affairs Healthcare Syst, Boston, MA USA. RP Tsugawa, Y (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Hlth Policy & Management, 42 Church St, Cambridge, MA 02138 USA. EM ytsugawa@hsph.harvard.edu FU Early Independence Award from National Institutes of Health [1DP50D017897-01] FX Dr Jena was supported by the Early Independence Award, grant 1DP50D017897-01, from the National Institutes of Health. NR 41 TC 2 Z9 2 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD FEB PY 2017 VL 177 IS 2 BP 206 EP 213 DI 10.1001/jamainternmed.2016.7875 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA EM9PS UT WOS:000395644200012 PM 27992617 ER PT J AU Berkowitz, SA Hulberg, AC Standish, S Reznor, G Atlas, SJ AF Berkowitz, Seth A. Hulberg, Amy Catherine Standish, Sara Reznor, Gally Atlas, Steven J. TI Addressing Unmet Basic Resource Needs as Part of Chronic Cardiometabolic Disease Management SO JAMA INTERNAL MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; COMMUNITY-HEALTH WORKERS; FOOD INSECURITY; LOW-INCOME; CARDIOVASCULAR-DISEASE; SOCIAL DETERMINANTS; GLYCEMIC CONTROL; CARE MANAGEMENT; GLUCOSE CONTROL; CLINICAL-TRIAL AB IMPORTANCE It is unclear if helping patients meet resource needs, such as difficulty affording food, housing, or medications, improves clinical outcomes. OBJECTIVE To determine the effectiveness of the Health Leads program on improvement in systolic and diastolic blood pressure (SBP and DBP, respectively), low-density lipoprotein cholesterol (LDL-C) level, and hemoglobin A1c (HbA1c) level. DESIGN, SETTING, AND PARTICIPANTS A difference-in-difference evaluation of the Health Leads program was conducted from October 1, 2012, through September 30, 2015, at 3 academic primary care practices. Health Leads consists of screening for unmet needs at clinic visits, and offering those who screen positive to meet with an advocate to help obtain resources, or receive brief information provision. MAIN OUTCOMES AND MEASURES Changes in SBP, DBP, LDL-C level, and HbA1c level. We compared those who screened positive for unmet basic needs (Health Leads group) with those who screened negative, using intention-to-treat, and, secondarily, between those who did and did not enroll in Health Leads, using linear mixed modeling, examining the period before and after screening. RESULTS A total of 5125 people were screened, using a standardized form, for unmet basic resource needs; 3351 screened negative and 1774 screened positive. For those who screened positive, the mean age was 57.6 years and 1811 (56%) were women. For those who screened negative, the mean age was 56.7 years and 909 (57%) were women. Of 5125 people screened, 1774 (35%) reported at least 1 unmet need, and 1021 (58%) of those enrolled in Health Leads. Median follow-up for those who screened positive and negative was 34 and 32 months, respectively. In unadjusted intention-to-treat analyses of 1998 participants with hypertension, the Health Leads group experienced greater reduction in SBP (differential change, -1.2; 95% CI, -2.1 to -0.4) and DBP (differential change, -1.0; 95% CI, -1.5 to -0.5). For 2281 individuals with an indication for LDL-C level lowering, results also favored the Health Leads group (differential change, -3.7; 95% CI -6.7 to -0.6). For 774 individuals with diabetes, the Health Leads group did not show HbA1c level improvement (differential change, -0.04%; 95% CI, -0.17% to 0.10%). Results adjusted for baseline demographic and clinical differences were not qualitatively different. Among those who enrolled in Health Leads program, there were greater BP and LDL-C level improvements than for those who declined (SBP differential change -2.6; 95% CI,-3.5 to -1.7; SBP differential change, -1.4; 95% CI, -1.9 to -0.9; LDL-C level differential change, -6.3; 95% CI, -9.7 to -2.8). CONCLUSIONS AND RELEVANCE Screening for and attempting to address unmet basic resource needs in primary care was associated with modest improvements in blood pressure and lipid, but not blood glucose, levels. C1 [Berkowitz, Seth A.; Reznor, Gally; Atlas, Steven J.] Massachusetts Gen Hosp, Div Gen Internal Med, 50 Staniford St,Ninth Floor, Boston, MA 02114 USA. [Berkowitz, Seth A.] Massachusetts Gen Hosp, Diabet Populat Hlth Res Ctr, Boston, MA 02114 USA. [Berkowitz, Seth A.; Atlas, Steven J.] Harvard Med Sch, Boston, MA USA. [Hulberg, Amy Catherine; Standish, Sara] Hlth Leads, Boston, MA USA. RP Berkowitz, SA (reprint author), Massachusetts Gen Hosp, Div Gen Internal Med, 50 Staniford St,Ninth Floor, Boston, MA 02114 USA. EM saberkowitz@partners.org FU Division of General Internal Medicine; Diabetes Population Health Research Center at Massachusetts General Hospital FX Dr Berkowitz was supported by the Division of General Internal Medicine and the Diabetes Population Health Research Center at Massachusetts General Hospital. NR 38 TC 0 Z9 0 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD FEB PY 2017 VL 177 IS 2 BP 244 EP 252 DI 10.1001/jamainternmed.2016.7691 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA EM9PS UT WOS:000395644200018 PM 27942709 ER PT J AU Cook, JW Baker, TB Beckham, JC McFall, M AF Cook, Jessica W. Baker, Timothy B. Beckham, Jean C. McFall, Miles TI Smoking-Induced Affect Modulation in Nonwithdrawn Smokers With Posttraumatic Stress Disorder, Depression, and in Those With No Psychiatric Disorder SO JOURNAL OF ABNORMAL PSYCHOLOGY LA English DT Article DE Smoking; PTSD; depression; psychiatric comorbidity ID ECOLOGICAL MOMENTARY ASSESSMENT; COMORBIDITY SURVEY REPLICATION; ACOUSTIC STARTLE RESPONSE; VIETNAM COMBAT VETERANS; NEGATIVE AFFECT; CIGARETTE-SMOKING; NICOTINE DEPENDENCE; PSYCHOPHYSIOLOGICAL ASSESSMENT; OUTCOME EXPECTANCIES; TOBACCO WITHDRAWAL AB This research sought to determine whether smoking influences affect by means other than withdrawal reduction. Little previous evidence suggests such an effect. We surmised that such an effect would be especially apparent in posttraumatic stress disorder (PTSD) and major depressive disorder (MDD), 2 disorders that are frequently comorbid with smoking and that involve dysregulated affect. Participants were U.S. veterans who were regular smokers (N = 159): 52 with PTSD (58% with comorbid MDD), 51 with MDD, and 56 controls with no psychiatric disorder. During 3 positive and 3 negative mood induction trials (scheduled over 2 sessions), nonwithdrawn participants smoked either a nicotine-containing cigarette (NIC+), a nicotine-free cigarette (NIC-), or held a pen. Positive and negative affect were each measured before and after mood induction. Results showed a significant 2-way interaction of Smoking Condition = Time on negative affect during the negative mood induction (F(6, 576) = 2.41, p = .03) in those with PTSD and controls. In these groups, both NIC+ and NIC-, relative to pen, produced lower negative affect ratings after the negative mood induction. There was also a 2-way interaction of Smoking Condition = Time on positive affect response to the positive mood induction among those with PTSD and controls (F(6, 564) = 3.17, p = .005) and among MDD and controls (F(6, 564) = 2.27, p = .036). Among all smokers, NIC+ enhanced the magnitude and duration of positive affect more than did NIC-. Results revealed affect modulation outside the context of withdrawal relief; such effects may motivate smoking among those with psychiatric diagnoses, and among smokers in general. C1 [Cook, Jessica W.; Baker, Timothy B.] Univ Wisconsin, Sch Med & Publ Hlth, Ctr Tobacco Res & Intervent, 1930 Monroe St,Suite 200, Madison, WI 53711 USA. [Cook, Jessica W.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. [Beckham, Jean C.] Durham VA Med Ctr, Durham, NC USA. [Beckham, Jean C.] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27706 USA. [McFall, Miles] Univ Washington, Dept Psychiat & Behav Sci, Sch Med & Publ Hlth, Seattle, WA 98195 USA. [McFall, Miles] VA Puget Sound Healthcare Syst, Seattle, WA USA. RP Cook, JW (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, Ctr Tobacco Res & Intervent, 1930 Monroe St,Suite 200, Madison, WI 53711 USA. EM jwcook@ctri.medicine.wisc.edu FU National Institutes of Health [K08DA02131, K05CA139871]; U.S. Department of Veterans Affairs [101CX00056]; Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Clinical Science Research and Development FX This research was supported by Grants K08DA02131 and K05CA139871 from National Institutes of Health and by VA Merit Review Award 101CX00056 from the U.S. Department of Veterans Affairs, and by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Clinical Science Research and Development. NR 96 TC 0 Z9 0 U1 1 U2 1 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0021-843X EI 1939-1846 J9 J ABNORM PSYCHOL JI J. Abnorm. Psychol. PD FEB PY 2017 VL 126 IS 2 BP 184 EP 198 DI 10.1037/abn0000247 PG 15 WC Psychology, Clinical; Psychology, Multidisciplinary SC Psychology GA EM9WV UT WOS:000395663000004 PM 28004948 ER PT J AU Van de Bittner, GC Riley, MM Cao, LX Ehses, J Herrick, SP Ricq, EL Wey, HY O'Neill, MJ Ahmed, Z Murray, TK Smith, JE Wang, CN Schroeder, FA Albers, MW Hooker, JM AF Van de Bittner, Genevieve C. Riley, Misha M. Cao, Luxiang Ehses, Janina Herrick, Scott P. Ricq, Emily L. Wey, Hsiao-Ying O'Neill, Michael J. Ahmed, Zeshan Murray, Tracey K. Smith, Jaclyn E. Wang, Changning Schroeder, Frederick A. Albers, Mark W. Hooker, Jacob M. TI Nasal neuron PET imaging quantifies neuron generation and degeneration SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID OLFACTORY IDENTIFICATION DEFICITS; ALZHEIMERS-DISEASE; ODOR IDENTIFICATION; HIPPOCAMPAL NEUROGENESIS; COGNITIVE IMPAIRMENT; MARKER PROTEIN; NERVOUS-SYSTEM; MOUSE MODEL; OLD-AGE; EPITHELIUM AB Olfactory dysfunction is broadly associated with neurodevelopmental and neurodegenerative diseases and predicts increased mortality rates in healthy individuals. Conventional measurements of olfactory health assess odor processing pathways within the brain and provide a limited understanding of primary odor detection. Quantification of the olfactory sensory neurons (OSNs), which detect odors within the nasal cavity, would provide insight into the etiology of olfactory dysfunction associated with disease and mortality. Notably, OSNs are continually replenished by adult neurogenesis in mammals, including humans, so OSN measurements are primed to provide specialized insights into neurological disease. Here, we have evaluated a PET radiotracer, [C-11] GV1-57, that specifically binds mature OSNs and quantifies the mature OSN population in vivo. [C-11] GV1-57 monitored native OSN population dynamics in rodents, detecting OSN generation during postnatal development and aging-associated neurodegeneration. [C-11] GV1-57 additionally measured rates of neuron regeneration after acute injury and early-stage OSN deficits in a rodent tauopathy model of neurodegenerative disease. Preliminary assessment in nonhuman primates suggested maintained uptake and saturable binding of [F-18] GV1-57 in primate nasal epithelium, supporting its translational potential. Future applications for GV1-57 include monitoring additional diseases or conditions associated with olfactory dysregulation, including cognitive decline, as well as monitoring effects of neuroregenerative or neuroprotective therapeutics. C1 [Van de Bittner, Genevieve C.; Riley, Misha M.; Ehses, Janina; Ricq, Emily L.; Wey, Hsiao-Ying; Smith, Jaclyn E.; Wang, Changning; Schroeder, Frederick A.; Hooker, Jacob M.] Massachusetts Gen Hosp, Harvard Med Sch, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA USA. [Cao, Luxiang; Herrick, Scott P.; Albers, Mark W.] Massachusetts Gen Hosp, Harvard Med Sch, Dept Neurol, Charlestown, MA USA. [Ricq, Emily L.] Harvard Univ, Dept Chem & Biol Chem, Cambridge, MA 02138 USA. [O'Neill, Michael J.; Ahmed, Zeshan; Murray, Tracey K.] Eli Lilly & Co Ltd, Lilly Res Ctr, Windlesham, Surrey, England. [Van de Bittner, Genevieve C.] Agilent Technol, Agilent Res Labs, Santa Clara, CA USA. RP Hooker, JM (reprint author), Bldg 149,Room 2301,13th St, Charlestown, MA 02129 USA.; Albers, MW (reprint author), MassGen Inst Neurodegenerat Dis, 114 16th St, Charlestown, MA 02129 USA. EM albers.mark@mgh.harvard.edu; hooker@nmr.mgh.harvard.edu FU Department of Energy (DOE) [DE-SC0008430]; Phyllis and Jerome Lyle Rappaport MGH Research Scholar Award; National Institutes of Health [NIH R21 NS085711]; National Institute of Mental Health's Psychoactive Drug Screening Program (NIMH PDSP) [HHSN271-2013-00017-C]; National Center for Advancing Translational Sciences [UL1 TR001102]; Harvard University FX We acknowledge the Department of Energy (DOE Training Grant DE-SC0008430, awarded to J.M.H.), the Phyllis and Jerome Lyle Rappaport MGH Research Scholar Award (awarded to J.M.H) and National Institutes of Health (NIH R21 NS085711, awarded to M.W.A.) for funding this work. We also acknowledge the National Center for Research Resources (NCRR; P41 RR14075 to the Athinoula A. Martinos Center for Biomedical Imaging), the NIH (S10 RR015728), and the Athinoula A. Martinos Center for Biomedical Imaging for resource support. WT and age-matched rTg4510 animals were generously provided by Eli Lilly through a colony housed at Taconic. Purinergic and adenosine agonist and antagonist functional data were generously provided by the National Institute of Mental Health's Psychoactive Drug Screening Program (NIMH PDSP), contract HHSN271-2013-00017-C. The NIMH PDSP is directed by Bryan L. Roth at the University of North Carolina at Chapel Hill and project officer Jamie Driscoll at NIMH, Bethesda, Maryland, USA. Biostatistical analysis was conducted in part with assistance from Mark Vangel at Harvard Catalyst (NIH NCRR and National Center for Advancing Translational Sciences through grant UL1 TR001102) and financial contributions from Harvard University and its affiliated academic health care centers. We thank radiologists Umar Mahmood and Pedram Heidari for classification of WT and rTg4510 animal scans, and we thank Nicole Zurcher for insightful discussion. We are grateful to Aijun Zhu, Alana Ross, Martin Strebl, Michael Placzek, and Diego Dos Santos Ferreira for technical assistance with rodent imaging. We thank the Martinos Center Radiopharmacy team (Garima Gautam, Nathan Schauer, Kari Phan, Ehimen Aisaborhale, Samantha To, Judit Sore) for technical assistance with radiotracer synthesis. We acknowledge histological support from the neuropathology team at Eli Lilly (UK). NR 56 TC 1 Z9 1 U1 6 U2 6 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD FEB 1 PY 2017 VL 127 IS 2 BP 681 EP 694 DI 10.1172/JCI89162 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EK8HI UT WOS:000394164100028 PM 28112682 ER PT J AU Bryan, AW Qian, QF Kirby, JE AF Bryan, Allen W., Jr. Qian, Qinfang Kirby, James E. TI Photo Quiz: A Man with Fever and Headache SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Editorial Material C1 [Kirby, James E.] Beth Israel Deaconess Med Ctr, Dept Pathol, 330 Brookline Ave, Boston, MA 02215 USA. Harvard Med Sch, Boston, MA USA. [Bryan, Allen W., Jr.] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. [Qian, Qinfang] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Kirby, JE (reprint author), Beth Israel Deaconess Med Ctr, Dept Pathol, 330 Brookline Ave, Boston, MA 02215 USA. EM jekirby@bidmc.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD FEB PY 2017 VL 55 IS 2 BP 351 EP 351 DI 10.1128/JCM.00193-15 PG 1 WC Microbiology SC Microbiology GA EK0LF UT WOS:000393617300001 PM 28122992 ER PT J AU Bryan, AW Qian, QF Kirby, JE AF Bryan, Allen W., Jr. Qian, Qinfang Kirby, James E. TI Answer to Photo Quiz: Plasmodium falciparum Infection with Hyperparasitemia SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Editorial Material ID EXCHANGE-TRANSFUSION; SEVERE MALARIA C1 [Kirby, James E.] Beth Israel Deaconess Med Ctr, Dept Pathol, 330 Brookline Ave, Boston, MA 02215 USA. Harvard Med Sch, Boston, MA USA. [Bryan, Allen W., Jr.] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. [Qian, Qinfang] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Kirby, JE (reprint author), Beth Israel Deaconess Med Ctr, Dept Pathol, 330 Brookline Ave, Boston, MA 02215 USA. EM jekirby@bidmc.harvard.edu NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD FEB PY 2017 VL 55 IS 2 BP 660 EP 661 DI 10.1128/JCM.00194-15 PG 2 WC Microbiology SC Microbiology GA EK0LF UT WOS:000393617300041 PM 28122997 ER PT J AU DeAngelo, DJ AF DeAngelo, Daniel J. TI Tailored Approaches to Induction Therapy for Acute Promyelocytic Leukemia SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID TRANS-RETINOIC ACID; EARLY DEATH RATE; ARSENIC TRIOXIDE; RISK; CHEMOTHERAPY; SURVIVAL; PETHEMA AB The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. C1 [DeAngelo, Daniel J.] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA 02115 USA. RP DeAngelo, DJ (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Boston, MA 02115 USA. NR 17 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB PY 2017 VL 35 IS 6 BP 583 EP + DI 10.1200/JCO.2016.68.4761 PG 5 WC Oncology SC Oncology GA EL2LJ UT WOS:000394450900003 PM 28095152 ER PT J AU Choueiri, TK Halabi, S Sanford, BL Hahn, O Michaelson, MD Walsh, MK Feldman, DR Olencki, T Picus, J Small, EJ Dakhil, S George, DJ Morris, MJ AF Choueiri, Toni K. Halabi, Susan Sanford, Ben L. Hahn, Olwen Michaelson, M. Dror Walsh, Meghara K. Feldman, Darren R. Olencki, Thomas Picus, Joel Small, Eric J. Dakhil, Shaker George, Daniel J. Morris, Michael J. TI Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID MET; EVEROLIMUS; SURVIVAL; INHIBITOR; PAZOPANIB; KINASE; IMPACT; GROWTH; BONE; VEGF AB Purpose Cabozantinib is an oral potent inhibitor of vascular endothelial growth factor receptor 2, MET, and AXL and is a standard second-line therapy for metastatic renal cell carcinoma (mRCC). This randomized phase II multicenter trial evaluated cabozantinib compared with sunitinib as first-line therapy in patients with mRCC. Patients and Methods Eligible patients had untreated clear cell mRCC and Eastern Cooperative Oncology Group performance status of 0 to 2 and were intermediate or poor risk per International Metastatic Renal Cell Carcinoma Database Consortium criteria. Patients were randomly assigned at a one-to-one ratio to cabozantinib (60 mg once per day) or sunitinib (50 mg once per day; 4 weeks on, 2 weeks off). Progression-free survival (PFS) was the primary end point. Objective response rate (ORR), overall survival, and safety were secondary end points. Results From July 2013 to April 2015, 157 patients were randomly assigned (cabozantinib, n = 79; sunitinib, n = 78). Compared with sunitinib, cabozantinib treatment significantly increased median PFS (8.2 v 5.6 months) and was associated with a 34% reduction in rate of progression or death (adjusted hazard ratio, 0.66; 95% CI, 0.46 to 0.95; one-sided P=.012). ORR was 46% (95% CI, 34 to 57) for cabozantinib versus 18% (95% CI, 10 to 28) for sunitinib. All-causality grade 3 or 4 adverse events were 67% for cabozantinib and 68% for sunitinib and included diarrhea (cabozantinib, 10% v sunitinib, 11%), fatigue (6% v 15%), hypertension (28% v 22%), palmar-plantar erythrodysesthesia (8% v 4%), and hematologic adverse events (3% v 22%). Conclusion Cabozantinib demonstrated a significant clinical benefit in PFS and ORR over standard-of-care sunitinib as first-line therapy in patients with intermediate-or poor-risk mRCC. (C) 2016 by American Society of Clinical Oncology C1 [Choueiri, Toni K.; Walsh, Meghara K.] Dana Farber Canc Inst, 450 Brookline Ave,DANA 1230, Boston, MA 02215 USA. [Michaelson, M. Dror] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Halabi, Susan; Sanford, Ben L.] Alliance Stat & Data Ctr, Durham, NC USA. [Halabi, Susan; Sanford, Ben L.] Duke Univ, Durham, NC 27706 USA. [George, Daniel J.] Duke Univ, Med Ctr, Duke Canc Inst, Durham, NC 27706 USA. [Hahn, Olwen] Alliance Protocol Operat Off, Chicago, IL USA. [Feldman, Darren R.; Morris, Michael J.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Olencki, Thomas] Ohio State Univ, Med Ctr, Columbus, OH 43210 USA. [Picus, Joel] Washington Univ, Sch Med, Siteman Canc Ctr, St Louis, MO USA. [Small, Eric J.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Dakhil, Shaker] Univ Kansas Wichita, Wichita, KS USA. RP Choueiri, TK (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,DANA 1230, Boston, MA 02215 USA. EM toni_choueiri@dfci.harvard.edu FU Novartis; Pfizer; Merck; Exelixis; TRACON Pharma; Bristol-Myers Squibb; AstraZeneca; Peloton Therapeutics; Genentech; Celldex; Takeda Pharmaceuticals; Eisai; Argos Therapeutics; Millennium Pharmaceuticals; Bioclin; Altor BioScience; Agensys; Oncogenex; Mirati Therapeutics; Astex Pharmaceuticals; Janssen Oncology; Progenics; Astellas Pharma; GlaxoSmithKline; Innocrin Pharma; Bayer HealthCare Pharmaceuticals; Sanofi; Endocyte FX Pfizer (Inst), Novartis (Inst), Merck (Inst), Exelixis (Inst), TRACON Pharma (Inst), Bristol-Myers Squibb (Inst), AstraZeneca (Inst), Peloton Therapeutics (Inst), Genentech (Inst), Celldex (Inst), Takeda Pharmaceuticals (Inst); Pfizer (Inst), Eisai (Inst), Argos Therapeutics (Inst), Millennium Pharmaceuticals (Inst), Novartis (Inst), TRACON Pharma (Inst); Novartis; Bristol-Myers Squibb (Inst), Pfizer (Inst), TRACON Pharma (Inst); Novartis, Bioclin, Altor BioScience, Agensys, Oncogenex, Mirati Therapeutics, Astex Pharmaceuticals; Exelixis, Genentech, Janssen Oncology, Novartis, Pfizer, Progenics, Astellas Pharma, Bristol-Myers Squibb, GlaxoSmithKline, Millennium Pharmaceuticals, Innocrin Pharma; Bayer HealthCare Pharmaceuticals (Inst), Sanofi (Inst), Janssen Oncology (Inst), Endocyte (Inst) NR 29 TC 3 Z9 3 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 FEB PY 2017 VL 35 IS 6 BP 591 EP + DI 10.1200/JCO.2016.70.7398 PG 9 WC Oncology SC Oncology GA EL2LJ UT WOS:000394450900005 PM 28199818 ER PT J AU Meggetto, O Maunsell, E Chlebowski, R Goss, P Tu, DS Richardson, H AF Meggetto, Olivia Maunsell, Elizabeth Chlebowski, Rowan Goss, Paul Tu, Dongsheng Richardson, Harriet TI Factors Associated With Early Discontinuation of Study Treatment in the Mammary Prevention. 3 Breast Cancer Chemoprevention Trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID QUALITY-OF-LIFE; SURGICAL ADJUVANT BREAST; BOWEL PROJECT P-1; ADHERENCE; HEALTH; MENOPAUSE; TAMOXIFEN; SYMPTOMS; QUESTIONNAIRE; INTERVENTION AB Purpose Aromatase inhibitors are established breast cancer chemoprevention interventions. However, nonadherence remains a significant challenge. We investigated the association between worsening menopause-specific quality of life, baseline participant characteristics, and early treatment discontinuation within the Mammary Prevention. 3 (MAP. 3) breast cancer prevention trial. Methods In the MAP. 3 randomized, placebo-controlled trial evaluating exemestane, participants completed the Menopause-Specific Quality of Life Questionnaire (MENQOL) at entry and at 6 months. Multivariable log- binomial regression was used to assess the associations of baseline participant characteristics and clinically meaningful worsening in menopause-specific quality of life (QOL) with treatment discontinuation at 1 year. Results Of the 4,501 participants eligible for this analysis, 724 (17%) discontinued assigned treatment within the first year of random assignment of treatment (19% of the exemestane group and 13% of the placebo group). Between 19% and 35% of women experienced a clinically meaningful worsening in the vasomotor, sexual, physical, and psychosocial domains of the MENQOL within 6 months of treatment initiation. Regardless of receiving exemestane or not, experiencing a worsening in any MENQOL domain or, especially, overall menopause- specific QOL, was associated with early treatment discontinuation (relative risk, 1.79; 95% CI, 1.53 to 2.10 for overall worsening). Assignment to exemestane, having a smoking history, and current employment also were significantly associated with early discontinuation. Conclusion Negative changes in menopause- specific QOL influence a woman's decision to stop chemoprevention therapy. Attention to such symptoms may improve QOL and potentially improve chemoprevention adherence. (C) 2017 by American Society of Clinical Oncology C1 [Meggetto, Olivia; Tu, Dongsheng; Richardson, Harriet] Queens Univ, Kingston, ON, Canada. [Tu, Dongsheng; Richardson, Harriet] Canadian Canc Trials Grp, Kingston, ON, Canada. [Maunsell, Elizabeth] Ctr Hosp Univ Quebec, Ctr Rech, Quebec City, PQ, Canada. [Chlebowski, Rowan] Harbor UCLA Med Ctr, Torrance, CA 90509 USA. [Goss, Paul] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Richardson, H (reprint author), Queens Canc Res Inst, 10 Stuart St, Kingston, ON K7L 3N6, Canada. EM hr1@queensu.ca FU Canadian Cancer Society Research Institute; Ontario Graduate Scholarship FX Supported by the Canadian Cancer Society Research Institute and by an Ontario Graduate Scholarship (O.M.). NR 28 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 FEB PY 2017 VL 35 IS 6 BP 629 EP + DI 10.1200/JCO.2016.68.8895 PG 8 WC Oncology SC Oncology GA EL2LJ UT WOS:000394450900010 PM 28068170 ER PT J AU Gray, SW Gollust, SE Carere, DA Chen, CA Cronin, A Kalia, SS Rana, HQ Ruffin, MT Wang, C Roberts, JS Green, RC AF Gray, Stacy W. Gollust, Sarah E. Carere, Deanna Alexis Chen, Clara A. Cronin, Angel Kalia, Sarah S. Rana, Huma Q. Ruffin, Mack T. Wang, Catharine Roberts, J. Scott Green, Robert C. TI Personal Genomic Testing for Cancer Risk: Results From the Impact of Personal Genomics Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PROSTATE-CANCER; PERCEIVED RISK; GENETIC TESTS; CUSTOMERS; DIETARY; FDA; SUSCEPTIBILITY; INTERVENTIONS; ASSOCIATION; PERCEPTIONS AB Purpose Significant concerns exist regarding the potential for unwarranted behavior changes and the overuse of health care resources in response to direct-to-consumer personal genomic testing (PGT). However, little is known about customers' behaviors after PGT. Methods Longitudinal surveys were given to new customers of 23andMe (Mountain View, CA) and Pathway Genomics (San Diego, CA). Survey data were linked to individual-level PGT results through a secure data transfer process. Results Of the 1,042 customers who completed baseline and 6-month surveys (response rate, 71.2%), 762 had complete cancer-related data and were analyzed. Most customers reported that learning about their genetic risk of cancers was a motivation for testing (colorectal, 88%; prostate, 95%; breast, 94%). No customers tested positive for pathogenic mutations in highly penetrant cancer susceptibility genes. A minority of individuals received elevated single nucleotide polymorphism-based PGT cancer risk estimates (colorectal, 24%; prostate, 24%; breast, 12%). At 6 months, customers who received elevated PGT cancer risk estimates were not significantly more likely to change their diet, exercise, or advanced planning behaviors or engage in cancer screening, compared with individuals at average or reduced risk. Men who received elevated PGT prostate cancer risk estimates changed their vitamin and supplement use more than those at average or reduced risk (22% v7.6%, respectively; adjusted odds ratio, 3.41; 95% CI, 1.44 to 8.18). Predictors of 6-month behavior include baseline behavior (exercise, vitamin or supplement use, and screening), worse health status (diet and vitamin or supplement use), and older age (advanced planning, screening). Conclusion Most adults receiving elevated direct-to-consumer PGT single nucleotide polymorphism-based cancer risk estimates did not significantly change their diet, exercise, advanced care planning, or cancer screening behaviors. (C) 2016 by American Society of Clinical Oncology C1 [Gray, Stacy W.] City Hope Natl Med Ctr, 1500 E Duarte Rd, Duarte, CA 91010 USA. [Gollust, Sarah E.] Univ Minnesota, Sch Publ Hlth, Minneapolis, MN USA. [Carere, Deanna Alexis] McMaster Univ, Hamilton, ON, Canada. [Carere, Deanna Alexis] Hamilton Hlth Sci, Populat Hlth Res Inst, Hamilton, ON, Canada. [Chen, Clara A.; Wang, Catharine] Boston Univ, Sch Publ Hlth, Boston, MA 02215 USA. [Cronin, Angel; Rana, Huma Q.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Kalia, Sarah S.; Green, Robert C.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Rana, Huma Q.; Green, Robert C.] Harvard Med Sch, Boston, MA USA. [Green, Robert C.] Partners Healthcare Personalized Med, Boston, MA USA. [Ruffin, Mack T.] Univ Michigan, Sch Med, Ann Arbor, MI 48109 USA. [Roberts, J. Scott] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. RP Gray, SW (reprint author), City Hope Natl Med Ctr, Div Clin Canc Genet, Dept Populat Sci, 1500 E Duarte Rd, Duarte, CA 91010 USA. EM stagray@coh.org FU National Institutes of Health (NIH) National Human Genome Research Institute [R01-HG005092]; National Human Genome Research Institute [U01HG006492]; American Cancer Society [120529-MRSG-11-006-01-CPPB]; Canadian Institutes of Health Research; [NIH K07CA131103]; [U01-HG006500]; [U19-HD077671]; [U01-HG008685]; [U41-HG006834] FX Supported by the National Institutes of Health (NIH) National Human Genome Research Institute (Grant No. R01-HG005092). S.W.G. is supported by National Human Genome Research Institute (Grant No. U01HG006492) and by the American Cancer Society (Grant No. 120529-MRSG-11-006-01-CPPB). D.A.C. was supported by a Canadian Institutes of Health Research Doctoral Foreign Study Award when these analyses were performed. C.W. is supported by Grant No. NIH K07CA131103. R.C.G. is supported by Grants No. U01-HG006500, U19-HD077671, U01-HG008685, and U41-HG006834. NR 51 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB PY 2017 VL 35 IS 6 BP 636 EP + DI 10.1200/JCO.2016.67.1503 PG 14 WC Oncology SC Oncology GA EL2LJ UT WOS:000394450900011 PM 27937091 ER PT J AU Trippa, L Alexander, BM AF Trippa, Lorenzo Alexander, Brian Michael TI Bayesian Baskets: A Novel Design for Biomarker-Based Clinical Trials SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID BREAST-CANCER; LUNG-CANCER; THERAPIES AB Purpose Biomarker-based clinical trials provide efficiencies during therapeutic development and form the foundation for precision medicine. These trials must generate information on both experimental therapeutics and putative predictive biomarkers in the context of varying pretrial information. We generated an efficient, flexible design that accommodates various pretrial levels of evidence supporting the predictive capacity of biomarkers while making pretrial design choices explicit. Methods We generated a randomization procedure that explicitly incorporates pretrial estimates of the predictive capacity of biomarkers. To compare the utility of this Bayesian basket (BB) design with that of a balanced randomized, biomarker agnostic (BA) design and a traditional basket (TB) design that includes only biomarker-positive patients, we iteratively simulated hypothetical multiarm clinical trials under various scenarios. Results BB was more efficient than BA while generating more information on the predictive capacity of putative biomarkers than both BA and TB. For simulations of hypothetical multiarm trials of experimental therapies and associated biomarkers of varying incident frequency, BB increased power over BA in cases when the biomarker was predictive and when the experimental therapeutic worked in all patients in a variety of scenarios. BB also generated more information about the predictive capacity of biomarkers than BA and categorically relative to TB, which generates no new biomarker information. Conclusion The BB design offers an efficient way to generate information on both experimental therapeutics and the predictive capacity of putative biomarkers. The design is flexible enough to accommodate varying levels of pretrial biomarker confidence within the same platform structure and makes clinical trial design decisions more explicit. (C) 2017 by American Society of Clinical Oncology C1 [Trippa, Lorenzo; Alexander, Brian Michael] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. [Trippa, Lorenzo] Harvard Sch Publ Hlth, Boston, MA USA. [Alexander, Brian Michael] Harvard Med Sch, Boston, MA USA. RP Alexander, BM (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. EM Brian_Alexander@dfci.harvard.edu FU Burroughs-Wellcome Innovations in Regulatory Science Award FX Supported by a Burroughs-Wellcome Innovations in Regulatory Science Award. NR 22 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 FEB PY 2017 VL 35 IS 6 BP 681 EP + DI 10.1200/JCO.2016.68.2864 PG 16 WC Oncology SC Oncology GA EL2LJ UT WOS:000394450900016 PM 28045624 ER PT J AU Eddy, KT Tabri, N Thomas, JJ Murray, HB Keshaviah, A Hastings, E Edkins, K Krishna, M Herzog, DB Keel, PK Franko, DL AF Eddy, Kamryn T. Tabri, Nassim Thomas, Jennifer J. Murray, Helen B. Keshaviah, Aparna Hastings, Elizabeth Edkins, Katherine Krishna, Meera Herzog, David B. Keel, Pamela K. Franko, Debra L. TI Recovery From Anorexia Nervosa and Bulimia Nervosa at 22-Year Follow-Up SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID QUALITY-OF-LIFE; EATING-DISORDERS; LONG-TERM; 12-YEAR COURSE; RELIABILITY; MORTALITY; METAANALYSIS; PROGNOSIS; TRIAL AB Objective: The course of eating disorders is often protracted, with fewer than half of adults achieving recovery from anorexia nervosa or bulimia nervosa. Some argue for palliative management when duration exceeds a decade, yet outcomes beyond 20 years are rarely described. This study investigates early and long-term recovery in the Massachusetts General Hospital Longitudinal Study of Anorexia and Bulimia Nervosa. Methods: Females with DSM-III-R/DSM-IV anorexia nervosa or bulimia nervosa were assessed at 9 and at 20 to 25 years of follow-up (mean [SD] = 22.10 [1.10] years; study initiated in 1987, last follow-up conducted in 2013) via structured clinical interview (Longitudinal Interval Follow-Up Evaluation of Eating Disorders [LIFE-EAT-II]). Seventy-seven percent of the original cohort was re-interviewed, and multiple imputation was used to include all surviving participants from the original cohort (N = 228). Kaplan-Meier curves estimated recovery by 9-year follow-up, and McNemar test examined concordance between recovery at 9-year and 22-year follow-up. Results: At 22-year follow-up, 62.8% of participants with anorexia nervosa and 68.2% of participants with bulimia nervosa recovered, compared to 31.4% of participants with anorexia nervosa and 68.2% of participants with bulimia nervosa by 9-year follow-up. Approximately half of those with anorexia nervosa who had not recovered by 9 years progressed to recovery at 22 years. Early recovery was associated with increased likelihood of long-term recovery in anorexia nervosa (odds ratio [OR] = 10.5; 95% CI, 3.77-29.28; McNemar chi(2) 1 = 31.39; P <.01) but not in bulimia nervosa (OR = 1.0; 95% CI, 0.49-2.05; McNemar chi(2) 1 = 0; P = 1.0). Conclusion: At 22 years, approximately two-thirds of females with anorexia nervosa and bulimia nervosa were recovered. Recovery from bulimia nervosa happened earlier, but recovery from anorexia nervosa continued over the long term, arguing against the implementation of palliative care for most individuals with eating disorders. C1 [Eddy, Kamryn T.; Tabri, Nassim; Thomas, Jennifer J.; Murray, Helen B.; Keshaviah, Aparna; Hastings, Elizabeth; Edkins, Katherine; Krishna, Meera; Franko, Debra L.] Massachusetts Gen Hosp, Eating Disorders Clin & Res Program, 2 Longfellow Pl,Ste 200, Boston, MA 02114 USA. [Eddy, Kamryn T.; Tabri, Nassim; Thomas, Jennifer J.; Herzog, David B.] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Keel, Pamela K.] Florida State Univ, Dept Psychol, Tallahassee, FL 32306 USA. [Franko, Debra L.] Northeastern Univ, Dept Appl Psychol, Boston, MA 02115 USA. RP Eddy, KT (reprint author), Massachusetts Gen Hosp, Eating Disorders Clin & Res Program, 2 Longfellow Pl,Ste 200, Boston, MA 02114 USA. EM keddy@mgh.harvard.edu FU US National Institute of Mental Health [R01 MH-38333, R03 MH-094832] FX Supported by US National Institute of Mental Health grants R01 MH-38333 and R03 MH-094832. NR 34 TC 0 Z9 0 U1 2 U2 2 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 EI 1555-2101 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD FEB PY 2017 VL 78 IS 2 BP 184 EP 189 DI 10.4088/JCP.15m10393 PG 6 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA EN9QT UT WOS:000396335400009 PM 28002660 ER PT J AU Driscoll, KC Hirshfeld-Becker, DR AF Driscoll, Katherine C. Hirshfeld-Becker, Dina R. TI Parent-Child Cognitive Behavioral Therapy for Anxiety in Young Children with Autism Spectrum Disorders: A Pilot Study SO JOURNAL OF DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS LA English DT Meeting Abstract C1 [Driscoll, Katherine C.] Harvard Med Sch, Dev Med, Boston Childrens Hosp, Boston, MA USA. [Hirshfeld-Becker, Dina R.] Harvard Med Sch, Psychiat, Massachusetts Gen Hosp, Boston, MA USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0196-206X EI 1536-7312 J9 J DEV BEHAV PEDIATR JI J. Dev. Behav. Pediatr. PD FEB-MAR PY 2017 VL 38 IS 2 MA 5 BP S2 EP S2 PG 1 WC Behavioral Sciences; Psychology, Developmental; Pediatrics SC Behavioral Sciences; Psychology; Pediatrics GA EK5EZ UT WOS:000393951000006 ER PT J AU Martinod, K Witsch, T Erpenbeck, L Savchenko, A Hayashi, H Cherpokova, D Gallant, M Mauler, M Cifuni, SM Wagner, DD AF Martinod, Kimberly Witsch, Thilo Erpenbeck, Luise Savchenko, Alexander Hayashi, Hideki Cherpokova, Deya Gallant, Maureen Mauler, Maximilian Cifuni, Stephen M. Wagner, Denisa D. TI Peptidylarginine deiminase 4 promotes age-related organ fibrosis SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID NEUTROPHIL EXTRACELLULAR TRAPS; LEFT-VENTRICULAR HYPERTROPHY; DEEP-VEIN THROMBOSIS; HEART-FAILURE; DNA TRAPS; CHROMATIN DECONDENSATION; PULMONARY-FIBROSIS; PRESSURE-OVERLOAD; OXIDATIVE STRESS; CARDIAC FIBROSIS AB Aging promotes inflammation, a process contributing to fibrosis and decline in organ function. The release of neutrophil extracellular traps (NETs [NETosis]), orchestrated by peptidylarginine deiminase 4 (PAD4), damages organs in acute inflammatory models. We determined that NETosis is more prevalent in aged mice and investigated the role of PAD4/NETs in age-related organ fibrosis. Reduction in fibrosis was seen in the hearts and lungs of aged PAD4(-/-) mice compared with wild-type (WT) mice. An increase in left ventricular interstitial collagen deposition and a decline in systolic and diastolic function were present only in WT mice, and not in PAD4(-/-) mice. In an experimental model of cardiac fibrosis, cardiac pressure overload induced NETosis and significant platelet recruitment in WT but not PAD4(-/-) myocardium. DNase 1 was given to assess the effects of extracellular chromatin. PAD4 deficiency or DNase 1 similarly protected hearts from fibrosis. We propose a role for NETs in cardiac fibrosis and conclude that PAD4 regulates age-related organ fibrosis and dysfunction. C1 [Martinod, Kimberly; Witsch, Thilo; Erpenbeck, Luise; Savchenko, Alexander; Hayashi, Hideki; Cherpokova, Deya; Gallant, Maureen; Cifuni, Stephen M.; Wagner, Denisa D.] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Wagner, Denisa D.] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Martinod, Kimberly; Witsch, Thilo; Erpenbeck, Luise; Savchenko, Alexander; Hayashi, Hideki; Cherpokova, Deya; Wagner, Denisa D.] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA. [Mauler, Maximilian] Univ Freiburg, Fac Biol, D-79106 Freiburg, Germany. [Mauler, Maximilian] Univ Freiburg, Ctr Heart, Dept Cardiol & Angiol 1, D-79106 Freiburg, Germany. [Erpenbeck, Luise] Univ Med Ctr Gottingen, Dept Dermatol Venereol & Allergol, D-37075 Gottingen, Germany. RP Wagner, DD (reprint author), Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA.; Wagner, DD (reprint author), Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA.; Wagner, DD (reprint author), Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA. EM denisa.wagner@childrens.harvard.edu FU National Heart, Lung, and Blood Institute of the National Institutes of Health [R01HL102101, R01HL125501, 5T32HL066987-13]; Boston Children's Hospital Research Faculty Council Award for Pilot Study; Deutsche Akademie der Naturforscher Leopoldina (Nationale Akademie der Wissenschaften); German Cardiac Society (Deutsche Gesellschaft fuer Kardiologie); Deutsche Forschungsgemeinschaft [CH 1734/1-1] FX This work was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health (grants R01HL102101 and R01HL125501 to D.D. Wagner and grant 5T32HL066987-13 to K. Martinod) and by a Boston Children's Hospital Research Faculty Council Award for Pilot Study (D.D. Wagner). L. Erpenbeck received a fellowship from the Deutsche Akademie der Naturforscher Leopoldina (Nationale Akademie der Wissenschaften). T. Witsch received a fellowship from the German Cardiac Society (Deutsche Gesellschaft fuer Kardiologie). D. Cherpokova received a fellowship from the Deutsche Forschungsgemeinschaft (CH 1734/1-1). NR 87 TC 0 Z9 0 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD FEB PY 2017 VL 214 IS 2 BP 439 EP 458 DI 10.1084/jem.20160530 PG 20 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA EK9NO UT WOS:000394251400012 PM 28031479 ER PT J AU Reddy, HM Cho, KA Lek, M Estrella, E Valkanas, E Jones, MD Mitsuhashi, S Darras, BT Amato, AA Lidov, HGW Brownstein, CA Margulies, DM Yu, TW Salih, MA Kunkel, LM MacArthur, DG Kang, PB AF Reddy, Hemakumar M. Cho, Kyung-Ah Lek, Monkol Estrella, Elicia Valkanas, Elise Jones, Michael D. Mitsuhashi, Satomi Darras, Basil T. Amato, Anthony A. Lidov, Hart G. W. Brownstein, Catherine A. Margulies, David M. Yu, Timothy W. Salih, Mustafa A. Kunkel, Louis M. MacArthur, Daniel G. Kang, Peter B. TI The sensitivity of exome sequencing in identifying pathogenic mutations for LGMD in the United States SO JOURNAL OF HUMAN GENETICS LA English DT Article ID GIRDLE MUSCULAR-DYSTROPHY; LAMA2 MUTATIONS; BETHLEM MYOPATHY; SMCHD1 MUTATION; POINT MUTATIONS; PHENOTYPE; DISEASE; GENE; IDENTIFICATION; DIAGNOSIS AB The current study characterizes a cohort of limb-girdle muscular dystrophy (LGMD) in the United States using whole-exome sequencing. Fifty-five families affected by LGMD were recruited using an institutionally approved protocol. Exome sequencing was performed on probands and selected parental samples. Pathogenic mutations and cosegregation patterns were confirmed by Sanger sequencing. Twenty-two families (40%) had novel and previously reported pathogenic mutations, primarily in LGMD genes, and also in genes for Duchenne muscular dystrophy, facioscapulohumeral muscular dystrophy, congenital myopathy, myofibrillar myopathy, inclusion body myopathy and Pompe disease. One family was diagnosed via clinical testing. Dominant mutations were identified in COL6A1, COL6A3, FLNC, LMNA, RYR1, SMCHD1 and VCP, recessive mutations in ANO5, CAPN3, GAA, LAMA2, SGCA and SGCG, and X-linked mutations in DMD. A previously reported variant in DMD was confirmed to be benign. Exome sequencing is a powerful diagnostic tool for LGMD. Despite careful phenotypic screening, pathogenic mutations were found in other muscle disease genes, largely accounting for the increased sensitivity of exome sequencing. Our experience suggests that broad sequencing panels are useful for these analyses because of the phenotypic overlap of many neuromuscular conditions. The confirmation of a benign DMD variant illustrates the potential of exome sequencing to help determine pathogenicity. C1 [Reddy, Hemakumar M.; Cho, Kyung-Ah; Jones, Michael D.; Kang, Peter B.] Univ Florida, Coll Med, Dept Pediat, Div Pediat Neurol, POB 100296, Gainesville, FL 32610 USA. [Lek, Monkol; Valkanas, Elise; MacArthur, Daniel G.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Lek, Monkol; Estrella, Elicia; Valkanas, Elise; Mitsuhashi, Satomi; Darras, Basil T.; Amato, Anthony A.; Lidov, Hart G. W.; Brownstein, Catherine A.; Margulies, David M.; Yu, Timothy W.; Kunkel, Louis M.; MacArthur, Daniel G.; Kang, Peter B.] Harvard Med Sch, Boston, MA USA. [Lek, Monkol; Valkanas, Elise; MacArthur, Daniel G.] Broad Inst Massachusetts Inst Technol & Harvard U, Program Med & Populat Genet, Cambridge, MA USA. [Lek, Monkol; Valkanas, Elise; MacArthur, Daniel G.] Harvard Univ, Cambridge, MA 02138 USA. [Estrella, Elicia; Brownstein, Catherine A.; Margulies, David M.; Yu, Timothy W.; Kunkel, Louis M.] Boston Childrens Hosp, Div Genet & Genom, Boston, MA USA. [Mitsuhashi, Satomi; Darras, Basil T.; Kang, Peter B.] Boston Childrens Hosp, Dept Neurol, Boston, MA USA. [Amato, Anthony A.] Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA. [Lidov, Hart G. W.] Boston Childrens Hosp, Dept Pathol, Boston, MA USA. [Brownstein, Catherine A.; Margulies, David M.] Boston Childrens Hosp, Div Genet & Genom, Res Connect & Manton Ctr Orphan Dis Res, Boston, MA USA. [Salih, Mustafa A.] King Saud Univ, Coll Med, Div Neurol, Dept Pediat, Riyadh, Saudi Arabia. [Salih, Mustafa A.] King Saud Univ, King Khalid Univ Hosp, Riyadh, Saudi Arabia. [Kang, Peter B.] Univ Florida, Coll Med, Dept Neurol, Gainesville, FL 32611 USA. [Kang, Peter B.] Univ Florida, Coll Med, Dept Mol Genet & Microbiol, Gainesville, FL USA. [Kang, Peter B.] Univ Florida, Genet Inst, Gainesville, FL USA. [Cho, Kyung-Ah] Ewha Womans Univ, Sch Med, Dept Microbiol, Seoul 07985, South Korea. [Mitsuhashi, Satomi] Tokai Univ, Sch Med, Dept Mol Life Sci, Biomed Informat Lab, 143 Shimokasuya, Isehara, Kanagawa 2591193, Japan. RP Kang, PB (reprint author), Univ Florida, Coll Med, Dept Pediat, Div Pediat Neurol, POB 100296, Gainesville, FL 32610 USA. EM pbkang@ufl.edu RI Mutra, Hemakumara/D-3876-2014 OI Mutra, Hemakumara/0000-0002-3769-6609 FU NIH [R01 NS080929, R01 GM104371]; Department of Pediatrics at the University of Florida College of Medicine; Muscular Dystrophy Association Research Grant [186796]; Bernard F and Alva B Gimbel Foundation; Medical Sequencing Program from the National Human Genome Research Institute [U54HG003067]; Deanship of Scientific Research, King Saud University, Riyadh, Saudi Arabia [RGP-VPP-301] FX We thank all the study participants for their valuable contributions to this study. The work was supported by NIH R01 NS080929 (HMR, KAC, EE and PBK), NIH R01 GM104371 (DGM), Department of Pediatrics at the University of Florida College of Medicine (KAC and PBK), Muscular Dystrophy Association Research Grant 186796 (PBK) and the Bernard F and Alva B Gimbel Foundation (LMK). Exome sequencing was supported by Medical Sequencing Program Grant U54HG003067 from the National Human Genome Research Institute. MAS was supported by the Deanship of Scientific Research, King Saud University, Riyadh, Saudi Arabia via research group project number RGP-VPP-301. NR 46 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1434-5161 EI 1435-232X J9 J HUM GENET JI J. Hum. Genet. PD FEB PY 2017 VL 62 IS 2 BP 243 EP 252 DI 10.1038/jhg.2016.116 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA EK7EB UT WOS:000394087600016 PM 27708273 ER PT J AU Tritos, NA AF Tritos, Nicholas A. TI How concerned should we be over the long-term safety of growth hormone therapy? SO LANCET DIABETES & ENDOCRINOLOGY LA English DT Editorial Material ID CHILDHOOD; MORTALITY; ADULTS; SAGHE C1 [Tritos, Nicholas A.] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Tritos, Nicholas A.] Harvard Med Sch, Boston, MA 02115 USA. RP Tritos, NA (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA.; Tritos, NA (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM ntritos@mgh.harvard.edu NR 10 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2213-8587 J9 LANCET DIABETES ENDO JI Lancet Diabetes Endocrinol. PD FEB PY 2017 VL 5 IS 2 BP 79 EP 81 DI 10.1016/S2213-8587(16)30423-5 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EN9RU UT WOS:000396338100005 PM 28011066 ER PT J AU Gupta, V Mason-Sharma, A Caty, SN Kerry, V AF Gupta, Vin Mason-Sharma, Alexandre Caty, Stephanie N. Kerry, Vanessa TI Adapting global health aid in the face of climate change SO LANCET GLOBAL HEALTH LA English DT Editorial Material C1 [Gupta, Vin; Kerry, Vanessa] Harvard Univ, Harvard Global Hlth Inst, Cambridge, MA 02138 USA. [Gupta, Vin] Brigham & Womens Hosp, Div Pulm & Crit Care Med, 75 Francis St, Boston, MA 02115 USA. [Mason-Sharma, Alexandre] Boston Univ, Sch Med, Boston, MA 02118 USA. [Caty, Stephanie N.] Harvard TH Chan Sch Publ Hlth, Dept Hlth Policy & Management, Cambridge, MA USA. [Kerry, Vanessa] Harvard Med Sch, Dept Global Hlth & Social Med, Boston, MA USA. [Kerry, Vanessa] Massachusetts Gen Hosp, Div Pulm & Crit Care, Boston, MA 02114 USA. RP Gupta, V (reprint author), Harvard Univ, Harvard Global Hlth Inst, Cambridge, MA 02138 USA.; Gupta, V (reprint author), Brigham & Womens Hosp, Div Pulm & Crit Care Med, 75 Francis St, Boston, MA 02115 USA. EM vgupta7@partners.org NR 9 TC 1 Z9 1 U1 5 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2214-109X J9 LANCET GLOB HEALTH JI Lancet Glob. Health PD FEB PY 2017 VL 5 IS 2 BP E133 EP E134 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EN9SW UT WOS:000396340900010 PM 28104175 ER PT J AU Ilbawi, AM Ayoo, E Bhadelia, A Chidebe, RCW Fadelu, T Herrera, CA Htun, HW Jadoon, NA James, OW May, L Maza, M Murgor, M Nency, YM Oraegbunam, C Pratt-Chapman, M Qin, XJ Rodin, D Tripathi, N Wainer, Z Yap, ML AF Ilbawi, Andre M. Ayoo, Elizabeth Bhadelia, Afsan Chidebe, Runcie C. W. Fadelu, Temidayo Herrera, Cristian A. Htun, Han Win Jadoon, Nauman Arif James, Oluwafunmilola W. May, Leana Maza, Mauricio Murgor, Mellany Nency, Yetty M. Oraegbunam, Chukwuma Pratt-Chapman, Mandi Qin, Xiaojian Rodin, Danielle Tripathi, Neha Wainer, Zoe Yap, Mei Ling TI Advancing access and equity: the vision of a new generation in cancer control SO LANCET ONCOLOGY LA English DT Editorial Material C1 [Ilbawi, Andre M.] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. [Ayoo, Elizabeth] Maseno Univ, Maseno, Kenya. [Bhadelia, Afsan] Harvard TH Chan Sch Publ Hlth, Dept Global Hlth & Populat, Boston, MA USA. [Bhadelia, Afsan] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA. [Chidebe, Runcie C. W.] Hlth & Psychol Trust Ctr, Project Pink Blue, Abuja, Nigeria. [Fadelu, Temidayo] Dana Farber Canc Inst, Boston, MA 02115 USA. [Herrera, Cristian A.] Minist Hlth Santiago, Dept Strateg Dev, Santiago, Chile. [Herrera, Cristian A.] Pontificia Univ Catolica Chile, Sch Med, Dept Publ Hlth, Santiago, Chile. [Htun, Han Win] Univ Auckland, Auckland, New Zealand. [Jadoon, Nauman Arif] Ctr Biomed Res, Lahore, Pakistan. [Jadoon, Nauman Arif] Hull Royal Infirm, Kingston Upon Hull, N Humberside, England. [James, Oluwafunmilola W.] Breast Spot, Lagos, Nigeria. [May, Leana] Univ Colorado, Sch Med, Childrens Hosp Colorado, Denver, CO USA. [Maza, Mauricio] Basic Hlth Int, San Salvador, El Salvador. [Murgor, Mellany] Young Profess Chron Dis Network, Nairobi, Kenya. [Nency, Yetty M.] Diponegoro Univ, Fac Med, Dept Child Hlth, Semarang, Indonesia. [Oraegbunam, Chukwuma] Univ Nigeria, Teaching Hosp, Dept Psychol Med, Ituku Ozalla, Nigeria. [Pratt-Chapman, Mandi] George Washington Univ, Ctr Canc, Patient Ctr Initiat & Hlth Equ, Washington, DC USA. [Qin, Xiaojian] Fudan Univ, Shanghai Canc Ctr, Shanghai, Peoples R China. [Rodin, Danielle] Univ Toronto, Dept Radiat Oncol, Toronto, ON, Canada. [Tripathi, Neha] Canc Aid Soc, Int Affairs, Lucknow, Uttar Pradesh, India. [Wainer, Zoe] Univ Melbourne, St Vincents Hosp, Dept Surg, Melbourne, Vic, Australia. [Yap, Mei Ling] Univ New South Wales, Ingham Inst Appl Med Res, Liverpool, NSW, Australia. [Yap, Mei Ling] Univ Western Sydney, Liverpool Canc Therapy Ctr, Campbelltown, NSW, Australia. [Yap, Mei Ling] Univ Western Sydney, Macarthur Canc Therapy Ctr, Campbelltown, NSW, Australia. RP Ilbawi, AM (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. EM ilbawia@who.int NR 10 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD FEB PY 2017 VL 18 IS 2 BP 172 EP 175 PG 5 WC Oncology SC Oncology GA EN9TR UT WOS:000396343000033 ER PT J AU Plimack, ER Bellmunt, J Gupta, S Berger, R Chow, LQM Juco, J Lunceford, J Saraf, S Perini, RF O'Donnell, PH AF Plimack, Elizabeth R. Bellmunt, Joaquim Gupta, Shilpa Berger, Raanan Chow, Laura Q. M. Juco, Jonathan Lunceford, Jared Saraf, Sanatan Perini, Rodolfo F. O'Donnell, Peter H. TI Safety and activity of pembrolizumab in patients with locally advanced or metastatic urothelial cancer (KEYNOTE-012): a non-randomised, open-label, phase 1b study SO LANCET ONCOLOGY LA English DT Article ID CELL LUNG-CANCER; CLINICAL ACTIVITY; CTLA-4 BLOCKADE; PD-1 BLOCKADE; B7-H1 PD-L1; MELANOMA; CARCINOMA; ANTI-PD-1; IMMUNITY; TRIAL AB Background PD-1 and its ligands are expressed in urothelial cancer, and fi ndings have shown that inhibition of the PD-1 pathway has clinical benefi t. We aimed to assess the safety and activity of an anti-PD-1 antibody pembrolizumab in patients with locally advanced or metastatic urothelial cancer. Methods This study was part of the non-randomised, multi-cohort, open-label, phase 1b KEYNOTE-012 basket trial. We enrolled patients aged 18 years and older with a histologically or cytologically confi rmed diagnosis of locally advanced or metastatic urothelial cancer, including cancers of the renal pelvis, ureter, bladder, or urethra, from eight hospitals in the USA and Israel. Patients were required to have at least 1% PD-L1 expression detected on the tumour cells or in tumour stroma, as determined by immunohistochemistry. Patients were given 10 mg/kg intravenous pembrolizumab every 2 weeks until disease progression, unacceptable toxic eff ects, or the end of the study (ie, 24 months of treatment). Primary endpoints were safety and overall response (defi ned by Response Evaluation Criteria In Solid Tumors [RECIST] version 1.1), as assessed by a masked, independent central review. Safety was assessed in patients who received one or more doses of pembrolizumab (all-patients-as-treated population); activity was assessed in patients who received pembrolizumab, had measurable disease at baseline, and had one or more post-baseline scans, or discontinued because of progressive disease or treatment-related adverse events (full analysis set). This study is registered with ClinicalTrials. gov, number NCT01848834, and is no longer enrolling patients; follow-up is ongoing. Findings Between May 14, 2013, and Dec 10, 2013, 115 patients were tissue pre-screened as part of a two-part consent process. 61 (53%) patients were PD-L1 positive, of whom 33 were enrolled in this study. All enrolled patients received at least one dose of pembrolizumab and were included in the safety analyses. 27 patients comprised the full analysis set and were deemed assessable for activity. Six patients were not assessable: three discontinued study drug because of a non-treatment-related adverse event before the fi rst post-baseline scan, two withdrew before the fi rst post-baseline scan, and one had no measurable disease at baseline. The most common treatment-related adverse events were fatigue (six [18%] of 33 patients) and peripheral oedema (4 [12%]). Five (15%) patients had 11 grade 3 treatment-related adverse events; no single event occurred in more than one patient. Three (9%) patients experienced fi ve serious treatment-related adverse events. After median follow-up of 13 months (range 1-26, IQR 5-23), an overall response was achieved in seven (26% [95% CI 11-46]) of 27 assessable patients, with three (11% [2-29]) complete and four (15% [4-34]) partial responses. Of the four deaths that occurred during the study (cardiac arrest, pneumonia, sepsis, and subarachnoid haemorrhage), none were deemed treatment related. Interpretation Pembrolizumab showed anti-tumour activity and acceptable safety in patients with advanced urothelial cancer, supporting ongoing phase 2 and 3 studies of pembrolizumab in this population. C1 [Plimack, Elizabeth R.] Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Bellmunt, Joaquim] Dana Farber Canc Inst, Boston, MA 02115 USA. [Gupta, Shilpa] Univ Minnesota, Minneapolis, MN USA. [Berger, Raanan] Chaim Sheba Med Ctr Tel Hashomer, Ramat Gan, Israel. [Chow, Laura Q. M.] Univ Washington, Seattle, WA 98195 USA. [Juco, Jonathan; Lunceford, Jared; Saraf, Sanatan; Perini, Rodolfo F.] Merck & Co Inc, Kenilworth, NJ USA. [O'Donnell, Peter H.] Univ Chicago, Chicago, IL 60637 USA. RP Plimack, ER (reprint author), Temple Hlth, Fox Chase Canc Ctr, Dept Hematol Oncol, Philadelphia, PA 19111 USA. EM elizabeth.plimack@fccc.edu FU Merck Co., Inc. FX Merck & Co., Inc. NR 30 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD FEB PY 2017 VL 18 IS 2 BP 212 EP 220 DI 10.1016/S1470-2045(17)30007-4 PG 9 WC Oncology SC Oncology GA EN9TR UT WOS:000396343000047 PM 28081914 ER PT J AU Seymour, JF Ma, S Brander, DM Choi, MY Barrientos, J Davids, MS Anderson, MA Beaven, AW Rosen, ST Tam, CS Prine, B Agarwal, SK Munasinghe, W Zhu, M Lash, LL Desai, M Cerri, E Verdugo, M Kim, SY Humerickhouse, RA Gordon, GB Kipps, TJ Roberts, AW AF Seymour, John F. Ma, Shuo Brander, Danielle M. Choi, Michael Y. Barrientos, Jacqueline Davids, Matthew S. Anderson, Mary Ann Beaven, Anne W. Rosen, Steven T. Tam, Constantine S. Prine, Betty Agarwal, Suresh K. Munasinghe, Wijith Zhu, Ming Lash, L. Leanne Desai, Monali Cerri, Elisa Verdugo, Maria Kim, Su Young Humerickhouse, Rod A. Gordon, Gary B. Kipps, Thomas J. Roberts, Andrew W. TI Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study SO LANCET ONCOLOGY LA English DT Article ID BCL2 INHIBITOR NAVITOCLAX; LYMPHOID MALIGNANCIES; UNTREATED PATIENTS; ANTITUMOR-ACTIVITY; DOSE-ESCALATION; OPEN-LABEL; FLUDARABINE; CANCER; CYCLOPHOSPHAMIDE; PHARMACOKINETICS AB Background Selective BCL2 inhibition with venetoclax has substantial activity in patients with relapsed or refractory chronic lymphocytic leukaemia. Combination therapy with rituximab enhanced activity in preclinical models. The aim of this study was to assess the safety, pharmacokinetics, and activity of venetoclax in combination with rituximab. Methods Adult patients with relapsed or refractory chronic lymphocytic leukaemia (according to the 2008 Modifi ed International Workshop on CLL guidelines) or small lymphocytic lymphoma were eligible for this phase 1b, dose-escalation trial. The primary outcomes were to assess the safety profi le, to determine the maximum tolerated dose, and to establish the recommended phase 2 dose of venetoclax when given in combination with rituximab. Secondary outcomes were to assess the pharmacokinetic profi le and analyse effi cacy, including overall response, duration of response, and time to tumour progression. Minimal residual disease was a protocol-specifi ed exploratory objective. Central review of the endpoints was not done. Venetoclax was dosed daily using a stepwise escalation to target doses (200-600 mg) and then monthly rituximab commenced (375 mg/m(2) in month 1 and 500 mg/m(2) in months 2-6). Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for adverse events version 4.0. Protocol-guided drug cessation was allowed for patients who achieved complete response (including complete response with incomplete marrow recovery) or negative bone marrow minimal residual disease. Analyses were done per protocol for all patients who commenced drug and included all patients who received at least one dose of venetoclax. Data were pooled across dose cohorts. Patients are still receiving therapy and follow-up is ongoing. The trial is registered at ClinicalTrials. gov, number NCT01682616. Findings Between Aug 6, 2012, and May 28, 2014, we enrolled 49 patients. Common grade 1-2 toxicities included upper respiratory tract infections (in 28 [57%] of 49 patients), diarrhoea (27 [55%]), and nausea (25 [51%]). Grade 3-4 adverse events occurred in 37 (76%) of 49 patients; most common were neutropenia (26 [53%]), thrombocytopenia (eight [16%]), anaemia (seven [14%]), febrile neutropenia (six [12%]), and leucopenia (six [12%]). The most common serious adverse events were pyrexia (six [12%]), febrile neutropenia (fi ve [10%]), lower respiratory tract infection, and pneumonia (each three [6%]). Clinical tumour lysis syndrome occurred in two patients (resulting in one death) who initiated venetoclax at 50 mg. After enhancing tumour lysis syndrome prophylaxis measures and commencing venetoclax at 20 mg, clinical tumour lysis syndrome did not occur. The maximum tolerated dose was not identifi ed; the recommended phase 2 dose of venetoclax in combination with rituximab was 400 mg. Overall, 42 (86%) of 49 patients achieved a response, including a complete response in 25 (51%) of 49 patients. 2 year estimates for progression-free survival and ongoing response were 82% (95% CI 66-91) and 89% (95% CI 72-96), respectively. Negative marrow minimal residual disease was attained in 20 (80%) of 25 complete responders and 28 (57%) of 49 patients overall. 13 responders ceased all therapy; among these all 11 minimal residual disease-negative responders remain progression-free off therapy. Two with minimal residual disease-positive complete response progressed after 24 months off therapy and re-attained response after re-initiation of venetoclax. Interpretation A substantial proportion of patients achieved an overall response with the combination of venetoclax and rituximab including 25 (51%) of 49 patients who achieved a complete response and 28 (57%) of 49 patients who achieved negative marrow minimal residual disease with acceptable safety. The depth and durability of responses observed with the combination off ers an attractive potential treatment option for patients with relapsed or refractory chronic lymphocytic leukaemia and could allow some patients to maintain response after discontinuing therapy, a strategy that warrants further investigation in randomised studies. C1 [Seymour, John F.; Tam, Constantine S.] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Seymour, John F.; Tam, Constantine S.; Roberts, Andrew W.] Victorian Comprehens Canc Ctr, Melbourne, Vic, Australia. [Seymour, John F.; Tam, Constantine S.; Roberts, Andrew W.] Univ Melbourne, Fac Med, Melbourne, Vic, Australia. [Ma, Shuo] Northwestern Univ, Feinberg Sch Med, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Brander, Danielle M.; Beaven, Anne W.] Duke Univ, Med Ctr, Durham, NC USA. [Choi, Michael Y.; Kipps, Thomas J.] Univ Calif San Diego, San Diego, CA 92103 USA. [Barrientos, Jacqueline] Hofstra Northwell Sch Med, Hempstead, NY USA. [Davids, Matthew S.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Anderson, Mary Ann; Roberts, Andrew W.] Royal Melbourne Hosp, Dept Clin Haematol & BMT, Melbourne, Vic, Australia. [Anderson, Mary Ann; Roberts, Andrew W.] Walter & Eliza Hall Inst Med Res, Div Canc & Haematol, Melbourne, Vic, Australia. [Rosen, Steven T.] City Hope Natl Med Ctr, 1500 E Duarte Rd, Duarte, CA 91010 USA. [Prine, Betty; Agarwal, Suresh K.; Munasinghe, Wijith; Zhu, Ming; Lash, L. Leanne; Desai, Monali; Cerri, Elisa; Verdugo, Maria; Kim, Su Young; Humerickhouse, Rod A.; Gordon, Gary B.] AbbVie Inc, N Chicago, IL USA. RP Seymour, JF (reprint author), Peter MacCallum Canc Ctr, Dept Haematol, 305 Grattan St, Melbourne, Vic 3000, Australia. EM john.seymour@petermac.org FU AbbVie Inc; Genentech Inc. FX AbbVie Inc and Genentech Inc. NR 23 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 FEB PY 2017 VL 18 IS 2 BP 230 EP 240 DI 10.1016/S1470-2045(17)30012-8 PG 11 WC Oncology SC Oncology GA EN9TR UT WOS:000396343000049 PM 28089635 ER PT J AU Dimopoulos, MA Trotman, J Tedeschi, A Matous, JRV Macdonald, D Tam, C Tournilhac, O Ma, S Oriol, A Heffner, LT Shustik, C Garcia-Sanz, R Cornell, RF de Larrea, CF Castillo, JJ Granell, M Kyrtsonis, MC Leblond, V Symeonidis, A Kastritis, E Singh, P Li, JL Graef, T Bilotti, E Treon, S Buske, C AF Dimopoulos, Meletios A. Trotman, Judith Tedeschi, Alessandra Matous, Jeff Rey V. Macdonald, David Tam, Constantine Tournilhac, Olivier Ma, Shuo Oriol, Albert Heffner, Leonard T. Shustik, Chaim Garcia-Sanz, Ramon Cornell, Robert F. de Larrea, Carlos Fernandez Castillo, Jorge J. Granell, Miquel Kyrtsonis, Marie-Christine Leblond, Veronique Symeonidis, Argiris Kastritis, Efstathios Singh, Priyanka Li, Jianling Graef, Thorsten Bilotti, Elizabeth Treon, Steven Buske, Christian CA iNNOVATE Study Grp European Consortium Waldenstroms TI Ibrutinib for patients with rituximab-refractory Waldenstrm's macro globulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial SO LANCET ONCOLOGY LA English DT Article ID CONSENSUS PANEL RECOMMENDATIONS; MACROGLOBULINEMIA; MYD88; THERAPY; BORTEZOMIB; MUTATIONS; SURVIVAL; WORKSHOP; LYMPHOMA; TARGET AB Background In the era of widespread rituximab use for Waldenstrm's macro globulinaemia, new treatment options for patients with rituximab-refractory disease are an important clinical need. Ibrutinib has induced durable responses in previously treated patients with Waldenstrm's macro globulinaemia. We assessed the effi cacy and safety of ibrutinib in a population with rituximab-refractory disease. Methods This multicentre, open-label substudy was done at 19 sites in seven countries in adults aged 18 years and older with confi rmed Waldenstrm's macro globulinaemia, refractory to rituximab and requiring treatment. Disease refractory to the last rituximab-containing therapy was defi ned as either relapse less than 12 months since last dose of rituximab or failure to achieve at least a minor response. Key exclusion criteria included: CNS involvement, a stroke or intracranial haemorrhage less than 12 months before enrolment, clinically signifi cant cardiovascular disease, hepatitis B or hepatitis C viral infection, and a known bleeding disorder. Patients received oral ibrutinib 420 mg once daily until progression or unacceptable toxicity. The substudy was not prospectively powered for statistical comparisons, and as such, all the analyses are descriptive in nature. This study objectives were the proportion of patients with an overall response, progression-free survival, overall survival, haematological improvement measured by haemoglobin, time to next treatment, and patient-reported outcomes according to the Functional Assessment of Cancer TherapyAnemia (FACT-An) and the Euro Qol 5 Dimension Questionnaire (EQ-5D-5L). All analyses were per protocol. The study is registered at ClinicalTrials. gov, number NCT02165397, and follow-up is ongoing but enrolment is complete. Findings Between Aug 18, 2014, and Feb 18, 2015, 31 patients were enrolled. Median age was 67 years (IQR 58-74); 13 (42%) of 31 patients had high-risk disease per the International Prognostic Scoring System Waldenstrm Macroglobulinaemia, median number of previous therapies was four (IQR 2-6), and all were rituximab-refractory. At a median follow-up of 18.1 months (IQR 17.5-18.9), the proportion of patients with an overall response was 28 [90%] of 31 (22 [71%] of patients had a major response), the estimated 18 month progression-free survival rate was 86% (95% CI 66-94), and the estimated 18 month overall survival rate was 97% (95% CI 79-100). Baseline median haemoglobin of 10.3 g/dL (IQR 9.3-11.7) increased to 114 mu g/dL (10.9-12.4) after 4 weeks of ibrutinib treatment and reached 127 g/dL (11.8-13.4) at week 49. A clinically meaningful improvement from baseline in FACT-An score, anaemia subscale score, and the EQ-5D-5L were reported at all post-baseline visits. Time to next treatment will be presented at a later date. Common grade 3 or worse adverse events included neutropenia in four patients (13%), hypertension in three patients (10%), and anaemia, thrombocytopenia, and diarrhoea in two patients each (6%). Serious adverse events occurred in ten patients (32%) and were most often infections. Five (16%) patients discontinued ibrutinib: three due to progression and two due to adverse events, while the remaining 26 [84%] of patients are continuing ibrutinib at the time of this report. Interpretation The sustained responses and median progression-free survival time, combined with a manageable toxicity profi le observed with single-agent ibrutinib indicate that this chemotherapy-free approach is a potential new treatment choice for patients who had heavily pretreated, rituximab-refractory Waldenstrm's macro globulinaemia. C1 [Dimopoulos, Meletios A.; Kyrtsonis, Marie-Christine; Kastritis, Efstathios] Univ Athens, Sch Med, Athens, Greece. [Trotman, Judith] Univ Sydney, Concord Hosp, Concord, NSW, Australia. [Tedeschi, Alessandra] Osped Niguarda Ca Granda, Milan, Italy. [Matous, Jeff Rey V.] Colorado Blood Canc Inst, Denver, CO USA. [Macdonald, David] Dalhousie Univ, Halifax, NS, Canada. [Tam, Constantine] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Tam, Constantine] St Vincents Hosp, Melbourne, Vic, Australia. [Tournilhac, Olivier] CHU Clermont Ferrand, Hematol Clin Adulte & Therapie Cellulaire, Clermont Ferrand, France. [Tournilhac, Olivier] Univ Auvergne, EA 7283, Clermont Ferrand, France. [Ma, Shuo] Northwestern Univ, Feinberg Sch Med, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Oriol, Albert] Hosp Badalona Germans Trias & Pujol, Inst Catala Oncol, Barcelona, Spain. [Oriol, Albert] Hosp Badalona Germans Trias & Pujol, Inst Josep Carreras, Barcelona, Spain. [Heffner, Leonard T.] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. [Shustik, Chaim] McGill Univ, Ctr Hlth, Royal Victoria Hosp, Montreal, PQ, Canada. [Garcia-Sanz, Ramon] Hosp Univ Salamanca, Salamanca, Spain. [Cornell, Robert F.] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [de Larrea, Carlos Fernandez] Hosp Clin Barcelona, IDIBAPS, Barcelona, Spain. [Castillo, Jorge J.; Treon, Steven] Dana Farber Canc Inst, Boston, MA 02115 USA. [Granell, Miquel] Hosp Santa Creu & Sant Pau, Barcelona, Spain. [Leblond, Veronique] UPMC Univ Paris, Hop Pitie Salpetriere, AP HP, Paris, France. [Symeonidis, Argiris] Univ Patras, Sch Med, Patras, Greece. [Singh, Priyanka; Li, Jianling; Graef, Thorsten; Bilotti, Elizabeth] Pharmacyclics LLC, Sunnyvale, CA USA. [Singh, Priyanka; Li, Jianling; Graef, Thorsten; Bilotti, Elizabeth] AbbVie Co, Sunnyvale, CA USA. [Buske, Christian] Univ Hosp Ulm, Inst Expt Canc Res, Comprehens Canc Ctr Ulm, Ulm, Germany. RP Dimopoulos, MA (reprint author), Univ Athens, Dept Clin Therapeut, Sch Med, 80 Vas Sofias Ave, Athens 11528, Greece. EM mdimop@med.uoa.gr FU Pharmacyclics LLC, an AbbVie Company FX Pharmacyclics LLC, an AbbVie Company. NR 26 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 FEB PY 2017 VL 18 IS 2 BP 241 EP 250 DI 10.1016/S1470-2045(16)30632-5 PG 10 WC Oncology SC Oncology GA EN9TR UT WOS:000396343000050 PM 27956157 ER PT J AU Haroche, J Cohen-Aubart, F Rollins, BJ Donadieu, J Charlotte, F Idbaih, A Vaglio, A Abdel-Wahab, O Emile, JF Amoura, Z AF Haroche, Julien Cohen-Aubart, Fleur Rollins, Barret J. Donadieu, Jean Charlotte, Frederic Idbaih, Ahmed Vaglio, Augusto Abdel-Wahab, Omar Emile, Jean-Francois Amoura, Zahir TI Histiocytoses: emerging neoplasia behind inflammation SO LANCET ONCOLOGY LA English DT Review ID LANGERHANS-CELL HISTIOCYTOSIS; ERDHEIM-CHESTER-DISEASE; ROSAI-DORFMAN-DISEASE; DOSE INTERFERON-ALPHA; BRAF V600E MUTATION; MASSIVE LYMPHADENOPATHY; SINUS HISTIOCYTOSIS; MONOCENTRIC SERIES; HIGH PREVALENCE; CNS DISEASE AB Histiocytoses are disorders characterised by inflammation and the accumulation of cells derived from the monocyte and macrophage lineages, which results in tissue damage. Although they are often considered rare disorders with protean clinical manifestations, considerable advances in the understanding of their genetics have led to increased clinical recognition of these conditions, and fuelled further insights into their pathogenesis. In this Review, we describe insights into the cells of origin, molecular pathology, clinical features, and treatment strategies for some of the most common histiocytic disorders, including Langerhans cell histiocytosis, Erdheim-Chester disease, and Rosai-Dorfman disease. With the discovery of recurrent mutations affecting the mitogen-activated protein kinase and mTOR-AKT pathways in some of these histiocytoses, our understanding of these diseases has now evolved from the concept of a primary inflammatory condition to that of a clonal neoplastic disease. This understanding has led to the development of effective mechanism-based therapeutic strategies for patients with histiocytic diseases. C1 [Haroche, Julien; Cohen-Aubart, Fleur; Amoura, Zahir] Hop La Pitie Salpetriere, Serv Med Interne 2, Ctr Natl Reference Malad Auto Immunes Syst Rares, Inst E3M, F-75013 Paris, France. [Charlotte, Frederic] Hop La Pitie Salpetriere, AP HP, Serv Anatomocytopathol, Paris, France. [Idbaih, Ahmed] Hop La Pitie Salpetriere, AP HP, Serv Neurol Mazarin, Paris, France. [Rollins, Barret J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Donadieu, Jean] Hop Trousseau, AP HP, Serv Hematol, Paris, France. [Vaglio, Augusto] Univ Hosp, Nephrol Unit, Parma, Italy. [Abdel-Wahab, Omar] Mem Sloan Kettering Canc Ctr, Leukemia Serv, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA. [Emile, Jean-Francois] Ambroise Pare Hosp, AP HP, EA4340, Boulogne, France. [Emile, Jean-Francois] Ambroise Pare Hosp, AP HP, Dept Pathol, Boulogne, France. [Emile, Jean-Francois] Univ Versailles, Boulogne, France. RP Haroche, J (reprint author), Hop La Pitie Salpetriere, Serv Med Interne 2, Ctr Natl Reference Malad Auto Immunes Syst Rares, Inst E3M, F-75013 Paris, France. EM julien.haroche@aphp.fr FU Fondation ARC pour la recherche sur le Cancer; IntselChimos; Novartis; Hoffmann-La Roche; Beta-Innov; Lettre du Cancerologue; CArthera; Bristol-Myers Squibb; Roche; Cipla FX AI reports grants from Fondation ARC pour la recherche sur le Cancer, research support from IntselChimos, personal fees from Novartis, travel compensation from Hoffmann-La Roche, research support from Beta-Innov, personal fees from Lettre du Cancerologue, research support from CArthera, personal fees from Bristol-Myers Squibb, personal fees from Roche, and personal fees from Cipla (certified continuing education), outside the submitted work. The other authors declare no competing interests. NR 107 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD FEB PY 2017 VL 18 IS 2 BP E113 EP E125 PG 13 WC Oncology SC Oncology GA EN9TR UT WOS:000396343000019 ER PT J AU Labarca, G Jantz, MA Mehta, HJ Folch, E Majid, A Fernandez-Bussy, S AF Labarca, Gonzalo Jantz, Michael A. Mehta, Hiren J. Folch, Erik Majid, Adnan Fernandez-Bussy, Sebastian TI Is there added value in adding EUS to EBUS? SO LANCET RESPIRATORY MEDICINE LA English DT Letter ID LUNG-CANCER C1 [Labarca, Gonzalo] Univ San Sebastian, Fac Med, Concepcion, Chile. [Labarca, Gonzalo] Complejo Asistencial Dr Victor Rios Ruiz, Div Internal Med, Los Angeles 4450227, Chile. [Jantz, Michael A.; Mehta, Hiren J.] Univ Florida, Div Pulm Crit Care & Sleep Med, Gainesville, FL USA. [Folch, Erik] Harvard Med Sch, Massachusetts Gen Hosp, Div Pulm & Crit Care Med, Boston, MA USA. [Majid, Adnan] Harvard Med Sch, Div Thorac Surg, Beth Israel Deaconess Med Ctr, Boston, MA USA. [Majid, Adnan] Harvard Med Sch, Div Intervent Pulm, Beth Israel Deaconess Med Ctr, Boston, MA USA. [Fernandez-Bussy, Sebastian] Univ Desarrollo, Clin Alemana, Unidad Neumol Intervenc, Santiago, Chile. RP Labarca, G (reprint author), Univ San Sebastian, Fac Med, Concepcion, Chile.; Labarca, G (reprint author), Complejo Asistencial Dr Victor Rios Ruiz, Div Internal Med, Los Angeles 4450227, Chile. EM glabarcat@gmail.com NR 4 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 2213-2600 J9 LANCET RESP MED JI Lancet Resp. Med. PD FEB PY 2017 VL 5 IS 2 BP E8 EP E8 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA EN9WA UT WOS:000396349100001 PM 28145236 ER PT J AU Medeiros, BC Fathi, AT DiNardo, CD Pollyea, DA Chan, SM Swords, R AF Medeiros, B. C. Fathi, A. T. DiNardo, C. D. Pollyea, D. A. Chan, S. M. Swords, R. TI Isocitrate dehydrogenase mutations in myeloid malignancies SO LEUKEMIA LA English DT Review ID LEUKEMIA FRENCH ASSOCIATION; MELTING-CURVE-ANALYSIS; IDH2 MUTATIONS; MYELODYSPLASTIC SYNDROMES; PROGNOSTIC-SIGNIFICANCE; OLDER PATIENTS; MUTANT IDH2; ONCOMETABOLITE 2-HYDROXYGLUTARATE; HYPOMETHYLATING AGENTS; CLONAL HEMATOPOIESIS AB Alterations to genes involved in cellular metabolism and epigenetic regulation are implicated in the pathogenesis of myeloid malignancies. Recurring mutations in isocitrate dehydrogenase (IDH) genes are detected in approximately 20% of adult patients with acute myeloid leukemia (AML) and 5% of adults with myelodysplastic syndromes (MDS). IDH proteins are homodimeric enzymes involved in diverse cellular processes, including adaptation to hypoxia, histone demethylation and DNA modification. The IDH2 protein is localized in the mitochondria and is a critical component of the tricarboxylic acid (also called the 'citric acid' or Krebs) cycle. Both IDH2 and IDH1 (localized in the cytoplasm) proteins catalyze the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (alpha-KG). Mutant IDH enzymes have neomorphic activity and catalyze reduction of alpha-KG to the (R) enantiomer of 2-hydroxyglutarate, which is associated with DNA and histone hypermethylation, altered gene expression and blocked differentiation of hematopoietic progenitor cells. The prognostic significance of mutant IDH (mIDH) is controversial but appears to be influenced by co-mutational status and the specific location of the mutation (IDH1-R132, IDH2-R140, IDH2-R172). Treatments specifically or indirectly targeted to mIDH are currently under clinical investigation; these therapies have been generally well tolerated and, when used as single agents, have shown promise for inducing responses in some mIDH patients when used as first-line treatment or in relapsed or refractory AML or MDS. Use of mIDH inhibitors in combination with drugs with non-overlapping mechanisms of action is especially promising, as such regimens may address the clonal heterogeneity and the multifactorial pathogenic processes involved in mIDH myeloid malignancies. Advances in mutational analysis have made testing more rapid and convenient, and less expensive; such testing should become part of routine diagnostic workup and repeated at relapse to identify patients who may benefit from treatments that target mIDH. C1 [Medeiros, B. C.] Stanford Univ, Sch Med, Stanford Canc Ctr, Div Hematol,Dept Med, 875 Blake Wilbur Dr,MC 5821, Stanford, CA 94305 USA. [Fathi, A. T.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [DiNardo, C. D.] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA. [Pollyea, D. A.] Univ Colorado, Sch Med, Div Hematol, Aurora, CO USA. [Chan, S. M.] Princess Margaret Canc Ctr, Toronto, ON, Canada. [Swords, R.] Univ Miami, Sylvester Comprehens Canc Ctr, Miami, FL USA. RP Medeiros, BC (reprint author), Stanford Univ, Sch Med, Stanford Canc Ctr, Div Hematol,Dept Med, 875 Blake Wilbur Dr,MC 5821, Stanford, CA 94305 USA. EM Bruno.medeiros@stanford.edu FU Celgene Corporation FX We received editorial support during manuscript development from Sheila Truten and Kelly Dittmore of MC2 Inc., Wynnewood, PA, USA who were funded by Celgene Corporation. Celgene did not contribute to content or participate in development of this paper. The authors are fully responsible for all content and editorial decisions. NR 105 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD FEB PY 2017 VL 31 IS 2 BP 272 EP 281 DI 10.1038/leu.2016.275 PG 10 WC Oncology; Hematology SC Oncology; Hematology GA EK6UE UT WOS:000394058800002 PM 27721426 ER PT J AU Verstovsek, S Talpaz, M Ritchie, E Wadleigh, M Odenike, O Jamieson, C Stein, B Uno, T Mesa, RA AF Verstovsek, S. Talpaz, M. Ritchie, E. Wadleigh, M. Odenike, O. Jamieson, C. Stein, B. Uno, T. Mesa, R. A. TI A phase I, open-label, dose-escalation, multicenter study of the JAK2 inhibitor NS-018 in patients with myelofibrosis SO LEUKEMIA LA English DT Article ID INTERNATIONAL-WORKING-GROUP; C-REACTIVE PROTEIN; TREATMENT IWG-MRT; ESSENTIAL THROMBOCYTHEMIA MYELOFIBROSIS; BONE-MARROW FIBROSIS; JANUS KINASE 2; MYELOPROLIFERATIVE NEOPLASMS; MYELOID METAPLASIA; POLYCYTHEMIA-VERA; AVAILABLE THERAPY AB NS-018 is a Janus-activated kinase 2 (JAK2)-selective inhibitor, targeting the JAK-signal transducer and activator of transcription (STAT) pathway that is deregulated in myelofibrosis. In this phase I, dose-escalation portion of a phase I/II study, patients with myelofibrosis received oral NS-018 in continuous 28-day cycles. The primary study objective was to evaluate safety, tolerability and clinically active dose of NS-018. Forty-eight patients were treated; 23 (48%) had previously received a JAK inhibitor (JAKi). The most common drug-related adverse events were thrombocytopenia (27%)/anemia (15%) for hematologic events, and dizziness (23%)/nausea (19%) for non-hematologic events. Once daily NS-018 at 300 mg was chosen as the phase II study dose based on improved tolerability compared with higher doses. A >= 50% reduction in palpable spleen size was achieved in 56% of patients (47% of patients with prior JAKi treatment), and improvements were observed in myelofibrosis-associated symptoms. Bone marrow fibrosis grade (local assessment) improved from baseline in 11/30 evaluable patients (37%) after 3 cycles of NS-018. JAK2 allele burden was largely unchanged. Changes in cytokine/protein levels were noted after 4 weeks of treatment. NS-018 reached peak plasma concentration in 1-2 h and did not accumulate with multiple dosing. NS-018 will be assessed in patients with previous JAKi exposure in the phase II portion. C1 [Verstovsek, S.] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA. [Talpaz, M.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Ritchie, E.] Cornell Univ, Div Hematol & Med Oncol, New York, NY USA. [Wadleigh, M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Odenike, O.] Univ Chicago, Med Ctr, Chicago, IL 60637 USA. [Jamieson, C.] Univ Calif San Diego, Moores Canc Ctr, San Diego, CA 92103 USA. [Stein, B.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Uno, T.] NS Pharma Inc, Paramus, NJ USA. [Mesa, R. A.] Mayo Clin, Scottsdale, AZ USA. RP Verstovsek, S (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA. EM sverstov@mdanderson.org FU NS Pharma, Inc. FX We thank Taishi Yamashita of NS Pharma, Inc. and Thomas J Myers and Linda J Paradiso of Strategia Therapeutics, Inc. for their data analysis, manuscript preparation and critical review. The authors received editorial and writing support from Adelphi Communications Ltd, funded by NS Pharma, Inc. NR 54 TC 3 Z9 3 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD FEB PY 2017 VL 31 IS 2 BP 393 EP 402 DI 10.1038/leu.2016.215 PG 10 WC Oncology; Hematology SC Oncology; Hematology GA EK6UE UT WOS:000394058800015 PM 27479177 ER PT J AU Smith, MR Hong, F Li, H Gordon, L Gascoyne, RD Paietta, EM Advani, RH Forero-Torres, A Horning, SJ Kahl, BS AF Smith, M. R. Hong, F. Li, H. Gordon, L. I. Gascoyne, R. D. Paietta, E. M. Advani, R. H. Forero-Torres, A. Horning, S. J. Kahl, B. S. TI Mantle cell lymphoma initial therapy with abbreviated R-CHOP followed by Y-90-ibritumomab tiuxetan: 10-year follow-up of the phase 2 ECOG-ACRIN study E1499 SO LEUKEMIA LA English DT Letter ID 1ST-LINE TREATMENT; MULTICENTER TRIAL; MTX/ARA-C; RITUXIMAB; IMMUNOCHEMOTHERAPY; METHOTREXATE; CYTARABINE; SURVIVAL C1 [Smith, M. R.] Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Hong, F.; Li, H.] ECOG ACRIN Biostat Ctr, Dana Farber Canc Inst, Boston, MA USA. [Gordon, L. I.] Northwestern Univ, Chicago, IL 60611 USA. [Gascoyne, R. D.] British Columbia Canc Agcy, Vancouver, BC, Canada. [Paietta, E. M.] Montefiore Med Ctr, 111 E 210th St, Bronx, NY 10467 USA. [Advani, R. H.; Horning, S. J.] Stanford Univ, Stanford, CA 94305 USA. [Forero-Torres, A.] Univ Alabama Birmingham, Birmingham, AL USA. [Kahl, B. S.] Univ Wisconsin, Madison, WI USA. [Smith, M. R.] Cleveland Clin Fdn, 9500 Euclid Ave, Cleveland, OH 44195 USA. [Horning, S. J.] Genentech Inc, San Francisco, CA 94080 USA. [Kahl, B. S.] Washington Univ, Sch Med, St Louis, MO USA. RP Smith, MR (reprint author), Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA.; Smith, MR (reprint author), Cleveland Clin Fdn, 9500 Euclid Ave, Cleveland, OH 44195 USA. EM Smithm14@ccf.org FU Public Health Service [CA180794, CA180820, CA180853, CA189859, CA180816, CA180855, CA180799]; National Cancer Institute, National Institutes of Health and the Department of Health and Human Services FX This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L Comis, MD and Mitchell D Schnall, MD, PhD, Group Co-Chairs) and supported in part by Public Health Service Grants CA180794, CA180820, CA180853, CA189859, CA180816, CA180855, CA180799, and from the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services. Its content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. 90Y-ibritumomab tiuxetan was supplied by Spectrum Pharmaceuticals. NR 15 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD FEB PY 2017 VL 31 IS 2 BP 517 EP 519 DI 10.1038/leu.2016.305 PG 4 WC Oncology; Hematology SC Oncology; Hematology GA EK6UE UT WOS:000394058800031 PM 27780968 ER PT J AU McCarthy, CJ Thabet, A Yamada, K Mueller, PR Vagefi, PA AF McCarthy, Colin J. Thabet, Ashraf Yamada, Kei Mueller, Peter R. Vagefi, Parsia A. TI Percutaneous Creation of Biliary-Enteric Neoanastomosis for Anastomotic Biliary Occlusion Following Living Donor Liver Transplantation SO LIVER TRANSPLANTATION LA English DT Letter C1 [McCarthy, Colin J.; Thabet, Ashraf; Yamada, Kei; Mueller, Peter R.] Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St,GRB 293, Boston, MA 02114 USA. [Vagefi, Parsia A.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP McCarthy, CJ (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St,GRB 293, Boston, MA 02114 USA. EM colin.mccarthy@mgh.harvard.edu NR 4 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1527-6465 EI 1527-6473 J9 LIVER TRANSPLANT JI Liver Transplant. PD FEB PY 2017 VL 23 IS 2 BP 262 EP 265 DI 10.1002/lt.24674 PG 4 WC Gastroenterology & Hepatology; Surgery; Transplantation SC Gastroenterology & Hepatology; Surgery; Transplantation GA EK5DD UT WOS:000393946200015 PM 27862931 ER PT J AU Fang, YJ Zhao, L Xiao, HP Cook, KM Bai, Q Herrick, EJ Chen, XH Qin, CL Zhu, ZW Wakefield, MR Nicholl, MB AF Fang, Yujiang Zhao, Lei Xiao, Huaping Cook, Kathryn M. Bai, Qian Herrick, Elizabeth J. Chen, Xuhui Qin, Chenglu Zhu, Ziwen Wakefield, Mark R. Nicholl, Michael B. TI IL-33 acts as a foe to MIA PaCa-2 pancreatic cancer SO MEDICAL ONCOLOGY LA English DT Article DE IL-33; Apoptosis; Proliferation ID THYROID EPITHELIAL-CELLS; EXPERIMENTAL AUTOIMMUNE-THYROIDITIS; INDUCED ARTHRITIS; TUMOR-GROWTH; MICE; APOPTOSIS; PATHWAY; ST2; PROTEIN; T1/ST2 AB IL-33 is a member of the IL-1 family of cytokines, and no study has been performed to address its direct anti-tumor effect. This study is designed to investigate whether IL-33 has any direct effect on pancreatic cancer. Clonogenic survival assay, immunohistochemistry, TUNEL staining, proliferation, caspase-3 activity kits and RT-PCR were used to evaluate the effects of IL-33 on cell survival, proliferation and apoptosis of a pancreatic cancer cell line, MIA PaCa-2. We found that the percentage of colonies of MIA PaCa-2 cells, PCNA+ cells and the OD value of cancer cells were all decreased in the presence of IL-33. TUNEL+ cells and the relative caspase-3 activity in cancer cells were increased in the presence of IL-33. We further found that its anti-proliferative effect on cancer cells correlated with downregulation of pro-proliferative molecules cdk2 and cdk4 and upregulation of anti-proliferative molecules p15, p21 and p53. Its pro-apoptotic effect correlated with downregulation of anti-apoptotic molecule FLIP and upregulation of pro-apoptotic molecule TRAIL. These results suggest that IL-33 presents significant anti-tumor effects by inhibition of proliferation and induction of apoptosis of MIA PaCa-2 pancreatic cancer cells. Thus, strength of IL-33/ST2 signal pathway might be a promising way to treat pancreatic cancer. C1 [Fang, Yujiang; Xiao, Huaping; Chen, Xuhui] Des Moines Univ, Coll Osteopath Med, Dept Microbiol Immunol & Pathol, Des Moines, IA 50312 USA. [Fang, Yujiang; Cook, Kathryn M.; Bai, Qian; Herrick, Elizabeth J.; Qin, Chenglu; Zhu, Ziwen; Wakefield, Mark R.; Nicholl, Michael B.] Univ Missouri, Sch Med, Dept Surg, Columbia, MO 65212 USA. [Zhao, Lei] Anhui Med Univ, Affiliated Hosp 1, Dept Infect Dis, Hefei, Anhui, Peoples R China. [Nicholl, Michael B.] South Texas Vet Hlth Care Syst, Dept Surg, 7400 Merton Minter Blvd, San Antonio, TX 78229 USA. [Xiao, Huaping] Xiangnan Univ, Affiliated Hosp, Chenzhou, Hunan, Peoples R China. [Chen, Xuhui; Qin, Chenglu] Luohu Hosp, Shenzhen, Peoples R China. RP Fang, YJ (reprint author), Des Moines Univ, Coll Osteopath Med, Dept Microbiol Immunol & Pathol, Des Moines, IA 50312 USA.; Fang, YJ; Nicholl, MB (reprint author), Univ Missouri, Sch Med, Dept Surg, Columbia, MO 65212 USA.; Nicholl, MB (reprint author), South Texas Vet Hlth Care Syst, Dept Surg, 7400 Merton Minter Blvd, San Antonio, TX 78229 USA. EM yujiang.fang@dmu.edu; michaelnicholl@gmail.com FU Des Moines University [ISF 16-8, IOER 05-14-01, IOER 112-3749, IOER 112-3104]; University of Missouri FX This study was partially supported by grants from Des Moines University for Yujiang Fang (Iowa Science Foundation Grant ISF 16-8, IOER 05-14-01, IOER 112-3749 and IOER 112-3104). This study was also supported by a grant from University of Missouri for Michael B. Nicholl and Yujiang Fang. NR 50 TC 0 Z9 0 U1 2 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1357-0560 EI 1559-131X J9 MED ONCOL JI Med. Oncol. PD FEB PY 2017 VL 34 IS 2 AR 23 DI 10.1007/s12032-016-0880-3 PG 9 WC Oncology SC Oncology GA EK1MF UT WOS:000393689000009 PM 28058630 ER PT J AU Mossman, JA Tross, JG Jourjine, NA Li, N Wu, ZJ Rand, DM AF Mossman, Jim A. Tross, Jennifer G. Jourjine, Nick A. Li, Nan Wu, Zhijin Rand, David M. TI Mitonuclear Interactions Mediate Transcriptional Responses to Hypoxia in Drosophila SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Article DE mtDNA; epistasis; hypoxia; G x G x E; Drosophila; transcriptome; mitonuclear ID INDUCIBLE FACTOR-I; GENE-EXPRESSION; MITOCHONDRIAL-DNA; HIF-ALPHA; RNA-SEQ; OXIDATIVE-PHOSPHORYLATION; INTERPOPULATION HYBRIDS; SUCCINATE-DEHYDROGENASE; MISSING HERITABILITY; COMPLEX-III AB Among the major challenges in quantitative genetics and personalized medicine is to understand how gene x gene interactions (G x G: epistasis) and gene x environment interactions (G x E) underlie phenotypic variation. Here, we use the intimate relationship between mitochondria and oxygen availability to dissect the roles of nuclear DNA (nDNA) variation, mitochondrial DNA (mtDNA) variation, hypoxia, and their interactions on gene expression in Drosophila melanogaster. Mitochondria provide an important evolutionary and medical context for understanding G x G andG x E given their central role in integrating cellular signals. We hypothesized that hypoxia would alter mitonuclear communication and gene expression patterns. We show that first order nDNA, mtDNA, and hypoxia effects vary between the sexes, along with mitonuclear epistasis and G x G x E effects. Females were generally more sensitive to genetic and environmental perturbation. While dozens to hundreds of genes are altered by hypoxia in individual genotypes, we found very little overlap among mitonuclear genotypes for genes that were significantly differentially expressed as a consequence of hypoxia; excluding the gene hairy. Oxidative phosphorylation genes were among the most influenced by hypoxia and mtDNA, and exposure to hypoxia increased the signature of mtDNA effects, suggesting retrograde signaling between mtDNA and nDNA. We identified nDNA-encoded genes in the electron transport chain (succinate dehydrogenase) that exhibit female-specific mtDNA effects. Our findings have important implications for personalized medicine, the sex-specific nature of mitonuclear communication, and gene x gene coevolution under variable or changing environments. C1 [Mossman, Jim A.; Tross, Jennifer G.; Jourjine, Nick A.; Rand, David M.] Brown Univ, Dept Ecol & Evolutionary Biol, Box G, Providence, RI 02912 USA. [Tross, Jennifer G.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Tross, Jennifer G.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Tross, Jennifer G.] Harvard Med Sch, Harvard MIT Div Hlth Sci & Technol, Boston, MA USA. [Jourjine, Nick A.] Univ Calif Berkeley, Dept Mol & Cell Biol, 229 Stanley Hall, Berkeley, CA 94720 USA. [Li, Nan; Wu, Zhijin] Brown Univ, Dept Biostat, Providence, RI 02912 USA. RP Mossman, JA; Rand, DM (reprint author), Brown Univ, Dept Ecol & Evolutionary Biol, Box G, Providence, RI 02912 USA. EM Jim_Mossman@brown.edu; david_rand@brown.edu FU National Institutes of Health [R01-GM067862, AG027849] FX We gratefully thank Christoph Schorl for assistance in the processing of RNA-seq libraries, and Mark Howison for demultiplexing the samples. Leann Biancani provided assistance with fly husbandry. We thank A.M. Hernandez for critical comments on the manuscript. This work was conducted using computational resources and services at the Center for Computation and Visualization, Brown University. This work was supported by National Institutes of Health grants R01-GM067862 and AG027849 to DMR. NR 120 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0737-4038 EI 1537-1719 J9 MOL BIOL EVOL JI Mol. Biol. Evol. PD FEB PY 2017 VL 34 IS 2 BP 447 EP 466 DI 10.1093/molbev/msw246 PG 20 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA EO2FF UT WOS:000396511300013 PM 28110272 ER PT J AU Walline, HM Carey, TE Goudsmit, CM Bellile, EL D'Souza, G Peterson, LA McHugh, JB Pai, SI Lee, JJ Shin, DM Ferris, RL AF Walline, Heather M. Carey, Thomas E. Goudsmit, Christine M. Bellile, Emily L. D'Souza, Gypsyamber Peterson, Lisa A. McHugh, Jonathan B. Pai, Sara I. Lee, J. Jack Shin, Dong M. Ferris, Robert L. CA HNC SPORE HIV Supplement TI High-Risk HPV, Biomarkers, and Outcome in Matched Cohorts of Head and Neck Cancer Patients Positive and Negative for HIV SO MOLECULAR CANCER RESEARCH LA English DT Article ID SQUAMOUS-CELL CARCINOMA; HUMAN-PAPILLOMAVIRUS INFECTION; CERVICAL-CANCER; ANTIRETROVIRAL THERAPY; OROPHARYNGEAL CANCER; UNITED-STATES; INDIVIDUALS; SURVIVAL; DISEASE; P16 AB In this study, high-risk HPV (hrHPV) incidence, prognostic biomarkers, and outcome were assessed in HIV-positive (case) and HIV-negative (control) patients with head and neck squamous cell cancer (HNSCC). HIV-positive cases were matched to controls by tumor site, sex, and age at cancer diagnosis. A tissue microarray (TMA) was constructed and DNA isolated from tumor tissue. MultiPlex-PCR MassArray, L1-PCR, and in situ hybridization were used to assess hrHPV. TMA sections were stained for p16ink4a, TP53, RB, CCND1, EGFR, and scored for intensity and proportion of positive tumor cells. The HNSCC cohort included 41 HIV-positive cases and 41 HIV-negative controls. Tumors from 11 of 40 (28%) cases, and 10 of 41 (24%) controls contained hrHPV. p16 expression, indicative of E7 oncogene activity, was present in 10 of 11 HPV-positive cases and 7 of 10 HPV-positive controls. Low p16 and high TP53 expression in some HPV-positive tumors suggested HPV-independent tumorigenesis. Survival did not differ in cases and controls. RB expression was significantly associated with poor survival (P = 0.01). High TP53 expression exhibited a trend for poorer survival (P = 0.12), but among cases, association with poor survival reached statistical significance (P = 0.04). The proportion of HPV-positive tumors was similar, but the heterogeneity of HPV types was higher in the HIV-positive cases than in HIV-negative controls. High RB expression predicted poor survival, and high TP53 expression was associated with poorer survival in the HIV-positive cases but not HIV-negative controls. (C) 2016 AACR. C1 [Walline, Heather M.; Carey, Thomas E.; Goudsmit, Christine M.] Univ Michigan, Dept Otolaryngol Head & Neck Surg, Ann Arbor, MI 48109 USA. [Walline, Heather M.] Univ Michigan, Canc Biol Training Program, Ann Arbor, MI 48109 USA. [Bellile, Emily L.] Univ Michigan, Biostat Core, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [D'Souza, Gypsyamber] Johns Hopkins Univ, Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Peterson, Lisa A.] Univ Michigan, Ctr Canc, Head & Neck SPORE, Ann Arbor, MI 48109 USA. [McHugh, Jonathan B.] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Pai, Sara I.] Johns Hopkins Univ, Dept Otolaryngol Head & Neck Surg, Baltimore, MD USA. [Lee, J. Jack] MD Anderson Canc Ctr, Dept Biostat, Houston, TX USA. [Shin, Dong M.] Emory Univ, Dept Med, Med Oncol Winship Canc Ctr, Atlanta, GA 30322 USA. [Ferris, Robert L.] Univ Pittsburgh, Dept Otolaryngol Head & Neck Surg, Pittsburgh, PA USA. [Pai, Sara I.] Harvard Univ, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02115 USA. RP Carey, TE (reprint author), Univ Michigan, Med Sci 5311, 1150 West Med Ctr Dr, Ann Arbor, MI 48109 USA. EM Careyte@umich.edu FU NCI HIV; ARRA: University of Michigan [P50 CA097248 R01 CA194536]; University of Michigan Cancer Center Core Grant [P30 CA46592]; MD Anderson: [5P50 CA097007]; University of Pittsburgh [P50 CA097190]; Johns Hopkins University [P50 DE019032, 3P50 DE019032-14S2]; Emory University [R01 DE021395, P50 CA128613, P50 CA128613-02S1] FX This work was supported by the NCI HIV Supplement to the Head and Neck SPORE Consortium. This study was also supported by grants to the following institutions: ARRA: University of Michigan: P50 CA097248 R01 CA194536 (to T. Carey); University of Michigan Cancer Center Core Grant P30 CA46592; MD Anderson: 5P50 CA097007; University of Pittsburgh: P50 CA097190; Johns Hopkins University, P50 DE019032 and 3P50 DE019032-14S2; Emory University: P50 CA128613, R01 DE021395 (to G. D'Souza), P50 CA128613, and P50 CA128613-02S1. NR 32 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 EI 1557-3125 J9 MOL CANCER RES JI Mol. Cancer Res. PD FEB PY 2017 VL 15 IS 2 BP 179 EP 188 DI 10.1158/1541-7786.MCR-16-0255 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EK4IB UT WOS:000393889200006 PM 27899422 ER PT J AU Smith, JD Schlecht, U Xu, WH Suresh, S Horecka, J Proctor, MJ Aiyar, RS Bennett, RAO Chu, A Li, YFG Roy, K Davis, RW Steinmetz, LM Hyman, RW Levy, SF St Onge, RP AF Smith, Justin D. Schlecht, Ulrich Xu, Weihong Suresh, Sundari Horecka, Joe Proctor, Michael J. Aiyar, Raeka S. Bennett, Richard A. O. Chu, Angela Li, Yong Fuga Roy, Kevin Davis, Ronald W. Steinmetz, Lars M. Hyman, Richard W. Levy, Sasha F. St Onge, Robert P. TI A method for high-throughput production of sequence-verified DNA libraries and strain collections SO MOLECULAR SYSTEMS BIOLOGY LA English DT Article DE arrayed strain collection; CRISPR interference; DNA libraries; oligonucleotide pools; synthetic biology ID SITE-SPECIFIC RECOMBINATION; SACCHAROMYCES-CEREVISIAE; GENE-EXPRESSION; FUNCTIONAL-ANALYSIS; YEAST GENOME; PROTEIN; CRISPR; INTERFERENCE; INTEGRATION; EXPLORATION AB The low costs of array-synthesized oligonucleotide libraries are empowering rapid advances in quantitative and synthetic biology. However, high synthesis error rates, uneven representation, and lack of access to individual oligonucleotides limit the true potential of these libraries. We have developed a cost-effective method called Recombinase Directed Indexing (REDI), which involves integration of a complex library into yeast, site-specific recombination to index library DNA, and next-generation sequencing to identify desired clones. We used REDI to generate a library of similar to 3,300 DNA probes that exhibited > 96% purity and remarkable uniformity (> 95% of probes within twofold of the median abundance). Additionally, we created a collection of similar to 9,000 individually accessible CRISPR interference yeast strains for > 99% of genes required for either fermentative or respiratory growth, demonstrating the utility of REDI for rapid and cost-effective creation of strain collections from oligonucleotide pools. Our approach is adaptable to any complex DNA library, and fundamentally changes how these libraries can be parsed, maintained, propagated, and characterized. C1 [Smith, Justin D.; Schlecht, Ulrich; Xu, Weihong; Suresh, Sundari; Horecka, Joe; Proctor, Michael J.; Aiyar, Raeka S.; Chu, Angela; Li, Yong Fuga; Roy, Kevin; Davis, Ronald W.; Steinmetz, Lars M.; Hyman, Richard W.; St Onge, Robert P.] Stanford Univ, Stanford Genome Technol Ctr, Palo Alto, CA 94304 USA. [Smith, Justin D.; Roy, Kevin; Davis, Ronald W.; Steinmetz, Lars M.] Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. [Schlecht, Ulrich; Suresh, Sundari; Horecka, Joe; Proctor, Michael J.; Aiyar, Raeka S.; Chu, Angela; Davis, Ronald W.; Hyman, Richard W.; St Onge, Robert P.] Stanford Univ, Sch Med, Dept Biochem, Stanford, CA 94305 USA. [Xu, Weihong] Harvard Med Sch, Dept Surg, Boston, MA USA. [Xu, Weihong] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Bennett, Richard A. O.; Levy, Sasha F.] SUNY Stony Brook, Laufer Ctr Phys & Quantitat Biol, Stony Brook, NY 11794 USA. [Bennett, Richard A. O.; Levy, Sasha F.] SUNY Stony Brook, Dept Biochem & Cellular Biol, Stony Brook, NY 11794 USA. [Steinmetz, Lars M.] Genome Biol Unit, European Mol Biol Lab, Heidelberg, Germany. RP St Onge, RP (reprint author), Stanford Univ, Stanford Genome Technol Ctr, Palo Alto, CA 94304 USA.; St Onge, RP (reprint author), Stanford Univ, Sch Med, Dept Biochem, Stanford, CA 94305 USA. EM bstonge@stanford.edu OI Smith, Justin/0000-0003-3079-3534 FU US National Institutes of Health [P01HG000205, U01GM110706-02, R01HG008354]; Louis and Beatrice Laufer Center FX The authors are grateful to Mia Jaffe for the control strain used in Figs 3 and EV7, to Leo Parts for help with generating Table EV6, to Marie Evangelista for critically reading the manuscript, and to Billy Lau and other members of the Ji Research Group for helpful discussion. This work was supported by grants from the US National Institutes of Health (P01HG000205 to L.M.S. and R.W.D., U01GM110706-02 to R.W.D., and R01HG008354 to S.F.L.) and by the The Louis and Beatrice Laufer Center. NR 54 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1744-4292 J9 MOL SYST BIOL JI Mol. Syst. Biol. PD FEB PY 2017 VL 13 IS 2 AR 913 DI 10.15252/msb.20167233 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EK5QQ UT WOS:000393981300004 PM 28193641 ER PT J AU Hopf, TA Ingraham, JB Poelwijk, FJ Scharfe, CPI Springer, M Sander, C Marks, DS AF Hopf, Thomas A. Ingraham, John B. Poelwijk, Frank J. Scharfe, Charlotta P. I. Springer, Michael Sander, Chris Marks, Debora S. TI Mutation effects predicted from sequence co-variation SO NATURE BIOTECHNOLOGY LA English DT Article ID BETA-LACTAMASE TEM-1; FITNESS LANDSCAPE; PROTEIN FUNCTION; THERMODYNAMIC STABILITY; MOLECULAR EVOLUTION; FUNCTIONAL-ANALYSIS; GENETIC-VARIANTS; HIGH-RESOLUTION; DOMAIN; YEAST AB Many high-throughput experimental technologies have been developed to assess the effects of large numbers of mutations (variation) on phenotypes. However, designing functional assays for these methods is challenging, and systematic testing of all combinations is impossible, so robust methods to predict the effects of genetic variation are needed. Most prediction methods exploit evolutionary sequence conservation but do not consider the interdependencies of residues or bases. We present EVmutation, an unsupervised statistical method for predicting the effects of mutations that explicitly captures residue dependencies between positions. We validate EVmutation by comparing its predictions with outcomes of high-throughput mutagenesis experiments and measurements of human disease mutations and show that it outperforms methods that do not account for epistasis. EVmutation can be used to assess the quantitative effects of mutations in genes of any organism. We provide pre-computed predictions for similar to 7,000 human proteins at http://evmutation.org/. C1 [Hopf, Thomas A.; Ingraham, John B.; Scharfe, Charlotta P. I.; Springer, Michael; Marks, Debora S.] Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA. [Hopf, Thomas A.; Sander, Chris] Harvard Med Sch, Dept Cell Biol, Boston, MA USA. [Hopf, Thomas A.] Tech Univ Munich, Dept Informat, Garching, Germany. [Poelwijk, Frank J.; Sander, Chris] Dana Farber Canc Inst, cBio Ctr, Boston, MA 02115 USA. [Scharfe, Charlotta P. I.] Univ Tubingen, Dept Comp Sci, Appl Bioinformat, Tubingen, Germany. RP Marks, DS (reprint author), Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA. EM debbie@hms.harvard.edu FU NIGMS [R01GM106303]; Raymond and Beverley Sackler Foundation; NSF Graduate Research Fellowship [DGE1144152] FX The authors would like to thank A. Lapedes, B. Rost, and members of the Marks laboratory for scientific discussion, and J. Reeb for help with existing mutation prediction software. CS. was funded by NIGMS (R01GM106303). D.S.M. and T.A.H. were funded by NIGMS (R0IGM106303) and the Raymond and Beverley Sackler Foundation. J.B.I. was funded by an NSF Graduate Research Fellowship (DGE1144152). NR 66 TC 1 Z9 1 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 EI 1546-1696 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD FEB PY 2017 VL 35 IS 2 BP 128 EP 135 DI 10.1038/nbt.3769 PG 8 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA EK7BP UT WOS:000394080800018 PM 28092658 ER PT J AU Kamihara, J Ma, C Alabi, SLF Garrido, C Frazier, AL Rodriguez-Galindo, C Orjuela, MA AF Kamihara, Junne Ma, Clement Alabi, Soad Linneth Fuentes Garrido, Claudia Frazier, A. Lindsay Rodriguez-Galindo, Carlos Orjuela, Manuela A. TI Socioeconomic status and global variations in the incidence of neuroblastoma: call for support of population-based cancer registries in low-middle-income countries SO PEDIATRIC BLOOD & CANCER LA English DT Article DE cancer registries; neuroblastoma; pediatric oncology; socioeconomic status ID SUSCEPTIBILITY AB Global variations in the incidence of pediatric cancers have been described; however, the causes of such differences are not known. We investigated the relationship between the incidence of embryonal tumors and human development index on a global scale. Increasing incidence of neuroblastoma correlates significantly with an increasing index of human development, with greater incidence among countries with high socioeconomic development, in apparent contrast to the incidence of retinoblastoma. While more data are needed to corroborate this observation, our findings suggest new avenues for etiological research and serve as a call for support of population-based cancer registries in low-middle-income countries. C1 [Kamihara, Junne; Ma, Clement; Frazier, A. Lindsay] Harvard Med Sch, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA USA. [Kamihara, Junne; Ma, Clement; Frazier, A. Lindsay] Harvard Med Sch, Boston Childrens Hosp, Boston, MA USA. [Alabi, Soad Linneth Fuentes] Benjamin Bloom Natl Childrens Hosp, Dept Oncol, San Salvador, El Salvador. [Garrido, Claudia] Francisco Marroquin Med Sch, Natl Pediat Oncol Unit, Guatemala City, Guatemala. [Rodriguez-Galindo, Carlos] St Jude Childrens Res Hosp, 332 N Lauderdale St, Memphis, TN 38105 USA. [Orjuela, Manuela A.] Columbia Univ, Div Oncol, Dept Epidemiol & Pediat, New York, NY USA. RP Kamihara, J (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM junne_kamihara@dfci.harvard.edu OI Fuentes Alabi, Soad/0000-0003-4245-3537 FU NIH [CA167833, CA192662] FX The authors would like to thank P. Friedrich-Medina, MD, and A. Ricci, MD, for their input in manuscript preparation, as well as S. Bhatt Carreno and S. Block for their assistance with data management. M.A.O. is supported by NIH CA167833 and CA192662. NR 20 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD FEB PY 2017 VL 64 IS 2 BP 321 EP 323 DI 10.1002/pbc.26244 PG 3 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA EK4NM UT WOS:000393903800020 PM 27734570 ER PT J AU Quiles, CIW Gottsch, S Thakrar, U Fraile, B Billett, AL AF Quiles, Chris I. Wong Gottsch, Stephanie Thakrar, Usha Fraile, Belen Billett, Amy L. TI Health care institutional charges associated with ambulatory bloodstream infections in pediatric oncology and stem cell transplant patients SO PEDIATRIC BLOOD & CANCER LA English DT Article DE central venous line; charges; infections; length of stay; pediatric oncology; stem cell transplantation ID LENGTH-OF-STAY; ATTRIBUTABLE COST; CLABSIS; CHILDREN; CANCER AB Background: The impact of ambulatory bloodstream infections (Amb-BSIs) in pediatric oncology and stem cell transplant (PO/SCT) patients is poorly understood, although a large portion of their treatment increasingly occurs in this setting. This study aimed to understand the economic impact and length of stay (LOS) associated with these infections. Procedure: Charges and LOS were retrospectively collected and analyzed for Amb-BSI events leading to a hospital admission between 2012 and 2013 in a tertiary, university-affiliated hospital. Events were grouped as BSI-MIXED when hospitalizations with care unrelated to the infectio-nextended LOS by more than 24 hr or as BSI-PURE for all others. Billing codes were used to group charges and main drivers were analyzed. Results: Seventy-four BSI events were identified in 61 patients. Sixty-nine percent met definition for central line-associated BSI (CLABSI). Median total charge and LOS for an Amb-BSI were $40,852 (interquartile range [IQR] $44,091) and 7 days (IQR 6), respectively. Median charges for BSI-PURE group (N = 62) were $36,611 (IQR $34,785) and $ 89,935 (IQR $153,263) in the BSI-MIXED (N = 12) group. Median LOS was 6 (IQR 5) days in the BSI-PURE group and 15 (IQR 24) in the BSI-MIXED. Room, pharmacy, and procedure charges accounted for more than 70% of total charges in all groups. Conclusions: Amb-BSIs in PO/SCT patients result in significant healthcare charges and unplanned extended hospital admissions. This analysis suggests that efforts aiming at reducing rates of infections could result in substantial system savings, validating the need for increased efforts to prevent Amb-BSIs. C1 [Quiles, Chris I. Wong; Thakrar, Usha; Billett, Amy L.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Quiles, Chris I. Wong; Billett, Amy L.] Boston Childrens Hosp, Dept Med, Boston, MA USA. [Gottsch, Stephanie; Fraile, Belen] Dana Farber Canc Inst, Dept Populat Management & Value, Boston, MA 02115 USA. RP Quiles, CIW (reprint author), 450 Brookline Ave,Dana 3, Boston, MA 02215 USA. EM Chris_Wong@dfci.harvard.edu NR 16 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD FEB PY 2017 VL 64 IS 2 BP 324 EP 329 DI 10.1002/pbc.26194 PG 6 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA EK4NM UT WOS:000393903800021 ER PT J AU Samsel, C Muriel, AC AF Samsel, Chase Muriel, Anna C. TI Risk factors and treatment for steroid-related mood and behavior symptoms in preschool children with leukemia: A case series SO PEDIATRIC BLOOD & CANCER LA English DT Article DE leukemia; corticosteroids; mood; behavior; supportive care ID ACUTE LYMPHOBLASTIC-LEUKEMIA; CONSORTIUM PROTOCOL 00-01; FARBER CANCER INSTITUTE; RISPERIDONE; ADOLESCENTS; AUTISM; CORTICOSTEROIDS; DEXAMETHASONE; DISORDER AB Treatment of pediatric acute lymphoblastic leukemia (ALL) relies on systemic corticosteroids for remission; however, they can cause significant mood and behavior changes that interfere with quality of life and may increase risk for injury. This case series reports on preschool children with preexisting developmental and psychiatric risk factors who presented with behavioral side effects that required intervention. Identification of these vulnerable children may provide opportunities for early intervention, anticipatory guidance, and effective treatment to minimize behavioral side effects and improve quality of life and safety during ALL treatment. C1 [Samsel, Chase; Muriel, Anna C.] Boston Childrens Hosp, Dept Psychiat, Boston, MA USA. [Samsel, Chase; Muriel, Anna C.] Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, SW360A,450 Brookline Ave, Boston, MA 02115 USA. [Samsel, Chase; Muriel, Anna C.] Harvard Med Sch, Boston, MA USA. RP Samsel, C (reprint author), Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, SW360A,450 Brookline Ave, Boston, MA 02115 USA. EM chase_samsel@dfci.harvard.edu NR 20 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD FEB PY 2017 VL 64 IS 2 BP 343 EP 345 DI 10.1002/pbc.26220 PG 3 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA EK4NM UT WOS:000393903800024 PM 27615378 ER PT J AU Kenney, LB Melvin, P Fishman, LN O'Sullivan-Oliveira, J Sawicki, GS Ziniel, S Diller, L Fernandes, SM AF Kenney, Lisa B. Melvin, Patrice Fishman, Laurie N. O'Sullivan-Oliveira, Joanne Sawicki, Gregory S. Ziniel, Sonja Diller, Lisa Fernandes, Susan M. TI Transition and transfer of childhood cancer survivors to adult care: A national survey of pediatric oncologists SO PEDIATRIC BLOOD & CANCER LA English DT Article DE adolescents/young adults; childhood cancer survivors; transitioning ID QUALITATIVE CONTENT-ANALYSIS; YOUNG-ADULTS; HEALTH-CARE; KNOWLEDGE; ADOLESCENT; DISEASE; TRUSTWORTHINESS; PREFERENCES; READINESS; DIAGNOSIS AB Background: Pediatric oncologists are responsible for ensuring that adolescent and young adult (AYA) childhood cancer survivors have the knowledge and skills necessary to manage their followup care in adult healthcare systems. Procedures: To describe transition practices and barriers to transfer, we electronically surveyed U.S. Children's Oncology Group members: 507/1449 responded (35%) and 347/507 (68%) met eligibility criteria. Results: Of 347 respondents, 50% are male, median years in practice 10 (range 5-22), 37% practice in freestanding children's hospitals. Almost all care for survivors up to age 21 years (96%), 42% care for survivors over age 25 years, and only 16% over age 30 years. While 66% of oncologists reported providing transition education to their patients, very few (8%) reported using standardized transition assessments. The most frequent barriers to transfer were perceived attachment to provider (91%), lack of adult providerswith cancer survivor expertise (86%), patient's cognitive delay (81%), or unstable social situation (80%). Oncologistswhocontinue to care for patients older than 25 years are more likely to perceive parents' attachment to provider (P=0.037) and patients' social situation as barriers to transfer (P = 0.044). Four themes emerged from a content analysis of 75 respondents to the open-ended question inviting comments on transition/transfer practices: desire for flexible transfer criteria; providers as barriers; provider lack of transition knowledge, skills, and resources; and desire for collaboration. Conclusions: Although most pediatric oncologists reported transferring AYA cancer survivors to adult care and providing some transition education, they endorse deficits in transition skills, emotional readiness, and institutional resources. C1 [Kenney, Lisa B.; Diller, Lisa] Dana Farber Childrens Canc & Blood Disorders, Boston, MA USA. [Melvin, Patrice; Fishman, Laurie N.; O'Sullivan-Oliveira, Joanne; Sawicki, Gregory S.; Ziniel, Sonja] Boston Childrens Hosp, Boston, MA USA. [Fernandes, Susan M.] Lucile Packard Childrens Hosp Stanford, Palo Alto, CA USA. RP Kenney, LB (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,SW 311, Boston, MA 02215 USA. EM lisa_kenney@DFCI.harvard.edu NR 27 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD FEB PY 2017 VL 64 IS 2 BP 346 EP 352 DI 10.1002/pbc.26156 PG 7 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA EK4NM UT WOS:000393903800025 PM 27463688 ER PT J AU Covert, KL Mardis, CR Fleming, JN Pilch, NA Meadows, HB Mardis, BA Mohan, P Posadas-Salas, M Srinivas, T Taber, DJ AF Covert, Kelly L. Mardis, Caitlin R. Fleming, James N. Pilch, Nicole A. Meadows, Holly B. Mardis, Benjamin A. Mohan, Prince Posadas-Salas, Maria Srinivas, Titte Taber, David J. TI Development of a Predictive Model for Drug-Related Problems in Kidney Transplant Recipients SO PHARMACOTHERAPY LA English DT Article DE transplant; drug safety; outcomes; pharmacy practice; renal ID MEDICATION ERRORS; RISK-FACTORS; PHARMACIST; PATIENT; EVENTS; RECONCILIATION; PREVENTABILITY; DISCHARGE; LEVEL; TEAM AB Study ObjectiveDrug-related problems (DRPs) are associated with increased rates of infection, rejection, and graft loss in kidney transplant recipients. This study aimed to develop a model to predict which patients are at highest risk of DRPs to streamline pharmacists' workflow in a chronic kidney transplant clinic. DesignProspective observational study. SettingChronic kidney transplant clinic at a large, tertiary care, academic hospital. PatientsTwo hundred thirty-seven adults seen in the kidney transplant clinic between September 16, 2015, and November 30, 2015, who were at least 90 days posttransplantation at the time of their clinic visit. Measurements and Main ResultsProspective data detailing DRPs and a survey assessing baseline characteristics and patient-related outcomes were used to generate a predictive model to identify patients at risk of having six or more DRPs; the cutoff of six DRPs provided a threshold for identifying a subset of high-risk patients on whom the transplant pharmacists could focus their efforts. DRPs were categorized as nonadherence, overdosing or underdosing, duplication of therapy, preventable adverse drug reaction, missing medication, erroneous medication, conflicting provider information, undermonitoring or lack of monitoring, and wrong medication received. In total, 865 unique DRPs were identified, and the most common were erroneous medication, missing medication, and nonadherence, accounting for 38%, 21%, and 16% of the DRPs, respectively. A nine-variable model with a sensitivity of 62.5% and specificity of 66.7% (area under the receiver operating characteristic curve of 0.720) was developed to identify patients at risk of having six or more DRPs. The model included the following variables: age, Medicaid for prescription insurance, current employment status, medication affordability, difficulty or lack of difficulty obtaining medications from the pharmacy, negative impact of medications on quality of life, medication nonadherence, poor rating of current health status, and moderate or poor medication understanding. ConclusionThese results demonstrated that a straightforward, 5-minute survey completed by renal transplant recipients prior to their clinic visit may be capable of effectively determining those at risk of having six or more DRPs, potentially allowing use as a screening tool for transplant pharmacists' workflow prioritization. External validation is needed before this tool can be used in the outpatient setting. C1 [Covert, Kelly L.] East Tennessee State Univ, Bill Gatton Coll Pharm, Dept Pharm Practice, Johnson City, TN USA. [Mardis, Caitlin R.] Med Univ South Carolina, Transplant Serv Line, Charleston, SC USA. [Fleming, James N.; Pilch, Nicole A.; Meadows, Holly B.; Mardis, Benjamin A.] Med Univ South Carolina, Dept Pharm Serv, Charleston, SC USA. [Mohan, Prince; Posadas-Salas, Maria; Srinivas, Titte] Med Univ South Carolina, Dept Transplant Nephrol, Charleston, SC USA. [Taber, David J.] Med Univ South Carolina, Dept Surg, Charleston, SC USA. [Taber, David J.] Ralph H Johnson VAMC, Dept Pharm, Charleston, SC USA. RP Covert, KL (reprint author), Maple Ave,Bldg 7,Room 312, Johnson City, TN 37614 USA. EM covertk@etsu.edu NR 26 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-0008 EI 1875-9114 J9 PHARMACOTHERAPY JI Pharmacotherapy PD FEB PY 2017 VL 37 IS 2 BP 159 EP 169 DI 10.1002/phar.1886 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EL4JV UT WOS:000394588400002 PM 27997676 ER PT J AU Frei, CR Rehani, S Lee, GC Boyd, NK Attia, E Pechal, A Britt, RS Mortensen, EM AF Frei, Christopher R. Rehani, Sylvie Lee, Grace C. Boyd, Natalie K. Attia, Erene Pechal, Ashley Britt, Rachel S. Mortensen, Eric M. TI Application of a Risk Score to Identify Older Adults with Community-Onset Pneumonia Most Likely to Benefit From Empiric Pseudomonas Therapy SO PHARMACOTHERAPY LA English DT Article DE evidence-based medicine; infectious disease; outcomes; pharmacy practice; pulmonary ID CARE-ASSOCIATED PNEUMONIA; MULTIDRUG-RESISTANT PATHOGENS; INFECTIOUS-DISEASES-SOCIETY; ACQUIRED PNEUMONIA; ANTIBIOTIC-THERAPY; THORACIC-SOCIETY; OUTCOMES; EPIDEMIOLOGY; AERUGINOSA; BACTERIA AB Study ObjectiveTo assess the impact of empiric Pseudomonas pharmacotherapy on 30-day mortality in hospitalized patients with community-onset pneumonia stratified according to their risk (low, medium, or high) of drug-resistant pathogens. DesignRetrospective cohort study. Data SourceVeterans Health Administration database. PatientsA total of 50,119 patients who were at least 65 years of age, hospitalized with pneumonia, and received antibiotics within 48 hours of admission between fiscal years 2002 and 2007. Patients were stratified into empiric Pseudomonas therapy (31,027 patients) and no Pseudomonas therapy (19,092 patients) groups based on antibiotics received during their first 48 hours of admission. Measurements and Main ResultsA clinical prediction scoring system developed in 2014 that stratifies patients with community-onset pneumonia according to their risk of drug-resistant pathogens was used to identify patients who were likely to benefit from empiric Pseudomonas therapy as well as those in whom antipseudomonal therapy could be spared; patients were classified into low-risk (68%), medium-risk (21%), and high-risk (11%) groups. Of the 50,119 patients, 62% received Pseudomonas therapy. All-cause 30-day mortality was the primary outcome. Empiric Pseudomonas therapy (adjusted odds ratio 0.72, 95% confidence interval 0.62-0.84) was associated with lower 30-day mortality in the high-risk group but not the low- or medium-risk groups. ConclusionApplication of a risk score for patients with drug-resistant pathogens can identify patients likely to benefit from empiric Pseudomonas therapy. Widespread use of this score could reduce overuse of anti-Pseudomonas antibiotics in low- to medium-risk patients and improve survival in high-risk patients. C1 [Frei, Christopher R.; Rehani, Sylvie; Lee, Grace C.; Boyd, Natalie K.; Attia, Erene; Pechal, Ashley; Britt, Rachel S.] Univ Texas Austin, Coll Pharm, Pharmacotherapy Div, Austin, TX 78712 USA. [Frei, Christopher R.; Rehani, Sylvie; Lee, Grace C.; Boyd, Natalie K.; Attia, Erene; Pechal, Ashley; Britt, Rachel S.] Univ Texas Hlth Sci Ctr San Antonio, Sch Med, Pharmacotherapy Educ & Res Ctr, 7703 Floyd Curl Dr,MSC 6220, San Antonio, TX 78229 USA. [Frei, Christopher R.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Mortensen, Eric M.] VA North Texas Hlth Care Syst, Dallas, TX USA. [Mortensen, Eric M.] Univ Texas Southwestern Med Ctr Dallas, Dallas, TX 75390 USA. RP Frei, CR (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Sch Med, Pharmacotherapy Educ & Res Ctr, 7703 Floyd Curl Dr,MSC 6220, San Antonio, TX 78229 USA. EM freic@uthscsa.edu FU University of Texas Southwestern Center for Patient-Centered Outcomes Research FX Dr. Mortensen was supported in part by the University of Texas Southwestern Center for Patient-Centered Outcomes Research. This material is the result of work supported with resources and the use of facilities at the South Texas Veterans Health Care System. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs or the National Institutes of Health. NR 44 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-0008 EI 1875-9114 J9 PHARMACOTHERAPY JI Pharmacotherapy PD FEB PY 2017 VL 37 IS 2 BP 195 EP 203 DI 10.1002/phar.1891 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EL4JV UT WOS:000394588400006 PM 28035692 ER PT J AU Gerhard, F Deger, M Truccolo, W AF Gerhard, Felipe Deger, Moritz Truccolo, Wilson TI On the stability and dynamics of stochastic spiking neuron models: Nonlinear Hawkes process and point process GLMs SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID TIME-RESCALING THEOREM; TRAIN DATA-ANALYSIS; MOTOR CORTEX; POPULATION; ADAPTATION; CONNECTIVITY; VARIABILITY; INFERENCE; ENSEMBLE; SPECTRA AB Point process generalized linear models (PP-GLMs) provide an important statistical framework for modeling spiking activity in single-neurons and neuronal networks. Stochastic stability is essential when sampling from these models, as done in computational neuroscience to analyze statistical properties of neuronal dynamics and in neuro-engineering to implement closed-loop applications. Here we show, however, that despite passing common goodness-of-fit tests, PP-GLMs estimated from data are often unstable, leading to divergent firing rates. The inclusion of absolute refractory periods is not a satisfactory solution since the activity then typically settles into unphysiological rates. To address these issues, we derive a framework for determining the existence and stability of fixed points of the expected conditional intensity function (CIF) for general PP-GLMs. Specifically, in nonlinear Hawkes PP-GLMs, the CIF is expressed as a function of the previous spike history and exogenous inputs. We use a mean-field quasi-renewal (QR) approximation that decomposes spike history effects into the contribution of the last spike and an average of the CIF over all spike histories prior to the last spike. Fixed points for stationary rates are derived as self-consistent solutions of integral equations. Bifurcation analysis and the number of fixed points predict that the original models can show stable, divergent, and metastable (fragile) dynamics. For fragile models, fluctuations of the single-neuron dynamics predict expected divergence times after which rates approach unphysiologically high values. This metric can be used to estimate the probability of rates to remain physiological for given time periods, e.g., for simulation purposes. We demonstrate the use of the stability framework using simulated single-neuron examples and neurophysiological recordings. Finally, we show how to adapt PPGLM estimation procedures to guarantee model stability. Overall, our results provide a stability framework for data-driven PP-GLMs and shed new light on the stochastic dynamics of state-of-the-art statistical models of neuronal spiking activity. C1 [Gerhard, Felipe; Truccolo, Wilson] Brown Univ, Dept Neurosci, Providence, RI 02912 USA. [Deger, Moritz] Ecole Polytech Fed Lausanne, Sch Comp & Commun Sci, Lausanne, Switzerland. [Deger, Moritz] Ecole Polytech Fed Lausanne, Sch Life Sci, Lausanne, Switzerland. [Deger, Moritz] Univ Cologne, Inst Zool, Fac Math & Nat Sci, Cologne, Germany. [Truccolo, Wilson] Brown Univ, Inst Brain Sci, Providence, RI 02912 USA. [Truccolo, Wilson] US Dept Vet Affairs, Ctr Neurorestorat & Neurotechnol, Providence, RI USA. RP Truccolo, W (reprint author), Brown Univ, Dept Neurosci, Providence, RI 02912 USA.; Truccolo, W (reprint author), Brown Univ, Inst Brain Sci, Providence, RI 02912 USA.; Truccolo, W (reprint author), US Dept Vet Affairs, Ctr Neurorestorat & Neurotechnol, Providence, RI USA. EM Wilson_Truccolo@brown.edu RI Deger, Moritz/F-2191-2011 OI Deger, Moritz/0000-0002-2775-2611 FU National Institute of Neurological Disorders and Stroke (NINDS) [R01NS079533]; U.S. Department of Veterans Affairs, Merit Review Award [I01RX000668]; Pablo J. Salame '88 Goldman Sachs endowed Assistant Professorship of Computational Neuroscience at Brown University; Swiss National Science Foundation [P2ELP3-155278]; European Union [604102]; [200020_147200] FX We acknowledge support from the National Institute of Neurological Disorders and Stroke (NINDS), grant R01NS079533 (WT); the U.S. Department of Veterans Affairs, Merit Review Award I01RX000668 (WT); the Pablo J. Salame '88 Goldman Sachs endowed Assistant Professorship of Computational Neuroscience at Brown University (WT); the Swiss National Science Foundation, grant no. P2ELP3-155278 (FG) and grant no. 200020_147200 (MD); and the European Union Seventh Framework Program (FP7) under grant agreement no. 604102, Human Brain Project (MD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 0 Z9 0 U1 4 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD FEB PY 2017 VL 13 IS 2 AR e1005390 DI 10.1371/journal.pcbi.1005390 PG 31 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA EO0OW UT WOS:000396398700015 ER PT J AU de Oliveira, FL Carneiro, K Brito, JM Cabanel, M Pereira, JX Paiva, LD Syn, W Henderson, NC El-Cheikh, MC AF de Oliveira, Felipe Leite Carneiro, Katia Brito, Jose Marques Cabanel, Mariana Pereira, Jonathas Xavier Paiva, Ligia de Almeida Syn, Wingkin Henderson, Neil C. El-Cheikh, Marcia Cury TI Galectin-3, histone deacetylases, and Hedgehog signaling: Possible convergent targets in schistosomiasis-induced liver fibrosis SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Review ID EXPERIMENTAL MURINE SCHISTOSOMIASIS; MARROW-DERIVED MACROPHAGES; HEPATIC STELLATE CELLS; GRANULOMA-FORMATION; SONIC HEDGEHOG; T-CELLS; MANSONI; EXPRESSION; INHIBITORS; ACTIVATION AB Schistosomiasis affects approximately 240 million people in the world. Schistosoma mansoni eggs in the liver induce periportal fibrosis and hepatic failure driven by monocyte recruitment and macrophage activation, resulting in robust Th2 response. Here, we suggested a possible involvement of Galectin-3 (Gal-3), histone deacetylases (HDACs), and Hedgehog (Hh) signaling with macrophage activation during Th1/Th2 immune responses, fibrogranuloma reaction, and tissue repair during schistosomiasis. Gal-3 is highly expressed by liver macrophages (Kupffer cells) around Schistosoma eggs. HDACs and Hh regulate macrophage polarization and hepatic stellate cell activation during schistosomiasis-associated fibrogenesis. Previously, we demonstrated an abnormal extracellular matrix distribution in the liver that correlated with atypical monocyte-macrophage differentiation in S. mansoni-infected, Gal-3-deficient (Lgals3-/-) mice. New findings explored in this review focus on the chronic phase, when wild-type (Lgals3+/+) and Lgals3-/- mice were analyzed 90 days after cercariae infection. In Lgals3-/- infected mice, there was significant inflammatory infiltration with myeloid cells associated with egg destruction (hematoxylin and eosin staining), phagocytes (specifically Kupffer cells), numerically reduced and diffuse matrix extracellular deposition in fibrotic areas (Gomori trichrome staining), and severe disorganization of collagen fibers surrounding the S. mansoni eggs (reticulin staining). Granuloma-derived stromal cells (GR cells) of Lgals3-/- infected mice expressed lower levels of alpha smooth muscle actin (alpha-SMA) and eotaxin and higher levels of IL-4 than Lgals3+/+ mice (real-time PCR). The relevant participation of macrophages in these events led us to suggest distinct mechanisms of activation that culminate in defective fibrosis in the liver of Lgals3-/- infected mice. These aspects were discussed in this review, as well as the possible interference between Gal-3, HDACs, and Hh signaling during progressive liver fibrosis in S. mansoni-infected mice. Further studies focused on macrophage roles could elucidate these questions and clear the potential utility of these molecules as antifibrotic targets. C1 [de Oliveira, Felipe Leite; Carneiro, Katia; Brito, Jose Marques; Cabanel, Mariana; Pereira, Jonathas Xavier; El-Cheikh, Marcia Cury] Univ Fed Rio de Janeiro, Inst Ciencias Biomed, Rio De Janeiro, Brazil. [Paiva, Ligia de Almeida] Inst Oswaldo Cruz, Dept Fisiologia Farmacodinamica, Rio De Janeiro, Brazil. [Syn, Wingkin] Gastroenterol Sect, Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29401 USA. [Syn, Wingkin] Med Univ South Carolina, Div Gastroenterol & Hepatol, Charleston, SC 29425 USA. [Henderson, Neil C.] Univ Edinburgh, MRC Ctr Inflammat Res, Queens Med Res Inst, Edinburgh, Midlothian, Scotland. RP El-Cheikh, MC (reprint author), Univ Fed Rio de Janeiro, Inst Ciencias Biomed, Rio De Janeiro, Brazil. EM marcia@histo.ufrj.br FU CNPq (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico) [442308/2014-0]; FAPERJ (Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro) [E-26/203.217/2015]; CAPES (Coordenacao de Aperfeigoamento de Pessoal de Nivel Superior) FX Funding was provided by CNPq (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico), grant number: 442308/2014-0; FAPERJ (Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro), grant number: E-26/203.217/2015; and CAPES (Coordenacao de Aperfeigoamento de Pessoal de Nivel Superior) to MC and JXP. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 70 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD FEB PY 2017 VL 11 IS 2 AR e0005137 DI 10.1371/journal.pntd.0005137 PG 17 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA EN1AD UT WOS:000395741700004 PM 28231240 ER PT J AU Zumsteg, ZS Chen, ZN Howard, LE Amling, CL Aronson, WJ Cooperberg, MR Kane, CJ Terris, MK Spratt, DE Sandler, HM Freedland, SJ AF Zumsteg, Zachary S. Chen, Zinan Howard, Lauren E. Amling, Christopher L. Aronson, William J. Cooperberg, Matthew R. Kane, Christopher J. Terris, Martha K. Spratt, Daniel E. Sandler, Howard M. Freedland, Stephen J. TI Number of Unfavorable Intermediate-Risk Factors Predicts Pathologic Upstaging and Prostate Cancer-Specific Mortality Following Radical Prostatectomy: Results From the SEARCH Database SO PROSTATE LA English DT Article DE prostate cancer; intermediate risk; unfavorable intermediate risk; favorable intermediate risk ID ANDROGEN DEPRIVATION THERAPY; POSITIVE SURGICAL MARGINS; AFRICAN-AMERICAN MEN; ACTIVE SURVEILLANCE; ONCOLOGIC OUTCOMES; RADIATION-THERAPY; DEATH; DISEASE; BIOPSY; RECURRENCE AB BACKGROUND. To validate and further improve the stratification of intermediate risk prostate cancer into favorable and unfavorable subgroups for patients undergoing radical prostatectomy. MATERIALS AND METHODS. The SEARCH database was queried for IR patients undergoing radical prostatectomy without adjuvant radiotherapy. UIR disease was defined any patient with at least one unfavorable risk factor (URF), including primary Gleason pattern 4, 50% of more biopsy cores containing cancer, or multiple National Comprehensive Cancer Network IR factors. RESULTS. One thousand five hundred eighty-six patients with IR prostate cancer comprised the study cohort. Median follow-up was 62 months. Patients classified as UIR were significantly more likely to have pathologic high-risk features, such as Gleason score 8 - 10, pT3-4 disease, or lymph node metastases, than FIR patients (P < 0.001). Furthermore, UIR patients had significantly higher rates of PSA-relapse (PSA, hazard ratio [HR] = 1.89, P < 0.001) and distant metastasis (DM, HR = 2.92, P = 0.001), but no difference in prostate cancer- specific mortality (PCSM) or all-cause mortality in multivariable analysis. On secondary analysis, patients with >= 2 URF had significantly worse PSA-RFS, DM, and PCSM than those with 0 or 1 URF. Moreover, 40% of patients with >= 2 URF had high- risk pathologic features. CONCLUSIONS. Patients with UIR prostate cancer are at increased risk of PSA relapse, DM, and pathologic upstaging following prostatectomy. However, increased risk of PCSM was only detected in those with >= 2 URF. This suggests that further refinement of the UIR subgroup may improve risk stratification. (C) 2016 Wiley Periodicals, Inc. C1 [Zumsteg, Zachary S.; Sandler, Howard M.; Freedland, Stephen J.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. [Zumsteg, Zachary S.; Sandler, Howard M.] Cedars Sinai Med Ctr, Dept Radiat Oncol, 8700 Beverly Blvd, Los Angeles, CA 90048 USA. [Chen, Zinan; Howard, Lauren E.] Duke Univ, Sch Med, Dept Biostat & Bioinformat, Durham, NC USA. [Amling, Christopher L.] Oregon Hlth & Sci Univ, Div Urol, Portland, OR 97201 USA. [Aronson, William J.] Vet Affairs Greater Los Angeles Healthcare Syst, Dept Surg, Urol Sect, Los Angeles, CA USA. [Aronson, William J.] Univ Calif Los Angeles, Sch Med, Dept Urol, Los Angeles, CA USA. [Cooperberg, Matthew R.] UCSF, Helen Diller Family Comprehens Canc Ctr, Dept Urol, San Francisco, CA USA. [Kane, Christopher J.] Univ Calif San Diego Hlth Syst, Dept Urol, San Diego, CA USA. [Terris, Martha K.] Vet Affairs Med Ctr, Urol Sect, Augusta, GA USA. [Terris, Martha K.] Med Coll Georgia, Urol Sect, Augusta, GA 30912 USA. [Spratt, Daniel E.] Univ Michigan, Dept Radiat Oncol, Ann Arbor, MI 48109 USA. [Freedland, Stephen J.] Cedars Sinai Med Ctr, Dept Urol, Los Angeles, CA 90048 USA. RP Zumsteg, ZS (reprint author), Cedars Sinai Med Ctr, Dept Radiat Oncol, 8700 Beverly Blvd, Los Angeles, CA 90048 USA. EM zachary.zumsteg@cshs.org FU Department of Veterans Affairs; NIH [K24 CA160653] FX The SEARCH database is funded in part by the Department of Veterans Affairs and NIH K24 CA160653. NR 30 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-4137 EI 1097-0045 J9 PROSTATE JI Prostate PD FEB 1 PY 2017 VL 77 IS 2 BP 154 EP 163 DI 10.1002/pros.23255 PG 10 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA EK4JO UT WOS:000393893100003 PM 27683213 ER PT J AU Reardon, DA Mitchell, DA AF Reardon, David A. Mitchell, Duane A. TI The development of dendritic cell vaccine-based immunotherapies for glioblastoma SO SEMINARS IN IMMUNOPATHOLOGY LA English DT Review ID NEWLY-DIAGNOSED GLIOBLASTOMA; RANDOMIZED PHASE-III; NERVOUS-SYSTEM TUMORS; MURINE GLIOMA MODEL; CANCER STEM-CELLS; HIGH-GRADE GLIOMA; GROWTH-FACTOR; T-CELLS; MALIGNANT GLIOMA; ANTITUMOR IMMUNITY AB In this review, we focus on the biologic advantages of dendritic cell-based vaccinations as a therapeutic strategy for cancer as well as preclinical and emerging clinical data associated with such approaches for glioblastoma patients. C1 [Reardon, David A.] Dana Farber Canc Inst, Ctr Neurooncol, 450 Brookline Ave,Dana 2134, Boston, MA 02215 USA. [Mitchell, Duane A.] Univ Florida, Preston Wells Jr Ctr Brain Tumor Therapy, Lillian S Wells Dept Neurosurg, McKnight Brain Inst, Gainesville, FL 32605 USA. RP Reardon, DA (reprint author), Dana Farber Canc Inst, Ctr Neurooncol, 450 Brookline Ave,Dana 2134, Boston, MA 02215 USA. EM David_Reardon@dfci.harvard.edu FU Incyte; Midatech; Celldex; Immunomic Technologies, Inc. FX David A. Reardon received honoraria from and has a consulting or advisory role with Abbvie, Bristol Myers Squibb, Cavion, Celldex, Inovio, Juno Pharmaceuticals, Merck, Novartis, Roche/Genentech, Amgen, Novocure, Oxigene, Regeneron, and Stemline Therapeutics; is involved in speakers' bureaus with Roche and Merck; and received research funding from Incyte, Midatech, and Celldex.; Duane A. Mitchell received honoraria from and has a consulting or advisory role with Tocagen, Inc.; has patents that have been licensed to the Celldex Therapeutics, Inc.; and received research funding from Immunomic Technologies, Inc. NR 142 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1863-2297 EI 1863-2300 J9 SEMIN IMMUNOPATHOL JI Semin. Immunopathol. PD FEB PY 2017 VL 39 IS 2 BP 225 EP 239 DI 10.1007/s00281-016-0616-7 PG 15 WC Immunology; Pathology SC Immunology; Pathology GA EL0MI UT WOS:000394316100012 PM 28138787 ER PT J AU McIvor, WR Banerjee, A Boulet, JR Bekhuis, T Tseytlin, E Torsher, L DeMaria, S Rask, JP Shotwell, MS Burden, A Cooper, JB Gaba, DM Levine, A Park, C Sinz, E Steadman, RH Weinger, MB AF McIvor, William R. Banerjee, Arna Boulet, John R. Bekhuis, Tanja Tseytlin, Eugene Torsher, Laurence DeMaria, Samuel, Jr. Rask, John P. Shotwell, Matthew S. Burden, Amanda Cooper, Jeffrey B. Gaba, David M. Levine, Adam Park, Christine Sinz, Elizabeth Steadman, Randolph H. Weinger, Matthew B. TI A Taxonomy of Delivery and Documentation Deviations During Delivery of High-Fidelity Simulations SO SIMULATION IN HEALTHCARE-JOURNAL OF THE SOCIETY FOR SIMULATION IN HEALTHCARE LA English DT Article DE Educational assessment; Patient simulation; Classification; Vocabulary; Controlled; Terminology as topic ID QUALITY-ASSURANCE; CERTIFICATION; ASSESSMENTS AB Introduction: We developed a taxonomy of simulation delivery and documentation deviations noted during a multicenter, high-fidelity simulation trial that was conducted to assess practicing physicians' performance. Eight simulation centers sought to implement standardized scenarios over 2 years. Rules, guidelines, and detailed scenario scripts were established to facilitate reproducible scenario delivery; however, pilot trials revealed deviations from those rubrics. A taxonomy with hierarchically arranged terms that define a lack of standardization of simulation scenario delivery was then created to aid educators and researchers in assessing and describing their ability to reproducibly conduct simulations. Methods: Thirty-six types of delivery or documentation deviations were identified from the scenario scripts and study rules. Using a Delphi technique and open card sorting, simulation experts formulated a taxonomy of high-fidelity simulation execution and documentation deviations. The taxonomy was iteratively refined and then tested by 2 investigators not involved with its development. Results: The taxonomy has 2 main classes, simulation center deviation and participant deviation, which are further subdivided into as many as 6 subclasses. Inter-rater classification agreement using the taxonomy was 74% or greater for each of the 7 levels of its hierarchy. Cohen kappa calculations confirmed substantial agreement beyond that expected by chance. All deviations were classified within the taxonomy. Conclusions: This is a useful taxonomy that standardizes terms for simulation delivery and documentation deviations, facilitates quality assurance in scenario delivery, and enables quantification of the impact of deviations upon simulation-based performance assessment. C1 [McIvor, William R.] Univ Pittsburgh, Med Ctr, Dept Anesthesiol, Pittsburgh, PA USA. [McIvor, William R.] Winter Inst Simulat Educ & Res, Pittsburgh, PA USA. [Banerjee, Arna] Vanderbilt Univ, Sch Med, Div Anesthesiol Crit Care Med, Dept Anesthesiol, Nashville, TN 37212 USA. [Boulet, John R.] Fdn Adv Int Med Educ & Res, Res & Data Resources, Philadelphia, PA USA. [Bekhuis, Tanja; Tseytlin, Eugene] Univ Pittsburgh, Sch Med, Dept Biomed Informat, Pittsburgh, PA USA. [Bekhuis, Tanja] Univ Pittsburgh, Sch Dent Med, Dept Dent Publ Hlth, Pittsburgh, PA USA. [Torsher, Laurence] Mayo Clin, Dept Anesthesiol, Rochester, MN USA. [DeMaria, Samuel, Jr.] Icahn Sch Med Mt Sinai, Med Ctr, Anesthesiol, New York, NY 10029 USA. [Rask, John P.] Univ New Mexico, Sch Med, Dept Anesthesiol & Crit Care Med, Albuquerque, NM 87131 USA. [Rask, John P.] Univ New Mexico, Sch Med, UNM BATCAVE Simulat Ctr, Albuquerque, NM 87131 USA. [Shotwell, Matthew S.] Vanderbilt Univ, Dept Biostat, 221 Kirkland Hall, Nashville, TN 37235 USA. [Burden, Amanda] Rowan Univ, Cooper Univ Hosp, Cooper Med Sch, Clin Skills & Simulat, Camden, NJ USA. [Cooper, Jeffrey B.] Harvard Med Sch, Dept Anesthesia Crit Care & Pain Med, Massachusetts Gen Hosp, Boston, MA USA. [Cooper, Jeffrey B.] Ctr Med Simulat, Boston, MA USA. [Gaba, David M.] Stanford Univ, Immers Learning, Stanford, CA 94305 USA. [Gaba, David M.] VA Palo Alto, Palo Alto, CA USA. [Levine, Adam] Icahn Sch Med Mt Sinai, Med Ctr, Dept Anesthesiol, New York, NY 10029 USA. [Park, Christine] Northwestern Univ, Feinberg Sch Med, Dept Anesthesiol, Chicago, IL 60611 USA. [Sinz, Elizabeth] Penn State Univ, Coll Med, Dept Anesthesiol & Neurosurg, Hershey, PA USA. [Steadman, Randolph H.] Univ Calif Los Angeles, Dept Anesthesiol, Los Angeles, CA 90024 USA. [Weinger, Matthew B.] Vanderbilt Univ, Ctr Res & Innovat Syst Safety, Inst Med & Publ Hlth, 221 Kirkland Hall, Nashville, TN 37235 USA. [Weinger, Matthew B.] Geriatr Res Educ & Clin Ctr, Nashville, TN USA. [Weinger, Matthew B.] VA Tennessee Valley Healthcare Syst, Nashville, TN USA. [Weinger, Matthew B.] Vanderbilt Univ, Sch Med, Anesthesiol Biomed Informat & Med Educ, Nashville, TN 37212 USA. RP McIvor, WR (reprint author), Inst Simulat Educ Res, 230 McKee Pl,Suite 300, Pittsburgh, PA 15213 USA. EM mcivorwr@anes.upmc.edu FU Agency from Healthcare Research and Quality (Rockville, MD) [R18-HS020415] FX This study was funded in part by grant R18-HS020415 to Dr Weinger from the Agency from Healthcare Research and Quality (Rockville, MD). NR 18 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1559-2332 EI 1559-713X J9 SIMUL HEALTHC JI Simul. Healthc. PD FEB PY 2017 VL 12 IS 1 BP 1 EP 8 DI 10.1097/SIH.0000000000000184 PG 8 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EK5DS UT WOS:000393947700001 PM 28146449 ER PT J AU Min, L Zhao, Y Zhu, ST Qiu, XT Cheng, R Xing, J Shao, LL Guo, SL Zhang, ST AF Min, Li Zhao, Yu Zhu, Shengtao Qiu, Xintao Cheng, Rui Xing, Jie Shao, Linlin Guo, Shuilong Zhang, Shutian TI Integrated Analysis Identifies Molecular Signatures and Specific Prognostic Factors for Different Gastric Cancer Subtypes SO TRANSLATIONAL ONCOLOGY LA English DT Article ID EPIGENETIC REGULATION; COLORECTAL-CANCER; EXPRESSION; EFEMP1; CELLS; RISK AB BACKGROUND: Gastric cancer (GC) is the fifth leading cause of cancer-related deaths worldwide. As an effective and easily performed method, microscopy-based Lauren classification has been widely accepted by gastrointestinal surgeons and pathologists for GC subtyping, but molecular characteristics of different Lauren subtypes were poorly revealed. METHODS: GSE62254 was used as a derivation cohort, and GSE15459 was used as a validation cohort. The difference between diffuse and intestinal GC on the gene expression level was measured. Gene ontology (GO) enrichment analysis was performed for both subgroups. Hierarchical clustering and heatmap exhibition were also performed. Kaplan-Meier plot and Cox proportional hazards model were used to evaluate survival grouped by the given genes or hierarchical clusters. RESULTS: A total of 4598 genes were found differentially expressed between diffuse and intestinal GC. Immunity-and cell adhesion-related GOs were enriched for diffuse GC, whereas DNA repair-and cell cycle-related GOs were enriched for intestinal GC. We proposed a 40-gene signature (chi(2) = 30.71, P<.001) that exhibits better discrimination for prognosis than Lauren classification (chi(2) = 12.11, P=.002). FRZB [RR (95% CI) = 1.824 (1.115-2.986), P=.017] and EFEMP1 [RR (95% CI) = 1.537 (0.969-2.437), P=.067] were identified as independent prognostic factors only in diffuse GC but not in intestinal GC patients. KRT23 [RR (95% CI) = 1.616 (0.938-2.785), P=.083] was identified as an independent prognostic factor only in intestinal GC patients but not in diffuse GC patients. Similar results were achieved in the validation cohort. CONCLUSION: We found that GCs with different Lauren classifications had different molecular characteristics and identified FRZB, EFEMP1, and KRT23 as subtype-specific prognostic factors for GC patients. C1 [Min, Li; Zhao, Yu; Zhu, Shengtao; Cheng, Rui; Xing, Jie; Shao, Linlin; Guo, Shuilong; Zhang, Shutian] Capital Med Univ, Beijing Friendship Hosp, Natl Clin Res Ctr Digest Dis, Beijing Digest Dis Ctr,Dept Gastroenterol,Beijing, Beijing 100050, Peoples R China. [Min, Li] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Qiu, Xintao] Harvard Sch Publ Hlth, Dept Biomed Informat, Boston, MA 02115 USA. RP Guo, SL; Zhang, ST (reprint author), Capital Med Univ, Beijing Friendship Hosp, Natl Clin Res Ctr Digest Dis, Beijing Digest Dis Ctr,Dept Gastroenterol,Beijing, Beijing 100050, Peoples R China. EM slong.guo@163.com; zhangshutian@ccmu.edu.cn OI Min, Li/0000-0001-9595-5536 FU National Key Technologies RD Program [2015BAI13B09]; National Natural Science Foundation of China [81302160, 81272447, 81670474]; Natural Science Foundation of Beijing [7152043] FX This study was supported by the National Key Technologies R&D Program (2015BAI13B09), National Natural Science Foundation of China (81302160, 81272447, 81670474), and Natural Science Foundation of Beijing (7152043). NR 38 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-5233 J9 TRANSL ONCOL JI Transl. Oncol. PD FEB PY 2017 VL 10 IS 1 BP 99 EP 107 DI 10.1016/j.tranon.2016.11.003 PG 9 WC Oncology SC Oncology GA EK4OQ UT WOS:000393906900013 PM 28013168 ER PT J AU Cheng, FX Loscalzo, J AF Cheng, Feixiong Loscalzo, Joseph TI Autoimmune Cardiotoxicity of Cancer Immunotherapy SO TRENDS IN IMMUNOLOGY LA English DT Editorial Material AB Contemporary immunotherapies (e.g., immune checkpoint inhibitors), which enhance the immune response to cancer cells, improve clinical outcomes in several malignancies. A recent study reported the cases of two patients with metastatic melanoma who developed fatal myocarditis during ipilimumab and nivolumab combination immunotherapy; these examples highlight the risk of unbridled activation of the immune system. C1 [Cheng, Feixiong] Northeastern Univ, Ctr Complex Networks Res, Boston, MA 02115 USA. [Cheng, Feixiong] Harvard Med Sch, Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02215 USA. [Loscalzo, Joseph] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA 02215 USA. RP Cheng, FX (reprint author), Northeastern Univ, Ctr Complex Networks Res, Boston, MA 02115 USA.; Cheng, FX (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02215 USA.; Loscalzo, J (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA 02215 USA. EM fxcheng1985@gmail.com; jloscalzo@partners.org NR 10 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 1471-4906 EI 1471-4981 J9 TRENDS IMMUNOL JI Trends Immunol. PD FEB PY 2017 VL 38 IS 2 BP 77 EP 78 DI 10.1016/j.it.2016.11.007 PG 2 WC Immunology SC Immunology GA EK8TH UT WOS:000394197000001 PM 27919707 ER PT J AU Fabbri, C Hosak, L Mossner, R Giegling, I Mandelli, L Bellivier, F Claes, S Collier, DA Corrales, A Delisi, LE Gallo, C Gill, M Kennedy, JL Leboyer, M Lisoway, A Maier, W Marquez, M Massat, I Mors, O Muglia, P Nothen, MM O'Donovan, MC Ospina-Duque, J Propping, P Shi, YY St Clair, D Thibaut, F Cichon, S Mendlewicz, J Rujescu, D Serretti, A AF Fabbri, Chiara Hosak, Ladislav Moessner, Rainald Giegling, Ina Mandelli, Laura Bellivier, Frank Claes, Stephan Collier, David A. Corrales, Alejo Delisi, Lynn E. Gallo, Carla Gill, Michael Kennedy, James L. Leboyer, Marion Lisoway, Amanda Maier, Wolfgang Marquez, Miguel Massat, Isabelle Mors, Ole Muglia, Pierandrea Noethen, Markus M. O'Donovan, Michael C. Ospina-Duque, Jorge Propping, Peter Shi, Yongyong St Clair, David Thibaut, Florence Cichon, Sven Mendlewicz, Julien Rujescu, Dan Serretti, Alessandro TI Consensus paper of the WFSBP Task Force on Genetics: Genetics, epigenetics and gene expression markers of major depressive disorder and antidepressant response SO WORLD JOURNAL OF BIOLOGICAL PSYCHIATRY LA English DT Review DE Major depression; antidepressant; genetics-epigenetics; transcriptomics-proteomics ID C-REACTIVE PROTEIN; SEROTONIN TRANSPORTER GENE; BDNF PROMOTER METHYLATION; TUMOR-NECROSIS-FACTOR; ELEMENT-BINDING PROTEIN; STRESSFUL-LIFE EVENTS; BLOOD PERIPHERAL LYMPHOCYTES; NUTRITION EXAMINATION SURVEY; REUPTAKE INHIBITOR THERAPY; MESSENGER-RNA EXPRESSION AB Major depressive disorder (MDD) is a heritable disease with a heavy personal and socio-economic burden. Antidepressants of different classes are prescribed to treat MDD, but reliable and reproducible markers of efficacy are not available for clinical use. Further complicating treatment, the diagnosis of MDD is not guided by objective criteria, resulting in the risk of under- or overtreatment. A number of markers of MDD and antidepressant response have been investigated at the genetic, epigenetic, gene expression and protein levels. Polymorphisms in genes involved in antidepressant metabolism (cytochrome P450 isoenzymes), antidepressant transport (ABCB1), glucocorticoid signalling (FKBP5) and serotonin neurotransmission (SLC6A4 and HTR2A) were among those included in the first pharmacogenetic assays that have been tested for clinical applicability. The results of these investigations were encouraging when examining patient-outcome improvement. Furthermore, a nine-serum biomarker panel (including BDNF, cortisol and soluble TNF- receptor type II) showed good sensitivity and specificity in differentiating between MDD and healthy controls. These first diagnostic and response-predictive tests for MDD provided a source of optimism for future clinical applications. However, such findings should be considered very carefully because their benefit/cost ratio and clinical indications were not clearly demonstrated. Future tests may include combinations of different types of biomarkers and be specific for MDD subtypes or pathological dimensions. C1 [Fabbri, Chiara; Mandelli, Laura; Serretti, Alessandro] Univ Bologna, Dept Biomed & Neuromotor Sci, Bologna, Italy. [Hosak, Ladislav] Charles Univ Prague, Dept Psychiat, Fac Med, Hradec Kralove, Czech Republic. [Hosak, Ladislav] Univ Hosp, Hradec Kralove, Czech Republic. [Moessner, Rainald] Univ Tubingen, Dept Psychiat & Psychotherapy, Tubingen, Germany. [Giegling, Ina; Rujescu, Dan] Martin Luther Univ Halle Wittenberg, Dept Psychiat Psychotherapy & Psychosomat, Julius Kuhn Str 7, D-06112 Halle, Germany. [Bellivier, Frank] Fdn Fondamental, Creteil, France. [Bellivier, Frank] GH St Louis Lariboisiere Fernand Widal, AP HP, Pole Neurosci, Paris, France. [Claes, Stephan] Univ Leuven, Dept Neurosci, GRASP Res Grp, Leuven, Belgium. [Collier, David A.] Kings Coll London, Inst Psychiat, Social Genet & Dev Psychiat Ctr, London, England. [Corrales, Alejo] Natl Univ UNT Argentina, Argentinean Assoc Biol Psychiat, Buenos Aires, DF, Argentina. [Delisi, Lynn E.] VA Boston Hlth Care Syst, Brockton, MA USA. [Gallo, Carla] Univ Peruana Cayetano Heredia, Fac Ciencias & Filosofia, Labs Invest & Desarrollo, Dept Ciencias Celulares & Mol, Lima, Peru. [Gill, Michael] Trinity Coll Dublin, Dept Psychiat, Neuropsychiat Genet Res Grp, Dublin, Ireland. [Kennedy, James L.; Lisoway, Amanda] Ctr Addict & Mental Hlth, Neurogenet Sect, Toronto, ON, Canada. [Leboyer, Marion] Univ Paris Est Creteil, Fac Med, Inserm U955, Equipe Psychiatrie Translat, Creteil, France. [Maier, Wolfgang] Univ Bonn, Dept Psychiat, Bonn, Germany. [Marquez, Miguel] ADINEU Asistencia Docencia & Invest Neurociencia, Buenos Aires, DF, Argentina. [Massat, Isabelle] ULB, UNI ULB Neurosci Inst, Brussels, Belgium. [Mors, Ole] Aarhus Univ Hosp, Dept P, Risskov, Denmark. [Muglia, Pierandrea] UCB Biopharma, Brussels, Belgium. [Noethen, Markus M.] Univ Bonn, Inst Human Genet, Bonn, Germany. [O'Donovan, Michael C.] Cardiff Univ, Sch Med, Inst Psychol Med & Clin Neurosci, MRC Ctr Neuropsychiat Genet & Genom, Cardiff, S Glam, Wales. [Ospina-Duque, Jorge] Univ Antioquia, Fac Med, Dept Psiquiatria, Grp Invest Psiquiatria, Medellin, Colombia. [Propping, Peter] Univ Bonn, Bonn, Germany. [Shi, Yongyong] Shanghai Jiao Tong Univ, Minist Educ, Key Lab Genet Dev & Neuropsychiat Disorders, BioX Inst, Shanghai, Peoples R China. [St Clair, David] Univ Aberdeen, Inst Med Sci, Aberdeen, Scotland. [Thibaut, Florence] Univ Sorbonne Paris Cite, Fac Med Paris Descartes, INSERM U 894, Univ Hosp Cochin Site Tarnier,Ctr Psychiat & Neur, Paris, France. [Cichon, Sven] Univ Basel, Dept Biomed, Div Med Genet, Basel, Switzerland. [Mendlewicz, Julien] Univ Libre Bruxelles, Ctr Europeen Psychol Med, Lab Psychol Med, Brussels, Belgium. [Mendlewicz, Julien] Psy Pluriel, Brussels, Belgium. RP Rujescu, D (reprint author), Martin Luther Univ Halle Wittenberg, Dept Psychiat Psychotherapy & Psychosomat, Julius Kuhn Str 7, D-06112 Halle, Germany. EM dan.rujescu@uk-halle.de NR 263 TC 1 Z9 1 U1 2 U2 2 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1562-2975 EI 1814-1412 J9 WORLD J BIOL PSYCHIA JI World J. Biol. Psychiatry PD FEB PY 2017 VL 18 IS 1 BP 5 EP 28 DI 10.1080/15622975.2016.1208843 PG 24 WC Psychiatry SC Psychiatry GA EK5OZ UT WOS:000393977000002 PM 27603714 ER PT J AU D'Andrea, MS Fisichella, PM AF D'Andrea, Melissa S. Fisichella, P. Marco TI Improvement of Postoperative Pain Control Processes and Outcomes in Veterans of a Surgical Intensive Care Unit SO WORLD JOURNAL OF SURGERY LA English DT Article ID OBSERVATION TOOL AB Postoperative pain remains undertreated in critically ill patients. We hypothesized that the adequacy of pain control in our Surgical Intensive Care Unit (SICU) was above the reported average of 71 % in the literature and that the introduction of the critical care pain observation tool (CPOT) could improve it. We used a Lean Six Sigma methodology to improve our processes and quantify our improvement. We retrospectively review 713 consecutive veterans admitted to our SICU. Between December 2014 and February 2015, postoperative pain was assessed every 2 h and rated "acceptable," "unacceptable," or "unable to assess". Between March 2015 and October 2015, postoperative pain was assessed with CPOT. Concurrently, we implemented a postoperative pain education program and documented this activity in the electronic medical record. The baseline adequacy of pain control was 78 %, which improved to 99 % after the introduction of CPOT. We concurrently achieved a 100 % median documentation of postoperative pain education in the electronic medical record. The introduction of CPOT improved the process sigma from 2.3 to 3.8. The process of documenting pain education achieved a process sigma of 3.1. The proportion of veterans with acceptable pain control in our SICU is higher than that reported in the literature and the application of a Six Sigma methodology that involved the introduction of the CPOT has allowed us to improve the perception of pain control and comply with the newest regulatory directives. C1 [D'Andrea, Melissa S.] Boston Healthcare Syst, Vet Hlth Adm, Nursing Serv, Boston, MA USA. [Fisichella, P. Marco] Harvard Med Sch, VA Boston Healthcare Syst, Brigham & Womens Hosp, Dept Surg, 1400 VFW Pkwy, West Roxbury, MA 02132 USA. RP Fisichella, PM (reprint author), Harvard Med Sch, VA Boston Healthcare Syst, Brigham & Womens Hosp, Dept Surg, 1400 VFW Pkwy, West Roxbury, MA 02132 USA. EM piero.fisichella@va.gov NR 8 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2313 EI 1432-2323 J9 WORLD J SURG JI World J.Surg. PD FEB PY 2017 VL 41 IS 2 BP 419 EP 422 DI 10.1007/s00268-016-3728-2 PG 4 WC Surgery SC Surgery GA EK5LJ UT WOS:000393967600010 PM 27704172 ER PT J AU Valle, JA Graham, L DeRussy, A Itani, K Hawn, MT Maddox, TM AF Valle, Javier A. Graham, Laura DeRussy, Aerin Itani, Kamal Hawn, Mary T. Maddox, Thomas M. TI Triple Antithrombotic Therapy and Outcomes in Post-PCI Patients Undergoing Non-cardiac Surgery SO WORLD JOURNAL OF SURGERY LA English DT Article ID ATRIAL-FIBRILLATION PATIENTS; PERCUTANEOUS CORONARY INTERVENTION; ELEVATION MYOCARDIAL-INFARCTION; ELUTING STENT IMPLANTATION; CARDIOLOGY WORKING GROUP; RHYTHM ASSOCIATION EHRA; ADVERSE CARDIAC EVENTS; ANTIPLATELET THERAPY; ANTICOAGULATION THERAPY; ORAL ANTICOAGULATION AB Triple therapy, or the use of anticoagulants with dual antiplatelet therapy (DAPT), is often used to protect against ischemic events in post-percutaneous coronary intervention (PCI) patients with indications for anticoagulation, but is associated with increased bleeding. As both ischemic and bleeding risks increase in the perioperative period, the impact of triple therapy may be especially pronounced in patients undergoing surgery. Outcomes in this population are currently unknown. We identified patients undergoing non-cardiac surgeries within 2 years of PCI in Veterans Affairs hospitals from 2004 to 2012. We compared perioperative major adverse cardiovascular and cerebrovascular events (MACCE: mortality, myocardial infarction, stroke, revascularization) and bleeding events (in-hospital bleeding, transfusion) between surgeries in patients prescribed triple therapy and DAPT, adjusting for clinical, demographic, and operative characteristics. Among 7811 surgeries, 391 (5.0 %) occurred in patients receiving triple therapy. 44 (11.3 %) MACCE and 107 (27.4 %) bleeding events occurred with surgeries in triple therapy patients, compared to 366 (4.9 %) MACCE and 980 (13.2 %) bleeding events in DAPT patients. After adjustment, surgery in triple therapy patients was associated with higher rates of MACCE [odds ratio (OR) 1.65, 95 % confidence interval (CI) 1.16-2.34] or bleeding (OR 1.52, 95 % CI 1.17-1.99) as compared to surgery in DAPT patients. One in twenty post-PCI patients undergoing non-cardiac surgery were on triple therapy. Surgery in these patients was associated with higher MACCE and bleeding events compared to surgery in patients on DAPT, independent of clinical and operative characteristics. These findings identify a high-risk population for surgery, which may warrant increased surveillance for adverse perioperative events. C1 [Valle, Javier A.; Maddox, Thomas M.] Univ Colorado, Sch Med, VA Eastern Colorado Hlth Care Syst, Denver, CO 80204 USA. [Graham, Laura; DeRussy, Aerin] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Itani, Kamal] Boston Univ, Vet Affairs Boston Hlth Care Syst, Boston, MA 02215 USA. [Itani, Kamal] Harvard Med Sch, Boston, MA USA. [Hawn, Mary T.] Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. [Valle, Javier A.] Univ Colorado Hosp, Div Cardiol, 12631 E 17th St,B130, Aurora, CO 80045 USA. RP Valle, JA (reprint author), Univ Colorado, Sch Med, VA Eastern Colorado Hlth Care Syst, Denver, CO 80204 USA.; Valle, JA (reprint author), Univ Colorado Hosp, Div Cardiol, 12631 E 17th St,B130, Aurora, CO 80045 USA. EM Javier.valle@ucdenver.edu FU NIH T32 training Grant at the University of Colorado, Aurora, CO [HL0782] FX There are no relationships with industry to disclose. Dr. Valle is supported by a NIH T32 training Grant HL0782 at the University of Colorado, Aurora, CO. NR 37 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2313 EI 1432-2323 J9 WORLD J SURG JI World J.Surg. PD FEB PY 2017 VL 41 IS 2 BP 423 EP 432 DI 10.1007/s00268-016-3725-5 PG 10 WC Surgery SC Surgery GA EK5LJ UT WOS:000393967600011 PM 27734083 ER PT J AU Knight, AM Nobili, A van den Bergh, T Genz, M Joosten, HJ Albrecht, D Riedel, K Pavlidis, IV Bornscheuer, UT AF Knight, Anders M. Nobili, Alberto van den Bergh, Tom Genz, Maika Joosten, Henk-Jan Albrecht, Dirk Riedel, Katharina Pavlidis, Ioannis V. Bornscheuer, Uwe T. TI Bioinformatic analysis of fold-type III PLP-dependent enzymes discovers multimeric racemases SO APPLIED MICROBIOLOGY AND BIOTECHNOLOGY LA English DT Article DE Decarboxylase; PLP-dependent enzymes; Protein-function analysis; Racemase ID ALANINE RACEMASE; BACILLUS-STEAROTHERMOPHILUS; ORNITHINE-DECARBOXYLASE; AMINO-ACIDS; PROTEIN; SPECIFICITY; TREES AB Pyridoxal-5'-phosphate (PLP)-dependent enzymes are ubiquitous in nature and catalyze a variety of important metabolic reactions. The fold-type III PLP-dependent enzyme family is primarily comprised of decarboxylases and alanine racemases. In the development of a multiple structural alignment database (3DM) for the enzyme family, a large subset of 5666 uncharacterized proteins with high structural, but low sequence similarity to alanine racemase and decarboxylases was found. Compared to these two classes of enzymes, the protein sequences being the object of this study completely lack the C-terminal domain, which has been reported important for the formation of the dimer interface in other fold-type III enzymes. The 5666 sequences cluster around four protein templates, which also share little sequence identity to each other. In this work, these four template proteins were solubly expressed in Escherichia coli, purified, and their substrate profiles were evaluated by HPLC analysis for racemase activity using a broader range of amino acids. They were found active only against alanine or serine, where they exhibited Michaelis constants within the range of typical bacterial alanine racemases, but with significantly lower turnover numbers. As the already described racemases were proposed to be active and appeared to be monomers as judged from their crystal structures, we also investigated this aspect for the four new enzymes. Here, size exclusion chromatography indicated the presence of oligomeric states of the enzymes and a native-PAGE in-gel assay showed that the racemase activity was present only in an oligomeric state but not as monomer. This suggests the likelihood of a different behavior of these enzymes in solution compared to the one observed in crystalline form. C1 [Knight, Anders M.; Nobili, Alberto; Genz, Maika; Pavlidis, Ioannis V.; Bornscheuer, Uwe T.] Ernst Moritz Arndt Univ Greifswald, Inst Biochem, Dept Biotechnol & Enzyme Catalysis, Felix Hausdorff Str 4, D-17487 Greifswald, Germany. [Knight, Anders M.] CALTECH, Div Biol & Bioengn, 1200 E Calif Blvd MC 210-41, Pasadena, CA 91125 USA. [Nobili, Alberto] Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02115 USA. [Nobili, Alberto] Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [van den Bergh, Tom; Joosten, Henk-Jan] Bioprodict, Marktstr 54E, NL-6511 AA Nijmegen, Netherlands. [Albrecht, Dirk; Riedel, Katharina] Ernst Moritz Arndt Univ Greifswald, Inst Microbiol, Dept Microbial Physiol & Mol Biol, Friedrich Ludwig Jahn Str 15, D-17487 Greifswald, Germany. [Pavlidis, Ioannis V.] Univ Kassel, Dept Biochem, Heinrich Plett Str 40, D-34132 Kassel, Germany. RP Bornscheuer, UT (reprint author), Ernst Moritz Arndt Univ Greifswald, Inst Biochem, Dept Biotechnol & Enzyme Catalysis, Felix Hausdorff Str 4, D-17487 Greifswald, Germany. EM uwe.bornscheuer@uni-greifswald.de FU European Union [KBBE-2011-5, 289350]; DFG [INST 292/118-1 FUGG]; federal state Mecklenburg-Vorpommern; Deutscher Akademischer Austauschdienst through the DAAD Study Scholarship FX We thank the European Union (KBBE-2011-5, Grant No. 289350), the DFG (INST 292/118-1 FUGG), and the federal state Mecklenburg-Vorpommern for their financial support. A.M.K. thanks the Deutscher Akademischer Austauschdienst for financial support through the DAAD Study Scholarship. Furthermore, we thank Ina Menyes, Martin Weiss, and Dr. Mark Dorr (all Institute of Biochemistry, Greifswald University) for the analytical support. NR 35 TC 0 Z9 0 U1 4 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0175-7598 EI 1432-0614 J9 APPL MICROBIOL BIOT JI Appl. Microbiol. Biotechnol. PD FEB PY 2017 VL 101 IS 4 BP 1499 EP 1507 DI 10.1007/s00253-016-7940-7 PG 9 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA EK1LR UT WOS:000393687400016 PM 27787586 ER PT J AU Li, X Liu, WP Huang, XD Xiong, JP Wei, XY AF Li, Xue Liu, Wenping Huang, Xinduo Xiong, Jianping Wei, Xiaoyong TI Interaction of AR and iNOS in lens epithelial cell: A new pathogenesis and potential therapeutic targets of diabetic cataract SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE Diabetic cataract; Aldose reductase; Inducible nitric oxide synthase; Interaction ID NITRIC-OXIDE SYNTHASE; ALDOSE REDUCTASE INHIBITORS; KAPPA-B ACTIVATION; SELECTIVE-INHIBITION; MOLECULAR-DYNAMICS; NERVE-CONDUCTION; PROTEIN-PROTEIN; MESANGIAL CELLS; EYE DISEASES; EXPRESSION AB Although there is significant interest in revealing the role of aldose reductase (AR) and inducible nitric oxide synthase (iNOS) in diabetic cataract (DC), the interaction of AR and iNOS remains unknown. The aim of this study is to investigate the pathogenesis mechanisms and explore as a new potential therapeutic targets for DC. This study investigated the interaction of AR-iNOS through the methods of enzyme kinetics, molecular docking and molecular dynamics simulation, co-immunoprecipitation and fluorescence resonance energy transfer (FRET). The IC50 of AR for inhibition of iNOS activity is 0.04 mu M, and the IC50 of iNOS for inhibition of AR activity is 0.042 mu M through enzyme kinetics; the interface showed that ARG99 on AR and GLU317 on iNOS played the key roles in the interaction of AR-iNOS predicted by molecular docking and molecular dynamics simulation. Co-immunoprecipitation of protein complexes in human lens epithelial cell (HLEC) demonstrated that AR could association with iNOS in cell; and the interaction distance of AR-iNOS was 6.50 +/- 0.22 nm detected by FRET. This study exhibited a direct inhibition interaction between AR and iNOS in HLECs. It is the first report of inhibition interaction between AR and iNOS, suggesting a new pathophysiological mechanism and providing a new insight into the therapeutic mechanism of DC. (C) 2017 Elsevier Inc. All rights reserved. C1 [Li, Xue; Huang, Xinduo; Wei, Xiaoyong] Guangzhou Univ Chinese Med, Sch Basic Med Sci, Guangzhou 510006, Guangdong, Peoples R China. [Liu, Wenping] South China Univ Technol, Sch Biosci & Bioengn, Guangzhou 510006, Guangdong, Peoples R China. [Xiong, Jianping] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Xiong, Jianping] Harvard Med Sch, Boston, MA USA. [Wei, Xiaoyong] Tufts Univ, Antioxidants Res Lab, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. RP Wei, XY (reprint author), Guangzhou Univ Chinese Med, Sch Basic Med Sci, Guangzhou 510006, Guangdong, Peoples R China. EM xiaoxuesnowflak@163.com; 710304675@qq.com; 504782301@qq.com; xiong@helix.mgh.harvard.edu; jidewowxy2@163.com FU National Natural Science Foundation of China [81274157, 81102674, 30850012]; Guangdong Natural Science Foundation [S2011010005661]; Guangdong Science & Technology Planning Project [20118031700076, 2009B090300335, 2014J4100082]; U.S. Department of Agriculture (USDA)/Agricultural Research Service [1950-5100-087] FX This study was supported by grants from the National Natural Science Foundation of China (81274157, 81102674, 30850012), Guangdong Natural Science Foundation (S2011010005661), Guangdong Science & Technology Planning Project (20118031700076, 2009B090300335), Guangzhou Science & Technology Planning Project (2014J4100082) and the U.S. Department of Agriculture (USDA)/Agricultural Research Service (Cooperative Agreement No. 1950-5100-087). NR 58 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-9861 EI 1096-0384 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD FEB 1 PY 2017 VL 615 BP 44 EP 52 DI 10.1016/j.abb.2017.01.007 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA EK1YY UT WOS:000393724900006 PM 28108234 ER PT J AU Fenn, AM Swirski, FK AF Fenn, Ashley M. Swirski, Filip K. TI Monocytosis, Hypercholesterolemia, and the Kinase That Binds Them SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Editorial Material DE Editorials; atherosclerosis; bone marrow; hypercholesterolemia; macrophages; peritoneum ID ATHEROSCLEROSIS; ACCUMULATION; INFLAMMATION; MICE; PROLIFERATION; MACROPHAGES; SUBSETS; CX3CR1; CCR5 C1 [Fenn, Ashley M.; Swirski, Filip K.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. RP Swirski, FK (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. EM fswirski@mgh.harvard.edu NR 18 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1079-5642 EI 1524-4636 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD FEB PY 2017 VL 37 IS 2 BP 173 EP 175 DI 10.1161/ATVBAHA.116.308768 PG 3 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA EJ9ZI UT WOS:000393585700003 PM 28122772 ER PT J AU Zhu, QM Ko, KA Ture, S Mastrangelo, MA Chen, MH Johnson, AD O'Donnell, CJ Morrell, CN Miano, JM Lowenstein, CJ AF Zhu, Qiuyu Martin Ko, Kyung Ae Ture, Sara Mastrangelo, Michael A. Chen, Ming-Huei Johnson, Andrew D. O'Donnell, Christopher J. Morrell, Craig N. Miano, Joseph M. Lowenstein, Charles J. TI Novel Thrombotic Function of a Human SNP in STXBP5 Revealed by CRISPR/Cas9 Gene Editing in Mice SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE gene editing; genome-wide association study; phenotype; thrombosis; von Willebrand factor ID VON-WILLEBRAND-FACTOR; GENOME-WIDE ASSOCIATION; BINDING PROTEIN STXBP5; NEUROTRANSMITTER RELEASE; ARTERIAL THROMBOSIS; PLATELET SECRETION; PLASMA-LEVELS; TOMOSYN; EXOCYTOSIS; SYNTAXIN AB Objective-To identify and characterize the effect of a SNP (single-nucleotide polymorphism) in the STXBP5 locus that is associated with altered thrombosis in humans. GWAS (genome-wide association studies) have identified numerous SNPs associated with human thrombotic phenotypes, but determining the functional significance of an individual candidate SNP can be challenging, particularly when in vivo modeling is required. Recent GWAS led to the discovery of STXBP5 as a regulator of platelet secretion in humans. Further clinical studies have identified genetic variants of STXBP5 that are linked to altered plasma von Willebrand factor levels and thrombosis in humans, but the functional significance of these variants in STXBP5 is not understood. Approach and Results-We used CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated 9) techniques to produce a precise mouse model carrying a human coding SNP rs1039084 (encoding human p. N436S) in the STXBP5 locus associated with decreased thrombosis. Mice carrying the orthologous human mutation (encoding p. N437S in mouse STXBP5) have lower plasma von Willebrand factor levels, decreased thrombosis, and decreased platelet secretion compared with wild-type mice. This thrombosis phenotype recapitulates the phenotype of humans carrying the minor allele of rs1039084. Decreased plasma von Willebrand factor and platelet activation may partially explain the decreased thrombotic phenotype in mutant mice. Conclusions-Using precise mammalian genome editing, we have identified a human nonsynonymous SNP rs1039084 in the STXBP5 locus as a causal variant for a decreased thrombotic phenotype. CRISPR/Cas9 genetic editing facilitates the rapid and efficient generation of animals to study the function of human genetic variation in vascular diseases. C1 [Zhu, Qiuyu Martin; Ko, Kyung Ae; Ture, Sara; Mastrangelo, Michael A.; Morrell, Craig N.; Miano, Joseph M.; Lowenstein, Charles J.] Univ Rochester, Med Ctr, Dept Med, Aab Cardiovasc Res Inst, Rochester, NY 14627 USA. [Chen, Ming-Huei; Johnson, Andrew D.; O'Donnell, Christopher J.] NHLBI, Div Intramural Res, NIH, Framingham, MA USA. [Chen, Ming-Huei; Johnson, Andrew D.; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [O'Donnell, Christopher J.] Harvard Med Sch, Massachusetts Gen Hosp, Cardiovasc Div, Boston, MA USA. RP Lowenstein, CJ (reprint author), Box CVRI,601 Elmwood Ave, Rochester, NY 14642 USA. EM charles_lowenstein@urmc.rochester.edu FU National Institutes of Health (NIH)/NHLBI grant [HL108372, HL124042, HL117907, HL124018]; Howard Hughes Medical Institute Med-into-Grad Fellowship in Cardiovascular Sciences; American Heart Association [14GRNT19020033, 13PRE17050105] FX This work was supported by National Institutes of Health (NIH)/NHLBI grant HL108372 (C.J. Lowenstein), HL124042 (C.J. Lowenstein), HL117907 (J.M. Miano), and HL124018 (C.N. Morrell); the Howard Hughes Medical Institute Med-into-Grad Fellowship in Cardiovascular Sciences (C.J. Lowenstein, Q.M. Zhu); the American Heart Association 14GRNT19020033 (C.J. Lowenstein) and 13PRE17050105 (Q.M. Zhu). NR 44 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1079-5642 EI 1524-4636 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD FEB PY 2017 VL 37 IS 2 BP 264 EP + DI 10.1161/ATVBAHA.116.308614 PG 24 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA EJ9ZI UT WOS:000393585700014 PM 28062498 ER PT J AU Berkey, CS Rosner, B Tamimi, RM Willett, WC Hickey, M Toriola, A Frazier, AL Colditz, GA AF Berkey, Catherine S. Rosner, Bernard Tamimi, Rulla M. Willett, Walter C. Hickey, Martha Toriola, Adetunji Frazier, A. Lindsay Colditz, Graham A. TI Body size from birth through adolescence in relation to risk of benign breast disease in young women SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Maternal pre-pregnancy BMI; Gestational weight gain; Prenatal; Birth weight; Childhood adiposity; Height growth ID GENOME-WIDE ASSOCIATION; MASS INDEX; EARLY-LIFE; CANCER RISK; AMERICAN WOMEN; HEIGHT GROWTH; WEIGHT-GAIN; CHILDHOOD; OBESITY; PREVENTION AB Body size, from birth throughout adulthood, is associated with breast cancer risk, but few studies have investigated early-life body size and benign breast disease (BBD), a well-established breast cancer risk factor. We consider whether prenatal factors and size at birth, 10, 18 year, and intervening growth, are related to BBD risk. The Growing Up Today Study includes 9032 females who completed questionnaires annually from 1996 to 2001, then 2003, 2005, 2007, 2010, and 2013. In 1996, their mothers provided pregnancy-related data. From 2005 to 2013, participants (18 year+) reported whether they had ever been diagnosed with biopsy-confirmed BBD (N = 142 cases). Girls had greater adiposity (BMI; kg/m(2)) at 10 year if they were larger at birth, if mother's pre-pregnancy BMI was higher, or if gestational weight gain was greater (all p < .01). Maternal height was (positively) associated (p < .05) with adolescent peak height growth velocity (PHV; in./year). Greater 10 year adiposity was associated with lower PHV and less height growth 10-18 year (both p < .01). Adiposity at 10 year was inversely associated with BBD (OR 0.83/(kg/m(2)), p < .01) as was increasing adiposity 10-18 year (OR 0.85/(kg/m(2)), p = .01). In a separate model, 10 year height (OR 1.13/in., p = .02) and height growth 10-18 year (OR 1.19/in.; p < .01) were positively associated. PHV was similarly positively associated (OR 2.58, p = .01, fastest versus slowest growth quartiles). In a multivariable model of BBD risk, gestational weight gain (daughters at highest risk if < 20 lb gained), PHV (slowest growing girls at lowest risk), age 10 year height (positive), and BMI (inverse) were the most critical childhood risk factors (each p < .05). Body size factors from pregnancy through adolescence were independently associated with BBD risk in young women. C1 [Berkey, Catherine S.; Rosner, Bernard; Tamimi, Rulla M.] Brigham & Womens Hosp, Channing Div Network Med, Dept Med, 181 Longwood Ave, Boston, MA 02115 USA. [Berkey, Catherine S.; Rosner, Bernard; Tamimi, Rulla M.] Harvard Med Sch, 181 Longwood Ave, Boston, MA 02115 USA. [Willett, Walter C.] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Willett, Walter C.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Hickey, Martha] Univ Melbourne, Dept Obstet & Gynaecol, Melbourne, Vic, Australia. [Hickey, Martha] Royal Womens Hosp, Melbourne, Vic, Australia. [Toriola, Adetunji] Washington Univ, Sch Med, Dept Surg, Div Publ Hlth Sci,Alvin J Siteman Canc Ctr, St Louis, MO 63110 USA. [Frazier, A. Lindsay] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Colditz, Graham A.] Washington Univ, Sch Med, Alvin J Siteman Canc Ctr, St Louis, MO USA. RP Berkey, CS (reprint author), Brigham & Womens Hosp, Channing Div Network Med, Dept Med, 181 Longwood Ave, Boston, MA 02115 USA.; Berkey, CS (reprint author), Harvard Med Sch, 181 Longwood Ave, Boston, MA 02115 USA. EM Catherine.Berkey@channing.harvard.edu FU Breast Cancer Research Foundation (NYC, NY); National Institutes of Health (Bethesda, MD) [DK046834]; American Institute for Cancer Research; American Cancer Society Clinical Research Professorship FX Supported by a Grant from The Breast Cancer Research Foundation (NYC, NY) to Dr. Colditz and by DK046834 from the National Institutes of Health (Bethesda, MD). Dr. Frazier was supported by an award from the American Institute for Cancer Research. Dr. Colditz, who founded GUTS, was supported, in part, by an American Cancer Society Clinical Research Professorship. The authors appreciate the ongoing, since 1996, dedication of our female GUTS participants and their mothers in NHSII. NR 49 TC 0 Z9 0 U1 5 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 FEB PY 2017 VL 162 IS 1 BP 139 EP 149 DI 10.1007/s10549-016-4084-5 PG 11 WC Oncology SC Oncology GA EK7XE UT WOS:000394137700015 PM 28062981 ER PT J AU Gupta, A Das, A Naina, HVK AF Gupta, Arjun Das, Avash Naina, Harris V. K. TI Cholecystitis as the initial presentation of acute myeloid leukaemia SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Editorial Material C1 [Gupta, Arjun] Univ Texas Southwestern, Dept Internal Med, Dallas, TX USA. [Das, Avash] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Naina, Harris V. K.] Plaza Med Ctr, Dept Internal Med, Dallas, TX USA. RP Das, A (reprint author), Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. EM adas2@mgh.harvard.edu OI Gupta, Arjun/0000-0003-0875-4731 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 0007-1048 EI 1365-2141 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD FEB PY 2017 VL 176 IS 3 BP 344 EP 344 DI 10.1111/bjh.14442 PG 1 WC Hematology SC Hematology GA EK0HV UT WOS:000393608300004 PM 27982426 ER PT J AU Hope, TA Pampaloni, MH Flavell, RR Nakakura, EK Bergsland, EK AF Hope, Thomas A. Pampaloni, Miguel Hernandez Flavell, Robert R. Nakakura, Eric K. Bergsland, Emily K. TI Somatostatin receptor PET/MRI for the evaluation of neuroendocrine tumors SO CLINICAL AND TRANSLATIONAL IMAGING LA English DT Review DE Somatostatin receptor PET; PET/MRI; Neuroendocrine tumor; DOTA-TATE; DOTA-TOC ID DIFFUSION-WEIGHTED MRI; HEPATOCELLULAR-CARCINOMA; GA-68-DOTATATE PET/CT; RESPIRATORY MOTION; LIVER; QUANTIFICATION; CLASSIFICATION; METASTASES; UTILITY AB With the introduction of simultaneous PET/MRI scanners, concurrent acquisition of PET and MRI data is feasible, allowing for improved patient convenience and decreased radiation dose. Although PET/MRI has been used in many settings, not all cancers benefit from the combined modality. With the availability of somatostatin receptor-targeted PET tracers such as Ga-68-DOTA-TOC and Ga-68-DOTA-TATE, imaging of NET patients has refocused on targeted imaging, particularly with the development of peptide receptor radiotherapy. Nonetheless, there are many patients who continue to benefit from dedicated MR imaging, such as those with liver-predominant disease. In these patients, SSR PET/MRI is an important option for optimal imaging. Both diffusion-weighted imaging and hepatobiliary phase imaging provide improved lesion detection compared to conventional MRI and CT, and the results can effect therapeutic decisions. Additionally, the use of motion correction techniques can be used to leverage the additional PET data acquired in dedicated liver PET/MRI to remove respiratory artifacts. C1 [Hope, Thomas A.; Pampaloni, Miguel Hernandez; Flavell, Robert R.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, 505 Parnassus Ave 0628, San Francisco, CA 94143 USA. [Hope, Thomas A.] San Francisco VA Med Ctr, Dept Radiol, San Francisco, CA USA. [Nakakura, Eric K.] Univ Calif San Francisco, Dept Surg, Div Surg Oncol, San Francisco, CA 94143 USA. [Bergsland, Emily K.] Univ Calif San Francisco, Dept Med, Div Hematol Oncol, San Francisco, CA 94143 USA. RP Hope, TA (reprint author), Univ Calif San Francisco, Dept Radiol & Biomed Imaging, 505 Parnassus Ave 0628, San Francisco, CA 94143 USA.; Hope, TA (reprint author), San Francisco VA Med Ctr, Dept Radiol, San Francisco, CA USA. EM thomas.hope@ucsf.edu FU Wylie J. Dodds Research Award; Society of Abdominal Radiology FX Dr. Hope received grant support from Wylie J. Dodds Research Award, Society of Abdominal Radiology, and is on the speakers' bureau for GE Healthcare. Drs. Pampaloni, Flavell, Nakakura, and Bergsland have no conflicts of interest. NR 40 TC 1 Z9 1 U1 1 U2 1 PU SPRINGER-VERLAG ITALIA SRL PI MILAN PA VIA DECEMBRIO, 28, MILAN, 20137, ITALY SN 2281-5872 EI 2281-7565 J9 CLIN TRANSL IMAGING JI Clin. Transl. Imaging PD FEB PY 2017 VL 5 IS 1 BP 63 EP 69 DI 10.1007/s40336-016-0193-8 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EK0WV UT WOS:000393648700006 ER PT J AU Miller, MA Sullivan, RJ Lauffenburger, DA AF Miller, Miles A. Sullivan, Ryan J. Lauffenburger, Douglas A. TI Molecular Pathways: Receptor Ectodomain Shedding in Treatment, Resistance, and Monitoring of Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR RECEPTOR; INHIBITS TUMOR-GROWTH; NATURAL-KILLER-CELLS; TGF-BETA RECEPTOR; SOLUBLE C-MET; TYROSINE KINASE; BREAST-CANCER; MONOCLONAL-ANTIBODY; CLEAVAGE; ADAM17 AB Proteases known as sheddases cleave the extracellular domains of their substrates from the cell surface. The A Disintegrin and Metalloproteinases ADAM10 and ADAM17 are among the most prominent sheddases, being widely expressed in many tissues, frequently overexpressed in cancer, and promiscuously cleaving diverse substrates. It is increasingly clear that the proteolytic shedding of transmembrane receptors impacts pathophysiology and drug response. Receptor substrates of sheddases include the cytokine receptors TNFR1 and IL6R; the Notch receptors; type-I and -III TGF beta receptors; receptor tyrosine kinases (RTK) such as HER2, HER4, and VEGFR2; and, in particular, MET and TAM-family RTKs AXL and Mer (MerTK). Activation of receptor shedding by mechanical cues, hypoxia, radiation, and phosphosignaling offers insight into mechanisms of drug resistance. This particularly holds for kinase inhibitors targeting BRAF (such as vemurafenib and dabrafenib) and MEK (such as trametinib and cobimetinib), along with direct sheddase inhibitors. Receptor proteolysis can be detected in patient fluids and is especially relevant in melanoma, glioblastoma, lung cancer, and triple-negative breast cancer where RTK substrates, MAPK signaling, and ADAMs are frequently dysregulated. Translatable strategies to exploit receptor shedding include combination kinase inhibitor regimens, recombinant decoy receptors based on endogenous counterparts, and, potentially, immunotherapy. (C) 2016 AACR. C1 [Miller, Miles A.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Miller, Miles A.] Harvard Med Sch, Boston, MA USA. [Sullivan, Ryan J.] Harvard Med Sch, Massachusetts Gen Hosp, Div Med Oncol, Ctr Canc, Boston, MA USA. [Lauffenburger, Douglas A.] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Lauffenburger, DA (reprint author), MIT, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM lauffen@mit.edu FU [NIHNCIK99-CA207744]; [NIHNCIR01-CA96504]; [NIHNCIU54-CA112967] FX The study was supported by NIHNCIK99-CA207744, NIHNCIR01-CA96504, NIHNCIU54-CA112967. NR 71 TC 0 Z9 0 U1 2 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB PY 2017 VL 23 IS 3 BP 623 EP 629 DI 10.1158/1078-0432.CCR-16-0869 PG 7 WC Oncology SC Oncology GA EK4GB UT WOS:000393884000003 PM 27895032 ER PT J AU Srivastava, RM Trivedi, S Concha-Benavente, F Gibson, SP Reeder, C Ferrone, S Ferris, RL AF Srivastava, Raghvendra M. Trivedi, Sumita Concha-Benavente, Fernando Gibson, Sandra P. Reeder, Carly Ferrone, Soldano Ferris, Robert L. TI CD137 Stimulation Enhances Cetuximab-Induced Natural Killer: Dendritic Cell Priming of Antitumor T-Cell Immunity in Patients with Head and Neck Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID 4-1BB LIGAND; TUMOR; EXPRESSION; THERAPY; SURVIVAL; PROLIFERATION; IMMUNOTHERAPY; ACTIVATION; BIOMARKERS; CARCINOMA AB Purpose: Cetuximab, an EGFR-specific antibody (mAb), modestly improves clinical outcome in patients with head and neck cancer (HNC). Cetuximab mediates natural killer (NK) cell: dendritic cell (DC) cross-talk by cross-linking FcgRIIIa, which is important for inducing antitumor cellular immunity. Cetuximab-activated NK cells upregulate the costimulatory receptor CD137 (4-1BB), which, when triggered by agonistic mAb urelumab, might enhance NK-cell functions, to promote T-cell-based immunity. Experimental design: CD137 expression on tumor-infiltrating lymphocytes was evaluated in a prospective cetuximab neoadjuvant trial, and CD137 stimulation was evaluated in a phase Ib trial, in combining agonistic urelumab with cetuximab. Flow cytometry and cytokine release assays using NK cells and DC were used in vitro, testing the addition of urelumab to cetuximab-activated NK, DC, and cross presentation to T cells. Results: CD137 agonist mAb urelumab enhanced cetuximab-activated NK-cell survival, DC maturation, and tumor antigen cross-presentation. Urelumab boosted DC maturation markers, CD86 and HLA DR, and antigen-processing machinery (APM) components TAP1/2, leading to increased tumor antigen cross-presentation. In neoadjuvant cetuximab-treated patients with HNC, upregulation of CD137 by intratumoral, cetuximab-activated NK cells correlated with FcgRIIIa V/F polymorphism and predicted clinical response. Moreover, immune biomarker modulation was observed in an open label, phase Ib clinical trial, of patients with HNC treated with cetuximab plus urelumab. Conclusions: These results suggest a beneficial effect of combination immunotherapy using cetuximab and CD137 agonist in HNC. (C) 2016 AACR. C1 [Srivastava, Raghvendra M.; Trivedi, Sumita; Gibson, Sandra P.; Reeder, Carly; Ferris, Robert L.] Univ Pittsburgh, Dept Otolaryngol, Pittsburgh, PA 15260 USA. [Concha-Benavente, Fernando; Ferris, Robert L.] Univ Pittsburgh, Dept Immunol, Pittsburgh, PA USA. [Ferrone, Soldano] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Boston, MA USA. [Ferris, Robert L.] Univ Pittsburgh, Inst Canc, Canc Immunol Program, Pittsburgh, PA USA. RP Ferris, RL (reprint author), Univ Pittsburgh, Inst Canc, Sch Med, Hillman Canc Ctr Res Pavil,5117 Ctr Ave,Room 2-26, Pittsburgh, PA 15213 USA. EM ferrisrl@upmc.edu FU National Institute of Health [R01 DE019727, P50 CA097190]; University of Pittsburgh Cancer Center [P30CA047904] FX The study was supported by National Institute of Health grants R01 DE019727, P50 CA097190, University of Pittsburgh Cancer Center Support Grant P30CA047904. NR 34 TC 2 Z9 2 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB PY 2017 VL 23 IS 3 BP 707 EP 716 DI 10.1158/1078-0432.CCR-16-0879 PG 10 WC Oncology SC Oncology GA EK4GB UT WOS:000393884000012 PM 27496866 ER PT J AU Qu, FF Xie, WL Nakabayashi, M Zhang, HT Jeong, SH Wang, XD Komura, K Sweeney, CJ Sartor, O Lee, GSM Kantoff, PW AF Qu, Fangfang Xie, Wanling Nakabayashi, Mari Zhang, Haitao Jeong, Seong Ho Wang, Xiaodong Komura, Kazumasa Sweeney, Christopher J. Sartor, Oliver Lee, Gwo-Shu Mary Kantoff, Philip W. TI Association of AR-V7 and Prostate-Specific Antigen RNA Levels in Blood with Efficacy of Abiraterone Acetate and Enzalutamide Treatment in Men with Prostate Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID ANDROGEN-DEPRIVATION THERAPY; POLYMERASE-CHAIN-REACTION; DROPLET DIGITAL PCR; PROGNOSTIC-SIGNIFICANCE; SPLICE VARIANTS; INCREASED SURVIVAL; RECEPTOR; RESISTANCE; CHEMOTHERAPY; MECHANISMS AB Purpose: We evaluated the association of PSA and androgen receptor splice variant-7 (AR-V7) transcript levels in patients' blood with time to treatment failure (TTF) and overall survival (OS) with abiraterone acetate and/or enzalutamide treatment in castration-resistant prostate cancer (CRPC) patients. Experimental Design: RNA levels of AR-V7 and PSA in peripheral blood collected before treatment were quantified using droplet digital-PCR in retrospective cohorts treated with abiraterone acetate (N = 81) or enzalutamide (N = 51) for CRPC. Multivariable Cox regression adjusted for known prognostic factors was used for analyses. Results: PSA transcripts were detected in 57% of abiraterone acetate-treated patients and in 63% of enzalutamide-treated patients. PSA-positive patients had a shorter TTF than PSA-negative patients [adjusted HR = 2.27 (95% confidence interval (CI) 1.26-4.10) and 2.60 (95% CI, 1.19-5.69); P = 0.006 and 0.017 in abiraterone acetate and enzalutamide cohorts, respectively]. Patients with a higher-AR-V7 transcript level had a shorter TTF with abiraterone acetate and enzalutamide in univariate analysis (median 8.0 months vs. 15.6 months, P = 0.046 in abiraterone acetate-cohort and 3.6 months vs. 5.6 months; P = 0.050 in enzalutamide cohort). In multivariable models, the association with TTF remained significant in the enzalutamide cohort (adjusted HR = 2.02; 95% CI, 1.01-4.05; P = 0.048), but statistically insignificant in the abiraterone acetate cohort. In both cohorts, we observed potential prognostic value of both PSA and AR-V7 RNA expression on OS; patients with detectable PSA transcripts and high AR-V7 predicted the poorest OS. Conclusions: PSA and AR-V7 transcripts in blood potentially serve as biomarkers predicting TTF and OS with abiraterone acetate or enzalutamide treatment. If validated prospectively, their detection could be facilitated without isolation of circulating tumor cells. (C) 2016 AACR. C1 [Qu, Fangfang; Nakabayashi, Mari; Jeong, Seong Ho; Wang, Xiaodong; Komura, Kazumasa; Sweeney, Christopher J.; Lee, Gwo-Shu Mary; Kantoff, Philip W.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Qu, Fangfang; Nakabayashi, Mari; Jeong, Seong Ho; Wang, Xiaodong; Komura, Kazumasa; Sweeney, Christopher J.; Lee, Gwo-Shu Mary; Kantoff, Philip W.] Harvard Med Sch, Boston, MA USA. [Xie, Wanling] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Zhang, Haitao; Sartor, Oliver] Tulane Univ, Sch Med, Dept Urol & Med, 1430 Tulane Ave, New Orleans, LA 70112 USA. [Kantoff, Philip W.] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. RP Kantoff, PW (reprint author), Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10065 USA. EM kantoff@mskcc.org FU Dana-Farber Prostate Cancer SPORE [P50CA090381] FX This study was supported by the Dana-Farber Prostate Cancer SPORE P50CA090381. NR 49 TC 3 Z9 3 U1 2 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB PY 2017 VL 23 IS 3 BP 726 EP 734 DI 10.1158/1078-0432.CCR-16-1070 PG 9 WC Oncology SC Oncology GA EK4GB UT WOS:000393884000014 PM 27489290 ER PT J AU Yu, LJ Kim, HT Kasar, SN Benien, P Du, W Hoang, K Aw, A Tesar, B Improgo, R Fernandes, SM Radhakrishnan, S Klitgaard, JL Lee, C Getz, G Setlur, SR Brown, JR AF Yu, Lijian Kim, Haesook T. Kasar, Siddha N. Benien, Parul Du, Wei Hoang, Kevin Aw, Andrew Tesar, Bethany Improgo, Reina Fernandes, Stacey M. Radhakrishnan, Saranya Klitgaard, Josephine L. Lee, Charles Getz, Gad Setlur, Sunita R. Brown, Jennifer R. TI Survival of Del17p CLL Depends on Genomic Complexity and Somatic Mutation SO CLINICAL CANCER RESEARCH LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; CLINICAL IMPACT; GENETIC-CHARACTERIZATION; NOTCH1 MUTATIONS; TP53 MUTATION; 17P DELETION; FOLLOW-UP; CANCER; ABERRATIONS; PREDICTOR AB Purpose: Chronic lymphocytic leukemia (CLL) with 17p deletion typically progresses quickly and is refractory to most conventional therapies. However, some del(17p) patients do not progress for years, suggesting that del(17p) is not the only driving event in CLL progression. We hypothesize that other concomitant genetic abnormalities underlie the clinical heterogeneity of del(17p) CLL. Experimental Design: We profiled the somatic mutations and copy number alterations (CNA) in a large group of del(17p) CLLs as well as wild-type CLL and analyzed the genetic basis of their clinical heterogeneity. Results: We found that increased somatic mutation number associates with poor overall survival independent of 17p deletion (P = 0.003). TP53 mutation was present in 81% of del(17p) CLL, mostly clonal (82%), and clonal mutations with del(17p) exhibit shorter overall survival than subclonal mutations with del(17p) (P = 0.019). Del(17p) CLL has a unique driver mutation profile, including NOTCH1 (15%), RPS15 (12%), DDX3X (8%), and GPS2 (6%). We found that about half of del(17p) CLL cases have recurrent deletions at 3p, 4p, or 9p and that any of these deletions significantly predicts shorter overall survival. In addition, the number of CNAs, but not somatic mutations, predicts shorter time to treatment among patients untreated at sampling. Indolent del(17p) CLLs were characterized by absent or subclonal TP53 mutation and few CNAs, with no difference in somatic mutation number. Conclusions: Weconclude that del(17p) has a unique genomic profile and that clonal TP53 mutations, 3p, 4p, or 9p deletions, and genomic complexity are associated with shorter overall survival. (C) 2016 AACR. C1 [Yu, Lijian; Kasar, Siddha N.; Hoang, Kevin; Tesar, Bethany; Improgo, Reina; Fernandes, Stacey M.; Klitgaard, Josephine L.; Brown, Jennifer R.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Yu, Lijian; Kasar, Siddha N.; Improgo, Reina; Klitgaard, Josephine L.; Setlur, Sunita R.; Brown, Jennifer R.] Harvard Med Sch, Boston, MA USA. [Kim, Haesook T.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Benien, Parul; Du, Wei; Radhakrishnan, Saranya; Setlur, Sunita R.] Brigham & Womens Hosp, 221 Longwood Ave, Boston, MA 02115 USA. [Aw, Andrew] Ottawa Hosp, Div Hematol, Ottawa, ON, Canada. [Lee, Charles] Jackson Lab Genom Med, Farmington, CT USA. [Getz, Gad] Broad Inst Harvard & MIT, Cambridge, MA USA. [Getz, Gad] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Getz, Gad] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. RP Setlur, SR (reprint author), Brigham & Womens Hosp, 221 Longwood Ave, Boston, MA 02115 USA.; Brown, JR (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM ssetlur@partners.org; Jennifer_Brown@dfci.harvard.edu OI Benien, Parul/0000-0002-6980-9049 FU American Cancer Society [RSG-13-002-01-CCE]; National Comprehensive Cancer Network FX This work was supported by American Cancer Society Grant RSG-13-002-01-CCE (to J.R. Brown), as well as the National Comprehensive Cancer Network. NR 50 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB PY 2017 VL 23 IS 3 BP 735 EP 745 DI 10.1158/1078-0432.CCR-16-0594 PG 11 WC Oncology SC Oncology GA EK4GB UT WOS:000393884000015 PM 27503198 ER PT J AU Pikman, Y Alexe, G Roti, G Conway, AS Furman, A Lee, ES Place, AE Kim, S Saran, C Modiste, R Weinstock, DM Harris, M Kung, AL Silverman, LB Stegmaier, K AF Pikman, Yana Alexe, Gabriela Roti, Giovanni Conway, Amy Saur Furman, Andrew Lee, Emily S. Place, Andrew E. Kim, Sunkyu Saran, Chitra Modiste, Rebecca Weinstock, David M. Harris, Marian Kung, Andrew L. Silverman, Lewis B. Stegmaier, Kimberly TI Synergistic Drug Combinations with a CDK4/6 Inhibitor in T-cell Acute Lymphoblastic Leukemia SO CLINICAL CANCER RESEARCH LA English DT Article ID ACUTE MYELOID-LEUKEMIA; DEPENDENT KINASE 6; DNA-DAMAGE; EXPRESSION; RECEPTOR; CANCER; DEXAMETHASONE; PROLIFERATION; CYTOTOXICITY; CHEMOTHERAPY AB Purpose: Although significant progress has been made in the treatment of T-cell acute lymphoblastic leukemia (T-ALL), many patients will require additional therapy for relapsed/refractory disease. Cyclin D3 (CCND3) and CDK6 are highly expressed in T-ALL and have been effectively targeted inmutant NOTCH1-driven mouse models of this disease with a CDK4/6 small-molecule inhibitor. Combination therapy, however, will be needed for the successful treatment of human disease. Experimental Design: We performed preclinical drug testing using a panel of T-ALL cell lines first with LEE011, a CDK4/6 inhibitor, and next with the combination of LEE011 with a panel of drugs relevant to T-ALL treatment. We then tested the combination of LEE011 with dexamethasone or everolimus in three orthotopicmouse models and measured on-target drug activity. Results: We first determined that both NOTCH1-mutant and wild-type T-ALL are highly sensitive to pharmacologic inhibition of CDK4/6 when wild-type RB is expressed. Next, we determined that CDK4/6 inhibitors are antagonistic when used either concurrently or in sequence with many of the drugs used to treat relapsed T-ALL (methotrexate, mercaptopurine, asparaginase, and doxorubicin) but are synergistic with glucocorticoids, an mTOR inhibitor, and gamma secretase inhibitor. The combinations of LEE011 with the glucocorticoid dexamethasone or the mTOR inhibitor everolimus were tested in vivo and prolonged survival in three orthotopic mouse models of T-ALL. On-target activity was measured in peripheral blood and tissue of treated mice. Conclusions: We conclude that LEE011 is active in T-ALL and that combination therapy with corticosteroids and/or mTOR inhibitors warrants further investigation. 2016 AACR. C1 [Pikman, Yana; Alexe, Gabriela; Roti, Giovanni; Conway, Amy Saur; Furman, Andrew; Lee, Emily S.; Place, Andrew E.; Modiste, Rebecca; Silverman, Lewis B.; Stegmaier, Kimberly] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Pikman, Yana; Alexe, Gabriela; Roti, Giovanni; Conway, Amy Saur; Furman, Andrew; Lee, Emily S.; Place, Andrew E.; Modiste, Rebecca; Silverman, Lewis B.; Stegmaier, Kimberly] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA. [Alexe, Gabriela; Stegmaier, Kimberly] Broad Inst Massachusetts Inst Technol & Harvard U, Cambridge, MA USA. [Alexe, Gabriela] Boston Univ, Bioinformat Grad Program, Boston, MA 02215 USA. [Kim, Sunkyu; Saran, Chitra] Novartis Inst BioMed Res Inc, Cambridge, MA USA. [Weinstock, David M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Harris, Marian] Boston Childrens Hosp, Dept Pathol, Boston, MA USA. [Kung, Andrew L.] Mem Sloan Kettering Canc Ctr, Dept Pediat, 1275 York Ave, New York, NY 10021 USA. RP Stegmaier, K (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,Dana 640C, Boston, MA 02215 USA. EM kimberly_stegmaier@dfci.harvard.edu OI Pikman, Yana/0000-0002-5336-0216 FU Boston Children's Hospital Translational Research Program Pilot grant; Alex's Lemonade Stand Young Investigator Award; NIH National Institute of Child Health & Human Development [5K12HD052896-09] FX This research was supported by Team Ari and the Boston Children's Hospital Translational Research Program Pilot grant. K. Stegmaier is a Leukemia and Lymphoma Society Scholar. Y. Pikman is the recipient of an Alex's Lemonade Stand Young Investigator Award and NIH National Institute of Child Health & Human Development (5K12HD052896-09). NR 48 TC 1 Z9 1 U1 2 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB PY 2017 VL 23 IS 4 BP 1012 EP 1024 DI 10.1158/1078-0432.CCR-15-2869 PG 13 WC Oncology SC Oncology GA EK4GS UT WOS:000393885700016 PM 28151717 ER PT J AU Sacchet, MD Levy, BJ Hamilton, JP Maksimovskiy, A Hertel, PT Joormann, J Anderson, MC Wagner, AD Gotlib, IH AF Sacchet, Matthew D. Levy, Benjamin J. Hamilton, J. Paul Maksimovskiy, Arkadiy Hertel, Paula T. Joormann, Jutta Anderson, Michael C. Wagner, Anthony D. Gotlib, Ian H. TI Cognitive and neural consequences of memory suppression in major depressive disorder SO COGNITIVE AFFECTIVE & BEHAVIORAL NEUROSCIENCE LA English DT Article DE Major depressive disorder (MDD); Functional magnetic resonance imaging (fMRI); Memory suppression; Think/No-Think (TNT); Cognitive neuroscience; Negative valence ID UNWANTED MEMORIES; PREFRONTAL ACTIVATION; UNIPOLAR DEPRESSION; INHIBITORY-CONTROL; NEGATIVE MATERIAL; WORKING-MEMORY; HUMAN BRAIN; FMRI; MECHANISMS; RETRIEVAL AB Negative biases in cognition have been documented consistently in major depressive disorder (MDD), including difficulties in the ability to control the processing of negative material. Although negative information-processing biases have been studied using both behavioral and neuroimaging paradigms, relatively little research has been conducted examining the difficulties of depressed persons with inhibiting the retrieval of negative information from long-term memory. In this study, we used the think/no-think paradigm and functional magnetic resonance imaging to assess the cognitive and neural consequences of memory suppression in individuals diagnosed with depression and in healthy controls. The participants showed typical behavioral forgetting effects, but contrary to our hypotheses, there were no differences between the depressed and nondepressed participants or between neutral and negative memories. Relative to controls, depressed individuals exhibited greater activity in right middle frontal gyrus during memory suppression, regardless of the valence of the suppressed stimuli, and differential activity in the amygdala and hippocampus during memory suppression involving negatively valenced stimuli. These findings indicate that depressed individuals are characterized by neural anomalies during the suppression of long-term memories, increasing our understanding of the brain bases of negative cognitive biases in MDD. C1 [Sacchet, Matthew D.; Wagner, Anthony D.; Gotlib, Ian H.] Stanford Univ, Neurosci Program, Stanford, CA 94305 USA. [Sacchet, Matthew D.; Wagner, Anthony D.; Gotlib, Ian H.] Stanford Univ, Dept Psychol, Jordan Hall,Bldg 01-420,450 Serra Mall, Stanford, CA 94305 USA. [Sacchet, Matthew D.; Levy, Benjamin J.; Hamilton, J. Paul; Maksimovskiy, Arkadiy; Hertel, Paula T.; Joormann, Jutta; Anderson, Michael C.; Wagner, Anthony D.; Gotlib, Ian H.] VA Boston Healthcare Syst, Translat Res Ctr TBI & Stress Related Disorders T, Boston, MA 02130 USA. [Levy, Benjamin J.] Univ San Francisco, Dept Psychol, San Francisco, CA 94117 USA. [Hamilton, J. Paul] Linkoping Univ, Dept Clin & Expt Med, Ctr Social & Affect Neurosci, Linkoping, Sweden. [Maksimovskiy, Arkadiy] Boston Univ, Sch Med, Dept Behav Neurosci, Boston, MA 02118 USA. [Hertel, Paula T.] Trinity Univ, Dept Psychol, San Antonio, TX 78212 USA. [Joormann, Jutta] Yale Univ, Dept Psychol, New Haven, CT USA. [Anderson, Michael C.] Univ Cambridge, MRC Cognit & Brain Sci Unit, Cambridge, England. RP Sacchet, MD (reprint author), Stanford Univ, Neurosci Program, Stanford, CA 94305 USA.; Sacchet, MD (reprint author), Stanford Univ, Dept Psychol, Jordan Hall,Bldg 01-420,450 Serra Mall, Stanford, CA 94305 USA.; Sacchet, MD (reprint author), VA Boston Healthcare Syst, Translat Res Ctr TBI & Stress Related Disorders T, Boston, MA 02130 USA. EM msacchet@stanford.edu FU NSF [0801700, DGE-1147470]; NIMH [T32 MH020016, R01-MH59259]; UK Medical Research Council [MC-A060-5PR00] FX This study was supported by NSF Integrative Graduate Education and Research Traineeship Recipient Award No. 0801700, NSF Graduate Research Fellowship Program (GRFP) DGE-1147470, and NIMH Neuroscience Research Training Award No. T32 MH020016, to M.D.S.; by NIMH Grant No. R01-MH59259 to I.H.G.; and UK Medical Research Council Grant No. MC-A060-5PR00 to M.C.A. NR 67 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1530-7026 EI 1531-135X J9 COGN AFFECT BEHAV NE JI Cogn. Affect. Behav. Neurosci. PD FEB PY 2017 VL 17 IS 1 BP 77 EP 93 DI 10.3758/s13415-016-0464-x PG 17 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA EK2QW UT WOS:000393772800004 PM 27649971 ER PT J AU Lehavot, K Litz, B Millard, SP Hamilton, AB Sadler, A Simpson, T AF Lehavot, Keren Litz, Brett Millard, Steven P. Hamilton, Alison B. Sadler, Anne Simpson, Tracy TI Study adaptation, design, and methods of a web-based PTSD intervention for women Veterans SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Posttraumatic stress disorder; Clinical trial; Women veterans; Internet; Web-based intervention ID POSTTRAUMATIC-STRESS-DISORDER; COGNITIVE PROCESSING THERAPY; RANDOMIZED CONTROLLED-TRIAL; OF-LIFE ENJOYMENT; MENTAL-HEALTH; FEMALE VETERANS; SATISFACTION QUESTIONNAIRE; NONINFERIORITY TRIAL; PERSON DELIVERY; SELF-MANAGEMENT AB Women Veterans are a rapidly growing population with high risk of exposure to potentially traumatizing events and PTSD diagnoses. Despite the dissemination of evidence-based treatments for PTSD in the VA, most women Veteran VA users underutilize these treatments. Web-based PTSD treatment has the potential to reach and engage women Veterans with PTSD who do not receive treatment in VA settings. Our objective is to modify and evaluate Delivery of Self Training and Education for Stressful Situations (DESTRESSS), a web-based cognitive-behavioral intervention for PTSD, to target PTSD symptoms among women Veterans. The specific aims are to: (1) obtain feedback about DESTRESS, particularly on its relevance and sensitivity to women, using semi-structured interviews with expert clinicians and women Veterans with PTSD, and make modifications based on this feedback; (2) conduct a pilot study to finalize study procedures and make further refinements to the intervention; and (3) conduct a randomized clinical trial (RCT) evaluating a revised, telephone-assisted DESTRESS compared to telephone monitoring only. We describe the results from the first two aims, and the study design and procedures for the ongoing RCT. This line of research has the potential to result in a gender-sensitive, empirically based, online treatment option for women Veterans with PTSD. Published by Elsevier Inc. C1 [Lehavot, Keren] Denver Seattle Ctr Innovat Vet Ctr Value Driven C, VA Puget Sound Hlth Serv Res & Dev, Seattle, WA USA. [Lehavot, Keren; Millard, Steven P.; Simpson, Tracy] VA Puget Sound Hlth Care Syst, MIRECC, Seattle, WA USA. [Lehavot, Keren; Simpson, Tracy] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Lehavot, Keren] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Litz, Brett] Vet Affairs Boston Healthcare Syst, Boston, MA USA. [Hamilton, Alison B.] VA Greater Los Angeles Healthcare Syst, VA HSR&D Ctr, Study Healthcare Innovat Implementat & Policy, Los Angeles, CA USA. [Hamilton, Alison B.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA USA. [Sadler, Anne] Iowa City VA Hlth Care Syst, Ctr Comprehens Access & Delivery Res & Evaluat CA, Iowa City, IA USA. [Sadler, Anne] Univ Iowa, Dept Psychiat, Carver Coll Med, Iowa City, IA 52242 USA. [Simpson, Tracy] VA Puget Sound Hlth Care Syst, CESATE, Seattle, WA USA. [Simpson, Tracy] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Lehavot, K (reprint author), 1660 South Columbian Way, Seattle, WA 98108 USA. EM keren.lehavot@va.gov FU CSR&D Service of the VA Office of Research and Development [IK2 CX000867] FX This work was supported by a VA Career Development Award from the CSR&D Service of the VA Office of Research and Development to Dr. Lehavot (IK2 CX000867). The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans. NR 57 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 1551-7144 EI 1559-2030 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD FEB PY 2017 VL 53 BP 68 EP 79 DI 10.1016/j.cct.2016.12.002 PG 12 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA EK1ZA UT WOS:000393725200009 PM 27940187 ER PT J AU Kangovi, S Mitra, N Turr, L Huo, HR Grande, D Long, JA AF Kangovi, Shreya Mitra, Nandita Turr, Lindsey Huo, Hairong Grande, David Long, Judith A. TI A randomized controlled trial of a community health worker intervention in a population of patients with multiple chronic diseases: Study design and protocol SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Randomized controlled trial; Upstream medicine; Socioeconomic determinants ID AFRICAN-AMERICAN; SELF-MANAGEMENT; PRIMARY-CARE; BLOOD-PRESSURE; RISK REDUCTION; CLINICAL-TRIAL; SCREENING-TEST; OUTCOMES; ADULTS; ADOLESCENTS AB Upstream interventions - e.g. housing programs and community health worker interventions address socioeconomic and behavioral factors that influence health outcomes across diseases. Studying these types of interventions in clinical trials raises a methodological challenge: how should researchers measure the effect of an upstream intervention in a sample of patients with different diseases? This paper addresses this question using an illustrative protocol of a randomized controlled trial of collaborative-goal setting versus goal-setting plus community health worker support among patients multiple chronic diseases: diabetes, obesity, hypertension and tobacco dependence. At study enrollment, patients met with their primary care providers to select one of their chronic diseases to focus on during the study, and to collaboratively set a goal for that disease. Patients randomly assigned to a community health worker also received six months of support to address socioeconomic and behavioral barriers to chronic disease control. The primary hypothesis was that there Would be differences in patients' selected chronic disease control as measured by HbA1c, body mass index, systolic blood pressure and cigarettes per day, between the goal-setting alone and community health worker support arms. To test this hypothesis, we will conduct a stratum specific multivariate analysis of variance which allows all patients (regardless of their selected chronic disease) to be included in a single model for the primary outcome. Population health researchers can use this approach to measure clinical outcomes across diseases. (C) 2016 Elsevier Inc. All rights reserved. C1 [Kangovi, Shreya; Turr, Lindsey; Huo, Hairong; Grande, David; Long, Judith A.] Univ Penn, Perelman Sch Med, Div Gen Internal Med, 1233 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. [Kangovi, Shreya] Penn Med, Penn Ctr Community Hlth Workers, Philadelphia, PA 19104 USA. [Mitra, Nandita] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Long, Judith A.] Corporal Michael J Crescenz VA, Ctr Hlth Equ Res & Promot, Philadelphia, PA 19104 USA. RP Kangovi, S (reprint author), Univ Penn, Perelman Sch Med, Div Gen Internal Med, 1233 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM kangovi@mail.med.upenn.edu; nanditam@mail.med.upenn.edu; lindsey.turr@uphs.upenn.edu; huoh@mail.med.upenn.edu; dgrande@wharton.upenn.edu; jalong@mail.med.upenn.edu FU NHLBI NIH HHS [K23 HL128837] NR 54 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 EI 1559-2030 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD FEB PY 2017 VL 53 BP 115 EP 121 DI 10.1016/j.cct.2016.12.009 PG 7 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA EK1ZA UT WOS:000393725200014 PM 27965180 ER PT J AU Grubbs, V Garcia, F Jue, BL Vittinghoff, E Ryder, M Lovett, D Carrillo, J Offenbacher, S Ganz, P Bibbins-Domingo, K Powe, NR AF Grubbs, Vanessa Garcia, Faviola Jue, Bonnie L. Vittinghoff, Eric Ryder, Mark Lovett, David Carrillo, Jacqueline Offenbacher, Steven Ganz, Peter Bibbins-Domingo, Kirsten Powe, Neil R. TI The Kidney and Periodontal Disease (KAPD) study: A pilot randomized controlled trial testing the effect of non-surgical periodontal therapy on chronic kidney disease SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE (max 6) chronic kidney disease; Periodontal disease; Non-surgical periodontal disease treatment; Periodontitis, oral health ID GELATINASE-ASSOCIATED LIPOCALIN; STAGE RENAL-DISEASE; FLOW-MEDIATED DILATION; ASYMMETRICAL DIMETHYLARGININE; FUNCTION DECLINE; RETROSPECTIVE COHORT; NEPHROPATHY; PROGRESSION; UPDATE; MARKER AB Introduction: Chronic kidney disease (CID) remains a prevalent public health problem that disproportionately affects minorities and the poor, despite intense efforts targeting traditional risk factors. Perioddntal diseases are common bacterial plaque-induced inflammatory conditions that can respond to treatment and have been implicated as a CKD risk factor. However there is limited evidence that treatment of periodontal disease slows the progression of CKD. Methods/design: We describe the protocol of the Kidney and Periodontal Disease (KAPD) study, a 12-month unblinded, randomized, controlled pilot trial with two intent-to-treat treatment arms: 1. immediate intensive nonsurgical periodontal treatment or 2. rescue treatment with delayed intensive treatment. The goals of this pilot study are to test the feasibility of conducting a larger trial in an ethnically and racially diverse, underserved population (mostly poor and/or low literacy) with both CKD and significant periodontal disease to determine the effect of intensive periodontal treatment on renal and inflammatory biotnarkers over a 12-mohth period. Results: To date, KAPD has identified 634 potentially eligible patients who were invited to in-person screening. Of the 83 (13.1%) of potentially eligible patients who attended in-person screening, 51 (61.4%) were eligible for participation and 46 enrolled in the study. The mean age of participants is 59.2 years (range 34 to 73). Twenty of the participants (43.5%) are Black and 22 (47.8%) are Hispanic. Discussion: Results from the KAPD study will provide needed preliminary evidence of the effectiveness of nonsurgical periodontal treatment to slow CKD progression and inform the design future clinical research trials. (C) 2016 Published by Elsevier Inc. C1 [Grubbs, Vanessa; Garcia, Faviola] Univ Calif San Francisco, Div Nephrol, 1001 Potrero Ave,Bldg 100,Room 342, San Francisco, CA 94110 USA. [Jue, Bonnie L.] Univ Calif San Francisco, Dept Prevent & Restorat Dent Sci, Div Oral Epidemiol & Dent Publ Hlth, 3333 Calif St,Ste 495, San Francisco, CA 94118 USA. [Vittinghoff, Eric] Univ Calif San Francisco, Div Epidemiol &Biostat, 550 16th St, San Francisco, CA 94158 USA. [Ryder, Mark] Univ Calif San Francisco, Sch Dent, Dept Orofacial Sci, Div Periodontol, 533 Parnassus Ave,UC Hall, San Francisco, CA 94143 USA. [Lovett, David] San Francisco VA Med Ctr, Div Nephrol, 4150 Clement St, San Francisco, CA 94121 USA. [Carrillo, Jacqueline] Univ Calif San Francisco, Div Gen Internal Med, 1001 Potrero Ave,Bldg 10, San Francisco, CA 94110 USA. [Offenbacher, Steven] UNC Sch Dent, Ctr Oral & System Dis, Dept Periodontol, Koury Hlth Sci Bldg,385 S Columbia St,Room 3501F, Chapel Hill, NC 27599 USA. [Ganz, Peter] Univ Calif San Francisco, Div Cardiol, 1001 Potrero Ave,Bldg 5, San Francisco, CA 94110 USA. [Bibbins-Domingo, Kirsten] Univ Calif San Francisco, Div Gen Internal Med, 550 16th St, San Francisco, CA 94158 USA. [Powe, Neil R.] Univ Calif San Francisco, Dept Med, 1001 Potrero Ave,Bldg 5, San Francisco, CA 94110 USA. RP Grubbs, V (reprint author), Univ Calif San Francisco, Div Nephrol, 1001 Potrero Ave,Bldg 100,Room 342, San Francisco, CA 94110 USA. EM vanessa.grubbs@ucsf.edu; faviola.garcia@ucsf.edu; bonnie.jue@ucsf.edu; Eric.Vittinghoff@ucsf.edu; Mark.Ryder@ucsf.edu; David.Lovett@ucsf.edu; jacqueline.carrillo@ucsf.edu; steven_offenbacher@unc.edu; Peter.Ganz@ucsf.edu; Kirsten.bibbins-domingo@ucsf.edu; neil.powe@ucsf.edu FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK, Bethesda, MD) [1K23DK093710-01A1]; Harold Amos Medical Faculty Development Program of the Robert Wood Johnson Foundation, Princeton, NJ [P0045259] FX KAPD and VG are supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK, Bethesda, MD) [grant number 1K23DK093710-01A1] and by the Harold Amos Medical Faculty Development Program of the Robert Wood Johnson Foundation (P0045259), Princeton, NJ. NR 43 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 1551-7144 EI 1559-2030 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD FEB PY 2017 VL 53 BP 143 EP 150 DI 10.1016/j.cct.2016.12.017 PG 8 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA EK1ZA UT WOS:000393725200018 PM 28011387 ER PT J AU Cipres, D Seidman, D Cloniger, C Nova, C O'Shea, A Obedin-Maliver, J AF Cipres, Danielle Seidman, Dominika Cloniger, Charles, III Nova, Cyd O'Shea, Anita Obedin-Maliver, Juno TI Contraceptive use and pregnancy intentions among transgender men presenting to a clinic for sex workers and their families in San Francisco SO CONTRACEPTION LA English DT Article DE Transgender; Female-to-male; Contraception; Testosterone; Family planning; Reproductive health ID FEMALE; CARE AB Purpose: Although many transgender men may be able to conceive, their reproductive health needs are understudied. Methods: We retrospectively reviewed charts of transgender men presenting to a clinic for sex workers to describe the proportion at risk for pregnancy, pregnancy intentions, and contraceptive use. Results: Of 26 transgender men identified, half were at risk for pregnancy. Most desired to avoid pregnancy but used only condoms or no contraception. Two individuals desired pregnancy, were taking testosterone (a teratogen), and not using contraception. Conclusion: Further research is needed to explore how to best provide family planning services including preconception and contraception care to transgender men. (C) 2017 Elsevier Inc. All rights reserved. C1 [Cipres, Danielle] Univ Calif San Francisco, Sch Med, 513 Parnassus Ave, San Francisco, CA 94143 USA. [Seidman, Dominika; Obedin-Maliver, Juno] Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, 550 16th St, San Francisco, CA 94158 USA. [Cloniger, Charles, III] Univ Calif San Francisco, Dept Social & Behav Sci, 3333 Calif St, San Francisco, CA 94118 USA. [Cloniger, Charles, III] San Francisco Dept Publ Hlth, Populat Hlth Div, 25 Van Ness Ave,Suite 500, San Francisco, CA 94102 USA. [Cloniger, Charles, III; Nova, Cyd; O'Shea, Anita] St James Infirm, 234 Eddy St, San Francisco, CA 94102 USA. [Obedin-Maliver, Juno] San Francisco VA Med Ctr, Dept Med, Div Gen Internal Med, 4150 Clement St,Bldg 18,Room 111A1, San Francisco, CA 94121 USA. RP Seidman, D (reprint author), Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, 550 16th St, San Francisco, CA 94158 USA. EM Danielle.cipres@ucsf.edu; Dominika.seidman@ucsf.edu; Chuck.sjimedical@yahoo.com; Registration@stjamesinfirmnary.org; Juno.obedin-maliver@ucsf.edu FU UCSF PROF-PATH program, National Institute on Minority Health and Health Disparities [R25MD006832] FX DC received support from the UCSF PROF-PATH program, National Institute on Minority Health and Health Disparities (R25MD006832). NR 10 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0010-7824 EI 1879-0518 J9 CONTRACEPTION JI Contraception PD FEB PY 2017 VL 95 IS 2 BP 186 EP 189 DI 10.1016/j.contraception.2016.09.005 PG 4 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EJ0JU UT WOS:000392895300011 PM 27621044 ER PT J AU Feuerstein, JD Sehgal, P Rao, V Malladi, VR Baroni, E Cheifetz, AS AF Feuerstein, Joseph D. Sehgal, Priya Rao, Varun Malladi, Vijayram Reddy Baroni, Emily Cheifetz, Adam S. TI Inflammatory Bowel Disease-Related Abstracts Presented at National Conferences in the USA Are Frequently Unpublished as Full Manuscripts SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article DE Inflammatory bowel disease; Abstracts; Conferences ID REPORTING QUALITY; PUBLICATION; ASSOCIATION; MEETINGS; TRIALS AB Numerous abstracts related to inflammatory bowel disease (IBD) are presented at national conferences in the USA. The overall rate of publication of these abstracts as complete manuscripts is unknown . Abstracts submitted to the 2010 American College of Gastroenterology (ACG), Advances in Inflammatory Bowel Diseases (AIBD), and the American Gastroenterological Association abstracts at Digestive Disease Week (DDW) were reviewed. Each abstract was reviewed manually by two authors for type of research, study design, patient population, and outcome. Both PubMed and Google were then searched to determine whether the abstract was published as a full manuscript within five years of the conference. Univariate and multivariate logistic regression analysis was carried out using Stata 14.1. In total, 872 abstracts were reviewed. 49% (426/872) were published as complete manuscripts within five years of the conference. The average length of time to publication was 1.87 years (range 0-5). 42% of abstracts from ACG, 58% from AIBD, and 23% from DDW were eventually published (p < 0.0001). However, abstracts presented at DDW had the shortest time to publication compared to the other conferences (p = 0.002). Factors predictive of eventual publication include: number of authors (mean 7.5 for published vs 6.4 for unpublished p = 0.0001), clinical research compared to basic and translational (p = 0.026), and studies assessing drug safety with no adverse effects reported (p = 0.006). Nearly 50% of the abstracts presented at major gastroenterology conferences in the USA are published as full manuscripts 5 years after the conference. Further studies are needed to assess why so many abstracts are not published. C1 [Feuerstein, Joseph D.; Sehgal, Priya; Rao, Varun; Baroni, Emily; Cheifetz, Adam S.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Div Gastroenterol, Dept Med, 110 Francis St,8E Gastroenterol, Boston, MA 02215 USA. [Malladi, Vijayram Reddy] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Boston, MA USA. RP Feuerstein, JD (reprint author), Harvard Med Sch, Beth Israel Deaconess Med Ctr, Div Gastroenterol, Dept Med, 110 Francis St,8E Gastroenterol, Boston, MA 02215 USA. EM jfeuerst@bidmc.harvard.edu; prs895@mail.harvard.edu; vraoboston@gmail.com; vijayramreddym@gmail.com; ebaroni@Bu.edu; acheifet@bidmc.harvard.edu FU Abbott Laboratories; Janssen Pharaceuticals; Warner-Chilcott; Given Imaging; Prometheus Labs; Pfizer FX None of the authors have any relevant conflicts of interest related to this manuscript. In full disclosure, the following industry relationships are noted: Dr. Adam Cheifetz: Consulting or Grants from the following: (1) Abbott Laboratories, (2) Janssen Pharaceuticals, (3) Warner-Chilcott, (4) Given Imaging, (5) Prometheus Labs, (6) Pfizer. NR 7 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 EI 1573-2568 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD FEB PY 2017 VL 62 IS 2 BP 352 EP 357 DI 10.1007/s10620-016-4394-9 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EK0VI UT WOS:000393644800011 PM 27975235 ER PT J AU Stevens, BW Borren, NZ Velonias, G Conway, G Cleland, T Andrews, E Khalili, H Garber, JJ Xavier, RJ Yajnik, V Ananthakrishnan, AN AF Stevens, Betsy W. Borren, Nynke Z. Velonias, Gabriella Conway, Grace Cleland, Thom Andrews, Elizabeth Khalili, Hamed Garber, John J. Xavier, Ramnik J. Yajnik, Vijay Ananthakrishnan, Ashwin N. TI Vedolizumab Therapy Is Associated with an Improvement in Sleep Quality and Mood in Inflammatory Bowel Diseases (vol 62, pg 197, 2017) SO DIGESTIVE DISEASES AND SCIENCES LA English DT Correction C1 [Stevens, Betsy W.; Borren, Nynke Z.; Velonias, Gabriella; Conway, Grace; Cleland, Thom; Andrews, Elizabeth; Khalili, Hamed; Garber, John J.; Xavier, Ramnik J.; Yajnik, Vijay; Ananthakrishnan, Ashwin N.] Massachusetts Gen Hosp, Crohns & Colitis Ctr, Div Gastroenterol, 165 Cambridge St,9th Floor, Boston, MA 02114 USA. [Borren, Nynke Z.] Univ Groningen, Groningen, Netherlands. [Khalili, Hamed; Garber, John J.; Xavier, Ramnik J.; Yajnik, Vijay; Ananthakrishnan, Ashwin N.] Harvard Med Sch, Boston, MA 02115 USA. RP Ananthakrishnan, AN (reprint author), Massachusetts Gen Hosp, Crohns & Colitis Ctr, Div Gastroenterol, 165 Cambridge St,9th Floor, Boston, MA 02114 USA.; Ananthakrishnan, AN (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM aananthakrishnan@mgh.harvard.edu NR 1 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 EI 1573-2568 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD FEB PY 2017 VL 62 IS 2 BP 552 EP 552 DI 10.1007/s10620-016-4380-2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EK0VI UT WOS:000393644800034 PM 27864657 ER PT J AU Krail, EB Wang, B Munoz, DM Ilic, N Raghavan, S Niederst, MJ Yu, K Ruddy, DA Aguirre, AJ Kim, JW Redig, AJ Gainor, JF Williams, JA Asara, JM Doench, JG Janne, PA Shaw, AT McDonald, RE Engelman, JA Stegmeier, F Schlabach, MR Hahn, WC AF Krail, Elsa B. Wang, Belinda Munoz, Diana M. Ilic, Nina Raghavan, Srivatsan Niederst, Matthew J. Yu, Kristine Ruddy, David A. Aguirre, Andrew J. Kim, Jong Wook Redig, Amanda J. Gainor, Justin F. Williams, Juliet A. Asara, John M. Doench, John G. Janne, Pasi A. Shaw, Alice T. McDonald, Robert E., III Engelman, Jeffrey A. Stegmeier, Frank Schlabach, Michael R. Hahn, William C. TI KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer SO ELIFE LA English DT Article ID GROWTH-FACTOR-RECEPTOR; KRAS-MUTANT LUNG; ACQUIRED-RESISTANCE; RAF INHIBITION; HUMAN-CELLS; MEK INHIBITION; COLON-CANCER; E3 LIGASE; NRF2; MUTATIONS AB Inhibitors that target the receptor tyrosine kinase (RTK)/Ras/mitogen-activated protein kinase (MAPK) pathway have led to clinical responses in lung and other cancers, but some patients fail to respond and in those that do resistance inevitably occurs (Balak et al., 2006; Kosaka et al., 2006; Rudin et al., 2013; Wagle et al., 2011). To understand intrinsic and acquired resistance to inhibition of MAPK signaling, we performed CRISPR-Cas9 gene deletion screens in the setting of BRAF, MEK, EGFR, and ALK inhibition. Loss of KEAP1, a negative regulator of NFE2L2/NRF2, modulated the response to BRAF, MEK, EGFR, and ALK inhibition in BRAF-, NRAS-, KRAS-, EGFR-, and ALK-mutant lung cancer cells. Treatment with inhibitors targeting the RTK/MAPK pathway increased reactive oxygen species (ROS) in cells with intact KEAP1, and loss of KEAP1 abrogated this increase. In addition, loss of KEAP1 altered cell metabolism to allow cells to proliferate in the absence of MAPK signaling. These observations suggest that alterations in the KEAP1/NRF2 pathway may promote survival in the presence of multiple inhibitors targeting the RTK/Ras/MAPK pathway. C1 [Krail, Elsa B.; Wang, Belinda; Ilic, Nina; Raghavan, Srivatsan; Aguirre, Andrew J.; Kim, Jong Wook; Redig, Amanda J.; Janne, Pasi A.; Hahn, William C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Krail, Elsa B.; Wang, Belinda; Ilic, Nina; Raghavan, Srivatsan; Aguirre, Andrew J.; Kim, Jong Wook; Doench, John G.; Hahn, William C.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Krail, Elsa B.; Wang, Belinda; Ilic, Nina; Raghavan, Srivatsan; Aguirre, Andrew J.; Kim, Jong Wook; Redig, Amanda J.; Janne, Pasi A.; Hahn, William C.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Krail, Elsa B.; Wang, Belinda; Ilic, Nina; Raghavan, Srivatsan; Aguirre, Andrew J.; Kim, Jong Wook; Redig, Amanda J.; Janne, Pasi A.; Hahn, William C.] Harvard Med Sch, Boston, MA 02115 USA. [Munoz, Diana M.; Niederst, Matthew J.; Yu, Kristine; Ruddy, David A.; Williams, Juliet A.; McDonald, Robert E., III; Engelman, Jeffrey A.; Stegmeier, Frank; Schlabach, Michael R.] Novartis Inst Biomed Res, Oncol Dis Area, Cambridge, MA USA. [Shaw, Alice T.] Massachusetts Gen Hosp, Dept Med, Harvard Med Sch, Boston, MA 02114 USA. [Asara, John M.] Beth Israel Deaconess Med Ctr, Harvard Med Sch, Dept Med, Boston, MA 02215 USA. [Asara, John M.] Beth Israel Deaconess Med Ctr, Harvard Med Sch, Ctr Canc, Boston, MA 02215 USA. RP Hahn, WC (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA.; Hahn, WC (reprint author), Broad Inst Harvard & MIT, Cambridge, MA 02142 USA.; Hahn, WC (reprint author), Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA.; Hahn, WC (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM william_hahn@dfci.harvard.edu FU National Cancer Institute [R01CA130998, U01CA176058, U01CA199253]; Hope Funds for Cancer Research Postdoctoral Fellowship [HFCR-11-03-03]; National Institutes of Health [F32 CA189306]; Susan G. Komen Foundation [PDF12230602]; Terri Brodeur Breast Cancer Foundation; Pancreatic Cancer Action Network; American Society of Clinical Oncology; Dana-Farber Cancer Institute Hale Center for Pancreatic Cancer; Perry S. Levy Endowed Fellowship; Harvard Catalyst and Harvard Clinical and Translational Science Center [UL1TR001102] FX National Cancer Institute R01CA130998 William C Hahn; National Cancer Institute U01CA176058 William C Hahn; National Cancer Institute U01CA199253 William C Hahn; Hope Funds for Cancer Research Postdoctoral Fellowship HFCR-11-03-03 Elsa B Krall; National Institutes of Health Postdoctoral Fellowship F32 CA189306 Elsa B Krall; Susan G. Komen Foundation Postdoctoral Fellowship PDF12230602 Nina Ilic; Terri Brodeur Breast Cancer Foundation Postdoctoral Fellowship Nina Ilic; Pancreatic Cancer Action Network Samuel Stroum Fellowship Andrew J Aguirre; American Society of Clinical Oncology Young Investigator Award Andrew J Aguirre; Dana-Farber Cancer Institute Hale Center for Pancreatic Cancer Andrew J Aguirre; Perry S. Levy Endowed Fellowship Andrew J Aguirre; Harvard Catalyst and Harvard Clinical and Translational Science Center UL1TR001102 Andrew J Aguirre NR 51 TC 0 Z9 0 U1 1 U2 1 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD FEB 1 PY 2017 VL 6 AR e18970 DI 10.7554/eLife.18970 PG 21 WC Biology SC Life Sciences & Biomedicine - Other Topics GA EK9OY UT WOS:000394255000001 ER PT J AU Nguyen, K Kempfle, JS Jung, DH McKenna, CE AF Nguyen, Kim Kempfle, Judith S. Jung, David H. McKenna, Charles E. TI Recent advances in therapeutics and drug delivery for the treatment of inner ear diseases: a patent review (2011-2015) SO EXPERT OPINION ON THERAPEUTIC PATENTS LA English DT Review DE Hearing loss; tinnitus; Meniere's disease; inner ear disorders; ototoxicity; local drug delivery; sustained drug delivery; hair cell regeneration; hair cell protection ID HAIR-CELL REGENERATION; N-TERMINAL KINASE; INDUCED HEARING-LOSS; MENIERES-DISEASE; COCHLEAR IMPLANTATION; DOMINANT DEAFNESS; AUDITORY NEURONS; SUPPORTING CELLS; ACOUSTIC TRAUMA; ROUND WINDOW AB Introduction: Inner ear disorders such as hearing loss, tinnitus, and Meniere's disease significantly impact the quality of life of affected individuals. Treatment of such disorders is an ongoing challenge. Current clinical approaches relieve symptoms but do not fully restore hearing, and the search for more effective therapeutic methods represents an area of urgent current interest. Areas covered: Thirty four patents and patent applications published from 2011 to 2015 were selected from the database of the U.S. Patent and Trademark Office (USPTO) and World Intellectual Property Organization (WIPO), covering new approaches for the treatment of inner ear disorders described in the patent literature: 1) identification of new therapeutic agents, 2) development of sustained release formulations, and 3) medical devices that facilitate delivery of such agents to the inner ear. Expert opinion: The search for effective treatments of inner ear disorders is ongoing. Increased understanding of the molecular mechanisms of hearing loss, Meniere's disease, and tinnitus is driving development of new therapeutic agents. However, delivery of these agents to the inner ear is a continuing challenge. At present, combination of a suitable drug with an appropriate mode of drug delivery is the key focus of innovative research to cure inner ear disorders. C1 [Nguyen, Kim; McKenna, Charles E.] Univ Southern Calif, Dept Chem, LJS 268,840 Downey Way, Los Angeles, CA 90089 USA. [Kempfle, Judith S.; Jung, David H.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. [Kempfle, Judith S.; Jung, David H.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Kempfle, Judith S.; Jung, David H.] Harvard Med Sch, Dept Otol & Laryngol, Boston, MA USA. RP McKenna, CE (reprint author), Univ Southern Calif, Dept Chem, LJS 268,840 Downey Way, Los Angeles, CA 90089 USA. EM mckenna@usc.edu FU Herbert Silverstein Award from the American Neurotology Society; USC Dornsife College of Letters, Arts and Sciences FX This paper was funded by the Herbert Silverstein Award from the American Neurotology Society (DJ) and by the USC Dornsife College of Letters, Arts and Sciences (KN, CEMcK). NR 140 TC 0 Z9 0 U1 2 U2 2 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1354-3776 EI 1744-7674 J9 EXPERT OPIN THER PAT JI Expert Opin. Ther. Patents PD FEB PY 2017 VL 27 IS 2 BP 191 EP 202 DI 10.1080/13543776.2017.1252751 PG 12 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EK1UG UT WOS:000393710700007 PM 27855527 ER PT J AU Hou, L Sun, N Mane, S Sayward, F Rajeevan, N Cheung, KH Cho, K Pyarajan, S Aslan, M Miller, P Harvey, PD Gaziano, JM Concato, J Zhao, HY AF Hou, Lin Sun, Ning Mane, Shrikant Sayward, Fred Rajeevan, Nallakkandi Cheung, Kei-Hoi Cho, Kelly Pyarajan, Saiju Aslan, Mihaela Miller, Perry Harvey, Philip D. Gaziano, J. Michael Concato, John Zhao, Hongyu TI Impact of genotyping errors on statistical power of association tests in genomic analyses: A case study SO GENETIC EPIDEMIOLOGY LA English DT Article DE genome wide association test; genotyping; genotyping error; sequencing; statistical power ID DOUBLE SAMPLING SCHEME; GENETIC ASSOCIATION; WIDE ASSOCIATION; COMMON DISEASES; RARE VARIANTS; BINOMIAL DATA; TREND TESTS; MISCLASSIFICATIONS; SCHIZOPHRENIA; HERITABILITY AB A key step in genomic studies is to assess high throughput measurements across millions of markers for each participant's DNA, either using microarrays or sequencing techniques. Accurate genotype calling is essential for downstream statistical analysis of genotype-phenotype associations, and next generation sequencing (NGS) has recently become a more common approach in genomic studies. How the accuracy of variant calling in NGS-based studies affects downstream association analysis has not, however, been studied using empirical data in which both microarrays and NGS were available. In this article, we investigate the impact of variant calling errors on the statistical power to identify associations between single nucleotides and disease, and on associations between multiple rare variants and disease. Both differential and nondifferential genotyping errors are considered. Our results show that the power of burden tests for rare variants is strongly influenced by the specificity in variant calling, but is rather robust with regard to sensitivity. By using the variant calling accuracies estimated from a substudy of a Cooperative Studies Program project conducted by the Department of Veterans Affairs, we show that the power of association tests is mostly retained with commonly adopted variant calling pipelines. An R package, GWAS.PC, is provided to accommodate power analysis that takes account of genotyping errors (). C1 [Hou, Lin; Sun, Ning; Sayward, Fred; Rajeevan, Nallakkandi; Cheung, Kei-Hoi; Aslan, Mihaela; Miller, Perry; Concato, John; Zhao, Hongyu] VA Connecticut Healthcare Syst, CERC, Vet Affairs VA Cooperat Studies Program, West Haven, CT USA. [Hou, Lin; Sun, Ning; Zhao, Hongyu] Yale Sch Publ Hlth, Dept Biostat, 60 Coll St, New Haven, CT 06520 USA. [Mane, Shrikant] Yale Univ Sch Med, Dept Genet, New Haven, CT USA. [Sayward, Fred; Rajeevan, Nallakkandi; Cheung, Kei-Hoi; Miller, Perry] Yale Univ, Sch Med, Ctr Med Informat, New Haven, CT USA. [Cho, Kelly; Pyarajan, Saiju; Gaziano, J. Michael] VA Boston Healthcare Syst, MAVERIC, VA Cooperat Studies Program, Boston, MA USA. [Cho, Kelly; Pyarajan, Saiju; Gaziano, J. Michael] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Aslan, Mihaela; Concato, John] Yale Univ, Sch Med, Dept Med, New Haven, CT 06510 USA. [Harvey, Philip D.] Bruce W Carter Miami Vet Affairs VA Med Ctr, Miami, FL USA. [Harvey, Philip D.] Univ Miami, Miller Sch Med, Dept Psychiat, Miami, FL 33136 USA. [Hou, Lin] Tsinghua Univ, Ctr Stat Sci, Beijing 100084, Peoples R China. RP Zhao, HY (reprint author), Yale Sch Publ Hlth, Dept Biostat, 60 Coll St, New Haven, CT 06520 USA. EM hongyu.zhao@yale.edu FU VA Office of Research and Development [572, G002]; VA Office of Research and Development FX This research was supported by the VA Office of Research and Development (Cooperative Studies Program #572 and Million Veteran Program #G002). The authors thank staff members on the corresponding projects, Sandra Augustitus for assistance with the manuscript, and especially participants who previously served their country and agreed to enroll in these studies. Dr. Harvey has served as a consultant to Boeheringer-Ingelheim, Forum Pharma, Lundbeck, Otsuka-America, Sanofi, Sunovion, and Takeda, and he has received a research grant from Takeda; these activities are not related to the content of this paper. Support from the VA Office of Research and Development included input from Drs. Grant Huang, Jennifer Moser, Sumitra Muralidhar, Ronald Przygodzki, and Timothy O'Leary. NR 40 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD FEB PY 2017 VL 41 IS 2 BP 152 EP 162 DI 10.1002/gepi.22027 PG 11 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA EK2WW UT WOS:000393788600006 PM 28019059 ER PT J AU Chen, YW Simancas-Pallares, M Marincola, M Chuang, SK AF Chen, Ya-Wei Simancas-Pallares, Miguel Marincola, Mauro Chuang, Sung-Kiang TI Grafting and Dental Implantation in Patients With Jawbone Cavitation: Case Series and 3-Year Follow-Up SO IMPLANT DENTISTRY LA English DT Article DE bone graft; cavitation; dental implant; jawbone; osteoporosis ID BONE-MARROW DEFECT; OSTEONECROSIS; DISPLACEMENT; JAWS; MAXILLA; UPDATE AB Purpose: Jawbone cavitation (BC) is not uncommon and is considered to be related to some cases of unexpected implant displacement into deep jawbone space. Here, a series of cases with BC is described, in which the lesions were accidentally found and successfully treated by bone grafting and dental implantation. Methods: Thirty-four partially edentulous patients who were found to have BC during dental implant surgeries were included in this study. Alloplast bone substitute (beta-tricalcium phosphate) grafting with immediate or staged lockingtaper implant placement was performed. Bone filling and implants on BC were followed up to 36 months, and they were evaluated clinically and radiographically to verify treatment outcome. Results: A total of 41 BCs were found at premolar and molar regions, which involved one or more teeth breadth. Nearly most of the lesions occurred in the mandible (95.1%, 39/41). Histologically, they were compatible with focal osteoporotic marrow defects. Fifty-two locking-taper implants and final restorations were delivered on 38 BCs. One implant failed due to loss of integration. The overall cumulative 3-year implant survival rate was 98.1%. Conclusion: By carefully examining and managing the surgical bed, the current treatment modality was shown to yield a satisfactory outcome for restoration of edentulous ridge with underneath BC. C1 [Chen, Ya-Wei] Taipei Vet Gen Hosp, Dept Stomatol, Oral & Maxillofacial Surg, Taipei, Taiwan. [Chen, Ya-Wei] Sch Dent, Taipei, Taiwan. [Chen, Ya-Wei] Natl Yang Ming Univ, Taipei, Taiwan. [Chen, Ya-Wei] Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. [Chen, Ya-Wei] Harvard Sch Dent Med, Boston, MA USA. [Simancas-Pallares, Miguel; Marincola, Mauro] Univ Cartagena, Fac Dent, Dent Implant Unit, Cartagena, Colombia. [Simancas-Pallares, Miguel; Marincola, Mauro] Univ Cartagena, Fac Dent, Res Dept, Cartagena, Colombia. [Chuang, Sung-Kiang] Brockton Oral & Maxillofacial Surg Inc, Good Samaritan Med Ctr, Brockton, MA USA. RP Chuang, SK (reprint author), POB 67376, Chestnut Hill, MA 02467 USA. EM sungkiangchuang@gmail.com NR 26 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1056-6163 J9 IMPLANT DENT JI Implant Dent. PD FEB PY 2017 VL 26 IS 1 BP 158 EP 164 DI 10.1097/ID.0000000000000558 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA EK1EJ UT WOS:000393668300022 PM 28098576 ER PT J AU Guo, YY Yang, ZY Wu, S Xu, P Peng, YB Yao, M AF Guo, Yuanyuan Yang, Zhiyin Wu, Shan Xu, Peng Peng, Yinbo Yao, Min TI Inhibition of IRF8 Negatively Regulates Macrophage Function and Impairs Cutaneous Wound Healing SO INFLAMMATION LA English DT Article DE IRF8; wound healing; macrophage; inflammation ID PROGENITOR CELLS; TARGET GENES; TRANSCRIPTION; EXPRESSION; LINEAGE; APOPTOSIS; LEUKEMIA AB The inflammatory response is essential for normal cutaneous wound healing. Macrophages, as critical inflammatory cells, coordinate inflammation and angiogenesis phases during wound healing. It has been reported that the transcription factor interferon regulatory factor 8 (IRF8), a member of the IRF family, plays a critical role in the development and function of macrophages and is associated with inflammation. However, the role of IRF8 in cutaneous wound healing and its underlying mechanism remain elusive. Through immunohistochemical (IHC) staining, we showed that IRF8 is involved in the wound repair process in mice and patients. Furthermore, we ascertain that the repression of IRF8 by small interfering RNA (siRNA) leads to delayed wound healing. To explore the mechanism by which IRF8 impacts wound healing, we observed its effect on macrophage-related mediators by IHC or real-time PCR. The results demonstrated that the inhibition of IRF8 decreases the mRNA expression of inflammatory mediators associated with M1 macrophage (il-1b, il-6, inos, and tnf-a) but no impact on M2 macrophage-related mediators (arg-1, mrc-1, and il-10) and the number of macrophages in the wounds. Furthermore, the inhibition of IRF8 induced apoptosis in the wounds. In summary, this study demonstrates that the down-regulation of IRF8 in the wound leads to impaired wound healing possibly through the regulation of macrophage function and apoptosis in skin wound. C1 [Guo, Yuanyuan; Wu, Shan; Xu, Peng; Peng, Yinbo; Yao, Min] Shanghai Jiao Tong Univ, Sch Med, Inst Traumat Med, Dept Burns & Plast Surg,Shanghai Peoples Hosp 9, 280 Mohe Rd, Shanghai 201900, Peoples R China. [Yang, Zhiyin] Shanghai Jiao Tong Univ, Sch Med, Shanghai Peoples Hosp 9, Dept Thorac Surg,Inst Traumat Med, Shanghai 201900, Peoples R China. [Yao, Min] Harvard Med Sch, Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. RP Yao, M (reprint author), Shanghai Jiao Tong Univ, Sch Med, Inst Traumat Med, Dept Burns & Plast Surg,Shanghai Peoples Hosp 9, 280 Mohe Rd, Shanghai 201900, Peoples R China. EM minyao1228@sina.com FU National Natural Science Foundation of China [81272113, 81201469] FX This work was supported partially by the National Natural Science Foundation of China (Nos. 81272113 and 81201469). NR 32 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0360-3997 EI 1573-2576 J9 INFLAMMATION JI Inflammation PD FEB PY 2017 VL 40 IS 1 BP 68 EP 78 DI 10.1007/s10753-016-0454-8 PG 11 WC Cell Biology; Immunology SC Cell Biology; Immunology GA EK0ZL UT WOS:000393655500007 PM 27709315 ER PT J AU Bozkurt, SB Hakki, SS Hakki, EE Durak, Y Kantarci, A AF Bozkurt, S. Buket Hakki, Sema S. Hakki, Erdogan E. Durak, Yusuf Kantarci, Alpdogan TI Porphyromonas gingivalis Lipopolysaccharide Induces a Pro-inflammatory Human Gingival Fibroblast Phenotype SO INFLAMMATION LA English DT Article DE Porphyromonas gingivalis; lipopolysaccharide; fibroblast; cytokine ID PERIODONTAL-LIGAMENT FIBROBLASTS; TOLL-LIKE RECEPTORS; MATRIX METALLOPROTEINASES; TISSUE INHIBITORS; GENE-EXPRESSION; P. GINGIVALIS; HOST-RESPONSE; IL-6; INTERLEUKIN-6; DISEASE AB Human gingival fibroblasts (HGFs) are the major constituents of the gingival tissues responsible for the synthesis and degradation of the connective tissue while actively participating in immune reactions and inflammation. The aim of this study was to test the impact of lipopolysaccharide (LPS) from Porphyromonas gingivalis (P. gingivalis) on human gingival fibroblasts. Human gingival fibroblasts were treated with different P. gingivalis LPS concentrations. Cell survival rate was evaluated with 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) after 24 h. Cell proliferation was determined by counting cells on days 3 and 12. Expression of matrix metalloproteinases (MMPs), tissue inhibitors of MMPs (TIMPs), and pro-inflammatory cytokine transcripts in HGFs was determined by quantitative PCR (Q-PCR) analysis on days 3 and 8. P. gingivalis LPS decreased cell proliferation on day 3 (p < 0.05) compared to the control group without significantly impacting the cell survival (p > 0.05).The experiments showed that P. gingivalis LPS dose-dependently and differentially modulated the expression of MMP-1, 2, and 3 and TIMP-1 and 2 on days 3 and 8. TIMP-1 expression was significantly induced in P. gingivalis LPS-treated cells while TIMP-2 was increased in response to 10 and 30 ng/ml of LPS on day 3. P. gingivalis LPS induced up-regulation of MMP-1/TIMP-1 ratio on day 3 and increased MMP-2/TIMP-2 ratio on day 8 dose-dependently. Expression of interleukin (IL)-6 and IL-8 was stimulated at higher concentrations (1000 and 3000 ng/ml) of LPS. These findings demonstrate that P. gingivalis LPS suppresses cell proliferation and leads to increased pro-inflammatory changes in HGFs, suggesting that P. gingivalis LPS-induced modification of phenotypic and inflammatory characteristics in HGF could potentially be a pathogenic mechanism underlying the tissue destruction. C1 [Bozkurt, S. Buket] Selcuk Univ, Res Ctr, Fac Dent, Konya, Turkey. [Hakki, Sema S.] Selcuk Univ, Fac Dent, Dept Periodontol, Konya, Turkey. [Hakki, Erdogan E.] Selcuk Univ, Dept Soil Sci & Plant Nutr, Fac Agr, Konya, Turkey. [Durak, Yusuf] Selcuk Univ, Dept Biol, Fac Sci, Konya, Turkey. [Kantarci, Alpdogan] Forsyth Inst, Dept Periodontol, Boston, MA USA. RP Bozkurt, SB (reprint author), Selcuk Univ, Res Ctr, Fac Dent, Konya, Turkey. EM buketbozkurt@yahoo.com FU Research Fund, Selcuk University [BAP/08201022] FX This study was performed at the Selcuk University Faculty of Dentistry, Research Center and was supported by the Research Fund, Selcuk University (BAP/08201022). NR 61 TC 0 Z9 0 U1 4 U2 4 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0360-3997 EI 1573-2576 J9 INFLAMMATION JI Inflammation PD FEB PY 2017 VL 40 IS 1 BP 144 EP 153 DI 10.1007/s10753-016-0463-7 PG 10 WC Cell Biology; Immunology SC Cell Biology; Immunology GA EK0ZL UT WOS:000393655500015 PM 27812843 ER PT J AU Baldwin, K Lyons, J Ghazi, P Kissil, J Haas, W Yajnik, V Haigis, K AF Baldwin, Katherine Lyons, Jesse Ghazi, Phaedra Kissil, Joseph Haas, Wilhelm Yajnik, Vijay Haigis, Kevin TI New Targets of Interest: Inhibition of PAK-1 Improves Inflammation in a Mouse Model of Colitis SO INFLAMMATORY BOWEL DISEASES LA English DT Meeting Abstract CT Advances-in-Inflammatory-Bowel-Diseases-Crohn's-and-Colitis Foundation's National Clinical and Research Conference CY DEC 08-10, 2016 CL Orlando, FL SP Advances Inflammatory Bowel Dis Crohns & Colitis Fdn C1 [Baldwin, Katherine; Haas, Wilhelm; Yajnik, Vijay] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Lyons, Jesse] MIT, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Ghazi, Phaedra] BIDMC, Boston, MA USA. [Kissil, Joseph] Scripps, Jupiter, FL USA. [Haigis, Kevin] Beth Israel Deaconess Med Ctr, Canc Res Inst, Dept Med, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1078-0998 EI 1536-4844 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD FEB PY 2017 VL 23 SU 1 MA P-252 BP S82 EP S83 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EK4MX UT WOS:000393902100258 ER PT J AU Kochar, B Long, M Galanko, J Raffals, L Ananthakrishnan, A Sandler, R AF Kochar, Bharati Long, Millie Galanko, Joseph Raffals, Laura Ananthakrishnan, Ashwin Sandler, Robert TI Inflammatory Bowel Disease Is Similar in Older Onset and Young Patients SO INFLAMMATORY BOWEL DISEASES LA English DT Meeting Abstract CT Advances-in-Inflammatory-Bowel-Diseases-Crohn's-and-Colitis Foundation's National Clinical and Research Conference CY DEC 08-10, 2016 CL Orlando, FL SP Advances Inflammatory Bowel Dis Crohns & Colitis Fdn C1 [Kochar, Bharati; Long, Millie; Galanko, Joseph; Sandler, Robert] Univ North Carolina Chapel Hill, Chapel Hill, NC USA. [Raffals, Laura] Mayo Clin, Rochester, MN USA. [Ananthakrishnan, Ashwin] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1078-0998 EI 1536-4844 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD FEB PY 2017 VL 23 SU 1 MA P-047 BP S20 EP S20 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EK4MX UT WOS:000393902100061 ER PT J AU Williams, RF Hoang, MP Kroshinsky, D Smith, GP AF Williams, Ramone F. Hoang, Mai P. Kroshinsky, Daniela Smith, Gideon P. TI Infliximab-induced follicular mucinosis of the face SO INTERNATIONAL JOURNAL OF DERMATOLOGY LA English DT Editorial Material ID LUPUS C1 [Williams, Ramone F.] Mt Auburn Hosp, Boston, MA USA. [Hoang, Mai P.; Kroshinsky, Daniela; Smith, Gideon P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Williams, RF; Smith, GP (reprint author), Massachusetts Gen Hosp, Dept Dermatol, Suite 200,50 Staniford St, Boston, MA 02114 USA. EM ramone.f.williams@gmail.com FU Allergan FX RFW, MPH, and DK have no disclosures. GPS has served as consultant to Cynosure in the past and is currently PI on an industry sponsored clinical study through Allergan. Neither of these relationships is relevant to the current article. NR 8 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0011-9059 EI 1365-4632 J9 INT J DERMATOL JI Int. J. Dermatol. PD FEB PY 2017 VL 56 IS 2 BP 215 EP 217 DI 10.1111/ijd.13335 PG 3 WC Dermatology SC Dermatology GA EK3AO UT WOS:000393798500031 PM 27336710 ER PT J AU Kligerman, MP Alexandre, A Jean-Gilles, P Walmer, D Cheney, ML Messner, AH AF Kligerman, Maxwell P. Alexandre, Anahuma Jean-Gilles, Patrick Walmer, David Cheney, Mack L. Messner, Anna H. TI Otorhinolaryngology/Head and Neck Surgery in a low income country: The Haitian experience SO INTERNATIONAL JOURNAL OF PEDIATRIC OTORHINOLARYNGOLOGY LA English DT Article DE Otolaryngology; Head and Neck Surgery; Haiti; Global health ID PEDIATRIC-SURGERY; HEALTH; OTOLARYNGOLOGY; EPIDEMIOLOGY; INJURIES; CAPACITY; ENT AB Objective: Little is known regarding the diagnosis and management of pediatric surgical conditions of the head and neck in low-income countries. Haiti, the western hemisphere's poorest country, recently developed its first Otorhinolaryngology (ORL) department at the Hopital de L'Universite d'Etat d'Haiti (HUEH). This manuscript assesses the caseload at HUEH with a special emphasis on pediatric cases, with the aim of characterizing ORL related conditions and their treatments in low-income countries. Methods: We conducted a retrospective chart review of surgical case logs at HUEH for the calendar year of 2014 and recorded patient age, diagnosis, and surgical intervention for all ORL surgeries. Results: A total of 229 ORL surgeries were performed at HUEH during this time. The average age of the patient was 21.8 years and 54.2% of patients were 18 years or younger. The five most common diagnoses were tonsillar hypertrophy (23.6%), ingested foreign body (18%), mandibular fracture (9.2%), unspecified head or neck mass (6%), and thyroid goiter (4.8%). The five most common surgeries performed were tonsillectomy (23.6%), foreign body retrieval (17.9%), open reduction of mandibular fracture with direct skeletal fixation (6.9%), thyroidectomy (7.9%), and excision of unspecified mass. Trauma accounted for 33.6% of all ORL surgeries. Conclusions: Diseases related to the head and neck constitute a common yet underserved surgical problem. Strengthening ORL surgical capacity in Haiti should focus on improving capacity for the most common conditions including tonsillar disease, ingested foreign bodies, and facial trauma, as well as improving capacity for rarely performed surgeries, such as ear surgery, nose and sinus surgery, and cancer resections. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Kligerman, Maxwell P.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Alexandre, Anahuma; Jean-Gilles, Patrick] Hop Univ Etat Haiti, Dept Otorhinolatyngol, Port Au Prince, Haiti. [Walmer, David] Duke Univ, Duke Global Hlth Inst, Durham, NC 27706 USA. [Kligerman, Maxwell P.; Walmer, David] Family Hlth Minist, 501-C3, Durham, NC USA. [Cheney, Mack L.] Harvard Sch Med, Massachusetts Eye & Ear Infirm, Boston, MA USA. [Messner, Anna H.] Stanford Univ, Dept Otolaryngol Head & Neck Surg, Stanford, CA 94305 USA. RP Kligerman, MP (reprint author), 1240 Beacon St, Brookine, MA 02446 USA. EM maxwell.kligerman@gmail.com FU Stanford School of Medicine (Medical Scholars Student Grant) FX Stanford School of Medicine (Medical Scholars Student Grant). NR 25 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-5876 EI 1872-8464 J9 INT J PEDIATR OTORHI JI Int. J. Pediatr. Otorhinolaryngol. PD FEB PY 2017 VL 93 BP 128 EP 132 DI 10.1016/j.ijporl.2016.12.041 PG 5 WC Otorhinolaryngology; Pediatrics SC Otorhinolaryngology; Pediatrics GA EK1XL UT WOS:000393721000024 PM 28109483 ER PT J AU de Moor, JS Dowling, EC Ekwueme, DU Guy, GP Rodriguez, J Virgo, KS Han, XS Kent, EE Li, CY Litzelman, K McNeel, TS Liu, BM Yabroff, KR AF de Moor, Janet S. Dowling, Emily C. Ekwueme, Donatus U. Guy, Gery P., Jr. Rodriguez, Juan Virgo, Katherine S. Han, Xuesong Kent, Erin E. Li, Chunyu Litzelman, Kristen McNeel, Timothy S. Liu, Benmei Yabroff, K. Robin TI Employment implications of informal cancer caregiving SO JOURNAL OF CANCER SURVIVORSHIP LA English DT Article DE Neoplasms; Caregivers; Employment; Cost-of-illness; Quality of life ID DISTRESSED FAMILY CAREGIVERS; BREAST-CANCER; HEALTH-CARE; SURVIVORS; BURDEN; WORK; LUNG; ACCESS; IMPACT; TIME AB Purpose Previous research describing how informal cancer caregiving impacts employment has been conducted in small samples or a single disease site. This paper provides population-based estimates of the effect of informal cancer caregiving on employment and characterizes employment changes made by caregivers. Methods The samples included cancer survivors with a friend or family caregiver, participating in either the Medical Expenditure Panel Survey Experiences with Cancer Survivorship Survey (ECSS) (n = 458) or the LIVESTRONG 2012 Survey for People Affected by Cancer (SPAC) (n = 4706). Descriptive statistics characterized the sample of survivors and their caregivers' employment changes. Multivariable logistic regression identified predictors of caregivers' extended employment changes, comprising time off and changes to hours, duties, or employment status. Results Among survivors with an informal caregiver, 25 % from the ECSS and 29 % from the SPAC reported that their caregivers made extended employment changes. Approximately 8 % of survivors had caregivers who took time off from work lasting >= 2 months. Caregivers who made extended employment changes were more likely to care for survivors: treated with chemotherapy or transplant; closer to diagnosis or end of treatment; who experienced functional limitations; and made work changes due to cancer themselves compared to caregivers who did not make extended employment changes. Conclusions Many informal cancer caregivers make employment changes to provide care during survivors' treatment and recovery. Implications for cancer survivors This study describes cancer caregiving in a prevalent sample of cancer survivors, thereby reflecting the experiences of individuals with many different cancer types and places in the cancer treatment trajectory. C1 [de Moor, Janet S.; Kent, Erin E.; Litzelman, Kristen; Liu, Benmei; Yabroff, K. Robin] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Dowling, Emily C.] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Ekwueme, Donatus U.; Guy, Gery P., Jr.; Rodriguez, Juan; Li, Chunyu] Ctr Dis Control & Prevent, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA USA. [Han, Xuesong] Amer Canc Soc, Surveillance & Hlth Serv Res Program, Atlanta, GA 30329 USA. [Virgo, Katherine S.] Emory Univ, Rollins Sch Publ Hlth, Dept Hlth Policy & Management, Atlanta, GA 30322 USA. [McNeel, Timothy S.] Informat Management Serv Inc, Calverton, MD USA. [de Moor, Janet S.] NCI, Healthcare Assessment Res Branch, Healthcare Delivery Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,3E438,MSC 9764, Bethesda, MD 20892 USA. RP de Moor, JS (reprint author), NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA.; de Moor, JS (reprint author), NCI, Healthcare Assessment Res Branch, Healthcare Delivery Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,3E438,MSC 9764, Bethesda, MD 20892 USA. EM demoorjs@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 32 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1932-2259 EI 1932-2267 J9 J CANCER SURVIV JI J. Cancer Surviv.-Res. Pract. PD FEB PY 2017 VL 11 IS 1 BP 48 EP 57 DI 10.1007/s11764-016-0560-5 PG 10 WC Oncology; Social Sciences, Biomedical SC Oncology; Biomedical Social Sciences GA EK1GZ UT WOS:000393675100006 PM 27423439 ER PT J AU Zhou, ES Partridge, AH Syrjala, KL Michaud, AL Recklitis, CJ AF Zhou, Eric S. Partridge, Ann H. Syrjala, Karen L. Michaud, Alexis L. Recklitis, Christopher J. TI Evaluation and treatment of insomnia in adult cancer survivorship programs SO JOURNAL OF CANCER SURVIVORSHIP LA English DT Article DE Insomnia; Sleep disorders; Cancer survivorship; Oncology; Evaluation and treatment ID BREAST-CANCER; SLEEP DISTURBANCES; CHILDHOOD-CANCER; PROSTATE-CANCER; FATIGUE; THERAPY; CHEMOTHERAPY; PHYSICIANS; DISORDERS; EDUCATION AB Insomnia is commonly experienced by cancer survivors. Chronic insomnia is associated with significant physical and psychosocial consequences if not properly treated. Both the National Cancer Institute (NCI) and the National Comprehensive Cancer Network (NCCN) recommend the evaluation of sleep disturbances and evidence-based treatment of insomnia during routine survivorship care. To better understand current clinical practices, we conducted a survey of major cancer centers across the United States (US). Adult survivorship programs at the 25 US cancer centers that are both NCI-designated comprehensive cancer centers and NCCN member institutions were surveyed about the evaluation and treatment of insomnia in their hospital. All institutions responded to the survey. Thirteen centers (56 %) reported screening < 25 % of survivors for sleep disorders, and few clinicians providing survivorship care were well-prepared to conduct a proper sleep evaluation. Insomnia was most commonly treated with sleep hygiene, or pharmacotherapy, rather than cognitive-behavioral therapy. No program reported that > 50 % of their survivors were receiving optimal insomnia-related care. A variety of methods to improve insomnia care were endorsed by respondents. There is a clear need to improve the evaluation and treatment of insomnia for cancer survivors at institutions across the country. Cancer centers deemed a number of modalities relevant for improving provider confidence in addressing sleep challenges. To improve the quality of insomnia care for survivors, systematic interventions to increase standardized screening for sleep disorders, providing additional sleep medicine training for survivorship clinicians, and optimizing the role of sleep medicine specialists in the oncology setting should be considered. C1 [Zhou, Eric S.; Partridge, Ann H.; Michaud, Alexis L.; Recklitis, Christopher J.] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. [Zhou, Eric S.; Partridge, Ann H.; Recklitis, Christopher J.] Harvard Med Sch, 25 Shattuck St, Boston, MA 02115 USA. [Syrjala, Karen L.] Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave N, Seattle, WA 98109 USA. RP Zhou, ES (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA.; Zhou, ES (reprint author), Harvard Med Sch, 25 Shattuck St, Boston, MA 02115 USA. EM eric_zhou@dfci.harvard.edu FU Dana-Farber Cancer Institute FX This study was funded by internal support at the Dana-Farber Cancer Institute. NR 43 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1932-2259 EI 1932-2267 J9 J CANCER SURVIV JI J. Cancer Surviv.-Res. Pract. PD FEB PY 2017 VL 11 IS 1 BP 74 EP 79 DI 10.1007/s11764-016-0564-1 PG 6 WC Oncology; Social Sciences, Biomedical SC Oncology; Biomedical Social Sciences GA EK1GZ UT WOS:000393675100009 PM 27495283 ER PT J AU Kunitake, H Russell, MM Zheng, P Yothers, G Land, SR Petersen, L Fehrenbacher, L Giguere, JK Wickerham, DL Ko, CY Ganz, PA AF Kunitake, Hiroko Russell, Marcia M. Zheng, Ping Yothers, Greg Land, Stephanie R. Petersen, Laura Fehrenbacher, Louis Giguere, Jeffery K. Wickerham, D. Lawrence Ko, Clifford Y. Ganz, Patricia A. TI Quality of life and symptoms in long-term survivors of colorectal cancer: results from NSABP protocol LTS-01 SO JOURNAL OF CANCER SURVIVORSHIP LA English DT Article DE Quality of life; Colorectal cancer; Survivors ID SURGICAL ADJUVANT BREAST; COLON-CANCER; HEALTH SURVEY; STAGE-II; PROJECT; VALIDATION; LEUCOVORIN; FATIGUE; FLUOROURACIL; CHEMOTHERAPY AB Purpose Little is known about health-related quality of life (HRQL) in long-term survivors (LTS) of colorectal cancer (CRC). Methods Long-term CRC survivors (>= 5 years) treated in previous National Surgical Adjuvant Breast and Bowel Project trials were recruited from 60 sites. After obtaining consent, a telephone survey was administered, which included HRQL instruments to measure physical health (Instrumental Activities of Daily Living [IADL], SF-12 Physical Component Scale [PCS], SF-36 Vitality Scale), mental health (SF-12 Mental Component Scale [MCS], Life Orientation Test, and Impact of Cancer), and clinical symptoms (Fatigue Symptom Inventory [FSI], European Organization for Research and Treatment of Cancer Colorectal Module [EORTC-CR38], and Brief Pain Inventory). A multivariable model identified predictors of overall quality of life (global health rating). Results Participants (N = 708) had significantly higher HRQL compared with age group-matched non-cancer controls with higher mean scores on SF-12 PCS (49.5 vs. 43.7, p = < 0.05), MCS (55.6 vs. 52.1, p = < 0.05), and SF-36 Vitality Scale (67.1 vs. 59.9, p = < 0.05). Multivariable modeling has demonstrated that better overall physical and mental health (PCS and MCS), positive body image (EORTC-CR38 scale), and less fatigue (FSI), were strongly associated with overall quality of life as measured by the global health rating. Interestingly, ability to perform IADLs, experience of cancer, gastrointestinal complaints, and pain, were not important predictors. Conclusions In long-term CRC survivors, overall physical and mental health was excellent compared with general population. Other disease-related symptoms did not detract from good overall health. Implications for cancer survivors LTS of CRC within the setting of a clinical trial have higher HRQL than the general population, and treatment regimens do not appear to be associated with any significant late effects on quality of life. Trial Registration: NSABP LTS-01: NCT00410579. C1 [Kunitake, Hiroko; Russell, Marcia M.; Wickerham, D. Lawrence; Ko, Clifford Y.; Ganz, Patricia A.] NRG Oncol, Natl Surg Adjuvant Breast & Bowel Project NSABP, Pittsburgh, PA 15213 USA. [Kunitake, Hiroko] Boston Univ, Sch Med, Boston, MA 02118 USA. [Russell, Marcia M.; Ko, Clifford Y.] Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, David Geffen Sch Med, 11301 Wilshire Blvd,Mail Code 10H2, Los Angeles, CA 90073 USA. [Zheng, Ping; Yothers, Greg] Univ Pittsburgh, Dept Hlth Policy & Management, Pittsburgh, PA USA. [Yothers, Greg] Univ Pittsburgh, Pittsburgh, PA USA. [Land, Stephanie R.] NCI, Bethesda, MD 20892 USA. [Petersen, Laura] UCLA Jonsson Comprehens Canc Ctr, Los Angeles, CA USA. [Fehrenbacher, Louis] Kaiser Permanente Oncol Clin Trials Northern Cali, Vallejo, CA USA. [Giguere, Jeffery K.] Greenville Hlth Syst Canc Inst, Greenville, SC USA. [Wickerham, D. Lawrence] Allegheny Hlth Network Canc Inst, Pittsburgh, PA USA. [Ganz, Patricia A.] Univ Calif Los Angeles, UCLA Sch Med, Los Angeles, CA USA. [Ganz, Patricia A.] Univ Calif Los Angeles, UCLA Sch Publ Hlth, Los Angeles, CA USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA. [Yothers, Greg] NRG Oncol, Pittsburgh, PA USA. RP Russell, MM (reprint author), NRG Oncol, Natl Surg Adjuvant Breast & Bowel Project NSABP, Pittsburgh, PA 15213 USA.; Russell, MM (reprint author), Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, David Geffen Sch Med, 11301 Wilshire Blvd,Mail Code 10H2, Los Angeles, CA 90073 USA. EM Marcia.Russell2@va.gov FU National Institutes of Health, US Department of Health and Human Services, Public Health Service [U10-CA180868, U10-CA180822, UG1CA189867]; American Cancer Society [RSGPB-05-236-01-CPPB] FX The National Cancer Institute at the National Institutes of Health, US Department of Health and Human Services, Public Health Service grants U10-CA180868 (NCTN), U10-CA180822 (NRG SDMC), and UG1CA189867 (NCORP), and grant RSGPB-05-236-01-CPPB from the American Cancer Society (UCLA) are acknowledged. NR 34 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1932-2259 EI 1932-2267 J9 J CANCER SURVIV JI J. Cancer Surviv.-Res. Pract. PD FEB PY 2017 VL 11 IS 1 BP 111 EP 118 DI 10.1007/s11764-016-0567-y PG 8 WC Oncology; Social Sciences, Biomedical SC Oncology; Biomedical Social Sciences GA EK1GZ UT WOS:000393675100013 PM 27562475 ER PT J AU Horick, NK Manful, A Lowery, J Domchek, S Moorman, P Griffin, C Visvanathan, K Isaacs, C Kinney, AY Finkelstein, DM AF Horick, Nora K. Manful, Adoma Lowery, Jan Domchek, Susan Moorman, Patricia Griffin, Constance Visvanathan, Kala Isaacs, Claudine Kinney, Anita Y. Finkelstein, Dianne M. TI Physical and psychological health in rare cancer survivors SO JOURNAL OF CANCER SURVIVORSHIP LA English DT Article DE Quality of life; SF-12; Brief symptom survey; Loneliness; Rare cancer ID QUALITY-OF-LIFE; OVARIAN-CANCER; LONELINESS; PREDICTORS; DISTRESS; VALIDITY; SAMPLE; SCALE AB Registries provide a unique tool for tracking quality of life in rare cancer survivors, whose survivorship experience is less known than for common cancers. This paper reports on these outcomes in 321 patients enrolled in the Rare Cancer Genetics Registry diagnosed with rare gastrointestinal, genitourinary, gynecologic, sarcoma, head/neck, or hematologic cancers. Four outcomes were assessed, reflecting registrants' self-reported physical and mental health, psychological distress, and loneliness. Combining all patients into a single analysis, regression was used to evaluate the association between outcomes and socio-demographic and clinical factors. Median time since diagnosis was 3 years (range 0-9); 69 % were no longer in treatment. Poorer physical health was reported in registrants who were older at diagnosis, unmarried, and still in treatment. Poorer mental status was associated with younger diagnosis age and unmarried status. Psychological distress varied by cancer type and was higher among currently treated and unmarried registrants. Greater loneliness was reported in registrants with gynecological cancers, and those who were less educated or unmarried. The physical and mental health profile of rare cancer survivors is similar to what is reported for common cancers. Unmarried participants reported poorer outcomes on all measures of quality of life. Furthermore, physical and mental health were not significantly different by cancer type after adjustment for diagnosis age, whether currently in treatment and marital status. Thus, the combined analysis performed here is a useful way to analyze outcomes in less common diseases. Our findings could be valuable in guiding evaluation and intervention for issues impacting quality of life. Rare cancer survivors, particularly those without spousal support, should be monitored for challenges to the physical as well as psychological aspects of quality of life. C1 [Horick, Nora K.; Manful, Adoma; Finkelstein, Dianne M.] Massachusetts Gen Hosp, Biostat Ctr, 50 Staniford St,Suite 560, Boston, MA 02114 USA. [Lowery, Jan] Univ Colorado, Sch Publ Hlth, Dept Epidemiol, Denver, CO 80202 USA. [Domchek, Susan] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Moorman, Patricia] Duke Univ, Med Ctr, Durham, NC USA. [Griffin, Constance] Johns Hopkins, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Visvanathan, Kala] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Isaacs, Claudine] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. [Kinney, Anita Y.] Univ New Mexico, Dept Internal Med, Albuquerque, NM 87131 USA. [Finkelstein, Dianne M.] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Finkelstein, DM (reprint author), Massachusetts Gen Hosp, Biostat Ctr, 50 Staniford St,Suite 560, Boston, MA 02114 USA.; Finkelstein, DM (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. EM dfinkelstein@mgh.harvard.edu FU NIH [RC1 CA 144706, R01 CA160233] FX NIH grants RC1 CA 144706 and R01 CA160233. NR 21 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1932-2259 EI 1932-2267 J9 J CANCER SURVIV JI J. Cancer Surviv.-Res. Pract. PD FEB PY 2017 VL 11 IS 1 BP 158 EP 165 DI 10.1007/s11764-016-0573-0 PG 8 WC Oncology; Social Sciences, Biomedical SC Oncology; Biomedical Social Sciences GA EK1GZ UT WOS:000393675100018 PM 27761785 ER PT J AU Rusanescu, G Mao, JR AF Rusanescu, Gabriel Mao, Jianren TI Peripheral nerve injury induces adult brain neurogenesis and remodelling SO JOURNAL OF CELLULAR AND MOLECULAR MEDICINE LA English DT Article DE structural plasticity; adult neurogenesis; chronic pain; cerebellum; cross-modal perception; proprioception; Notch3; Purkinje neurons ID GRAY-MATTER VOLUME; NEURAL STEM-CELLS; NEURONAL DIFFERENTIATION; DNA-SYNTHESIS; SPINAL-CORD; PAIN; CEREBELLUM; CORTEX; GABA; RAT AB Unilateral peripheral nerve chronic constriction injury (CCI) has been widely used as a research model of human neuropathic pain. Recently, CCI has been shown to induce spinal cord adult neurogenesis, which may contribute to the chronic increase in nociceptive sensitivity. Here, we show that CCI also induces rapid and profound asymmetrical anatomical rearrangements in the adult rodent cerebellum and pons. This remodelling occurs throughout the hindbrain, and in addition to regions involved in pain processing, also affects other sensory modalities. We demonstrate that these anatomical changes, partially reversible in the long term, result from adult neurogenesis. Neurogenic markers Mash1, Ngn2, doublecortin and Notch3 are widely expressed in the rodent cerebellum and pons, both under normal and injured conditions. CCI-induced hindbrain structural plasticity is absent in Notch3 knockout mice, a strain with impaired neuronal differentiation, demonstrating its dependence on adult neurogenesis. Grey matter and white matter structural changes in human brain, as a result of pain, injury or learned behaviours have been previously detected using non-invasive neuroimaging techniques. Because neurogenesis-mediated structural plasticity is thought to be restricted to the hippocampus and the subventricular zone, such anatomical rearrangements in other parts of the brain have been thought to result from neuronal plasticity or glial hypertrophy. Our findings suggest the presence of extensive neurogenesis-based structural plasticity in the adult mammalian brain, which may maintain a memory of basal sensory levels, and act as an adaptive mechanism to changes in sensory inputs. C1 [Rusanescu, Gabriel; Mao, Jianren] Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, MGH Ctr Translat Pain Res, Boston, MA 02115 USA. RP Rusanescu, G (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, MGH Ctr Translat Pain Res, Boston, MA 02115 USA. EM grusanes@gmail.com OI Rusanescu, Gabriel/0000-0002-2811-905X NR 68 TC 0 Z9 0 U1 6 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1582-4934 J9 J CELL MOL MED JI J. Cell. Mol. Med. PD FEB PY 2017 VL 21 IS 2 BP 299 EP 314 DI 10.1111/jcmm.12965 PG 16 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA EJ9XK UT WOS:000393580400010 PM 27665307 ER PT J AU Maguire, LH Alavi, K Sudan, R Wise, PE Kaiser, AM Bordeianou, L AF Maguire, Lillias Holmes Alavi, Karim Sudan, Ranjan Wise, Paul E. Kaiser, Andreas M. Bordeianou, Liliana TI Surgical Considerations in the Treatment of Small Bowel Crohn's Disease SO JOURNAL OF GASTROINTESTINAL SURGERY LA English DT Review DE Crohn's disease; Stricturoplasty; Small bowel ID OPEN ILEOCOLIC RESECTION; RANDOMIZED CONTROLLED-TRIAL; NECROSIS FACTOR THERAPY; TO-SIDE ANASTOMOSIS; LONG-TERM OUTCOMES; POSTOPERATIVE RECURRENCE; ENDOSCOPIC RECURRENCE; INTESTINAL RESECTION; ABDOMINAL-SURGERY; REGIONAL ENTERITIS AB Surgery remains a cornerstone of the management of Crohn's disease (CD). Despite the rise of biologic therapy, most CD patients require surgery for penetrating, obstructing, or malignant complications. Optimal surgical therapy requires sophisticated operative judgment and medical optimization. Intraoperatively, surgeons must balance treatment of CD complications against bowel preservation and functional outcome. This demands mastery of multiple techniques for anastomosis and strictureplasty, accurate assessment of bowel integrity for margin minimization, and a comprehensive skillset for navigating adhesions and altered anatomy, controlling thickened mesentery, and safely managing the hostile abdomen. Outside of the operating room, a multi-disciplinary team is critical for pre-operative optimization, patient support, and medical management. Postoperatively, prevention and surveillance of recurrence remain a matter of research and debate, and medical options include older drugs with limited efficacy and tolerability versus biologic agents with greater effect sizes and shorter track records. The evidence base for current management is limited by the inherent challenges of studying a chronic disease marked by heterogeneity and recurrence, but also by a lack of prospective trials incorporating both medical and surgical therapies. C1 [Maguire, Lillias Holmes; Bordeianou, Liliana] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Maguire, Lillias Holmes] Univ Minnesota, Dept Surg, Box 242 UMHC, Minneapolis, MN 55455 USA. [Alavi, Karim] UMass Mem Med Ctr, Dept Surg, Worcester, MA USA. [Sudan, Ranjan] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Wise, Paul E.] Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA. [Kaiser, Andreas M.] Univ Southern Calif, Dept Colorectal Surg, Los Angeles, CA USA. RP Bordeianou, L (reprint author), Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. EM lbordeianou@mgh.harvard.edu NR 75 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1091-255X EI 1873-4626 J9 J GASTROINTEST SURG JI J. Gastrointest. Surg. PD FEB PY 2017 VL 21 IS 2 BP 398 EP 411 DI 10.1007/s11605-016-3330-9 PG 14 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA EK3KN UT WOS:000393825300024 PM 27966058 ER PT J AU Wheeler, DJ Mihara, K Chiovaro, J AF Wheeler, Daniel J. Mihara, Kip Chiovaro, Joe TI Seeing Wisely SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material ID MEDICAL-EDUCATION C1 [Wheeler, Daniel J.] Univ Minnesota, Sch Med, Dept Med, Mayo Mem Bldg,420 Delaware St SE,MMC 741, Minneapolis, MN 55455 USA. [Mihara, Kip] San Francisco VA Med Ctr, Emergency Dept, San Francisco, CA USA. [Mihara, Kip] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Chiovaro, Joe] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Chiovaro, Joe] Portland VA Med Ctr, Dept Med, Div Hosp Med, Portland, OR USA. RP Wheeler, DJ (reprint author), Univ Minnesota, Sch Med, Dept Med, Mayo Mem Bldg,420 Delaware St SE,MMC 741, Minneapolis, MN 55455 USA. EM wheel237@umn.edu NR 5 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD FEB PY 2017 VL 32 IS 2 BP 139 EP 139 DI 10.1007/s11606-016-3933-6 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA EK2JL UT WOS:000393753500001 PM 27896695 ER PT J AU Reddy, KP AF Reddy, Krishna P. TI Herpes Zoster Vaccine: Time for a Boost? SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material ID POSTHERPETIC NEURALGIA; COST-EFFECTIVENESS; OLDER-ADULTS; EFFICACY C1 [Reddy, Krishna P.] Massachusetts Gen Hosp, Div Pulm & Crit Care Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. [Reddy, Krishna P.] Massachusetts Gen Hosp, Med Practice Evaluat Ctr, 50 Staniford St,9th Floor, Boston, MA 02114 USA. RP Reddy, KP (reprint author), Massachusetts Gen Hosp, Div Pulm & Crit Care Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA.; Reddy, KP (reprint author), Massachusetts Gen Hosp, Med Practice Evaluat Ctr, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM kpreddy@mgh.harvard.edu NR 10 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD FEB PY 2017 VL 32 IS 2 BP 145 EP 147 DI 10.1007/s11606-016-3885-x PG 3 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA EK2JL UT WOS:000393753500004 PM 27730484 ER PT J AU Hanchate, AD AF Hanchate, Amresh D. TI Capsule Commentary on Kern et al., Healthcare Fragmentation and the Frequency of Radiology and Other Diagnostic Tests: a Cross-Sectional Study SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material C1 [Hanchate, Amresh D.] VA Boston Healthcare Syst, Boston, MA 02130 USA. [Hanchate, Amresh D.] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Hanchate, AD (reprint author), VA Boston Healthcare Syst, Boston, MA 02130 USA.; Hanchate, AD (reprint author), Boston Univ, Sch Med, Boston, MA 02118 USA. EM hanchate@bu.edu NR 5 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD FEB PY 2017 VL 32 IS 2 BP 190 EP 190 DI 10.1007/s11606-016-3953-2 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA EK2JL UT WOS:000393753500014 PM 27957664 ER PT J AU Oehler, A Chiovaro, J AF Oehler, Andrew Chiovaro, Joseph TI The Electrocardiogram Following Dynamic Cardiomyoplasty SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material DE heart failure; electrocardiography; cardiomyoplasty C1 [Oehler, Andrew; Chiovaro, Joseph] Oregon Hlth & Sci Univ, Dept Gen Internal Med, Portland, OR 97201 USA. [Chiovaro, Joseph] Portland VA Med Ctr, Div Hosp & Subspecialty Med, Portland, OR USA. RP Oehler, A (reprint author), Oregon Hlth & Sci Univ, Dept Gen Internal Med, Portland, OR 97201 USA. EM oehler@ohsu.edu NR 3 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD FEB PY 2017 VL 32 IS 2 BP 223 EP 224 DI 10.1007/s11606-016-3827-7 PG 2 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA EK2JL UT WOS:000393753500023 PM 27488972 ER PT J AU Buchanan, AH Voils, CI Schildkraut, JM Fine, C Horick, NK Marcom, PK Wiggins, K Skinner, CS AF Buchanan, Adam H. Voils, Corrine I. Schildkraut, Joellen M. Fine, Catherine Horick, Nora K. Marcom, P. Kelly Wiggins, Kristi Skinner, Celette Sugg TI Adherence to Recommended Risk Management among Unaffected Women with a BRCA Mutation SO JOURNAL OF GENETIC COUNSELING LA English DT Article DE BRCA1 gene; BRCA2 gene; Genetic counseling; Breast cancer; Ovarian cancer ID BILATERAL PROPHYLACTIC OOPHORECTOMY; REDUCING SALPINGO-OOPHORECTOMY; GENETIC CANCER-RISK; BREAST-CANCER; OVARIAN-CANCER; PROSPECTIVE COHORT; SELF-REPORTS; FOLLOW-UP; CARRIERS; SURGERY AB Identifying unaffected women with a BRCA mutation can have a significant individual and population health impact on morbidity and mortality if these women adhere to guidelines for managing cancer risk. But, little is known about whether such women are adherent to current guidelines. We conducted telephone surveys of 97 unaffected BRCA mutation carriers who had genetic counseling at least one year prior to the survey to assess adherence to current guidelines, factors associated with adherence, and common reasons for performing and not performing recommended risk management. More than half of participants reported being adherent with current risk management recommendations for breast cancer (69 %, n = 67), ovarian cancer (82 %, n = 74) and both cancers (66 %, n = 64). Older age (OR = 10.53, p = 0.001), white race (OR = 8.93, p = 0.019), higher breast cancer genetics knowledge (OR = 1.67, p = 0.030), higher cancer-specific distress (OR = 1.07, p = 0.002) and higher physical functioning (OR = 1.09, p = 0.009) were significantly associated with adherence to recommended risk management for both cancers. Responses to open-ended questions about reasons for performing and not performing risk management behaviors indicated that participants recognized the clinical utility of these behaviors. Younger individuals and those with lower physical functioning may require targeted interventions to improve adherence, perhaps in the setting of long-term follow-up at a multi-disciplinary hereditary cancer clinic. C1 [Buchanan, Adam H.] Geisinger Hlth Syst, Genom Med Inst, MC 26-20,100 N Acad Ave, Danville, PA 17822 USA. [Voils, Corrine I.] Durham VA Med Ctr, Ctr Hlth Serv Res Primary Care, Durham, NC USA. [Voils, Corrine I.; Marcom, P. Kelly] Duke Univ, Dept Med, Med Ctr, Durham, NC USA. [Schildkraut, Joellen M.; Marcom, P. Kelly] Duke Univ, Duke Canc Inst, Med Ctr, Durham, NC USA. [Fine, Catherine] UNC Lineberger Comprehens Canc Ctr, Dept Genet, Chapel Hill, NC USA. [Horick, Nora K.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Wiggins, Kristi] Duke Univ, Div Cellular Therapy, Med Ctr, Durham, NC USA. [Skinner, Celette Sugg] Univ Texas Southwestern, Dept Clin Sci, Dallas, TX USA. [Skinner, Celette Sugg] Univ Texas Southwestern, Harold C Simmons Canc Ctr, Dallas, TX USA. RP Buchanan, AH (reprint author), Geisinger Hlth Syst, Genom Med Inst, MC 26-20,100 N Acad Ave, Danville, PA 17822 USA. EM ahbuchanan@geisinger.edu FU NIH; Susan G. Komen for the Cure; Department of Veterans Affairs; Department of Defense; NCI; Cancer Prevention Research Institute of Texas FX Mr. Buchanan's work has been funded by the NIH and Susan G. Komen for the Cure. Dr. Voils' work has been funded by the Department of Veterans Affairs and the NIH. Dr. Schildkraut's work has been funded by the NIH. Dr. Marcom's work has been funded by the NIH and Department of Defense. Dr. Skinner's work has been funded by the NCI and the Cancer Prevention Research Institute of Texas. NR 76 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1059-7700 EI 1573-3599 J9 J GENET COUNS JI J. Genet. Couns. PD FEB PY 2017 VL 26 IS 1 BP 79 EP 92 DI 10.1007/s10897-016-9981-6 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA EK3KY UT WOS:000393826500009 PM 27265406 ER PT J AU Movassagh, H Saati, A Nandagopal, S Mohammed, A Tatari, N Shan, LY Duke-Cohan, JS Fowke, KR Lin, F Gounni, AS AF Movassagh, Hesam Saati, Abeer Nandagopal, Saravanan Mohammed, Ashfaque Tatari, Nazanin Shan, Lianyu Duke-Cohan, Jonathan S. Fowke, Keith R. Lin, Francis Gounni, Abdelilah S. TI Chemorepellent Semaphorin 3E Negatively Regulates Neutrophil Migration In Vitro and In Vivo SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PULMONARY INFLAMMATION; AIRWAY EPITHELIUM; DENDRITIC CELLS; LUNG; ASTHMA; RECRUITMENT; CHEMOTAXIS; SURVIVAL; TARGETS; NEUROPILINS AB Neutrophil migration is an essential step in leukocyte trafficking during inflammatory responses. Semaphorins, originally discovered as axon guidance cues in neural development, have been shown to regulate cell migration beyond the nervous system. However, the potential contribution of semaphorins in the regulation of neutrophil migration is not well understood. This study examines the possible role of a secreted chemorepellent, Semaphorin 3E (Sema3E), in neutrophil migration. In this study, we demonstrated that human neutrophils constitutively express Sema3E high-affinity receptor, PlexinDl. Sema3E displayed a potent ability to inhibit CXCL8IIL-8 induced neutrophil migration as determined using a microfluidic device coupled to real-time microscopy and a transwell system in vitro. The antimigratory effect of Sema3E on human neutrophil migration was associated with suppression of CXCL8IIL-8 mediated Ras-related C3 botulinum toxin substrate 1 GTPase activity and actin polymerization. We further addressed the regulatory role of Sema3E in the regulation of neutrophil migration in vivo. Allergen airway exposure induced higher neutrophil recruitment into the lungs of Seim3e(-/-) mice compared with wild-type controls. Administration of exogenous recombinant Sema3E markedly reduced allergen-induced neutrophil recruitment into the lungs, which was associated with alleviation of allergic airway inflammation and improvement of lung function. Our data suggest that Sema3E could be considered an essential regulatory mediator involved in modulation of neutrophil migration throughout the course of neutrophilic inflammation. C1 [Movassagh, Hesam; Saati, Abeer; Nandagopal, Saravanan; Mohammed, Ashfaque; Tatari, Nazanin; Shan, Lianyu; Lin, Francis; Gounni, Abdelilah S.] Univ Manitoba, Max Rady Coll Med, Rady Fac Hlth Sci, Dept Immunol, 419 Apotex Ctr,750 McDermot Ave, Winnipeg, MB R3E 0T5, Canada. [Nandagopal, Saravanan; Lin, Francis] Univ Manitoba, Fac Sci, Dept Phys & Astron, Winnipeg, MB R3T 2N2, Canada. [Duke-Cohan, Jonathan S.] Dana Farber Canc Inst, Dept Med Oncol, Immunobiol Lab, Boston, MA 02215 USA. [Duke-Cohan, Jonathan S.] Harvard Med Sch, Dept Med, Boston, MA 02215 USA. [Fowke, Keith R.] Univ Manitoba, Max Rady Coll Med, Rady Fac Hlth Sci, Dept Med Microbiol, Winnipeg, MB R3E 0T5, Canada. RP Gounni, AS (reprint author), Univ Manitoba, Max Rady Coll Med, Rady Fac Hlth Sci, Dept Immunol, 419 Apotex Ctr,750 McDermot Ave, Winnipeg, MB R3E 0T5, Canada. EM abdel.gounni@umanitoba.ca OI Duke-Cohan, Jonathan/0000-0002-9478-9609 FU Canadian Institute of Health Research Grant [115115]; Natural Sciences and Engineering Research Council [RGPIN/386289-2011]; Research Manitoba-Children's Hospital Research Institute of Manitoba FX This work was supported by Canadian Institute of Health Research Grant 115115 and Natural Sciences and Engineering Research Council Grant RGPIN/386289-2011 (to A.S.G.). H.M., NT., and A.M. were financially supported by studentships from Research Manitoba-Children's Hospital Research Institute of Manitoba. NR 59 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD FEB 1 PY 2017 VL 198 IS 3 BP 1023 EP 1033 DI 10.4049/jimmunol.1601093 PG 11 WC Immunology SC Immunology GA EI3SX UT WOS:000392412700008 PM 27913633 ER PT J AU Freedberg, KA Sax, PE AF Freedberg, Kenneth A. Sax, Paul E. TI Improving on effective antiretroviral therapy: how good will a cure have to be? SO JOURNAL OF MEDICAL ETHICS LA English DT Article ID COST-EFFECTIVENESS; UNITED-STATES; HIV C1 [Freedberg, Kenneth A.] Massachusetts Gen Hosp, Med Practice Evaluat Ctr, 50 Staniford St,Suite 901, Boston, MA 02114 USA. [Freedberg, Kenneth A.] Massachusetts Gen Hosp, Div Gen Internal Med & Infect Dis, Boston, MA 02114 USA. [Freedberg, Kenneth A.; Sax, Paul E.] Harvard Med Sch, Boston, MA USA. [Freedberg, Kenneth A.] Harvard TH Chan Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. [Sax, Paul E.] Brigham & Womens Hosp, Div Infect Dis, 75 Francis St, Boston, MA 02115 USA. RP Freedberg, KA (reprint author), Massachusetts Gen Hosp, Med Practice Evaluat Ctr, 50 Staniford St,Suite 901, Boston, MA 02114 USA. EM KFREEDBERG@mgh.harvard.edu FU National Institute of Allergy and Infectious Diseases [R01 AI42006, R01 AI114617, R56 AI114617]; Harvard University Center for AIDS Research from the National Institute of Allergy and Infectious Diseases [NIH P30 AI060354] FX Supported in part by R01 AI42006, R01 AI114617, R56 AI114617 and the Harvard University Center for AIDS Research (NIH P30 AI060354), all from the National Institute of Allergy and Infectious Diseases. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 21 TC 0 Z9 0 U1 1 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0306-6800 EI 1473-4257 J9 J MED ETHICS JI J. Med. Ethics PD FEB PY 2017 VL 43 IS 2 BP 71 EP 73 DI 10.1136/medethics-2016-103907 PG 3 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA EK0NU UT WOS:000393624200003 PM 27920163 ER PT J AU Vargas, MV Moawad, GN Sievers, C Opoku-Anane, J Marfori, CQ Tyan, P Robinson, JK AF Vargas, Maria V. Moawad, Gaby N. Sievers, Cem Opoku-Anane, Jessica Marfori, Cherie Q. Tyan, Paul Robinson, James K. TI Feasibility, Safety, and Prediction of Complications for Minimally Invasive Myomectomy in Women With Large and Numerous Myomata SO JOURNAL OF MINIMALLY INVASIVE GYNECOLOGY LA English DT Article DE Complications; Laparoscopy; Minimally invasive surgery; Myomata; Myomectomy; Predictors; Robotic surgery ID LAPAROSCOPIC MYOMECTOMY; ABDOMINAL MYOMECTOMY; MORCELLATION; UTERUS AB Objective: To assess perioperative outcomes and identify predictors of complications for minimally invasive surgery (MIS) myomectomy in a cohort of women with large and numerous myomata. Design: Case-control study (Canadian Task Force classification II-2). Setting: Academic tertiary care medical center. Patients: Women undergoing MIS myomectomy performed by 3 high-volume surgeons between April 2011 and December 2014. Interventions: Characteristics were compared between women who experienced complications and those who did not. Factors predictive of complications were then identified. Measurements and Main Results: A total of 221 women underwent an MIS myomectomy, 47.5% via a laparoscopic approach and 52.5% via robotic surgery. The mean SD specimen weight was 408.1 +/- 384.9 g, uterine volume was 586.1 +/- 534.1 cm(3), dominant myoma diameter was 9.6 +/- 5.1 cm, and number of myomata removed was 4.5 +/- 4.1. The most common complications were hemorrhage >1000 mL (8.6%) and blood transfusion (4.1%). The conversion rate was 1.8%. A dominant myoma diameter of >= 12 cm and a uterine volume of >= 750 cm(3) increased the odds of complications (odds ratio [OR], 7.44; 95% confidence interval [CI], 2.03-31.84; p = .004 and OR, 6.15; 95% CI, 1.55-30.02; p =.014 respectively). A receiver operating characteristic curve considering dominant myoma diameter and uterine volume had an area under the curve of 0.81. A combination of dominant myoma diameter of >= 10 cm and uterine volume of 600 cm3 predicted complications with 79% sensitivity and 79% specificity. Conclusion: Our cohort had large and numerous myomata with high specimen weights, but complications were comparable to those reported in previous studies of MIS myomectomy with less complex pathology. Hemorrhage and transfusion accounted for the majority of complications, and a combination of dominant myoma diameter and uterine volume was predictive of complications. Both factors can be easily defined before surgery and may be used to guide patient counseling, referrals, and implementation of preventative measures for hemorrhage and transfusion. Published by Elsevier Inc. on behalf of AAGL. C1 [Vargas, Maria V.; Moawad, Gaby N.; Opoku-Anane, Jessica; Marfori, Cherie Q.; Tyan, Paul; Robinson, James K.] George Washington Univ, Med Ctr, Sch Med & Hlth Sci, Dept Obstet & Gynecol, Washington, DC 20037 USA. [Sievers, Cem] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Sievers, Cem] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA. [Sievers, Cem] Harvard Med Sch, Boston, MA USA. [Sievers, Cem] Broad Inst MIT & Harvard, Cambridge, MA USA. [Opoku-Anane, Jessica] Univ Calif San Francisco, Dept Obstet & Gynecol, Div Gynecol, San Francisco, CA 94143 USA. [Robinson, James K.] MedStar Washington Hosp Ctr, Div Minimally Invas Gynecol Surg, Dept Obstet & Gynecol, Washington, DC USA. RP Vargas, MV (reprint author), George Washington Univ, Med Fac Associates, Dept Obstet & Gynecol, Sch Med & Hlth Sci, 2150 Penn Ave NW,Suite 6a-408, Washington, DC 20037 USA. EM mvvargas@mfa.gwu.edu OI Marfori, Cherie/0000-0002-2158-723X; Opoku-Anane, Jessica/0000-0003-2252-1571 FU Intuitive Surgical; Applied Medical FX Dr. Moawad is a paid consultant for Intuitive Surgical and Applied Medical. Dr. Robinson has received compensation for speaking at symposia held by Bayer. The other authors declare that they have no conflicts of interest. NR 21 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1553-4650 EI 1553-4669 J9 J MINIM INVAS GYN JI J. Mimim. Invasive Gynecol. PD FEB PY 2017 VL 24 IS 2 BP 315 EP 322 DI 10.1016/j.jmig.2016.11.014 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EK2AJ UT WOS:000393729200028 PM 27939896 ER PT J AU Bali, T Self, W Liu, JX Siddique, T Wang, LH Bird, TD Ratti, E Atassi, N Boylan, KB Glass, JD Maragakis, NJ Caress, JB McCluskey, LF Appel, SH Wymer, JP Gibson, S Zinman, L Mozaffar, T Callaghan, B McVey, AL Jockel-Balsarotti, J Allred, P Fisher, ER Lopate, G Pestronk, A Cudkowicz, ME Miller, TM AF Bali, Taha Self, Wade Liu, Jingxia Siddique, Teepu Wang, Leo H. Bird, Thomas D. Ratti, Elena Atassi, Nazem Boylan, Kevin B. Glass, Jonathan D. Maragakis, Nicholas J. Caress, James B. McCluskey, Leo F. Appel, Stanley H. Wymer, James P. Gibson, Summer Zinman, Lorne Mozaffar, Tahseen Callaghan, Brian McVey, April L. Jockel-Balsarotti, Jennifer Allred, Peggy Fisher, Elena R. Lopate, Glenn Pestronk, Alan Cudkowicz, Merit E. Miller, Timothy M. TI Defining SOD1 ALS natural history to guide therapeutic clinical trial design SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; SUPEROXIDE-DISMUTASE GENE; ANTISENSE OLIGONUCLEOTIDE THERAPY; DISEASE PROGRESSION; MUTANT SOD1; MOUSE MODEL; MUTATIONS; SURVIVAL; ANTIBODY; FLUID AB Importance Understanding the natural history of familial amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations (ALS(SOD1)) will provide key information for optimising clinical trials in this patient population. Objective To establish an updated natural history of ALS(SOD1). Design, setting and participants Retrospective cohort study from 15 medical centres in North America evaluated records from 175 patients with ALS with genetically confirmed SOD1 mutations, cared for after the year 2000. Main outcomes and measures Age of onset, survival, ALS Functional Rating Scale (ALS-FRS) scores and respiratory function were analysed. Patients with the A4V (Ala-Val) SOD1 mutation (SOD1(A4V)), the largest mutation population in North America with an aggressive disease progression, were distinguished from other SOD1 mutation patients (SOD1(non-A4V)) for analysis. Results Mean age of disease onset was 49.7 +/- 12.3 years (mean +/- SD) for all SOD1 patients, with no statistical significance between SOD1(A4V) and SOD1(non-A4V) (p=0.72, Kruskal-Wallis). Total SOD1 patient median survival was 2.7 years. Mean disease duration for all SOD1 was 4.6 +/- 6.0 and 1.4 +/- 0.7 years for SOD1(A4V). SOD1(A4V) survival probability (median survival 1.2 years) was significantly decreased compared with SOD1(non-A4V) (median survival 6.8 years; p<0.0001, log-rank). A statistically significant increase in ALS-FRS decline in SOD1(A4V) compared with SOD1(non-A4V) participants (p=0.02) was observed, as well as a statistically significant increase in ALS-forced vital capacity decline in SOD1(A4V) compared with SOD1(non-A4V) (p=0.02). Conclusions and relevance SOD1(A4V) is an aggressive, but relatively homogeneous form of ALS. These SOD1-specific ALS natural history data will be important for the design and implementation of clinical trials in the ALS(SOD1) patient population. C1 [Bali, Taha; Self, Wade; Jockel-Balsarotti, Jennifer; Fisher, Elena R.; Lopate, Glenn; Pestronk, Alan; Miller, Timothy M.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Liu, Jingxia] Washington Univ, Sch Med, Div Publ Hlth Sci, St Louis, MO USA. [Siddique, Teepu] Northwestern Univ, Feinberg Sch Med, Davee Dept Neurol & Clin Neurosci, Chicago, IL 60611 USA. [Wang, Leo H.; Bird, Thomas D.] Univ Washington, Med Ctr, Dept Neurol, Seattle, WA 98195 USA. [Bird, Thomas D.] Seattle Vet Affairs Med Ctr, Geriatr Res, Seattle, WA USA. [Ratti, Elena; Atassi, Nazem; Cudkowicz, Merit E.] Massachusetts Gen Hosp, Neurol Clin Res Inst, Boston, MA 02114 USA. [Boylan, Kevin B.] Mayo Clin Florida, Dept Neurol, Jacksonville, FL USA. [Glass, Jonathan D.] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. [Maragakis, Nicholas J.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Caress, James B.] Wake Forest Sch Med, Dept Neurol, Winston Salem, NC USA. [McCluskey, Leo F.] Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA. [Appel, Stanley H.] Methodist Hosp, Dept Neurol, Methodist Neurol Inst, 6535 Fannin, Houston, TX 77030 USA. [Wymer, James P.] Albany Med Ctr, Neurosci Inst, Albany, NY USA. [Gibson, Summer] Univ Utah, Dept Neurol, Salt Lake City, UT USA. [Zinman, Lorne] Sunnybrook Hlth Sci Ctr, Toronto, ON, Canada. [Mozaffar, Tahseen] Univ Calif Irvine, Dept Neurol, Irvine, CA 92717 USA. [Callaghan, Brian] Univ Michigan, Dept Neurol, Ann Arbor, MI USA. [McVey, April L.] Univ Kansas, Med Ctr, Dept Neurol, Kansas City, KS 66103 USA. [Allred, Peggy] Cedars Sinai Med Ctr, Dept Neurol, Los Angeles, CA 90048 USA. RP Miller, TM (reprint author), Washington Univ, 660 S Euclid Ave,Campus Box 8111, St Louis, MO 63110 USA. EM millert@neuro.wustl.edu OI Ratti, Elena/0000-0002-9321-7908; Caress, James/0000-0002-5814-6083 FU Seattle VA Medical Center, Department of Veterans Affairs; Amyotrophic Lateral Sclerosis Association; Harvard NeuroDiscovery Center; Massachusetts General Hospital Neurology; Biogen Idec; Muscular Dystrophy Association; NIH/NINDS [R25NS065743, R01NS078398, U01NS084970] FX Funding provided by Seattle VA Medical Center, Department of Veterans Affairs research funds (TDB) for collection of SOD1 data at University of Washington; Amyotrophic Lateral Sclerosis Association (ER) for collection of SOD1 clinical information at MGH; Harvard NeuroDiscovery Center (ER) for collection of SOD1 clinical information at Massachusetts General Hospital; the Dr Anne B. Young Neuroscience Translational Medicine Fellowship (Massachusetts General Hospital Neurology and Biogen Idec; ER) for collection of SOD1 clinical information at Massachusetts General Hospital; Muscular Dystrophy Association (TMM) for design and conduct of the study, collection of clinical information, data management and analysis, interpretation of the data, and preparation and review of the manuscript; NIH/NINDS R25NS065743 (ER) for collection of SOD1 clinical information at Massachusetts General Hospital, R01NS078398 (TMM) for salary support to TMM during the conduct of the study, U01NS084970 (TMM) for salary support to TMM during the conduct of the study. NR 30 TC 0 Z9 0 U1 4 U2 4 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-3050 EI 1468-330X J9 J NEUROL NEUROSUR PS JI J. Neurol. Neurosurg. Psychiatry PD FEB PY 2017 VL 88 IS 2 BP 99 EP 105 DI 10.1136/jnnp-2016-313521 PG 7 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA EK4NL UT WOS:000393903700004 PM 27261500 ER PT J AU Lee, YC Karlamangla, AS Yu, Z Liu, CC Finkelstein, JS Greendale, GA Harlow, SD Solomon, DH AF Lee, Yvonne C. Karlamangla, Arun S. Yu, Zhi Liu, Chih-Chin Finkelstein, Joel S. Greendale, Gail A. Harlow, Sioban D. Solomon, Daniel H. TI Pain Severity in Relation to the Final Menstrual Period in a Prospective Multiethnic Observational Cohort: Results From the Study of Women's Health Across the Nation SO JOURNAL OF PAIN LA English DT Article DE Pain; perimenopause; menopause; female; aging ID BODY-MASS INDEX; MENOPAUSAL TRANSITION; MUSCULOSKELETAL PAIN; RHEUMATOID-ARTHRITIS; NATURAL MENOPAUSE; RISK-FACTORS; SYMPTOMS; AGE; PREVALENCE; DEPRESSION AB The development of pain is common in midlife, resulting in increased health care utilization and costs. The aim of this study was to determine the longitudinal trajectory of overall bodily pain among women during the transition between the reproductive years and menopause. We conducted analyses on a community-based, longitudinal cohort of women enrolled in the Study of Women's Health Across the Nation. One thousand four hundred ninety-five women met inclusion criteria, including: 1) defined date of the final menstrual period (FMP), and 2) complete data on Short Form 36 bodily pain. The primary exposure was time to/from the FMP. The primary outcome was the rate of change in Short Form-36 bodily pain, measured on a scale of 0 to 100 with 100 being the most severe pain. We performed within-person trajectory analyses using piecewise regression following nonpara-metric modeling of functional forms. Mean bodily pain score at the time of the FMP was 29. Mean bodily pain increased at a rate of .26 per year during the transmenopause (the interval spanning 4.5 years before the FMP through .5 years after the FMP), and decreased at a rate of .23 per year after that. Depression and sleep problems were associated with greater increases in pain during the late reproductive years, whereas abdominal cramps at baseline predicted greater decreases in pain during the late reproductive years. Perspective: This article shows that bodily pain increases during the transmenopause and then diminishes during postmenopause. These differences may reflect differences in underlying mechanisms of pain in the 2 periods. Although mean changes were small and unlikely to be clinically meaningful, the magnitude of change varied across subgroups of women. (C) 2016 by the American Pain Society C1 [Lee, Yvonne C.; Yu, Zhi; Liu, Chih-Chin; Solomon, Daniel H.] Harvard Med Sch, Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA USA. [Karlamangla, Arun S.; Greendale, Gail A.] Univ Calif Los Angeles, David Geffen Sch Med, Div Geriatr, Los Angeles, CA 90095 USA. [Finkelstein, Joel S.] Massachusetts Gen Hosp, Dept Med, Endocrine Unit, Boston, MA 02114 USA. [Harlow, Sioban D.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. RP Lee, YC (reprint author), Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, 75 Francis St,PBB B3, Boston, MA 02115 USA. EM ylee9@partners.org OI Lee, Yvonne/0000-0002-2105-3393 FU National Institutes of Health (NIH) [R01 AR064850]; National Institute on Aging (NIA) - UCLA Older Americans Independence Center [5 P30-AG028748]; Study of Women's Health Across the Nation (SWAN); NIH-National Institute of Arthritis and Musculoskeletal and Skin Diseases [ARK24055989]; NIH; Department of Health and Human Services, through the NIA; National Institute of Nursing Research; NIH Office of Research on Women's Health [U01NR004061, U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, U01AG012495] FX Y.C.L. was supported by the National Institutes of Health (NIH; R01 AR064850). A.S.K. was supported by the National Institute on Aging (NIA)-funded, UCLA Older Americans Independence Center (5 P30-AG028748). D.H.S. was supported by the Study of Women's Health Across the Nation (SWAN) and NIH-National Institute of Arthritis and Musculoskeletal and Skin Diseases ARK24055989. The SWAN has grant support from the NIH, Department of Health and Human Services, through the NIA, the National Institute of Nursing Research, and the NIH Office of Research on Women's Health (grants U01NR004061, U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, U01AG012495). The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the NIA, National Institute of Nursing Research, Office of Research on Women's Health, or the NIH. NR 50 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD FEB PY 2017 VL 18 IS 2 BP 178 EP 187 DI 10.1016/j.jpain.2016.10.012 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EK1ZP UT WOS:000393727200007 PM 27836812 ER PT J AU Huang, JH Park, H Iaconelli, J Berkovitch, SS Watmuff, B McPhie, D Ongur, D Cohen, BM Clish, CB Karmacharya, R AF Huang, Joanne H. Park, Hyoungjun Iaconelli, Jonathan Berkovitch, Shaunna S. Watmuff, Bradley McPhie, Donna Ongur, Dost Cohen, Bruce M. Clish, Clary B. Karmacharya, Rakesh TI Unbiased Metabolite Profiling of Schizophrenia Fibroblasts under Stressful Perturbations Reveals Dysregulation of Plasmalogens and Phosphatidylcholines SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE metabolic profiling; schizophrenia; phosphatidylcholine; plasmalogen ID MAJOR DEPRESSIVE DISORDER; MAGNETIC-RESONANCE-SPECTROSCOPY; BIPOLAR DISORDER; 1ST-EPISODE SCHIZOPHRENIA; ANTIPSYCHOTIC-DRUGS; NAIVE SCHIZOPHRENIA; DYSFUNCTIONAL GLYCOSYNAPSES; C.-ELEGANS; BLOOD; BIOMARKER AB We undertook an unbiased metabolite profiling of fibroblasts from schizophrenia patients and healthy controls to identify metabolites and pathways that are dysregulated in disease, seeking to gain new insights into the disease biology of schizophrenia and to discover potential disease-related biomarkers. We measured polar and nonpolar metabolites in the fibroblasts under normal conditions and under two stressful physiological perturbations: growth in low-glucose media and exposure to the steroid hormone dexamethasone. We found that metabolites that were significantly different between schizophrenia and control subjects showed separation of the two groups by partial least-squares discriminant analysis methods. This separation between schizophrenia and healthy controls was more robust with metabolites identified under the perturbation conditions. The most significant individual metabolite differences were also found in the perturbation experiments. Metabolites that were significantly different between schizophrenia and healthy controls included a number of plasmalogens and phosphatidylcholines. We present these results in the context of previous reports of metabolic profiling of brain tissue and plasma in schizophrenia. These results show the applicability of metabolite profiling under stressful perturbations to reveal cellular pathways that may be involved in disease biology. C1 [Huang, Joanne H.; Iaconelli, Jonathan; Berkovitch, Shaunna S.; Watmuff, Bradley; Karmacharya, Rakesh] Harvard Med Sch, Ctr Human Genet Res, Ctr Expt Drugs & Diagnost, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Huang, Joanne H.; Iaconelli, Jonathan; Berkovitch, Shaunna S.; Watmuff, Bradley; Karmacharya, Rakesh] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Huang, Joanne H.; Iaconelli, Jonathan; Berkovitch, Shaunna S.; Watmuff, Bradley; Clish, Clary B.; Karmacharya, Rakesh] Broad Inst Harvard & MIT, Chem Biol Program, Cambridge, MA 02142 USA. [Park, Hyoungjun] ETH, Inst Neuroinformat, CH-8057 Zurich, Switzerland. [Park, Hyoungjun] Univ Zurich, CH-8057 Zurich, Switzerland. [McPhie, Donna; Ongur, Dost; Cohen, Bruce M.; Karmacharya, Rakesh] Harvard Med Sch, Schizophrenia & Bipolar Disorder Program, Belmont, MA 02478 USA. [McPhie, Donna; Ongur, Dost; Cohen, Bruce M.; Karmacharya, Rakesh] McLean Hosp, Belmont, MA 02478 USA. RP Karmacharya, R (reprint author), Harvard Med Sch, Ctr Human Genet Res, Ctr Expt Drugs & Diagnost, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA.; Karmacharya, R (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA.; Karmacharya, R (reprint author), Broad Inst Harvard & MIT, Chem Biol Program, Cambridge, MA 02142 USA.; Karmacharya, R (reprint author), Harvard Med Sch, Schizophrenia & Bipolar Disorder Program, Belmont, MA 02478 USA.; Karmacharya, R (reprint author), McLean Hosp, Belmont, MA 02478 USA. EM karmacharya@mgh.harvard.edu FU Ryan Licht Sang Bipolar Foundation; National Institute of Mental Health; Doris Duke Charitable Foundation; Phyllis & Jerome Lyle Rappaport Foundation FX This study was carried out with funding from the Ryan Licht Sang Bipolar Foundation, the National Institute of Mental Health, the Doris Duke Charitable Foundation, the Phyllis & Jerome Lyle Rappaport Foundation, and Steve Willis and Elissa Freud. NR 99 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 EI 1535-3907 J9 J PROTEOME RES JI J. Proteome Res. PD FEB PY 2017 VL 16 IS 2 BP 481 EP 493 DI 10.1021/acs.jproteome.6b00628 PG 13 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA EJ9IK UT WOS:000393539600012 PM 28152600 ER PT J AU O'Brien, EC Wu, JJ Zhao, X Schulte, PJ Fonarow, GC Hernandez, AF Schwamm, LH Peterson, ED Bhatt, DL Smith, EE AF O'Brien, Emily C. Wu, Jingjing Zhao, Xin Schulte, Phillip J. Fonarow, Gregg C. Hernandez, Adrian F. Schwamm, Lee H. Peterson, Eric D. Bhatt, Deepak L. Smith, Eric E. TI Healthcare Resource Availability, Quality of Care, and Acute Ischemic Stroke Outcomes SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE healthcare resources; outcomes research; stroke care ID GUIDELINES-STROKE; PERFORMANCE-MEASURES; ASSOCIATION; ATTACK; PATIENT; SYSTEMS; ACCESS AB Background-Healthcare resources vary geographically, but associations between hospital-based resources and acute stroke quality and outcomes remain unclear. Methods and Results-Using Get With The Guidelines-Stroke and Dartmouth Atlas of Health Care data, we examined associations between healthcare resource availability, stroke care, and outcomes. We categorized hospital referral regions with high-, medium-, or low-resource levels based on the 2006 national per-capita availability median of 6 relevant acute stroke care resources. Using multivariable logistic regression, we examined healthcare resource level and in-hospital quality and outcomes. Of 1 480 308 admitted ischemic stroke patients (2006-2013), 28.8% were hospitalized in low-, 44.4% in medium-, and 26.9% in high-resource hospital referral regions. Quality-of-care/timeliness metrics, adjusted length of stay, and in-hospital mortality were similar across all resource levels. Conclusions-Significant variation exists in regional availability of healthcare resources for acute ischemic stroke treatment, yet among Get With the Guidelines-Stroke hospitals, quality of care and in-hospital outcomes did not differ by regional resource availability. C1 [O'Brien, Emily C.; Wu, Jingjing; Zhao, Xin; Hernandez, Adrian F.; Peterson, Eric D.] Duke Clin Res Inst, 2400 Pratt St, Durham, NC 27705 USA. [Schulte, Phillip J.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Fonarow, Gregg C.] UCLA Div Cardiol, Los Angeles, CA USA. [Schwamm, Lee H.] Harvard Med Sch, Massachusetts Gen Hosp, Stroke Serv, Boston, MA USA. [Bhatt, Deepak L.] Harvard Med Sch, Brigham & Womens Hosp, Heart & Vasc Ctr, Boston, MA USA. [Smith, Eric E.] Univ Calgary, Calgary, AB T2N 1N4, Canada. RP O'Brien, EC (reprint author), Duke Clin Res Inst, 2400 Pratt St, Durham, NC 27705 USA. EM emily.obrien@duke.edu FU American Heart Association; Guidelines-Stroke; Pfizer, Inc., New York, NY; Merck-Schering Plough Partnership (North Wales, PA); American Heart Association's Young Investigator Database Research Seed Grant FX The American Heart Association funded Get With The Guidelines-Stroke. The program has been supported in part by unrestricted educational grants to the American Heart Association by Pfizer, Inc., New York, NY, and the Merck-Schering Plough Partnership (North Wales, PA). This project was funded by the American Heart Association's Young Investigator Database Research Seed Grant. NR 23 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD FEB PY 2017 VL 6 IS 2 AR e003813 DI 10.1161/JAHA.116.003813 PG 14 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EK0CS UT WOS:000393594700019 ER PT J AU Salinas, J Ray, RM Nassir, R Lakshminarayan, K Dording, C Smoller, J Wassertheil-Smoller, S Rosand, J Dunn, EC AF Salinas, Joel Ray, Roberta M. Nassir, Rami Lakshminarayan, Kamakshi Dording, Christina Smoller, Jordan Wassertheil-Smoller, Sylvia Rosand, Jonathan Dunn, Erin C. TI Factors Associated With New-Onset Depression Following Ischemic Stroke: The Women's Health Initiative SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE epidemiology; risk factor; stroke; women ID POSTMENOPAUSAL WOMEN; SOCIAL SUPPORT; POSTSTROKE DEPRESSION; ANTIDEPRESSANT USE; MAJOR DEPRESSION; POSITIVE AFFECT; OLDER WOMEN; SELF-ESTEEM; LONG-TERM; MORTALITY AB Background-Psychosocial characteristics have a strong effect on risk of depression, and their direct treatment with behavioral interventions reduces rates of depression. Because new-onset poststroke depression (NPSD) is frequent, devastating, and often treatment-resistant, novel preventive efforts are needed. As a first step toward developing behavioral interventions for NPSD, we investigated whether prestroke psychosocial factors influenced rates of NPSD in a manner similar to the general population. Methods and Results-Using the Women's Health Initiative, we analyzed 1424 respondents who were stroke-free at enrollment and had no self-reported history of depression from enrollment to their nonfatal ischemic stroke based on initiation of treatment for depression or the Burnam screening instrument for detecting depressive disorders. NPSD was assessed using the same method during the 5-year poststroke period. Logistic regression provided odds ratios of NPSD controlling for multiple covariates. NPSD occurred in 21.4% (305/1424) of the analytic cohort and varied by stroke severity as measured by the Glasgow scale, ranging from 16.7% of those with good recovery to 31.6% of those severely disabled. Women with total anterior circulation infarction had the highest level (31.4%) of NPSD while those with lacunar infarction had the lowest (16.1%). Prestroke psychosocial measures had different associations with NPSD depending on functional recovery of the individual. Conclusions-There is a difference in the relationship of prestroke psychosocial status and risk of NPSD depending on stroke severity; thus it may be that the same preventive interventions might not work for all stroke patients. One size does not fit all. C1 [Salinas, Joel; Rosand, Jonathan] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Boston, MA USA. [Dording, Christina; Smoller, Jordan; Dunn, Erin C.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA USA. [Smoller, Jordan; Rosand, Jonathan; Dunn, Erin C.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA USA. [Ray, Roberta M.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Nassir, Rami] Univ Calif, Dept Biochem & Mol Med, Davis, CA USA. [Lakshminarayan, Kamakshi] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Smoller, Jordan; Dunn, Erin C.] Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Wassertheil-Smoller, Sylvia] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. RP Dunn, EC (reprint author), Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, 185 Cambridge St, Boston, MA 02114 USA. EM edunn2@mgh.harvard.edu OI Salinas, Joel/0000-0002-3735-0018 FU National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services [HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, HHSN268201600004C]; Schwamm Marriott Clinical Care Research Fellowship Program; National Institutes of Health [T32NS048005]; National Institute of Mental Health [K01MH102403] FX The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. Research reported in this publication was supported by the Schwamm Marriott Clinical Care Research Fellowship Program and National Institutes of Health training grant T32NS048005 (Salinas) as well as the National Institute of Mental Health under award number K01MH102403 (Dunn). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 53 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD FEB PY 2017 VL 6 IS 2 AR e003828 DI 10.1161/JAHA.116.003828 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EK0CS UT WOS:000393594700009 ER PT J AU Zhou, WH Arellano, RS AF Zhou, Wenhui Arellano, Ronald S. TI Hydrodissection-Assisted Percutaneous Drainage of Deep Pelvic Abscess SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Letter C1 [Zhou, Wenhui] Tufts Univ, Sch Med, 145 Harrison Ave, Boston, MA 02111 USA. [Arellano, Ronald S.] Massachusetts Gen Hosp, Div Intervent Radiol, Dept Radiol, Boston, MA 02114 USA. RP Zhou, WH (reprint author), Tufts Univ, Sch Med, 145 Harrison Ave, Boston, MA 02111 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1051-0443 EI 1535-7732 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD FEB PY 2017 VL 28 IS 2 BP 308 EP 310 DI 10.1016/j.jvir.2016.10.011 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA EJ9JU UT WOS:000393543200025 PM 28110764 ER PT J AU Damar, U Gersner, R Johnstone, JT Schachter, S Rotenberg, A AF Damar, Ugur Gersner, Roman Johnstone, Joshua T. Schachter, Steven Rotenberg, Alexander TI Huperzine A: A promising anticonvulsant, disease modifying, and memory enhancing treatment option in Alzheimer's disease SO MEDICAL HYPOTHESES LA English DT Article DE Huperzine A; Acetylcholinesterase; Nicotinic; Seizure; Alzheimer's disease; Antiepileptic; ppTMS ID NICOTINIC ACETYLCHOLINE-RECEPTORS; NEUROPEPTIDE-Y; MOUSE MODEL; NEURONAL HYPEREXCITABILITY; POSTSYNAPTIC CURRENTS; COGNITIVE IMPAIRMENTS; HIPPOCAMPAL-NEURONS; ANTIEPILEPTIC DRUGS; NETWORK DYSFUNCTION; GABAERGIC NEURONS AB Alzheimer's disease (AD) is the most frequent cause of dementia. Besides cognitive deterioration, patients with AD are prone to seizures - more than 20% of patients diagnosed with AD experience at least one unprovoked seizure and up to 7% have recurrent seizures. Although available antiepileptic drugs (AEDs) may suppress seizures in patients with AD, they may also worsen cognitive dysfunction and increase the risk of falls. On the basis of preclinical studies, we hypothesize that Huperzine A (HupA), a safe and potent acetylcholinesterase (AChE) inhibitor with potentially disease-modifying qualities in AD, may have a realistic role as an anticonvulsant in AD. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Damar, Ugur; Gersner, Roman; Rotenberg, Alexander] Harvard Med Sch, Boston Childrens Hosp, FM Kirby Neurobiol Ctr, Dept Neurol, Boston, MA USA. [Johnstone, Joshua T.] Biscayne Pharmaceut Inc, Miami, FL USA. [Schachter, Steven] Harvard Med Sch, Dept Neurol, Beth Israel Deaconess Med Ctr, Boston, MA USA. [Schachter, Steven] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. RP Rotenberg, A (reprint author), Boston Childrens Hosp, Dept Neurol, 300 Longwood Ave, Boston, MA 02115 USA. EM Alexander.Rotenberg@childrens.harvard.edu NR 95 TC 0 Z9 0 U1 3 U2 3 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0306-9877 EI 1532-2777 J9 MED HYPOTHESES JI Med. Hypotheses PD FEB PY 2017 VL 99 BP 57 EP 62 DI 10.1016/j.mehy.2016.12.006 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EK1XT UT WOS:000393721800013 PM 28110700 ER PT J AU Styer, AK AF Styer, Aaron K. TI The impact of estrogen alone hormone therapy on breast cancer risk and health outcomes: reassurance for the treatment of climacteric symptoms in black women? SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Editorial Material ID RANDOMIZED CONTROLLED-TRIAL; POSTMENOPAUSAL WOMEN; REPLACEMENT THERAPY; VASOMOTOR SYMPTOMS; PLUS PROGESTIN; ASSOCIATION; DISEASE; DESIGN; COHORT; HEART C1 [Styer, Aaron K.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02115 USA. RP Styer, AK (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02115 USA. NR 26 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1072-3714 EI 1530-0374 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD FEB PY 2017 VL 24 IS 2 BP 124 EP 125 DI 10.1097/GME.0000000000000821 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EK2LM UT WOS:000393758800002 PM 28072609 ER PT J AU Pasquale, LR Aschard, H Kang, JH Bailey, JNC Lindstrom, S Chasman, DI Christen, WG Allingham, RR Ashley-Koch, A Lee, RK Moroi, SE Brilliant, MH Wollstein, G Schuman, JS Fingert, J Budenz, DL Realini, T Gaasterland, T Gaasterland, D Scott, WK Singh, K Sit, AJ Igo, RP Song, YE Hark, L Ritch, R Rhee, DJ Gulati, V Havens, S Vollrath, D Zack, DJ Medeiros, F Weinreb, RN Pericak-Vance, MA Liu, YT Kraft, P Richards, JE Rosner, BA Hauser, MA Haines, JL Wiggs, JL AF Pasquale, Louis R. Aschard, Hugues Kang, Jae H. Bailey, Jessica N. Cooke Lindstrom, Sara Chasman, Daniel I. Christen, William G. Allingham, R. Rand Ashley-Koch, Allison Lee, Richard K. Moroi, Sayoko E. Brilliant, Murray H. Wollstein, Gadi Schuman, Joel S. Fingert, John Budenz, Donald L. Realini, Tony Gaasterland, Terry Gaasterland, Douglas Scott, William K. Singh, Kuldev Sit, Arthur J. Igo, Robert P., Jr. Song, Yeunjoo E. Hark, Lisa Ritch, Robert Rhee, Douglas J. Gulati, Vikas Havens, Shane Vollrath, Douglas Zack, Donald J. Medeiros, Felipe Weinreb, Robert N. Pericak-Vance, Margaret A. Liu, Yutao Kraft, Peter Richards, Julia E. Rosner, Bernard A. Hauser, Michael A. Haines, Jonathan L. Wiggs, Janey L. TI Age at natural menopause genetic risk score in relation to age at natural menopause and primary open-angle glaucoma in a US-based sample SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Article DE Age at natural menopause; Genetic risk score; Primary open-angle glaucoma ID FEMALE REPRODUCTIVE FACTORS; NURSES HEALTH; UNITED-STATES; DNA-REPAIR; ASSOCIATION; WOMEN; LOCI; EYE; 17-BETA-ESTRADIOL; SUSCEPTIBILITY AB Objective: Several attributes of female reproductive history, including age at natural menopause (ANM), have been related to primary open-angle glaucoma (POAG). We assembled 18 previously reported common genetic variants that predict ANM to determine their association with ANM or POAG. Methods: Using data from the Nurses' Health Study (7,143 women), we validated the ANM weighted genetic risk score in relation to self-reported ANM. Subsequently, to assess the relation with POAG, we used data from 2,160 female POAG cases and 29,110 controls in the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database (NEIGHBORHOOD), which consists of 8 datasets with imputed genotypes to 5.6+ million markers. Associations with POAG were assessed in each dataset, and site-specific results were meta-analyzed using the inverse weighted variance method. Results: The genetic risk score was associated with self-reported ANM (P = 2.2 +/- 10(-77)) and predicted 4.8% of the variance in ANM. The ANM genetic risk score was not associated with POAG (Odds Ratio (OR) = 1.002; 95% Confidence Interval (CI): 0.998, 1.007; P = 0.28). No single genetic variant in the panel achieved nominal association with POAG (P >= 0.20). Compared to the middle 80 percent, there was also no association with the lowest 10th percentile or highest 90th percentile of genetic risk score with POAG (OR = 0.75; 95% CI: 0.47, 1.21; P = 0.23 and OR = 1.10; 95% CI: 0.72, 1.69; P = 0.65, respectively). Conclusions: A genetic risk score predicting 4.8% of ANM variation was not related to POAG; thus, genetic determinants of ANM are unlikely to explain the previously reported association between the two phenotypes. C1 [Pasquale, Louis R.; Wiggs, Janey L.] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. [Pasquale, Louis R.; Kang, Jae H.; Rosner, Bernard A.] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Aschard, Hugues; Lindstrom, Sara; Kraft, Peter; Rosner, Bernard A.] Harvard Med Sch, Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Bailey, Jessica N. Cooke; Igo, Robert P., Jr.; Song, Yeunjoo E.; Haines, Jonathan L.] Case Western Reserve Univ, Sch Med, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Bailey, Jessica N. Cooke; Haines, Jonathan L.] Case Western Reserve Univ, Sch Med, Inst Computat Biol, Cleveland, OH USA. [Chasman, Daniel I.; Christen, William G.] Harvard Med Sch, Brigham & Womens Hosp, Div Prevent Med, Boston, MA USA. [Allingham, R. Rand; Hauser, Michael A.] Duke Univ, Med Ctr, Dept Ophthalmol, Durham, NC 27710 USA. [Ashley-Koch, Allison; Hauser, Michael A.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Lee, Richard K.] Univ Miami, Miller Sch Med, Bascom Palmer Eye Inst, Miami, FL 33136 USA. [Moroi, Sayoko E.; Richards, Julia E.] Univ Michigan, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. [Brilliant, Murray H.] Marshfield Clin Res Fdn, Ctr Human Genet, Marshfield, WI USA. [Wollstein, Gadi; Schuman, Joel S.] Univ Pittsburgh, Dept Ophthalmol, UPMC, Ctr Eye, Pittsburgh, PA 15260 USA. [Fingert, John] Univ Iowa, Coll Med, Dept Ophthalmol, Iowa City, IA 52242 USA. [Fingert, John] Univ Iowa, Coll Med, Dept Anat Cell Biol, Iowa City, IA USA. [Budenz, Donald L.] Univ N Carolina, Dept Ophthalmol, Chapel Hill, NC USA. [Realini, Tony] WVU Eye Inst, Dept Ophthalmol, Morgantown, WV USA. [Gaasterland, Terry] Univ Calif San Diego, Scripps Genome Ctr, San Diego, CA 92103 USA. [Gaasterland, Douglas] Emmes Corp, Chevy Chase, MD USA. [Scott, William K.; Pericak-Vance, Margaret A.] Univ Miami, Miller Sch Med, Hussman Inst Human Genom, Miami, FL 33136 USA. [Singh, Kuldev] Stanford Univ, Dept Ophthalmol, Palo Alto, CA 94304 USA. [Sit, Arthur J.] Mayo Clin, Dept Ophthalmol, Rochester, MN USA. [Hark, Lisa] Wills Eye Inst, Philadelphia, PA USA. [Ritch, Robert] New York Eye & Ear Infirm Mt Sinai, Einhorn Clin Res Ctr, New York, NY USA. [Rhee, Douglas J.] Case Western Reserve Univ, Sch Med, Dept Ophthalmol, Cleveland, OH USA. [Gulati, Vikas; Havens, Shane] Univ Nebraska Med Ctr, Dept Ophthalmol & Visual Sci, Omaha, NE USA. [Vollrath, Douglas] Stanford Univ, Dept Genet, Palo Alto, CA 94304 USA. [Zack, Donald J.] Johns Hopkins Univ Hosp, Wilmer Eye Inst, Baltimore, MD USA. [Medeiros, Felipe; Weinreb, Robert N.] Univ Calif San Diego, Hamilton Eye Ctr, Dept Ophthalmol, San Diego, CA 92103 USA. [Liu, Yutao] Augusta Univ, Dept Cellular Biol & Anat, Augusta, GA USA. RP Pasquale, LR (reprint author), Mass Eye & Ear Infirm, 243 Charles St, Boston, MA 02115 USA. EM Louis_Pasquale@meei.harvard.edu OI Ashley-Koch, Allison/0000-0001-5409-9155 FU National Eye Institute (NEI) [HG005259-01]; National Institutes of Health [HHSN268200782096C]; NEI through ARRA grants [3R01EY015872-05S1, 3R01EY019126-02S1]; NIH grants [EY015543, U02HG004608, HG006389, UL1TR000427, EY006827, HL073389, HL73042, EY13315, CA87969, CA49449, CA55075, EY009149, HG004608, EY008208, EY015473, EY012118, EY015682, EY011671, EY09580, EY013178, EY010886, EY009847, EY011008, EY144428, EY144448, EY18660]; Research to Prevent Blindness (multiple institutions); NCATS/NIH grant [UL1TR000427]; National Heart, Lung, and Blood Institute [HL043851, HL080467]; National Cancer Institute [CA047988]; Donald W. Reynolds Foundation; Foundation Leducq; Amgen; New York Glaucoma Research Institute; GENEVA project grant [HG004728, U01-HG004424]; [1U02HG004608-01]; [5U01HG006389-02]; [R01 CA131332]; [UM1 CA186107]; [UM1 CA167552]; [R01 CA49449]; [P01 CA87969]; [3RO1 EY015473-05S1] FX The NIH/NEI R01EY022305 (J.L.W.) supports data collection and analysis for the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database (NEIGHBORHOOD) consortium. Support for collection of cases, controls, and analysis for individual datasets is as follows. Genotyping services for the predecessor National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) study were provided by the Center for Inherited Disease Research (CIDR) and were supported by the National Eye Institute (NEI) through grant HG005259-01 (J.L.W.). In addition, CIDR is funded through a federal contract from the National Institutes of Health to The Johns Hopkins University-contract number HHSN268200782096C. Genotyping for the Mass Eye and Ear dataset and some Nurses Health Study (NHS) and Health Professionals Follow-up Study (HPFS) participants that formed the Glaucoma Genes and Environment (GLAUGEN) study was completed at the Broad Institute and supported by GENEVA project grant HG004728 (L.R.P.) and U01-HG004424 (Broad Institute). NIH/NHGRI U01 HG004446 (C Laurie) supported genotype data cleaning and analysis for the GLAUGEN study. The NEI through ARRA grants 3R01EY015872-05S1 (J.L.W.) and 3R01EY019126-02S1 (M.A.H.) supported the collection and processing samples for the NEIGHBOR dataset. The funding for the collection of NEIGHBOR cases and controls was provided by NIH grants: EY015543 (R.R.A.), U02HG004608 (M.H.B.), HG006389 (M.H.B.), UL1TR000427 (M.H.B.), EY006827 (D.G.), HL73042, HL073389, EY13315 (M.A.H.); CA87969, CA49449, CA55075, EY009149 (PR Lichter), HG004608 (C McCarty), EY008208 (F.M.), EY015473(L.R.P.), EY012118 (M.A.P.-V.), EY015682 (T.R.),EY011671 (J.E.R.), EY09580 (J.E.R.), EY013178 (J.S.S.), EY010886 (J.L.W.), EY009847 (J.L.W.), EY011008, EY144428 (K Zhang), EY144448 (K Zhang), EY18660 (K Zhang), and Research to Prevent Blindness (multiple institutions). The collection of Marshfield clinic cases and controls was supported by 1U02HG004608-01, 5U01HG006389-02, and NCATS/NIH grant UL1TR000427. In addition, some NHS/HPFS cases and controls and analysis of genome-wide data were supported by R01 CA131332 (RM Tamimi, I De Vivo), UM1 CA186107, UM1 CA167552, R01 CA49449, P01 CA87969. The Women's Genome Health Study (WGHS) is supported by HL043851 and HL080467 from the National Heart, Lung, and Blood Institute and CA047988 from the National Cancer Institute, the Donald W. Reynolds Foundation and the Foundation Leducq, with collaborative scientific support and funding for genotyping provided by Amgen. POAG case identification in Women's Genome Health Study was supported by 3RO1 EY015473-05S1 (LR Pasquale). Blood collection at New York Eye & Ear Infirmary was supported by the New York Glaucoma Research Institute. NR 38 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1072-3714 EI 1530-0374 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD FEB PY 2017 VL 24 IS 2 BP 150 EP 156 DI 10.1097/GME.0000000000000741 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EK2LM UT WOS:000393758800006 PM 27760082 ER PT J AU Otto, T Sicinski, P AF Otto, Tobias Sicinski, Piotr TI Cell cycle proteins as promising targets in cancer therapy SO NATURE REVIEWS CANCER LA English DT Review ID DEPENDENT KINASE INHIBITOR; POLO-LIKE-KINASE; ADVANCED BREAST-CANCER; PRECLINICAL TESTING PROGRAM; ACUTE MYELOID-LEUKEMIA; ADVANCED SOLID TUMORS; DNA-DAMAGING AGENTS; VOLASERTIB BI 6727; NEUROENDOCRINE PROSTATE-CANCER; INVESTIGATIONAL AURORA KINASE AB Cancer is characterized by uncontrolled tumour cell proliferation resulting from aberrant activity of various cell cycle proteins. Therefore, cell cycle regulators are considered attractive targets in cancer therapy. Intriguingly, animal models demonstrate that some of these proteins are not essential for proliferation of non-transformed cells and development of most tissues. By contrast, many cancers are uniquely dependent on these proteins and hence are selectively sensitive to their inhibition. After decades of research on the physiological functions of cell cycle proteins and their relevance for cancer, this knowledge recently translated into the first approved cancer therapeutic targeting of a direct regulator of the cell cycle. In this Review, we focus on proteins that directly regulate cell cycle progression (such as cyclin-dependent kinases (CDKs)), as well as checkpoint kinases, Aurora kinases and Polo-like kinases (PLKs). We discuss the role of cell cycle proteins in cancer, the rationale for targeting them in cancer treatment and results of clinical trials, as well as the future therapeutic potential of various cell cycle inhibitors. C1 [Otto, Tobias; Sicinski, Piotr] Harvard Med Sch, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Otto, Tobias; Sicinski, Piotr] Harvard Med Sch, Dept Genet, Boston, MA 02215 USA. [Otto, Tobias] Univ Hosp RWTH Aachen, Dept Internal Med 3, D-52074 Aachen, Germany. RP Sicinski, P (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.; Sicinski, P (reprint author), Harvard Med Sch, Dept Genet, Boston, MA 02215 USA. EM Peter_Sicinski@dfci.harvard.edu FU [R01 CA132740]; [R01 CA202634]; [P01 CA080111] FX The authors thank S. Goel for advice and critical discussions related to the clinical data in this manuscript. This work was supported by R01 CA132740, R01 CA202634 and P01 CA080111 (to P.S.). NR 245 TC 0 Z9 0 U1 5 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X EI 1474-1768 J9 NAT REV CANCER JI Nat. Rev. Cancer PD FEB PY 2017 VL 17 IS 2 BP 93 EP 115 DI 10.1038/nrc.2016.138 PG 23 WC Oncology SC Oncology GA EK2BZ UT WOS:000393733600006 PM 28127048 ER PT J AU Ffytche, DH Creese, B Politis, M Chaudhuri, KR Weintraub, D Ballard, C Aarsland, D AF Ffytche, Dominic H. Creese, Byron Politis, Marios Chaudhuri, K. Ray Weintraub, Daniel Ballard, Clive Aarsland, Dag TI The psychosis spectrum in Parkinson disease SO NATURE REVIEWS NEUROLOGY LA English DT Review ID DOPAMINERGIC-INDUCED HALLUCINATIONS; ANGIOTENSIN-CONVERTING ENZYME; ATTENTIONAL CONTROL NETWORKS; SLEEP BEHAVIOR DISORDER; DRUG-INDUCED PSYCHOSIS; LEWY BODY DEMENTIAS; VISUAL HALLUCINATIONS; RISK-FACTORS; ALZHEIMERS-DISEASE; GLUCOCEREBROSIDASE MUTATIONS AB In 2007, the clinical and research profile of illusions, hallucinations, delusions and related symptoms in Parkinson disease (PD) was raised with the publication of a consensus definition of PD psychosis. Symptoms that were previously deemed benign and clinically insignificant were incorporated into a continuum of severity, leading to the rapid expansion of literature focusing on clinical aspects, mechanisms and treatment. Here, we review this literature and the evolving view of PD psychosis. Key topics include the prospective risk of dementia in individuals with PD psychosis, and the causal and modifying effects of PD medication. We discuss recent developments, including recognition of an increase in the prevalence of psychosis with disease duration, addition of new visual symptoms to the psychosis continuum, and identification of frontal executive, visual perceptual and memory dysfunction at different disease stages. In addition, we highlight novel risk factors-for example, autonomic dysfunction-that have emerged from prospective studies, structural MRI evidence of frontal, parietal, occipital and hippocampal involvement, and approval of pimavanserin for the treatment of PD psychosis. The accumulating evidence raises novel questions and directions for future research to explore the clinical management and biomarker potential of PD psychosis. C1 [Ffytche, Dominic H.; Creese, Byron; Politis, Marios; Chaudhuri, K. Ray; Weintraub, Daniel; Ballard, Clive; Aarsland, Dag] Kings Coll London, Inst Psychiat Psychol & Neurosci, KCL PARCOG Grp, De Crespigny Pk, London SE5 8AF, England. [Ffytche, Dominic H.; Aarsland, Dag] Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Old Age Psychiat, De Crespigny Pk, London SE5 8AF, England. [Creese, Byron; Ballard, Clive] Univ Exeter, Sch Med, Exeter EX1 2LU, Devon, England. [Politis, Marios] Kings Coll London, Inst Psychiat Psychol & Neurosci, Maurice Wohl Clin Neurosci Inst, Neurodegenerat Imaging Grp, 125 Coldharbour Lane, London SE5 9NU, England. [Chaudhuri, K. Ray] Kings Coll London, Kings Coll Hosp London, Natl Parkinson Fdn Ctr Excellence, Maurice Wohl Clin Neurosci Inst,Dept Basic & Clin, 5 Cutcombe Rd, London SE5 9RT, England. [Weintraub, Daniel] Univ Penn, Perelman Sch Med, Dept Psychiat, 3615 Chestnut St,330, Philadelphia, PA 19104 USA. [Weintraub, Daniel] Univ Penn, Perelman Sch Med, Dept Neurol, 3615 Chestnut St,330, Philadelphia, PA 19104 USA. [Weintraub, Daniel] Philadelphia Vet Affairs Med Ctr, Parkinsons Dis & Mental Illness Res Educ & Clin C, 3900 Woodland Ave, Philadelphia, PA 19104 USA. [Weintraub, Daniel] Philadelphia Vet Affairs Med Ctr, MIRECC, 3900 Woodland Ave, Philadelphia, PA 19104 USA. RP Ffytche, DH (reprint author), Kings Coll London, Inst Psychiat Psychol & Neurosci, KCL PARCOG Grp, De Crespigny Pk, London SE5 8AF, England.; Ffytche, DH (reprint author), Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Old Age Psychiat, De Crespigny Pk, London SE5 8AF, England. EM dominic.ffytche@kcl.ac.uk OI Aarsland, Dag/0000-0001-6314-216X FU European Union; Parkinson's UK; NIHR; Parkinson's Disease Non Motor group; Wolfson Foundation; Royal Society; National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre and Dementia Unit; NIHR Programme Grants [SHAPED RP-PG-0610-10100] FX The authors thank Dr Michael Haworth for help in preparing the final manuscript, Dr Rowena Carter for help preparing Figure 1, and the National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre and Dementia Unit and NIHR Programme Grants for Applied Research (SHAPED RP-PG-0610-10100) for supporting their involvement in this work. K.R.C. acknowledges support from the European Union, Parkinson's UK, the NIHR and the Parkinson's Disease Non Motor group. D.A. is a Royal Society Wolfson Research Merit Award Holder and thanks the Wolfson Foundation and the Royal Society for their support. The views expressed are those of the authors and not necessarily those of the National Health Service, the NIHR or the Department of Health. NR 188 TC 0 Z9 0 U1 7 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4758 EI 1759-4766 J9 NAT REV NEUROL JI Nat. Rev. Neurol. PD FEB PY 2017 VL 13 IS 2 BP 81 EP 95 DI 10.1038/nrneurol.2016.200 PG 15 WC Clinical Neurology SC Neurosciences & Neurology GA EK2CT UT WOS:000393735700007 PM 28106066 ER PT J AU Uppal, S Chapman, C Spencer, RJ Jolly, S Maturen, K Rauh-Hain, JA Delcarmen, MG Rice, LW AF Uppal, Shitanshu Chapman, Christina Spencer, Ryan J. Jolly, Shruti Maturen, Kate Rauh-Hain, J. Alejandro delCarmen, Marcela G. Rice, Laurel W. TI Association of Hospital Volume With Racial and Ethnic Disparities in Locally Advanced Cervical Cancer Treatment SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID TREATMENT GUIDELINES; UNITED-STATES; COLON-CANCER; SURVIVAL; RACE; ADHERENCE; MORTALITY; THERAPY; STAGE; WOMEN AB OBJECTIVE: To evaluate racial-ethnic disparities in guideline-based care in locally advanced cervical cancer and their relationship to hospital case volume. METHODS: Using the National Cancer Database, we performed a retrospective cohort study of women diagnosed between 2004 and 2012 with locally advanced squamous or adenocarcinoma of the cervix undergoing definitive primary radiation therapy. The primary outcome was the race-ethnicity-based rates of adherence to the National Comprehensive Cancer Network guideline-based care. The secondary outcome was the effect of guideline-based care on overall survival. Multivariable models and propensity matching were used to compare the hospital risk-adjusted rates of guideline-based adherence and overall survival based on hospital case volume. RESULTS: The final cohort consisted of 16,195 patients. The rate of guideline-based care was 58.4% (95% confidence interval [CI] 57.4-59.4%) for nonHispanic white, 53% (95% CI 51.4-54.9%) for non-Hispanic black, and 51.5% (95% CI 49.4-53.7%) for Hispanic women (P<.001). From 2004 to 2012, the rate of guideline-based care increased from 49.5% (95% CI 47.1-51.9%) to 59.1% (95% CI 56.9-61.2%) (Ptrend,. 001). Based on a propensity score-matched analysis, patients receiving guideline-based care had a lower risk of mortality (adjusted hazard ratio 0.65, 95% CI 0.62-0.68). Compared with low-volume hospitals, the increase in adherence to guideline-based care in high-volume hospitals was 48-63% for non-Hispanic white, 47-53% for non-Hispanic black, and 41-54% for Hispanic women. CONCLUSION: Racial and ethnic disparities in the delivery of guideline-based care are the highest in high-volume hospitals. Guideline-based care in locally advanced cervical cancer is associated with improved survival. C1 Univ Michigan, Div Gynecol Oncol, Ann Arbor, MI 48109 USA. Univ Michigan, Inst Healthcare Policy & Innovat, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Radiat Oncol, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Diagnost Radiol, Ann Arbor, MI 48109 USA. Univ Wisconsin, Div Gynecol Oncol, Madison, WI USA. Harvard Med Sch, Massachusetts Gen Hosp, Div Gynecol Oncol, Vincent Obstet & Gynecol, Boston, MA USA. RP Uppal, S (reprint author), Univ Michigan, 1500 E Med Dr, Ann Arbor, MI 48109 USA. EM uppal@med.umich.edu NR 32 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD FEB PY 2017 VL 129 IS 2 BP 295 EP 304 DI 10.1097/AOG.0000000000001819 PG 10 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EK1CE UT WOS:000393662600008 PM 28079775 ER PT J AU Crema, MD Roemer, FW Li, L Alexander, RC Chessell, IP Dudley, AD Karlsten, R Rosen, LB Guermazi, A AF Crema, M. D. Roemer, F. W. Li, L. Alexander, R. C. Chessell, I. P. Dudley, A. D. Karlsten, R. Rosen, L. B. Guermazi, A. TI Comparison between semiquantitative and quantitative methods for the assessment of knee synovitis in osteoarthritis using non-enhanced and gadolinium-enhanced MRI SO OSTEOARTHRITIS AND CARTILAGE LA English DT Article DE Osteoarthritis; Knee; Synovitis; Magnetic resonance imaging ID JOINT EFFUSION; CARTILAGE LOSS; ASSOCIATION; RISK; DISEASE AB Objective: To compare different semiquantitative and quantitative methods using both non-enhanced and gadolinium-enhanced MRI techniques for the assessment of synovitis in knee osteoarthritis (OA). Methods: Knees with end-stage clinical OA in patients undergoing total knee replacement surgery were included in this cross-sectional study. MRI was performed on all knees. Standard non-enhanced and gadolinium-enhanced sequences were acquired. Using non-enhanced MRI, we semiquantitatively assessed two features widely used as surrogates for synovitis: effusion-synovitis and Hoffa-synovitis. Using gadolinium-enhanced sequences, we semiquantitatively assessed synovial thickness. We quantitatively evaluated the total synovial volume on the gadolinium-enhanced sequences as well. We assessed the correlations of effusion-synovitis and Hoffa-synovitis with synovial thickness and volume, applying Spearman correlation analysis. The diagnostic performance of both synovitis features on non-enhanced MRI was assessed using synovial thickness on gadolinium-enhanced MRI as the reference. Results: A total of 104 subjects (one knee per subject) were included. Correlations of effusion-synovitis with synovial thickness and volume were r = 0.41 and r = 0.43 (P < .001) r = 0.32 and r = 0.39 (P < .0001). Conclusion: Using synovial thickness assessed on gadolinium-enhanced sequences as the reference, effusion-synovitis showed superior correlations and sensitivity. Effusion-synovitis should be preferred over Hoffa-synovitis as a surrogate marker for synovial thickening, in studies of knee OA for which gadolinium-enhanced sequences are not available. (C) 2016 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. C1 [Crema, M. D.; Roemer, F. W.; Chessell, I. P.; Dudley, A. D.; Guermazi, A.] Boston Univ, Sch Med, Dept Radiol, Quantitat Imaging Ctr, 820 Harrison Ave,FGH Bldg,3rd Floor, Boston, MA 02118 USA. [Crema, M. D.] Univ Paris 06, St Antoine Hosp, Dept Radiol, Paris, France. [Roemer, F. W.] Univ Erlangen Nurnberg, Dept Radiol, Erlangen, Germany. [Li, L.] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA USA. [Alexander, R. C.] Pfizer Neurosci, Cambridge, MA USA. [Chessell, I. P.; Dudley, A. D.] AZ Neuro, Cambridge, England. [Karlsten, R.] Uppsala Univ, Dept Surg Sci Anaesthesiol & Intens Care, Uppsala, Sweden. [Rosen, L. B.] Flex Pharma, Boston, MA USA. [Alexander, R. C.; Karlsten, R.; Rosen, L. B.] AstraZeneca, London, England. RP Crema, MD (reprint author), Boston Univ, Sch Med, Dept Radiol, Quantitat Imaging Ctr, 820 Harrison Ave,FGH Bldg,3rd Floor, Boston, MA 02118 USA. EM michelcrema@gmail.com OI Guermazi, Ali/0000-0002-9374-8266 FU AstraZeneca (AstraZeneca Study) [D2285M00029] FX This study was funded by AstraZeneca (AstraZeneca Study D2285M00029). NR 15 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1063-4584 EI 1522-9653 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD FEB PY 2017 VL 25 IS 2 BP 267 EP 271 DI 10.1016/j.joca.2016.09.016 PG 5 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA EJ9EN UT WOS:000393529500012 PM 27697506 ER PT J AU Dagogo-Jack, I Gill, CM Cahill, DP Santagata, S Brastianos, PK AF Dagogo-Jack, Ibiayi Gill, Corey M. Cahill, Daniel P. Santagata, Sandro Brastianos, Priscilla K. TI Treatment of brain metastases in the modern genomic era SO PHARMACOLOGY & THERAPEUTICS LA English DT Review DE Brain metastases; Genomics; Targeted therapies; Sequencing ID CELL LUNG-CANCER; CENTRAL-NERVOUS-SYSTEM; TYROSINE KINASE INHIBITORS; HER2-POSITIVE BREAST-CANCER; PROPHYLACTIC CRANIAL IRRADIATION; STEREOTACTIC RADIOSURGERY BOOST; FACTOR-RECEPTOR MUTATIONS; RANDOMIZED PHASE-3 TRIAL; LAPATINIB PLUS CAPECITABINE; ACTIVE METABOLITE OSI-420 AB Development of brain metastasis (BM) portends a dismal prognosis for patients with cancer. Melanomas and carcinomas of the lung, breast, and kidney are the most common malignancies to metastasize to the brain. Recent advances in molecular genetics have enabled the identification of actionable, clinically relevant genetic alterations within primary tumors and their corresponding metastases. Adoption of genotype-guided treatment strategies for the management of systemic malignancy has resulted in dramatic and durable responses. Unfortunately, despite these therapeutic advances, central nervous system (CNS) relapses are not uncommon. Although these relapses have historically been attributed to limited blood brain barrier penetration of anti-neoplastic agents, recent work has demonstrated genetic heterogeneity such that metastatic sites, including BM, harbor relevant genetic alterations that are not present in primary tumor biopsies. This improved insight into molecular mechanisms underlying site specific recurrences can inform strategies for targeting these oncogenic drivers. Thus, development of rational, genomically guided CNS-penetrant therapies is crucial for ongoing therapeutic success. (C) 2016 Published by Elsevier Inc. C1 [Dagogo-Jack, Ibiayi; Brastianos, Priscilla K.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Dagogo-Jack, Ibiayi; Gill, Corey M.; Cahill, Daniel P.; Santagata, Sandro; Brastianos, Priscilla K.] Harvard Med Sch, 55 Fruit St,YAW 9E, Boston, MA 02114 USA. [Gill, Corey M.; Brastianos, Priscilla K.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Gill, Corey M.; Brastianos, Priscilla K.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Cahill, Daniel P.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Santagata, Sandro] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Brastianos, PK (reprint author), Harvard Med Sch, 55 Fruit St,YAW 9E, Boston, MA 02114 USA.; Brastianos, PK (reprint author), Massachusetts Gen Hosp, 55 Fruit St,YAW 9E, Boston, MA 02114 USA. EM pbrastianos@mgh.harvard.edu NR 190 TC 1 Z9 1 U1 2 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0163-7258 J9 PHARMACOL THERAPEUT JI Pharmacol. Ther. PD FEB PY 2017 VL 170 BP 64 EP 72 DI 10.1016/j.pharmthera.2016.10.011 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EK0QF UT WOS:000393631200005 PM 27773784 ER PT J AU Aziz, F Raffetto, JD Diaz, JA Myers, DD Ozsvath, KJ Carman, TL Lal, BK AF Aziz, Faisal Raffetto, Joseph D. Diaz, Jose A. Myers, Daniel D., Jr. Ozsvath, Kathleen J. Carman, Teresa L. Lal, Brajesh K. CA Amer Venous Forum AVF Res Comm TI Practice patterns of adjunctive therapy for venous leg ulcers SO PHLEBOLOGY LA English DT Article DE Wound care; venous ulceration; venous stasis ID SOCIOECONOMIC IMPACT; COMPRESSION THERAPY; INSUFFICIENCY; DRESSINGS; TRIAL AB Objectives Venous leg ulcers (VLU) are the most severe clinical sequelae of venous reflux and post thrombotic syndrome. There is a consensus that ablation of refluxing vein segments and treatment of significant venous obstruction can heal VLUs. However, there is wide disparity in the use and choice of adjunctive therapies for VLUs. The purpose of this study was to assess these practice patterns among members of the American Venous Forum. Methods The AVF Research Committee conducted an online survey of its own members, which consisted of 16 questions designed to determine the specialty of physicians, location of treatment, treatment practices and reimbursement for treatment of VLUs Results The survey was distributed to 667 practitioners and a response rate of 18.6% was achieved. A majority of respondents (49.5%) were vascular specialists and the remaining were podiatrists, dermatologists, primary care doctors and others. It was found that 85.5% were from within the USA, while physicians from 14 other countries also responded. Most of the physicians (45%) provided adjunctive therapy at a private office setting and 58% treated less than 5 VLU patients per week. All respondents used some form of compression therapy as the primary mode of treatment for VLU. Multilayer compression therapy was the most common form of adjunctive therapy used (58.8%) and over 90% of physicians started additional modalities (biologics, negative pressure, hyperbaric oxygen and others) when VLUs failed compression therapy, with a majority (65%) waiting less than three months to start them. Medicare was the most common source of reimbursement (52.4%). Conclusions Physicians from multiple specialties treat VLU. While most physicians use compression therapy, there is wide variation in the selection and point of initiation for additional therapies once compression fails. There is a need for high-quality data to help establish guidelines for adjunctive treatment of VLUs and to disseminate them to physicians across multiple specialties to ensure standardized high-quality treatment of patients with VLUs. C1 [Aziz, Faisal] Penn State Hershey Coll Med, Penn State Heart & Vasc Inst, Vasc Surg, Hershey, PA USA. [Raffetto, Joseph D.] Harvard Med Sch, Brigham & Womens Hosp, Vasc Surg, VA Boston HCS, Boston, MA USA. [Diaz, Jose A.; Myers, Daniel D., Jr.] Univ Michigan, Vasc Surg, Ann Arbor, MI 48109 USA. [Ozsvath, Kathleen J.] Albany Med Coll, Vasc Surg, Albany, NY 12208 USA. [Carman, Teresa L.] Univ Hosp Case Med Ctr, Vasc Med, Cleveland, OH USA. [Lal, Brajesh K.] Univ Maryland, Sch Med, Vasc Surg, Baltimore, MD 21201 USA. RP Aziz, F (reprint author), Penn State Hershey Coll Med, Div Vasc Surg, Penn State Heart & Vasc Inst, Dept Surg, 500 Univ Dr,Mail Code H053, Hershey, PA 17033 USA. EM faziz@hmc.psu.edu OI Diaz, MD, Jose Antonio/0000-0001-5205-2118 NR 19 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0268-3555 EI 1758-1125 J9 PHLEBOLOGY JI Phlebology PD FEB PY 2017 VL 32 IS 1 BP 19 EP 26 DI 10.1177/0268355515625526 PG 8 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA EK7CZ UT WOS:000394084800004 PM 26769720 ER PT J AU Dolz-Marco, R Phasukkijwatana, N Sarraf, D Freund, KB AF Dolz-Marco, Rosa Phasukkijwatana, Nopasak Sarraf, David Freund, K. Bailey TI REGRESSION OF TYPE 2 NEOVASCULARIZATION INTO A TYPE 1 PATTERN AFTER INTRAVITREAL ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION SO RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES LA English DT Article DE age-related macular degeneration; AMD; choroidal neovascularization; OCT-A; OCT-angiography; type 1 neovascularization; type 2 neovascularization ID COHERENCE TOMOGRAPHY-ANGIOGRAPHY; ANTI-VEGF THERAPY; CHOROIDAL NEOVASCULARIZATION; EYES; RANIBIZUMAB; BEVACIZUMAB; MANAGEMENT; OUTCOMES AB Purpose: To study eyes with Type 2 (subretinal) neovascularization (NV) secondary to neovascular age-related macular degeneration (nAMD) that shows lesion regression into a Type 1 (subretinal pigment epithelium) pattern after treatment with intravitreal anti-vascular endothelial growth factor (VEGF) therapy. Methods: Retrospective consecutive case series. Patients showing regression of Type 2 neovascularization into a Type 1 pattern after envelopment by retinal pigment epithelium were included in this analysis. A review of the clinical records and multimodal imaging of these cases was performed at baseline, 1, 3, 6, and 12 months. Demographic data, best-corrected visual acuity (BCVA), color fundus photography, fundus autofluorescence (FAF), fluorescein angiography, near-infrared reflectance (NIR), and structural spectral-domain optical coherence tomography (SD-OCT) were reviewed and analyzed. When available, optical coherence tomography angiography images were analyzed as well. Results: Ten eyes of 9 patients (6 males) diagnosed with treatment-naive pure Type 2 neovascularization secondary to nAMD were included. The mean age was 80.7 years (SD +/- 4.30). Mean best-corrected visual acuity expressed in logMAR (Snellen) was 0.45 +/- 0.20 (20/55) at baseline and significantly improved to 0.22 +/- 0.13 (20/32) at 3-month follow-up (P-value: 0.007). At baseline, color photographs and fundus autofluorescence showed a pigment ring around the neovascular lesion in 6 eyes. A hyperreflective ring was visible on NIR in all eyes at 3-month follow-up. Color photographs showed a tessellated fundus appearance in 9 of the 10 eyes. Serial structural spectral-domain optical coherence tomography scans showed the gradual regression of the Type 2 lesions into a Type 1 pattern with envelopment by the retinal pigment epithelium. En face and cross-sectional optical coherence tomography angiography showed baseline subretinal flow patterns which, after treatment, exhibited reduced flow beneath an intact hyperreflective retinal pigment epithelium (RPE) band. Conclusion: Pure Type 2 lesions are infrequent in nAMD, often leading to poor visual outcomes related to subretinal fibrosis. We describe an alternate regression pattern occurring in eyes with early Type 2 lesions treated with intravitreal anti-vascular endothelial growth factor therapy in which the neovascular tissue is enveloped by retinal pigment epithelium producing a Type 1 pattern. These eyes appear to have better visual outcomes than typically seen with Type 2 lesions related to reduced outer retinal damage. C1 [Dolz-Marco, Rosa; Freund, K. Bailey] Vitreous Retina Macula Consultants New York, 460 Pk Ave, New York, NY 10022 USA. [Dolz-Marco, Rosa] Manhattan Eye Ear & Throat Hosp, LuEsther T Mertz Retinal Res Ctr, New York, NY 10021 USA. [Phasukkijwatana, Nopasak; Sarraf, David] Univ Calif Los Angeles, Jules Stein Eye Inst, Retinal Disorders & Ophthalm Genet Div, Los Angeles, CA 90024 USA. [Sarraf, David] Greater Los Angeles VA Healthcare Ctr, Los Angeles, CA USA. [Freund, K. Bailey] Columbia Univ, Coll Phys & Surg, Edward S Harkness Eye Inst, Dept Ophthalmol, New York, NY USA. [Freund, K. Bailey] NYU, Sch Med, Dept Ophthalmol, New York, NY USA. RP Freund, KB (reprint author), Vitreous Retina Macula Consultants New York, 460 Pk Ave, New York, NY 10022 USA. EM kbfnyf@aol.com FU LuEsther T. Mertz Retinal Research Center, Manhattan Eye, Ear, and Throat Hospital, New York, NY; Macula Foundation Inc, New York, NY; Alcon; Allergan; Bayer; Heidelberg Engineering; Novartis; Thea; Genentech; Regeneron; Optovue FX This work was supported by a research grant from the LuEsther T. Mertz Retinal Research Center, Manhattan Eye, Ear, and Throat Hospital, New York, NY, and The Macula Foundation Inc, New York, NY.; R. Dolz-Marco: Research grants from Alcon, Allergan, Bayer, Heidelberg Engineering, Novartis, Thea; N. Phasukkijwatana: None; D. Sarraf: Research grants from Genentech, Regeneron and Optovue. Consultant to Genentech and Optovue; K. B. Freund: Consultant to Genentech, Optos, Optovue, Heidelberg Engineering, and Bayer HealthCare. NR 26 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0275-004X EI 1539-2864 J9 RETINA-J RET VIT DIS JI Retin.-J. Retin. Vitr. Dis. PD FEB PY 2017 VL 37 IS 2 BP 222 EP 233 PG 12 WC Ophthalmology SC Ophthalmology GA EK1FO UT WOS:000393671400011 PM 27627752 ER PT J AU Tan, ACS Dansingani, KK Yannuzzi, LA Sarraf, D Freund, KB AF Tan, Anna C. S. Dansingani, Kunal K. Yannuzzi, Lawrence A. Sarraf, David Freund, K. Bailey TI TYPE 3 NEOVASCULARIZATION IMAGED WITH CROSS-SECTIONAL AND EN FACE OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY SO RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES LA English DT Article DE type 3 neovascularization; optical coherence tomography angiography ID RETINAL ANGIOMATOUS PROLIFERATION; PIGMENT EPITHELIAL DETACHMENT; MACULAR DEGENERATION; ARTIFACTS; SPECTRUM AB Purpose: To study the cross-sectional and en face optical coherence tomography angiography (OCTA) findings in Type 3 neovascularization (NV). Methods: Optical coherence tomography angiography imaging of 27 eyes of 23 patients with Type 3 NV was analyzed with 9 eyes having consecutive follow-up OCTA studies. Results: Type 3 NV appeared as a linear high-flow structure on cross-sectional OCTA corresponding to a high-flow tuft of vessels seen on en face OCTA. Cross-sectional OCTA seemed to enable the distinction between vascular and nonvascular intraretinal hyper-reflective foci. Two patterns of flow were observed; Pattern 1 (11%): a flow signal confined to the neurosensory retina and Pattern 2 (74%): a flow signal extending through the retinal pigment epithelium. No definitive retinal-choroidal anastomosis was observed; however, projection artifacts confounded the interpretation of deeper structures. An increase in the intensity of the high-flow tuft was seen during the progression or recurrence of Type 3 NV. Intravitreal anti-vascular endothelial growth factor therapy caused a reduction in the intensity of the high-flow tuft which was not sustained. Conclusion: Compared with conventional imaging, OCTA may improve detection and delineation of vascular changes occurring in Type 3 NV. Cross-sectional and en face OCTA may prove useful in studying the pathogenesis and guiding the management of these lesions. C1 [Tan, Anna C. S.; Dansingani, Kunal K.; Yannuzzi, Lawrence A.; Freund, K. Bailey] Vitreous Retina Macula Consultants New York, 460 Pk Ave,5th Floor, New York, NY 10022 USA. [Tan, Anna C. S.; Dansingani, Kunal K.; Yannuzzi, Lawrence A.; Freund, K. Bailey] Manhattan Eye Ear & Throat Hosp, LuEsther T Mertz Retinal Res Ctr, New York, NY 10021 USA. [Tan, Anna C. S.] Singapore Eye Res Inst, Singapore Natl Eye Ctr, Singapore, Singapore. [Dansingani, Kunal K.] Moorfield Eye Hosp, London, England. [Dansingani, Kunal K.] Univ Nebraska, Truhlsen Eye Inst, Omaha, NE 68182 USA. [Sarraf, David] Univ Calif Los Angeles, Stein Eye Inst, Los Angeles, CA USA. [Sarraf, David] Greater Los Angeles VA Healthcare Ctr, Los Angeles, CA USA. [Freund, K. Bailey] NYU, Sch Med, Dept Ophthalmol, New York, NY USA. RP Freund, KB (reprint author), Vitreous Retina Macula Consultants New York, 460 Pk Ave,5th Floor, New York, NY 10022 USA. EM kbfnyf@aol.com FU Allergan; Genenetch; Optoivue; Regeneron FX K. B. Freund is a consultant for Genentech, Optovue, Optos, Bayer Healthcare, and Heidelberg Engineering. D. Sarraf is a consultant for Genentech and Optovue and receives research grants from Allergan, Genenetch, Optoivue and Regeneron. The remaining authors have no financial/conflicting interests to disclose. NR 22 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0275-004X EI 1539-2864 J9 RETINA-J RET VIT DIS JI Retin.-J. Retin. Vitr. Dis. PD FEB PY 2017 VL 37 IS 2 BP 234 EP 246 PG 13 WC Ophthalmology SC Ophthalmology GA EK1FO UT WOS:000393671400012 PM 27749497 ER PT J AU Duran-Struuck, R Sondermeijer, HP Buhler, L Alonso-Guallart, P Zitsman, J Kato, Y Wu, A McMurchy, AN Woodland, D Griesemer, A Martinez, M Boskovic, S Kawai, T Cosimi, AB Wuu, CS Slate, A Mapara, MY Baker, S Tokarz, R D'Agati, V Hammer, S Pereira, M Lipkin, WI Wekerle, T Levings, MK Sykes, M AF Duran-Struuck, Raimon Sondermeijer, Hugo P. Buhler, Leo Alonso-Guallart, Paula Zitsman, Jonah Kato, Yojiro Wu, Anette McMurchy, Alicia N. Woodland, David Griesemer, Adam Martinez, Mercedes Boskovic, Svetlan Kawai, Tatsuo Cosimi, A. Benedict Wuu, Cheng-Shie Slate, Andrea Mapara, Markus Y. Baker, Sam Tokarz, Rafal D'Agati, Vivette Hammer, Scott Pereira, Marcus Lipkin, W. Ian Wekerle, Thomas Levings, Megan K. Sykes, Megan TI Effect of Ex Vivo-Expanded Recipient Regulatory T Cells on Hematopoietic Chimerism and Kidney Allograft Tolerance Across MHC Barriers in Cynomolgus Macaques SO TRANSPLANTATION LA English DT Review ID BONE-MARROW-TRANSPLANTATION; ANTIBODY MAB INJECTIONS; WHOLE-BODY IRRADIATION; MIXED-CHIMERISM; RENAL-ALLOGRAFT; MONOCLONAL-ANTIBODY; THYMIC IRRADIATION; PERIPHERAL-BLOOD; INDUCTION; MONKEYS AB Background. Infusion of recipient regulatory T (Treg) cells promotes durable mixed hematopoietic chimerism and allograft tolerance in mice receiving allogeneic bone marrow transplant (BMT) with minimal conditioning. We applied this strategy in a Cynomolgus macaque model. Methods. CD4(+) CD25(high) Treg cells that were polyclonally expanded in culture were highly suppressive in vitro and maintained high expression of FoxP3. Eight monkeys underwent nonmyeloablative conditioning and major histocompatibility complex mismatched BMT with or without Treg cell infusion. Renal transplantation (from the same BMT donor) was performed 4 months post-BMT without immunosuppression to assess for robust donor-specific tolerance. Results. Transient mixed chimerism, without significant T cell chimerism, was achieved in the animals that received BMT without Treg cells (N = 3). In contrast, 2 of 5 recipients of Treg cell(+) BMT that were evaluable displayed chimerism in all lineages, including T cells, for up to 335 days post-BMT. Importantly, in the animal that survived long-term, greater than 90% of donor T cells were CD45RA(+) CD31(+), suggesting they were new thymic emigrants. In this animal, the delayed (to 4 months) donor kidney graft was accepted more than 294 days without immunosuppression, whereas non-Treg cell BMT recipients rejected delayed donor kidneys within 3 to 4 weeks. Early CMV reactivation and treatment was associated with early failure of chimerism, regardless of Treg cell administration. Conclusions. Our studies provide proof-of-principle that, in the absence of early CMV reactivation (and BM-toxic antiviral therapy), cotransplantation of host Treg cell can promote prolonged and high levels of multilineage allogeneic chimerism and robust tolerance to the donor. C1 [Duran-Struuck, Raimon; Sondermeijer, Hugo P.; Alonso-Guallart, Paula; Zitsman, Jonah; Kato, Yojiro; Wu, Anette; Woodland, David; Griesemer, Adam; Martinez, Mercedes; Mapara, Markus Y.; Sykes, Megan] Columbia Univ, Dept Med, Med Ctr, Columbia Ctr Translat Immunol, New York, NY USA. [Duran-Struuck, Raimon; Kato, Yojiro; Woodland, David; Griesemer, Adam; Sykes, Megan] Columbia Univ, Dept Surg, Med Ctr, New York, NY USA. [Buhler, Leo] Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02114 USA. [McMurchy, Alicia N.; Levings, Megan K.] Univ British Columbia, Dept Surg, Vancouver, BC, Canada. [McMurchy, Alicia N.; Levings, Megan K.] British Columbia Childrens Hosp, Res Inst, Vancouver, BC, Canada. [Martinez, Mercedes] Columbia Univ, Dept Pediat, Med Ctr, Div Gastroenterol, New York, NY 10027 USA. [Boskovic, Svetlan; Kawai, Tatsuo; Cosimi, A. Benedict] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Wuu, Cheng-Shie] Columbia Univ, Dept Radiat Oncol, Med Ctr, New York, NY USA. [Slate, Andrea; Baker, Sam] Columbia Univ, Inst Comparat Med, New York, NY USA. [Mapara, Markus Y.; Sykes, Megan] Columbia Univ, Dept Med, Med Ctr, Div Hematol Oncol, New York, NY USA. [Tokarz, Rafal; Lipkin, W. Ian] Columbia Univ, Ctr Infect & Immun, Mailman Sch Publ Hlth, New York, NY USA. [D'Agati, Vivette] Columbia Univ, Dept Pathol, Med Ctr, New York, NY USA. [Hammer, Scott; Pereira, Marcus] Columbia Univ, Div Infect Dis, Med Ctr, New York, NY USA. [Wekerle, Thomas] Med Univ Vienna, Dept Surg, Sect Transplantat Immunol, Vienna, Austria. [Sykes, Megan] Columbia Univ, Med Ctr, Dept Microbiol & Immunol, New York, NY USA. RP Sykes, M (reprint author), Columbia Ctr Translat Immunol, 630 W 168th St,Mailbox 127, New York, NY 10032 USA. EM megan.sykes@columbia.edu FU NIH [RO1OD017949]; Columbia University Departments of Medicine and Surgery; Banting Foundation; Columbia University; Irving Pilot Translational science award for new investigators; Office of the Director, National Institutes of Health [S10RR027050] FX Funding for these studies was provided by NIH grant RO1OD017949, by startup funds from Columbia University Departments of Medicine and Surgery (to MS and RDS), the Banting Foundation (to MS), the Columbia University core award (to RDS), and the Irving Pilot Translational science award for new investigators (to RDS). Research reported in this publication was performed in the CCTI Flow Cytometry Core, supported in part by the Office of the Director, National Institutes of Health under awards S10RR027050. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 48 TC 1 Z9 1 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD FEB PY 2017 VL 101 IS 2 BP 274 EP 283 DI 10.1097/TP.0000000000001559 PG 10 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA EK0WI UT WOS:000393647400021 PM 27846155 ER PT J AU Tena, AA Sachs, DH Mallard, C Yang, YG Tasaki, M Farkash, E Rosales, IA Colvin, RB Leonard, DA Hawley, RJ AF Tena, Aseda A. Sachs, David H. Mallard, Christopher Yang, Yong-Guang Tasaki, Masayuki Farkash, Evan Rosales, Ivy A. Colvin, Robert B. Leonard, David A. Hawley, Robert J. TI Prolonged Survival of Pig Skin on Baboons After Administration of Pig Cells Expressing Human CD47 SO TRANSPLANTATION LA English DT Article ID BONE-MARROW-TRANSPLANTATION; RENAL-ALLOGRAFT TOLERANCE; LARGE-ANIMAL-MODEL; MIXED CHIMERISM; HEMATOPOIETIC-CELLS; PREPARATIVE REGIMEN; XENOGRAFT REJECTION; MACROPHAGES; SPECIFICITY; INDUCTION AB Background. Successful xenotransplantation will likely depend, in part, on the induction of immunological tolerance, because the high levels of immunosuppression otherwise required would likely have unacceptable side effects. Rapid clearance of administered porcine hematopoietic stem cells by primate macrophages has hampered previous attempts to induce tolerance through mixed hematopoietic chimerism across a pig-to-primate barrier. Phagocytosis is normally inhibited by binding of cell surface protein CD47 to macrophage signal regulatory protein a receptors. However, pig CD47 has previously been shown to be ineffective in transducing signals through primate signal regulatory protein a. Methods. Mobilized peripheral blood hematopoietic cells from transgenic swine expressing high or low levels of human CD47 were infused into conditioned baboons at 3 time points over a 9-week period. Xenogeneic peripheral blood chimerism was assessed after each infusion. Split thickness skin grafts from the hematopoietic cell donor swine were placed on recipients 5 weeks after the last cell infusion and 7 weeks after the discontinuation of all immunosuppression to test immune response. Results. The level and duration of transient chimerism were substantially greater in baboons receiving hematopoietic cells from a pig expressing high levels of human CD47. Skin graft survival on high CD47 recipients was prolonged as well, in 1 case showing no signs of rejection at least 53 days after placement. Conclusions. Prolongation of transient porcine chimerism via transgenic expression of human CD47 in a primate model is associated with an immune modulating effect, leading to markedly prolonged survival of donor swine skin xenografts that may be applicable to clinical solid organ xenotransplantation. C1 [Tena, Aseda A.; Sachs, David H.; Mallard, Christopher; Tasaki, Masayuki; Leonard, David A.; Hawley, Robert J.] MGH, Transplantat Biol Res Ctr, Boston, MA USA. [Sachs, David H.; Colvin, Robert B.; Hawley, Robert J.] Harvard Med Sch, Boston, MA USA. [Yang, Yong-Guang] Columbia Univ, Columbia Ctr Translat Immunol, New York, NY USA. [Farkash, Evan; Rosales, Ivy A.; Colvin, Robert B.] Massachusetts Gen Hosp, Pathol Serv, Boston, MA 02114 USA. RP Hawley, RJ (reprint author), Massachusetts Gen Hosp, Ctr Transplantat Sci, Bldg 149,13th St, Charlestown, MA 02129 USA. EM rhawley1@partners.org FU [NIH5R42AI082853]; [NIH2PO1AI45897]; [NIHRR020135-01]; [NIHR01AI064569] FX This work was supported by the following grants: NIH5R42AI082853; NIH2PO1AI45897; NIHRR020135-01 and NIHR01AI064569. NR 30 TC 0 Z9 0 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD FEB PY 2017 VL 101 IS 2 BP 316 EP 321 DI 10.1097/TP.0000000000001267 PG 6 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA EK0WI UT WOS:000393647400026 PM 27232934 ER PT J AU Taber, DJ Gebregziabher, M Payne, EH Srinivas, T Baliga, PK Egede, LE AF Taber, David J. Gebregziabher, Mulugeta Payne, Elizabeth H. Srinivas, Titte Baliga, Prabhakar K. Egede, Leonard E. TI Overall Graft Loss Versus Death-Censored Graft Loss: Unmasking the Magnitude of Racial Disparities in Outcomes Among US Kidney Transplant Recipients SO TRANSPLANTATION LA English DT Article ID RENAL-ALLOGRAFT SURVIVAL; AFRICAN-AMERICANS; RISK-FACTORS; SCIENTIFIC REGISTRY; ETHNIC DISPARITIES; ACUTE REJECTION; UNITED-STATES; ACCESS; RACE; IMMUNOSUPPRESSION AB Background. Black kidney transplant recipients experience disproportionately high rates of graft loss. This disparity has persisted for 40 years, and improvements may be impeded based on the current public reporting of overall graft loss by US regulatory organizations for transplantation. Methods. Longitudinal cohort study of kidney transplant recipients using a data set created by linking Veterans Affairs and US Renal Data System information, including 4918 veterans transplanted between January 2001 and December 2007, with follow-up through December 2010. Multivariable analysis was conducted using 2-stage joint modeling of random and fixed effects of longitudinal data (linear mixed model) with time to event outcomes (Cox regression). Results. Three thousand three hundred six non-Hispanic whites (67%) were compared with 1612 non-Hispanic black (33%) recipients with 6.0 +/- 2.2 years of follow-up. In the unadjusted analysis, black recipients were significantly more likely to have overall graft loss (hazard ratio [HR], 1.19; 95% confidence interval [95% CI], 1.07-1.33), death-censored graft loss (HR, 1.67; 95% CI, 1.45-1.92), and lower mortality (HR, 0.83; 95% CI, 0.72-0.96). In fully adjusted models, only death-censored graft loss remained significant (HR, 1.38; 95% CI, 1.12-1.71; overall graft loss [HR, 1.08; 95% CI, 0.91-1.28]; mortality [HR, 0.84; 95% CI, 0.67-1.06]). A composite definition of graft loss reduced the magnitude of disparities in blacks by 22%. Conclusions. Non-Hispanic black kidney transplant recipients experience a substantial disparity in graft loss, but not mortality. This study of US data provides evidence to suggest that researchers should focus on using death-censored graft loss as the primary outcome of interest to facilitate a better understanding of racial disparities in kidney transplantation. C1 [Taber, David J.; Baliga, Prabhakar K.] Med Univ South Carolina, Div Transplant Surg, Coll Med, Charleston, SC USA. [Gebregziabher, Mulugeta; Payne, Elizabeth H.] Med Univ South Carolina, Dept Publ Hlth Sci, Coll Med, Charleston, SC USA. [Srinivas, Titte] Med Univ South Carolina, Div Transplant Nephrol, Coll Med, Charleston, SC USA. [Egede, Leonard E.] Ralph H Johnson VAMC, Vet Affairs HSR&D Hlth Equ & Rural Outreach Innov, Charleston, SC USA. RP Taber, DJ (reprint author), Univ South Carolina, Coll Med, Div Transplant Surg, 96 Jonathan Lucas St,MSC 611, Charleston, SC 29425 USA. EM taberd@musc.edu OI Gebregziabher, Mulugeta/0000-0002-4826-481X FU National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health [K23DK099440] FX Research reported in this publication was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under Award Number K23DK099440. NR 42 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD FEB PY 2017 VL 101 IS 2 BP 402 EP 410 DI 10.1097/TP.0000000000001119 PG 9 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA EK0WI UT WOS:000393647400036 PM 26901080 ER PT J AU Fortenbaugh, FC Robertson, LC Esterman, M AF Fortenbaugh, Francesca C. Robertson, Lynn C. Esterman, Michael TI Changes in the distribution of sustained attention alter the perceived structure of visual space SO VISION RESEARCH LA English DT Article DE Peripheral visual localization; Space perception; Visual attention; Sustained attention; Peripheral visual field ID EYE-MOVEMENTS; SPATIAL LOCALIZATION; COVERT ATTENTION; FOVEAL BIAS; FIELD; PERCEPTION; LOCATION; MISLOCALIZATION; MICROSACCADES; DISTORTIONS AB Visual spatial attention is a critical process that allows for the selection and enhanced processing of relevant objects and locations. While studies have shown attentional modulations of perceived location and the representation of distance information across multiple objects, there remains disagreement regarding what influence spatial attention has on the underlying structure of visual space. The present study utilized a method of magnitude estimation in which participants must judge the location of briefly presented targets within the boundaries of their individual visual fields in the absence of any other objects or boundaries. Spatial uncertainty of target locations was used to assess perceived locations across distributed and focused attention conditions without the use of external stimuli, such as visual cues. Across two experiments we tested locations along the cardinal and 45 degrees oblique axes. We demonstrate that focusing attention within a region of space can expand the perceived size of visual space; even in cases where doing so makes performance less accurate. Moreover, the results of the present studies show that when fixation is actively maintained, focusing attention along a visual axis leads to an asymmetrical stretching of visual space that is predominantly focused across the central half of the visual field, consistent with an expansive gradient along the focus of voluntary attention. These results demonstrate that focusing sustained attention peripherally during active fixation leads to an asymmetrical expansion of visual space within the central visual field. Published by Elsevier Ltd. C1 [Fortenbaugh, Francesca C.; Esterman, Michael] Boston Healthcare Syst, Dept Vet Affairs, GRECC & Res Serv, Boston, MA USA. [Fortenbaugh, Francesca C.] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Robertson, Lynn C.] Univ Calif Berkeley, Dept Psychol, 3210 Tolman Hall, Berkeley, CA 94720 USA. [Esterman, Michael] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02215 USA. RP Fortenbaugh, FC (reprint author), VA Boston Healthcare Syst, 150 S Huntington Ave,182 JP, Boston, MA 02130 USA. EM Francesca.Fortenbaugh@va.gov FU Department of Veterans Affairs; Department of Veterans Affairs Clinical Sciences Research and Development [1IK2CX000706-01A2] FX We thank Stuart Hewitt for help with data collection. This research was supported by the Department of Veterans Affairs. F.C.F has an Advanced Geriatric Fellowship from the Department of Veterans Affairs. M.S.E. has a Career Development award from the Department of Veterans Affairs Clinical Sciences Research and Development (1IK2CX000706-01A2). The contents within do not represent the views of the Department of Veterans Affairs or the United States government. NR 39 TC 0 Z9 0 U1 4 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0042-6989 EI 1878-5646 J9 VISION RES JI Vision Res. PD FEB PY 2017 VL 131 BP 26 EP 36 DI 10.1016/j.visres.2016.12.002 PG 11 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA EK2BD UT WOS:000393731200003 PM 28025055 ER PT J AU Rinker, JA Fulmer, DB Trantham-Davidson, H Smith, ML Williams, RW Lopez, MF Randall, PK Chandler, LJ Miles, MF Becker, HC Mulholland, PJ AF Rinker, Jennifer A. Fulmer, Diana B. Trantham-Davidson, Heather Smith, Maren L. Williams, Robert W. Lopez, Marcelo F. Randall, Patrick K. Chandler, L. Judson Miles, Michael F. Becker, Howard C. Mulholland, Patrick J. TI Differential potassium channel gene regulation in BXD mice reveals novel targets for pharmacogenetic therapies to reduce heavy alcohol drinking SO ALCOHOL LA English DT Article DE K+ channels; Alcohol use disorder; Pharmacogenetics; BXD mice; Prefrontal cortex; Nucleus accumbens ID UNION-OF-PHARMACOLOGY; CHRONIC INTERMITTENT ETHANOL; GENOME-WIDE ASSOCIATION; CA1 PYRAMIDAL NEURONS; NUCLEUS-ACCUMBENS; MOLECULAR RELATIONSHIPS; PREFRONTAL CORTEX; DRUG-ADDICTION; NMDA RECEPTOR; NALTREXONE RESPONSE AB Alcohol (ethanol) dependence is a chronic relapsing brain disorder partially influenced by genetics and characterized by an inability to regulate harmful levels of drinking. Emerging evidence has linked genes that encode Kv7, KIR, and K(ca)2 K+ channels with variation in alcohol-related behaviors in rodents and humans. This led us to experimentally test relations between K+ channel genes and escalation of drinking in a chronic intermittent ethanol (CIE) exposure model of dependence in BXD recombinant inbred strains of mice. Transcript levels for K+ channel genes in the prefrontal cortex (PFC) and nucleus accumbens (NAc) covary with voluntary ethanol drinking in a non-dependent cohort. Transcripts that encode Kv7 channels covary negatively with drinking in non-dependent BXD strains. Using a pharmacological approach to validate the genetic findings, C57BL/6J mice were allowed intermittent access to ethanol to establish baseline consumption before they were treated with retigabine, an FDA-approved Kv7 channel positive modulator. Systemic administration significantly reduced drinking, and consistent with previous evidence, retigabine was more effective at reducing voluntary consumption in high-drinking than low-drinking subjects. We evaluated the specific K+ channel genes that were most sensitive to CIE exposure and identified a gene subset in the NAc and PFC that were dysregulated in the alcohol-dependent BXD cohort. CIE-induced modulation of nine genes in the NAc and six genes in the PFC covaried well with the changes in drinking induced by ethanol dependence. Here we identified novel candidate genes in the NAc and PFC that are regulated by ethanol dependence and correlate with voluntary drinking in non-dependent and dependent BXD mice. The findings that Kcnq expression correlates with drinking and that retigabine reduces consumption suggest that Kv7 channels could be pharmacogenetic targets to treat individuals with alcohol addiction. (C) 2016 Elsevier Inc. All rights reserved. C1 [Rinker, Jennifer A.; Fulmer, Diana B.; Trantham-Davidson, Heather; Chandler, L. Judson; Mulholland, Patrick J.] Med Univ South Carolina, Dept Neurosci, Charleston, SC 29425 USA. [Lopez, Marcelo F.; Randall, Patrick K.; Becker, Howard C.; Mulholland, Patrick J.] Med Univ South Carolina, Charleston Alcohol Res Ctr, Addict Sci Div, Dept Psychiat & Behav Sci, Charleston, SC 29425 USA. [Smith, Maren L.; Miles, Michael F.] Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Med Coll Virginia Campus, Richmond, VA 23298 USA. [Becker, Howard C.] Ralph H Johnson VA Med Ctr, Charleston, SC 29425 USA. [Williams, Robert W.] Univ Tennessee, Hlth Sci Ctr, Dept Genet Genom & Informat, Memphis, TN 38163 USA. RP Mulholland, PJ (reprint author), Charleston Alcohol Res Ctr, Dept Neurosci, Addict Sci Div, 67 President St,462N,MSC861, Charleston, SC 29425 USA. EM mulholl@musc.edu OI Williams, Robert/0000-0001-8924-4447 FU NIH grants [AA020930, AA023288, AA020929, AA014095, AA010761, AA016667, AA016662, AA022701, AA022475] FX These studies were supported by NIH grants AA020930 (PJM), AA023288 (PJM), AA020929 (MFL), AA014095 (HCB), AA010761 (HCB), AA016667 (MFM), AA016662 (RWW), AA022701 (LJC), and AA022475 (HTD). The authors declare no conflict of interest. NR 88 TC 1 Z9 1 U1 4 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-8329 EI 1873-6823 J9 ALCOHOL JI Alcohol PD FEB PY 2017 VL 58 SI SI BP 33 EP 45 DI 10.1016/j.alcohol.2016.05.007 PG 13 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA EJ5KG UT WOS:000393256300006 PM 27432260 ER PT J AU Buck, KJ Chen, G Kozell, LB AF Buck, Kari J. Chen, Gang Kozell, Laura B. TI Limbic circuitry activation in ethanol withdrawal is regulated by a chromosome 1 locus SO ALCOHOL LA English DT Article DE Ethanol; c-Fos; Limbic; Amygdala; Withdrawal ID MEDIAL PREFRONTAL CORTEX; C-FOS EXPRESSION; GENOME-WIDE ASSOCIATION; PHASEOLUS-VULGARIS-LEUKOAGGLUTININ; ALCOHOL PHYSICAL-DEPENDENCE; RAT SUBSTANTIA-NIGRA; BASAL GANGLIA; INDUCED ANXIETY; NERVOUS-SYSTEM; MESSENGER-RNA AB Physiological dependence and associated withdrawal episodes are thought to constitute a motivational force sustaining alcohol use/abuse and contributing to relapse in alcoholics. Although no animal model exactly duplicates alcoholism, models for specific factors, including the withdrawal syndrome, are useful for identifying potential genetic and neural determinants of liability in humans. We previously identified highly significant quantitative trait loci (QTLs) with large effects on predisposition to withdrawal after chronic and acute alcohol exposure in mice and mapped these loci to the same region of chromosome 1 (Alcdp1 and Alcw1, respectively). The present studies utilize a novel Alcdp1/Alcw1 congenic model (in which an interval spanning Alcdp1 and Alcw1 from the C57BL/6J donor strain [build GRCm38 150.3 -174.6 Mb] has been introgressed onto a uniform inbred DBA/2J genetic background) known to demonstrate significantly less severe chronic and acute withdrawal compared to appropriate background strain animals. Here, using c-Fos induction as a high-resolution marker of neuronal activation, we report that male Alcdp1/Alcw1 congenic animals demonstrate significantly less alcohol withdrawal-associated neural activation compared to appropriate background strain animals in the prelimbic and cingulate cortices of the prefrontal cortex as well as discrete regions of the extended amygdala (i.e., basolateral) and extended basal ganglia (i.e., dorsolateral striatum, and caudal substantia nigra pars reticulata). These studies are the first to begin to elucidate circuitry by which this confirmed addiction-relevant QTL could influence behavior. This circuitry overlaps limbic circuitry involved in stress, providing additional mechanistic information. Alcdp1/Alcw1 maps to a region syntenic with human chromosome 1 q, where multiple studies find significant associations with risk for alcoholism. Published by Elsevier Inc. C1 [Buck, Kari J.; Kozell, Laura B.] Oregon Hlth & Sci Univ, Portland Vet Affairs Med Ctr, Dept Behav Neurosci, Portland, OR 97239 USA. [Chen, Gang] Nanjing Univ, Ctr Translat Syst Biol & Neurosci, Nanjing, Jiangsu, Peoples R China. RP Buck, KJ (reprint author), Vet Affairs Med Ctr, R&D40, Res Serv, 3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM buckk@ohsu.edu OI Kozell, Laura/0000-0003-3059-2046 FU PHS [AA011114, AA010760, DA005228]; VA Merit grant [BX000222] FX Supported by PHS grants AA011114, AA010760, DA005228, and a VA Merit grant (BX000222). We are grateful to Dr. John Belknap, Dr. Robert Hitzemann, and Ms. Nicole Walter for helpful discussions of these experiments and comments on a draft of this manuscript. NR 51 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 0741-8329 EI 1873-6823 J9 ALCOHOL JI Alcohol PD FEB PY 2017 VL 58 SI SI BP 153 EP 160 DI 10.1016/j.alcohol.2016.09.030 PG 8 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA EJ5KG UT WOS:000393256300016 PM 27989609 ER PT J AU McLaughlin, PW Liss, AL Nguyen, PL Assimas, DG D'Amico, AV Gottschalk, AR Gustafson, GS Keol, SR Liauw, SL Lloyd, S Movsas, B Prestidg, BR Showalter, TN Taira, AV Vapiwal, N Davi, BJ AF McLaughlin, Patrick W. Liss, Adam L. Nguyen, Paul L. Assimas, Dean G. D'Amico, Anthony V. Gottschalk, Alexander R. Gustafson, Gary S. Keol, Sameer R. Liauw, Stanley L. Lloyd, Shane Movsas, Benjamin Prestidg, Bradley R. Showalter, Timothy N. Taira, Al V. Vapiwal, Neha Davi, Brian J. TI ACR Appropriateness Criteria (R) Locally Advanced, High-Risk Prostate Cancer SO AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS LA English DT Article DE appropriateness criteria; prostate cancer; high-risk prostate cancer; radiation therapy ID ANDROGEN-DEPRIVATION THERAPY; EXTERNAL-BEAM RADIOTHERAPY; QUALITY-OF-LIFE; PHASE-III TRIAL; PERMANENT INTERSTITIAL BRACHYTHERAPY; GLEASON PATTERN 5; RADICAL PROSTATECTOMY; RADIATION-THERAPY; SUPPRESSION THERAPY; HORMONAL-THERAPY AB Purpose: To present the most updated American College of Radiology consensus guidelines formed from an expert panel on treatment of locally advanced, high-risk prostate cancer Methods: The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. Results: The panel summarized the most recent and relevant literature on the topic and voted on 4 clinical variants illustrating the appropriate management of locally advanced, high-risk cancer. Numerical rating and commentary reflecting the panel consensus was given for each treatment approach in each variant. Conclusions: Aggressive local approaches including surgery followed by adjuvant XRT, beam combined with androgen deprivation therapy, and beam combined with brachytherapy have resulted in unpresented success in locally advanced, high-risk prostate cancer. By combining most recent medical literature and expert opinion, this guideline can aid clinicians in the appropriate integration of available therapeutic modalities. C1 [McLaughlin, Patrick W.; Liss, Adam L.] Univ Michigan, Novi, MI USA. [Gustafson, Gary S.] William Beaumont Hosp, Troy, NY USA. [Movsas, Benjamin] Henry Ford Hlth Syst, Detroit, MI USA. [Nguyen, Paul L.; D'Amico, Anthony V.] Brigham & Womens Hosp, Dana Farber Canc Inst, Amer Soc Clin Oncol, 75 Francis St, Boston, MA 02115 USA. [Assimas, Dean G.] Univ Alabama Birmingham, Sch Med, Birmingham, AL USA. [Assimas, Dean G.] Amer Urol Assoc, Linthicum, MD USA. [Gottschalk, Alexander R.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Taira, Al V.] Mills Peninsula Hosp, San Mateo, CA USA. [Keol, Sameer R.] Mayo Clin, Scottsdale, AZ USA. [Liauw, Stanley L.] Univ Chicago, Med Ctr, Chicago, IL 60637 USA. [Lloyd, Shane] Huntsman Canc Hosp, Salt Lake City, UT USA. [Prestidg, Bradley R.] Bon Secours Canc Inst, Norfolk, VA USA. [Showalter, Timothy N.] Univ Virginia, Charlottesville, VA USA. [Vapiwal, Neha] Univ Penn, Philadelphia, PA 19104 USA. [Davi, Brian J.] Mayo Clin, Rochester, MN USA. RP McLaughlin, PW (reprint author), Amer Coll Radiol, 1891 Preston White Dr, Reston, VA 20191 USA. EM mclaughb@umich.edu FU Varian Inc.; Philips Inc. FX B.M.: Research/educational support to department from Varian Inc. and Philips Inc. NR 76 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0277-3732 EI 1537-453X J9 AM J CLIN ONCOL-CANC JI Am. J. Clin. Oncol.-Cancer Clin. Trials PD FEB PY 2017 VL 40 IS 1 BP 1 EP 10 DI 10.1097/COC.0000000000000354 PG 10 WC Oncology SC Oncology GA EJ6SC UT WOS:000393348100001 PM 28059930 ER PT J AU Dhakal, S AF Dhakal, Sughosh TI ACR Appropriateness Criteria (R) Hodgkin Lymphoma-Favorable Prognosis Stage I and H: (vol 39, pg 535, 2016) SO AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS LA English DT Correction C1 Univ Rochester, Med Ctr, Rochester, NY 14642 USA. Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. Amer Soc Clin Oncol, Alexandria, VA USA. Stanford Canc Ctr, Stanford, CA USA. Univ Southern Calif, Keck Sch Med, Los Angeles, CA USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. Emory Univ, Atlanta, GA 30322 USA. Univ Florida, Proton Therapy Inst, Jacksonville, FL USA. Univ Florida, Gainesville, FL USA. St Jude Childrens Res Hosp, 332 N Lauderdale St, Memphis, TN 38105 USA. Univ Penn Hlth Syst, Philadelphia, PA USA. Yale Univ, Sch Med, New Haven, CT USA. Indiana Univ Sch Med, Richard L Roudebush VA Med Ctr, Indianapolis, IN 46202 USA. Univ Chicago, Chicago, IL 60637 USA. Amer Soc Hematol, Washington, DC USA. Johns Hopkins Univ Hosp, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21287 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Dhakal, S (reprint author), Amer Coll Radiol, 1891 Preston White Dr, Reston, VA 20191 USA. EM sughosh_dhakal@urmc.rochester.edu NR 1 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0277-3732 EI 1537-453X J9 AM J CLIN ONCOL-CANC JI Am. J. Clin. Oncol.-Cancer Clin. Trials PD FEB PY 2017 VL 40 IS 1 BP 108 EP 108 DI 10.1097/COC.0000000000000331 PG 1 WC Oncology SC Oncology GA EJ6SC UT WOS:000393348100018 ER PT J AU Curtis, N Corapi, J Roberts, R Devlin, JW AF Curtis, Nicole Corapi, Jennifer Roberts, Russel Devlin, John W. TI Rebranding of generic parenteral vasopressin: Effect on clinician practices and perceptions SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT Letter DE drug cost; generic rebranding; intensive care; severe sepsis; vasopressin ID SEPTIC SHOCK C1 [Curtis, Nicole; Corapi, Jennifer; Devlin, John W.] Northeastern Univ, Sch Pharm, Boston, MA 02115 USA. [Roberts, Russel] Massachusetts Gen Hosp, Dept Pharm Serv, Boston, MA 02114 USA. RP Devlin, JW (reprint author), Northeastern Univ, Sch Pharm, Boston, MA 02115 USA. EM j.devlin@neu.edu NR 6 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEALTH-SYSTEM PHARMACISTS PI BETHESDA PA 7272 WISCONSIN AVE, BETHESDA, MD 20814 USA SN 1079-2082 EI 1535-2900 J9 AM J HEALTH-SYST PH JI Am. J. Health-Syst. Pharm. PD FEB 1 PY 2017 VL 74 IS 3 BP 105 EP 106 DI 10.2146/ajhp160460 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EJ6TW UT WOS:000393352700005 PM 28122750 ER PT J AU Winestone, LE Getz, KD Miller, TP Wilkes, JJ Sack, L Li, YM Huang, YS Seif, AE Bagatell, R Fisher, BT Epstein, AJ Aplenc, R AF Winestone, Lena E. Getz, Kelly D. Miller, Tamara P. Wilkes, Jennifer J. Sack, Leah Li, Yimei Huang, Yuan-Shung Seif, Alix E. Bagatell, Rochelle Fisher, Brian T. Epstein, Andrew J. Aplenc, Richard TI The role of acuity of illness at presentation in early mortality in black children with acute myeloid leukemia SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; FREESTANDING PEDIATRIC HOSPITALS; UNITED-STATES; CHILDHOOD-CANCER; MEDIATION ANALYSIS; CLINICAL-TRIALS; ONCOLOGY-GROUP; BREAST-CANCER; SOCIOECONOMIC POSITION; CARE UTILIZATION AB Black patients with acute myeloid leukemia (AML) experience higher mortality than White patients. We compared induction mortality, acuity of illness prior to chemotherapy, and insurance type between Black and White patients to assess whether acuity of presentation mediates the disparity. Within a retrospective cohort of 1,122 children with AML treated with two courses of standard induction chemotherapy between 2004 and 2014 in the Pediatric Health Information System (PHIS) database, the association between race (Black versus White) and inpatient mortality during induction was examined. Intensive Care Unit (ICU)-level resource utilization during the first 72 hours following admission for initial AML chemotherapy was evaluated as a potential mediator. The total effect of race on mortality during Induction I revealed a strong association (unadjusted HR 2.75, CI: 1.18, 6.41). Black patients had a significantly higher unadjusted risk of requiring ICU-level resources within the first 72 hours after initial presentation (17% versus 11%; RR 1.52, CI: 1.04, 2.24). Mediation analyses revealed the indirect effect of race through acuity accounted for 61% of the relative excess mortality during Induction I. Publicly insured patients experienced greater induction mortality than privately insured patients regardless of race. Black patients with AML have significantly greater risk of induction mortality and are at increased risk for requiring ICU-level resources soon after presentation. Higher acuity amongst Black patients accounts for a substantial portion of the relative excess mortality during Induction I. Targeting factors affecting acuity of illness at presentation may lessen racial disparities in AML induction mortality. C1 [Winestone, Lena E.; Getz, Kelly D.; Miller, Tamara P.; Wilkes, Jennifer J.; Sack, Leah; Seif, Alix E.; Bagatell, Rochelle; Aplenc, Richard] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Winestone, Lena E.; Getz, Kelly D.; Miller, Tamara P.; Wilkes, Jennifer J.; Fisher, Brian T.; Aplenc, Richard] Childrens Hosp Philadelphia, Ctr Pediat Clin Effectiveness, Philadelphia, PA 19104 USA. [Winestone, Lena E.; Wilkes, Jennifer J.; Epstein, Andrew J.] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. [Li, Yimei] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Huang, Yuan-Shung] Childrens Hosp Philadelphia, Healthcare Analyt Unit, Philadelphia, PA USA. [Seif, Alix E.; Bagatell, Rochelle; Aplenc, Richard] Univ Penn, Perelman Sch Med, Dept Pediat, Philadelphia, PA 19104 USA. [Fisher, Brian T.] Childrens Hosp Philadelphia, Div Infect Dis, Philadelphia, PA USA. [Fisher, Brian T.; Aplenc, Richard] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Epstein, Andrew J.] Univ Penn, Perelman Sch Med, Div Gen Internal Med, Philadelphia, PA 19104 USA. [Epstein, Andrew J.] Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Dept Vet Affairs, Philadelphia, PA USA. RP Winestone, LE (reprint author), CTRB 10305,3501 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM winestonel@email.chop.edu OI Winestone, Lena/0000-0001-9982-1594 FU Pfizer; Merck FX Dr Brian Fisher receives research funding from Pfizer and Merck for projects unrelated to this research. NR 44 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD FEB PY 2017 VL 92 IS 2 BP 141 EP 148 DI 10.1002/ajh.24605 PG 8 WC Hematology SC Hematology GA EJ7TJ UT WOS:000393425200010 PM 27862214 ER PT J AU Dinardo, CD Luskin, MR Carroll, M Smith, C Harrison, J Pierce, S Kornblau, S Konopleva, M Kadia, T Kantarjian, H Wertheim, GB Master, SR AF Dinardo, Courtney D. Luskin, Marlise R. Carroll, Martin Smith, Catherine Harrison, Jenna Pierce, Sherry Kornblau, Steve Konopleva, Marina Kadia, Tapan Kantarjian, Hagop Wertheim, Gerald B. Master, Stephen R. TI Validation of a clinical assay of multi-locus DNA methylation for prognosis of newly diagnosed AML SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Letter ID ACUTE MYELOID-LEUKEMIA C1 [Dinardo, Courtney D.; Pierce, Sherry; Kornblau, Steve; Konopleva, Marina; Kadia, Tapan; Kantarjian, Hagop] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA. [Luskin, Marlise R.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Carroll, Martin] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Smith, Catherine; Harrison, Jenna; Wertheim, Gerald B.] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Master, Stephen R.] Weill Cornell Med Coll, Dept Pathol & Lab Med, 525 E 68th St Suite F 715,Box 79, New York, NY 10065 USA. RP Master, SR (reprint author), Weill Cornell Med Coll, Dept Pathol & Lab Med, 525 E 68th St Suite F 715,Box 79, New York, NY 10065 USA.; Wertheim, GB (reprint author), Childrens Hosp Philadelphia, Dept Pathol & Lab Med, 5140 Floor Main Bldg,324 S 34th St, Philadelphia, PA 19104 USA. EM wertheimg@email.chop.edu; srm9012@med.cornell.edu NR 7 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD FEB PY 2017 VL 92 IS 2 BP E14 EP E15 DI 10.1002/ajh.24597 PG 2 WC Hematology SC Hematology GA EJ7TJ UT WOS:000393425200001 PM 27804182 ER PT J AU Rastegar, M Nagami, GT AF Rastegar, Mandana Nagami, Glenn T. TI Non-Anion Gap Metabolic Acidosis: A Clinical Approach to Evaluation SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Non-anion gap metabolic acidosis; urine anion gap; urine osmolal gap; renal acidification; acid-base; high volume ileostomy output; urinary ammonium ID URINE OSMOLAL GAP; AMMONIA PRODUCTION; BASE DISTURBANCES; ANGIOTENSIN-II; DIAGNOSIS; ELECTROLYTE; LIMITATIONS; MECHANISMS; DISORDERS; EXCRETION AB Acid-base disturbances can result from kidney or nonkidney disorders. We present a case of high-volume ileostomy output causing large bicarbonate losses and resulting in a non-anion gap metabolic acidosis. Non-anion gap metabolic acidosis can present as a form of either acute or chronic metabolic acidosis. A complete clinical history and physical examination are critical initial steps to begin the evaluation process, followed by measuring serum electrolytes with a focus on potassium level, blood gas, urine pH, and either direct or indirect urine ammonium concentration. The present case was selected to highlight the differential diagnosis of a non-anion gap metabolic acidosis and illustrate a systematic approach to this problem. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. This is a US Government Work. There are no restrictions on its use. C1 [Rastegar, Mandana; Nagami, Glenn T.] Univ Calif Los Angeles, David Geffen Sch Med, VA Greater Los Angeles Healthcare Syst, Nephrol Sect, Los Angeles, CA 90095 USA. RP Nagami, GT (reprint author), VA Greater Los Angeles Healthcare Syst, Nephrol Sect 111L, 3, Los Angeles, CA 90073 USA. EM glenn.nagami@va.gov FU Department of Veterans Affairs FX This work was supported in part by the Department of Veterans Affairs. NR 40 TC 0 Z9 0 U1 13 U2 13 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 EI 1523-6838 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD FEB PY 2017 VL 69 IS 2 BP 296 EP 301 DI 10.1053/j.ajkd.2016.09.013 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA EJ2HS UT WOS:000393031300022 PM 28029394 ER PT J AU Al-Haddad, CE Abdulaal, M Al-Moujahed, A Ervin, AM Ismail, K AF Al-Haddad, Christiane E. Abdulaal, Marwan Al-Moujahed, Ahmad Ervin, Ann-Margret Ismail, Karine TI Fornix-Based Versus Limbal-Based Conjunctival Trabeculectomy Flaps for Glaucoma: Findings From a Cochrane Systematic Review SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Review ID MITOMYCIN-C; 2-SITE PHACOTRABECULECTOMY; CATARACT-SURGERY; OUTCOME MEASURES; FOLLOW-UP; EXTRACTION; TRIALS AB PURPOSE: To compare effectiveness of fornix- and limbal-based conjunctival flaps in trabeculectomy surgery. DESIGN: Systematic review. METHODS: SETTING: CENTRAL, MEDLINE, LILACS, ISRCTN registry, ClinicalTrials.gov, WHO, and ICTRP were searched to identify eligible randomized controlled trials (RCTs). STUDY POPULATION: RCTs in which benefits and complications of fornix- vs limbal-based trabeculectomy for glaucoma were compared in adult glaucoma patients. OBSERVATION PROCEDURE: We followed Cochrane methodology for data extraction. MAIN OUTCOME MEASURES: Proportion of failed trabeculectomies at 24 months, defined as the need for repeat surgery or uncontrolled intraocular pressure (TOP) > 22 mm Hg, despite topical/systemic medications. RESULTS: The review included 6 trials with a total of 361 participants, showing no difference in effectiveness between fornix-based vs limbal-based trabeculectomy surgery, although with a high level of uncertainty owing to low event rates. In the fornix-based and limbal-based surgery, mean IOP at 12 months was similar, with ranges of 12.5-15.5 mm Hg and 11.7-15.1 mm Hg, respectively. Mean difference was 0.44 mm Hg (95% CI -0.45 to 1.33) and 0.86 mm Hg (95% CI -0.52 to 2.24) at 12 and 24 months of follow-up, respectively. Mean number of postoperative glaucoma medications was similar between the 2 groups. Mean difference was 0.02 (95% CI -0.15 to 0.19) at 12 months. As far as postoperative complications, an increased risk of shallow anterior chamber was observed in the limbal-based group. CONCLUSION: Similar efficacy of trabeculectomy surgery with respect to bleb failure or IOP control was observed in both types of conjunctival flap incisions. A significant difference was detected in the risk of postoperative shallow anterior chamber, which was increased in the limbal-based group. (C) 2016 Elsevier Inc. All rights reserved.) C1 [Al-Haddad, Christiane E.; Abdulaal, Marwan; Ismail, Karine] Amer Univ Beirut, Dept Ophthalmol, Beirut, Lebanon. [Al-Moujahed, Ahmad] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA USA. [Ervin, Ann-Margret] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. RP Al-Haddad, CE (reprint author), Amer Univ Beirut, Pediat Ophthalmol & Adult Strabismus, Med Ctr, POB 110236, Beirut, Lebanon. EM ca12@aub.edu.lb FU NEI NIH HHS [U01 EY020522] NR 25 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 EI 1879-1891 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD FEB PY 2017 VL 174 BP 33 EP 41 DI 10.1016/j.ajo.2016.10.006 PG 9 WC Ophthalmology SC Ophthalmology GA EJ3YN UT WOS:000393148800005 PM 27794426 ER PT J AU Maron, BA Abman, SH AF Maron, Bradley A. Abman, Steven H. TI Focusing on Developmental Origins and Disease Inception for the Prevention of Pulmonary Hypertension SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article ID ARTERY SYSTOLIC PRESSURE; NITRIC-OXIDE SYNTHASE; LOW-BIRTH-WEIGHT; BRONCHOPULMONARY DYSPLASIA; HEART-FAILURE; GROWTH-FACTOR; VASCULAR DYSFUNCTION; LUNG GROWTH; CARDIOVASCULAR-DISEASE; MAMMALIAN TARGET C1 [Maron, Bradley A.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA. [Maron, Bradley A.] Harvard Med Sch, Boston, MA USA. [Maron, Bradley A.] Boston VA Healthcare Syst, Dept Cardiol, Boston, MA USA. [Abman, Steven H.] Univ Colorado Denver, Sect Pulm Med, Anschutz Med Ctr, Aurora, CO USA. [Abman, Steven H.] Univ Colorado Denver, Pediat Heart Lung Ctr, Dept Pediat, Anschutz Med Ctr, Aurora, CO USA. Childrens Hosp Colorado, Aurora, CO USA. RP Maron, BA (reprint author), 77 Ave Louis Pasteur,NRB Room 0630-N, Boston, MA 02115 USA. EM bmaron@partners.org FU National Institutes of Health [1K08HL11207-01A1]; American Heart Association [15GRNT25080016]; Pulmonary Hypertension Association; Cardiovascular Medical Research and Education Fund; Klarman Foundation at Brigham and Women's Hospital; NHLBI [U01 HL12118, R01 HL085703, R01 HL68702] FX Funded by National Institutes of Health grant 1K08HL11207-01A1, American Heart Association grant 15GRNT25080016, the Pulmonary Hypertension Association, the Cardiovascular Medical Research and Education Fund, and the Klarman Foundation at Brigham and Women's Hospital (B.A.M.); and NHLBI grants U01 HL12118, R01 HL085703, and R01 HL68702 (S.H.A.). NR 109 TC 0 Z9 0 U1 1 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD FEB 1 PY 2017 VL 195 IS 3 BP 292 EP 301 DI 10.1164/rccm.201604-0882PP PG 10 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA EJ6VP UT WOS:000393358200009 PM 27854133 ER PT J AU Dransfield, MT Kunisaki, KM Strand, MJ Anzueto, A Bhatt, SP Bowler, RP Criner, GJ Curtis, JL Hanania, NA Nath, H Putcha, N Roark, SE Wan, ES Washko, GR Wells, JM Wendt, CH Make, BJ AF Dransfield, Mark T. Kunisaki, Ken M. Strand, Matthew J. Anzueto, Antonio Bhatt, Surya P. Bowler, Russell P. Criner, Gerard J. Curtis, Jeffrey L. Hanania, Nicola A. Nath, Hrudaya Putcha, Nirupama Roark, Sarah E. Wan, Emily S. Washko, George R. Wells, J. Michael Wendt, Christine H. Make, Barry J. CA COPDGene Investigators TI Acute Exacerbations and Lung Function Loss in Smokers with and without Chronic Obstructive Pulmonary Disease SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE chronic obstructive pulmonary disease; exacerbations; spirometry ID COPD EXACERBATION; FUNCTION DECLINE; EX-SMOKERS; SPIROMETRY; EPIDEMIOLOGY; PREDICTORS; MORTALITY; FREQUENCY; RECOVERY; HEALTH AB Rationale: Acute exacerbations of chronic obstructive pulmonary disease (COPD) increase the risk of death and drive healthcare costs, but whether they accelerate loss of lung function remains controversial. Whether exacerbations in subjects with mild COPD or similar acute respiratory events in smokers without airflow obstruction affect lung function decline is unknown. Objectives: To determine the association between acute exacerbations of COPD (and acute respiratory events in smokers without COPD) and the change in lung function over 5 years of follow-up. Methods: We examined data on the first 2,000 subjects who returned for a second COPDGene visit 5 years after enrollment. Baseline data included demographics, smoking history, and computed tomography emphysema. We defined exacerbations (and acute respiratory events in those without established COPD) as acute respiratory symptoms requiring either antibiotics or systemic steroids, and severe events by the need for hospitalintion. Throughout the 5-year follow-up period, we collected self-reported acute respiratory event data at 6-month intervals. We used linear mixed models to fit FEV1 decline based on reported exacerbations or acute respiratory events. Measurements and Main Results: In subjects with COPD, exacerbations were associated with excess FEV1 decline, with the greatest effect in Global Initiative for Chronic Obstructive Lung Disease stage 1, where each exacerbation was associated with an additional 23 ml/yr decline (95% confidence interval, 2-44; P = 0.03), and each severe exacerbation with an additional 87 ml/yr decline (95% confidence interval, 23-151; P = 0.008); statistically significant but smaller effects were observed in Global Initiative for Chronic Obstructive Lung Disease stage 2 and 3 subjects. In subjects without airflow obstruction, acute respiratory events were not associated with additional FEV1 decline. Conclusions: Exacerbations are associated with accelerated lung function loss in subjects with established COPD, particularly those with mild disease. Trials are needed to test existing and novel therapies in subjects with early/mild COPD to potentially reduce the risk of progressing to more advanced lung disease. C1 [Dransfield, Mark T.; Bhatt, Surya P.; Nath, Hrudaya; Wells, J. Michael] Univ Alabama Birmingham, Lung Hlth Ctr, Birmingham, AL USA. [Dransfield, Mark T.; Wells, J. Michael] Birmingham VA Med Ctr, 422 THT 1900 Univ Blvd, Birmingham, AL 35294 USA. [Kunisaki, Ken M.; Wendt, Christine H.] Minneapolis VA Hlth Care Syst, Minneapolis, MN USA. [Kunisaki, Ken M.; Wendt, Christine H.] Univ Minnesota, Minneapolis, MN USA. [Strand, Matthew J.; Bowler, Russell P.; Make, Barry J.] Natl Jewish Hlth, Denver, CO USA. [Anzueto, Antonio] Univ Texas Hlth Sci Ctr San Antonio, Pulm Crit Care, San Antonio, TX 78229 USA. [Anzueto, Antonio] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Criner, Gerard J.] Temple Univ, Philadelphia, PA 19122 USA. [Curtis, Jeffrey L.; Roark, Sarah E.] Univ Michigan, Ann Arbor, MI 48109 USA. [Curtis, Jeffrey L.] VA Ann Arbor Hlth Care Syst, Ann Arbor, MI USA. [Hanania, Nicola A.] Baylor Coll Med, Houston, TX 77030 USA. [Putcha, Nirupama] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Wan, Emily S.; Washko, George R.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. RP Dransfield, MT (reprint author), Birmingham VA Med Ctr, 422 THT 1900 Univ Blvd, Birmingham, AL 35294 USA.; Dransfield, MT (reprint author), Univ Alabama Birmingham, Div Pulm Allergy & Crit Care Med, 422 THT 1900 Univ Blvd, Birmingham, AL 35294 USA. EM mdransfield@uabmc.edu FU National Institutes of Health [R01HL089897, R01HL089856]; COPD Foundation; AstraZeneca; Pfizer; Novartis; Boehringer Ingelheim; Siemens; Sunovion; GlaxoSmithKline FX Supported by National Institutes of Health grants R01HL089897 and R01HL089856. COPDGene is also supported by the COPD Foundation through contributions made to an Industry Advisory Board comprised of AstraZeneca, Pfizer, Novartis, Boehringer Ingelheim, Siemens, Sunovion, and GlaxoSmithKline. The industry funders had no role in study design, collection/analysis/interpretation of the data, preparation of the manuscript, or decision to submit the manuscript for publication. This material is also the result of work supported with resources and the use of facilities at the Minneapolis VA and VA Ann Arbor Health Care Systems. The views expressed in this article are those of the authors and do not reflect the views of the United States Government, the Department of Veterans Affairs, the authors' affiliated institutions, or the funders of the study. NR 35 TC 1 Z9 1 U1 4 U2 4 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD FEB 1 PY 2017 VL 195 IS 3 BP 324 EP 330 DI 10.1164/rccm.201605-1014OC PG 7 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA EJ6VP UT WOS:000393358200012 PM 27556408 ER PT J AU Famous, KR Delucchi, K Ware, LB Kangelaris, KN Liu, KD Thompson, BT Calfee, CS AF Famous, Katie R. Delucchi, Kevin Ware, Lorraine B. Kangelaris, Kirsten N. Liu, Kathleen D. Thompson, B. Taylor Calfee, Carolyn S. CA ARDS Network TI Acute Respiratory Distress Syndrome Subphenotypes Respond Differently to Randomized Fluid Management Strategy SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE subphenotype; acute lung injury; fluid therapy ID ACUTE LUNG INJURY; LATENT CLASS ANALYSIS; PLASMA ANGIOPOIETIN-2; CATHETER; TRIALS; CARE; ARDS AB Rationale: We previously identified two acute respiratory distress syndrome (ARDS) subphenotypes in two separate randomized controlled trials with differential response to positive end-expiratory pressure. Objectives: To identify these subphenotypes in a third ARDS cohort, to test whether subphenotypes respond differently to fluid management strategy, and to develop a practical model for subphenotype identification. Methods: We used latent class analysis of baseline clinical and plasma biomarker data to identify subphenotypes in FACTT (Fluid and Catheter Treatment Trial; n = 1,000). Logistic regression was used to test for an interaction between subphenotype and treatment for mortality. We used stepwise modeling to generate a model for subphenotype identification in FACTT and validated its accuracy in the two cohorts in which we previously identified ARDS subphenotypes. Measurements and Main Results: We confirmed that a two-class (two-subphenotype) model best described the study population. Subphenotype 2 was again characterized by higher inflammatory biomarkers and hypotension. Fluid management strategy had significantly different effects on 90-day mortality in the two subphenotypes (P = 0.0039 for interaction); mortality in subphenotype 1 was 26% with fluid-conservative strategy versus 18% with fluid-liberal, whereas mortality in subphenotype 2 was 40% with fluid-conservative strategy versus 50% in fluid-liberal. A three variable model of IL-8, bicarbonate, and tumor necrosis factor receptor-1 accurately classified the subphenotypes. Conclusions: This analysis confirms the presence of two ARDS subphenotypes that can be accurately identified with a limited number of variables and that responded differently to randomly assigned fluid management. These findings support the presence of ARDS subtypes that may require different treatment approaches. C1 [Famous, Katie R.; Calfee, Carolyn S.] Univ Calif San Francisco, Dept Med, Div Pulm & Crit Care Med, San Francisco, CA USA. [Delucchi, Kevin] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Kangelaris, Kirsten N.] Univ Calif San Francisco, Dept Med, Div Hosp Med, San Francisco, CA USA. [Liu, Kathleen D.] Univ Calif San Francisco, Dept Med, Div Nephrol, San Francisco, CA USA. [Liu, Kathleen D.; Calfee, Carolyn S.] Univ Calif San Francisco, Dept Anesthesia, San Francisco, CA USA. [Ware, Lorraine B.] Vanderbilt Univ, Dept Med, Nashville, TN USA. [Ware, Lorraine B.] Vanderbilt Univ, Dept Pathol Microbiol & Immunol, 221 Kirkland Hall, Nashville, TN 37235 USA. [Thompson, B. Taylor] Massachusetts Gen Hosp, Dept Med, Div Pulm & Crit Care, Boston, MA 02114 USA. RP Calfee, CS (reprint author), 505 Parnassus Ave,M1088, San Francisco, CA 94143 USA. EM carolyn.calfee@ucsf.edu FU National Institutes of Health [T32 HL7185-39, F32 HL129680-01, K23 HL116800, HL103836, HL112656, HL110969, HL131621, HL133390]; National Institutes of Health/NHLBI ARDS Network [N01-HR 46046-64, N01-HR 16146-54] FX Supported by National Institutes of Health grants T32 HL7185-39 and F32 HL129680-01 (K.R.F.), K23 HL116800 (K.N.K.), HL103836 and HL112656 (L.B.W.), HL110969 (C.S.C.), HL131621 (C.S.C.), and HL133390 (C.S.C.); and by National Institutes of Health/NHLBI ARDS Network contracts N01-HR 46046-64 and N01-HR 16146-54. NR 18 TC 4 Z9 4 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD FEB 1 PY 2017 VL 195 IS 3 BP 331 EP 338 DI 10.1164/rccm.201603-0645OC PG 8 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA EJ6VP UT WOS:000393358200013 PM 27513822 ER PT J AU Hess, KL Andorko, JI Tostanoski, LH Jewell, CM AF Hess, Krystina L. Andorko, James I. Tostanoski, Lisa H. Jewell, Christopher M. TI Polyplexes assembled from self-peptides and regulatory nucleic acids blunt toll-like receptor signaling to combat autoimmunity SO BIOMATERIALS LA English DT Article DE Self-assembly; Polyplex; Toll-like receptor; Tolerance and autoimmunity; Nanoparticle; Immunology ID ANTIGEN-PRESENTING CELLS; MULTIPLE-SCLEROSIS; POLYELECTROLYTE MULTILAYERS; IMMUNOLOGICAL-TOLERANCE; DENDRITIC CELLS; T-CELLS; PENETRATING PEPTIDES; IMMUNE SIGNALS; STING ADAPTER; CPG MOTIFS AB Autoimmune diseases occur when the immune system incorrectly recognizes self-molecules as foreign; in the case of multiple sclerosis (MS), myelin is attacked. Intriguingly, new studies reveal toll-like receptors (TLRs), pathways usually involved in generating immune responses against pathogens, play a significant role in driving autoimmune disease in both humans and animal models. We reasoned polyplexes formed from myelin self-antigen and regulatory TLR antagonists might limit TLR signaling during differentiation of myelin-specific T cells, inducing tolerance by biasing T cells away from inflammatory phenotypes. Complexes were formed by modifying myelin peptide with cationic amino acids to create peptides able to condense the anionic nucleic-acid based TLR antagonist. These immunological polyplexes eliminate synthetic polymers commonly used to condense polyplexes and do not rely on gene expression; however, the complexes mimic key features of traditional polyplexes such as tunable loading and co-delivery. Using these materials and classic polyplex analysis techniques, we demonstrate condensation of both immune signals, protection from enzymatic degradation, and tunable physicochemical properties. We show polyplexes reduce TLR signaling, and in primary dendritic cell and T cell co-culture, reduce myelin-driven inflammation. During mouse models of MS, these tolerogenic polyplexes improve the progression, severity, and incidence of disease. (C) 2016 The Authors. Published by Elsevier Ltd. C1 [Hess, Krystina L.; Andorko, James I.; Tostanoski, Lisa H.; Jewell, Christopher M.] Univ Maryland, Fischell Dept Bioengn, 8228 Paint Branch Dr, College Pk, MD 20742 USA. [Jewell, Christopher M.] Univ Maryland, Dept Microbiol & Immunol, Sch Med, 685 West Baltimore St, Baltimore, MD 21201 USA. [Jewell, Christopher M.] Marlene & Stewart Greenebaum Canc Ctr, 22 S Greene St, Baltimore, MD 21201 USA. [Jewell, Christopher M.] US Dept Vet Affairs, 10 North Greene St, Baltimore, MD 21201 USA. RP Jewell, CM (reprint author), Fischell Dept Bioengn, 2212 Jeong H Kim Engn Bldg,8228 Paint Branch Dr, College Pk, MD 20742 USA. EM cmjewell@umd.edu FU National Multiple Sclerosis Society Award [RG-1501-02968, PP2103]; NSF CAREER Award [1351688]; University of Maryland Venture Fund; ASD/RE; Defense National Defense Education Program (NDEP) [Wide/PE0601120D8Z, BA-1]; NIH [T32 AI089621]; American Association of Pharmaceutical Scientists Foundation; Damon Runyon Foundation [DRR3415]; Young Investigator of the Alliance for Cancer Gene Therapy [15051543]; Melanoma Research Alliance [348963] FX This work was supported in part by the National Multiple Sclerosis Society Award # RG-1501-02968 and # PP2103, NSF CAREER Award # 1351688, and the University of Maryland Venture Fund. K.LH. is a SMART Graduate Fellow funded by ASD/R&E, Defense Wide/PE0601120D8Z National Defense Education Program (NDEP)/BA-1, Basic Research. J.I.A. is a trainee on NIH Grant #T32 AI089621 and a Graduate Fellow supported by the American Association of Pharmaceutical Scientists Foundation. L.H.T. is a NSF Graduate Fellow (# DGE1322106). C.M.J. is a Damon Runyon-Rachleff Innovator supported by the Damon Runyon Foundation (# DRR3415), and a Young Investigator of the Alliance for Cancer Gene Therapy (# 15051543) and the Melanoma Research Alliance (# 348963). NR 65 TC 1 Z9 1 U1 8 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 EI 1878-5905 J9 BIOMATERIALS JI Biomaterials PD FEB PY 2017 VL 118 BP 51 EP 62 DI 10.1016/j.biomaterials.2016.11.052 PG 12 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA EJ5JQ UT WOS:000393254700004 PM 27940382 ER PT J AU Dhaliwal, G AF Dhaliwal, Gurpreet TI Premature closure? Not so fast SO BMJ QUALITY & SAFETY LA English DT Editorial Material ID DIAGNOSTIC-ACCURACY; INTERNAL-MEDICINE; CONTROLLED-TRIAL; RESIDENTS; BIAS; ERROR; THINK C1 [Dhaliwal, Gurpreet] Univ Calif San Francisco, Dept Med, San Francisco VA Med Ctr, Med Serv, 4150 Clement St, San Francisco, CA 94121 USA. RP Dhaliwal, G (reprint author), Univ Calif San Francisco, Dept Med, San Francisco VA Med Ctr, Med Serv, 4150 Clement St, San Francisco, CA 94121 USA. EM gurpreet.dhaliwal@ucsf.edu NR 23 TC 2 Z9 2 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 2044-5415 EI 2044-5423 J9 BMJ QUAL SAF JI BMJ Qual. Saf. PD FEB PY 2017 VL 26 IS 2 BP 87 EP 89 DI 10.1136/bmjqs-2016-005267 PG 3 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA EJ4PI UT WOS:000393198900002 PM 26980778 ER PT J AU Schnock, KO Dykes, PC Albert, J Ariosto, D Call, R Cameron, C Carroll, DL Drucker, AG Fang, L Garcia-Palm, CA Husch, MM Maddox, RR McDonald, N McGuire, J Rafie, S Robertson, E Saine, D Sawyer, MD Smith, LP Stinger, KD Vanderveen, TW Wade, E Yoon, CS Lipsitz, S Bates, DW AF Schnock, Kumiko O. Dykes, Patricia C. Albert, Jennifer Ariosto, Deborah Call, Rosemary Cameron, Caitlin Carroll, Diane L. Drucker, Adrienne G. Fang, Linda Garcia-Palm, Christine A. Husch, Marla M. Maddox, Ray R. McDonald, Nicole McGuire, Julie Rafie, Sally Robertson, Emilee Saine, Deb Sawyer, Melinda D. Smith, Lisa P. Stinger, Kristy Dixon Vanderveen, Timothy W. Wade, Elizabeth Yoon, Catherine S. Lipsitz, Stuart Bates, David W. TI The frequency of intravenous medication administration errors related to smart infusion pumps: a multihospital observational study SO BMJ QUALITY & SAFETY LA English DT Article ID TECHNOLOGY; SETTINGS; SAFETY AB Introduction Intravenous medication errors persist despite the use of smart pumps. This suggests the need for a standardised methodology for measuring errors and highlights the importance of identifying issues around smart pump medication administration in order to improve patient safety. Objectives We conducted a multisite study to investigate the types and frequency of intravenous medication errors associated with smart pumps in the USA. Methods 10 hospitals of various sizes using smart pumps from a range of vendors participated. Data were collected using a prospective point prevalence approach to capture errors associated with medications administered via smart pumps and evaluate their potential for harm. Results A total of 478 patients and 1164 medication administrations were assessed. Of the observed infusions, 699 (60%) had one or more errors associated with their administration. Identified errors such as labelling errors and bypassing the smart pump and the drug library were predominantly associated with violations of hospital policy. These types of errors can result in medication errors. Errors were classified according to the National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP). 1 error of category E (0.1%), 4 of category D (0.3%) and 492 of category C (excluding deviations of hospital policy) (42%) were identified. Of these, unauthorised medication, bypassing the smart pump and wrong rate were the most frequent errors. Conclusion We identified a high rate of error in the administration of intravenous medications despite the use of smart pumps. However, relatively few errors were potentially harmful. The results of this study will be useful in developing interventions to eliminate errors in the intravenous medication administration process. C1 [Schnock, Kumiko O.; Dykes, Patricia C.; Yoon, Catherine S.; Lipsitz, Stuart; Bates, David W.] Brigham & Womens Hosp, Div Gen Internal Med & Primary Care, 1620 Tremont St,OBC 3, Boston, MA 02120 USA. [Albert, Jennifer; Carroll, Diane L.] Massachusetts Gen Hosp, Munn Ctr Nursing Res, Boston, MA 02114 USA. [Ariosto, Deborah] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Call, Rosemary; Sawyer, Melinda D.] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. [Cameron, Caitlin; McDonald, Nicole] Maricopa Cty Gen Hosp, Dept Pharm, Phoenix, AZ USA. [Drucker, Adrienne G.] Partners Healthcare, Partners ECare, Boston, MA USA. [Fang, Linda; Saine, Deb] Winchester Med Ctr, Winchester, VA USA. [Garcia-Palm, Christine A.; McGuire, Julie] Cent DuPage Hosp, Winfield, IL USA. [Husch, Marla M.; Vanderveen, Timothy W.] BD, Solut Management & Business Dev, San Diego, CA USA. [Maddox, Ray R.] Univ Georgia, Coll Pharm, Savannah, GA USA. [Rafie, Sally] UC San Diego Hlth, Dept Pharm, San Diego, CA USA. [Robertson, Emilee] St Josephs Candler Hlth Syst, Savannah, GA USA. [Smith, Lisa P.; Stinger, Kristy Dixon] Western Connecticut Hlth Network, Dept Nursing, Danbury, CT USA. [Wade, Elizabeth] Concord Hosp, Concord, NH USA. RP Schnock, KO (reprint author), Brigham & Womens Hosp, Div Gen Internal Med & Primary Care, 1620 Tremont St,OBC 3, Boston, MA 02120 USA. EM kschnock@partners.org FU Carefusion Foundation; Association for the Advancement of Medical Instrumentation (AAMI) FX Carefusion Foundation; Association for the Advancement of Medical Instrumentation (AAMI). NR 19 TC 1 Z9 1 U1 3 U2 3 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 2044-5415 EI 2044-5423 J9 BMJ QUAL SAF JI BMJ Qual. Saf. PD FEB PY 2017 VL 26 IS 2 BP 131 EP 140 DI 10.1136/bmjqs-2015-004465 PG 10 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA EJ4PI UT WOS:000393198900009 PM 26908900 ER PT J AU Reinhold, WC Varma, S Sunshine, M Rajapakse, V Luna, A Kohn, KW Stevenson, H Wang, YH Heyn, H Nogales, V Moran, S Goldstein, DJ Doroshow, JH Meltzer, PS Esteller, M Pommier, Y AF Reinhold, William C. Varma, Sudhir Sunshine, Margot Rajapakse, Vinodh Luna, Augustin Kohn, Kurt W. Stevenson, Holly Wang, Yonghong Heyn, Holger Nogales, Vanesa Moran, Sebastian Goldstein, David J. Doroshow, James H. Meltzer, Paul S. Esteller, Manel Pommier, Yves TI The NCI-60 Methylome and Its Integration into CellMiner SO CANCER RESEARCH LA English DT Article ID DNA METHYLATION; SYSTEMS PHARMACOLOGY; MESSENGER-RNA; CANCER-CELLS; SLFN11; MAINTENANCE; SENSITIVITY; EPIGENETICS; CHALLENGES; PROFILES AB A unique resource for systems pharmacology and genomic studies is the NCI-60 cancer cell line panel, which provides data for the largest publicly available library of compounds with cytotoxic activity (similar to 21,000 compounds), including 108 FDA-approved and 70 clinical trial drugs as well as genomic data, including whole-exome sequencing, gene and miRNA transcripts, DNA copy number, and protein levels. Here, we provide the first readily usable genome-wide DNA methylation database for the NCI-60, including 485,577 probes from the Infinium HumanMethylation450k BeadChip array, which yielded DNA methylation signatures for 17,559 genes integrated into our open access CellMiner version 2.0 (https://discover.nci.nih.gov/cellminer). Among new insights, transcript versus DNA methylation correlations revealed the epithelial/mesenchymal gene functional category as being influenced most heavily by methylation. DNA methylation and copy number integration with transcript levels yielded an assessment of their relative influence for 15,798 genes, including tumor suppressor, mitochondrial, and mismatch repair genes. Four forms of molecular data were combined, providing rationale for microsatellite instability for 8 of the 9 cell lines in which it occurred. Individual cell line analyses showed globalmethylome patterns with overall methylation levels ranging from 17% to 84%. A six-gene model, including PARP1, EP300, KDM5C, SMARCB1, and UHRF1 matched this pattern. In addition, promoter methylation of two translationally relevant genes, Schlafen 11 (SLFN11) and methylguanine methyltransferase (MGMT), served as indicators of therapeutic resistance or susceptibility, respectively. Overall, our database provides a resource of pharmacologic data that can reinforce known therapeutic strategies and identify novel drugs and drug targets across multiple cancer types. (C) 2016 AACR. C1 [Reinhold, William C.; Varma, Sudhir; Sunshine, Margot; Rajapakse, Vinodh; Luna, Augustin; Kohn, Kurt W.; Doroshow, James H.; Pommier, Yves] NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Varma, Sudhir; Sunshine, Margot] Syst Res & Applicat Corp, Fairfax, VA USA. [Varma, Sudhir] HiThru Analyt LLC, Laurel, MD USA. [Luna, Augustin] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Luna, Augustin] Harvard Med Sch, Dept Cell Biol, Boston, MA USA. [Stevenson, Holly; Wang, Yonghong; Meltzer, Paul S.] NCI, Genet Branch, Dev Therapeut Program, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Heyn, Holger; Nogales, Vanesa; Moran, Sebastian; Esteller, Manel] Bellvitge Biomed Res Inst IDIBELL, Canc Epigenet & Biol Program, Barcelona, Catalonia, Spain. [Goldstein, David J.] NCI, Off Director, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Doroshow, James H.] NCI, Div Canc Treatment & Diag, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Esteller, Manel] Univ Barcelona, Sch Med, Dept Physiol Sci 2, Barcelona, Catalonia, Spain. [Esteller, Manel] ICREA, Barcelona, Catalonia, Spain. RP Reinhold, WC (reprint author), NCI, 9000 Rockville Pike,Bldg 37,Room 5041, Bethesda, MD 20892 USA. EM wcr@mail.nih.gov; pommier@nih.gov RI Moran, Sebastian /G-5293-2013; OI Moran, Sebastian /0000-0003-4192-8983; Heyn, Holger/0000-0002-3276-1889 FU Intramural NIH HHS [ZIC BC011475-01] NR 36 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 2017 VL 77 IS 3 BP 601 EP 612 DI 10.1158/0008-5472.CAN-16-0655 PG 12 WC Oncology SC Oncology GA EJ4NP UT WOS:000393194400003 PM 27923837 ER PT J AU Joyce, CE Yanez, AG Mori, A Yoda, A Carroll, JS Novina, CD AF Joyce, Cailin E. Yanez, Adrienne G. Mori, Akihiro Yoda, Akinori Carroll, Johanna S. Novina, Carl D. TI Differential Regulation of the Melanoma Proteome by eIF4A1 and eIF4E SO CANCER RESEARCH LA English DT Article ID EUKARYOTIC TRANSLATION INITIATION; MESSENGER-RNAS; MALIGNANT-MELANOMA; TUMOR PROGRESSION; ANTISENSE RNA; CANCER; EXPRESSION; SURVIVAL; CAP; METASTASIS AB Small molecules and antisense oligonucleotides that inhibit the translation initiation factors eIF4A1 and eIF4E have been explored as broad-based therapeutic agents for cancer treatment, based on the frequent upregulation of these two subunits of the eIF4F cap-binding complex in many cancer cells. Here, we provide support for these therapeutic approaches with mechanistic studies of eIF4F-driven tumor progression in a preclinical model of melanoma. Silencing eIF4A1 or eIF4E decreases melanoma proliferation and invasion. There were common effects on the level of cell-cycle proteins that could explain the antiproliferative effects in vitro. Using clinical specimens, we correlate the common cell-cycle targets of eIF4A1 and eIF4E with patient survival. Finally, comparative proteomic and transcriptomic analyses reveal extensive mechanistic divergence in response to eIF4A1 or eIF4E silencing. Current models indicate that eIF4A1 and eIF4E function together through the 5'UTR to increase translation of oncogenes. In contrast, our data demonstrate that the common effects of eIF4A1 and eIF4E on translation are mediated by the coding region and 3'UTR. Moreover, their divergent effects occur through the 5'UTR. Overall, our work shows that it will be important to evaluate subunit-specific inhibitors of eIF4F in different disease contexts to fully understand their anticancer actions. (C) 2016 AACR. C1 [Joyce, Cailin E.; Yanez, Adrienne G.; Yoda, Akinori; Carroll, Johanna S.; Novina, Carl D.] Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02115 USA. [Joyce, Cailin E.; Yanez, Adrienne G.; Yoda, Akinori; Carroll, Johanna S.; Novina, Carl D.] Harvard Med Sch, Dept Med, Boston, MA USA. [Joyce, Cailin E.; Yanez, Adrienne G.; Yoda, Akinori; Carroll, Johanna S.; Novina, Carl D.] Broad Inst Harvard & MIT, Cambridge, MA USA. [Mori, Akihiro] Univ Massachusetts, Program Syst Biol, Worcester, MA 01605 USA. [Mori, Akihiro] Univ Massachusetts, Program Mol Med, Worcester, MA 01605 USA. [Mori, Akihiro] Syst Biol Inst, Onami Team, Tokyo, Japan. [Mori, Akihiro] RIKEN Quantitat Biol Ctr, Lab Dev Dynam, Kobe, Hyogo, Japan. RP Novina, CD (reprint author), Dana Farber Canc Inst, Dana 1420B,450 Brookline Ave, Boston, MA 02215 USA. EM carl_novina@dfci.harvard.edu FU NIH [R01 CA140986, T32 CA070083, F32 HL124941, GM07266, F31 GM087947] FX This work was supported by NIH grant R01 CA140986 (C.D. Novina). C.E. Joyce was supported by NIH training grant T32 CA070083 and postdoctoral fellowship F32 HL124941. A.G. Yanez was supported by NIH training grant GM07266 and predoctoral fellowship F31 GM087947. NR 49 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 2017 VL 77 IS 3 BP 613 EP 622 DI 10.1158/0008-5472.CAN-16-1298 PG 10 WC Oncology SC Oncology GA EJ4NP UT WOS:000393194400004 PM 27879264 ER PT J AU Choudhury, AD Schinzel, AC Cotter, MB Lis, RT Labella, K Lock, YJ Izzo, F Guney, I Bowden, M Li, YY Patel, J Hartman, E Carr, SA Schenone, M Jaffe, JD Kantoff, PW Hammerman, PS Hahn, WC AF Choudhury, Atish D. Schinzel, Anna C. Cotter, Maura B. Lis, Rosina T. Labella, Katherine Lock, Ying Jie Izzo, Francesca Guney, Isil Bowden, Michaela Li, Yvonne Y. Patel, Jinal Hartman, Emily Carr, Steven A. Schenone, Monica Jaffe, Jacob D. Kantoff, Philip W. Hammerman, Peter S. Hahn, William C. TI Castration Resistance in Prostate Cancer Is Mediated by the Kinase NEK6 SO CANCER RESEARCH LA English DT Article ID ANDROGEN RECEPTOR ACTIVATION; RAF INHIBITION; CELLS; DIFFERENTIATION; OVEREXPRESSION; TRANSFORMATION; MECHANISMS; EXPRESSION; CARCINOMA; PROMOTES AB In prostate cancer, the development of castration resistance is pivotal in progression to aggressive disease. However, understanding of the pathways involved remains incomplete. In this study, we performed a high-throughput genetic screen to identify kinases that enable tumor formation by androgen-dependent prostate epithelial (LHSR-AR) cells under androgen-deprived conditions. In addition to the identification of known mediators of castration resistance, which served to validate the screen, we identified a mitotic-related serine/threonine kinase, NEK6, as a mediator of androgen-independent tumor growth. NEK6 was overexpressed in a subset of human prostate cancers. Silencing NEK6 in castration-resistant cancer cells was sufficient to restore sensitivity to castration in a mouse xenograft model system. Tumors in which castration resistance was conferred by NEK6 were predominantly squamous in histology with no evidence of AR signaling. Gene expression profiling suggested that NEK6 overexpression stimulated cytoskeletal, differentiation and immune signaling pathways and maintained gene expression patterns normal decreased by castration. Phosphoproteome profiling revealed the transcription factor FOXJ2 as a novel NEK6 substrate, with FOXJ2 phosphorylation associated with increased expression of newly identified NEK6 transcriptional targets. Overall, our studies establish NEK6 signaling as a central mechanism mediating castration-resistant prostate cancer. (C) 2016 AACR. C1 [Choudhury, Atish D.; Schinzel, Anna C.; Cotter, Maura B.; Lis, Rosina T.; Labella, Katherine; Lock, Ying Jie; Izzo, Francesca; Guney, Isil; Bowden, Michaela; Li, Yvonne Y.; Kantoff, Philip W.; Hammerman, Peter S.; Hahn, William C.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Choudhury, Atish D.; Guney, Isil; Kantoff, Philip W.; Hammerman, Peter S.; Hahn, William C.] Harvard Med Sch, Boston, MA USA. [Choudhury, Atish D.; Schinzel, Anna C.; Izzo, Francesca; Patel, Jinal; Hartman, Emily; Carr, Steven A.; Schenone, Monica; Jaffe, Jacob D.; Hammerman, Peter S.; Hahn, William C.] Broad Inst Harvard & MIT, Cambridge, MA USA. [Lis, Rosina T.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. RP Hahn, WC (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,Dana 1538, Boston, MA 02215 USA. EM william_hahn@dfci.harvard.edu FU NCI [U01CA176058]; Prostate Cancer Foundation; Prostate Cancer Foundation Young Investigator Award; Department of Defense Prostate Cancer Research Program FX This work was supported in part by NCI grant U01CA176058 and the Prostate Cancer Foundation. A.D. Choudhury and I. Guney have been supported by the Prostate Cancer Foundation Young Investigator Award and by the Department of Defense Prostate Cancer Research Program through the Physician Scientist Training Award and Postdoctoral Trainee Award, respectively. NR 49 TC 0 Z9 0 U1 2 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 2017 VL 77 IS 3 BP 753 EP 765 DI 10.1158/0008-5472.CAN-16-0455 PG 13 WC Oncology SC Oncology GA EJ4NP UT WOS:000393194400016 PM 27899381 ER PT J AU Cejas, P Cavazza, A Yandava, CN Moreno, V Horst, D Moreno-Rubio, J Burgos, E Mendiola, M Taing, L Goel, A Feliu, J Shivdasani, RA AF Cejas, Paloma Cavazza, Alessia Yandava, C. N. Moreno, Victor Horst, David Moreno-Rubio, Juan Burgos, Emilio Mendiola, Marta Taing, Len Goel, Ajay Feliu, Jaime Shivdasani, Ramesh A. TI Transcriptional Regulator CNOT3 Defines an Aggressive Colorectal Cancer Subtype SO CANCER RESEARCH LA English DT Article ID HUMAN CCR4-NOT COMPLEX; STEM-CELLS; GENE-EXPRESSION; EMBRYONIC STEM; COLON-CANCER; CHIP-SEQ; CHROMATIN PATTERN; SMALL-INTESTINE; MESSENGER-RNA; SELF-RENEWAL AB Cancer cells exhibit dramatic alterations of chromatin organization at cis-regulatory elements, but the molecular basis, extent and impact of these alterations are still being unraveled. Here we identify extensive genome-wide modification of sites bearing the active histone mark H3K4me2 in primary human colorectal cancers (CRC), as compared to corresponding benign precursor adenomas. Modification of certain CRC sites highlighted the activity of the transcription factor CNOT3, which is known to control self-renewal of embryonic stem cells (ESC). In primary CRC cells, we observed a scattered pattern of CNOT3 expression, as might be expected for a tumor-initiating cell marker. CRC cells exhibited nuclear and cytoplasmic expression of CNOT3, suggesting possible roles in both transcription and mRNA stability. We found that CNOT3 was bound primarily to genes whose expression was affected by CNOT3 loss, and also at sites modulated in certain types of CRC. These target genes were implicated in ESC and cancer self-renewal and fell into two distinct groups: those dependent on CNOT3 and MYC for optimal transcription and those repressed by CNOT3 binding and promoter hypermethylation. Silencing CNOT3 in CRC cells resulted in replication arrest. In clinical specimens, early stage tumors that included >5% CNOT3(+) cells exhibited a correlation to worse clinical outcomes compared to tumors with little to no CNOT3 expression. Together, our findings implicate CNOT3 in the coordination of colonic epithelial cell self-renewal, suggesting this factor as a new biomarker for molecular and prognostic classification of early-stage CRC. (C) 2016 AACR. C1 [Cejas, Paloma; Cavazza, Alessia; Yandava, C. N.; Taing, Len; Shivdasani, Ramesh A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Cejas, Paloma; Cavazza, Alessia; Yandava, C. N.; Taing, Len; Shivdasani, Ramesh A.] Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02115 USA. [Cejas, Paloma; Cavazza, Alessia; Shivdasani, Ramesh A.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Cejas, Paloma; Cavazza, Alessia; Shivdasani, Ramesh A.] Harvard Med Sch, Boston, MA USA. [Cejas, Paloma; Moreno, Victor; Moreno-Rubio, Juan; Mendiola, Marta; Feliu, Jaime] Hosp La Paz, Inst Hlth Res CIBERONC, Dept Med Oncol, Madrid, Spain. [Horst, David] Ludwig Maximilians Univ Munchen, Inst Pathol, Munich, Germany. [Burgos, Emilio; Mendiola, Marta] Hosp La Paz, Inst Hlth Res, Dept Pathol, Madrid, Spain. [Goel, Ajay] Baylor Univ, Med Ctr, Ctr Gastrointestinal Canc Res, Dallas, TX USA. RP Shivdasani, RA (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,Dana 720, Boston, MA 02215 USA. EM ramesh_shivdasani@dfci.harvard.edu FU DFCI-Novartis Drug Discovery Program; NIH [P50CA127003, R01CA72851, CA181572]; Instituto de Salud Carlos III, Spanish Economy and Competitiveness Ministry [PI13-01818]; Asociacion Espanola Contra el Cancer (Programa de Formacion Avanzada en Oncologia); Fundacion Caja Madrid; American-Italian Cancer Foundation FX This work was supported by the DFCI-Novartis Drug Discovery Program (R.A. Shivdasani); a gift from the Lind family (R.A. Shivdasani); NIH grants P50CA127003 (Dana-Farber/Harvard), R01CA72851, and CA181572 (A. Goel); Instituto de Salud Carlos III, Spanish Economy and Competitiveness Ministry (PI13-01818, P. Cejas.); and fellowships from Asociacion Espanola Contra el Cancer (Programa de Formacion Avanzada en Oncologia 2010; P. Cejas), Fundacion Caja Madrid (P. Cejas), and the American-Italian Cancer Foundation (A. Cavazza). NR 52 TC 0 Z9 0 U1 2 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 2017 VL 77 IS 3 BP 766 EP 779 DI 10.1158/0008-5472.CAN-16-1346 PG 14 WC Oncology SC Oncology GA EJ4NP UT WOS:000393194400017 PM 27899379 ER PT J AU Greenblatt, MB Tsai, JN Wein, MN AF Greenblatt, Matthew B. Tsai, Joy N. Wein, Marc N. TI Bone Turnover Markers in the Diagnosis and Monitoring of Metabolic Bone Disease SO CLINICAL CHEMISTRY LA English DT Review ID PYRIDINOLINE CROSS-LINKS; VERTEBRAL FRACTURE RISK; C-TERMINAL TELOPEPTIDE; COLLAGEN TYPE-I; BIOCHEMICAL MARKERS; POSTMENOPAUSAL OSTEOPOROSIS; RHEUMATOID-ARTHRITIS; ZOLEDRONIC ACID; MINERAL DENSITY; BIOLOGICAL VARIABILITY AB BACKGROUND: Disorders of bone metabolism, most notably osteoporosis, are highly prevalent and predispose to fractures, causing high patient morbidity and mortality. Diagnosis and monitoring of bone metabolic defects can present a major challenge as these disorders are largely asymptomatic and radiographic measures of bone mass respond slowly,to changes in bone physiology. CONTENT: Bone turnover markers (BTMs) are a series of protein or protein derivative biomarkers released during bone remodeling by osteoblasts or osteoclasts. BTMs can offer prognostic information on fracture risk that supplements radiographic measures of bone mass, but testing using BTMs has to take into account the large number of preanalytic factors and comorbid clinical conditions influencing BTM levels. BTMs respond rapidly to changes in bone physiology, therefore, they have utility in determining patient response to and compliance with therapies for osteoporosis. SUMMARY: BTMs are a useful adjunct for the diagnosis and therapeutic monitoring of bone metabolic disorders, but their use has to be tempered by the known limitations in their clinical utility and preanalytic variables' complicating interpretation. (C) 2016 American Association for Clinical Chemistry C1 [Greenblatt, Matthew B.] Weill Cornell Med, Dept Pathol & Lab Med, LC929a,1300 York Ave, New York, NY 10065 USA. [Tsai, Joy N.; Wein, Marc N.] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. RP Greenblatt, MB (reprint author), Weill Cornell Med, Dept Pathol & Lab Med, LC929a,1300 York Ave, New York, NY 10065 USA. EM mag3003@med.cornell.edu FU Burroughs Wellcome Fund; Office of the Director of the NIH [DP5OD021351]; Junior Investigator Award from the Musculoskeletal Transplant Foundation; NIAMS of the NIH [K23AR068447, K08AR067285] FX M.B. Greenblatt, Career Award for Medical Scientists from the Burroughs Wellcome Fund, the Office of the Director of the NIH under award DP5OD021351, and a Junior Investigator Award from the Musculoskeletal Transplant Foundation; J.N. Tsai, NIAMS of the NIH under award K23AR068447; M.N. Wein, NIAMS of the NIH under award K08AR067285. NR 93 TC 0 Z9 0 U1 1 U2 1 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 FEB PY 2017 VL 63 IS 2 BP 464 EP 474 DI 10.1373/clinchem.2016.259085 PG 11 WC Medical Laboratory Technology SC Medical Laboratory Technology GA EJ6WG UT WOS:000393360000008 PM 27940448 ER PT J AU Weber, MM Biller, BMK Pedersen, BT Pournara, E Christiansen, JS Hoybye, C AF Weber, Matthias M. Biller, Beverly M. K. Pedersen, Birgitte Tonnes Pournara, Effie Christiansen, Jens Sandahl Hoybye, Charlotte TI The effect of growth hormone (GH) replacement on blood glucose homeostasis in adult nondiabetic patients with GH deficiency: real-life data from the NordiNet((R)) International Outcome Study SO CLINICAL ENDOCRINOLOGY LA English DT Article ID INSULIN SENSITIVITY; HYPOPITUITARY PATIENTS; METABOLIC SYNDROME; DIABETES-MELLITUS; ENDOCRINE-SOCIETY; BODY-COMPOSITION; FASTING GLUCOSE; KIMS ANALYSIS; RISK-FACTORS; THERAPY AB ObjectiveTo assess the effect of 4 years' growth hormone (GH) replacement on glucose homeostasis and evaluate factors affecting glycosylated haemoglobin (HbA(1c)) in adults with growth hormone deficiency (GHD). DesignNordiNet((R)) International Outcome Study, a noninterventional study, monitors long-term effectiveness and safety of GH replacement [Norditropin((R)) (somatropin), Novo Nordisk A/S] in real-life clinical practice. PatientsNondiabetic patients (n = 245) with adult-onset GHD (age 20 years at GH start), 4 years' GH replacement and HbA(1c) values at baseline and 4 years were included in the analysis. MeasurementsChanges from baseline () to 4 years in HbA(1c), fasting plasma glucose (FPG), IGF-I, lipids (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total cholesterol, triglycerides), waist circumference, glycaemic (HbA(1c) <57%; HbA(1c), 57-65%; HbA(1c), 65%) and metabolic health status were evaluated. Effects of baseline HbA(1c), gender, baseline age, average GH dose and baseline body mass index (BMI) on HbA(1c) were investigated. The models were adjusted for concomitant medication use. ResultsMean (standard deviation) baseline HbA(1c) was 513 (065)% and remained at the same level at 4 years. Age at treatment start (P = 00094) and BMI (P = 00008) had a significant impact on HbA(1c). At 4 years, 85% of patients with HbA(1c) <57% (normal levels) at baseline and 55% of patients with HbA(1c) 57-65% (impaired glucose tolerance) at baseline remained in the same glycaemic health category. Nineteen patients improved from impaired glucose tolerance to normal HbA(1c). Seven patients developed diabetes. ConclusionsThese data demonstrate that 4 years' GH replacement therapy did not adversely affect glucose homeostasis in the majority of adults with GHD. C1 [Weber, Matthias M.] Johannes Gutenberg Univ Mainz, Med Clin, Dept Endocrinol & Metab, Mainz, Germany. [Biller, Beverly M. K.] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Pedersen, Birgitte Tonnes] Nordisk AS, Epidemiol, Soborg, Denmark. [Pournara, Effie] Novo Nordisk Hlth Care AG, Zurich, Switzerland. [Christiansen, Jens Sandahl] Aarhus Univ Hosp, NBG, MEA, Dept Endocrinol & Diabet, Aarhus, Denmark. [Hoybye, Charlotte] Karolinska Univ Hosp, Karolinska Inst, Dept Mol Med & Surg, Dept Endocrinol Metab & Diabetol, Stockholm, Sweden. RP Weber, MM (reprint author), Johannes Gutenberg Univ Mainz, Med Clin, Dept Endocrinol & Metab, Mainz, Germany. EM MMWeber@uni-mainz.de FU Novo Nordisk; Opko; Versartis FX This study was sponsored by Novo Nordisk. M Weber and C Hoybye are members of NordiNet (R) IOS International Study Committee; E Pournara and B Tonnes Pedersen are employees of Novo Nordisk. BMK Biller is the PI of research grants to Massachusetts General Hospital from Novo Nordisk, Opko and Versartis and has received consulting honoraria from Novo Nordisk, Pfizer and Versartis. JS Christiansen was a member of the NordiNet (R) IOS International Study Committee. NR 33 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0300-0664 EI 1365-2265 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD FEB PY 2017 VL 86 IS 2 BP 192 EP 198 DI 10.1111/cen.13256 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EJ8CO UT WOS:000393452300006 PM 27736009 ER PT J AU Pena-Polanco, JE Mor, MK Tohme, FA Fine, MJ Palevsky, PM Weisbord, SD AF Pena-Polanco, Julio E. Mor, Maria K. Tohme, Fadi A. Fine, Michael J. Palevsky, Paul M. Weisbord, Steven D. TI Acceptance of Antidepressant Treatment by Patients on Hemodialysis and Their Renal Providers SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID QUALITY-OF-LIFE; RECEIVING CHRONIC-HEMODIALYSIS; SYMPTOM MANAGEMENT STRATEGIES; RANDOMIZED CLINICAL-TRIAL; DISEASE PATIENTS; PSYCHOSOCIAL FACTORS; DEPRESSED-PATIENTS; DIALYSIS PATIENTS; PAIN; MORTALITY AB Background and objectives Depression is common in patients receiving chronic hemodialysis but seems to be ineffectively treated. We investigated the acceptance of antidepressant treatment by patients on chronic hemodialysis and their renal providers. Design, setting, participants, & measurements As part of a clinical trial of symptom management in patients on chronic hemodialysis conducted from 2009 to 2011, we assessed depression monthly using the Patient Health Questionnaire 9. For depressed patients (Patient Health Questionnaire 9 score-10), trained nurses generated treatment recommendations and helped implement therapy if patients and providers accepted the recommendations. We assessed patients' acceptance of recommendations, reasons for refusal, and provider willingness to implement antidepressant therapy. We analyzed data at the level of the monthly assessment. Results Of 101 patients followed for <= 12 months, 39 met criteria for depression (Patient Health Questionnaire 9 score >= 10 on one or more assessments). These 39 patients had depression on 147 of 373 (39%) monthly assessments. At 103 of these 147 (70%) assessments, patients were receiving antidepressant therapy, and at 51 of 70 (70%) assessments, patients did not accept nurses' recommendations to intensify treatment. At 44 assessments, patients with depression were not receiving antidepressant therapy, and in 40 (91%) instances, they did not accept recommendations to start treatment. The primary reason that patients refused the recommendations was athibution of their depression to an acute event, chronic illness, or dialysis (57%). In 11 of 18 (61%) instances in which patients accepted the recommendation, renal providers were unwilling to provide treatment. Conclusions Patients on chronic hemodialysis with depression are frequently not interested in modifying or initiating antidepressant treatment, commonly attributing their depression to a recent acute event, chronic illness, or dialysis. Renal providers are often unwilling to modify or initiate antidepressant therapy. Future efforts to improve depression management will need to address these patient- and provider-level obstacles to providing such care. C1 [Pena-Polanco, Julio E.; Tohme, Fadi A.; Palevsky, Paul M.; Weisbord, Steven D.] Univ Pittsburgh, Sch Med, Dept Med, Renal Electrolyte Div, Pittsburgh, PA 15213 USA. [Fine, Michael J.] Univ Pittsburgh, Sch Med, Div Gen Internal Med, Pittsburgh, PA USA. [Mor, Maria K.; Fine, Michael J.; Weisbord, Steven D.] Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Palevsky, Paul M.; Weisbord, Steven D.] Vet Affairs Pittsburgh Healthcare Syst, Med Serv Line, Renal Sect, Pittsburgh, PA USA. [Mor, Maria K.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. RP Weisbord, SD (reprint author), Vet Affairs Pittsburgh Healthcare Syst, 7E Room 120,111F-U, Pittsburgh, PA 15240 USA. EM weisbordsd@upmc.edu FU Department of Veterans Affairs Health Services Research and Development Merit Review award [IIR 07-190] FX This work was supported by Department of Veterans Affairs Health Services Research and Development Merit Review award IIR 07-190 (to S.D.W.). NR 29 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 EI 1555-905X J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD FEB PY 2017 VL 12 IS 2 BP 298 EP 303 DI 10.2215/CJN.07720716 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA EJ6VG UT WOS:000393357300013 PM 28126707 ER PT J AU Thenkondar, A Jafari, L Sooriash, R Hajsadeghi, F Berenji, GR Li, YX AF Thenkondar, Anuradha Jafari, Lida Sooriash, Robbie Hajsadeghi, Fereshteh Berenji, Gholam R. Li, Yuxin TI F-18-NaF PET Demonstrating Unusual Focal Tracer Activity in the Brain SO CLINICAL NUCLEAR MEDICINE LA English DT Editorial Material DE F-18-NaF; PET/CT; brain; extraosseous; cerebral infarct ID TC-99M MDP UPTAKE; FLUORIDE; METASTASIS C1 [Thenkondar, Anuradha] Univ Calif Los Angeles, Dept Nucl Med, VA Greater Los Angeles Healthcare Syst, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. [Thenkondar, Anuradha] Univ Calif Los Angeles, David Geffen Sch Med, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. RP Thenkondar, A (reprint author), Univ Calif Los Angeles, Dept Nucl Med, VA Greater Los Angeles Healthcare Syst, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA.; Thenkondar, A (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM Anuradha.Thenkondar@va.gov NR 9 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0363-9762 EI 1536-0229 J9 CLIN NUCL MED JI Clin. Nucl. Med. PD FEB PY 2017 VL 42 IS 2 BP 127 EP 128 DI 10.1097/RLU.0000000000001458 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EJ0UB UT WOS:000392924900028 PM 27879488 ER PT J AU Coley, JD Arenson, M Xu, Y Tanner, KD AF Coley, John D. Arenson, Melanie Xu, Yian Tanner, Kimberly D. TI Intuitive biological thought: Developmental changes and effects of biology education in late adolescence SO COGNITIVE PSYCHOLOGY LA English DT Article DE Intuitive biology; Science education; Conceptual change; Psychological essentialism; Anthropocentrism; Teleology ID FUNCTIONAL EXPLANATION; ESSENTIALIST BELIEFS; CONCEPTUAL CHANGE; CATEGORIES; EVOLUTION; KNOWLEDGE; CHILDREN; THINKING; DESIGN; ADULTS AB A large body of cognitive research has shown that people intuitively and effortlessly reason about the biological world in complex and systematic ways. We addressed two questions about the nature of intuitive biological reasoning: How does intuitive biological thinking change during adolescence and early adulthood? How does increasing biology education influence intuitive biological thinking? To do so, we developed a battery of measures to systematically test three components of intuitive biological thought: anthropocentric thinking, teleological thinking and essentialist thinking, and tested 8th graders and university students (both biology majors, and non-biology majors). Results reveal clear evidence of persistent intuitive reasoning among all populations studied, consistent but surprisingly small differences between 8th graders and college students on measures of intuitive biological thought, and consistent but again surprisingly small influence of increasing biology education on intuitive biological reasoning. Results speak to the persistence of intuitive reasoning, the importance of taking intuitive knowledge into account in science classrooms, and the necessity of interdisciplinary research to advance biology education. Further studies are necessary to investigate how cultural context and continued acquisition of expertise impact intuitive biology thinking. (C) 2016 Elsevier Inc. All rights reserved. C1 [Coley, John D.; Arenson, Melanie; Xu, Yian] Northeastern Univ, Dept Psychol, 125 Nightingale Hall,360 Huntington Ave, Boston, MA 02115 USA. [Arenson, Melanie] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Arenson, Melanie] San Francisco VA Med Ctr, San Francisco, CA USA. [Tanner, Kimberly D.] San Francisco State Univ, Dept Biol, San Francisco, CA 94132 USA. RP Coley, JD (reprint author), Northeastern Univ, Dept Psychol, 125 Nightingale Hall,360 Huntington Ave, Boston, MA 02115 USA. EM j.coley@northeastern.edu FU National Science Foundation EHR Core Research Grant [1535496] FX This research was funded by National Science Foundation EHR Core Research Grant #1535496 to J.D. Coley and K.D. Tanner. We thank Heather Krepelka, Rebeca Rosengaus and Fred Davis for their support making this research possible, Kathryn Hardin, Samantha Daoust and Nicole Betz for help in data collection, and Sarah Bissonnette for comments on the manuscript. NR 81 TC 0 Z9 0 U1 8 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0010-0285 EI 1095-5623 J9 COGNITIVE PSYCHOL JI Cogn. Psychol. PD FEB PY 2017 VL 92 BP 1 EP 21 DI 10.1016/j.cogpsych.2016.11.001 PG 21 WC Psychology; Psychology, Experimental SC Psychology GA EJ5NX UT WOS:000393266100001 PM 27865155 ER PT J AU Chen, D Bienvenu, OJ Krasnow, J Wang, Y Grados, MA Cullen, B Goes, FS Maher, B Greenberg, BD McLaughlin, NC Rasmussen, SA Fyer, AJ Knowles, JA McCracken, JT Piacentini, J Geller, D Pauls, DL Stewart, SE Murphy, DL Shugart, YY Riddle, MA Nestadt, G Samuels, J AF Chen, David Bienvenu, O. Joseph Krasnow, Janice Wang, Ying Grados, Marco A. Cullen, Bernadette Goes, Fernando S. Maher, Brion Greenberg, Benjamin D. McLaughlin, Nicole C. Rasmussen, Steven A. Fyer, Abby J. Knowles, James A. McCracken, James T. Piacentini, John Geller, Dan Pauls, David L. Stewart, S. Evelyn Murphy, Dennis L. Shugart, Yin-Yao Riddle, Mark A. Nestadt, Gerald Samuels, Jack TI Parental bonding and hoarding in obsessive compulsive disorder SO COMPREHENSIVE PSYCHIATRY LA English DT Article ID OCD COLLABORATIVE GENETICS; SYMPTOM DIMENSIONS; AFFECTIONLESS CONTROL; PERSONALITY-TRAITS; ANXIETY DISORDERS; CLINICAL-SAMPLE; MULTI-INFORMANT; RISK-FACTOR; ATTACHMENT; FAMILY AB Background: Hoarding behavior may indicate a clinically and possibly etiologically distinct subtype of obsessive compulsive disorder (OCD). Empirical evidence supports a relationship between hoarding and emotional over-attachment to objects. However, little is known about the relationship between hoarding and parental attachment in OCD. Method: The study sample included 894 adults diagnosed with DSM-IV OCD who had participated in family and genetic studies of OCD. Participants were assessed for Axis I disorders, personality disorders, and general personality dimensions. The Parental Bonding Instrument (PB1) was used to assess dimensions of perceived parental rearing (care, overprotection, and control). We compared parental PHI scores in the 334 hoarding and 560 non-hoarding participants, separately in men and women. We used logistic regression to evaluate the relationship between parenting scores and hoarding in women, adjusting for other clinical features associated with hoarding. Results: In men, there were no significant differences between hoarding and non-hoarding groups in maternal or paternal parenting scores. In women, the hoarding group had a lower mean score on maternal care (23.4 vs. 25.7, p < 0.01); a higher mean score on maternal protection (9.4 vs. 7.7, p < 0.001); and a higher mean score on maternal control (7.0 vs. 6.2, p < 0.05), compared to the non-hoarding group. The magnitude of the relationships between maternal bonding dimensions and hoarding in women did not change after adjustment for other clinical features. Women who reported low maternal care/high maternal protection had significantly greater odds of hoarding compared to women with high maternal care/low maternal protection (OR = 2.54, 95% CI = 1.60-4.02, p < 0.001). Conclusions: Perceived poor maternal care, maternal overprotection, and maternal overcontrol are associated with hoarding in women with OCD. Parenting dimensions are not related to hoarding in men. These findings provide further support for a hoarding subtype of OCD and for sex-specific differences in etiologic pathways for hoarding in OCD. (C) 2016 Elsevier Inc. All rights reserved. C1 [Chen, David] Loyola Univ, Dept Psychol, Baltimore, MD USA. [Bienvenu, O. Joseph; Krasnow, Janice; Wang, Ying; Grados, Marco A.; Cullen, Bernadette; Goes, Fernando S.; Riddle, Mark A.; Nestadt, Gerald; Samuels, Jack] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, 550 N Broadway 902, Baltimore, MD 21205 USA. [Maher, Brion] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. [Greenberg, Benjamin D.; McLaughlin, Nicole C.; Rasmussen, Steven A.] Butler Hosp, Dept Psychiat & Human Behav, Brown Med Sch, Providence, RI 02906 USA. [Fyer, Abby J.] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USA. [Fyer, Abby J.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Knowles, James A.] Univ Southern Calif, Dept Psychiat, Sch Med, Los Angeles, CA USA. [McCracken, James T.; Piacentini, John] Univ Calif Los Angeles, Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. [Geller, Dan] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Pauls, David L.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Pauls, David L.] Harvard Med Sch, Boston, MA USA. [Stewart, S. Evelyn] Univ British Columbia, Dept Psychiat, Fac Med, Vancouver, BC, Canada. [Murphy, Dennis L.] NIMH, Clin Sci Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Shugart, Yin-Yao] NIMH, Unit Stat Genom, Div Intramural Res, Bethesda, MD 20892 USA. RP Samuels, J (reprint author), Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, 550 N Broadway 902, Baltimore, MD 21205 USA. EM jacks@jhmi.edu FU National Institutes of Health [MH50214, MH071507, MH79487, MH079488, MH079489, MH079494, K23-MH-64543, NIH/NCRR/OPD-GCRC RR00052]; James E. Marshall OCD Foundation FX This research was supported by National Institutes of Health grants MH50214, MH071507, MH79487, MH079488, MH079489, MH079494, K23-MH-64543, NIH/NCRR/OPD-GCRC RR00052, and by the James E. Marshall OCD Foundation. The funding agencies had no role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript. NR 78 TC 0 Z9 0 U1 1 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0010-440X EI 1532-8384 J9 COMPR PSYCHIAT JI Compr. Psychiat. PD FEB PY 2017 VL 73 BP 43 EP 52 DI 10.1016/j.comppsych.2016.11.004 PG 10 WC Psychiatry SC Psychiatry GA EJ3YS UT WOS:000393149300007 PM 27915218 ER PT J AU Piper, ME Cook, JW Schlam, TR Smith, SS Bolt, DM Collins, LM Mermelstein, R Fiore, MC Baker, TB AF Piper, Megan E. Cook, Jessica W. Schlam, Tanya R. Smith, Stevens S. Bolt, Daniel M. Collins, Linda M. Mermelstein, Robin Fiore, Michael C. Baker, Timothy B. TI Toward precision smoking cessation treatment II: Proximal effects of smoking cessation intervention components on putative mechanisms of action SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Smoking cessation; Treatment; Mechanisms; Factorial design ID TOBACCO CESSATION; WITHDRAWAL SCALE; NICOTINE PATCH; CLINICAL-TRIAL; SELF-EFFICACY; BUPROPION; QUIT; VALIDATION; ABSTINENCE; REACTIVITY AB Background: Understanding how smoking cessation treatments exert their effects can inform treatment development and use. Factorial designs allow researchers to examine whether multiple intervention components affect hypothesized change mechanisms, and whether the affected mechanisms are related to cessation. Methods: This is a secondary data analysis of smokers recruited during primary care visits (N = 637, 55% women, 87% white) who were motivated to quit. Participants in this fractional factorial experiment were randomized to one level of each of six intervention factors: Prequit Nicotine Patch vs None, Pre-quit Nicotine Gum vs None, Preparation Counseling vs None, Intensive In-Person Counseling vs Minimal, Intensive Phone Counseling vs Minimal, and 16 vs 8 Weeks of Combination Nicotine Replacement (nicotine patch + nicotine gum). Data on putative mechanisms (e.g., medication use, withdrawal, self-efficacy) and smoking status were gathered using daily assessments and during follow-up assessment calls. Results: Some intervention components influenced hypothesized mechanisms. Prequit Gum and Patch each reduced prequit smoking and enhanced prequit coping and self-efficacy. In-Person Counseling increased prequit motivation to quit, postquit self-efficacy, and postquit perceived intratreatment support. Withdrawal reduction and reduced prequit smoking produced the strongest effects on cessation. The significant effect of combining Prequit Gum and In-Person Counseling on 26-week abstinence was mediated by increased prequit self-efficacy. Conclusions: This factorial experiment identified which putative treatment mechanisms were influenced by discrete intervention components and which mechanisms influenced cessation. Such information supports the combined use of prequit nicotine gum and intensive in-person counseling as cessation interventions that operate via increased prequit self-efficacy. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Piper, Megan E.; Cook, Jessica W.; Schlam, Tanya R.; Smith, Stevens S.; Fiore, Michael C.; Baker, Timothy B.] Univ Wisconsin, Sch Med & Publ Hlth, Ctr Tobacco Res & Intervent, 1930 Monroe St Suite 200, Madison, WI 53711 USA. [Piper, Megan E.; Cook, Jessica W.; Schlam, Tanya R.; Smith, Stevens S.; Fiore, Michael C.; Baker, Timothy B.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, Div Gen Internal Med, Madison, WI 53706 USA. [Cook, Jessica W.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. [Bolt, Daniel M.] Univ Wisconsin, Dept Educ Psychol, Madison, WI 53706 USA. [Collins, Linda M.] Penn State Univ, Methodol Ctr, University Pk, PA 16802 USA. [Collins, Linda M.] Penn State Univ, Dept Human Dev & Family Studies, University Pk, PA 16802 USA. [Mermelstein, Robin] Univ Illinois, Inst Hlth Res & Policy, Chicago, IL USA. RP Piper, ME (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, Ctr Tobacco Res & Intervent, 1930 Monroe St Suite 200, Madison, WI 53711 USA. EM mep@ctri.wisc.edu FU National Cancer Institute [9P50CA143188, 1K05CA139871]; Wisconsin Partnership Program; NIH [P50DA10075, R01DK097364, R01AA022931]; National Research Service Award from the Health Resources and Services Administration [T32HP10010]; US Department of Veterans Affairs [101CX00056]; NSF [DMS-1305725] FX This research was supported by grants 9P50CA143188 and 1K05CA139871 from the National Cancer Institute to the University of Wisconsin Center for Tobacco Research and Intervention and by the Wisconsin Partnership Program. Dr. Collins is also supported by NIH grants P50DA10075, R01DK097364, and R01AA022931. This work was carried out in part while Dr. Schlam was a Primary Care Research Fellow supported by a National Research Service Award (T32HP10010) from the Health Resources and Services Administration to the University of Wisconsin Department of Family Medicine. Dr. Cook is also supported by Merit Review Award 101CX00056 from the US Department of Veterans Affairs. Dr. Loh is also supported by NSF grant DMS-1305725. NR 44 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD FEB 1 PY 2017 VL 171 BP 50 EP 58 DI 10.1016/j.drugalcdep.2016.11.027 PG 9 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA EK0QA UT WOS:000393630700007 PM 28013097 ER PT J AU Piper, ME Schlam, TR Cook, JW Smith, SS Bolt, DM Loh, WY Mermelstein, R Collins, LM Fiore, MC Baker, TB AF Piper, Megan E. Schlam, Tanya R. Cook, Jessica W. Smith, Stevens S. Bolt, Daniel M. Loh, Wei-Yin Mermelstein, Robin Collins, Linda M. Fiore, Michael C. Baker, Timothy B. TI Toward precision smoking cessation treatment I: Moderator results from a factorial experiment SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Smoking cessation; Treatment; Moderators; Factorial design; Psychiatric comorbidity ID NICOTINE REPLACEMENT THERAPY; RANDOMIZED CLINICAL-TRIAL; CIGARETTE-SMOKING; PSYCHIATRIC-DISORDERS; TOBACCO WITHDRAWAL; ABSTINENCE RATES; DEPENDENCE; EFFICACY; SMOKERS; INTERVENTIONS AB Background: The development of tobacco use treatments that are effective for all smokers is critical to improving clinical and public health. The Multiphase Optimization Strategy (MOST) uses highly efficient factorial experiments to evaluate multiple intervention components for possible inclusion in an optimized tobacco use treatment. Factorial experiments permit analyses of the influence of patient characteristics on main and interaction effects of multiple, relatively discrete, intervention components. This study examined whether person-factor and smoking characteristics moderated the main or interactive effects of intervention components on 26-week self-reported abstinence rates. Methods: This fractional factorial experiment evaluated six smoking cessation intervention components among primary care patients (N = 637): Prequit Nicotine Patch vs. None, Prequit Nicotine Gum vs. None, Preparation Counseling vs. None, Intensive Cessation In-Person Counseling vs. Minimal, Intensive Cessation Telephone Counseling vs. Minimal, and 16 vs. 8 Weeks of Combination Nicotine Replacement Therapy (NRT; nicotine patch + nicotine gum). Results: Both psychiatric history and smoking heaviness moderated intervention component effects. In comparison with participants with no self-reported history of a psychiatric disorder, those with a positive history showed better response to 16- vs. 8-weeks of combination NRT, but a poorer response to counseling interventions. Also, in contrast to light smokers, heavier smokers showed a poorer response to counseling interventions. Conclusions: Heavy smokers and those with psychiatric histories demonstrated a differential response to intervention components. This research illustrates the use of factorial designs to examine the interactions between person characteristics and relatively discrete intervention components. Future research is needed to replicate these findings. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Piper, Megan E.; Schlam, Tanya R.; Cook, Jessica W.; Smith, Stevens S.; Fiore, Michael C.; Baker, Timothy B.] Univ Wisconsin, Ctr Tobacco Res & Intervent, Sch Med & Publ Hlth, 1930 Monroe St,Suite 200, Madison, WI 53711 USA. [Piper, Megan E.; Schlam, Tanya R.; Cook, Jessica W.; Smith, Stevens S.; Fiore, Michael C.; Baker, Timothy B.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, Div Gen Internal Med, Madison, WI 53706 USA. [Cook, Jessica W.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. [Bolt, Daniel M.] Univ Wisconsin, Dept Educ Psychol, Madison, WI 53706 USA. [Loh, Wei-Yin] Univ Wisconsin, Dept Stat, Madison, WI 53706 USA. [Mermelstein, Robin] Univ Illinois, Inst Hlth Res & Policy, Chicago, IL USA. [Collins, Linda M.] Penn State Univ, Methodol Ctr, University Pk, PA 16802 USA. [Collins, Linda M.] Penn State Univ, Dept Human Dev & Family Studies, University Pk, PA 16802 USA. RP Piper, ME (reprint author), Univ Wisconsin, Ctr Tobacco Res & Intervent, Sch Med & Publ Hlth, 1930 Monroe St,Suite 200, Madison, WI 53711 USA. EM mep@ctri.wisc.edu FU National Cancer Institute [9P50CA143188, 1K05CA139871]; Wisconsin Partnership Program; NIH [P50DA10075, R01 DK097364, R01AA022931]; National Research Service Award from the Health Resources and Services Administration [T32HP10010]; Merit Review Award from the US Department of Veterans Affairs [101CX00056]; NSF [DMS-1305725] FX This research was supported by grants 9P50CA143188 and 1K05CA139871 from the National Cancer Institute to the University of Wisconsin Center for Tobacco Research and Intervention and by the Wisconsin Partnership Program. Dr. Collins is also supported by NIH grants P50DA10075, R01 DK097364, and R01AA022931. This work was carried out in part while Dr. Schlam was a Primary Care Research Fellow supported by a National Research Service Award (T32HP10010) from the Health Resources and Services Administration to the University of Wisconsin Department of Family Medicine. Dr. Cook is also supported by Merit Review Award 101CX00056 from the US Department of Veterans Affairs. Dr. Loh is also supported by NSF grant DMS-1305725. NR 40 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD FEB 1 PY 2017 VL 171 BP 59 EP 65 DI 10.1016/j.drugalcdep.2016.11.025 PG 7 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA EK0QA UT WOS:000393630700008 PM 28013098 ER PT J AU Gradus, JL Leatherman, S Curreri, A Myers, LG Ferguson, R Miller, M AF Gradus, Jaimie L. Leatherman, Sarah Curreri, Andrew Myers, Lisa G. Ferguson, Ryan Miller, Matthew TI Gender differences in substance abuse, PTSD and intentional self-harm among veterans health administration patients SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Substance-related disorders; Stress disorders; Post-traumatic; Cohort studies; Veterans ID POSTTRAUMATIC-STRESS-DISORDER; SUICIDE ATTEMPT; RISK; PREDICTORS AB Background: Epidemiologic studies have reported substance abuse and posttraumatic stress disorder (PTSD) diagnoses as risk factors for suicide among Veterans Health Administration (VHA) patients. Research on risk factors for suicide may not generalize to our understanding of non-fatal intentional self harm (ISH), given the evidence that these outcomes have unique risk factors. The aims of this study were to examine (1) gender-stratified rates of non-fatal ISH in VHA patients with alcohol abuse/dependence, drug abuse/dependence, and PTSD and (2) gender-stratified interaction between alcohol abuse and dependence and drug abuse and dependence and PTSD in predicting non-fatal ISH. Methods: Participants include all VHA care users who received a PTSD diagnosis in Massachusetts from 2000 to 2008 (n=16,004) and an age- and gender-matched comparison group (n=52,502). Data were obtained from the VHA administrative registries. Results: We found evidence of stronger interactions between substance abuse diagnoses and PTSD in predicting non-fatal ISH for females than for males. The interaction contrast (IC) for alcohol abuse and dependence and PTSD in predicting non-fatal ISH among female VHA patients was 62.35/100,000 person years; for male VHA patients the comparable IC was 21.49/100,000 person-years. For female VHA patients the IC for drug abuse and dependence and PTSD predicting ISH was 256.33/100,000 person-years; no interaction was observed for male VHA patients. Conclusions: This study contributes to the scant literature on gender differences in substance abuse and PTSD among VHA patients. The findings highlight comorbid diagnoses as particularly important risk factors for non-fatal ISH among female VHA patients. Published by Elsevier Ireland Ltd. C1 [Gradus, Jaimie L.; Curreri, Andrew] VA Boston Healthcare Syst, Natl Ctr PTSD, 1505 Huntington Ave,116B-3, Boston, MA 02130 USA. [Gradus, Jaimie L.] Boston Univ, Sch Med, Dept Psychiat, 715 Albany St, Boston, MA 02118 USA. [Gradus, Jaimie L.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, 715 Albany St, Boston, MA 02118 USA. [Leatherman, Sarah] VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, 150S Huntington Ave,116B-3, Boston, MA 02130 USA. [Myers, Lisa G.] VA Boston Healthcare Syst, 940 Belmont St, Brockton, MA 02301 USA. [Myers, Lisa G.] Harvard Univ, Harvard Med Sch, Dept Psychiat, 25 Shattuck St, Boston, MA 02115 USA. [Miller, Matthew] Northeastern Univ, Dept Hlth Sci, Bouve Coll Hlth Sci, 360 Huntington Ave, Boston, MA 02115 USA. RP Gradus, JL (reprint author), 150S Huntington Ave,116B-3, Boston, MA 02130 USA. EM jaimie.gradus@va.gov FU American Foundation for Suicide Prevention [YIG-1-069-11] FX This project was supported by grant number YIG-1-069-11 to Jaimie L. Gradus, DSc, MPH from the American Foundation for Suicide Prevention. The content is solely the responsibility of the authors and does not necessarily represent the official views of the American Foundation for Suicide Prevention. NR 14 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD FEB 1 PY 2017 VL 171 BP 66 EP 69 DI 10.1016/j.drugalcdep.2016.11.012 PG 4 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA EK0QA UT WOS:000393630700009 PM 28013099 ER PT J AU Lammert, S Walker, AT Erskine, S Rao, SR Esposito, DH Ryan, ET Robbins, GK LaRocque, RC AF Lammert, Sara Walker, Allison Taylor Erskine, Stefanie Rao, Sowmya R. Esposito, Douglas H. Ryan, Edward T. Robbins, Gregory K. LaRocque, Regina C. TI Characteristics of US Travelers to Zika Virus-Affected Countries in the Americas, March 2015 October 2016 SO EMERGING INFECTIOUS DISEASES LA English DT Article ID UNITED-STATES; HEALTH-CARE; TRANSMISSION AB Zika virus has recently been introduced to the Americas and is spreading rapidly. We evaluated the characteristics of US travelers to Zika virus affected countries who were seen at Global TravEpiNet sites during March 2015 October 2016. Nearly three quarters of travelers were men or women of reproductive age. C1 [Lammert, Sara; Ryan, Edward T.; Robbins, Gregory K.; LaRocque, Regina C.] Massachusetts Gen Hosp, Travelers Advice & Immunizat Ctr, Boston, MA 02114 USA. [Walker, Allison Taylor; Erskine, Stefanie; Esposito, Douglas H.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Rao, Sowmya R.] Boston Univ, Med Ctr, Dept Surg, Boston, MA USA. [Rao, Sowmya R.] Massachusetts Gen Hosp, Biostat Ctr, Boston, MA 02114 USA. [Ryan, Edward T.; Robbins, Gregory K.; LaRocque, Regina C.] Harvard Med Sch, Boston, MA USA. RP LaRocque, RC (reprint author), Massachusetts Gen Hosp, Gray Jackson 504,55 Fruit St, Boston, MA 02114 USA. EM rclarocque@mgh.harvard.edu FU Centers for Disease Control and Prevention [U19CI000514, U01CK000175] FX This work was supported by Centers for Disease Control and Prevention Grants U19CI000514 and U01CK000175. NR 14 TC 0 Z9 0 U1 7 U2 7 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD FEB PY 2017 VL 23 IS 2 BP 324 EP 327 DI 10.3201/eid2302.161292 PG 4 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA EJ3CI UT WOS:000393088600025 PM 27926355 ER PT J AU Kelley, AS Covinsky, KE Gorges, RJ McKendrick, K Bollens-Lund, E Morrison, RS Ritchie, CS AF Kelley, Amy S. Covinsky, Kenneth E. Gorges, Rebecca J. McKendrick, Karen Bollens-Lund, Evan Morrison, R. Sean Ritchie, Christine S. TI Identifying Older Adults with Serious Illness: A Critical Step toward Improving the Value of Health Care SO HEALTH SERVICES RESEARCH LA English DT Article DE Medicare; population health; geriatrics; palliative medicine ID OF-LIFE CARE; RANDOMIZED CONTROLLED-TRIAL; PALLIATIVE CARE; END; CANCER; DISABILITY; COST AB ObjectiveTo create and test three prospective, increasingly restrictive definitions of serious illness. Data SourcesHealth and Retirement Study, 2000-2012. Study DesignWe evaluated subjects' 1-year outcomes from the interview date when they first met each definition: (A) one or more severe medical conditions (Condition) and/or receiving assistance with activities of daily living (Functional Limitation); (B) Condition and/or Functional Limitation and hospital admission in the last 12months and/or residing in a nursing home (Utilization); and (C) Condition and Functional Limitation and Utilization. Definitions are increasingly restrictive, but not mutually exclusive. Data CollectionOf 11,577 eligible subjects, 5,297 met definition A; 3,151 definition B; and 1,447 definition C. Principal FindingsOne-year outcomes were as follows: hospitalization 33 percent (A), 44 percent (B), 47 percent (C); total average Medicare costs $20,566 (A), $26,349 (B), and $30,828 (C); and mortality 13 percent (A), 19 percent (B), 28 percent (C). In comparison, among those meeting no definition, 12 percent had hospitalizations, total Medicare costs averaged $7,789, and 2 percent died. ConclusionsProspective identification of older adults with serious illness is feasible using clinically accessible criteria and may be a critical step toward improving health care value. These definitions may aid clinicians and health systems in targeting patients who could benefit from additional services. C1 [Kelley, Amy S.; McKendrick, Karen; Bollens-Lund, Evan; Morrison, R. Sean] Icahn Sch Med Mt Sinai, Brookdale Dept Geriatr & Palliat Med, 1 Gustave Levy Pl,Box 1070, New York, NY 10029 USA. [Kelley, Amy S.; Morrison, R. Sean] James J Peters VA Med Ctr, Geriatr Res Educ Ctr, Bronx, NY USA. [Kelley, Amy S.; Morrison, R. Sean] James J Peters VA Med Ctr, Ctr Clin, Bronx, NY USA. [Covinsky, Kenneth E.; Ritchie, Christine S.] Univ Calif San Francisco, Dept Med, Div Geriatr, San Francisco, CA USA. [Gorges, Rebecca J.] Univ Chicago, Harris Sch Publ Policy, Chicago, IL 60637 USA. RP Kelley, AS (reprint author), Icahn Sch Med Mt Sinai, Brookdale Dept Geriatr & Palliat Med, 1 Gustave Levy Pl,Box 1070, New York, NY 10029 USA. EM amy.kelley@mssm.edu FU National Institute on Aging (NIA) [1K23AG040774-01A1]; American Federation for Aging Research; National Palliative Care Research Center; NIA [1K07AG31779, 1K24 AG 22345-01] FX ASK receives support from the National Institute on Aging (NIA) (1K23AG040774-01A1), the American Federation for Aging Research, and the National Palliative Care Research Center. CSR receives support from the NIA (1K07AG31779). RSM receives support from the National Palliative Care Research Center and the NIA (1K24 AG 22345-01). The funding sources had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. NR 27 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0017-9124 EI 1475-6773 J9 HEALTH SERV RES JI Health Serv. Res. PD FEB PY 2017 VL 52 IS 1 BP 113 EP 131 DI 10.1111/1475-6773.12479 PG 19 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA EJ9XC UT WOS:000393579500007 PM 26990009 ER PT J AU Schussler-Fiorenza Rose, SM Stineman, MG Pan, Q Bogner, H Kurichi, JE Streim, JE Xie, DW AF Schussler-Fiorenza Rose, Sophia Miryam Stineman, Margaret G. Pan, Qiang Bogner, Hillary Kurichi, Jibby E. Streim, Joel E. Xie, Dawei TI Potentially Avoidable Hospitalizations among People at Different Activity of Daily Living Limitation Stages SO HEALTH SERVICES RESEARCH LA English DT Article DE Ambulatory care; hospitalization; primary health care; health services accessibility; disabled persons ID CARE-SENSITIVE CONDITIONS; HEALTH-CARE; ELDERLY-PEOPLE; PREVENTABLE HOSPITALIZATIONS; HOME ACCESSIBILITY; MEDICARE CLAIMS; OLDER PERSONS; UNMET NEED; DISABILITIES; COMMUNITY AB ObjectiveTo determine whether higher activity of daily living (ADL) limitation stages are associated with increased risk of hospitalization, particularly for ambulatory care sensitive (ACS) conditions. Data SourceSecondary data analysis, including 8,815 beneficiaries from 2005 to 2006 Medicare Current Beneficiary Survey (MCBS). Study DesignADL limitation stages (0-IV) were determined at the end of 2005. Hospitalization rates were calculated for 2006 and age adjusted using direct standardization. Multivariate negative binomial regression, adjusting for baseline demographic and health characteristics, with the outcome hospitalization count was performed to estimate the adjusted rate ratio of ACS and non-ACS hospitalizations for beneficiaries with ADL stages > 0 compared to beneficiaries without limitations. Data CollectionBaseline ADL stage and health conditions were assessed using 2005 MCBS data and count of hospitalization determined using 2006 MCBS data. Principal FindingsReferenced to stage 0, the adjusted rate ratios (95 percent confidence interval) for stage I to stage IV ranged from 1.9 (1.4-2.5) to 4.1 (2.2-7.8) for ACS hospitalizations compared with from 1.6 (1.3-1.9) to 1.8 (1.4-2.5) for non-ACS hospitalizations. ConclusionsHospitalization rates for ACS conditions increased more dramatically with ADL limitation stage than did rates for non-ACS conditions. Adults with ADL limitations appear particularly vulnerable to potentially preventable hospitalizations for conditions typically manageable in ambulatory settings. C1 [Pan, Qiang; Bogner, Hillary; Kurichi, Jibby E.; Xie, Dawei] Univ Penn, Ctr Clin Epidemiol & Biostat, 907 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. [Schussler-Fiorenza Rose, Sophia Miryam] Dept Vet Affairs Palo Alto Hlth Care Syst, Spinal Cord Injury & Disorders Ctr, Palo Alto, CA USA. [Schussler-Fiorenza Rose, Sophia Miryam] Stanford Univ, Sch Med, Dept Neurosurg, Stanford, CA 94305 USA. [Stineman, Margaret G.] Univ Penn, Dept Phys Med & Rehabil, Philadelphia, PA 19104 USA. [Stineman, Margaret G.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Streim, Joel E.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Streim, Joel E.] Philadelphia Vet Affairs Med Ctr, Mental Illness Res Educ & Clin Ctr, Philadelphia, PA USA. RP Kurichi, JE (reprint author), Univ Penn, Ctr Clin Epidemiol & Biostat, 907 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM jkurichi@mail.med.upenn.edu OI Schussler-Fiorenza Rose, Sophia Miryam/0000-0002-6311-6671 FU National Institute of Aging of the National Institutes of Health [AG032420-01A1, R01 AG 040105-01A1]; Ruth L. Kirschstein National Research Service Award Institutional Research Training grant [(T32) 5-T32-HD-007425]; Department of Veterans Affairs Office of Academic Affiliations Advanced Fellowship Program in Spinal Cord Injury Medicine; NIMH [MH082799, MH047447] FX This study was supported by grants from the National Institute of Aging of the National Institutes of Health (AG032420-01A1 and R01 AG 040105-01A1) for Drs. Stineman and Xie, Mr. Pan, and Ms. Kurichi. Dr. Schussler-Fiorenza Rose was supported by the Ruth L. Kirschstein National Research Service Award Institutional Research Training grant (T32) 5-T32-HD-007425 and the Department of Veterans Affairs Office of Academic Affiliations Advanced Fellowship Program in Spinal Cord Injury Medicine. Dr. Bogner was supported by NIMH grants MH082799 and MH047447. The opinions and conclusions of the authors are not necessarily those of the sponsoring agencies. NR 69 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0017-9124 EI 1475-6773 J9 HEALTH SERV RES JI Health Serv. Res. PD FEB PY 2017 VL 52 IS 1 BP 132 EP 155 DI 10.1111/1475-6773.12484 PG 24 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA EJ9XC UT WOS:000393579500008 PM 26990312 ER PT J AU Jena, AB Huang, J Fireman, B Fung, V Gazelle, S Landrum, MB Chernew, M Newhouse, JP Hsu, J AF Jena, Anupam B. Huang, Jie Fireman, Bruce Fung, Vicki Gazelle, Scott Landrum, Mary Beth Chernew, Michael Newhouse, Joseph P. Hsu, John TI Screening Mammography for Free: Impact of Eliminating Cost Sharing on Cancer Screening Rates SO HEALTH SERVICES RESEARCH LA English DT Article DE Cost sharing; mammography; Affordable Care Act ID HEALTH-INSURANCE COVERAGE; PREVENTIVE SERVICES; BREAST-CANCER; MEDICARE; BENEFITS; WOMEN; DECISIONS; DESIGN; TRIAL; PLANS AB ObjectivesTo study the impact of eliminating cost sharing for screening mammography on mammography rates in a large Medicare Advantage (MA) health plan which in 2010 eliminated cost sharing in anticipation of the Affordable Care Act mandate. Study SettingLarge MA health maintenance organization offering individual-subscriber MA insurance and employer-supplemented group MA insurance. Study DesignWe investigated the impact on breast cancer screening of a policy that eliminated a $20 copayment for screening mammography in 2010 among 53,188 women continuously enrolled from 2007 to 2012 in an individual-subscriber MA plan, compared with 42,473 women with employer-supplemented group MA insurance in the same health maintenance organization who had full screening coverage during this period. We used differences-in-differences analysis to study the impact of cost-sharing elimination on mammography rates. Principal FindingsAnnual screening rates declined over time for both groups, with similar trends pre-2010 and a slower decline after 2010 among women whose copayments were eliminated. Among women aged 65-74years in the individual-subscriber MA plan, 44.9 percent received screening in 2009 compared with 40.9 percent in 2012, while 49.5 percent of women in the employer-supplemented MA plan received screening in 2009 compared with 44.1 percent in 2012, that is, a difference-in-difference effect of 1.4 percentage points less decline in screening among women experiencing the cost-sharing elimination. Effects were concentrated among women without recent screening. There were no differences by neighborhood socioeconomic status or race/ethnicity. ConclusionsEliminating cost sharing for screening mammography was associated with modesty lower decline in screening rates among women with previously low screening adherence. C1 [Jena, Anupam B.; Landrum, Mary Beth; Chernew, Michael; Newhouse, Joseph P.] Harvard Med Sch, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. [Huang, Jie; Fireman, Bruce] Kaiser Permanente, Div Res, Oakland, CA USA. [Fung, Vicki; Hsu, John] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Gazelle, Scott] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. RP Jena, AB (reprint author), Harvard Med Sch, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. EM jena@hcp.med.harvard.edu FU National Institutes of Health [1DP5OD017897-01, R01CA164023] FX The authors report funding from the National Institutes of Health (Dr. Jena, NIH Early Independence Award, grant 1DP5OD017897-01; and Dr. Hsu, grant R01CA164023). NR 34 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0017-9124 EI 1475-6773 J9 HEALTH SERV RES JI Health Serv. Res. PD FEB PY 2017 VL 52 IS 1 BP 191 EP 206 DI 10.1111/1475-6773.12486 PG 16 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA EJ9XC UT WOS:000393579500011 PM 26990550 ER PT J AU Kashner, TM Hettler, DL Zeiss, RA Aron, DC Bernett, DS Brannen, JL Byrne, JM Cannon, GW Chang, BK Dougherty, MB Gilman, SC Holland, GJ Kaminetzky, CP Wicker, AB Keitz, SA AF Kashner, T. Michael Hettler, Debbie L. Zeiss, Robert A. Aron, David C. Bernett, David S. Brannen, Judy L. Byrne, John M. Cannon, Grant W. Chang, Barbara K. Dougherty, Mary B. Gilman, Stuart C. Holland, Gloria J. Kaminetzky, Catherine P. Wicker, Annie B. Keitz, Sheri A. TI Has Interprofessional Education Changed Learning Preferences? A National Perspective SO HEALTH SERVICES RESEARCH LA English DT Article DE Health workforce training; survey research and questionnaire design; interprofessional care; patient-centered care; VA health care system ID LEARNERS PERCEPTIONS SURVEY; RESIDENT PHYSICIANS; HEALTH-PROFESSIONS; MEDICAL-STUDENTS; CARE PRACTICE; COLLABORATION; SATISFACTION; NURSES; ATTITUDES; TEAMWORK AB ObjectiveTo assess how changes in curriculum, accreditation standards, and certification and licensure competencies impacted how medical students and physician residents value interprofessional team and patient-centered care. Primary Data SourceThe Department of Veterans Affairs Learners' Perceptions Survey (2003-2013). The nationally administered survey asked a representative sample of 56,569 U.S. medical students and physician residents, with a comparison group of 78,038 nonphysician trainees, to rate satisfaction with 28 elements, in two overall domains, describing their clinical learning experiences at VA medical centers. Study DesignValue preferences were scored as independent adjusted associations between an element (interprofessional team, patient-centered preceptor) and the respective overall domain (clinical learning environment, faculty, and preceptors) relative to a referent element (quality of clinical care, quality of preceptor). Principal FindingsPhysician trainees valued interprofessional (14 percent vs. 37 percent, p<.001) and patient-centered learning (21 percent vs. 36 percent, p<.001) less than their nonphysician counterparts. Physician preferences for interprofessional learning showed modest increases over time (2.5 percent/year, p<.001), driven mostly by internal medicine and surgery residents. Preferences did not increase with trainees' academic progress. ConclusionsDespite changes in medical education, physician trainees continue to lag behind their nonphysician counterparts in valuing experience with interprofessional team and patient-centered care. C1 [Kashner, T. Michael; Hettler, Debbie L.; Zeiss, Robert A.; Brannen, Judy L.; Chang, Barbara K.; Dougherty, Mary B.; Gilman, Stuart C.; Holland, Gloria J.; Wicker, Annie B.] Dept Vet Affairs, Off Acad Affiliat, 810 Vermont Ave, Washington, DC 20006 USA. [Kashner, T. Michael; Byrne, John M.] Loma Linda Univ, Sch Med, Loma Linda, CA USA. [Hettler, Debbie L.] Salus Univ, Penn Coll Optometry, Elkins Pk, PA USA. [Hettler, Debbie L.] Salus Univ, Coll Hlth Sci, Elkins Pk, PA USA. [Aron, David C.] Louis Stokes Cleveland DVA Med Ctr, Cleveland, OH USA. [Aron, David C.] Case Western Reserve Univ, Weatherhead Sch Management, Sch Med, Cleveland, OH 44106 USA. [Bernett, David S.] VA Med Ctr, Off Acad Affiliat, St Louis, MO USA. [Brannen, Judy L.] Virginia Commonwealth Univ, Richmond, VA USA. [Byrne, John M.] Jerry L Pettis Mem VA Med Ctr, Loma Linda, CA USA. [Cannon, Grant W.] George E Wahlen VA Med Ctr, Salt Lake City, UT USA. [Cannon, Grant W.] Univ Utah, Sch Med, Salt Lake City, UT USA. [Chang, Barbara K.] Univ New Mexico, Sch Med, Albuquerque, NM 87131 USA. [Gilman, Stuart C.] Univ Calif Irvine, Sch Med, Irvine, CA 92717 USA. [Kaminetzky, Catherine P.] VA Puget Sound Hlth Care Syst, Ctr Educ & Dev, Seattle, WA USA. [Kaminetzky, Catherine P.] Univ Washington, Sch Med, Seattle, WA USA. [Keitz, Sheri A.] Univ Massachusetts, UMass Mem Med Ctr, Dept Med, Worcester, MA 01605 USA. RP Kashner, TM (reprint author), Dept Vet Affairs, Off Acad Affiliat, 810 Vermont Ave, Washington, DC 20006 USA. EM michael.kashner@va.gov FU Office of Academic Affiliations (OAA); OAA National Evaluation Workgroup; Office of Academic Affiliations, Veterans Health Administration, Department of Veterans Affairs, Washington, DC FX Sincere gratitude is expressed for the support from the Office of Academic Affiliations (OAA), the OAA National Evaluation Workgroup (Sheri A. Keitz, M.D., Ph.D., Chair), Christopher T. Clarke, Ph.D., Terry V. Kruzan, George E. McKay, and Laura Stefanowycz of the OAA Data Management and Support Center in St. Louis, Missouri, and to the network of Designated Education Officers and Associated Chiefs of Staff for Education at VA Medical Centers. This study was supported, in part, by the Office of Academic Affiliations, Veterans Health Administration, Department of Veterans Affairs, Washington, DC. All statements and descriptions expressed herein do not necessarily reflect the opinions or positions of the Department of Veterans Affairs or its affiliated institutions. NR 66 TC 0 Z9 0 U1 5 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0017-9124 EI 1475-6773 J9 HEALTH SERV RES JI Health Serv. Res. PD FEB PY 2017 VL 52 IS 1 BP 268 EP 290 DI 10.1111/1475-6773.12485 PG 23 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA EJ9XC UT WOS:000393579500015 PM 26990439 ER PT J AU Pekary, E Sattin, A AF Pekary, E. Sattin, A. TI TRH and TRH-Like Peptide Levels Co-Vary with Reproductive and Metabolic Rhythms SO HORMONE AND METABOLIC RESEARCH LA English DT Article DE thyrotropin-releasing hormone; reproduction; metabolism ID THYROTROPIN-RELEASING-HORMONE; RAT-BRAIN; PERIPHERAL-TISSUES; CIRCADIAN-RHYTHMS; RAPID MODULATION; LEYDIG-CELLS; BODY-WEIGHT; MOUSE-LIVER; FOOD-INTAKE; EXPRESSION AB Photoperiod-synchronized rhythms in non-CSN tissues persist in total darkness. Clock genes involved in maintaining regular biorhythms within the suprachiasmatic nucleus (SCN) of the hypothalamus are expressed in extra-CNS tissues and continue periodic expression in vitro. Understanding the details of how the SCN clock is coupled with peripheral clocks is only incompletely understood and may involve a multiplicity of feedback systems. The present study is an extension of our previous work showing that brain levels of TRH (pGlu-His-Pro-NH2) and TRH-like peptides (X-TRH: pGlu-X-Pro-NH2, where "X" can be any amino acid residue) fluctuate throughout the day-night cycle. Male rats were maintained in a stable environment, lights on 6-18 h. TRH and TRH-like peptides in liver, pancreas, testis, prostate, epididymis, and heart were measured at 3, 10, 16, and 22 h. The greatest change in peptide level was a 12-fold increase for TRH in prostate at 16 h relative to the corresponding value at 3 h. The TRH, Tyr-TRH and Phe-TRH levels in liver declined steadily to about 40 % of the 3-h values by 22 h. Changes, in the order of decreasing number of significant increases (up arrow) and/or decreases (down arrow), were: testis (5 up arrow, 1 down arrow), liver (3 down arrow), epididymis (2 up arrow), prostate (1 up arrow, 1 down arrow) and heart (1 up arrow). Peptide levels in liver and testis correlated with serum leptin and serum corticosterone, respectively, which are potent releasers of these peptides. Testosterone and glucose were also highly correlated. These tripeptides may participate in the regulation of metabolic and reproductive functions, which change during the day-night cycle. C1 [Pekary, E.; Sattin, A.] VA Greater Los Angeles Healthcare Syst, Res Serv, Los Angeles, CA USA. [Pekary, E.] VA Greater Los Angeles Healthcare Syst, Ctr Ulcer Res & Educ, Los Angeles, CA USA. [Pekary, E.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [Sattin, A.] Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA USA. [Sattin, A.] Univ Calif Los Angeles, Dept Biobehav Sci, Los Angeles, CA USA. [Sattin, A.] Univ Calif Los Angeles, Brain Res Inst, Los Angeles, CA 90024 USA. RP Pekary, E (reprint author), VA Greater Los Angeles Healthcare Syst, Bldg 114,Rm 229,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM Albert.Pekary@va.gov NR 78 TC 0 Z9 0 U1 2 U2 2 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0018-5043 EI 1439-4286 J9 HORM METAB RES JI Horm. Metab. Res. PD FEB PY 2017 VL 49 IS 2 BP 86 EP 94 DI 10.1055/s-0042-111012 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EJ4XU UT WOS:000393221400002 PM 27434852 ER PT J AU Burt, LM Trifiletti, DM Nabavizadeh, N Katz, LM Morris, ZS Royce, TJ AF Burt, Lindsay M. Trifiletti, Daniel M. Nabavizadeh, Nima Katz, Leah M. Morris, Zachary S. Royce, Trevor J. TI Supply and Demand for Radiation Oncology in the United States: A Resident Perspective SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Editorial Material ID LOCALIZED PROSTATE-CANCER; WORKFORCE; BRACHYTHERAPY; FUTURE C1 [Burt, Lindsay M.] Univ Utah, Dept Radiat Oncol, Salt Lake City, UT USA. [Trifiletti, Daniel M.] Univ Virginia, Dept Radiat Oncol, Charlottesville, VA USA. [Nabavizadeh, Nima] Oregon Hlth & Sci Univ, Dept Radiat Med, Portland, OR 97201 USA. [Katz, Leah M.] NYU, Langone Med Ctr, Dept Radiat Oncol, New York, NY USA. [Morris, Zachary S.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Human Oncol, Madison, WI USA. [Royce, Trevor J.] Harvard Med Sch, Harvard Radiat Oncol Program, Boston, MA USA. RP Royce, TJ (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Harvard Radiat Oncol Program, Dept Radiat Oncol, 55 Fruit St Lunder LL2, Boston, MA 02114 USA. EM troyce@partners.org NR 34 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD FEB 1 PY 2017 VL 97 IS 2 BP 225 EP 227 DI 10.1016/j.ijrobp.2016.10.038 PG 3 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA EJ5YC UT WOS:000393294100007 PM 28068230 ER PT J AU Kabolizadeh, P Chen, YL Liebsch, N Hornicek, FJ Schwab, JH Choy, E Rosenthal, DI Niemierko, A DeLaney, TF AF Kabolizadeh, Peyman Chen, Yen-Lin Liebsch, Norbert Hornicek, Francis J. Schwab, Joseph H. Choy, Edwin Rosenthal, Daniel I. Niemierko, Andrzej DeLaney, Thomas F. TI Updated Outcome and Analysis of Tumor Response in Mobile Spine and Sacral Chordoma Treated With Definitive High-Dose Photon/Proton Radiation Therapy SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID SACROCOCCYGEAL CHORDOMA; PROGNOSTIC-FACTORS; SURGICAL-MANAGEMENT; EXPERIENCE; RADIOTHERAPY; SACRECTOMY AB Purpose: Treatment of spine and sacral chordoma generally involves surgical resection, usually in conjunction with radiation therapy. In certain circumstances where resection may result in significant neurologic or organ dysfunction, patients can be treated definitively with radiation therapy alone. Herein, we report the outcome and the assessment of tumor response to definitive radiation therapy. Methods and Materials: A retrospective analysis was performed on 40 patients with unresected chordoma treated with photon/proton radiation therapy. Nineteen patients had complete sets of imaging scans. The soft tissue and bone compartments of the tumor were defined separately. Tumor response was evaluated by the modified Response Evaluation Criteria in Solid Tumors (RECIST) and volumetric analysis. Results: With a median follow-up time of 50.3 months, the rates of 5-year local control, overall survival, disease-specific survival, and distant failure were 85.4%, 81.9%, 89.4%, and 20.2%, respectively. Eighty-four computed tomographic and magnetic resonance imaging scans were reviewed. Among the 19 patients, only 4 local failures occurred, and the median tumor dose was 77.4 GyRBE. Analysis at a median follow-up time of 18 months showed significant volumetric reduction of the total target volume (TTV) and the soft tissue target volume (STTV) within the first 24 months after treatment initiation, followed by further gradual reduction throughout the rest of the follow-up period. The median maximum percentage volumetric regressions of TTV and STTV were 43.2% and 70.4%, respectively. There was only a small reduction in bone target volume over time. In comparison with the modified RECIST, volumetric analysis was more reliable, more reproducible, and could help in measuring minimal changes in the tumor volume. Conclusion: These results continue to support the use of high-dose definitive radiation therapy for selected patients with unresected spine and sacral chordomas. Assessment of tumor response to radiation therapy by volumetric analysis is superior to modified RECIST in chordoma patients. Evaluating the soft tissue target volume is an excellent indicator of tumor response. (C) 2016 Elsevier Inc. All rights reserved. C1 [Kabolizadeh, Peyman; Chen, Yen-Lin; Liebsch, Norbert; Niemierko, Andrzej; DeLaney, Thomas F.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA USA. [Hornicek, Francis J.; Schwab, Joseph H.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Orthoped Surg, Boston, MA USA. [Choy, Edwin] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Boston, MA USA. [Rosenthal, Daniel I.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. RP Kabolizadeh, P (reprint author), Oakland Univ, William Beaumont Sch Med, William Beaumont Hosp, Dept Radiat Oncol, 3601 W 13 Mile Rd, Royal Oak, MI 48073 USA. EM peyman.kabolizadeh@beaumont.org NR 26 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD FEB 1 PY 2017 VL 97 IS 2 BP 254 EP 262 DI 10.1016/j.ijrobp.2016.10.006 PG 9 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA EJ5YC UT WOS:000393294100011 PM 27986348 ER PT J AU Verma, V Simone, CB Allen, PK Gajjar, SR Shah, C Zhen, WN Harkenrider, MM Hallemeier, CL Jabbour, SK Matthiesen, CL Braunstein, SE Lee, P Dilling, TJ Allen, BG Nichols, EM Attia, A Zeng, J Biswas, T Paximadis, P Wang, F Walker, JM Stahl, JM Daly, ME Decker, RH Hales, RK Willers, H Videtic, GMM Mehta, MP Lin, SH AF Verma, Vivek Simone, Charles B., II Allen, Pamela K. Gajjar, Sameer R. Shah, Chirag Zhen, Weining Harkenrider, Matthew M. Hallemeier, Christopher L. Jabbour, Salma K. Matthiesen, Chance L. Braunstein, Steve E. Lee, Percy Dilling, Thomas J. Allen, Bryan G. Nichols, Elizabeth M. Attia, Albert Zeng, Jing Biswas, Tithi Paximadis, Peter Wang, Fen Walker, Joshua M. Stahl, John M. Daly, Megan E. Decker, Roy H. Hales, Russell K. Willers, Henning Videtic, Gregory M. M. Mehta, Minesh P. Lin, Steven H. TI Multi-Institutional Experience of Stereotactic Ablative Radiation Therapy for Stage I Small Cell Lung Cancer SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID RADIOTHERAPY; SURGERY; CARCINOMA; TIME AB Purpose: For inoperable stage I (T1-T2N0) small cell lung cancer (SCLC), national guidelines recommend chemotherapy with or without conventionally fractionated radiation therapy. The present multi-institutional cohort study investigated the role of stereotactic ablative radiation therapy (SABR) for this population. Methods and Materials: The clinical and treatment characteristics, toxicities, outcomes, and patterns of failure were assessed in patients with histologically confirmed stage T1-T2N0M0 SCLC. Kaplan-Meier analysis was used to evaluate the survival outcomes. Univariate and multivariate analyses identified predictors of outcomes. Results: From 24 institutions, 76 lesions were treated in 74 patients (median follow-up 18 months). The median age and tumor size was 72 years and 2.5 cm, respectively. Chemotherapy and prophylactic cranial irradiation were delivered in 56% and 23% of cases, respectively. The median SABR dose and fractionation was 50 Gy and 5 fractions. The 1- and 3-year local control rate was 97.4% and 96.1%, respectively. The median disease-free survival (DFS) duration was 49.7 months. The DFS rate was 58.3% and 53.2% at 1 and 3 years, respectively. The median, 1-year, and 3-year disease-specific survival was 52.3 months, 84.5%, and 64.4%, respectively. The median, 1-year, and 3-year overall survival (OS) was 17.8 months, 69.9%, and 34.0% respectively. Patients receiving chemotherapy experienced an increased median DFS (61.3 vs 9.0 months; P = .02) and OS (31.4 vs 14.3 months; P = .02). The receipt of chemotherapy independently predicted better outcomes for DFS/OS on multivariate analysis (P = .01). Toxicities were uncommon; 5.2% experienced grade >= 2 pneumonitis. Post-treatment failure was most commonly distant (45.8% of recurrence), followed by nodal (25.0%) and "elsewhere lung" (20.8%). The median time to each was 5 to 7 months. Conclusions: From the findings of the largest report of SABR for stage T1-T2N0 SCLC to date, SABR (>= 50 Gy) with chemotherapy should be considered a standard option. (C) 2016 Published by Elsevier Inc. C1 [Verma, Vivek; Zhen, Weining] Univ Nebraska Med Ctr, Dept Radiat Oncol, Omaha, NE USA. [Simone, Charles B., II] Univ Penn, Dept Radiat Oncol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Allen, Pamela K.; Lin, Steven H.] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA. [Gajjar, Sameer R.] Baylor Coll Med, Houston, TX 77030 USA. [Shah, Chirag; Videtic, Gregory M. M.] Cleveland Clin, Dept Radiat Oncol, Taussig Canc Inst, Cleveland, OH 44106 USA. [Harkenrider, Matthew M.] Loyola Univ, Stritch Sch Med, Dept Radiat Oncol, 2160 S 1st Ave, Maywood, IL 60153 USA. [Hallemeier, Christopher L.] Mayo Clin, Dept Radiat Oncol, Rochester, MN USA. [Jabbour, Salma K.] Rutgers State Univ, Rutgers Canc Inst New Jersey, Dept Radiat Oncol, New Brunswick, NJ USA. [Matthiesen, Chance L.] Univ Oklahoma, Dept Radiat Oncol, Stephenson Canc Ctr, Oklahoma City, OK USA. [Braunstein, Steve E.] Univ Calif San Francisco, Sch Med, Dept Radiat Oncol, San Francisco, CA USA. [Lee, Percy] Univ Calif Los Angeles, David Geffen Sch Med, Dept Radiat Oncol, Los Angeles, CA 90095 USA. [Dilling, Thomas J.] H Lee Moffitt Canc Ctr & Res Inst, Dept Radiat Oncol, Tampa, FL USA. [Allen, Bryan G.] Univ Iowa Hosp & Clin, Dept Radiat Oncol, Iowa City, IA 52242 USA. [Nichols, Elizabeth M.] Univ Maryland, Med Ctr, Dept Radiat Oncol, Baltimore, MD 21201 USA. [Attia, Albert] Vanderbilt Univ, Sch Med, Dept Radiat Oncol, Nashville, TN 37212 USA. [Zeng, Jing] Univ Washington, Med Ctr, Dept Radiat Oncol, Seattle, WA 98195 USA. [Biswas, Tithi] Case Western Reserve Univ, Univ Hosp Siedman Canc Ctr, Dept Radiat Oncol, Cleveland, OH 44106 USA. [Paximadis, Peter] Wayne State Univ, Sch Med, Div Radiat Oncol, Dept Oncol,Barbara Ann Karmanos Canc Ctr, Detroit, MI USA. [Wang, Fen] Univ Kansas, Med Ctr, Dept Radiat Oncol, Kansas City, KS 66103 USA. [Walker, Joshua M.] Oregon Hlth & Sci Univ, Dept Radiat Med, Portland, OR 97201 USA. [Stahl, John M.; Decker, Roy H.] Yale Univ, Sch Med, Dept Therapeut Radiol, New Haven, CT 06510 USA. [Daly, Megan E.] Univ Calif Davis, Ctr Comprehens Canc, Dept Radiat Oncol, Sacramento, CA 95817 USA. [Hales, Russell K.] Johns Hopkins Univ, Sch Med, Dept Radiat Oncol & Mol Radiat Sci, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Willers, Henning] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Mehta, Minesh P.] Baptist Hlth South Florida, Miami Canc Inst, Coral Gables, FL USA. RP Lin, SH (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Unit 097, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM shlin@mdanderson.org OI mehta, minesh/0000-0002-4812-5713 FU Novocure; Cellectar; Elekta; STCube Pharmaceuticals; Peregrine; Roche/Genentech FX M.P.M. has served as a consultant for Abbott, Bristol-Meyers-Squibb, Celldex, Cavion, Elekta, Novartis, Novocure, and Roche, has received research funding from Novocure and Cellectar, and has served in a leadership capacity on the Pharmacyclics board of directors (with stock options). S.H.L. has received research funding from Elekta, STCube Pharmaceuticals, Peregrine, and Roche/Genentech, has served as a consultant for AstraZeneca, and has received honorarium from US Oncology and ProCure. NR 27 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 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD FEB 1 PY 2017 VL 97 IS 2 BP 362 EP 371 DI 10.1016/j.ijrobp.2016.10.041 PG 10 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA EJ5YC UT WOS:000393294100025 PM 28011047 ER PT J AU Giantsoudi, D Adams, J MacDonald, SM Paganetti, H AF Giantsoudi, Drosoula Adams, Judith MacDonald, Shannon M. Paganetti, Harald TI Proton Treatment Techniques for Posterior Fossa Tumors: Consequences for Linear Energy Transfer and Dose-Volume Parameters for the Brainstem and Organs at Risk SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID RELATIVE BIOLOGICAL EFFECTIVENESS; CENTRAL-NERVOUS-SYSTEM; THERAPY; RADIOTHERAPY AB Purpose: In proton therapy of posterior fossa tumors, at least partial inclusion of the brainstem in the target is necessary because of its proximity to the tumor and required margins. Additionally, the preferred beam geometry results in directing the field distal edge toward this critical structure, raising concerns for brainstem toxicity. Some treatment techniques place the beam's distal edge within the brainstem (dose-sparing techniques), and others avoid elevated linear energy transfer (LET) of the proton field by placing the distal edge beyond it (LET-sparing techniques). Hybrid approaches are also being used. We examine the dosimetric efficacy of these techniques, accounting for LET-dependent and dose-dependent variable relative biologic effectiveness (RBE) distributions. Methods: Six techniques were applied in ependymoma cases: (a) 3-field dose-sparing; (b) 3-field LET-sparing; (c) 2-field dose-sparing, wide angles; (d) 2-field LET-sparing, wide angles; (e) 2-field LET-sparing, steep angles; and (f) 2-field LET-sparing with feathered distal end. Monte Carlo calculated dose, LET, and RBE-weighted dose distributions were compared. Results: Decreased LET values in the brainstem by LET-sparing techniques were accompanied by higher, not statistically significant, median dose: 53.6 Gy(RBE), 53.4 Gy(RBE), and 54.3 Gy(RBE) for techniques (b), (d), and (e) versus 52.1 Gy(RBE) for technique (a). Accounting for variable RBE distributions, the brainstem volume receiving at least 55 Gy(RBE) increased from 72.5% for technique (a) to 80.3% for (b) (P<.01) and from 70.7% for technique (c) to 77.6% for (d) (P<.01). Less than 2%, but statistically significant, decrease in maximum variable RBE-weighted brainstem dose was observed for the LET-sparing techniques compared with the corresponding dose-sparing (P = .03 and .004). Conclusions: Extending the proton range beyond the brainstem to reduce LET results in clinically comparable maximum radiobiologic effective dose to this sensitive structure. However this method significantly increasing the brainstem volume receiving RBE-weighted dose higher than 55 Gy(RBE) with possible consequences based on known dose-volume parameters for increased toxicity. (C) 2016 Elsevier Inc. All rights reserved. C1 [Giantsoudi, Drosoula; Adams, Judith; MacDonald, Shannon M.; Paganetti, Harald] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Giantsoudi, D (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Francis H Burr Proton Therapy Ctr, 30 Fruit St, Boston, MA 02114 USA. EM dgiantsoudi@mgh.harvard.edu FU National Cancer Institute of the National Institutes of Health [U19 CA021239]; Proton Therapy Research and Treatment Center [C06 CA059267] FX Supported by the National Cancer Institute of the National Institutes of Health under Award Number U19 CA021239 and the Federal Share of program income earned by Massachusetts General Hospital on C06 CA059267, Proton Therapy Research and Treatment Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 15 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD FEB 1 PY 2017 VL 97 IS 2 BP 401 EP 410 DI 10.1016/j.ijrobp.2016.09.042 PG 10 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA EJ5YC UT WOS:000393294100029 PM 27986346 ER PT J AU Hom, MA Chu, C Schneider, ME Lim, IC Hirsch, JK Gutierrez, PM Joiner, TE AF Hom, Melanie A. Chu, Carol Schneider, Matthew E. Lim, Ingrid C. Hirsch, Jameson K. Gutierrez, Peter M. Joiner, Thomas E. TI Thwarted belongingness as an explanatory link between insomnia symptoms and suicidal ideation: Findings from three samples of military service members and veterans SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Insomnia; Suicidal ideation; Loneliness; Thwarted belongingness; Military; Veterans ID COGNITIVE-BEHAVIORAL THERAPY; INTERPERSONAL-PSYCHOLOGICAL THEORY; OLDER-ADULTS; PERCEIVED BURDENSOMENESS; ANXIETY SENSITIVITY; EMOTION-REGULATION; SLEEP DISTURBANCE; YOUNG-ADULTS; US ARMY; NEEDS QUESTIONNAIRE AB Background: Although insomnia has been identified as a robust predictor of suicidal ideation and behaviors, little is known about the mechanisms by which sleep disturbances confer risk for suicide. We investigated thwarted belongingness as an explanatory link between insomnia symptoms and suicidal ideation across three military service member and veteran samples. Methods: Data were collected among United States military service members and veterans (N-1=937, N-2=3,386, N-3=417) who completed self-report measures of insomnia symptoms, thwarted belongingness, suicidal ideation, and related psychiatric symptoms (e.g., anxiety, hopelessness). Bias-corrected bootstrap mediation analyses were utilized to examine the indirect effects of insomnia symptoms on suicidal ideation through thwarted belongingness, controlling for related psychiatric symptoms. Results: Consistent with study hypotheses, thwarted belongingness significantly accounted for the relationship between insomnia and suicidal ideation across all three samples; however, insomnia symptoms did not significantly account for the relationship between thwarted belongingness and suicidal ideation, highlighting the specificity of our findings. Limitations: This study utilized cross-sectional self-report data. Conclusions: Insomnia may confer suicide risk for military service members and veterans, in part, through the pathway of thwarted belongingness. Additional prospective studies are warranted to further delineate this model of risk. Our results offer a potential therapeutic target for the prevention of suicide, via the promotion of belongingness, among service members and veterans experiencing insomnia symptoms. C1 [Hom, Melanie A.; Chu, Carol; Schneider, Matthew E.; Joiner, Thomas E.] Florida State Univ, Dept Psychol, Tallahassee, FL 32306 USA. [Lim, Ingrid C.] Off Army Surg Gen, New York, NY USA. [Hirsch, Jameson K.] East Tennessee State Univ, Dept Psychol, Johnson City, TN 37614 USA. [Gutierrez, Peter M.] Denver Vet Affairs Med Ctr, Educ & Clin Ctr, Rocky Mt Mental Illness Res, Denver, CO USA. [Gutierrez, Peter M.] Univ Colorado, Sch Med, Dept Psychiat, Boulder, CO 80309 USA. RP Hom, MA (reprint author), Florida State Univ, Dept Psychol, Tallahassee, FL 32306 USA. EM hom@psy.fsu.edu FU NIMH NIH HHS [T32 MH093311] NR 92 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 EI 1573-2517 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD FEB PY 2017 VL 209 BP 114 EP 123 DI 10.1016/j.jad.2016.11.032 PG 10 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA EJ5EW UT WOS:000393241400019 PM 27898373 ER PT J AU Ibrahim, NE Gaggin, HK Rabideau, DJ Gandhi, PU Mallick, A Januzzi, JL AF Ibrahim, Nasrien E. Gaggin, Hanna K. Rabideau, Dustin J. Gandhi, Parul U. Mallick, Aditi Januzzi, James L., Jr. TI Worsening Renal Function during Management for Chronic Heart Failure with Reduced Ejection Fraction: Results From the Pro-BNP Outpatient Tailored Chronic Heart Failure Therapy (PROTECT) Study SO JOURNAL OF CARDIAC FAILURE LA English DT Article DE Heart failure; biomarkers; renal failure ID VENTRICULAR SYSTOLIC DYSFUNCTION; NATRIURETIC-PEPTIDE-MEASUREMENTS; CARDIORENAL SYNDROME; CYSTATIN C; CKD-EPI; EQUATIONS; OUTCOMES; DESIGN; KIDNEY; RISK AB Objectives: To assess prognostic meaning of worsening renal failure (WRF) occurring during management of chronic heart failure (HF) with reduced ejection fraction. Background: When WRF develops during titration of HF medical therapy, it commonly leads to less aggressive care. Methods: A total of 151 patients enrolled in a prospective, randomized study of standard of care (SOC) HF therapy versus SOC plus a goal N-terminal pro-B type natriuretic peptide (NT-proBNP) <1000 pg/mL were examined. Cardiovascular (CV) event (defined as worsening HF, hospitalization for HF, significant ventricular arrhythmia, acute coronary or cerebral ischemia, or CV death) at 1 year relative to WRF (defined as any reduction in estimated glomerular filtration rate) 90 days postenrollment were tabulated. Results: Those developing WRF by 3 months had an average 14% reduction in estimated glomerular filtration rate. There was no difference in incidence of WRF between study arms (43% in SOC, 57% in NT-proBNP, P=.29). During the first 3 months of therapy titration, incident WRF was associated with numerically fewer CV events at 1 year compared with those without WRF (mean 0.81 vs 1.16 events, P=.21). WRF was associated trend toward fewer CV events in the SOC arm (hazard ratio 0.45, 95% confidence interval 0.16-1.24, P=.12); the NT-proBNP-guided arm had numerically lower CV event rates regardless of WRF. Subjects with NT-proBNP <1000 pg/mL and WRF received higher doses of guideline directed medical therapies, lower doses of loop diuretics, and had significantly lower CV event rates (P<.001). Conclusions: Modest degrees of WRF are common during aggressive HF with reduced ejection fraction management, but we found no significant association with CV outcomes. HF care guided by NT-proBNP was not associated with more WRF compared with SOC, and led to benefit regardless of final renal function. C1 [Ibrahim, Nasrien E.; Gaggin, Hanna K.; Mallick, Aditi; Januzzi, James L., Jr.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Ibrahim, Nasrien E.; Gaggin, Hanna K.; Januzzi, James L., Jr.] Harvard Clin Res Inst, Boston, MA USA. [Rabideau, Dustin J.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Gandhi, Parul U.] Yale Univ, Sch Med, Div Cardiol, Vet Adm Connecticut Healthcare Syst, New Haven, CT USA. RP Januzzi, JL (reprint author), Massachusetts Gen Hosp, 32 Fruit St,Yawkey 5984, Boston, MA 02114 USA. EM jjanuzzi@partners.org FU Dennis and Marilyn Barry Fellowship in Cardiology; Ruth and James Clark Fund for Cardiac Research Innovation; Hutter Family Professorship in Cardiology FX Dr. Ibrahim is supported by the Dennis and Marilyn Barry Fellowship in Cardiology. Dr. Gaggin is supported in part by the Ruth and James Clark Fund for Cardiac Research Innovation. Dr. Januzzi is supported in part by the Hutter Family Professorship in Cardiology. NR 24 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 EI 1532-8414 J9 J CARD FAIL JI J. Card. Fail. PD FEB PY 2017 VL 23 IS 2 BP 121 EP 130 DI 10.1016/j.cardfail.2016.07.440 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EJ9GT UT WOS:000393535300006 PM 27469482 ER PT J AU Xie, K Gelfman, L Horton, JR Goldstein, NE AF Xie, Kira Gelfman, Laura Horton, Jay R. Goldstein, Nathan E. TI State of Research on Palliative Care in Heart Failure as Evidenced by Published Literature, Conference Proceedings, and NIH Funding SO JOURNAL OF CARDIAC FAILURE LA English DT Article DE Heart failure; aging; morbidity; palliative care ID QUANTITY; MEDICINE AB Background: Heart failure (HF) is the most common diagnosis in hospitalized patients older than 65 years of age. Although these patients often need specialist-directed palliative care, <10% ever receive these services. This may be due to a lack of evidence examining the benefits of palliative care for these patients. To understand the current state of research on the interface of palliative care and HF, we examined trends in publications, presentations at national meetings, and National Institutes of Health (NIH) funding. Methods: Using key terms, we identified items about palliative care and HF in the following sources: (1) the tables of contents of nine leading cardiology journals, (2) abstracts of conference proceedings from four cardiology societies, and (3) all NIH grants from 2009 to 2013. Results: Of the journals reviewed, fewer than 1% of their publications related to palliative care. Less than 2% of HF-related sessions in conference proceedings mentioned palliative care. Of the NIH's $45 billion directed to HF research, only $14 million (0.03%) was spent on palliative care research. Conclusions: Despite calls for improving palliative care for patients with advanced HF, a lack of sufficient attention persists in research abstracts, concurrent sessions at national meetings, and NIH funding to increase the evidence base. Without these improvements, the ability to deliver high-quality specialist palliative care to patients with HF and their families will remain severely limited. C1 [Xie, Kira] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Gelfman, Laura; Horton, Jay R.; Goldstein, Nathan E.] Icahn Sch Med Mt Sinai, Dept Geriatr & Palliat Med, Box 1070,One Gustave Levy Pl, New York, NY 10029 USA. [Gelfman, Laura; Goldstein, Nathan E.] James J Peters VA Med Ctr, Geriatr Res & Clin Care Ctr, Bronx, NY USA. RP Goldstein, NE (reprint author), Icahn Sch Med Mt Sinai, Dept Geriatr & Palliat Med, Box 1070,One Gustave Levy Pl, New York, NY 10029 USA. EM Nathan.Goldstein@mssm.edu FU Patricia S. Levinson Summer Fellowship from Icahn School of Medicine at Mount Sinai; Mount Sinai Claude D Pepper Older Americans Independence Center (National Institute on Aging) [2P30AG028741]; National Heart Lung and Blood Institute [5R01HL102084-05]; NIA [1 K23 AG049930-01A1] FX Ms. Xie was supported by a Patricia S. Levinson Summer Fellowship from Icahn School of Medicine at Mount Sinai. Drs. Goldstein, Horton, and Gelfman were supported by the Mount Sinai Claude D Pepper Older Americans Independence Center (National Institute on Aging 2P30AG028741). Dr. Goldstein was also supported by the National Heart Lung and Blood Institute (5R01HL102084-05) and Dr. Gelfman by the NIA (1 K23 AG049930-01A1). The content does not represent the views of the National Institutes of Health or the Veterans Affairs Health System. NR 13 TC 1 Z9 1 U1 1 U2 1 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 EI 1532-8414 J9 J CARD FAIL JI J. Card. Fail. PD FEB PY 2017 VL 23 IS 2 BP 197 EP 200 DI 10.1016/j.cardfail.2016.10.013 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EJ9GT UT WOS:000393535300014 PM 27989871 ER PT J AU Freedman, RA Foster, JC Seisler, DK Lafky, JM Muss, HB Cohen, HJ Mandelblatt, J Winer, EP Hudis, CA Partridge, AH Carey, LA Cirrincione, C Moreno-Aspitia, A Kimmick, G Jatoi, A Hurria, A AF Freedman, Rachel A. Foster, Jared C. Seisler, Drew K. Lafky, Jacqueline M. Muss, Hyman B. Cohen, Harvey J. Mandelblatt, Jeanne Winer, Eric P. Hudis, Clifford A. Partridge, Ann H. Carey, Lisa A. Cirrincione, Constance Moreno-Aspitia, Alvaro Kimmick, Gretchen Jatoi, Aminah Hurria, Arti TI Accrual of Older Patients With Breast Cancer to Alliance Systemic Therapy Trials Over Time: Protocol A151527 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID GROWTH-FACTOR RECEPTOR; PHASE-III TRIAL; PACLITAXEL PLUS TRASTUZUMAB; COOPERATIVE-ONCOLOGY-GROUP; ADJUVANT CHEMOTHERAPY; CLINICAL-TRIALS; POSTMENOPAUSAL WOMEN; RANDOMIZED-TRIAL; ENDOCRINE THERAPY; UNITED-STATES AB Purpose Despite increasing awareness of accrual challenges, it is unknown if accrual of older patients to breast cancer treatment trials is improving. Methods We examined accrual of older patients to Alliance for Clinical Trials in Oncology systemic therapy breast cancer trials during 1985-2012 and compared disease characteristics and reasons for therapy cessation for older (age >= 65 years and >= 70 years) versus younger (age, 65 years and, 70 years) participants. To examine accrual trends, we modeled age as a function of time, using logistic regression. Results Overall, 17% of study participants were >= 65 years of age. Approximately 15%, 24%, and 24% of participants in adjuvant, neoadjuvant, and metastatic trials were age >= 65 years, and 7%, 15%, and 13% were age >= 70 years, respectively. The odds of a patient age >= 65 years enrolling significantly increased over time for adjuvant trials (odds ratio [OR] per year, 1.04; 95% CI, 1.04 to 1.05) but decreased significantly for neoadjuvant and metastatic trials (OR, 0.62; 95% CI, 0.58 to 0.67 and OR, 0.98, 95% CI, 0.97 to 1.00). Similar trends were seen for those age >= 70 years but these were statistically significant for adjuvant and neoadjuvant trials only (OR, 1.05, 95% CI, 1.04 to 1.07; and OR, 0.57, 95% CI, 0.52 to 0.62). In general, those age >= 65 years (v those, 65 years) in adjuvant studies had a higher mean number of lymph nodes involved and more hormone receptor-negative tumors, although tumor sizes were similar. Early protocol treatment cessation was also more frequent in those age >= 65 years (50%) versus, 65 years (35.9%) across trials. Conclusion Older patients with breast cancer remain largely underrepresented in cooperative group therapeutic trials. We observed some improvement in accrual to adjuvant trials but worsening of accrual for neoadjuvant/metastatic trials. Novel strategies to increase accrual of older patients are critical to meaningfully change the evidence base for this growing patient population. (C) 2016 by American Society of Clinical Oncology C1 [Freedman, Rachel A.; Winer, Eric P.; Partridge, Ann H.] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. [Foster, Jared C.; Seisler, Drew K.; Lafky, Jacqueline M.; Jatoi, Aminah] Mayo Clin, Rochester, MN USA. [Foster, Jared C.; Seisler, Drew K.] Mayo Canc Ctr, Rochester, MN USA. [Muss, Hyman B.; Carey, Lisa A.] Univ N Carolina, Chapel Hill, NC USA. [Cohen, Harvey J.; Cirrincione, Constance; Kimmick, Gretchen] Duke Univ, Durham, NC USA. [Mandelblatt, Jeanne] Georgetown Univ, Washington, DC USA. [Hudis, Clifford A.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Moreno-Aspitia, Alvaro] Mayo Clin, Jacksonville, FL 32224 USA. [Hurria, Arti] City Hope Natl Med Ctr, Duarte, CA USA. RP Freedman, RA (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM rafreedman@partners.org FU National Cancer Institute [UG1CA189823, U10CA032291, U10CA047559, U10CA047577, U10CA077597, U10CA077651, U10CA180790, U10CA180791, U10CA180838, U10CA180857, U10CA180867]; Susan G. Komen Foundation; American Cancer Society FX Supported by the National Cancer Institute under Awards No. UG1CA189823 (Alliance for Clinical Trials in Oncology NCORP Grant), U10CA032291, U10CA047559, U10CA047577, U10CA077597, U10CA077651, U10CA180790, U10CA180791, U10CA180838, U10CA180857, and U10CA180867. R.A.F. also receives funding from the Susan G. Komen Foundation and American Cancer Society. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 62 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2017 VL 35 IS 4 BP 421 EP + DI 10.1200/JCO.2016.69.4182 PG 13 WC Oncology SC Oncology GA EJ4JJ UT WOS:000393182600007 PM 27992272 ER PT J AU Kumar, P Wright, AA Hatfield, LA Temel, JS Keating, NL AF Kumar, Pallavi Wright, Alexi A. Hatfield, Laura A. Temel, Jennifer S. Keating, Nancy L. TI Family Perspectives on Hospice Care Experiences of Patients with Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID OF-LIFE CARE; EARLY PALLIATIVE CARE; CELL LUNG-CANCER; MENTAL-HEALTH; END; QUALITY; DEATH; PLACE; ASSOCIATION; PERCEPTIONS AB Purpose To determine whether hospice use by patients with cancer is associated with their families' perceptions of patients' symptoms, goal attainment, and quality of end-of-life (EOL) care. Methods We interviewed 2,307 families of deceased patients with advanced lung or colorectal cancer who were enrolled in the Cancer Care Outcomes Research and Surveillance study (a multiregional, prospective, observational study) and died by 2011. We used propensity-score matching to compare family-reported outcomes for patients who did and did not receive hospice care, including the presence and relief of common symptoms (ie, pain, dyspnea), concordance with patients' wishes for EOL care and place of death, and quality of EOL care. We also examined associations between hospice length of stay and these outcomes among hospice enrollees. Results In a propensity-score-matched sample of 1,970 individuals, families of patients enrolled in hospice reported more pain in their patient compared with those not enrolled in hospice. However, families of patients enrolled in hospice more often reported that patients received "just the right amount" of pain medicine (80% v 73%; adjusted difference, 7 percentage points; 95% confidence interval [CI], 1 to 12 percentage points) and help with dyspnea (78% v 70%; adjusted difference, 8 percentage points; 95% CI, 2 to 13 percentage points). Families of patients enrolled in hospice also more often reported that patients' EOL wishes were followed (80% v 74%; adjusted difference, 6 percentage points; 95% CI, 2 to 11 percentage points) and "excellent" quality EOL care (57% v 42%; adjusted difference, 15 percentage points; 95% CI, 11 to 20). Families of patients who received. 30 days of hospice care reported the highest quality EOL outcomes. Conclusion Hospice care is associated with better symptom relief, patient-goal attainment, and quality of EOL care. Encouraging earlier and increased hospice enrollment may improve EOL experiences for patients with cancer and their families. (C) 2016 by American Society of Clinical Oncology C1 [Kumar, Pallavi] Univ Penn, Philadelphia, PA 19104 USA. [Wright, Alexi A.; Hatfield, Laura A.; Temel, Jennifer S.; Keating, Nancy L.] Harvard Med Sch, Boston, MA USA. [Keating, Nancy L.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. RP Wright, AA (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM alexi_wright@dfci.harvard.edu FU National Institutes of Health, National Cancer Institute (NCI) Cancer Care Outcomes Research and Surveillance (CanCORS) Consortium [U01 CA093344, U01 CA093324, U01 CA093332, U01 CA093348, U01 CA093329, U01 CA093326, R01 CA1604021]; NCI [5U01CA093344-08, K07 CA166210, K24 CA181510] FX This work was supported by the National Institutes of Health, National Cancer Institute (NCI) Cancer Care Outcomes Research and Surveillance (CanCORS) Consortium (Grants no. U01 CA093344 to Dana-Farber Cancer Institute; U01 CA093324 to Harvard Medical School and Northern California Cancer Center; U01 CA093332 to Dana-Farber Cancer Institute and Cancer Research Network; U01 CA093348 to RAND Corporation and University of California, Los Angeles; U01 CA093329 to University of Alabama at Birmingham; U01 CA093339 to University of Iowa; U01 CA093326 to University of North Carolina; and R01 CA1604021 to N.L.K.). The CanCORS II work was funded by Grant no. 5U01CA093344-08 from the NCI to the CanCORS Consortium Statistical Coordinating CenterA.A.W. is supported by Grant no. K07 CA166210 from the NCI. N.L.K. is also supported by Grant no. K24 CA181510 from the NCI. NR 33 TC 0 Z9 0 U1 7 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 FEB 1 PY 2017 VL 35 IS 4 BP 432 EP + DI 10.1200/JCO.2016.68.9257 PG 11 WC Oncology SC Oncology GA EJ4JJ UT WOS:000393182600008 PM 27992271 ER PT J AU Weinberg, OK Hasserjian, RP Li, B Pozdnyakova, O AF Weinberg, Olga K. Hasserjian, Robert P. Li, Betty Pozdnyakova, Olga TI Assessment of myeloid and monocytic dysplasia by flow cytometry in de novo AML helps define an AML with myelodysplasia-related changes category SO JOURNAL OF CLINICAL PATHOLOGY LA English DT Article ID CELL TRANSPLANTATION; LEUKEMIA; EXPRESSION; PROGNOSIS; RELEVANCE; PREDICTS; SYSTEM; IMPACT; CD11B AB Aims In recent years, multiparameter flow cytometry has been increasingly recognised as an important tool in diagnosis of myelodysplastic syndrome and acute myeloid leukaemia (AML). Assessment of myeloid and monocytic 'immunophenotypic' dysplasia by flow cytometry in de novo AML has not been evaluated. Methods 97 cases of de novo AML cases were identified and reviewed by three hematopathologists. 'Immunophenotypic' dysplasia was assessed on blasts, monocytes and granulocytes by mean fluorescence intensity. Results Using the 2008 WHO classification criteria, there were 53 AML-not otherwise specified (NOS) (55%) and 28 AML with myelodysplasia-related changes (AML-MRC) (29%), while 16 cases were ambiguous as to AML-MRC status due to limited maturing cells for morphologic but adequate events number for immunophenotypic evaluation (AML-not evaluable, 16%). Compared with AML-NOS, granulocytic cells in AML-MRC had higher CD33 expression but lower CD45, CD11b and CD15. Monocytes in AML-MRC had lower expression of CD14, CD56 and CD45. Morphologic dysplasia was associated with significantly lower granulocytic forward scatter, side scatter and CD10 but higher CD33 expression. Conclusions Our results suggest that the workup of AML cases should include flow cytometric assessment of granulocytes and monocytes. This analysis can aid a morphologic impression of multilineage dysplasia in distinguishing AML-MRC from AML-NOS, especially in cases with limited maturing myeloid cells. C1 [Weinberg, Olga K.] Boston Childrens Hosp, Dept Pathol, 300 Longwood Ave,Bader 126, Boston, MA 02115 USA. [Hasserjian, Robert P.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Li, Betty; Pozdnyakova, Olga] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. RP Weinberg, OK (reprint author), Boston Childrens Hosp, Dept Pathol, 300 Longwood Ave,Bader 126, Boston, MA 02115 USA. EM Olga.Weinberg@childrens.harvard.edu NR 21 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0021-9746 EI 1472-4146 J9 J CLIN PATHOL JI J. Clin. Pathol. PD FEB PY 2017 VL 70 IS 2 BP 109 EP 115 DI 10.1136/jclinpath-2016-203863 PG 7 WC Pathology SC Pathology GA EJ6JG UT WOS:000393324700004 PM 27387988 ER PT J AU Kuye, IO Smith, GP AF Kuye, Ifedayo O. Smith, Gideon P. TI The Use of Rituximab in the Management of Refractory Dermatomyositis SO JOURNAL OF DRUGS IN DERMATOLOGY LA English DT Article ID POLYMYOSITIS; THERAPY; TRIAL AB There is growing adoption of rituximab in the treatment of dermatomyositis patients whose disease is refractory to steroids. However, the effects have not been extensively studied. This is a retrospective study of 25 patients with dermatomyositis who were treated with rituximab. Data from January 2000 to July 2014 was obtained from a clinical data repository, which yielded results from two tertiary centers in the United States. We analyzed information on muscle weakness, skin disease, enzyme levels, and immunosuppressive medication use before and after treatment with rituximab. The follow-up time was six months. Among the patients with skin disease before treatment with rituximab, 72.2% had a clinical improvement in their skin disease at the follow-up visit (P<0.01). Among the patients with proximal muscle weakness before treatment with rituximab, 81.8% had clinical improvement in their symptoms at the follow-up visit (P<0.01). The average prednisone dose before rituximab therapy was 18.9 mg, and this dropped to 11.0 mg at follow up (P<0.05). The average number of immunosuppressive medications taken by patients dropped from 2.04 to 1.74 (P<0.05). These changes were less in magnitude and significance among the subset of patient that had an additional connective tissue autoimmune condition. C1 [Kuye, Ifedayo O.] Harvard Med Sch, Boston, MA 02115 USA. [Smith, Gideon P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Kuye, IO (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM Ifedaya_kuye@hms.harvard.edu NR 14 TC 0 Z9 0 U1 1 U2 1 PU JOURNAL OF DRUGS IN DERMATOLOGY PI NEW YORK PA 377 PARK AVE SOUTH, 6TH FLOOR, NEW YORK, NY 10016 USA SN 1545-9616 J9 J DRUGS DERMATOL JI J. Drugs Dermatol. PD FEB PY 2017 VL 16 IS 2 BP 162 EP 166 PG 5 WC Dermatology SC Dermatology GA EJ6XG UT WOS:000393363600010 PM 28300859 ER PT J AU Poterucha, JJ Friedman, LS AF Poterucha, John J. Friedman, Lawrence S. TI Evaluation of abnormal liver biochemical test results: Does the hare finally beat the tortoise? SO JOURNAL OF HEPATOLOGY LA English DT Editorial Material C1 [Poterucha, John J.] Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN USA. [Friedman, Lawrence S.] Newton Wellesley Hosp, Dept Med, Newton, MA USA. [Friedman, Lawrence S.] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [Friedman, Lawrence S.] Tufts Univ, Sch Med, Boston, MA 02111 USA. RP Poterucha, JJ (reprint author), Div Gastroenterol & Hepatol, Mayo 9,200 First St SW, Rochester, MN 55905 USA. EM Poterucha.john@mayo.edu NR 11 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 EI 1600-0641 J9 J HEPATOL JI J. Hepatol. PD FEB PY 2017 VL 66 IS 2 BP 273 EP 274 DI 10.1016/j.jhep.2016.09.017 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EJ5MC UT WOS:000393261200003 PM 27789236 ER PT J AU Ma, JT Hwang, SJ Pedley, A Massaro, JM Hoffmann, U Chung, RT Benjamin, EJ Levy, D Fox, CS Long, MT AF Ma, Jiantao Hwang, Shih-Jen Pedley, Alison Massaro, Joseph M. Hoffmann, Udo Chung, Raymond T. Benjamin, Emelia J. Levy, Daniel Fox, Caroline S. Long, Michelle T. TI Bi-directional analysis between fatty liver and cardiovascular disease risk factors SO JOURNAL OF HEPATOLOGY LA English DT Article DE Non-alcoholic fatty liver; Type 2 diabetes; Hypertension; Hypertriglyceridemia; Impaired fasting glucose; Metabolic syndrome; Cardiovascular disease risk factors ID METABOLIC SYNDROME; INSULIN-RESISTANCE; NONALCOHOLIC STEATOHEPATITIS; CARDIOMETABOLIC RISK; DIABETES-MELLITUS; ADIPOSE-TISSUE; VISCERAL FAT; HEART; ASSOCIATION; AMINOTRANSFERASE AB Background & Aims: The relations of non-alcoholic fatty liver disease to cardiovascular disease (CVD) risk factors are not fully understood. The objective of our study is to explore the bidirectional relationships of fatty liver to CVD risk factors. Methods: We prospectively evaluated whether liver fat predicted the development of CVD risk factors and whether CVD risk factors predicted new onset fatty liver during 6 years of follow-up in middle- to older-aged Framingham Heart Study participants. We estimated liver fat using multi-detector computed tomography. Results: We included 1051 participants (mean age 45 +/- 6 years, 46% women). The prevalence of fatty liver was 18% at baseline. In participants without fatty liver at baseline, 101 participants developed incident fatty liver over approximately 6 years. Baseline liver fat (per standard deviation increase) was associated with increased odds of incident hypertension (OR 1.42; 95% CI 1.15-1.76; p = 0.001) and incident type 2 diabetes (OR 1.43; 95% CI 1.09-1.88, p <0.001). In a parallel analysis, individuals with hypertension (OR 3.34; 95% CI 2.04-5.49), hypertriglyceridemia (OR 3.04; 95% CI: 1.84-5.02), impaired fasting glucose (OR 2.92; 95% CI 1.76-4.82), or type 2 diabetes (OR 4.15; 95% CI 1.19-14.46) at baseline had higher odds of incident fatty liver compared to individuals without those conditions (all p <0.03). In both analyses, the observed associations remained similar after additional adjustments for measures of adiposity. Conclusions: The present study demonstrated bi-directional relationships between fatty liver and CVD risk factors among middle- to older-aged Framingham Heart Study participants. Lay summary: It is not fully understood whether non-alcoholic fatty liver (NAFLD) disease precedes or develops after increased cardiovascular disease (CVD) risk factors. The findings of our study suggest a bi-directional relationship between NAFLD and CVD risk factors. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. C1 [Ma, Jiantao; Hwang, Shih-Jen; Pedley, Alison; Massaro, Joseph M.; Benjamin, Emelia J.; Levy, Daniel; Fox, Caroline S.] NHLBI, Framingham Heart Study, Div Intramural Res, Framingham, MA USA. [Ma, Jiantao; Hwang, Shih-Jen; Pedley, Alison; Massaro, Joseph M.; Levy, Daniel; Fox, Caroline S.] NHLBI, Populat Sci Branch, Div Intramural Res, Framingham, MA USA. [Massaro, Joseph M.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Hoffmann, Udo] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Chung, Raymond T.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Liver, Gastrointestinal Div, Boston, MA USA. [Benjamin, Emelia J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Evans Dept Med, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol & Metab, 75 Francis St, Boston, MA 02115 USA. [Fox, Caroline S.] Harvard Med Sch, Boston, MA USA. [Long, Michelle T.] Boston Univ, Sch Med, Evans Dept Med, Div Gastroenterol, Boston, MA 02118 USA. RP Long, MT (reprint author), Boston Univ, Sch Med, Sect Gastroenterol, 85 East Concord St 7th Floor, Boston, MA 02118 USA. EM mtlong@bu.edu FU NHLBI FHS [N01-HC-25195, HHSN268201500001I]; [2R01 HL092577]; [R01 HL128914]; [K24 DK078772] FX This work was conducted in part using resources and data from the Framingham Heart Study (FHS) of the National Heart, Lung, and Blood Institute (NHLBI) of the National Institute of Health and Boston University School of Medicine. This work was supported by the NHLBI FHS (N01-HC-25195; HHSN268201500001I). Dr. Benjamin is supported in part by 2R01 HL092577 and R01 HL128914. Dr. Chung is supported in part by K24 DK078772. NR 42 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 EI 1600-0641 J9 J HEPATOL JI J. Hepatol. PD FEB PY 2017 VL 66 IS 2 BP 390 EP 397 DI 10.1016/j.jhep.2016.09.022 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EJ5MC UT WOS:000393261200018 PM 27729222 ER PT J AU Tsai, PC Huang, CF Yu, ML AF Tsai, Pei-Chien Huang, Chung-Feng Yu, Ming-Lung TI Unexpected early tumor recurrence in patients with hepatitis C virus-related hepatocellular carcinoma undergoing interferon-free therapy: Issue of the interval between HCC treatment and antiviral therapy SO JOURNAL OF HEPATOLOGY LA English DT Letter C1 [Tsai, Pei-Chien; Huang, Chung-Feng; Yu, Ming-Lung] Kaohsiung Med Univ Hosp, Dept Internal Med, Hepatobiliary Div, 100 Tzyou 1st Rd, Kaohsiung 807, Taiwan. [Tsai, Pei-Chien; Huang, Chung-Feng; Yu, Ming-Lung] Kaohsiung Med Univ Hosp, Hepatitis Ctr, Kaohsiung, Taiwan. [Huang, Chung-Feng; Yu, Ming-Lung] Kaohsiung Med Univ, Coll Med, Sch Med, Fac Internal Med, Kaohsiung, Taiwan. [Huang, Chung-Feng; Yu, Ming-Lung] Kaohsiung Med Univ, Coll Med, Sch Med, Hepatitis Res Ctr, Kaohsiung, Taiwan. [Yu, Ming-Lung] Harvard Med Sch, Massachusetts Gen Hosp, Div Gastroenterol, Ctr Liver, Boston, MA USA. RP Yu, ML (reprint author), Kaohsiung Med Univ Hosp, Dept Internal Med, Hepatobiliary Div, 100 Tzyou 1st Rd, Kaohsiung 807, Taiwan. EM fish6069@gmail.com NR 3 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 EI 1600-0641 J9 J HEPATOL JI J. Hepatol. PD FEB PY 2017 VL 66 IS 2 BP 464 EP 464 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EJ5MC UT WOS:000393261200029 PM 27840227 ER PT J AU Matsuda, S Movila, A Suzuki, M Kajiya, M Wisitrasameewong, W Kayai, R Hirshfeld, J Al-Dharrab, A Savitri, IJ Mira, A Kurihara, H Taubman, MA Kawai, T AF Matsuda, S. Movila, A. Suzuki, M. Kajiya, M. Wisitrasameewong, W. Kayai, R. Hirshfeld, J. Al-Dharrab, A. Savitri, I. J. Mira, A. Kurihara, H. Taubman, M. A. Kawai, T. TI A novel method of sampling gingival crevicular fluid from a mouse model of periodontitis (vol 438, pg 21, 2016) SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Correction C1 [Matsuda, S.; Movila, A.; Suzuki, M.; Kajiya, M.; Wisitrasameewong, W.; Hirshfeld, J.; Savitri, I. J.; Taubman, M. A.; Kawai, T.] Forsyth Inst, Dept Immunol & Infect Dis, Cambridge, MA 02142 USA. [Matsuda, S.; Kajiya, M.; Kurihara, H.] Hiroshima Univ, Fac Dent, Dept Periodontol, Hiroshima, Japan. [Suzuki, M.] Ohio State Univ, Coll Dent, Columbus, OH 43210 USA. [Wisitrasameewong, W.; Kawai, T.] Harvard Univ, Harvard Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. [Wisitrasameewong, W.] Chulalongkorn Univ, Fac Dent, Dept Periodontol, Bangkok, Thailand. [Kayai, R.; Al-Dharrab, A.; Mira, A.] King Abdulaziz Univ, Fac Dent, Jeddah, Saudi Arabia. [Hirshfeld, J.] Univ Birmingham, Dept Restorat Dent, Birmingham, W Midlands, England. [Savitri, I. J.] Univ Airlangga, Fac Med Dent, Dept Periodontol, Jawa Timor, Indonesia. RP Kawai, T (reprint author), Forsyth Inst, Dept Immunol & Infect Dis, Cambridge, MA 02142 USA. EM tkawai@forsyth.org NR 1 TC 0 Z9 0 U1 0 U2 0 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 FEB PY 2017 VL 441 BP 72 EP 72 DI 10.1016/j.jim.2017.01.004 PG 1 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA EJ5IG UT WOS:000393250400010 PM 28129826 ER PT J AU Chu, CJ Chan, A Song, D Staley, KJ Stufflebeam, SM Kramer, MA AF Chu, Catherine J. Chan, Arthur Song, Dan Staley, Kevin J. Stufflebeam, Steven M. Kramer, Mark A. TI A semi-automated method for rapid detection of ripple events on interictal voltage discharges in the scalp electroencephalogram SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE EEG; High frequency oscillations; Ripples; Automated detection ID HIGH-FREQUENCY OSCILLATIONS; INTRACRANIAL EEG RECORDINGS; MEDIAL TEMPORAL-LOBE; 80-500 HZ; NEOCORTICAL EPILEPSY; FOCAL SEIZURES; IN-VITRO; SLEEP; BRAIN; GENERATION AB Background: High frequency oscillations are emerging as a clinically important indicator of epileptic networks. However, manual detection of these high frequency oscillations is difficult, time consuming, and subjective, especially in the scalp EEG, thus hindering further clinical exploration and application. Semi-automated detection methods augment manual detection by reducing inspection to a subset of time intervals. We propose a new method to detect high frequency oscillations that co-occur with interictal epileptiform discharges. New method: The new method proceeds in two steps. The first step identifies candidate time intervals during which high frequency activity is increased. The second step computes a set of seven features for each candidate interval. These features require that the candidate event contain a high frequency oscillation approximately sinusoidal in shape, with at least three cycles, that co-occurs with a large amplitude discharge. Candidate events that satisfy these features are stored for validation through visual analysis. Results: We evaluate the detector performance in simulation and on ten examples of scalp EEG data, and show that the proposed method successfully detects spike-ripple events, with high positive predictive value, low false positive rate, and high intra-rater reliability. Comparison with existing method: The proposed method is less sensitive than the existing method of visual inspection, but much faster and much more reliable. Conclusions: Accurate and rapid detection of high frequency activity increases the clinical viability of this rhythmic biomarker of epilepsy. The proposed spike-ripple detector rapidly identifies candidate spike ripple events, thus making clinical analysis of prolonged, multielectrode scalp EEG recordings tractable. (C) 2016 Elsevier B.V. All rights reserved. C1 [Chu, Catherine J.; Song, Dan; Staley, Kevin J.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Chan, Arthur] Voci Technol Inc, 6301 Forbes Ave 120, Pittsburgh, PA 15217 USA. [Stufflebeam, Steven M.] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Stufflebeam, Steven M.] MIT, Inst Med Engn & Sci, Harvard MIT Program Hlth Sci & Technol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Kramer, Mark A.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. RP Chu, CJ (reprint author), 175 Cambridge St,Ste 340, Boston, MA 02114 USA. EM cjchu@mgh.harvard.edu FU National Institutes of Health [P41RR14075, 1S10RR031599]; NINDS [K23NS092923, 5R01NS069696, R01NS095369, R01NS072023]; National Science Foundation DMS [1451384]; National Science Foundation CBET [1141995] FX This work was supported by the National Institutes of Health [Award Numbers P41RR14075, 1S10RR031599]; NINDS [Award Numbers K23NS092923, 5R01NS069696, R01NS095369, and R01NS072023]; the National Science Foundation DMS [Award #1451384], CBET [Award #1141995]]. We thank Wenting Xie, Rebecca Weiss, Erin Ross, Emily Thorn, and Lauren Ostrowski for assistance with clinical subject recruitment and data collection. NR 49 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 EI 1872-678X J9 J NEUROSCI METH JI J. Neurosci. Methods PD FEB 1 PY 2017 VL 277 BP 46 EP 55 DI 10.1016/j.jneumeth.2016.12.009 PG 10 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA EJ6RL UT WOS:000393346400005 PM 27988323 ER PT J AU Xu, LW Li, A Swinney, C Babu, M Veeravagu, A Wolfe, SQ Nahed, BV Ratliff, JK AF Xu, Linda W. Li, Amy Swinney, Christian Babu, Maya Veeravagu, Anand Wolfe, Stacey Quintero Nahed, Brian V. Ratliff, John K. CA Council State Neurosurg Soc TI An assessment of data and methodology of online surgeon scorecards SO JOURNAL OF NEUROSURGERY-SPINE LA English DT Article DE orthopedic surgery; surgeon ratings; Consumers' Checkbook; ProPublica; website ID SPINE SURGERY; PERIOPERATIVE COMPLICATIONS; HIP FRACTURE; POSTOPERATIVE COMPLICATIONS; PREOPERATIVE DIAGNOSIS; JOINT REPLACEMENT; KNEE ARTHROPLASTY; CLINICAL ARTICLE; LUMBAR SPINE; OUTCOME DATA AB OBJECTIVE Recently, 2 surgeon rating websites (Consumers' Checkbook and ProPublica) were published to allow the public to compare surgeons through identifying surgeon volume and complication rates. Among neurosurgeons and orthopedic surgeons, only cervical and lumbar spine, hip, and knee procedures were included in this assessment. METHODS The authors examined the methodology of each website to assess potential sources of inaccuracy. Each online tool was queried for reports on neurosurgeons specializing in spine surgery and orthopedic surgeons specializing in spine, hip, or knee surgery. Surgeons were chosen from top-ranked hospitals in the US, as recorded by a national consumer publication ranking system, within the fields of neurosurgery and orthopedic surgery. The results were compared for accuracy and surgeon representation, and the results of the 2 websites were also compared. RESULTS The methodology of each site was found to have opportunities for bias and limited risk adjustment. The end points assessed by each site were actually not complications, but proxies of complication occurrence. A search of 510 surgeons (401 orthopedic surgeons [79%] and 109 neurosurgeons [21%]) showed that only 28% and 56% of surgeons had data represented on Consumers' Checkbook and ProPublica, respectively. There was a significantly higher chance of finding surgeon data on ProPublica (p < 0.001). Of the surgeons from top-ranked programs with data available, 17% were quoted to have high complication rates, 13% with lower volume than other surgeons, and 79% had a 3-star out of 5-star rating. There was no significant correlation found,between the number of stars a surgeon received on Consumers' Checkbook and his or her adjusted complication rate on ProPublica. CONCLUSIONS Both the Consumers' Checkbook and ProPublica websites have significant methodological issues. Neither site assessed complication occurrence, but rather readmissions or prolonged length of stay. Risk adjustment was limited or nonexistent. A substantial number of neurosurgeons and orthopedic surgeons from top-ranked hospitals have no ratings on either site, or have data that suggests they are low-volume surgeons or have higher complication rates. Consumers' Checkbook and ProPublica produced different results with little correlation between the 2 websites in how surgeons were graded. Given the significant methodological issues, incomplete data, and lack of appropriate risk stratification of patients, the featured websites may provide erroneous information to the public. C1 [Xu, Linda W.; Li, Amy; Swinney, Christian; Veeravagu, Anand; Ratliff, John K.] Stanford Univ, Sch Med, Dept Neurosurg, Palo Alto, CA 94304 USA. [Babu, Maya] Mayo Clin, Dept Neurosurg, Rochester, MN USA. [Wolfe, Stacey Quintero] Wake Forest Univ, Bowman Gray Sch Med, Dept Neurosurg, Winston Salem, NC USA. [Nahed, Brian V.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. RP Ratliff, JK (reprint author), Stanford Univ, Sch Med, Dept Neurosurg, 300 Pasteur Dr, Stanford, CA 94305 USA. EM jratliff@stanford.edu FU Congress of State Neurological Surgeons Socioeconomic Fellowship FX This work was supported by a Congress of State Neurological Surgeons Socioeconomic Fellowship to Dr. Xu. NR 39 TC 0 Z9 0 U1 3 U2 3 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 1547-5654 EI 1547-5646 J9 J NEUROSURG-SPINE JI J. Neurosurg.-Spine PD FEB PY 2017 VL 26 IS 2 BP 235 EP 242 DI 10.3171/2016.7.SPINE16183 PG 8 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA EJ3CL UT WOS:000393088900015 PM 27661563 ER PT J AU Adams, JM Kelly, L AF Adams, Jeffrey M. Kelly, Lesly TI The Influence of Emerging Nursing Administrative and Leadership Researchers An Interview With Dr Lesly Kelly SO JOURNAL OF NURSING ADMINISTRATION LA English DT Editorial Material ID COMPASSION SATISFACTION; CARE NURSES; FATIGUE; BURNOUT C1 Arizona State Univ, Coll Nursing & Hlth Innovat, Workforce Outcomes Res & Leadership Dev Inst, Phoenix, AZ USA. Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Adams, JM (reprint author), Arizona State Univ, Coll Nursing & Hlth Innovat, 550 North 3rd St,Bldg Hlth North,Ste 538, Phoenix, AZ 85004 USA. EM jeffrey.m.adams@asu.edu NR 6 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0002-0443 EI 1539-0721 J9 J NURS ADMIN JI J. Nurs. Adm. PD FEB PY 2017 VL 47 IS 2 BP 79 EP 81 DI 10.1097/NNA.0000000000000442 PG 3 WC Nursing SC Nursing GA EJ7ZK UT WOS:000393441000004 PM 28106678 ER PT J AU Hickman, SE Hammes, BJ Torke, AM Sudore, RL Sachs, GA AF Hickman, Susan E. Hammes, Bernard J. Torke, Alexia M. Sudore, Rebecca L. Sachs, Greg A. TI The Quality of Physician Orders for Life-Sustaining Treatment Decisions: A Pilot Study SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Article DE advance directives; bioethics; geriatric palliative care end-of-life; nursing home ID TREATMENT PROGRAM; ADVANCE DIRECTIVES; TREATMENT PREFERENCES; NURSING FACILITIES; SERIOUS ILLNESS; CARE; STABILITY AB Background: Physician Orders for Life-Sustaining Treatment (POLST) forms are used to document patient treatment preferences as medical orders. Prior research demonstrates that use of POLST alters medical treatments in a way that is consistent with the POLST orders. However, there are minimal data about the quality of POLST decisions, including whether they reflect the current preferences of well-informed patients. Objective: Evaluate the quality of POLST decisions. Design: Chart abstraction; interviews. Subjects: Nursing home residents and healthcare agents of incapacitated nursing home residents (n = 28). Measurements: Characteristics of the POLST conversation were assessed. Brief vignettes were used to assess knowledge about how POLST orders guide medical treatment. Current treatment preferences were elicited and compared with the patient's POLST orders to assess discordance. Results: A majority (59%) of participants recognized the POLST form. Participants were generally accurate in their knowledge of how POLST orders guide treatment concerning cardiopulmonary resuscitation (CPR) (68%), antibiotics (74%), and artificial nutrition (79%), but less so for medical interventions (50%). Current treatment preferences were initially discordant with one or more POLST orders for 64% (18/28) of participants, but half of these discordances were resolved with further discussion (e. g., participant agreed with the existing order). Discordance by treatment decision was as follows: CPR (7%), level of medical intervention (18%), antibiotics (21%), and artificial nutrition (11%). Conclusions: Discordance between current preferences and POLST orders is complex. Interventions are needed to support high-quality POLST decisions that are informed and concordant with current preferences. C1 [Hickman, Susan E.] Indiana Univ, Sch Nursing, Dept Community & Hlth Syst, 600 Barnhill Dr,E419, Indianapolis, IN 46204 USA. [Hickman, Susan E.; Torke, Alexia M.; Sachs, Greg A.] Indiana Univ Purdue Univ Indianapolis, RESPECT Res Palliat & End of Life Commun & Traini, Indianapolis, IN USA. [Hammes, Bernard J.] Respecting Choices, Gundersen Hlth Syst, La Crosse, WI USA. [Torke, Alexia M.; Sachs, Greg A.] Indiana Univ Sch Med, Dept Gen Internal Med & Geriatr, Indianapolis, IN 46202 USA. [Torke, Alexia M.; Sachs, Greg A.] Indiana Univ, Ctr Aging Res, Indianapolis, IN 46204 USA. [Torke, Alexia M.; Sachs, Greg A.] Regenstrief Inst Hlth Care, Indianapolis, IN USA. [Sudore, Rebecca L.] Univ Calif San Francisco, Dept Med, Div Geriatr, San Francisco, CA 94143 USA. [Sudore, Rebecca L.] San Francisco VA Med Ctr, San Francisco, CA USA. RP Hickman, SE (reprint author), Indiana Univ, Sch Nursing, Dept Community & Hlth Syst, 600 Barnhill Dr,E419, Indianapolis, IN 46204 USA. EM hickman@iu.edu FU Indiana University School of Nursing Center for Enhancing Quality of Life in Chronic Illness FX This pilot research was funded by a grant from the Indiana University School of Nursing Center for Enhancing Quality of Life in Chronic Illness. The authors thank research assistant Rachel Podoski, MPH, for her assistance with data collection and oversight of the study. The authors are very grateful to the residents, family members, and nursing facilities that participated in this study. NR 29 TC 1 Z9 1 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1096-6218 EI 1557-7740 J9 J PALLIAT MED JI J. Palliat. Med. PD FEB PY 2017 VL 20 IS 2 BP 155 EP 162 DI 10.1089/jpm.2016.0059 PG 8 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EI9PC UT WOS:000392839600010 PM 27802064 ER PT J AU Leonard, MM Weir, DC DeGroote, M Mitchell, PD Singh, P Silvester, JA Leichtner, AM Fasano, A AF Leonard, Maureen M. Weir, Dascha C. DeGroote, Maya Mitchell, Paul D. Singh, Prashant Silvester, Jocelyn A. Leichtner, Alan M. Fasano, Alessio TI Value of IgA tTG in Predicting Mucosal Recovery in Children With Celiac Disease on a Gluten-Free Diet SO JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION LA English DT Article DE coeliac; duodenal; pediatric; remission; serology ID PEDIATRIC-GASTROENTEROLOGY; CHANGING PATTERN; FOLLOW-UP; DIAGNOSIS; RISK; PREVALENCE; GUIDELINES; MANAGEMENT; HEPATOLOGY; NUTRITION AB Objectives: Our objective was to determine the rate of mucosal recovery in pediatric patients with celiac disease on a gluten-free diet. We also sought to determine whether immunoglobulin A tissue transglutaminase (tTG) correlates with mucosal damage at the time of a repeat endoscopy with duodenal biopsy in these patients. Methods: We performed a retrospective chart review of 103 pediatric patients, younger than 21 years, with a diagnosis of celiac disease defined as Marsh 3 histology, and who underwent a repeat endoscopy with duodenal biopsy at least 12 months after initiating a gluten-free diet. Results: We found that 19% of pediatric patients treated with a gluten-free diet had persistent enteropathy. At the time of the repeat biopsy, tTG was elevated in 43% of cases with persistent enteropathy and 32% of cases in which there was mucosal recovery. Overall the positive predictive value of the autoantibody tTG was 25% and the negative predictive value was 83% in patients on a gluten-free diet for a median of 2.4 years. Conclusions: Nearly 1 in 5 children with celiac disease in our population had persistent enteropathy despite maintaining a gluten-free diet and immunoglobulin A tTG was not an accurate marker of mucosal recovery. Neither the presence of symptoms nor positive serology were predictive of a patient's histology at the time of repeat biopsy. These findings suggest a revisitation of monitring and management criteria of celiac disease in childhood. C1 [Leonard, Maureen M.; Fasano, Alessio] Harvard Med Sch, Dept Pediat Gastroenterol & Nutr, MassGen Hosp Children, Boston, MA USA. [Leonard, Maureen M.; Weir, Dascha C.; DeGroote, Maya; Silvester, Jocelyn A.; Leichtner, Alan M.; Fasano, Alessio] Harvard Med Sch, Celiac Res Program, Boston, MA USA. [Weir, Dascha C.; DeGroote, Maya; Silvester, Jocelyn A.; Leichtner, Alan M.] Boston Childrens Hosp, Div Gastroenterol & Nutr, Boston, MA USA. [Mitchell, Paul D.] Boston Childrens Hosp, Clin Res Ctr, Boston, MA USA. [Singh, Prashant] Massachusetts Gen Hosp, Dept Med, Boston, MA USA. [Silvester, Jocelyn A.] Univ Manitoba, Winnipeg, MB, Canada. RP Leonard, MM (reprint author), Massachusetts Gen Hosp Children, Dept Pediat, Div Pediat Gastroenterol Hepatol & Nutr, 175 Cambridge St,CPZ 575, Boston, MA 02114 USA. EM mleonard7@mgh.harvard.edu FU Harvard Digestive Disease Center HDDC (NIH/NIDDK) [5 P30 DK34854]; Harvard Catalyst \ The Harvard Clinical and Translational Science Center (NCRR, NIH) [UL1 TR001102]; Harvard Catalyst \ The Harvard Clinical and Translational Science Center (NCATS, NIH) [UL1 TR001102]; Harvard University; academic health care centers FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was conducted with support from the Harvard Digestive Disease Center HDDC (NIH/NIDDK, 5 P30 DK34854) and the Harvard Catalyst vertical bar The Harvard Clinical and Translational Science Center (NCRR and NCATS, NIH Award UL1 TR001102) and financial contributions from Harvard University and its affiliated academic health care centers. NR 30 TC 1 Z9 1 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0277-2116 EI 1536-4801 J9 J PEDIATR GASTR NUTR JI J. Pediatr. Gastroenterol. Nutr. PD FEB PY 2017 VL 64 IS 2 BP 286 EP 291 DI 10.1097/MPG.0000000000001460 PG 6 WC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics SC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics GA EJ5KL UT WOS:000393256800023 PM 28112686 ER PT J AU Hall, DL Lattie, EG Milrad, SF Czaja, S Fletcher, MA Klimas, N Perdomo, D Antoni, MH AF Hall, Daniel L. Lattie, Emily G. Milrad, Sara F. Czaja, Sara Fletcher, Mary Ann Klimas, Nancy Perdomo, Dolores Antoni, Michael H. TI Telephone-administered versus live group cognitive behavioral stress management for adults with CFS SO JOURNAL OF PSYCHOSOMATIC RESEARCH LA English DT Article DE CFS; Perceived stress; Cognitive behavioral stress management; Symptoms; Post-exertional malaise; Telehealth ID CHRONIC-FATIGUE-SYNDROME; RANDOMIZED CONTROLLED-TRIAL; FACE-TO-FACE; GRADED-EXERCISE; PRIMARY-CARE; PSYCHOSOCIAL INTERVENTION; COST-EFFECTIVENESS; CHILDHOOD TRAUMA; PACE TRIAL; THERAPY AB Objective: Chronic fatigue syndrome (CFS) symptoms have been shown to be exacerbated by stress and ameliorated by group-based psychosocial interventions such as cognitive behavioral stress management (CBSM). Still, patients may have difficulty attending face-to-face groups. This study compared the effects of a telephone-delivered (T-CBSM) vs a live (L-CBSM) group on perceived stress and symptomology in adults with CFS. Methods: Intervention data from 100 patients with CFS (mean age 50 years; 90% female) participating in T-CBSM (N = 56) or L-CBSM (N = 44) in previously conducted randomized clinical trials were obtained. Perceived Stress Scale (PSS) and the Centers for Disease Control and Prevention symptom checklist scores were compared with repeated measures analyses of variance in adjusted and unadjusted analyses. Results: Participants across groups showed no differences in most demographic and illness variables at study entry and had similar session attendance. Both conditions showed significant reductions in PSS scores, with L-CBSM showing a large effect (partial epsilon(2) = 0.16) and T-CBSM a medium effect (partial epsilon(2) = 0.095). For CFS symptom frequency and severity scores, L-CBSM reported large effect size improvements (partial epsilon(2) = 0.19-0.23), while T-CBSM showed no significant changes over time. Conclusions: Two different formats for delivering group-based CBSM live and telephone showed reductions in perceived stress among patients with CFS. However, only the live format was associated with physical symptom improvements, with specific effects on post-exertional malaise, chills, fever, and restful sleep. The added value of the live group format is discussed, along with implications for future technology-facilitated group interventions in this population. (C) 2016 Elsevier Inc. All rights reserved. C1 [Hall, Daniel L.; Lattie, Emily G.; Milrad, Sara F.; Antoni, Michael H.] Univ Miami, Dept Psychol, POB 248185, Coral Gables, FL 33124 USA. [Hall, Daniel L.] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [Hall, Daniel L.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Boston, MA USA. [Lattie, Emily G.] Northwestern Univ, Ctr Behav Intervent Technol CBITs, Chicago, IL USA. [Czaja, Sara; Perdomo, Dolores; Antoni, Michael H.] Univ Miami, Dept Psychiat & Behav Sci, Miami, FL USA. [Fletcher, Mary Ann; Klimas, Nancy] Nova Southeastern Univ, Inst Neuro Immune Med, Davie, FL USA. RP Hall, DL (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, One Bowdoin Sq,7th Floor, Boston, MA 02114 USA. EM dhall7@mgh.harvard.edu FU National Institutes of Health [5R01NS055672]; National Center for Complementary and Integrative Health at the National Institutes of Health [T32AT000051] FX Michael H. Antoni, the principal investigator of this study, as well as Daniel L. Hall, Emily G. Lathe, Sara Czaja, Mary Ann Fletcher, Nancy Klimas, and Dolores Perdomo received funding for this study through the National Institutes of Health (5R01NS055672). DIE was subsequently supported by an institutional National Research Service Award (T32AT000051) from the National Center for Complementary and Integrative Health at the National Institutes of Health. The authors report no conflicts of interest. NR 60 TC 0 Z9 0 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3999 EI 1879-1360 J9 J PSYCHOSOM RES JI J. Psychosomat. Res. PD FEB PY 2017 VL 93 BP 41 EP 47 DI 10.1016/j.jpsychores.2016.12.004 PG 7 WC Psychiatry SC Psychiatry GA EJ5PT UT WOS:000393270900007 PM 28107891 ER PT J AU Borsari, B Apodaca, TR Yurasek, A Monti, PM AF Borsari, Brian Apodaca, Timothy R. Yurasek, Ali Monti, Peter M. TI Does mental status impact therapist and patient communication in emergency department brief interventions addressing alcohol use? SO JOURNAL OF SUBSTANCE ABUSE TREATMENT LA English DT Article DE Motivational interviewing; Emergency departments; Mental status; Alcohol use; Brief intervention ID TRAUMATIC BRAIN-INJURY; RANDOMIZED CONTROLLED-TRIAL; CLIENT CHANGE TALK; CARE; LANGUAGE; CONSUMPTION; METAANALYSIS; ADOLESCENTS; MECHANISMS; DISORDERS AB Motivational interviewing (MI) is often incorporated into screening, brief intervention, and referral to treatment (SBIRT) interventions in critical care settings to address alcohol and other drug use. However, cognitive status has been linked to differential response to MI sessions in emergency department (ED) settings. The current study examined one possible explanation for this differential response: whether higher versus lower mental status impacts patient response to clinician statements during MI sessions conducted in an ED. Participants were 126 patients receiving an MI-based single-session alcohol brief intervention, and 13 therapists who provided treatment. Participants completed a mental status exam (MSE) as part of the screening process. Intervention sessions were audio-taped, and transcribed and coded using the Motivational Interviewing Skills Code (MISC 2.0; Miller, Moyers, Ernst, & Amrhein, 2003). The MISC 2.0 coded therapist behaviors that are related to the use of motivational interviewing, and patient language reflecting movement toward (change talk) or away from (sustain talk) changing personal alcohol use. Overall, patients responded in a similar manner to therapist MI behaviors regardless of high versus low level of mental functioning at the time of the intervention. Group differences emerged on patient response to only three specific therapist skills: giving information, open questions, and complex reflection. Thus, the differential effects of SBIRT in critical care settings do not appear to be a result of differences in the therapist and patient communication process. (C) 2016 Elsevier Inc. All rights reserved. C1 [Borsari, Brian] San Francisco VA Med Ctr, Mental Hlth Serv 116B, 4150 Clement St, San Francisco, CA 94121 USA. [Borsari, Brian; Yurasek, Ali; Monti, Peter M.] Brown Univ, Dept Behav & Social Sci, Box G-S121-4, Providence, RI 02912 USA. [Borsari, Brian; Yurasek, Ali; Monti, Peter M.] Brown Univ, Ctr Alcohol & Addict Studies, Box G-S121-4, Providence, RI 02912 USA. [Borsari, Brian] Univ Calif San Francisco, Dept Psychiat, 401 Parnassus Ave, San Francisco, CA 94143 USA. [Apodaca, Timothy R.] Childrens Mercy Kansas City, 2401 Gillham Rd, Kansas City, MO 64108 USA. [Apodaca, Timothy R.] Univ Missouri, Kansas City Sch Med, 3901 Rainbow Blvd, Kansas City, KS 66103 USA. RP Borsari, B (reprint author), San Francisco VA Med Ctr 116B, Bldg 8,Room 108,4150 Clement St, San Francisco, CA 94121 USA. EM Brian.Borsari.sfva.ucsf@gmail.com FU National Institute on Alcohol Abuse and Alcoholism [R01AA017427, K23AA015595, K05AA019681]; National Institute on Drug Abuse [T32 DA016184]; VISN1 Career Development Award [V1CDA2012-18] FX This manuscript was the result of a symposium presented at the Research Society on Alcoholism in June 2014 (Drs. Sayko-Adams, Organizer/Chair, Dr. Douglas Zatzick, Chair, Dr. Alana Conti, and Dr. Dennis Donovan, Discussant). This work was supported by National Institute on Alcohol Abuse and Alcoholism grants R01AA017427 to B. Borsari K23AA015595 to T. Apodaca, K05AA019681 to P. Monti, National Institute on Drug Abuse grant T32 DA016184 to A. Yurasek, and VISN1 Career Development Award V1CDA2012-18 to B. Borsari. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Alcohol Abuse and Alcoholism or the National Institutes of Health, or the Department of Veterans Affairs or the United States Government. The authors would like to thank the patients and therapists from the parent intervention trial who allowed their audiotapes to be utilized for this study. We also wish to acknowledge the efforts of our diligent team of coders. NR 50 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0740-5472 J9 J SUBST ABUSE TREAT JI J. Subst. Abus. Treat. PD FEB PY 2017 VL 73 BP 1 EP 8 DI 10.1016/j.jsat.2016.10.002 PG 8 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA EJ5OJ UT WOS:000393267300001 PM 28017179 ER PT J AU Bensley, KM Harris, AHS Gupta, S Rubinsky, AD Jones-Webb, R Glass, JE Williams, EC AF Bensley, Kara M. Harris, Alex H. S. Gupta, Shalini Rubinsky, Anna D. Jones-Webb, Rhonda Glass, Joseph E. Williams, Emily C. TI Racial/ethnic differences in initiation of and engagement with addictions treatment among patients with alcohol use disorders in the veterans health administration SO JOURNAL OF SUBSTANCE ABUSE TREATMENT LA English DT Article DE Treatment; Alcohol use disorder; Race; Ethnicity; Utilization, veterans ID SUBSTANCE-ABUSE TREATMENT; SCREENING SCORES; UNITED-STATES; CARE-SYSTEM; OUTPATIENT TREATMENT; PERFORMANCE-MEASURES; RACIAL DISPARITIES; PUBLIC-HEALTH; AFFAIRS; RISK AB Objective: Specialty addictions treatment can improve outcomes for patients with alcohol use disorders (AUD). Thus, initiation of and engagement with specialty addictions treatment are considered quality care for patients with AUD. Previous studies have demonstrated racial/ethnic differences in alcohol-related care but whether differences exist in initiation of and engagement with specialty addictions treatment among patients with clinically recognized alcohol use disorders is unknown. We investigated racial/ethnic variation in initiation of and engagement with specialty addictions treatment in a national sample of Black, Hispanic, and White patients with clinically recognized alcohol use disorders (AUD) from the US Veterans Health Administration (VA). Methods: National VA data were extracted for all Black, Hispanic, and White patients with a diagnosed AUD during fiscal year 2012. Mixed effects regression models estimated the odds of two measures of initiation (an initial visit within 180 days of diagnosis; and initiation defined consistent with Healthcare Effectiveness Data and Information Set (HEDIS) as a documented visit <= 14 days after index visit or inpatient admission), and three established measures of treatment engagement (>= 3 visits within first month after initiation; >= 2 visits in each of the first 3 months after initiation; and >= 2 visits within 30 days of HEDIS initiation) for Black and Hispanic relative to White patients after adjustment for facility- and patient-level characteristics. Results: Among 302,406 patients with AUD, 30% (90,879) initiated treatment within 180 days of diagnosis (38% Black, 32% Hispanic, and 27% White). Black patients were more likely to initiate treatment than Whites for both measures of initiation [odds ratio (OR) for initiation: 1.4, 95% confidence interval (CI) 1.41.4; OR for HEDIS initiation: 1.1, 95% CI: 1.11.1]. Hispanic patients were more likely than White patients to initiate treatment within 180 days (OR: 1.2, 95% CI 1.21.3) but HEDIS initiation did not differ between Hispanic and White patients. Engagement results varied depending on the measure but was more likely for Black patients relative to White for all measures (OR for engagement in first month: 1.1, 95% CI: 1.01.1; OR for engagement in first three months: 1.2, 95% CI: 1.11.2; OR for HEDIS measure: 1.1, 95% CI: 1.01.1), and did not differ between Hispanic and White patients. Conclusions: After accounting for facility- and patient-level characteristics, Black and Hispanic patients with AUD were more likely than Whites to initiate specialty addictions treatment, and Black patients were more likely than Whites to engage. Research is needed to understand underlying mechanisms and whether differences in initiation of and engagement with care influence health outcomes. Published by Elsevier Inc. C1 [Bensley, Kara M.; Williams, Emily C.] Univ Washington, Dept Hlth Serv, Magnuson Hlth Sci Ctr, 1959 NE Pacific St,Room H-680,Box 357660, Seattle, WA 98195 USA. [Bensley, Kara M.; Williams, Emily C.] Vet Hlth Adm VA, Denver Seattle Ctr Innovat Vet Ctr Value Driven C, VA Puget Sound Hlth Care Syst, 1660 S Columbian Way,Mailstop S-152, Seattle, WA 98108 USA. [Harris, Alex H. S.; Gupta, Shalini; Rubinsky, Anna D.] VA Palo Alto Hlth Care Syst, Ctr Innovat Implementat, 795 Willow Rd,152 MPD, Menlo Pk, CA 94025 USA. [Jones-Webb, Rhonda] Univ Minnesota, Dept Epidemiol & Community Hlth, 1300 South Second St,Suite 300, Minneapolis, MN 55454 USA. [Glass, Joseph E.] Univ Wisconsin, 307 Sch Social Work,1350 Univ Ave, Madison, WI 53706 USA. RP Bensley, KM (reprint author), Univ Washington, Dept Hlth Serv, Magnuson Hlth Sci Ctr, 1959 NE Pacific St,Room H-680,Box 357660, Seattle, WA 98195 USA.; Bensley, KM (reprint author), Vet Hlth Adm VA, Denver Seattle Ctr Innovat Vet Ctr Value Driven C, VA Puget Sound Hlth Care Syst, 1660 S Columbian Way,Mailstop S-152, Seattle, WA 98108 USA. EM kbensley@uw.edu; Alexander.Harris2@va.gov; Shalini.Gupta2@va.gov; Anna.Rubinsky@va.gov; jones010@umn.edu; jglass2@wisc.edu; Emily.Williams3@va.gov FU Veterans Affairs (VA) Substance Use Disorders Quality Enhancement Research Initiative (SUD QUERI) locally initiated project [QLP 59-031]; AHRQ/NRSA T-32 training grant at the University of Washington; VA Puget Sound Health Services Research Development; VA Health Services Research Development [CDA 12-276, RCS-14-232]; National Institutes of Health [1R03AA023639] FX This study was funded by a Veterans Affairs (VA) Substance Use Disorders Quality Enhancement Research Initiative (SUD QUERI) locally initiated project (QLP 59-031). Ms. Bensley was supported by an AHRQ/NRSA T-32 training grant at the University of Washington and is currently supported by a Research Assistantship with VA Puget Sound Health Services Research & Development. Dr. Williams is supported by a Career Development Award from VA Health Services Research & Development (CDA 12-276). Dr. Harris is supported by a Career Scientist Award from VA Health Services Research & Development (RCS-14-232). Dr. Glass is supported by National Institutes of Health award 1R03AA023639. NR 64 TC 0 Z9 0 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0740-5472 J9 J SUBST ABUSE TREAT JI J. Subst. Abus. Treat. PD FEB PY 2017 VL 73 BP 27 EP 34 DI 10.1016/j.jsat.2016.11.001 PG 8 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA EJ5OJ UT WOS:000393267300004 PM 28017181 ER PT J AU Mackie, SE McHugh, RK McDermott, K Griffin, ML Winkelman, JW Weiss, RD AF Mackie, Susan E. McHugh, R. Kathryn McDermott, Katherine Griffin, Margaret L. Winkelman, John W. Weiss, Roger D. TI Prevalence of restless legs syndrome during detoxification from alcohol and opioids SO JOURNAL OF SUBSTANCE ABUSE TREATMENT LA English DT Article DE Opioids; Detoxification; Restless legs syndrome ID STAGE RENAL-DISEASE; SLEEP HEART HEALTH; DOUBLE-BLIND; DIAGNOSTIC-CRITERIA; WITHDRAWAL; PLACEBO; GABAPENTIN; PARAMETERS; MORTALITY; OXYCODONE AB Background and Aims: Restless legs syndrome (RLS) is a movement disorder associated with adverse health outcomes and decreased quality of life. Small case series suggest that symptoms of RLS occur during opioid withdrawal. However, the prevalence is unknown. Methods: We conducted an observational study to determine the prevalence of RLS among inpatients patients receiving buprenorphine detoxification from opioids. To assess the specificity of RLS to opioid detoxification, we also evaluated patients receiving detoxification from alcohol as a comparison group. The diagnosis of RLS was established using a validated questionnaire. Results: The sample consisted of 124 adults with primary opioid use disorder and 180 with primary alcohol use disorder. In the total sample, 33.6% met a likely RLS diagnosis: 50.8% of those with opioid use disorder and 21.7% of those with alcohol use disorder (X-2 = 27.96[1,304] p < .001). In the logistic regression analysis controlling for socio-demographic and clinical variables, diagnosis of opioid use disorder was associated with more than twice the likelihood of RLS diagnosis (OR=2.05, 95% CI 1.093.88) relative to diagnosis of alcohol use disorder. Conclusions: Approximately half of patients undergoing inpatient opioid detoxification exhibited the symptoms characteristic of RLS. We believe that these data support the existence of a secondary form of RLS associated with opioid withdrawal. (C) 2016 Elsevier Inc. All rights reserved. C1 [Mackie, Susan E.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02215 USA. [Mackie, Susan E.; McHugh, R. Kathryn; Griffin, Margaret L.; Winkelman, John W.; Weiss, Roger D.] Harvard Med Sch, 25 Shattuck St, Boston, MA 02115 USA. [McHugh, R. Kathryn; McDermott, Katherine; Griffin, Margaret L.; Weiss, Roger D.] McLean Hosp, 115 Mill St, Belmont, MA 02478 USA. [Mackie, Susan E.; Winkelman, John W.] Massachusetts Gen Hosp, 1 Bowdoin Sq,9th Floor, Boston, MA 02114 USA. RP Mackie, SE (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02215 USA. EM semackie@partners.org FU National Institute on Drug Abuse [K24 DA022288]; Purdue; Xenoport; UCB Pharma; NeuroMetrix; NIMH; [K23 DA035297] FX Dr. McHugh is supported by K23 DA035297.; Dr. Weiss has served on the Scientific Advisory Board for Indivior. He is supported by K24 DA022288, from the National Institute on Drug Abuse.; Dr. Winkelman is a consultant for UCB Pharma, Xenoport, Merck, and Flex Pharma. He has received research grants from Purdue, Xenoport, UCB Pharma, NeuroMetrix, and NIMH. NR 27 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0740-5472 J9 J SUBST ABUSE TREAT JI J. Subst. Abus. Treat. PD FEB PY 2017 VL 73 BP 35 EP 39 DI 10.1016/j.jsat.2016.10.001 PG 5 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA EJ5OJ UT WOS:000393267300005 PM 28017182 ER PT J AU Swaroop, MN Brunelle, CL Asdourian, MS Sayegh, HE Skolny, MN Salama, L Taghian, AG AF Swaroop, Meyha N. Brunelle, Cheryl L. Asdourian, Maria S. Sayegh, Hoda E. Skolny, Melissa N. Salama, Laura Taghian, Alphonse G. TI Bioimpedance Spectroscopy Does Have a Valid and Evidence-Based Role in Detection and Monitoring of Lymphoedema Response SO JOURNAL OF SURGICAL ONCOLOGY LA English DT Letter ID CANCER-RELATED LYMPHEDEMA; BREAST-CANCER; OPTOELECTRONIC VOLUMETRY; WATER DISPLACEMENT; PROSPECTIVE-COHORT; LIMB VOLUME; RISK; RELIABILITY; PREDICTS; SURGERY C1 [Swaroop, Meyha N.; Asdourian, Maria S.; Sayegh, Hoda E.; Skolny, Melissa N.; Salama, Laura; Taghian, Alphonse G.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA USA. [Brunelle, Cheryl L.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Phys & Occupat Therapy, Boston, MA USA. RP Taghian, AG (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 100 Blossom St, Boston, MA 02114 USA. EM ataghian@partners.org FU National Cancer Institute [R01CA139118, P50CA089393]; Adele McKinnon Research Fund FX Grant sponsor: National Cancer Institute; Grant numbers: R01CA139118, P50CA089393; Grant sponsor: Adele McKinnon Research Fund. NR 30 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-4790 EI 1096-9098 J9 J SURG ONCOL JI J. Surg. Oncol. PD FEB 1 PY 2017 VL 115 IS 2 BP 223 EP 225 DI 10.1002/jso.24496 PG 3 WC Oncology; Surgery SC Oncology; Surgery GA EJ1BI UT WOS:000392944800020 PM 27813099 ER PT J AU Gu, C Lee, HW Garborcauskas, G Reiser, J Gupta, V Sever, S AF Gu, Changkyu Lee, Ha Won Garborcauskas, Garrett Reiser, Jochen Gupta, Vineet Sever, Sanja TI Dynamin Autonomously Regulates Podocyte Focal Adhesion Maturation SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID KIDNEY-DISEASE; MEDIATED ENDOCYTOSIS; ACTIN INTERACTIONS; GTPASES; CELLS; OLIGOMERIZATION; CYTOSKELETON; NEPHROPATHY; DETACHMENT; MOTILITY AB Rho family GTPases, the prototypical members of which are Cdc42, Rac1, and RhoA, are molecular switches best known for regulating the actin cytoskeleton. In addition to the canonical small GTPases, the large GTPase dynamin has been implicated in regulating the actin cytoskeleton via direct dynamin-actin interactions. The physiologic role of dynamin in regulating the actin cytoskeleton has been linked to the maintenance of the kidney filtration barrier. Additionally, the small molecule Bis-T-23, which promotes actin-dependent dynamin oligomerization and thus, increases actin polymerization, improved renal health in diverse models of CKD, implicating dynamin as a potential therapeutic target for the treatment of CKD. Here, we show that treating cultured mouse podocytes with Bis-T-23 promoted stress fiber formation and focal adhesion maturation in a dynamin-dependent manner. Furthermore, Bis-T-23 induced the formation of focal adhesions and stress fibers in cells in which the RhoA signaling pathway was downregulated by multiple experimental approaches. Our study suggests that dynamin regulates focal adhesion maturation by a mechanism parallel to and synergistic with the RhoA signaling pathway. Identification of dynamin as one of the essential and autonomous regulators of focal adhesion maturation suggests a molecular mechanism that underlies the beneficial effect of Bis-T-23 on podocyte physiology. C1 [Gu, Changkyu; Garborcauskas, Garrett; Sever, Sanja] Harvard Med Sch, Div Nephrol, Dept Med, Massachusetts Gen Hosp, Charlestown, MA USA. [Lee, Ha Won; Reiser, Jochen; Gupta, Vineet] Rush Univ, Med Ctr, Dept Internal Med, Chicago, IL 60612 USA. RP Gu, C; Sever, S (reprint author), 149 13th St, Charlestown, MA 02129 USA. EM Gu.Changkyu@mgh.harvard.edu; ssever@mgh.harvard.edu FU National Institutes of Health [R01DK093773] FX This work was supported by National Institutes of Health grant R01DK093773 (to S.S.). NR 30 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD FEB PY 2017 VL 28 IS 2 BP 446 EP 451 DI 10.1681/ASN.2016010008 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA EJ2CN UT WOS:000393017600010 PM 27432739 ER PT J AU Sandholm, N Van Zuydam, N Ahlqvist, E Juliusdottir, T Deshmukh, HA Rayner, NW Di Camillo, B Forsblom, C Fadista, J Ziemek, D Salem, RM Hiraki, LT Pezzolesi, M Tregouet, D Dahlstrom, E Valo, E Oskolkov, N Ladenvall, C Marcovecchio, ML Cooper, J Sambo, F Malovini, A Manfrini, M McKnight, AJ Lajer, M Harjutsalo, V Gordin, D Parkkonen, M Tuomilehto, J Lyssenko, V McKeigue, PM Rich, SS Brosnan, MJ Fauman, E Bellazzi, R Rossing, P Hadjadj, S Krolewski, A Paterson, AD Florez, JC Hirschhorn, JN Maxwell, AP Dunger, D Cobelli, C Colhoun, HM Groop, L McCarthy, MI Groop, PH AF Sandholm, Niina Van Zuydam, Natalie Ahlqvist, Emma Juliusdottir, Thorhildur Deshmukh, Harshal A. Rayner, N. William Di Camillo, Barbara Forsblom, Carol Fadista, Joao Ziemek, Daniel Salem, Rany M. Hiraki, Linda T. Pezzolesi, Marcus Tregouet, David Dahlstrom, Emma Valo, Erkka Oskolkov, Nikolay Ladenvall, Claes Marcovecchio, M. Loredana Cooper, Jason Sambo, Francesco Malovini, Alberto Manfrini, Marco McKnight, Amy Jayne Lajer, Maria Harjutsalo, Valma Gordin, Daniel Parkkonen, Maija Tuomilehto, Jaakko Lyssenko, Valeriya McKeigue, Paul M. Rich, Stephen S. Brosnan, Mary Julia Fauman, Eric Bellazzi, Riccardo Rossing, Peter Hadjadj, Samy Krolewski, Andrzej Paterson, Andrew D. Florez, Jose C. Hirschhorn, Joel N. Maxwell, Alexander P. Dunger, David Cobelli, Claudio Colhoun, Helen M. Groop, Leif McCarthy, Mark I. Groop, Per-Henrik CA FinnDiane Study Grp DCCT EDIC Study Grp GENIE Consortium SUMMIT Consortium TI The Genetic Landscape of Renal Complications in Type 1 Diabetes SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID GENOME-WIDE ASSOCIATION; CHRONIC KIDNEY-DISEASE; BODY-FAT DISTRIBUTION; INSULIN-RESISTANCE; RISK-FACTORS; CARDIOVASCULAR-DISEASE; ALBUMIN EXCRETION; COMMON VARIANTS; GLYCEMIC TRAITS; BLOOD-PRESSURE AB Diabetes is the leading cause of ESRD. Despite evidence for a substantial heritability of diabetic kidney disease, efforts to identify genetic susceptibility variants have had limited success. We extended previous efforts in three dimensions, examining a more comprehensive set of genetic variants in larger numbers of subjects with type 1 diabetes characterized for a wider range of cross-sectional diabetic kidney disease phenotypes. In 2843 subjects, we estimated that the heritability of diabetic kidney disease was 35% (P=6.4x10(-3)). Genome-wide association analysis and replication in 12,540 individuals identified no single variants reaching stringent levels of significance and, despite excellent power, provided little independent confirmation of previously published associated variants. Whole-exome sequencing in 997 subjects failed to identify any large-effect coding alleles of lower frequency influencing the risk of diabetic kidney disease. However, sets of alleles increasing body mass index (P=2.2x10(-5)) and the risk of type 2 diabetes (P=6.1x10(-4)) associated with the risk of diabetic kidney disease. We also found genome-wide genetic correlation between diabetic kidney disease and failure at smoking cessation (P=1.1x10(-4)). Pathway analysis implicated ascorbate and aldarate metabolism (P=9.0x10(-6)), and pentose and glucuronate interconversions (P=3.0x10(-6)) in pathogenesis of diabetic kidney disease. These data provide further evidence for the role of genetic factors influencing diabetic kidney disease in those with type 1 diabetes and highlight some key pathways that may be responsible. Altogether these results reveal important biology behind the major cause of kidney disease. C1 [Sandholm, Niina; Forsblom, Carol; Dahlstrom, Emma; Valo, Erkka; Harjutsalo, Valma; Gordin, Daniel; Parkkonen, Maija; Groop, Per-Henrik] Univ Helsinki, Abdominal Ctr, Nephrol, Haartmaninkatu 8, FIN-00290 Helsinki, Finland. [Sandholm, Niina; Forsblom, Carol; Dahlstrom, Emma; Valo, Erkka; Harjutsalo, Valma; Gordin, Daniel; Parkkonen, Maija; Groop, Per-Henrik] Folkhalsan Res Ctr, Folkhalsan Inst Genet, Helsinki, Finland. [Sandholm, Niina; Forsblom, Carol; Dahlstrom, Emma; Valo, Erkka; Harjutsalo, Valma; Gordin, Daniel; Parkkonen, Maija; Groop, Per-Henrik] Helsinki Univ Hosp, Helsinki, Finland. [Sandholm, Niina; Forsblom, Carol; Dahlstrom, Emma; Valo, Erkka; Harjutsalo, Valma; Gordin, Daniel; Parkkonen, Maija; Groop, Per-Henrik] Univ Helsinki, Res Programs Unit, Diabet & Obes, Helsinki, Finland. [Van Zuydam, Natalie; Juliusdottir, Thorhildur; Rayner, N. William; McCarthy, Mark I.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Van Zuydam, Natalie; McCarthy, Mark I.] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [McCarthy, Mark I.] Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford, England. [Van Zuydam, Natalie] Univ Dundee, Med Res Inst, Dundee, Scotland. [Deshmukh, Harshal A.; Colhoun, Helen M.] Univ Dundee, Div Populat Hlth Sci, Dundee, Scotland. [Ahlqvist, Emma; Fadista, Joao; Oskolkov, Nikolay; Ladenvall, Claes; Lyssenko, Valeriya; Groop, Leif] Lund Univ, Skane Univ Hosp, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden. [Rayner, N. William] Wellcome Trust Sanger Inst, Human Genet, Hinxton, England. [Di Camillo, Barbara; Sambo, Francesco; Manfrini, Marco; Cobelli, Claudio] Univ Padua, Dept Informat Engn, Padua, Italy. [Ziemek, Daniel; Tregouet, David] Pfizer Worldwide Res & Dev, Computat Sci, Berlin, Germany. [Salem, Rany M.; Hirschhorn, Joel N.] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Florez, Jose C.] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Salem, Rany M.; Hirschhorn, Joel N.] MIT, Broad Inst, Program Metab, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Salem, Rany M.; Hirschhorn, Joel N.] MIT, Broad Inst, Program Med & Populat Genet, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Salem, Rany M.; Hirschhorn, Joel N.] Harvard Univ, Cambridge, MA 02138 USA. [Salem, Rany M.; Hirschhorn, Joel N.] Boston Childrens Hosp, Div Endocrinol, Boston, MA USA. [Salem, Rany M.; Hirschhorn, Joel N.] Boston Childrens Hosp, Div Genet, Boston, MA USA. [Hiraki, Linda T.; Paterson, Andrew D.] Hosp Sick Children, Genet & Genome Biol Program, Toronto, ON, Canada. [Pezzolesi, Marcus; Krolewski, Andrzej] Joslin Diabet Ctr, Sect Genet & Epidemiol, Boston, MA USA. [Tregouet, David] Univ Paris 06, Sorbonne Univ, Paris, France. [Tregouet, David] Natl Inst Hlth & Med Res, Mixed Res Unit Hlth UMR S 1166, Paris, France. [Tregouet, David] Inst Cardiometab & Nutr, Genom & Pathophysiol Cardiovasc Dis, Paris, France. [Marcovecchio, M. Loredana; Dunger, David] Univ Cambridge, Inst Metab Sci, Dept Paediat, Cambridge, England. [Cooper, Jason] Univ Cambridge, Dept Chem Engn & Biotechnol, Cambridge, England. [Malovini, Alberto; Bellazzi, Riccardo] Univ Pavia, Dept Elect Comp & Biomed Engn, Pavia, Italy. [Malovini, Alberto] IRCCS, Sci Inst Res Hospitalizat & Hlth Care, Lab Informat & Syst Engn Clin Res, Pavia, Italy. [Malovini, Alberto] Salvatore Maugeri Fdn, Pavia, Italy. [McKnight, Amy Jayne] Queens Univ Belfast, Ctr Publ Hlth, Nephrol Res, Belfast, Antrim, North Ireland. [Lajer, Maria; Lyssenko, Valeriya; Rossing, Peter] Steno Diabet Ctr, Diabet Complicat, Gentofte, Denmark. [Tuomilehto, Jaakko] Natl Inst Hlth & Welf, Chron Dis Prevent Unit, Helsinki, Finland. [Tuomilehto, Jaakko] Danube Univers Krems, Ctr Vasc Prevent, Krems, Austria. [Tuomilehto, Jaakko] King Abdulaziz Univ, Diabet Res Grp, Jeddah, Saudi Arabia. [Tuomilehto, Jaakko] Dasman Diabet Inst, Dasman, Kuwait. [McKeigue, Paul M.] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA 22903 USA. [Brosnan, Mary Julia] Cardiovasc & Metab Dis Res Unit, Cambridge, MA USA. [Fauman, Eric] Pfizer Worldwide Res & Dev, Computat Sci, Cambridge, MA USA. [Rossing, Peter] Aarhus Univ, Dept Hlth, Aarhus, Denmark. [Rossing, Peter] Univ Copenhagen, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark. [Hadjadj, Samy] Univ Poitiers, Funct Res Unit Med & Pharm, Poitiers, France. [Hadjadj, Samy] Univ Poitiers Hosp, Dept Endocrinol Diabetol, Poitiers, France. [Hadjadj, Samy] Univ Poitiers Hosp, Ctr Clin Investigat, Poitiers, France. [Hadjadj, Samy] INSERM, Natl Inst Hlth & Med Res, Ctr Clin Investigat 1402, Poitiers, France. [Hadjadj, Samy] INSERM, Natl Inst Hlth & Med Res, Unit 1082, Poitiers, France. [Florez, Jose C.] Broad Inst, Program Metab, Cambridge, MA 02142 USA. [Florez, Jose C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Maxwell, Alexander P.] Belfast City Hosp, Reg Nephrol Unit, Belfast, Antrim, North Ireland. [Groop, Per-Henrik] Heart & Diabet Inst, Baker IDI Int Diabet Inst, Melbourne, Vic, Australia. RP Groop, PH (reprint author), Univ Helsinki, Abdominal Ctr, Nephrol, Haartmaninkatu 8, FIN-00290 Helsinki, Finland.; Groop, PH (reprint author), Helsinki Univ Hosp, Biomedicum Helsinki C318b, Haartmaninkatu 8, FIN-00290 Helsinki, Finland. EM per-henrik.groop@helsinki.fi OI Maxwell, Alexander P./0000-0002-6110-7253 FU European Union [IMI/115006]; Folkhalsan Research Foundation; Wilhelm and Else Stockmann Foundation; Liv och Halsa Foundation; Helsinki University Central Hospital Research Funds; Signe and Ane Gyllenberg Foundation; Finska Lakaresallskapet; Novo Nordisk Foundation [NNF14SA0003]; Academy of Finland [134379, 275614]; European Union's Biomedicine and Health Programme; NIHR/Wellcome Trust; National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases [R01-DK081923]; Northern Ireland Research and Development Office; Science Foundation Ireland; DCCT/EDIC with the Division of Diabetes Endocrinology [1982-1993, 2012-2017, 1982-2012]; Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Disease [U01 DK094176, U01 DK094157]; National Eye Institute; National Institute of Neurologic Disorders and Stroke; General Clinical Research Centers Program; Clinical Translational Science Center Program; Juvenile Diabetes Research Foundation [17-2012-542] FX The research was supported by the European Union's Seventh Framework Program (FP7/2007-2013) for the Innovative Medicine Initiative under grant agreement IMI/115006 (the SUMMIT consortium). The FinnDiane Study was supported by grants from the Folkhalsan Research Foundation, the Wilhelm and Else Stockmann Foundation, the Liv och Halsa Foundation, Helsinki University Central Hospital Research Funds (EVO), the Signe and Ane Gyllenberg Foundation, Finska Lakaresallskapet, the Novo Nordisk Foundation (NNF14SA0003), and the Academy of Finland (134379 and 275614). The EURODIAB Family Study was funded by the European Union's Biomedicine and Health Programme. The NFS-ORPS Study was supported by NIHR/Wellcome Trust Cambridge Clinical Research Facility. The GENIE consortium was funded by the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK081923) to J.N.H., J.C.F., and P.-H.G., the Northern Ireland Research and Development Office (A.P.M.) and Science Foundation Ireland. The DCCT/EDIC has been supported by cooperative agreement grants (1982-1993, 2012-2017), and contracts (1982-2012) with the Division of Diabetes Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Disease (current grant numbers U01 DK094176 and U01 DK094157), and through support by the National Eye Institute, the National Institute of Neurologic Disorders and Stroke, the General Clinical Research Centers Program (1993-2007), and Clinical Translational Science Center Program (2006 to present), Bethesda, MD. S.S.R. was supported by Juvenile Diabetes Research Foundation (grant 17-2012-542). NR 92 TC 1 Z9 1 U1 5 U2 5 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD FEB PY 2017 VL 28 IS 2 BP 557 EP 574 DI 10.1681/ASN.2016020231 PG 18 WC Urology & Nephrology SC Urology & Nephrology GA EJ2CN UT WOS:000393017600019 PM 27647854 ER PT J AU Warth, A Beasley, MB Mino-Kenudson, M AF Warth, Arne Beasley, Mary Beth Mino-Kenudson, Mari TI Breaking New Ground: The Evolving Concept of Spread through Air Spaces (STAS) SO JOURNAL OF THORACIC ONCOLOGY LA English DT Editorial Material ID SQUAMOUS-CELL CARCINOMA; I LUNG ADENOCARCINOMA; PULMONARY ADENOCARCINOMA; POOR-PROGNOSIS; TUMOR SPREAD; INVASION; RESECTION; IMPACT C1 [Warth, Arne] Heidelberg Univ, Inst Pathol, INF 224, D-69120 Heidelberg, Germany. [Warth, Arne] Translat Lung Res Ctr Heidelberg, Heidelberg, Germany. [Beasley, Mary Beth] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Mino-Kenudson, Mari] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Mino-Kenudson, Mari] Harvard Med Sch, Boston, MA USA. RP Warth, A (reprint author), Heidelberg Univ, Inst Pathol, INF 224, D-69120 Heidelberg, Germany. EM arne.warth@med.uni-heidelberg.de NR 16 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD FEB PY 2017 VL 12 IS 2 BP 176 EP 178 DI 10.1016/j.jtho.2016.10.020 PG 3 WC Oncology; Respiratory System SC Oncology; Respiratory System GA EJ5NW UT WOS:000393266000003 PM 28115109 ER PT J AU Thunnissen, E Borczuk, AC Flieder, DB Witte, B Beasley, MB Chung, JH Dacic, S Lantuejoul, S Russell, PA den Bakker, M Botling, J Brambilla, E de Cuba, E Geisinger, KR Hiroshima, K Marchevsky, AM Minami, Y Moreira, A Nicholson, AG Yoshida, A Tsao, MS Warth, A Duhig, E Chen, G Matsuno, Y Travis, WD Butnor, K Cooper, W Mino-Kenudson, M Motoi, N Poleri, C Pelosi, G Kerr, K Aisner, SC Ishikawa, Y Buettner, RH Keino, N Yatabe, Y Noguchi, M AF Thunnissen, Erik Borczuk, Alain C. Flieder, Douglas B. Witte, Birgit Beasley, Mary Beth Chung, Jin-Haeng Dacic, Sanja Lantuejoul, Sylvie Russell, Prudence A. den Bakker, Michael Botling, Johan Brambilla, Elisabeth de Cuba, Erienne Geisinger, Kim R. Hiroshima, Kenzo Marchevsky, Alberto M. Minami, Yuko Moreira, Andre Nicholson, Andrew G. Yoshida, Akihiko Tsao, Ming-Sound Warth, Arne Duhig, Edwina Chen, Gang Matsuno, Yoshihiro Travis, William D. Butnor, Kelly Cooper, Wendy Mino-Kenudson, Mari Motoi, Noriko Poleri, Claudia Pelosi, Giuseppe Kerr, Keith Aisner, Seena C. Ishikawa, Yuichi Buettner, Reinhard H. Keino, Naoto Yatabe, Yasushi Noguchi, Masayuki TI The Use of Immunohistochemistry Improves the Diagnosis of Small Cell Lung Cancer and Its Differential Diagnosis. An International Reproducibility Study in a Demanding Set of Cases SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article DE SCLC; Histopathology; Reproducibility; Immunohistochemistry ID GRADE NEUROENDOCRINE CARCINOMA; INTEROBSERVER VARIABILITY; PULMONARY CARCINOIDS; CLINICAL-FEATURES; TISSUE MICROARRAY; EXPRESSION; TUMORS; NEOPLASMS; TTF-1; CLASSIFICATION AB Introduction: The current WHO classification of lung cancer states that a diagnosis of SCLC can be reliably made on routine histological and cytological grounds but immunohistochemistry (IHC) may be required, particularly (1) in cases in which histologic features are equivocal and (2) in cases in which the pathologist wants to increase confidence in diagnosis. However, reproducibility studies based on hematoxylin and eosin-stained slides alone for SCLC versus large cell neuroendocrine carcinoma (LCNEC) have shown pairwise K scores ranging from 0.35 to 0.81. This study examines whether judicious use of IHC improves diagnostic reproducibility for SCLC. Methods: Nineteen lung pathologists studied interactive digital images of 79 tumors, predominantly neuroendocrine lung tumors. Images of resection and biopsy specimens were used to make diagnoses solely on the basis of morphologic features (level 1), morphologic features along with requested IHC staining results (level 2), and all available IHC staining results (level 3). Results: For the 19 pathologists reading all 79 cases, the rate of agreement for level 1 was 64.7%, and it increased to 73.2% and 77.5% in levels 2 and 3, respectively. With IHC, K scores for four tumor categories (SCLC, LCNEC, carcinoid tumors, and other) increased in resection samples from 0.43 to 0.60 and in biopsy specimens from 0.43 to 0.64. Conclusions: Diagnosis using hematoxylin and eosin staining alone showeds moderate agreement among pathologists in tumors with neuroendocrine morphology, but agreement improved to good in most cases with the judicious use of IHC, especially in the diagnosis of SCLC. An approach for IHC in the differential diagnosis of SCLC is provided. (C) 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. C1 [Thunnissen, Erik; de Cuba, Erienne] Vrije Univ Amsterdam Med Ctr, Dept Pathol, De Boelelaan 1117, NL-1081 HV Amsterdam, Netherlands. [Borczuk, Alain C.] Weill Cornell Med, Dept Pathol, New York, NY USA. [Flieder, Douglas B.] Fox Chase Canc Ctr, Dept Pathol, Philadelphia, PA 19111 USA. [Witte, Birgit] Vrije Univ Amsterdam Med Ctr, Dept Epidemiol & Biostat, Amsterdam, Netherlands. [Beasley, Mary Beth] Mt Sinai Med Ctr, Dept Pathol, New York, NY 10029 USA. [Chung, Jin-Haeng] Seoul Natl Univ, Bundang Hosp, Coll Med, Dept Pathol, Seoul 151, South Korea. [Dacic, Sanja] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA USA. [Lantuejoul, Sylvie] Ctr Leon Berard UNICANCER, Dept Biopathol, Lyon, France. [Russell, Prudence A.] St Vincent Pathol, Melbourne, Vic, Australia. [Russell, Prudence A.] Univ Melbourne, Melbourne, Vic, Australia. [den Bakker, Michael] Maasstad Ziekenhuis, Dept Pathol, Rotterdam, Netherlands. [Botling, Johan] Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden. [Brambilla, Elisabeth] CHU Albert Michallon, Inst Biol, Dept Anat & Cytol Pathol, Grenoble, France. [Geisinger, Kim R.] Univ Mississippi, Med Ctr, Dept Pathol, Jackson, MS 39216 USA. [Hiroshima, Kenzo] Tokyo Womens Med Univ, Yachiyo Med Ctr, Dept Pathol, Yachiyo, Japan. [Marchevsky, Alberto M.] Cedars Sinai Med Ctr, Dept Pathol, Los Angeles, CA 90048 USA. [Minami, Yuko; Noguchi, Masayuki] Univ Tsukuba, Inst Basic Med Sci, Dept Pathol, Tsukuba, Ibaraki, Japan. [Moreira, Andre] NYU, Ctr Biospecimen Res & Dev, Pulm Pathol, New York, NY USA. [Nicholson, Andrew G.] Royal Brompton & Harefield Hosp Natl Hlth Serv Fd, Dept Histopathol, London, England. [Nicholson, Andrew G.] Imperial Coll, Natl Heart & Lung Inst, London, England. [Yoshida, Akihiko; Motoi, Noriko] Natl Canc Ctr, Dept Pathol & Clin Labs, Tokyo, Japan. [Tsao, Ming-Sound] Princess Margaret Hosp, Univ Hlth Network, Dept Pathol, Toronto, ON, Canada. [Tsao, Ming-Sound] Univ Toronto, Toronto, ON, Canada. [Warth, Arne] Heidelberg Univ, Inst Pathol, Heidelberg, Germany. [Duhig, Edwina] John Flynn Hosp, Sullivan Nicolaides Pathol, Tugun, Qld, Australia. [Chen, Gang] Fudan Univ, Zhongshan Hosp, Dept Pathol, Shanghai, Peoples R China. [Matsuno, Yoshihiro] Hokkaido Univ Hosp, Dept Surg Pathol, Sapporo, Hokkaido, Japan. [Travis, William D.] Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA. [Butnor, Kelly] Univ Vermont, Dept Pathol, Burlington, VT 05405 USA. [Cooper, Wendy] Royal Prince Alfred Hosp, Tissue Pathol & Diagnost Oncol, Sydney, NSW, Australia. [Mino-Kenudson, Mari] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Mino-Kenudson, Mari] Harvard Med Sch, Boston, MA USA. [Poleri, Claudia] Lab Patol Torac, Buenos Aires, DF, Argentina. [Pelosi, Giuseppe] Univ Milan, Dept Oncol & Hematol Oncol, Milan, Italy. [Kerr, Keith] Aberdeen Royal Infirm, Dept Pathol, Aberdeen, Scotland. [Aisner, Seena C.] Rutgers State Univ, Rutgers New Jersey Med Sch, Dept Pathol & Lab Med, Newark, NJ USA. [Ishikawa, Yuichi] Japan Fdn Canc Res, Inst Canc, Div Pathol, Tokyo, Japan. [Buettner, Reinhard H.] Cologne Inst Pathol, Cologne, Germany. [Keino, Naoto] Univ Tsukuba, Tsukuba Clin Res & Dev Org, Tsukuba, Ibaraki, Japan. [Yatabe, Yasushi] Aichi Canc Ctr, Dept Pathol & Mol Diagnost, Nagoya, Aichi, Japan. RP Thunnissen, E (reprint author), Vrije Univ Amsterdam Med Ctr, Dept Pathol, De Boelelaan 1117, NL-1081 HV Amsterdam, Netherlands. EM e.thunnissen@vumc.nl FU International Association for the Study of Lung Cancer FX Part of this study was funded by the International Association for the Study of Lung Cancer. The support for website application and statistical analysis is greatly appreciated. NR 58 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD FEB PY 2017 VL 12 IS 2 BP 334 EP 346 DI 10.1016/j.jtho.2016.12.004 PG 13 WC Oncology; Respiratory System SC Oncology; Respiratory System GA EJ5NW UT WOS:000393266000017 PM 27998793 ER PT J AU Maung, AA Johnson, DC Barre, K Peponis, T Mesar, T Velmahos, GC McGrail, D Kasotakis, G Gross, RI Rosenblatt, MS Sihler, KC Winchell, RJ Cholewczynski, W Butler, KL Odom, SR Davis, KA AF Maung, Adrian A. Johnson, Dirk C. Barre, Kimberly Peponis, Thomas Mesar, Tomaz Velmahos, George C. McGrail, Daniel Kasotakis, George Gross, Ronald I. Rosenblatt, Michael S. Sihler, Kristen C. Winchell, Robert J. Cholewczynski, Walter Butler, Kathryn L. Odom, Stephen R. Davis, Kimberly A. CA ReCONECT MRI C-SPINE Study Grp TI Cervical spine MRI in patients with negative CT: A prospective, multicenter study of the Research Consortium of New England Centers for Trauma (ReCONECT) SO JOURNAL OF TRAUMA AND ACUTE CARE SURGERY LA English DT Article; Proceedings Paper CT 75th Annual Meeting of the American-Association-for-the-Surgery-of-Trauma / Clinical Congress of Acute Care Surgery CY SEP 14-17, 2016 CL Waikoloa, HI SP Amer Assoc Surg Trauma DE Cervical spine injury; magnetic resonance imaging; MRI; computed tomography; CT ID COMPUTED-TOMOGRAPHY; BLUNT TRAUMA; EASTERN ASSOCIATION; CLEARANCE; INJURY; SURGERY; RULE AB BACKGROUND: Although cervical spine CT (CSCT) accurately detects bony injuries, it may not identify all soft tissue injuries. Although some clinicians rely exclusively on a negative CT to remove spine precautions in unevaluable patients or patients with cervicalgia, others use MRI for that purpose. The objective of this study was to determine the rates of abnormal MRI after a negative CSCT. METHODS: Blunt trauma patients who either were unevaluable or had persistent midline cervicalgia and underwent an MRI of the C-spine after a negative CSCT were enrolled prospectively in eight Level I and II New England trauma centers. Demographics, injury patterns, CT and MRI results, and any changes in cervical spine management as a result of MRI imaging were recorded. RESULTS: A total of 767 patients had MRI because of cervicalgia (43.0%), inability to evaluate (44.1%), or both (9.4%). MRI was abnormal in 23.6% of all patients, including ligamentous injury (16.6%), soft tissue swelling (4.3%), vertebral disc injury (1.4%), and dural hematomas (1.3%). Rates of abnormal neurological signs or symptoms were not different among patients with normal versus abnormal MRI. (15.2 vs. 18.8%, p = 0.25). The c-collar was removed in 88.1% of patients with normal MRI and 13.3% of patients with an abnormal MRI. No patient required halo placement, but 11 patients underwent cervical spine surgery after the MRI results. Six of the eleven had neurological signs or symptoms. CONCLUSIONS: In a select population of patients, MRI identified additional injuries in 23.6% of patients despite a normal CSCT. It is uncertain if this is a true limitation of CT technology or represents subtle injuries missed in the interpretation of the scan. The clinical significance of these abnormal MRI findings cannot be determined from this study group. (Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.) LEVEL OF EVIDENCE: Therapeutic study, level IV. C1 [Maung, Adrian A.; Johnson, Dirk C.; Barre, Kimberly; Davis, Kimberly A.] Yale Sch Med, New Haven, CT USA. [Peponis, Thomas; Mesar, Tomaz; Velmahos, George C.; Butler, Kathryn L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [McGrail, Daniel; Kasotakis, George] Boston Med Ctr, Boston, MA USA. [Gross, Ronald I.] Baystate Med Ctr, Springfield, MA USA. [Rosenblatt, Michael S.] Lahey Hosp & Med Ctr, Burlington, MA USA. [Sihler, Kristen C.; Winchell, Robert J.] Maine Med Ctr, Portland, ME 04102 USA. [Cholewczynski, Walter] Bridgeport Hosp, Bridgeport, CT USA. [Odom, Stephen R.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RP Maung, AA (reprint author), Yale Sch Med, Sect Gen Surg Trauma & Surg Crit Care, Dept Surg, 330 Cedar St BB310, New Haven, CT 06520 USA. EM adrian.maung@yale.edu NR 15 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 2163-0755 EI 2163-0763 J9 J TRAUMA ACUTE CARE JI J. Trauma Acute Care Surg. PD FEB PY 2017 VL 82 IS 2 BP 263 EP 268 DI 10.1097/TA.0000000000001322 PG 6 WC Critical Care Medicine; Surgery SC General & Internal Medicine; Surgery GA EJ8GO UT WOS:000393463600007 PM 27893647 ER PT J AU Rahimi, A Anmole, G Soto-Nava, M Escamilla-Gomez, T Markle, T Jin, SW Lee, GQ Harrigan, PR Bangsberg, DR Martin, J Avila-Rios, S Reyes-Teran, G Brockman, MA Brumme, ZL AF Rahimi, Asa Anmole, Gursev Soto-Nava, Maribel Escamilla-Gomez, Tania Markle, Tristan Jin, Steven W. Lee, Guinevere Q. Harrigan, P. Richard Bangsberg, David R. Martin, Jeffrey Avila-Rios, Santiago Reyes-Teran, Gustavo Brockman, Mark A. Brumme, Zabrina L. TI In vitro functional assessment of natural HIV-1 group M Vpu sequences using a universal priming approach SO JOURNAL OF VIROLOGICAL METHODS LA English DT Article DE HIV-1 Vpu; Sequence diversity; CD4; BST2/tetherin; Downregulation; Rev/RRE ID SUBTYPE-C; CELL-SURFACE; DOWN-REGULATION; CD4; NEF; INFECTIVITY; PROTEINS; RELEASE; EXPRESSION; RETROVIRUS AB The HIV-1 accessory protein Vpu exhibits high inter- and intra- subtype genetic diversity that may influence Vpu function and possibly contribute to HIV-1 pathogenesis. However, scalable methods to evaluate genotype/phenotype relationships in natural Vpu sequences are limited, particularly those expressing the protein in CD4+ T-cells, the natural target of HIV-1 infection. A major impediment to assay scalability is the extensive genetic diversity within, and immediately upstream of, Vpu's initial 5' coding region, which has necessitated the design of oligonucleotide primers specific for each individual HIV-1 isolate (or subtype). To address this, we developed two universal forward primers, located in relatively conserved regions 38 and 90 bases upstream of Vpu, and a single universal reverse primer downstream of Vpu, which are predicted to cover the vast majority of global HIV-1 group M sequence diversity. We show that inclusion of up to 90 upstream bases of HIV-1 genomic sequence does not significantly influence in vitro Vpu expression or function when a Rev/Rev Response Element (RRE)-dependent expression system is used. We further assess the function of four diverse HIV-1 Vpu sequences, revealing reproducible and significant differences between them. Our approach represents a scalable option to measure the in vitro function of genetically diverse natural Vpu isolates in a CD4+ T-cell line. (C) 2016 Elsevier B.V. All rights reserved. C1 [Rahimi, Asa; Brockman, Mark A.; Brumme, Zabrina L.] Simon Fraser Univ, Fac Hlth Sci, Burnaby, BC, Canada. [Anmole, Gursev; Markle, Tristan; Jin, Steven W.; Brockman, Mark A.] Simon Fraser Univ, Fac Sci, Dept Mol Biol & Biochem, Burnaby, BC, Canada. [Soto-Nava, Maribel; Escamilla-Gomez, Tania; Avila-Rios, Santiago; Reyes-Teran, Gustavo] Natl Inst Resp Dis, Ctr Res Infect Dis, Mexico City, DF, Mexico. [Lee, Guinevere Q.; Harrigan, P. Richard; Brockman, Mark A.; Brumme, Zabrina L.] British Columbia Ctr Excellence HIV AIDS, Vancouver, BC, Canada. [Bangsberg, David R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Bangsberg, David R.] Harvard Med Sch, Cambridge, MA USA. [Martin, Jeffrey] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Brumme, ZL (reprint author), Simon Fraser Univ, 8888 Univ Dr, Burnaby, BC V6A 1S6, Canada. EM zbrumme@sfu.ca OI Brockman, Mark/0000-0001-6432-1426 FU Canadian Institutes for Health Research [HOP-115700, PJT - 148621]; Canada-Sub Saharan Africa (CANSSA) HIV/AIDS Network through Global Health Research Initiative; IDRC; CIHR; Global Affairs Canada; National Institutes of Health [P30 AI027763, R01 MH054907, UM1 CA181255]; Canada Research Chair in Viral Pathogenesis and Immunity; Michael Smith Foundation for Health Research (MSFHR) Scholar award FX This work was supported by an operating grant (HOP-115700) and a project grant (PJT - 148621) from the Canadian Institutes for Health Research to ZLB/MAB, and the Canada-Sub Saharan Africa (CANSSA) HIV/AIDS Network, through funding provided by the Global Health Research Initiative, itself a collaborative partnership of IDRC, CIHR, and Global Affairs Canada to MAB/ZLB. The UARTO cohort is supported by grants from the National Institutes of Health P30 AI027763, R01 MH054907 and UM1 CA181255 to DRB and JNM. MAB is supported by a Canada Research Chair in Viral Pathogenesis and Immunity. ZLB holds a Michael Smith Foundation for Health Research (MSFHR) Scholar award. NR 43 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-0934 EI 1879-0984 J9 J VIROL METHODS JI J. Virol. Methods PD FEB PY 2017 VL 240 BP 32 EP 41 DI 10.1016/j.jviromet.2016.11.004 PG 10 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Virology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Virology GA EJ2CT UT WOS:000393018200006 PM 27865749 ER PT J AU Madani, N Princiotto, AM Zhao, C Jahanbakhshsefidi, F Mertens, M Herschhorn, A Melillo, B Smith, AB Sodroski, J AF Madani, Navid Princiotto, Amy M. Zhao, Connie Jahanbakhshsefidi, Fatemeh Mertens, Max Herschhorn, Alon Melillo, Bruno Smith, Amos B., III Sodroski, Joseph TI Activation and Inactivation of Primary Human Immunodeficiency Virus Envelope Glycoprotein Trimers by CD4-Mimetic Compounds SO JOURNAL OF VIROLOGY LA English DT Article DE antibody; conformation; envelope glycoprotein; inhibitor; neutralization; sensitization; stoichiometry; virus entry ID SMALL-MOLECULE INHIBITORS; HIV-1 ENTRY INHIBITORS; STRUCTURE-BASED DESIGN; CRYO-EM STRUCTURE; SOLUBLE CD4; NEUTRALIZATION SENSITIVITY; SYNCYTIUM FORMATION; ATOMIC-STRUCTURE; CELL-CULTURES; TYPE-1 GP120 AB Human immunodeficiency virus type 1 (HIV-1) entry into cells is mediated by the viral envelope glycoproteins (Env), a trimer of three gp120 exterior glycoproteins, and three gp41 transmembrane glycoproteins. The metastable Env is triggered to undergo entry-related conformational changes when gp120 binds sequentially to the receptors, CD4 and CCR5, on the target cell. Small-molecule CD4-mimetic compounds (CD4mc) bind gp120 and act as competitive inhibitors of gp120-CD4 engagement. Some CD4mc have been shown to trigger Env prematurely, initially activating Env function, followed by rapid and irreversible inactivation. Here, we study CD4mc with a wide range of anti-HIV-1 potencies and demonstrate that all tested CD4mc are capable of activating as well as inactivating Env function. Biphasic dose-response curves indicated that the occupancy of the protomers in the Env trimer governs viral activation versus inactivation. One CD4mc bound per Env trimer activated HIV-1 infection. Envs with two CD4mc bound were activated for infection of CD4-negative, CCR5-positive cells, but the infection of CD4-positive, CCR5-positive cells was inhibited. Virus was inactivated when all three Env protomers were occupied by the CD4mc, and gp120 shedding from the Env trimer was increased in the presence of some CD4mc. Env reactivity and the on rates of CD4mc binding to the Env trimer were found to be important determinants of the potency of activation and entry inhibition. Cross-sensitization of Env protomers that do not bind the CD4mc to neutralization by an anti-V3 antibody was not evident. These insights into the mechanism of antiviral activity of CD4mc should assist efforts to optimize their potency and utility. IMPORTANCE The trimeric envelope glycoproteins of human immunodeficiency virus type 1 (HIV-1) mediate virus entry into host cells. Binding to the host cell receptors, CD4 and CCR5, triggers changes in the conformation of the HIV-1 envelope glycoprotein trimer important for virus entry. Small-molecule CD4-mimetic compounds inhibit HIV-1 infection by multiple mechanisms: (i) direct blockade of the interaction between the gp120 exterior envelope glycoprotein and CD4; (ii) premature triggering of conformational changes in the envelope glycoproteins, leading to irreversible inactivation; and (iii) exposure of cryptic epitopes to antibodies, allowing virus neutralization. The consequences of the binding of the CD4-mimetic compound to the HIV-1 envelope glycoproteins depends upon how many of the three subunits of the trimer are bound and upon the propensity of the envelope glycoproteins to undergo conformational changes. Understanding the mechanistic factors that influence the activity of CD4-mimetic compounds can help to improve their potency and coverage of diverse HIV-1 strains. C1 [Madani, Navid; Princiotto, Amy M.; Zhao, Connie; Jahanbakhshsefidi, Fatemeh; Mertens, Max; Herschhorn, Alon; Sodroski, Joseph] Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02115 USA. [Madani, Navid; Herschhorn, Alon; Sodroski, Joseph] Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA USA. [Melillo, Bruno; Smith, Amos B., III] Univ Penn, Dept Chem, Philadelphia, PA 19104 USA. [Sodroski, Joseph] Harvard TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA USA. RP Sodroski, J (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02115 USA.; Sodroski, J (reprint author), Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA USA.; Sodroski, J (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA USA. EM joseph_sodroski@dfci.harvard.edu FU National Institutes of Health [GM56550, AI24755]; amfAR [107431-45-RFNT, 109285-58-RKVA]; NIH [AI90682]; Ragon Institute Innovation Award FX This study was supported by the National Institutes of Health (GM56550 and AI24755) and the late William F. McCarty-Cooper. N.M. was supported by amfAR grant 107431-45-RFNT, NIH grant AI90682, and a Ragon Institute Innovation Award. A.H. was supported by amfAR research grant 109285-58-RKVA. NR 69 TC 1 Z9 1 U1 4 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD FEB PY 2017 VL 91 IS 3 AR UNSP e01880 DI 10.1128/JVI.01880-16 PG 20 WC Virology SC Virology GA EJ4NR UT WOS:000393194600014 ER PT J AU Moy, AP Duncan, LM Kraft, S AF Moy, Andrea P. Duncan, Lyn M. Kraft, Stefan TI Lymphatic invasion and angiotropism in primary cutaneous melanoma SO LABORATORY INVESTIGATION LA English DT Article ID EXTRAVASCULAR MIGRATORY METASTASIS; MONOCLONAL-ANTIBODY D2-40; SPITZOID MELANOCYTIC TUMORS; MALIGNANT-MELANOMA; LYMPHOVASCULAR INVASION; NODE METASTASIS; THIN MELANOMA; IMMUNOHISTOCHEMICAL OBSERVATIONS; CHORIOALLANTOIC MEMBRANE; PROGNOSTIC-FACTORS AB Access of melanoma cells to the cutaneous vasculature either via lymphatic invasion or angiotropism is a proposed mechanism for metastasis. Lymphatic invasion is believed to be a mechanism by which melanoma cells can disseminate to regional lymph nodes and to distant sites and may be predictive of adverse outcomes. Although it can be detected on hematoxylin- and eosin-stained sections, sensitivity is markedly improved by immunohistochemistry for lymphatic endothelial cells. Multiple studies have reported a significant association between the presence of lymphatic invasion and sentinel lymph node metastasis and survival. More recently, extravascular migratory metastasis has been suggested as another means by which melanoma cells can spread. Angiotropism, the histopathologic correlate of extravascular migratory metastasis, has also been associated with melanoma metastasis and disease recurrence. Although lymphatic invasion and angiotropism are not currently part of routine melanoma reporting, the detection of these attributes using ancillary immunohistochemical stains may be useful in therapeutic planning for patients with melanoma. C1 [Moy, Andrea P.; Duncan, Lyn M.; Kraft, Stefan] Massachusetts Gen Hosp, Pathol Serv, Dermatopathol Unit, 55 Fruit St,Warren 829A, Boston, MA USA. RP Kraft, S (reprint author), Massachusetts Gen Hosp, Pathol Serv, Dermatopathol Unit, 55 Fruit St,Warren 829A, Boston, MA USA. EM skraft@mgh.harvard.edu NR 83 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 IS 2 BP 118 EP 129 DI 10.1038/labinvest.2016.131 PG 12 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EJ3BV UT WOS:000393087000002 PM 27991909 ER PT J AU Bresler, SC Min, L Rodig, SJ Walls, AC Xu, SY Geng, SM Hodi, FS Murphy, GF Lian, CG AF Bresler, Scott C. Min, Le Rodig, Scott J. Walls, Andrew C. Xu, Shuyun Geng, Songmei Hodi, F. Stephen Murphy, George F. Lian, Christine G. TI Gene expression profiling of anti-CTLA4-treated metastatic melanoma in patients with treatment-induced autoimmunity SO LABORATORY INVESTIGATION LA English DT Article ID SPINDLE ASSEMBLY CHECKPOINT; T-LYMPHOCYTE ANTIGEN-4; SURVIVIN EXPRESSION; TARGETING SURVIVIN; TUMOR-REGRESSION; CTLA-4 BLOCKADE; DENDRITIC CELLS; CANCER CELLS; PHASE-I; PROTEIN AB Ipilimumab (IPI) is a monoclonal antibody that targets the inhibitory CTLA4 receptor of T cells, enhancing T-cell-driven antitumor responses. IPI therapy in metastatic melanoma results in significant improvement in disease-free and overall survival, although after initial responses disease progression generally ensues. Identification of specific responses in tissue where melanoma tumor cells are subjected to IPI-driven immune attack may reveal mechanisms of treatment efficacy or resistance, permitting refinement of targeted therapeutic approaches. We used NanoString digital barcoding chemistry to identify changes in the transcriptome of metastatic melanoma cells before and after IPI treatment using two comprehensive panels containing a total of 1330 unique genes. Only patients who developed autoimmune disorders following treatment, signifying a robust immune response, were included. Despite evidence of an enhanced immune response, most patients eventually exhibited disease progression. Overall, data from five pre-IPI tumors and four post-IPI tumor samples (from three patients) permitted identification of several candidate genes that showed increased expression based on normalized counts after therapy. These included TTK (similar to 3.1-fold, P = 1.18e - 4), which encodes a dual-specificity protein tyrosine kinase, a known cell cycle regulator, and BIRC5 (similar to 3.0-fold, P = 9.36e - 4), which encodes the antiapoptotic protein survivin. Both TTK (MPS1) and survivin are targetable proteins against which a number of pharmacologic agents have been developed. CDK1, which encodes a protein tyrosine kinase known to phosphorylate survivin, was also upregulated (similar to 3.2-fold, P=2.80-3). Tumor cell expression of TTK and survivin proteins was confirmed using immunohistochemistry in an expanded patient cohort. Differences in gene expression for several commonly encountered immune antigens, such as CD3, CD4, CD8, and CTLA4, were not statistically significant, likely reflecting the long length of time (average 323 days) between the last IPI dose and post-treatment biopsies. Although our sample size is limited, these results for the first time identify targetable genes that are significantly altered by interaction between a highly activated, IPI-treated immune system and melanoma cells. C1 [Bresler, Scott C.; Rodig, Scott J.; Xu, Shuyun; Geng, Songmei; Murphy, George F.; Lian, Christine G.] Brigham & Womens Hosp, Dept Pathol, Program Dermatopathol, 221 Longwood Ave,EBRC Suite 401, Boston, MA 02115 USA. [Bresler, Scott C.; Min, Le; Rodig, Scott J.; Walls, Andrew C.; Xu, Shuyun; Geng, Songmei; Hodi, F. Stephen; Murphy, George F.; Lian, Christine G.] Harvard Med Sch, Boston, MA USA. [Min, Le] Brigham & Womens Hosp, Dept Med, Div Endocrinol, 75 Francis St, Boston, MA 02115 USA. [Walls, Andrew C.] Brigham & Womens Hosp, Dept Dermatol, 75 Francis St, Boston, MA 02115 USA. [Hodi, F. Stephen] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Lian, CG (reprint author), Brigham & Womens Hosp, Dept Pathol, Program Dermatopathol, 221 Longwood Ave,EBRC Suite 401, Boston, MA 02115 USA. EM cglian@bwh.harvard.edu FU Brigham Research Institute FX We thank Ronald Brown for technical assistance in performing NanoString experiments and Qian Zhan for technical assistance in performing immunohistochemistry. We also thank Brigham Research Institute for providing funding in the form of a BRI Microgrant. NR 57 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 IS 2 BP 207 EP 216 DI 10.1038/labinvest.2016.126 PG 10 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EJ3BV UT WOS:000393087000010 PM 27918555 ER PT J AU Graber, CJ AF Graber, Christopher J. TI Clostridium difficile infection: stewardship's lowest hanging fruit? SO LANCET INFECTIOUS DISEASES LA English DT Editorial Material ID METAANALYSIS C1 [Graber, Christopher J.] Univ Calif Los Angeles, David Geffen Sch Med, VA Greater Los Angeles Healthcare Syst, Infect Dis Sect, Los Angeles, CA 90073 USA. RP Graber, CJ (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, VA Greater Los Angeles Healthcare Syst, Infect Dis Sect, Los Angeles, CA 90073 USA. EM christopher.graber@va.gov NR 8 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD FEB PY 2017 VL 17 IS 2 BP 123 EP 124 DI 10.1016/51473-3099(16)30416-9 PG 2 WC Infectious Diseases SC Infectious Diseases GA EJ0NJ UT WOS:000392906000005 PM 27825596 ER PT J AU Harwood, JM Azocar, F Thalmayer, A Xu, HY Ong, MK Tseng, CH Wells, KB Friedman, S Ettner, SL AF Harwood, Jessica M. Azocar, Francisca Thalmayer, Amber Xu, Haiyong Ong, Michael K. Tseng, Chi-Hong Wells, Kenneth B. Friedman, Sarah Ettner, Susan L. TI The Mental Health Parity and Addiction Equity Act Evaluation Study Impact on Specialty Behavioral Health Care Utilization and Spending Among Carve-In Enrollees SO MEDICAL CARE LA English DT Article DE behavioral health care; health service research; policy evaluation; health insurance; claims data ID INTERRUPTED TIME-SERIES; USE DISORDER TREATMENT; REGRESSION-ANALYSIS; FEDERAL PARITY; SERVICES; MEDICAID; ACCESS; POLICY AB Objective: The federal Mental Health Parity and Addiction Equity Act (MHPAEA) sought to eliminate historical disparities between insurance coverage for behavioral health (BH) treatment and coverage for medical treatment. Our objective was to evaluate MHPAEA's impact on BH expenditures and utilization among "carve-in" enrollees. Methods: We received specialty BH insurance claims and eligibility data from Optum, sampling 5,987,776 adults enrolled in self-insured plans from large employers. An interrupted time series study design with segmented regression analysis estimated monthly time trends of per-member spending and use before (2008-2009), during (2010), and after (2011-2013) MHPAEA compliance (N = 179,506,951 member-month observations). Outcomes included: total, plan, patient out-of-pocket spending; outpatient utilization (assessment/diagnostic evaluation visits, medication management, individual and family psychotherapy); intermediate care utilization (structured outpatient, day treatment, residential); and inpatient utilization. Results: MHPAEA was associated with increases in monthly per-member total spending, plan spending, assessment/diagnostic evaluation visits [respective immediate increases of: $1.05 (P = 0.02); $0.88 (P = 0.04); 0.00045 visits (P = 0.00)], and individual psychotherapy visits [immediate increase of 0.00578 visits (P = 0.00) and additional increases of 0.00017 visits/mo (P = 0.03)]. Conclusions: MHPAEA was associated with modest increases in total and plan spending and outpatient utilization; for example, in July 2012 predicted per-enrollee plan spending was $4.92 without MHPAEA and $6.14 with MHPAEA. Efforts should focus on understanding how other barriers to BH care unaddressed by MHPAEA may affect access/utilization. Future research should evaluate effects produced by the Affordable Care Act's inclusion of BH care as an essential health benefit and expansion of MHPAEA protections to the individual and small group markets. C1 [Harwood, Jessica M.; Xu, Haiyong; Ong, Michael K.; Tseng, Chi-Hong; Ettner, Susan L.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Gen Internal Med & Hlth Serv Res, Los Angeles, CA 90095 USA. [Azocar, Francisca; Thalmayer, Amber] Optum, United Hlth Grp, San Francisco, CA USA. [Ong, Michael K.] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Wells, Kenneth B.] Univ Calif Los Angeles, Neuropsychiat Inst, Dept Psychiat, Los Angeles, CA 90024 USA. [Friedman, Sarah; Ettner, Susan L.] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Hlth Policy & Management, Los Angeles, CA USA. RP Harwood, JM (reprint author), 911 Broxton Plaza, Los Angeles, CA 90024 USA. EM JHarwood@mednet.ucla.edu FU National Institute on Drug Abuse (NIDA) [1R01DA032619-01]; Optum, United Health Group FX Supported by the National Institute on Drug Abuse (NIDA, 1R01DA032619-01, PI: Ettner), and data from Optum.; F.A. is an employee of Optum, United Health Group and as such receives salary and stock options as part of her compensation. A.T. was a contractor for and received salary from Optum, United Health Group. The remaining authors declare no conflict of interest. NR 27 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD FEB PY 2017 VL 55 IS 2 BP 164 EP 172 PG 9 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA EJ0RY UT WOS:000392919300015 PM 27632769 ER PT J AU Mays, VM Jones, AL Delany-Brumsey, A Coles, C Cochran, SD AF Mays, Vickie M. Jones, Audrey L. Delany-Brumsey, Ayesha Coles, Courtney Cochran, Susan D. TI Perceived Discrimination in Health Care and Mental Health/Substance Abuse Treatment Among Blacks, Latinos, and Whites SO MEDICAL CARE LA English DT Article DE race/ethnicity; provider discrimination; mental health; substance abuse ID QUALITY-OF-CARE; RACIAL-DISCRIMINATION; ETHNIC DISPARITIES; COLLABORATIVE CARE; AFRICAN-AMERICAN; UNITED-STATES; LIFE SURVEY; BORN BLACK; DRUG-ABUSE; US-BORN AB Background: Experiences of discrimination in health care settings may contribute to disparities in mental health outcomes for blacks and Latinos. We investigate whether perceived discrimination in mental health/substance abuse visits contributes to participants' ratings of treatment helpfulness and stopped treatment. Research Methods: We used data from 3 waves of the California Quality of Life Survey, a statewide population-based telephone survey assessing mental health/substance disorders and their treatment. In a sample of 1099 adults (age 18-72) who indicated prior year mental health/substance abuse visits, we examined: experiences of discrimination that occurred during health care and mental health/substance abuse visits, ratings of treatment helpfulness, and reports of stopping treatment early. Results: Fifteen percent of California adults reported discrimination during a health care visit and 4% specifically during mental health/substance abuse visits. Latinos, the uninsured, and those with past year mental disorders were twice as likely as others to report health care discrimination [adjusted odds ratio (AORs) = 2.08, 2.77, and 2.51]. Uninsured patients were 7 times more likely to report discrimination in mental health/substance abuse visits (AOR = 7.27, P < 0.01). The most commonly reported reasons for health care discrimination were race/ethnicity for blacks (52%) and Latinos (31%), and insurance status for whites (40%). Experiences of discrimination in mental health/substance abuse visits were associated with less helpful treatment ratings for Latinos (AOR = 0.09, P < 0.05) and whites (AOR = 0.25, P < 0.01), and early treatment termination for blacks (AOR = 13.38, P < 0.05). Conclusions: Experiences of discrimination are associated with negative mental health/substance abuse treatment experiences and stopped treatment, and could be a factor in mental health outcomes. C1 [Mays, Vickie M.; Coles, Courtney; Cochran, Susan D.] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Hlth Policy & Management, 405 Hilgard Ave,POB 951563, Los Angeles, CA 90095 USA. [Mays, Vickie M.; Jones, Audrey L.; Delany-Brumsey, Ayesha; Coles, Courtney; Cochran, Susan D.] Univ Calif Los Angeles, Ctr Bridging Res, Innovat Training & Educ Minor Hlth Dispar Solut, 405 Hilgard Ave,POB 951563, Los Angeles, CA 90095 USA. [Jones, Audrey L.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Delany-Brumsey, Ayesha] Vera Inst Justice, New York, NY USA. RP Mays, VM (reprint author), Univ Calif Los Angeles, Dept Psychol, Fielding Sch Publ Hlth, 405 Hilgard Ave,POB 951563, Los Angeles, CA 90095 USA. EM mays@ucla.edu FU National Institute of Drug Abuse [DA 15539, DA 20826]; National Institute of Minority Health Disparities [MD 00508, MD006923]; VA Office of Academic Affiliations Associated Health Professions FX Supported by funding from the National Institute of Drug Abuse (DA 15539; DA 20826) and National Institute of Minority Health Disparities (MD 00508, MD006923).; Dr Jones is supported as a VA Office of Academic Affiliations Associated Health Professions Post-doctoral Fellow in Health Services Research. The contents of this article do not represent the views of the Department of Veterans Affairs or the United States Government. NR 50 TC 1 Z9 1 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD FEB PY 2017 VL 55 IS 2 BP 173 EP 181 PG 9 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA EJ0RY UT WOS:000392919300016 PM 27753743 ER PT J AU Dubach, JM Kim, E Yang, K Cuccarese, M Giedt, RJ Meirnetis, LG Vinegoni, C Weissleder, R AF Dubach, J. Matthew Kim, Eunha Yang, Katherine Cuccarese, Michael Giedt, Randy J. Meirnetis, Libros G. Vinegoni, Claudio Weissleder, Ralph TI Quantitating drug-target engagement in single cells in vitro and in vivo SO NATURE CHEMICAL BIOLOGY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; ACTIVITY-BASED PROBES; PARP INHIBITOR; IMMUNOFLUORESCENCE; IDENTIFICATION; RESISTANCE; BINDING; AGENTS; TUMORS; MODELS AB Quantitation of drug target engagement in single cells has proven to be difficult, often leaving unanswered questions in the drug development process. We found that intracellular target engagement of unlabeled new therapeutics can be quantitated using polarized microscopy combined with competitive binding of matched fluorescent companion imaging probes. We quantitated the dynamics of target engagement of covalent BTK inhibitors, as well as reversible PARP inhibitors, in populations of single cells using a single companion imaging probe for each target. We then determined average in vivo tumor concentrations and found marked population heterogeneity following systemic delivery, revealing single cells with low target occupancy at high average target engagement in vivo. C1 [Dubach, J. Matthew; Kim, Eunha; Yang, Katherine; Cuccarese, Michael; Giedt, Randy J.; Meirnetis, Libros G.; Vinegoni, Claudio; Weissleder, Ralph] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA USA. [Weissleder, Ralph] Harvard Med Sch, Dept Syst Biol, Boston, MA USA. [Kim, Eunha] Ajou Univ, Dept Mol Sci & Technol, Suwon, South Korea. RP Vinegoni, C; Weissleder, R (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA USA.; Weissleder, R (reprint author), Harvard Med Sch, Dept Syst Biol, Boston, MA USA. EM cvinegoni@mgh.harvard.edu; rweissleder@mgh.harvard.edu FU US National Institutes of Health [T32CA079443, K99CA198857, R01CA164448, P50CA086355, R01HL122208]; Department of Defense grant BCRP [BC134081] FX We thank T. Mitchison for his thoughts on experimental approaches and comments on the manuscript. This work was supported by US National Institutes of Health grants T32CA079443 (J.M.D., M.C. and R.W.), K99CA198857 (J.M.D.), R01CA164448, P50CA086355 and R01HL122208 (R.W.), and Department of Defense grant BCRP #BC134081 (R.J.G.). NR 41 TC 1 Z9 1 U1 9 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 EI 1552-4469 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD FEB PY 2017 VL 13 IS 2 BP 168 EP 173 DI 10.1038/NCHEMBIO.2248 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EJ9FW UT WOS:000393533000011 PM 27918558 ER PT J AU Park, RJ Wang, T Koundakjian, D Hultquist, JF Lamothe-Molina, P Monel, B Schumann, K Yu, HY Krupzcak, KM Garcia-Beltran, W Piechocka-Trocha, A Krogan, NJ Marson, A Sabatini, DM Lander, ES Hacohen, N Walker, BD AF Park, Ryan J. Wang, Tim Koundakjian, Dylan Hultquist, Judd F. Lamothe-Molina, Pedro Monel, Blandine Schumann, Kathrin Yu, Haiyan Krupzcak, Kevin M. Garcia-Beltran, Wilfredo Piechocka-Trocha, Alicja Krogan, Nevan J. Marson, Alexander Sabatini, David M. Lander, Eric S. Hacohen, Nir Walker, Bruce D. TI A genome-wide CRISPR screen identifies a restricted set of HIV host dependency factors SO NATURE GENETICS LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ADHESION MOLECULE; CELL-ADHESION; T-CELLS; ANTIRETROVIRAL THERAPY; TYROSINE SULFATION; TYROSYLPROTEIN SULFOTRANSFERASES; GP120 BINDING; EARLY-STAGE; REPLICATION AB Host proteins are essential for HIV entry and replication and can be important nonviral therapeutic targets. Large-scale RNA interference (RNAi)-based screens have identified nearly a thousand candidate host factors, but there is little agreement among studies and few factors have been validated. Here we demonstrate that a genome-wide CRISPR-based screen identifies host factors in a physiologically relevant cell system. We identify five factors, including the HIV co-receptors CD4 and CCR5, that are required for HIV infection yet are dispensable for cellular proliferation and viability. Tyrosylprotein sulfotransferase 2 (TPST2) and solute carrier family 35 member B2 (SLC3562) function in a common pathway to sulfate CCR5 on extracellular tyrosine residues, facilitating CCR5 recognition by the HIV envelope. Activated leukocyte cell adhesion molecule (ALCAM) mediates cell aggregation, which is required for cell-to-cell HIV transmission. We validated these pathways in primary human CD4(+) T cells through Cas9-mediated knockout and antibody blockade. Our findings indicate that HIV infection and replication rely on a limited set of host-dispensable genes and suggest that these pathways can be studied for therapeutic intervention. C1 [Park, Ryan J.; Koundakjian, Dylan; Lamothe-Molina, Pedro; Monel, Blandine; Garcia-Beltran, Wilfredo; Piechocka-Trocha, Alicja; Walker, Bruce D.] MIT, Massachusetts Gen Hosp, Ragon Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Park, Ryan J.; Koundakjian, Dylan; Lamothe-Molina, Pedro; Monel, Blandine; Garcia-Beltran, Wilfredo; Piechocka-Trocha, Alicja; Walker, Bruce D.] Harvard Univ, Cambridge, MA 02138 USA. [Park, Ryan J.; Garcia-Beltran, Wilfredo] Harvard Med Sch, Harvard MIT Hlth Sci & Technol, Boston, MA 02115 USA. [Park, Ryan J.; Wang, Tim; Yu, Haiyan; Sabatini, David M.; Lander, Eric S.; Hacohen, Nir; Walker, Bruce D.] Broad Inst MIT & Harvard Univ, Cambridge, MA 02142 USA. [Wang, Tim; Sabatini, David M.; Lander, Eric S.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Wang, Tim; Krupzcak, Kevin M.; Sabatini, David M.] Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA. [Wang, Tim; Sabatini, David M.] MIT, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Hultquist, Judd F.; Krogan, Nevan J.] Univ Calif San Francisco, Calif Inst Quantitat Biosci QB3, Dept Mol & Cellular Pharmacol, San Francisco, CA 94143 USA. [Hultquist, Judd F.; Marson, Alexander] J David Gladstone Inst, Gladstone Inst Virol & Immunol, San Francisco, CA USA. [Lamothe-Molina, Pedro] Harvard TH Chan Sch Publ Hlth, Biol Sci Publ Hlth, Boston, MA 02115 USA. [Monel, Blandine; Walker, Bruce D.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. [Monel, Blandine; Walker, Bruce D.] Harvard Med Sch, Boston, MA 02115 USA. [Schumann, Kathrin; Marson, Alexander] Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USA. [Marson, Alexander] Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA. [Marson, Alexander] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Marson, Alexander] Univ Calif Berkeley, Innovat Genom Initiat, Berkeley, CA 94720 USA. [Marson, Alexander] Univ Calif San Francisco, UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Sabatini, David M.] MIT, Howard Hughes Med Inst, Dept Biol, Cambridge, MA 02139 USA. [Lander, Eric S.] Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA. [Hacohen, Nir] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Walker, Bruce D.] MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Walker, BD (reprint author), MIT, Massachusetts Gen Hosp, Ragon Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Walker, BD (reprint author), Harvard Univ, Cambridge, MA 02138 USA.; Sabatini, DM; Lander, ES; Hacohen, N; Walker, BD (reprint author), Broad Inst MIT & Harvard Univ, Cambridge, MA 02142 USA.; Sabatini, DM; Lander, ES (reprint author), MIT, Dept Biol, Cambridge, MA 02139 USA.; Sabatini, DM (reprint author), Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA.; Sabatini, DM (reprint author), MIT, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Walker, BD (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA.; Walker, BD (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Sabatini, DM (reprint author), MIT, Howard Hughes Med Inst, Dept Biol, Cambridge, MA 02139 USA.; Lander, ES (reprint author), Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA.; Hacohen, N (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA.; Walker, BD (reprint author), MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM sabatini@wi.mit.edu; lander@broadinstitute.org; nhacohen@mgh.harvard.edu; bwalker@mgh.harvard.edu FU Howard Hughes Medical Institute; National Institutes of Health [CA103866, F31 CA189437, P50 GM082250, U19 AI106754, P01 AI090935]; National Human Genome Research Institute [2U54HG003067-10]; National Science Foundation; MIT Whitaker Health Sciences Fund; UCSF Sandler Fellowship; UCSF MPHD T32 Training Grant; Deutsche Forschungsgemeinschaft [SCHU3020/2-1]; NIH [P30 AI027763, P30 AI060354]; Harvard University Center for AIDS Research [P30 AI060354]; NIH; NIAID; NCI; NICHD; NHLBI; NIDA; NIMH; NIA; FIC; OAR FX We would like to thank the Ragon Institute Virology, Imaging, and Flow Cytometry cores, as well as the Center for Computational and Integrative Biology (CCIB) DNA Core Facility at Massachusetts General Hospital. We would like to thank A. McKeon, P. Jani, N.W. Hughes, and B.X. Liu for superb technical assistance, and A. Brass, G. Gaiha, and J.S. Park for helpful discussions. pMM310 was obtained through the AIDS Reagent Program, Division of AIDS, NIAID, NIH from M. Miller (Merck Research Laboratories). All plasmid reagents generated in this study have been deposited in Addgene. This work was supported by the Howard Hughes Medical Institute (D.M.S. and B.D.W.), the National Institutes of Health (grants CA103866 (D.M.S.), F31 CA189437 (T.W.), P50 GM082250 (A.M. and N.J.K.), U19 AI106754 (J.F.H. and N.J.K.), and P01 AI090935 (N.J.K.)), the National Human Genome Research Institute (grant 2U54HG003067-10; E.S.L.), the National Science Foundation (T.W.), the MIT Whitaker Health Sciences Fund(T.W.), the UCSF Sandler Fellowship(A.M.), a gift from J. Aronov (A.M.), the UCSF MPHD T32 Training Grant (J.F.H.), and the Deutsche Forschungsgemeinschaft (grant SCHU3020/2-1; KS.). Support was also provided by NIH-funded Centers for AIDS Research (grant P30 AI027763, UCSF Center for AIDS Research (N.J.K.) and grant P30 AI060354, Harvard University Center for AIDS Research (B.D.W.)), which are supported by the following NIH co-funding and participating Institutes and Centers: NIAID, NCI, NICHD, NHLBI, NIDA, NIMH, NIA, FIC, and OAR. D.M.S. and B.D.W. are investigators of the Howard Hughes Medical Institute. R.J.P. is a Howard Hughes Medical Institute Research Fellow. NR 69 TC 2 Z9 2 U1 10 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD FEB PY 2017 VL 49 IS 2 BP 193 EP 203 DI 10.1038/ng.3741 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA EJ3YM UT WOS:000393148600008 PM 27992415 ER PT J AU Kadoch, C Williams, RT Calarco, JP Miller, EL Weber, CM Braun, SMG Pulice, JL Chory, EJ Crabtree, GR AF Kadoch, Cigall Williams, Robert T. Calarco, Joseph P. Miller, Erik L. Weber, Christopher M. Braun, Simon M. G. Pulice, John L. Chory, Emma J. Crabtree, Gerald R. TI Dynamics of BAF-Polycomb complex opposition on heterochromatin in normal and oncogenic states SO NATURE GENETICS LA English DT Article ID CHROMATIN-REMODELING COMPLEX; COFFIN-SIRIS SYNDROME; NEURAL DEVELOPMENT; SWI/SNF COMPLEXES; SYNOVIAL SARCOMA; HOMEOTIC GENES; CANCER; PRC2; NUCLEOSOME; MUTATIONS AB The opposition between Polycomb repressive complexes (PRCs) and BAF (mSWI/SNF) complexes has a critical role in both development and disease. Mutations in the genes encoding BAF subunits contribute to more than 20% of human malignancies, yet the underlying mechanisms remain unclear, owing largely to a lack of assays to assess BAF function in living cells. To address this, we have developed a widely applicable recruitment assay system through which we find that BAF opposes PRC by rapid, ATP-dependent eviction, leading to the formation of accessible chromatin. The reversal of this process results in reassembly of facultative heterochromatin. Surprisingly, BAF-mediated PRC eviction occurs in the absence of RNA polymerase II (Pol II) occupancy, transcription, and replication. Further, we find that tumor-suppressor and oncogenic mutant BAF complexes have different effects on PRC eviction. The results of these studies define a mechanistic sequence underlying the resolution and formation of facultative heterochromatin, and they demonstrate that BAF opposes PRC on a minute-by-minute basis to provide epigenetic plasticity. C1 [Kadoch, Cigall; Williams, Robert T.; Pulice, John L.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Kadoch, Cigall; Williams, Robert T.; Pulice, John L.] Harvard Med Sch, Boston, MA 02115 USA. [Kadoch, Cigall; Pulice, John L.] Broad Inst & MIT Harvard, Cambridge, MA 02142 USA. [Calarco, Joseph P.; Miller, Erik L.; Weber, Christopher M.; Braun, Simon M. G.; Chory, Emma J.; Crabtree, Gerald R.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Calarco, Joseph P.; Miller, Erik L.; Weber, Christopher M.; Braun, Simon M. G.; Chory, Emma J.; Crabtree, Gerald R.] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA. [Calarco, Joseph P.; Miller, Erik L.; Weber, Christopher M.; Braun, Simon M. G.; Chory, Emma J.; Crabtree, Gerald R.] Stanford Univ, Dept Dev Biol, Sch Med, Stanford, CA 94305 USA. RP Kadoch, C (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA.; Kadoch, C (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Kadoch, C (reprint author), Broad Inst & MIT Harvard, Cambridge, MA 02142 USA.; Crabtree, GR (reprint author), Howard Hughes Med Inst, Chevy Chase, MD 20815 USA.; Crabtree, GR (reprint author), Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA.; Crabtree, GR (reprint author), Stanford Univ, Dept Dev Biol, Sch Med, Stanford, CA 94305 USA. EM cigall_kadoch@dfci.harvard.edu; crabtree@stanford.edu FU NIH Director's New Innovator Award DP2 [1DP2CA195762-01]; American Cancer Society Scholar Award [RSG-14-051-01-DMC]; Pew Scholar Award; A.P. Giannini Foundation; Alex's Lemonade Stand Foundation (ALSF) Young Investigator Award; NIH SARC Sarcoma SPORE Career Development and SPORE Project [5U54 CA168512-04]; NIH grants [CA163915, NS046789]; CIRM [RB4-05886]; Howard Hughes Medical Institute; SPARS FX We are grateful to N. Hathaway, O. Bell, L. Chen, and J. Ronan, for insightful comments and technical assistance. We thank M. Alhamadsheh for synthesis of FK1012. We also thank J. Buenrostro and B. Wu for helpful advice and technical assistance with accessibility studies and V. Petkova. C.K. was supported by the NIH Director's New Innovator Award DP2 (1DP2CA195762-01), the American Cancer Society Scholar Award (RSG-14-051-01-DMC), the Pew Scholar Award, the A.P. Giannini Foundation, the Alex's Lemonade Stand Foundation (ALSF) Young Investigator Award, and the NIH SARC Sarcoma SPORE Career Development and SPORE Project (5U54 CA168512-04) awards. G.R.C. is supported by NIH grants (CA163915, NS046789), CIRM RB4-05886, SPARS and the Howard Hughes Medical Institute. NR 58 TC 3 Z9 3 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD FEB PY 2017 VL 49 IS 2 BP 213 EP 222 DI 10.1038/ng.3734 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA EJ3YM UT WOS:000393148600010 PM 27941796 ER PT J AU Shaw, ND Brand, H Kupchinsky, ZA Bengani, H Plummer, L Jones, TI Erdin, S Williamson, KA Rainger, J Stortchevoi, A Samocha, K Curra, BB Dunican, DS Collins, RL Willer, JR Lek, A Lek, M Nassan, M Pereira, S Kammin, T Lucente, D Silva, A Seabra, CM Chiang, C Ana, Y Ansari, M Rainger, JK Joss, S Smith, JC Lippincott, MF Singh, SS Patel, N Jing, JW Law, JR Ferraro, N Verloes, M Rauch, A Steindl, K Zweier, M Scheer, I Sato, D Okamoto, N Jacobsen, C Tryggestad, J Chernausek, S Schimmenti, LA Brasseur, B Cesaretti, C Garcia-Ortiz, JE Buitrago, TP Silva, OP Hoffman, JD Muhlbauer, W Ruprecht, KW Loeys, BL Shino, M Kaind, AM Cho, CH Morton, CC Meehan, RR van Heyningen, V Liao, EC Balasubramanian, R Hall, JE Seminara, SB Macarthur, D Moore, SA Yoshiura, K Gusella, JF Marsh, JA Graham, JM Lin, AE Katsanis, N Jones, PL Crowley, WF Davis, EE FitzPatrick, DR Talkowski, ME AF Shaw, Natalie D. Brand, Harrison Kupchinsky, Zachary A. Bengani, Hemant Plummer, Lacey Jones, Takako I. Erdin, Serkan Williamson, Kathleen A. Rainger, Joe Stortchevoi, Alexei Samocha, Kaitlin Curra, Benjamin B. Dunican, Donncha S. Collins, Ryan L. Willer, Jason R. Lek, Angela Lek, Monkol Nassan, Malik Pereira, Shahrin Kammin, Tammy Lucente, Diane Silva, Alexandra Seabra, Catarina M. Chiang, Colby Ana, Yu Ansari, Morad Rainger, Jacqueline K. Joss, Shelagh Smith, Jill Clayton Lippincott, Margaret F. Singh, Sylvia S. Patel, Nirav Jing, Jenny W. Law, Jennifer R. Ferraro, Nalton Verloes, Main Rauch, Anita Steindl, Katharina Zweier, Markus Scheer, Ianina Sato, Daisuke Okamoto, Nobuhiko Jacobsen, Christina Tryggestad, Jeanie Chernausek, Steven Schimmenti, Lisa A. Brasseur, Benjamin Cesaretti, Claudia Garcia-Ortiz, Jose E. Pineda Buitrago, Tatiana Perez Silva, Orlando Hoffman, Jodi D. Muehlbauer, Wolfgang Ruprecht, Klaus W. Loeys, Bart L. Shino, Masato Kaind, Angela M. Cho, Chie-Hee Morton, Cynthia C. Meehan, Richard R. van Heyningen, Veronica Liao, Eric C. Balasubramanian, Ravikumar Hall, Janet E. Seminara, Stephanie B. Macarthur, Daniel Moore, Steven A. Yoshiura, Koh-ichiro Gusella, James F. Marsh, Joseph A. Graham, John M., Jr. Lin, Angela E. Katsanis, Nicholas Jones, Peter L. Crowley, William F., Jr. Davis, Erica E. FitzPatrick, David R. Talkowski, Michael E. TI SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome SO NATURE GENETICS LA English DT Article ID X INACTIVATION; CHROMOSOME; EXPRESSION; DOMAIN; FSHD1; GNRH; METHYLATION; INHERITANCE; HYPOPLASIA; PREDICTION AB Arhinia, or absence of the nose, is a rare malformation of unknown etiology that is often accompanied by ocular and reproductive defects. Sequencing of 40 people with arhinia revealed that 84% of probands harbor a missense mutation localized to a constrained region of SMCHD1 encompassing the ATPase domain. SMCHD1 mutations cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) via a trans-acting loss-of function epigenetic mechanism. We discovered shared mutations and comparable DNA hypomethylation patterning between these distinct disorders. CRISPR/Cas9-mediated alteration of smchd1 in zebrafish yielded arhinia-relevant phenotypes. Transcriptome and protein analyses in arhinia probands and controls showed no differences in SMCHD1 mRNA or protein abundance but revealed regulatory changes in genes and pathways associated with craniofacial patterning. Mutations in SMCHD1 thus contribute to distinct phenotypic spectra, from craniofacial malformation and reproductive disorders to muscular dystrophy, which we speculate to be consistent with oligogenic mechanisms resulting in pleiotropic outcomes. C1 [Shaw, Natalie D.; Brand, Harrison; Plummer, Lacey; Lippincott, Margaret F.; Singh, Sylvia S.; Patel, Nirav; Jing, Jenny W.; Balasubramanian, Ravikumar; Hall, Janet E.; Seminara, Stephanie B.; Crowley, William F., Jr.] Massachusetts Gen Hosp, Dept Med, Reprod Endocrine Unit, Harvard Reprod Endocrine Sci Ctr, Boston, MA 02114 USA. [Shaw, Natalie D.; Brand, Harrison; Plummer, Lacey; Lippincott, Margaret F.; Singh, Sylvia S.; Patel, Nirav; Jing, Jenny W.; Balasubramanian, Ravikumar; Hall, Janet E.; Seminara, Stephanie B.; Crowley, William F., Jr.] Massachusetts Gen Hosp, Dept Med, Reprod Endocrine Unit, NICHD Ctr Excellence Translat Res Fertil & Infert, Boston, MA 02114 USA. [Shaw, Natalie D.; Hall, Janet E.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. [Brand, Harrison; Erdin, Serkan; Stortchevoi, Alexei; Curra, Benjamin B.; Collins, Ryan L.; Lucente, Diane; Silva, Alexandra; Seabra, Catarina M.; Chiang, Colby; Ana, Yu; Talkowski, Michael E.] Massachusetts Gen Hosp, Ctr Human Genet Res, Mol Neurogenet Unit, Boston, MA 02114 USA. [Brand, Harrison; Erdin, Serkan; Stortchevoi, Alexei; Curra, Benjamin B.; Collins, Ryan L.; Lucente, Diane; Silva, Alexandra; Seabra, Catarina M.; Chiang, Colby; Ana, Yu; Gusella, James F.; Talkowski, Michael E.] Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Brand, Harrison; Gusella, James F.; Talkowski, Michael E.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Brand, Harrison; Samocha, Kaitlin; Lek, Monkol; Jacobsen, Christina; Liao, Eric C.; Lin, Angela E.; Talkowski, Michael E.] Harvard Med Sch, Boston, MA 02115 USA. [Brand, Harrison; Erdin, Serkan; Samocha, Kaitlin; Lek, Monkol; Morton, Cynthia C.; Macarthur, Daniel; Gusella, James F.; Talkowski, Michael E.] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Kupchinsky, Zachary A.; Willer, Jason R.; Katsanis, Nicholas; Davis, Erica E.] Duke Univ, Med Ctr, Ctr Human Dis Modeling, Durham, NC 27708 USA. [Bengani, Hemant; Williamson, Kathleen A.; Rainger, Joe; Dunican, Donncha S.; Ansari, Morad; Rainger, Jacqueline K.; Meehan, Richard R.; van Heyningen, Veronica; Marsh, Joseph A.; FitzPatrick, David R.] Univ Edinburgh, Western Gen Hosp, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland. [Jones, Takako I.; Jones, Peter L.] Univ Massachusetts Med Sch, Dept Cell & Dev Biol, Worcester, MA 01655 USA. [Samocha, Kaitlin; Lek, Monkol; Macarthur, Daniel] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Collins, Ryan L.] Harvard Med Sch, Div Med Sci, Program Bioinformat & Integrat Genom, Boston, MA 02115 USA. [Lek, Angela; Gusella, James F.] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Nassan, Malik] Mayo Clin, Dept Psychiat & Psychol, Rochester, MN 55905 USA. [Pereira, Shahrin; Kammin, Tammy; Morton, Cynthia C.] Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, 75 Francis St, Boston, MA 02115 USA. [Seabra, Catarina M.] Univ Porto, GABBA Program, Oporto, Portugal. [Joss, Shelagh] South Glasgow Univ Hosp, West Scotland Genet Serv, Glasgow, Lanark, Scotland. [Smith, Jill Clayton] Univ Manchester, Manchester Acad Hlth Sci Ctr, Manchester Ctr Genom Med, Fac Med & Human Sci,Inst Human Dev, Manchester, Lancs, England. [Law, Jennifer R.] Univ N Carolina, Div Pediat Endocrinol, Chapel Hill, NC 27514 USA. [Ferraro, Nalton] Boston Childrens Hosp, Dept Oral & Maxillofacial Surg, Boston, MA USA. [Verloes, Main] Robert Debre Hosp, Dept Genet, Paris, France. [Rauch, Anita; Steindl, Katharina; Zweier, Markus] Univ Zurich, Clin Res Prior Program Rare Dis, Inst Med Genet, Schlieren, Switzerland. [Rauch, Anita; Steindl, Katharina; Zweier, Markus] Univ Zurich, Clin Res Prior Program Rare Dis, Radiz Rare Dis Initiat Zurich, Schlieren, Switzerland. [Scheer, Ianina] Childrens Hosp, Dept Diagnost Imaging, Zurich, Switzerland. [Sato, Daisuke] Hokkaido Univ, Grad Sch Med, Dept Pediat, Sapporo, Hokkaido, Japan. [Okamoto, Nobuhiko] Osaka Med Ctr, Dept Med Genet, Osaka, Japan. [Okamoto, Nobuhiko] Res Inst Maternal & Child Hlth, Osaka, Japan. [Jacobsen, Christina] Boston Childrens Hosp, Div Endocrinol & Genet, Boston, MA 02115 USA. [Tryggestad, Jeanie] Univ Oklahoma, Hlth Sci Ctr, Dept Pediat, Oklahoma City, OK 73190 USA. [Schimmenti, Lisa A.] Mayo Clin, Dept Otorhinolaryngol, Rochester, MN 55905 USA. [Schimmenti, Lisa A.] Mayo Clin, Dep Clin Genom, Rochester, MN 55905 USA. [Brasseur, Benjamin] Univ Miami, Leonard M Miller Sch Med, DeWitt Daughtry Family Dept Surg, Miami, FL 33146 USA. [Cesaretti, Claudia] Osped Maggiore Policlin, Fdn IRCCS Ca Granda, Med Genet Unit, Milan, Italy. [Garcia-Ortiz, Jose E.] Inst Mexicano Seguro Social, Ctr Invest Biomed Occidente, Div Genet, Guadalajara, Mexico. [Pineda Buitrago, Tatiana] San Jose State Univ, Fdn Hosp Infantil, Bogota, Colombia. [Perez Silva, Orlando] Acad Nacl Med Colombia, Bogota, Colombia. [Hoffman, Jodi D.] Tufts Med Ctr, Div Genet, Boston, MA 02111 USA. [Hoffman, Jodi D.] Tufts Med Ctr, Div Maternal Fetal Med, Boston, MA 02111 USA. [Muehlbauer, Wolfgang] ATOS Klin, Dept Plast & Aesthet Surg, Munich, Germany. [Ruprecht, Klaus W.] Univ Hosp Saarland, Dept Ophthalmol, Homburg, Germany. [Loeys, Bart L.] Univ Antwerp, Ctr Med Genet, Antwerp, Belgium. [Loeys, Bart L.] Univ Antwerp Hosp, Antwerp, Belgium. [Shino, Masato] Gunma Univ, Grad Sch Med, Dept Otolaryngol Head & Neck Surg, Gunma, Japan. [Kaind, Angela M.] Charite, Biol & Neurobiol, Berlin, Germany. [Kaind, Angela M.] Berlin Inst Hlth, Berlin, Germany. [Cho, Chie-Hee] Univ Hosp Bern, Inselspital, Dept Diagnost Intervent & Pediat Radiol, Bern, Switzerland. [Liao, Eric C.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Liao, Eric C.] Massachusetts Gen Hosp, Div Plast & Reconstruct Surg, Boston, MA 02114 USA. [Liao, Eric C.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Macarthur, Daniel; Talkowski, Michael E.] Broad Inst MIT & Harvard, Ctr Mendelian Genom, Cambridge, MA 02142 USA. [Moore, Steven A.] Univ Iowa, Carver Coll Med, Dept Pathol, Iowa City, IA 52242 USA. [Yoshiura, Koh-ichiro] Nagasaki Univ, Grad Sch Biomed Sci, Dept Human Genet, Nagasaki, Japan. [Graham, John M., Jr.] Cedars Sinai Med Ctr, Dept Pediat, Los Angeles, CA 90048 USA. [Lin, Angela E.] MassGeneral Hosp Children, Med Genet, Boston, MA 02114 USA. RP Talkowski, ME (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Mol Neurogenet Unit, Boston, MA 02114 USA.; Talkowski, ME (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA.; Talkowski, ME (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA.; Talkowski, ME (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Talkowski, ME (reprint author), Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA.; Davis, EE (reprint author), Duke Univ, Med Ctr, Ctr Human Dis Modeling, Durham, NC 27708 USA.; FitzPatrick, DR (reprint author), Univ Edinburgh, Western Gen Hosp, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland.; Talkowski, ME (reprint author), Broad Inst MIT & Harvard, Ctr Mendelian Genom, Cambridge, MA 02142 USA. EM erica.davis@duke.edu; david.fitzpatrick@igmm.ed.ac.uk; talkowski@chgr.mgh.harvard.edu OI van Heyningen, Veronica/0000-0003-0359-0141; Erdin, Serkan/0000-0001-6587-2625; Shaw, Natalie/0000-0002-0847-9170; Loeys, Bart/0000-0003-3703-9518; Hall, Janet/0000-0003-4644-3061; FitzPatrick, David R./0000-0003-4861-969X; Marsh, Joseph/0000-0003-4132-0628 FU National Institutes of Health ((NIH)) [R00MH095867, R01HD081256, P01GM061354, T32HD007396, P50HD028138]; MGH Robert and Laura Reynolds Research Scholar Award [R01HD043341]; March of Dimes [FY15-255]; Medical Research Council [MR/M02122X/1]; German Research Foundation [SFB665]; Berlin Institute of Health (BIH) [CRG1]; Medical Research Council (MRC) Human Genetics Unit award [MC_PC_U127574433]; University of Edinburgh Institute of Genomics and Molecular Medicine Translational Initiative Fund; [K23HD073304-02]; [1SI2ES025429-01]; [P50DK096415]; [R01AR062587]; [U54-NS053672] FX We thank all participants, family members and clinical staff for their generous contributions of time and materials to this research. We thank T. Gillis, J. Ruliera, C. Hanscom, C. Antolik and M. Anderson for technical assistance. This project was funded by grants from the National Institutes of Health ((NIH) R00MH095867 and R01HD081256 to M.E.T.; P01GM061354 to M.E.T., J.F.G., C.C.M. and E.C.L.; T32HD007396 to H. Brand; P50HD028138 to W.F.C., S.B.S., M.E.T., N.K. and E.E.D.; R01HD043341 and MGH Robert and Laura Reynolds Research Scholar Award to S.B.S.; K23HD073304-02 and 1SI2ES025429-01 to N.D.S.; P50DK096415 to N.K. and R01AR062587 to P.L.J.); the March of Dimes (FY15-255 to M.E.T.); the Medical Research Council (MR/M02122X/1 to J.A.M.); the German Research Foundation (SFB665 to A.M.K.) and the Berlin Institute of Health (BIH-CRG1 to A.M.K.). D.R.F., R.R.M. (MC_PC_U127574433), D.S.D., H. Bengani, K.A.W., J.R., J.K.R. and J.A.M. are funded by program grants from the Medical Research Council (MRC) Human Genetics Unit award to the University of Edinburgh. M.A. is funded by the University of Edinburgh Institute of Genomics and Molecular Medicine Translational Initiative Fund. S.A.M. is supported by U54-NS053672, which funds the Iowa, Paul D. Wellstone Muscular Dystrophy Cooperative Research Center. N.K. is supported as a Distinguished Jean and George Brumley Professor at Duke University, and M.E.T. is supported as the Desmond and Ann Heathwood MGH Research Scholar. NR 52 TC 1 Z9 1 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD FEB PY 2017 VL 49 IS 2 BP 238 EP 248 DI 10.1038/ng.3743 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA EJ3YM UT WOS:000393148600012 PM 28067909 ER PT J AU Lane, JM Liang, JJ Vlasac, I Anderson, SG Bechtold, DA Bowden, J Emsley, R Gill, S Little, MA Luik, AI Loudon, A Scheer, FAJL Purcell, SM Kyle, SD Lawlor, DA Zhu, XF Redline, S Ray, DW Rutter, MK Saxena, R AF Lane, Jacqueline M. Liang, Jingjing Vlasac, Irma Anderson, Simon G. Bechtold, David A. Bowden, Jack Emsley, Richard Gill, Shubhroz Little, Max A. Luik, Annemarie I. Loudon, Andrew Scheer, Frank A. J. L. Purcell, Shaun M. Kyle, Simon D. Lawlor, Deborah A. Zhu, Xiaofeng Redline, Susan Ray, David W. Rutter, Martin K. Saxena, Richa TI Genome-wide association analyses of sleep disturbance traits identify new loci and highlight shared genetics with neuropsychiatric and metabolic traits SO NATURE GENETICS LA English DT Article ID RESTLESS LEGS SYNDROME; CHROMOSOME FUSION SITE; SLOW-WAVE SLEEP; UK BIOBANK; DAYTIME SLEEPINESS; PARALOGOUS REGIONS; 5-HT2C RECEPTORS; SEROTONIN 5-HT2A; COMMON VARIANTS; MEIS1 AB Chronic sleep disturbances, associated with cardiometabolic diseases, psychiatric disorders and all-cause mortality(1,2), affect 25-30% of adults worldwide(3). Although environmental factors contribute substantially to self-reported habitual sleep duration and disruption, these traits are heritable(4-9) and identification of the genes involved should improve understanding of sleep, mechanisms linking sleep to disease and development of new therapies. We report single- and multiple-trait genome-wide association analyses of self-reported sleep duration, insomnia symptoms and excessive daytime sleepiness in the UK Biobank (n = 112,586). We discover loci associated with insomnia symptoms (near MEIS1, TMEM132E, CYCL1 and TGFBI in females and WDR27 in males), excessive daytime sleepiness (near AR-OPHN1) and a composite sleep trait (near PATJ (INADL) and HCRTR2) and replicate a locus associated with sleep duration (at PAX8). We also observe genetic correlation between longer sleep duration and schizophrenia risk (r(g) = 0.29, P = 1.90 x 10(-13)) and between increased levels of excessive daytime sleepiness and increased measures for adiposity traits (body mass index (BMI): r(g) = 0.20, P = 3.12 x 10(-9); waist circumference: r(g) = 0.20, P = 2.12 x 10(-7)). C1 [Lane, Jacqueline M.; Vlasac, Irma; Saxena, Richa] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Lane, Jacqueline M.; Saxena, Richa] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Lane, Jacqueline M.; Saxena, Richa] Harvard Med Sch, Boston, MA 02115 USA. [Lane, Jacqueline M.; Vlasac, Irma; Gill, Shubhroz; Purcell, Shaun M.; Saxena, Richa] Broad Inst, Cambridge, MA 02142 USA. [Liang, Jingjing; Zhu, Xiaofeng] Case Western Reserve Univ, Dept Epidemiol & Biostat, Sch Med, Cleveland, OH 44106 USA. [Anderson, Simon G.] Univ Manchester, Sch Med Sci, Fac Biol Med & Hlth, Div Cardiovasc Sci, Manchester, Lancs, England. [Anderson, Simon G.] Univ Oxford, Oxford Martin Sch, George Inst Global Hlth, Oxford, England. [Bechtold, David A.; Ray, David W.; Rutter, Martin K.] Univ Manchester, Fac Biol Med & Hlth, Sch Med Sci, Div Endocrinol Diabet & Gastroenterol, Manchester, Lancs, England. [Bowden, Jack; Lawlor, Deborah A.] Univ Bristol, MRC, Integrat Epidemiol Unit, Bristol, Avon, England. [Bowden, Jack; Lawlor, Deborah A.] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. [Emsley, Richard] Univ Manchester, Manchester Acad Hlth Sci Ctr, Fac Biol Med & Hlth, Sch Hlth Sci,Div Populat Hlth Hlth Serv Res & Pri, Manchester, Lancs, England. [Little, Max A.] Aston Univ, Engn & Appl Sci, Birmingham, W Midlands, England. [Little, Max A.] MIT, Media Lab, Cambridge, MA USA. [Luik, Annemarie I.] Univ Oxford, Nuffield Dept Clin Neurosci, Sleep & Circadian Neurosci Inst, Oxford, England. [Scheer, Frank A. J. L.; Saxena, Richa] Harvard Med Sch, Div Sleep & Circadian Disorders, Brigham & Womens Hosp, Boston, MA USA. [Scheer, Frank A. J. L.; Saxena, Richa] Harvard Med Sch, Div Sleep Med, Boston, MA USA. [Purcell, Shaun M.] Harvard Med Sch, Brigham & Womens Hosp, Dept Psychiat, Boston, MA USA. [Purcell, Shaun M.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Redline, Susan] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA USA. [Redline, Susan] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Boston, MA USA. Cent Manchester Univ Hosp NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Manchester Diabet Ctr, Manchester, Lancs, England. RP Saxena, R (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.; Saxena, R (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA.; Saxena, R (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Saxena, R (reprint author), Broad Inst, Cambridge, MA 02142 USA. EM rsaxena@partners.org OI Lawlor, Debbie A/0000-0002-6793-2262; Ray, David/0000-0002-4739-6773; Anderson, Simon/0000-0002-8896-073X; Kyle, Simon/0000-0002-9581-5311; Luik, Annemarie I/0000-0001-7517-197X FU US NIH grants [R01DK107859, R21HL121728, F32DK102323, R01HL113338, R01DK102696, R01DK105072, T32HL007567, HG003054]; University of Manchester (Research Infrastructure Fund); Wellcome Trust; UK Medical Research Council [MC_UU_12013/5] FX This research has been conducted using the UK Biobank Resource under application number 6818. We would like to thank the participants and researchers from the UK Biobank who contributed or collected data. This work was supported by US NIH grants R01DK107859 (R.S.), R21HL121728 (R.S.), F32DK102323 (J.M.L.), R01HL113338 (J.M.L., S.R. and R.S.), R01DK102696 (R.S. and F.A.J.L.S.), R01DK105072 (R.S. and F.A.J.L.S.), T32HL007567 (J.L.) and HG003054 (X.Z.), the University of Manchester (Research Infrastructure Fund), the Wellcome Trust (salary support for D.W.R. and A.L.) and UK Medical Research Council MC_UU_12013/5 (D.A.L.). Data on glycemic traits have been contributed by MAGIC investigators and were downloaded from http://www.magicinvestigators.org/. Data on coronary artery disease and myocardial infarction have been contributed by CARDIoGRAMplusC4D investigators and were downloaded from http://www.cardiogramplusc4d.org/. We thank the International Genomics of Alzheimer's Project (IGAP) for providing summary results data for these analyses. NR 81 TC 1 Z9 1 U1 6 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD FEB PY 2017 VL 49 IS 2 BP 274 EP 281 DI 10.1038/ng.3749 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA EJ3YM UT WOS:000393148600017 PM 27992416 ER PT J AU Stanton, BZ Hodges, C Calarco, JP Braun, SMG Ku, WL Kadoch, C Zhao, K Crabtree, GR AF Stanton, Benjamin Z. Hodges, Courtney Calarco, Joseph P. Braun, Simon M. G. Ku, Wai Lim Kadoch, Cigall Zhao, Keji Crabtree, Gerald R. TI Smarca4 ATPase mutations disrupt direct eviction of PRC1 from chromatin SO NATURE GENETICS LA English DT Article ID EMBRYONIC STEM-CELLS; REMODELING COMPLEXES; NEURAL DEVELOPMENT; CANCER GENOME; BAF COMPLEXES; POLYCOMB; FAMILY; GENE; DNA; TRANSFORMATION AB Trithorax-group proteins and their mammalian homologs, including those in BAF (mSWI/SNF) complexes, are known to oppose the activity of Polycomb repressive complexes (PRCs)(1-5). This opposition underlies the tumor-suppressive role of BAF subunits(3,5-7) and is expected to contribute to neurodevelopmental disorders(8,9). However, the mechanisms underlying opposition to Polycomb silencing are poorly understood. Here we report that recurrent disease-associated mutations in BAF subunits induce genome-wide increases in PRC deposition and activity. We show that point mutations in SMARCA4 (also known as BRG1) mapping to the ATPase domain cause loss of direct binding between BAF and PRC1 that occurs independently of chromatin. Release of this direct interaction is ATP dependent, consistent with a transient eviction mechanism. Using a new chemical-induced proximity assay, we find that BAF directly evicts Polycomb factors within minutes of its occupancy, thereby establishing a new mechanism for the widespread BAF-PRC opposition underlying development and disease. C1 [Stanton, Benjamin Z.; Hodges, Courtney; Calarco, Joseph P.; Braun, Simon M. G.; Crabtree, Gerald R.] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA. [Stanton, Benjamin Z.; Hodges, Courtney; Calarco, Joseph P.; Braun, Simon M. G.; Crabtree, Gerald R.] Stanford Univ, Dept Dev Biol, Sch Med, Stanford, CA 94305 USA. [Stanton, Benjamin Z.; Ku, Wai Lim; Zhao, Keji] NHLBI, Syst Biol Ctr, US Natl Inst Hlth, Bldg 10, Bethesda, MD 20892 USA. [Kadoch, Cigall] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Kadoch, Cigall] Harvard Med Sch, Boston, MA USA. [Kadoch, Cigall] Broad Inst MIT & Harvard, Cambridge, MA USA. [Crabtree, Gerald R.] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Crabtree, GR (reprint author), Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA.; Crabtree, GR (reprint author), Stanford Univ, Dept Dev Biol, Sch Med, Stanford, CA 94305 USA.; Zhao, K (reprint author), NHLBI, Syst Biol Ctr, US Natl Inst Hlth, Bldg 10, Bethesda, MD 20892 USA.; Crabtree, GR (reprint author), Howard Hughes Med Inst, Chevy Chase, MD USA. EM zhaok@hlbi.nih.gov; crabtree@stanford.edu OI Hodges, Courtney/0000-0003-4441-497X FU NIH S10 Shared Instrumentation Grant [1S10RR02664701]; SFARI Foundation; NIH grants [R37NS046789, R01CA163915]; Division of Intramural Research, NHLBI/NIH; Swiss National Science Foundation (SNSF) postdoctoral fellowship; NCI career transition award [K99CA187565] FX This paper is dedicated to the memory of Joseph P. Calarco, a great friend and passionate scientist. We apologize to our colleagues whose work we could not cite owing to space constraints. We thank G. Hu, W Jin, E. Chory, J. Bradner, and D. Hargreaves for helpful discussions and E. Miller for sharing curated GEO data sets. Aridla conditional deletion cells were a gift from D. Hargreaves (Salk Institute). All libraries were sequenced by the DNA Sequencing and Genomics Core facility of NHLBI. Analysis was performed using the Stanford BioX3 cluster, supported by NIH S10 Shared Instrumentation Grant 1S10RR02664701. This work was also supported by the SFARI Foundation (G.R.C.), NIH grants R37NS046789 (G.R.C.) and R01CA163915 (G.R.C.), and the Division of Intramural Research, NHLBI/NIH (K.Z.). G.R.C. is an HHMI Investigator. S.M.G.B. is supported by a Swiss National Science Foundation (SNSF) postdoctoral fellowship. C.H. is supported by NCI career transition award K99CA187565. NR 50 TC 3 Z9 3 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD FEB PY 2017 VL 49 IS 2 BP 282 EP 288 DI 10.1038/ng.3735 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA EJ3YM UT WOS:000393148600018 PM 27941795 ER PT J AU Wang, XF Lee, RS Alver, BH Haswel, JR Wang, S Mieczkowski, J Drier, Y Gillespie, SM Archer, TC Wu, JN Tzvetkov, EP Troisi, EC Pomeroy, SL Biegel, JA Tolstorukov, MY Bernstein, BE Park, PJ Roberts, CWM AF Wang, Xiaofeng Lee, Ryan S. Alver, Burak H. Haswel, Jeffrey R. Wang, Su Mieczkowski, Jakub Drier, Yotam Gillespie, Shawn M. Archer, Tenley C. Wu, Jennifer N. Tzvetkov, Evgeni P. Troisi, Emma C. Pomeroy, Scott L. Biegel, Jaclyn A. Tolstorukov, Michael Y. Bernstein, Bradley E. Park, Peter J. Roberts, Charles W. M. TI SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation SO NATURE GENETICS LA English DT Article ID ATYPICAL TERATOID/RHABDOID TUMORS; SUPER-ENHANCERS; RHABDOID TUMORS; CELL IDENTITY; TRANSCRIPTION FACTORS; CANCER; GENES; SUPPRESSOR; MUTATIONS; TRANSFORMATION AB SMARCB1 (also known as SNF5, INI1, and BAF47), a core subunit of the SWI/SNF (BAF) chromatin-remodeling complex(1,2), is inactivated in nearly all pediatric rhabdoid tumors(3-5). These aggressive cancers are among the most genomically stable(6-8), suggesting an epigenetic mechanism by which SMARCB1 loss drives transformation. Here we show that, despite having indistinguishable mutational landscapes, human rhabdoid tumors exhibit distinct enhancer H3K27ac signatures, which identify remnants of differentiation programs. We show that SMARCB1 is required for the integrity of SWI/SNF complexes and that its loss alters enhancer targeting-markedly impairing SWI/SNF binding to typical enhancers, particularly those required for differentiation, while maintaining SWI/SNF binding at super-enhancers. We show that these retained super-enhancers are essential for rhabdoid tumor survival, including some that are shared by all subtypes, such as SPRY1, and other lineage-specific super-enhancers, such as SOX2 in brain-derived rhabdoid tumors. Taken together, our findings identify a new chromatin based epigenetic mechanism underlying the tumor-suppressive activity of SMARCB1. C1 [Wang, Xiaofeng; Lee, Ryan S.; Haswel, Jeffrey R.; Wu, Jennifer N.; Tzvetkov, Evgeni P.; Troisi, Emma C.; Roberts, Charles W. M.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Wang, Xiaofeng; Lee, Ryan S.; Haswel, Jeffrey R.; Wu, Jennifer N.; Tzvetkov, Evgeni P.; Troisi, Emma C.; Roberts, Charles W. M.] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Wang, Xiaofeng; Lee, Ryan S.; Haswel, Jeffrey R.; Wu, Jennifer N.; Tzvetkov, Evgeni P.; Troisi, Emma C.; Roberts, Charles W. M.] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA. [Alver, Burak H.; Wang, Su; Park, Peter J.] Harvard Med Sch, Dept Biomed Informat, Boston, MA 02215 USA. [Mieczkowski, Jakub; Tolstorukov, Michael Y.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Drier, Yotam; Gillespie, Shawn M.; Bernstein, Bradley E.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Drier, Yotam; Gillespie, Shawn M.; Bernstein, Bradley E.] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA. [Drier, Yotam; Gillespie, Shawn M.; Bernstein, Bradley E.] Harvard Med Sch, Boston, MA 02115 USA. [Drier, Yotam; Gillespie, Shawn M.; Bernstein, Bradley E.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Archer, Tenley C.; Pomeroy, Scott L.] Harvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA USA. [Biegel, Jaclyn A.] Univ Southern Calif, Childrens Hosp Los Angeles, Dept Pathol & Lab Med, Los Angeles, CA USA. [Biegel, Jaclyn A.] Univ Southern Calif, Keck Sch Med, Los Angeles, CA USA. [Bernstein, Bradley E.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Park, Peter J.] Brigham & Womens Hosp, Div Genet, 75 Francis St, Boston, MA 02115 USA. [Roberts, Charles W. M.] St Jude Childrens Res Hosp, Ctr Comprehens Canc, 332 N Lauderdale St, Memphis, TN 38105 USA. [Roberts, Charles W. M.] St Jude Childrens Res Hosp, Dept Oncol, 332 N Lauderdale St, Memphis, TN 38105 USA. RP Roberts, CWM (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA.; Roberts, CWM (reprint author), Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA.; Roberts, CWM (reprint author), Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA.; Park, PJ (reprint author), Harvard Med Sch, Dept Biomed Informat, Boston, MA 02215 USA.; Bernstein, BE (reprint author), Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA.; Bernstein, BE (reprint author), Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA.; Bernstein, BE (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Bernstein, BE (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.; Bernstein, BE (reprint author), Howard Hughes Med Inst, Chevy Chase, MD 20815 USA.; Park, PJ (reprint author), Brigham & Womens Hosp, Div Genet, 75 Francis St, Boston, MA 02115 USA.; Roberts, CWM (reprint author), St Jude Childrens Res Hosp, Ctr Comprehens Canc, 332 N Lauderdale St, Memphis, TN 38105 USA.; Roberts, CWM (reprint author), St Jude Childrens Res Hosp, Dept Oncol, 332 N Lauderdale St, Memphis, TN 38105 USA. EM bernstein.bradley@mgh.harvard.edu; peter_park@hms.harvard.edu; charles.roberts@stjude.org OI Mieczkowski, Jakub/0000-0002-2091-012X; Drier, Yotam/0000-0003-1725-2995; Alver, Burak/0000-0002-5019-7652 FU Pathway to Independence Award from the US National Institutes of Health [K99CA197640]; Rally Foundation for Childhood Cancer Research; Truth 365; St. Baldrick's Foundation; NSF Graduate Research Fellowship; US National Institutes of Health grants [R01CA172152, R0ICA113794, U54HG006991]; Avalanna Fund; Cure AT/RT Now Foundation; Garrett B. Smith Foundation; Miles for Mary; ALSAC/St. Jude FX We thank members of the Roberts and Park laboratories for assistance and discussion. We thank J. Francois (Boston Children's Hospital), J. Roth (Children's Hospital of Philadelphia), M. Lear (St. Jude Children's Research Hospital), and J. Silterra (Broad Institute) for their help in acquiring and performing preliminary clinical analysis of primary tumor samples; R. Rubio (Dana-Farber Cancer Institute) and M. Uziel (Broad Institute) for their assistance in sequencing samples; N. Shoresh (Broad Institute) for assistance in accessing Roadmap Epigenomics data; and R. Tomaino (Harvard Medical School) for assistance in proteomic analysis. X.W. was supported by the Pathway to Independence Award from the US National Institutes of Health (K99CA197640), a postdoctoral fellowship from the Rally Foundation for Childhood Cancer Research and The Truth 365, and a research grant from St. Baldrick's Foundation. R.S.L. was partially supported by an NSF Graduate Research Fellowship. This work was supported by US National Institutes of Health grants R01CA172152 (C.W.M.R.), R0ICA113794 (C.W.M.R.), and U54HG006991 (B.E.B.). The Avalanna Fund, the Cure AT/RT Now Foundation, the Garrett B. Smith Foundation, Miles for Mary, and ALSAC/St. Jude (C.W.M.R.) provided additional support. NR 30 TC 3 Z9 3 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD FEB PY 2017 VL 49 IS 2 BP 289 EP 295 DI 10.1038/ng.3746 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA EJ3YM UT WOS:000393148600019 PM 27941797 ER PT J AU Mathur, R Alver, BH San Roman, AK Wilson, BG Wang, XF Agoston, AT Park, PJ Shivdasani, RA Roberts, CWM AF Mathur, Radhika Alver, Burak H. San Roman, Adrianna K. Wilson, Boris G. Wang, Xiaofeng Agoston, Agoston T. Park, Peter J. Shivdasani, Ramesh A. Roberts, Charles W. M. TI ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice SO NATURE GENETICS LA English DT Article ID COLORECTAL-CANCER; SWI/SNF COMPLEXES; GASTRIC-CANCER; TRANSCRIPTION; SUPPRESSOR; EXPRESSION; GASDERMIN; SUBUNITS; GENOME; TARGET AB Genes encoding subunits of SWI/SNF (BAF) chromatin remodeling complexes are collectively mutated in similar to 20% of all human cancers(1,2). Although ARID1A is the most frequent target of mutations, the mechanism by which its inactivation promotes tumorigenesis is unclear. Here we demonstrate that Arid1a functions as a tumor suppressor in the mouse colon, but not the small intestine, and that invasive ARID1A-deficient adenocarcinomas resemble human colorectal cancer (CRC). These tumors lack deregulation of APC/beta-catenin signaling components, which are crucial gatekeepers in common forms of intestinal cancer. We find that ARID1A normally targets SWI/SNF complexes to enhancers, where they function in coordination with transcription factors to facilitate gene activation. ARID1B preserves SWI/SNF function in ARID1A-deficient cells, but defects in SWI/SNF targeting and control of enhancer activity cause extensive dysregulation of gene expression. These findings represent an advance in colon cancer modeling and implicate enhancer-mediated gene regulation as a principal tumor-suppressor function of ARID1A. C1 [Mathur, Radhika; San Roman, Adrianna K.] Harvard Med Sch, Program Biol & Biomed Sci, Boston, MA 02115 USA. [Mathur, Radhika; Wilson, Boris G.; Wang, Xiaofeng; Roberts, Charles W. M.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Alver, Burak H.; Park, Peter J.] Harvard Med Sch, Dept Biomed Informat, Boston, MA USA. [San Roman, Adrianna K.; Shivdasani, Ramesh A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [San Roman, Adrianna K.; Shivdasani, Ramesh A.] Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02115 USA. [Agoston, Agoston T.] Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Boston, MA USA. [Park, Peter J.; Shivdasani, Ramesh A.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Park, Peter J.; Shivdasani, Ramesh A.] Harvard Med Sch, Boston, MA USA. [Roberts, Charles W. M.] St Jude Childrens Res Hosp, Dept Oncol, 332 N Lauderdale St, Memphis, TN 38105 USA. RP Roberts, CWM (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA.; Roberts, CWM (reprint author), St Jude Childrens Res Hosp, Dept Oncol, 332 N Lauderdale St, Memphis, TN 38105 USA. EM charles_roberts@dfci.harvard.edu OI Alver, Burak/0000-0002-5019-7652 FU US National Institutes of Health [R01CA172152, R01DK081113]; Claudia Adams Barr grant; Innovation Award from Alex's Lemonade Stand; US National Institutes of Health predoctoral fellowships [1F31CA199994, 1F31CA180784]; Pathway to Independence Award from the US National Institutes of Health [K99CA197640]; Cure AT/RT Now foundation; Avalanna Fund; Garrett B. Smith Foundation; Miles for Mary; ALSAC/St. Jude; Lind Family; NCI Cancer Center Support Grant [P30CA06516] FX We thank S. Robine (Institut Curie) for providing Vil1-CreERT2transgenic mice, S.H. Orkin for guidance, and members of the Roberts and Orkin laboratories for discussion. This work was supported by US National Institutes of Health grants R01CA172152 (C.W.M.R.) and R01DK081113 (R.A.S.), by a Claudia Adams Barr grant (C.W.M.R.), and by an Innovation Award from Alex's Lemonade Stand (C.W.M.R.). R.M. and A.K.S.R. were supported by US National Institutes of Health predoctoral fellowships (1F31CA199994 and 1F31CA180784). X.W. was supported by the Pathway to Independence Award from the US National Institutes of Health (K99CA197640). The Cure AT/RT Now foundation, the Avalanna Fund, the Garrett B. Smith Foundation, Miles for Mary, ALSAC/St. Jude (C.W.M.R.), and the Lind Family (R.A.S.) provided additional support. We also thank the Dana-Farber/Harvard Cancer Center Rodent Histopathology Core and Specialized Histopathology Core, which are supported in part by NCI Cancer Center Support Grant P30CA06516. NR 32 TC 2 Z9 2 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD FEB PY 2017 VL 49 IS 2 BP 296 EP 302 DI 10.1038/ng.3744 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA EJ3YM UT WOS:000393148600020 PM 27941798 ER PT J AU Davidson, SM Jonas, O Keibler, MA Hou, HW Luengo, A Mayers, JR Wyckoff, J Del Rosario, AM Whitman, M Chin, CR Condon, KJ Lammers, A Kellersberger, KA Stall, BK Stephanopoulos, G Bar-Sagi, D Han, J Rabinowitz, JD Cima, MJ Langer, R Vander Heiden, MG AF Davidson, Shawn M. Jonas, Oliver Keibler, Mark A. Hou, Han Wei Luengo, Alba Mayers, Jared R. Wyckoff, Jeffrey Del Rosario, Amanda M. Whitman, Matthew Chin, Christopher R. Condon, Kendall J. Lammers, Alex Kellersberger, Katherine A. Stall, Brian K. Stephanopoulos, Gregory Bar-Sagi, Dafna Han, Jongyoon Rabinowitz, Joshua D. Cima, Michael J. Langer, Robert Vander Heiden, Matthew G. TI Direct evidence for cancer-cell-autonomous extracellular protein catabolism in pancreatic tumors SO NATURE MEDICINE LA English DT Article ID SERUM-ALBUMIN; PICHIA-PASTORIS; IN-VIVO; MACROPINOCYTOSIS; ADENOCARCINOMA; DEGRADATION; METABOLISM; EXPRESSION; SURVIVAL AB Mammalian tissues rely on a variety of nutrients to support their physiological functions'. It is known that altered metabolism is involved in the pathogenesis of cancer, but which nutrients support the inappropriate growth of intact malignant tumors is incompletely understood(2,3). Amino acids are essential nutrients for many cancer cells(4,5) that can be obtained through the scavenging and catabolism of extracellular protein via macropinocytosis(6,7). In particular, macropinocytosis can be a nutrient source for pancreatic cancer cells, but it is not fully understood how the tumor environment influences metabolic phenotypes(8) and whether macropinocytosis supports the maintenance of amino acid levels within pancreatic tumors. Here we utilize miniaturized plasma exchange to deliver labeled albumin to tissues in live mice, and we demonstrate that breakdown of albumin contributes to the supply of free amino acids in pancreatic tumors. We also deliver albumin directly into tumors using an implantable microdevice, which was adapted and modified from ref. 9. Following implantation, we directly observe protein catabolism and macropinocytosis in situ by pancreatic cancer cells, but not by adjacent, non-cancerous pancreatic tissue. In addition, we find that intratumoral inhibition of macropinocytosis decreases amino acid levels. Taken together, these data suggest that pancreatic cancer cells consume extracellular protein, including albumin, and that this consumption serves as an important source of amino acids for pancreatic cancer cells in vivo. C1 [Davidson, Shawn M.; Jonas, Oliver; Luengo, Alba; Mayers, Jared R.; Wyckoff, Jeffrey; Del Rosario, Amanda M.; Whitman, Matthew; Chin, Christopher R.; Lammers, Alex; Cima, Michael J.; Langer, Robert; Vander Heiden, Matthew G.] MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Davidson, Shawn M.; Luengo, Alba; Mayers, Jared R.; Condon, Kendall J.; Vander Heiden, Matthew G.] MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Davidson, Shawn M.; Vander Heiden, Matthew G.] Broad Inst MIT & Harvard Univ, Cambridge, MA 02142 USA. [Jonas, Oliver] Brigham & Womens Hosp, Dept Radiol, Cambridge, MA USA. [Jonas, Oliver] Harvard Med Sch, Cambridge, MA USA. [Keibler, Mark A.; Stephanopoulos, Gregory; Langer, Robert] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Hou, Han Wei; Han, Jongyoon] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. [Kellersberger, Katherine A.; Stall, Brian K.] Bruker Daltron Inc, Billerica, MA USA. [Bar-Sagi, Dafna] NYU, Sch Med, New York, NY USA. [Han, Jongyoon] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Rabinowitz, Joshua D.] Princeton Univ, Dept Chem & Integrat Genom, Princeton, NJ 08544 USA. [Cima, Michael J.] MIT, Dept Mat Sci, Cambridge, MA 02139 USA. [Vander Heiden, Matthew G.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Vander Heiden, Matthew G.] Harvard Med Sch, Boston, MA 02115 USA. RP Vander Heiden, MG (reprint author), MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Vander Heiden, MG (reprint author), MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Vander Heiden, MG (reprint author), Broad Inst MIT & Harvard Univ, Cambridge, MA 02142 USA.; Vander Heiden, MG (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA.; Vander Heiden, MG (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM mvh@mit.edu OI Mayers, Jared/0000-0002-8607-1787 FU National Science Foundation [T32 GM007287]; Koch Institute Frontier Grant; Prostate Cancer Foundation; NCI [F30CA183474]; NIGMS [T32 GM007753]; NIH [1R01 DK075850-01, 1R01 CA160458-01A1, P30 CA1405141, R01 CA168653]; Lustgarten Foundation; Ludwig Center at MIT; Broad Institute SPARC program; Burroughs Wellcome Fund; SU2C; DARPA's Dialysis-Like Therapy (DLT) program [N66001-11-1-4182]; MIT's Microsystems Technology Laboratories FX The authors wish to dedicate this paper to the memory of Katherine Kellersberger. We thank the MIT Department of Chemical Engineering and). Francois-Hamel for access to bioreactor equipment, R. Bronson for pathological grading of tumors and A. Lau for providing tumor-bearing mice. S.M.D. and A.L. received support from a National Science Foundation Graduate Research Award Fellowship, and support from T32 GM007287 is also acknowledged. O.J. received support from the Koch Institute Frontier Grant and the Prostate Cancer Foundation. J.R.M. acknowledges support from grant F30CA183474 from the NCI and grant T32 GM007753 from NIGMS. M.A.K. and G.S. acknowledge support from NIH grants 1R01 DK075850-01 and 1R01 CA160458-01A1. M.G.V.H. acknowledges support from the Lustgarten Foundation, the Ludwig Center at MIT, the Broad Institute SPARC program, the Burroughs Wellcome Fund, SU2C and the NIH (P30 CA1405141, R01 CA168653). H.W.H. and J.H. acknowledge support by DARPA's Dialysis-Like Therapy (DLT) program under SSC Pacific grant N66001-11-1-4182. This work is also supported by the use of MIT's Microsystems Technology Laboratories. NR 36 TC 1 Z9 1 U1 7 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD FEB PY 2017 VL 23 IS 2 BP 235 EP 241 DI 10.1038/nm.4256 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA EK2AH UT WOS:000393729000015 PM 28024083 ER PT J AU Albiges, L Choueiri, TK AF Albiges, Laurence Choueiri, Toni K. TI Advances in treatment - jostling for pole position SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Editorial Material ID RENAL-CELL CARCINOMA; OPEN-LABEL; PHASE-3 TRIAL; ADJUVANT SUNITINIB; HIGH-RISK; EVEROLIMUS; CABOZANTINIB; MULTICENTER; NIVOLUMAB AB In 2016, two major trials provided conflicting evidence regarding the role of 1 year of adjuvant therapy with sunitinib for patients with high-risk renal-cell carcinoma. In the second-line metastatic setting, updated data from key trials showed that cabozantinib improved overall survival over everolimus, and nivolurnab was associated with a better quality of life compared with everolimus. Finally, a phase II study in previously untreated patients showed cabozantinib to be superior to sunitinib. C1 [Albiges, Laurence] Univ Paris Saclay, Gustave Roussy, Dept Med Oncol, 114 Rue Edouard Vaillant, F-94805 Villejuif, France. [Choueiri, Toni K.] Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, 450 Brookline Ave,Dana 1230, Boston, MA 02215 USA. RP Choueiri, TK (reprint author), Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, 450 Brookline Ave,Dana 1230, Boston, MA 02215 USA. EM toni_choueiri@dfci.harvard.edu FU Novartis; Pfizer; AstraZeneca; Bristol-Myers Squibb; Exelixis; GSK; Merck; Peloton; Roche; Tracon FX LA. declares that she is a consultant for and has an advisory role with Amgen, Bayer, Bristol-Myers Squibb, Cerulean, Novartis, Pfizer, and Sanofi, and receives research funding from Novartis and Pfizer. T.K.C. declares that he is a consultant for and has an advisory role to Bayer, Bristol-Myers Squibb, Exelixis, GSK, Merck, Novartis, and Pfizer. He also receives research funding from AstraZeneca, Bristol-Myers Squibb, Exelixis, GSK, Merck, Novartis, Peloton, Pfizer, Roche, and Tracon. NR 12 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4774 EI 1759-4782 J9 NAT REV CLIN ONCOL JI Nat. Rev. Clin. Oncol. PD FEB PY 2017 VL 14 IS 2 BP 82 EP 84 DI 10.1038/nrclinonc.2016.224 PG 3 WC Oncology SC Oncology GA EJ3YW UT WOS:000393149700007 PM 28071677 ER PT J AU Manier, S Salem, KZ Park, J Landau, DA Getz, G Ghobrial, IM AF Manier, Salomon Salem, Karma Z. Park, Jihye Landau, Dan A. Getz, Gad Ghobrial, Irene M. TI Genomic complexity of multiple myeloma and its clinical implications SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Review ID INTERNATIONAL STAGING SYSTEM; ADVERSE PROGNOSTIC-FACTOR; COPY-NUMBER ALTERATION; MATURE B-LYMPHOCYTES; CHROMOSOME BAND 1Q21; MONOCLONAL GAMMOPATHY; UNDETERMINED SIGNIFICANCE; POOR-PROGNOSIS; IGH TRANSLOCATIONS; GENE-EXPRESSION AB Multiple myeloma (MM) is a genetically complex disease that evolves from pre-malignant stages, such as monoclonal gammaopathy of undetermined significance and smouldering multiple myeloma, and progresses to symptomatic MM; this continuum provides a unique framework to study the sequential genomic evolution of MM. In the past 5 years, results from large-scale whole-exome sequencing studies have provided new insights into the clonal heterogeneity and evolution of the disease. Moreover, the recurrent co-occurrence of genomic events helps to dissect the genomic complexity underlying tumour progression. According to the primary genetic events involved in tumorigenesis, MM tumours are hierarchically subdivided into hyperdiploid and non-hyperdiploid subtypes; subsequently, secondary genetic events lead to tumour progression. In this Review, we describe the 'driver' gene alterations involved in the development and progression of MM, with a focus on the sequential acquisition of the main genomic aberrations. We also provide valuable insight into the clonal heterogeneity and clonal evolution of the disease, as well as into the therapeutic implications of a comprehensive understanding of the genomic complexity of MM. C1 [Manier, Salomon; Salem, Karma Z.; Park, Jihye; Ghobrial, Irene M.] Harvard Med Sch, Dana Farber Canc Inst, Med Oncol, HIM 237,77 Ave Louis Pasteur, Boston, MA 02115 USA. [Manier, Salomon; Salem, Karma Z.; Park, Jihye; Getz, Gad; Ghobrial, Irene M.] Board Inst MIT & Harvard, Canc Program, 415 Main St, Cambridge, MA 02142 USA. [Landau, Dan A.] New York Genome Ctr, 101 Ave Amer,Room 621, New York, NY 10013 USA. [Landau, Dan A.] Weill Cornell Med, Belfer Res Bldg,Room 1428, New York, NY 10021 USA. [Getz, Gad] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, 55 Fruit St, Boston, MA 02114 USA. [Getz, Gad] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St, Boston, MA 02114 USA. RP Ghobrial, IM (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Med Oncol, HIM 237,77 Ave Louis Pasteur, Boston, MA 02115 USA.; Ghobrial, IM (reprint author), Board Inst MIT & Harvard, Canc Program, 415 Main St, Cambridge, MA 02142 USA. EM irene_ghobrial@dfci.harvard.edu FU Leukaemia & Lymphoma Society; Multiple Myeloma Research Foundation; US NIH FX We acknowledge funding from the Leukaemia & Lymphoma Society, the Multiple Myeloma Research Foundation and the US NIH. NR 130 TC 1 Z9 1 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4774 EI 1759-4782 J9 NAT REV CLIN ONCOL JI Nat. Rev. Clin. Oncol. PD FEB PY 2017 VL 14 IS 2 BP 100 EP 113 DI 10.1038/nrclinonc.2016.122 PG 14 WC Oncology SC Oncology GA EJ3YW UT WOS:000393149700009 PM 27531699 ER PT J AU Smallwood, AJ Schapira, MM Fedders, M Neuner, JM AF Smallwood, A. J. Schapira, M. M. Fedders, M. Neuner, J. M. TI A pilot randomized controlled trial of a decision aid with tailored fracture risk tool delivered via a patient portal SO OSTEOPOROSIS INTERNATIONAL LA English DT Article DE Decision aids; Osteoporosis; Patient portal; Personalized risk; Shared decision making ID POSTMENOPAUSAL WOMEN; HIP FRACTURE; OSTEOPOROSIS; THERAPY AB We tested the feasibility of a fracture prevention decision aid in an online patient portal. The decision aid was acceptable for patients and successfully decreased decisional conflict. This study suggests the possible utility of leveraging the patient portal to enhance patient education and decision making in osteoporosis care. Although interventions have improved osteoporosis screening and/or treatment for certain populations of high-risk patients, recent national studies suggest that large-scale uptake of these interventions has been limited. We aimed to determine the feasibility and potential efficacy of a patient portal-based osteoporosis decision aid (DA). We conducted a pilot randomized controlled trial of primary care patients aged ae55 who were enrolled in a patient portal and had a T-score of <-1. Intervention subjects were provided a link to a patient DA. The DA contained a 10-year fracture risk calculator, summary of medication risks and benefits (prescription and nonprescription), and an elicitation of values. Subjects completed questionnaires assessing the primary outcomes of decisional conflict and preparation for decision making and secondary outcomes related to feasibility and planning for a larger trial. Charts were reviewed for physician-subject interactions and medication uptake. The DA was acceptable to subjects, but 17 % of the patients in the decision aid arm incorrectly entered their T-scores into FRAX-based risk calculator. Decisional conflict was lower post-intervention for those who were randomized to the decision aid arm compared to controls (17.8 vs. 47.1, p < .001), and there was a significant difference in the percentage of patients who made a treatment decision at 3 months. No significant differences were observed in medication uptake. A portal-based osteoporosis DA was acceptable and improved several measures of decision quality. Given its effect on improving the quality of patients' decisions, future studies should examine whether it improves physician guideline adherence or medication adherence uptake among treated patients. C1 [Smallwood, A. J.; Neuner, J. M.] Med Coll Wisconsin, Ctr Patient Care & Outcomes Res, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. [Schapira, M. M.] Univ Penn, Perelman Sch Med, Div Gen Internal Med, 423 Guardian Ave, Philadelphia, PA 19104 USA. [Schapira, M. M.] Crescenz VA Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA 19104 USA. [Fedders, M.] Froedtert, Clin Informat, 9200 W Wisconsin Ave, Milwaukee, WI 53226 USA. [Fedders, M.] Med Coll Wisconsin, 9200 W Wisconsin Ave, Milwaukee, WI 53226 USA. [Neuner, J. M.] Med Coll Wisconsin, Dept Med, Div Gen Internal Med, CLCC 5th Floor,9200 W Wisconsin Ave, Milwaukee, WI 53226 USA. RP Smallwood, AJ (reprint author), Med Coll Wisconsin, Ctr Patient Care & Outcomes Res, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. EM asmallwood@mcw.edu FU Clinical and Translational Science Institute of Southeast Wisconsin [5,520,204] FX This study was funded by the Clinical and Translational Science Institute of Southeast Wisconsin (project number 5,520,204). NR 25 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0937-941X EI 1433-2965 J9 OSTEOPOROSIS INT JI Osteoporosis Int. PD FEB PY 2017 VL 28 IS 2 BP 567 EP 576 DI 10.1007/s00198-016-3767-4 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EK0VW UT WOS:000393646200014 PM 27647529 ER PT J AU Mori, T Crandall, CJ Ganz, DA AF Mori, T. Crandall, C. J. Ganz, D. A. TI Cost-effectiveness of combined oral bisphosphonate therapy and falls prevention exercise for fracture prevention in the USA SO OSTEOPOROSIS INTERNATIONAL LA English DT Article DE Cost-effectiveness analysis; Falls prevention exercise; Fracture prevention; Oral bisphosphonate therapy; Osteoporosis ID QUALITY-OF-LIFE; HIP FRACTURE; POSTMENOPAUSAL OSTEOPOROSIS; VERTEBRAL FRACTURES; EXCESS MORTALITY; UNITED-STATES; METAANALYSIS; WOMEN; POPULATION; HEALTH AB We developed a Markov microsimulation model among hypothetical cohorts of community-dwelling US white women without prior major osteoporotic fractures over a lifetime horizon. At ages 75 and 80, adding 1 year of exercise to 5 years of oral bisphosphonate therapy is cost-effective at a conventionally accepted threshold compared with bisphosphonates alone. The purpose of this study was to examine the cost-effectiveness of the combined strategy of oral bisphosphonate therapy for 5 years and falls prevention exercise for 1 year compared with either strategy in isolation. We calculated incremental cost-effectiveness ratios [ICERs] (2014 US dollars per quality-adjusted life year [QALY]), using a Markov microsimulation model among hypothetical cohorts of community-dwelling US white women with different starting ages (65, 70, 75, and 80) without prior history of hip, vertebral, or wrist fractures over a lifetime horizon from the societal perspective. At ages 65, 70, 75, and 80, the combined strategy had ICERs of $202,020, $118,460, $46,870, and $17,640 per QALY, respectively, compared with oral bisphosphonate therapy alone. The combined strategy provided better health at lower cost than falls prevention exercise alone at ages 70, 75, and 80. In deterministic sensitivity analyses, results were particularly sensitive to the change in the opportunity cost of participants' time spent exercising. In probabilistic sensitivity analyses, the probabilities of the combined strategy being cost-effective compared with the next best alternative increased with age, ranging from 35 % at age 65 to 48 % at age 80 at a willingness-to-pay of $100,000 per QALY. Among community-dwelling US white women ages 75 and 80, adding 1 year of exercise to 5 years of oral bisphosphonate therapy is cost-effective at a willingness-to-pay of $100,000 per QALY, compared with oral bisphosphonate therapy only. This analysis will help clinicians and policymakers make better decisions about treatment options to reduce fracture risk. C1 [Mori, T.] Kameda Med Ctr, Dept Gen Internal Med, 929 Higashi Cho, Kamogawa City, Chiba 2968602, Japan. [Mori, T.] Univ Tsukuba, Grad Sch Comprehens Human Sci, Dept Primary Care & Med Educ, Tsukuba, Ibaraki, Japan. [Mori, T.] Univ Tsukuba, Dept Hlth Serv Res, Fac Med, Tsukuba, Ibaraki, Japan. [Crandall, C. J.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Gen Internal Med & Hlth Serv Res, Los Angeles, CA 90095 USA. [Ganz, D. A.] Vet Affairs Greater Los Angeles Healthcare Syst, Geriatr Res Educ & Clin Ctr, Los Angeles, CA USA. [Ganz, D. A.] Vet Affairs Greater Los Angeles Healthcare Syst, HSR&D Ctr Healthcare Innovat Implementat & Policy, Los Angeles, CA USA. [Ganz, D. A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Geriatr, Los Angeles, CA 90095 USA. [Ganz, D. A.] RAND Corp, Hlth Unit, Santa Monica, CA USA. RP Mori, T (reprint author), Kameda Med Ctr, Dept Gen Internal Med, 929 Higashi Cho, Kamogawa City, Chiba 2968602, Japan.; Mori, T (reprint author), Univ Tsukuba, Grad Sch Comprehens Human Sci, Dept Primary Care & Med Educ, Tsukuba, Ibaraki, Japan.; Mori, T (reprint author), Univ Tsukuba, Dept Hlth Serv Res, Fac Med, Tsukuba, Ibaraki, Japan. EM takahiromori@outlook.com FU Veterans Affairs Special Fellowship in Advanced Geriatrics FX The authors (Takahiro Mori, Carolyn J. Crandall, and David A. Ganz) declare that they have no conflict of interest. Takahiro Mori was supported by the Veterans Affairs Special Fellowship in Advanced Geriatrics. The Department of Veterans Affairs had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. NR 39 TC 0 Z9 0 U1 3 U2 3 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0937-941X EI 1433-2965 J9 OSTEOPOROSIS INT JI Osteoporosis Int. PD FEB PY 2017 VL 28 IS 2 BP 585 EP 595 DI 10.1007/s00198-016-3772-7 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EK0VW UT WOS:000393646200016 PM 27726000 ER PT J AU Perrin, JM Zimmerman, E Hertz, A Johnson, T Merrill, T Smith, D AF Perrin, James M. Zimmerman, Edward Hertz, Andrew Johnson, Timothy Merrill, Tom Smith, David TI Pediatric Accountable Care Organizations: Insight From Early Adopters SO PEDIATRICS LA English DT Article ID HEALTH AB Partly in response to incentives in the Affordable Care Act, there has been major growth in accountable care organizations (ACO) in both the private and public sectors. For several reasons, growth of ACOs in pediatric care has been more modest than for older populations. The American Academy of Pediatrics collaborated with Leavitt Partners, LLC, to carry out a study of pediatric ACOs, including a series of 5 case studies of diverse pediatric models, a scan of Medicaid ACOs, and a summit of leaders in pediatric ACO development. These collaborative activities identified several issues in ACO formation and sustainability in pediatric settings and outlined a number of opportunities for the pediatric community in areas of organization, model change, and market dynamics; payment, financing, and contracting; quality and value; and use of new technologies. These insights can guide future work in pediatric ACO development. C1 [Perrin, James M.] MassGen Hosp Children, Div Gen Acad Pediat, 125 Nashua St,Suite 860, Boston, MA 02114 USA. [Perrin, James M.] Harvard Med Sch, Dept Pediat, Boston, MA USA. [Zimmerman, Edward] Amer Acad Pediat, Elk Grove Village, IL USA. [Hertz, Andrew] Univ Hosp Rainbow Care Coalit, Cleveland, OH USA. [Hertz, Andrew] Case Western Reserve Univ, Sch Med, Dept Pediat, Cleveland, OH 44106 USA. [Johnson, Timothy] Valence Hlth, Chicago, IL USA. [Merrill, Tom; Smith, David] Leavitt Partners LLC, Salt Lake City, UT USA. RP Perrin, JM (reprint author), MassGen Hosp Children, Div Gen Acad Pediat, 125 Nashua St,Suite 860, Boston, MA 02114 USA. EM jperrin@mgh.harvard.edu FU American Academy of Pediatrics; Centers for Medicare and Medicaid Services, Center for Medicare and Medicaid Innovation [CMS-1C1-12-0001] FX This work was supported by an internal grant at the American Academy of Pediatrics. University Hospitals Rainbow Care Connection was supported by Funding Opportunity No. CMS- 1C1- 12- 0001 from the Centers for Medicare and Medicaid Services, Center for Medicare and Medicaid Innovation. The contents of this article are solely the responsibility of the authors and do not necessarily represent the offi cial views of the US Department of Health and Human Services or any of its agencies. NR 15 TC 0 Z9 0 U1 0 U2 0 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD FEB PY 2017 VL 139 IS 2 AR e20161840 DI 10.1542/peds.2016-1840 PG 8 WC Pediatrics SC Pediatrics GA EJ2JC UT WOS:000393035100052 ER PT J AU Besselink, MG van Rijssen, LB Bassi, C Dervenis, C Montorsi, M Adham, M Asbun, HJ Bockhorn, M Strobel, O Buchler, MW Busch, OR Charnley, RM Conlon, KC Fernandez-Cruz, L Fingerhut, A Friess, H Izbicki, JR Lillemoe, KD Neoptolemos, JP Sarr, MG Shrikhande, SV Sitarz, R Vollmer, CM Yeo, CJ Hartwig, W Wolfgang, CL Gouma, DJ AF Besselink, Marc G. van Rijssen, L. Bengt Bassi, Claudio Dervenis, Christos Montorsi, Marco Adham, Mustapha Asbun, Horacio J. Bockhorn, Maximilian Strobel, Oliver Buechler, Markus W. Busch, Olivier R. Charnley, Richard M. Conlon, Kevin C. Fernandez-Cruz, Laureano Fingerhut, Abe Friess, Helmut Izbicki, Jakob R. Lillemoe, Keith D. Neoptolemos, John P. Sarr, Michael G. Shrikhande, Shailesh V. Sitarz, Robert Vollmer, Charles M. Yeo, Charles J. Hartwig, Werner Wolfgang, Christopher L. Gouma, Dirk J. CA Int Study Grp Pancreatic Surg TI Definition and classification of chyle leak after pancreatic operation: A consensus statement by the International Study Group on Pancreatic Surgery SO SURGERY LA English DT Article ID INTRAPERITONEAL DRAINAGE; DUCTAL ADENOCARCINOMA; MANAGEMENT OPTIONS; CISTERNA-CHYLI; RISK-FACTORS; ASCITES; RESECTION; PANCREATICODUODENECTOMY; ISGPS; DIAGNOSIS AB Background. Recent literature suggests that chyle leak may complicate up to 10% of pancreatic resections. Treatment depends on its severity, which may include chylous ascites. No international consensus definition or grading system of chyle leak currently is available. Methods. The International Study Group on Pancreatic Surgery, an international panel of pancreatic surgeons working in well-known, high-volume centers, reviewed the literature and worked together to establish a consensus on the definition and classification of chyle leak after pancreatic operation. Results. Chyle leak was defined as output of milky-colored fluid from a drain, drain site, or wound on or after postoperative day 3, with a triglyceride content >= 110 mg/dL (>= 1.2 mmol/L). Three different grades of severity were defined according to the management needed: grade A, no specific intervention other than oral dietary restrictions; grade B, prolongation of hospital stay, nasoenteral nutrition with dietary restriction, total parenteral nutrition, octreotide, maintenance of surgical drains, or placement of new percutaneous drains; and grade C, need for other more invasive in-hospital treatment, intensive care unit admission, or mortality. Conclusion. This classification and grading system for chyle leak after pancreatic resection allows for comparison of outcomes between series. As with the other the International Study Group on Pancreatic Surgery consensus statements, this classification should facilitate communication and evaluation of different approaches to the prevention and treatment of this complication. C1 [Besselink, Marc G.; van Rijssen, L. Bengt; Busch, Olivier R.; Gouma, Dirk J.] Univ Amsterdam, Acad Med Ctr, Dept Surg, Amsterdam, Netherlands. [Bassi, Claudio] Univ Verona, Pancreas Inst, Dept Surg & Oncol, Verona, Italy. [Dervenis, Christos] Agia Olga Hosp, Dept Surg 1, Athens, Greece. [Montorsi, Marco] Humanitas Res Hosp & Univ, Dept Surg, Milan, Italy. [Adham, Mustapha] UCBL1, HCL, Hop Edouard Herriot, Dept HPB Surg, Lyon, France. [Asbun, Horacio J.] Mayo Clin, Dept Surg, Jacksonville, FL 32224 USA. [Bockhorn, Maximilian; Izbicki, Jakob R.] Univ Hosp Hamburg Eppendorf, Dept Gen Visceral & Thorac Surg, Hamburg, Germany. [Strobel, Oliver; Buechler, Markus W.] Heidelberg Univ, Dept Gen Visceral & Transplantat Surg, Heidelberg, Germany. [Charnley, Richard M.] Freeman Rd Hosp, Dept HPB & Transplant Surg, Newcastle Upon Tyne, Tyne & Wear, England. [Conlon, Kevin C.] Univ Dublin, Trinity Coll, Professorial Surg Unit, Dublin, Ireland. [Fernandez-Cruz, Laureano] Univ Barcelona, Hosp Clin Barcelona, Dept Surg, Barcelona, Spain. [Fingerhut, Abe] Univ Athens, Hippokrateon Hosp, Dept Digest Surg 1, Athens, Greece. [Fingerhut, Abe] Med Univ Graz, Dept Surg, Sect Surg Res, Graz, Austria. [Friess, Helmut] Tech Univ Munich, Klinikum Rechts Isar, Dept Surg, Munich, Germany. [Lillemoe, Keith D.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Lillemoe, Keith D.] Harvard Med Sch, Boston, MA USA. [Neoptolemos, John P.] Univ Liverpool, Dept Mol & Clin Canc Med, Liverpool, Merseyside, England. [Sarr, Michael G.] Mayo Clin, Div Subspecialty Gen Surg, Rochester, MN USA. [Shrikhande, Shailesh V.] Tata Mem Hosp, Dept GI & HPB Surg Oncol, Bombay, Maharashtra, India. [Sitarz, Robert] Med Univ Lublin, Dept Surg Oncol, Lublin, Poland. [Vollmer, Charles M.] Univ Penn, Penn Med, Dept Surg, Philadelphia, PA 19104 USA. [Yeo, Charles J.] Thomas Jefferson Univ, Jefferson Pancreas Biliary & Related Canc Ctr, Dept Surg, Philadelphia, PA 19107 USA. [Hartwig, Werner] Univ Munich, Ludwig Maximilians Univ, Dept Gen Visceral & Transplantat Surg, Div Pancreat Surg, Munich, Germany. [Wolfgang, Christopher L.] Johns Hopkins Med, Dept Surg, Baltimore, MD USA. RP Besselink, MG (reprint author), Acad Med Ctr Amsterdam, Dept Surg, G4-196,Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. EM besselink@amc.nl NR 42 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD FEB PY 2017 VL 161 IS 2 BP 365 EP 372 DI 10.1016/j.surg.2016.06.058 PG 8 WC Surgery SC Surgery GA EJ0MT UT WOS:000392904400013 PM 27692778 ER PT J AU Chatterjee, S Weinberg, I Yeh, RW Chakraborty, A Sardars, P Weinberg, MD Kabrhel, C Barnes, GD Mukherjee, D Kumbhani, D Bashir, R Vaidya, A Smith, A Fuchs, B Groeneveld, P Giri, J AF Chatterjee, Saurav Weinberg, Ido Yeh, Robert W. Chakraborty, Anasua Sardars, Partha Weinberg, Mitchell D. Kabrhel, Christopher Barnes, Geoffrey D. Mukherjee, Debabrata Kumbhani, Dharam Bashir, Riyaz Vaidya, Anjali Smith, Akaya Fuchs, Barry Groeneveld, Peter Giri, Jay TI Risk factors for intracranial haemorrhage in patients with pulmonary embolism treated with thrombolytic therapy Development of the PE-CH Score SO THROMBOSIS AND HAEMOSTASIS LA English DT Article DE Embolism; thrombolysis; (intracranial) haemorrhage ID ADMINISTRATIVE DATA; CAUSE MORTALITY; ICD-9-CM; DISEASE AB Pulmonary embolism (PE) is a major cause of morbidity and mortality world-wide, and the use of thrombolytic therapy has been associated with favourable clinical outcomes in certain patient subsets. These potential benefits are counterbalanced by the risk of bleeding complications, the most devastating of which is intracranial haemorrhage (ICH). We retrospectively evaluated 9703 patients from the 2003-2012 nationwide in-patient sample database (NIS) who received thrombolytics for PE. All patients with ICH during the PE hospitalisation were identified and a clinical risk score model was developed utilizing demographics and comorbidities. The dataset was divided 1:1 into derivation and validation cohorts. During 2003-2012, 176/9705 (1.8 %) patients with PE experienced ICH after thrombolytic use. Four independent prognostic factors were identified in a backward logistic regression model, and each was assigned a number of points proportional to its regression coefficient: pre-existing Peripheral vascular disease (1 point), age greater than 65 years (Elderly) (1 point), prior Cerebrovascular accident with residual deficit (5 points), and prior myocardial infarction (Heart attack) (1 point). In the derivation cohort, scores of 0, 1, 2 and 5 points were associated with ICH risks of 1.2 %,1.9 %, 2.4 % and 17.8 %, respectively. Rates of ICH were similar in the validation cohort. The C-statistic for the risk score was 0.65 (0.61-0.70) in the derivation cohort and 0.66 (0.60-0.72) in the validation cohort. A novel risk score, derived from simple clinical historical elements was developed to predict ICH in PE patients treated with thrombolytics. C1 [Chatterjee, Saurav] Mt Sinai Hlth Syst, St Lukes Roosevelt Hosp Ctr, Div Cardiol, New York, NY USA. [Weinberg, Ido] Harvard Med Sch, Massachusetts Gen Hosp, Inst Heart Vasc & Stroke Care, Boston, MA USA. [Yeh, Robert W.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Div Cardiovasc, Boston, MA USA. [Chakraborty, Anasua] Thomas Jefferson Univ Hosp, Div Pulmonol & Crit Care, Philadelphia, PA 19107 USA. [Sardars, Partha] Univ Utah, Div Cardiovasc Med, Salt Lake City, UT USA. [Weinberg, Mitchell D.] Northshore Univ Hosp, Dept Cardiol, Manhasset, NY USA. [Kabrhel, Christopher] Harvard Med Sch, Massachusetts Gen Hosp, Dept Emergency Med, Ctr Vasc Emergencies, Boston, MA USA. [Barnes, Geoffrey D.] Univ Michigan, Sch Med, Div Cardiovasc Med, Ann Arbor, MI USA. [Mukherjee, Debabrata] Texas Tech Univ, Div Cardiol, El Paso, TX USA. [Kumbhani, Dharam] Univ Texas Southwestern Med Ctr Dallas, Div Cardiol, Dallas, TX 75390 USA. [Bashir, Riyaz] Temple Univ, Sch Med, Div Cardiol, Philadelphia, PA 19122 USA. [Vaidya, Anjali; Giri, Jay] Univ Penn, Perelman Sch Med, Div Cardiovasc Med, Philadelphia, PA 19104 USA. [Smith, Akaya; Fuchs, Barry] Univ Penn, Perelman Sch Med, Pulm & Crit Care Div, Philadelphia, PA 19104 USA. [Groeneveld, Peter] Univ Penn, Perelman Sch Med, Div Gen Internal Med, Philadelphia, PA 19104 USA. [Chatterjee, Saurav] Temple Univ Hosp & Med Sch, Philadelphia, PA 19140 USA. RP Chatterjee, S (reprint author), Temple Univ Hosp & Med Sch, Philadelphia, PA 19140 USA.; Chatterjee, S (reprint author), Mt Sinai St Lukes West Hosp, Div Cardiovasc Med, 1111 Amsterdam Ave,3rd Floor Clark Bldg, New York, NY 10025 USA. EM sauravchatterjeemd@gmail.com FU Bristol-Myers Squibb/Pfizer; Blue Cross-Blue Shield of Michigan; Portola Pharmaceuticals; Diagnostica Stago; Siemens Healthcare; Janssen Pharmaceuticals; Boehringer-Ingelheim; American College of Cardiology; Actelion; Gilead Lifesciences; Bayer; United Therapeutics FX Dr. Yeh is an investigator for the Harvard Clinical Research Institute. Dr. Barnes reports research grants from Bristol-Myers Squibb/Pfizer and Blue Cross-Blue Shield of Michigan as well as consulting fees from Portola Pharmaceuticals. Dr. Kabrhel reports research grants to the institution from Diagnostica Stago, Siemens Healthcare, Janssen Pharmaceuticals, and Boehringer-Ingelheim as well as consulting fees from Diagnostica Stago, Siemens Healthcare, Janssen Pharmaceuticals, and Portola Pharmaceuticals. Dr. Kumbhani reports consulting fees from the American College of Cardiology. Dr. Vaidya reports consulting fees from Actelion, Gilead Lifesciences, Bayer, and United Therapeutics. Drs. Chatterjee, I. Weinberg, Chakraborty, Sardar, M. Weinberg, Mukherjee, Bashir, Smith, Fuchs, Groeneveld, and Giri have no relevant disclosures. NR 16 TC 0 Z9 0 U1 4 U2 4 PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN PI STUTTGART PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD FEB PY 2017 VL 117 IS 2 BP 246 EP 251 DI 10.1160/TH16-07-0588 PG 6 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA EJ6VU UT WOS:000393358700006 PM 27882375 ER PT J AU Obi, AT Andraska, E Kanthi, Y Kessinger, CW Elfline, M Luke, C Siahaan, TJ Jaffee, FA Wakefield, TW Henke, PK AF Obi, Andrea T. Andraska, Elizabeth Kanthi, Yogendra Kessinger, Chase W. Elfline, Megan Luke, Cathy Siahaan, Teruna J. Jaffee, Farouc A. Wakefield, Thomas W. Henke, Peter K. TI Endotoxaemia-augmented murine venous thrombosis is dependent on TLR-4 and ICAM-1, and potentiated by neutropenia SO THROMBOSIS AND HAEMOSTASIS LA English DT Article DE TLR4; cellular adhesion molecules; ICAM-1; sepsis; LPS; venous thrombosis; venous thromboembolism ID DEEP-VEIN THROMBOSIS; EXTRACELLULAR DNA TRAPS; IN-VIVO; SEVERE SEPSIS; TISSUE FACTOR; P-SELECTIN; SEPTIC SHOCK; FACTOR-XIII; RECEPTOR 4; MICROVASCULAR THROMBOSIS AB Venous thromboembolism is a major cause of death during and immediately post-sepsis. Venous thrombosis (VT) is mediated by cell adhesion molecules and leukocytes, including neutrophil extracellular traps (NETs). Sepsis, or experimentally, endotoxaemia, shares similar characteristics and is modulated via toll like receptor 4 (TLR4). This study was undertaken to determine if endotoxaemia potentiates early stasis thrombogenesis, and secondarily to determine the role of VT TLR4, ICAM-1 and neutrophils (PMNs). Wild-type (WT), ICAM-1(-/-) and TLR4(-/-) mice underwent treatment with saline or LPS (10 mg/kg i.p.) alone, or followed by inferior vena cava (IVC) ligation to generate stasis VT. In vivo microscopy of leukocyte trafficking was performed in non-thrombosed mice, and tissue and plasma were harvested during early VT formation. Pre-thrombosis, circulating ICAM-1 was elevated and increased leukocyte adhesion and rolling occurred on the IVC of LPS-treated mice. Post-thrombosis, endotoxaemic mice formed larger, platelet-poor thrombi. Endotoxaemic TLR4(-/-) mice did not have an augmented thrombotic response and exhibited significantly decreased circulating ICAM-1 compared to endotoxaemic WT controls. Endotoxaemic ICAM-1(-/-) mice had significantly smaller thrombi compared to controls. Hypothesising that PMNs localised to the inflamed endothelium were promoting thrombosis, PMN depletion using anti-Ly6G antibody was performed. Paradoxically, VT formed without PMNs was amplified, potentially related to endotoxaemia induced elevation of PAI-1 and circulating FXIII, and decreased uPA. Endotoxaemia enhanced early VT occurs in a TLR-4 and ICAM-1 dependent fashion, and is potentiated by neutropenia. ICAM-1 and/or TLR-4 inhibition may be a unique strategy to prevent sepsis-associated VT. C1 [Obi, Andrea T.; Andraska, Elizabeth; Elfline, Megan; Luke, Cathy; Wakefield, Thomas W.; Henke, Peter K.] Univ Michigan, Dept Surg, Vasc Surg Sect, Conrad Jobst Vasc Res Lab, Ann Arbor, MI 48109 USA. [Andraska, Elizabeth] Univ Michigan, Sch Med, Ann Arbor, MI 48109 USA. [Kanthi, Yogendra] Univ Michigan, Dept Cardiol, Ann Arbor, MI 48109 USA. [Kessinger, Chase W.; Jaffee, Farouc A.] Harvard Med Sch, Massachusetts Gen Hosp, Div Cardiol, Cardiovasc Res Ctr, Boston, MA USA. [Siahaan, Teruna J.] Univ Kansas, Sch Pharmacol, Lawrence, KS 66045 USA. RP Henke, PK (reprint author), Univ Michigan Hlth Syst, Cardiovasc Ctr 5463, 1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. EM henke@umich.edu FU NIH [5 T32 HL076123-09, HL089407, HL122388, K08HL131993]; Elizabeth Anne Baiardi Research Fund; Conrad and Caroline Jobst Foundation; [HL092129] FX This study was supported by: HL092129 (PKH), NIH 5 T32 HL076123-09 (TW and AO), HL089407 (TW), HL122388 (FAJ), K08HL131993 (YK), Elizabeth Anne Baiardi Research Fund, the Conrad and Caroline Jobst Foundation and the Mary Ann Tinker, M.D. Surgical Educational and Research Fund. NR 73 TC 0 Z9 0 U1 2 U2 2 PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN PI STUTTGART PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD FEB PY 2017 VL 117 IS 2 BP 339 EP 348 DI 10.1160/TH16-03-0218 PG 10 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA EJ6VU UT WOS:000393358700016 PM 27975098 ER PT J AU Ageno, W Casella, IB Han, CK Raskob, GE Schellong, S Schulman, S Singer, DE Kimura, K Tang, WB Desch, M Goldhaber, SZ AF Ageno, Walter Casella, Ivan B. Han, Chee Kok Raskob, Gary E. Schellong, Sebastian Schulman, Sam Singer, Daniel E. Kimura, Karen Tang, Wenbo Desch, Marc Goldhaber, Samuel Z. TI RE-COVERY DVT/PE: Rationale and design of a prospective observational study of acute venous thromboembolism with a focus on dabigatran etexilate SO THROMBOSIS AND HAEMOSTASIS LA English DT Article DE Deep-vein thrombosis; pulmonary embolism; dabigatran; anticoagulation ID PULMONARY-EMBOLISM; ORAL ANTICOAGULANTS; ANTITHROMBOTIC THERAPY; THROMBIN INHIBITOR; WARFARIN; GUIDELINES; MANAGEMENT; TRIALS; RISK AB The therapeutic management of venous thromboembolism (VTE) is rapidly evolving. Following the positive results of pivotal large-scale randomised trials, the non-vitamin K antagonist oral anticoagulants (NOACs) represent an important alternative to standard anticoagulation. In phase III studies, dabigatran was as effective as, and significantly safer than warfarin. Additional information on real-world data of dabigatran is now warranted. RE-COVERY DVT/PE is a multi-centre, international, observational (i.e. non-interventional) study enrolling patients with acute DVT and/or PE within 30 days after objective diagnosis. The study is designed with two phases. Phase 1 has a cross-sectional design, enrolling approximately 6000 patients independently of treatment choice, with the aim of providing a contemporary picture of the management of VIE worldwide. Phase 2 has a prospective cohort design, with follow-up of one year, enrolling 8000 patients treated with dabigatran or vitamin K antagonists (VKAs) with the aim of comparing their safety, defined by the occurrence of major bleeding, and effectiveness, defined by the occurrence of symptomatic recurrent VIE. RE-COVERY DVT/PE will complement both the results of other observational studies in this field and the results of phase Ill studies with dabigatran, in particular by assessing its clinical benefit in various patient subgroups treated in routine clinical practice. C1 [Ageno, Walter] Univ Insubria, Varese, Italy. [Casella, Ivan B.] Univ Sao Paulo, Sao Paulo, Brazil. [Han, Chee Kok] Univ Malaya, Kuala Lumpur, Malaysia. [Raskob, Gary E.] Univ Oklahoma, Hlth Sci Ctr, Norman, OK 73019 USA. [Schellong, Sebastian] Stadt Klinikum Dresden, Dresden, Germany. [Schulman, Sam] Thrombosis & Atherosclerosis Res Inst, Hamilton, ON, Canada. [Schulman, Sam] McMaster Univ, Hamilton, ON, Canada. [Singer, Daniel E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Singer, Daniel E.; Goldhaber, Samuel Z.] Harvard Med Sch, Boston, MA USA. [Kimura, Karen] Boehringer Ingelheim Canada, Burlington, ON, Canada. [Tang, Wenbo; Desch, Marc] Boehringer Ingelheim GmbH & Co KG, Ingelheim, Germany. [Goldhaber, Samuel Z.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. RP Ageno, W (reprint author), Univ Insubria, Dept Clin & Expt Med, Varese, Italy. EM walter.ageno@uninsubria.it FU Bayer; Boehringer Ingelheim; BMS; Daiichi Sankyo; Janssen; JJ; Pfizer; Portola; Eli Lilly; Bayer Healthcare FX W. Ageno has received research support from Bayer, and Boehringer Ingelheim, and has served on advisory boards for Bayer, Boehringer Ingelheim, and Daiichi Sankyo. I. B. Casella is a current or former consultant and/or speaker for Boehringer Ingelheim (Brazil and Germany), EMS (Brazil), Farmoquimica (Brazil), and Pfizer (Brazil). G. Raskob has received consultancy fees from Boehringer Ingelheim, Bayer, BMS, Daiichi Sankyo, Janssen, J&J, Pfizer, Portola, and Eli Lilly. S. Schellong has received consultancy fees and speaker fees from Bayer Healthcare, Boehringer Ingelheim, BMS, Pfizer, and Daiichi Sankyo. S. Schulman has received honoraria and research grants from Boehringer Ingelheim. D. E. Singer has served as a consultant and/or the advisory boards of Boehringer Ingelheim, BMS, Merck Johnson & Johnson, and Pfizer, and has received research grants from Boehringer Ingelheim, and BMS. K. Kimura is an employee of Boehringer Ingelheim Canada Ltd. W Tang is a full-time employee of Boehringer Ingelheim Pharmaceuticals Inc. M. Desch is an employee of Boehringer Ingelheim. S. Goldhaber is a consultant for Bayer, Boehringer Ingelheim, BMS, Daiichi Sankyo, Janssen, and Portola and has received research support from BiO2 Medical, Boehringer Ingelheim, BMS, BTG EKOS, Daiichi Sankyo, and Janssen. C. Han declares no conflicts of interest. NR 30 TC 0 Z9 0 U1 3 U2 3 PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN PI STUTTGART PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD FEB PY 2017 VL 117 IS 2 BP 415 EP 421 DI 10.1160/TH16-07-0566 PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA EJ6VU UT WOS:000393358700023 PM 27853808 ER PT J AU Cornell, RF D'Souza, A Kassim, AA Costa, LJ Innis-Shelton, RD Zhang, MJ Huang, JX Abidi, M Aiello, J Akpek, G Bashey, A Bashir, Q Cerny, J Comenzo, R Diaz, MA Freytes, C Gale, RP Ganguly, S Hamadani, M Hashmi, S Holmberg, L Hossain, N Kamble, RT Kharfan-Dabaja, M Kindwall-Keller, T Kyle, R Kumar, S Lazarus, H Lee, C Maiolino, A Marks, DI Meehan, K Mikhael, J Nath, R Nishihori, T Olsson, RF Ramanathan, M Saad, A Seo, S Usmani, S Vesole, D Vij, R Vogl, D Wirk, BM Yared, J Krishnan, A Mark, T Nieto, Y Hari, P AF Cornell, Robert F. D'Souza, Anita Kassim, Adetola A. Costa, Luciano J. Innis-Shelton, Racquel D. Zhang, Mei-Jie Huang, Jiaxing Abidi, Muneer Aiello, Jack Akpek, Gorgun Bashey, Asad Bashir, Qaiser Cerny, Jan Comenzo, Raymond Angel Diaz, Miguel Freytes, Cesar Gale, Robert Peter Ganguly, Siddhartha Hamadani, Mehdi Hashmi, Shahrukh Holmberg, Leona Hossain, Nasheed Kamble, Rammurti T. Kharfan-Dabaja, Mohamed Kindwall-Keller, Tamila Kyle, Robert Kumar, Shaji Lazarus, Hillard Lee, Cindy Maiolino, Angelo Marks, David I. Meehan, Kenneth Mikhael, Joe Nath, Rajneesh Nishihori, Taiga Olsson, Richard F. Ramanathan, Muthalagu Saad, Ayman Seo, Sachiko Usmani, Saad Vesole, David Vij, Ravi Vogl, Dan Wirk, Baldeep M. Yared, Jean Krishnan, Amrita Mark, Tomer Nieto, Yago Hari, Parameswaran TI Maintenance versus Induction Therapy Choice on Outcomes after Autologous Transplantation for Multiple Myeloma SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Myeloma; Transplantation; Survival; Relapse; Chemotherapy; Maintenance ID STEM-CELL TRANSPLANTATION; THALIDOMIDE PLUS DEXAMETHASONE; CONSOLIDATION THERAPY; RANDOMIZED PHASE-3; SURVIVAL; BORTEZOMIB; LENALIDOMIDE; TRIAL; ABNORMALITIES; HYBRIDIZATION AB Bortezomib (V), lenalidomide (R), cyclophosphamide (C), and dexamethasone (D) are components of the most commonly used modern doublet (RD, VD) or triplet (VRD, CVD) initial induction regimens before autologous hematopoietic cell transplantation (AHCT) for multiple myeloma (MM) in the United States. In this study we evaluated 693 patients receiving "upfront" AHCT after initial induction therapy with modern doublet or triplet regimens using data reported to the Center for International Blood and Marrow Transplant Research from 2008 to 2013. Analysis was limited to those receiving a single AHCT after 1 line of induction therapy within 12 months from treatment initiation for MM. In multivariate analysis, progression-free survival (PFS) and overall survival were similar irrespective of induction regimen. However, high-risk cytogenetics and nonreceipt of post transplant maintenance/consolidation therapy were associated with higher risk of relapse. Patients receiving post-transplant therapy had significantly improved 3-year PFS versus no post-transplant therapy (55% versus 39%, P =.0001). This benefit was most evident in patients not achieving at least a complete response post-AHCT (P =.005). In patients receiving upfront AHCT, the choice of induction regimen (doublet or triplet therapies) appears to be of lower impact than use of post-transplant therapy. (C) 2017 American Society for Blood and Marrow Transplantation. C1 [Cornell, Robert F.; Kassim, Adetola A.] Vanderbilt Univ, Med Ctr, Dept Med, Div Hematol Oncol, Nashville, TN USA. [D'Souza, Anita; Zhang, Mei-Jie; Huang, Jiaxing; Hamadani, Mehdi; Hari, Parameswaran] Med Coll Wisconsin, Dept Med, CIBMTR, Milwaukee, WI 53226 USA. [Costa, Luciano J.; Innis-Shelton, Racquel D.; Saad, Ayman] Univ Alabama Birmingham, Dept Med, Div Hematol Oncol, Birmingham, AL 35294 USA. [Zhang, Mei-Jie] Med Coll Wisconsin, Div Biostat, Inst Hlth & Soc, Milwaukee, WI 53226 USA. [Abidi, Muneer] Wayne State Univ, Dept Oncol, Karmanos Canc Inst, Div BMT, Detroit, MI USA. [Akpek, Gorgun] Rush Univ, Med Ctr, Dept Internal Med, Stem Cell Transplantat & Cell Therapy, Chicago, IL 60612 USA. [Bashey, Asad] Northside Hosp, Blood & Marrow Transplant Program, Atlanta, GA USA. [Bashir, Qaiser; Nieto, Yago] Univ Texas MD Anderson Canc Ctr, Div Canc Med, Dept Stem Cell Transplantat, Houston, TX 77030 USA. [Cerny, Jan; Nath, Rajneesh; Ramanathan, Muthalagu] UMass Mem Med Ctr, Dept Med, Div Hematol & Oncol, Worcester, MA USA. [Comenzo, Raymond] Tufts Med Ctr, Boston, MA USA. [Angel Diaz, Miguel] Hosp Infantil Univ Nino Jesus, Dept Hematol Oncol, Madrid, Spain. [Freytes, Cesar] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Freytes, Cesar] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Gale, Robert Peter] Imperial Coll London, Dept Med, Div Expt Med, Hematol Res Ctr, London, England. [Ganguly, Siddhartha] Univ Kansas, Med Ctr, Div Hematol & Oncol, Blood & Marrow Transplantat, Kansas City, KS 66103 USA. [Hashmi, Shahrukh; Kyle, Robert; Kumar, Shaji] Mayo Clin Rochester, Rochester, MN USA. [Holmberg, Leona] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Hossain, Nasheed] Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Kamble, Rammurti T.] Baylor Coll Med, Div Hematol & Oncol, Ctr Cell & Gene Therapy, Houston, TX 77030 USA. [Kharfan-Dabaja, Mohamed; Nishihori, Taiga] H Lee Moffitt Canc Ctr & Res Inst, Dept Blood & Marrow Transplantat, Tampa, FL USA. [Kindwall-Keller, Tamila] Univ Virginia Hlth Syst, Div Hematol Oncol, Charlottesville, VA USA. [Lazarus, Hillard] Univ Hosp, Case Med Ctr, Seidman Canc Ctr, Cleveland, OH USA. [Lee, Cindy] Royal Adelaide Hosp, Adelaide, SA, Australia. [Maiolino, Angelo] Univ Fed Rio de Janeiro, Hosp Univ Clementinio Fraga Filho, Rio De Janeiro, Brazil. [Marks, David I.] Univ Hosp Bristol NHS Trust, Adult Bone Marrow Transplant, Bristol, Avon, England. [Meehan, Kenneth] Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. [Mikhael, Joe] Mayo Clin Arizona, Phoenix, AZ USA. [Mikhael, Joe] Phoenix Childrens Hosp, Phoenix, AZ USA. [Olsson, Richard F.] Karolinska Inst, Dept Lab Med, Div Therapeut Immunol, Stockholm, Sweden. [Olsson, Richard F.] Uppsala Univ, Ctr Clin Res Sormland, Uppsala, Sweden. [Seo, Sachiko] East Hosp, Natl Canc Res Ctr, Chiba, Japan. [Usmani, Saad] Carolinas HealthCare Syst, Levine Canc Inst, Dept Med Hematol Oncol, Charlotte, NC USA. [Vesole, David] John Theurer Canc Ctr Hackensack UMC, Hackensack, NJ USA. [Vij, Ravi] Washington Univ, Sch Med, Div Hematol & Oncol, St Louis, MO USA. [Vogl, Dan] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Wirk, Baldeep M.] Seattle Canc Care Alliance, Div Bone Marrow Transplant, Seattle, WA USA. [Yared, Jean] Univ Maryland, Dept Med, Div Hematol Oncol,Greenebaum Canc Ctr, Blood & Marrow Transplantat Program, Baltimore, MD 21201 USA. [Krishnan, Amrita] City Hope Natl Med Ctr, 1500 E Duarte Rd, Duarte, CA 91010 USA. [Mark, Tomer] Weill Cornell Med Coll, Dept Med, New York, NY USA. RP D'Souza, A (reprint author), Med Coll Wisconsin, 9200 W Wisconsin Ave,Ste 5500, Milwaukee, WI 53226 USA. EM andsouza@mcw.edu OI Hari, Parameswaran/0000-0002-8800-297X; Saad, Ayman /0000-0003-0003-0130 FU Public Health Service Grant from the National Cancer Institute (NCI) [5U24-CA076518]; National Cancer Institute (NCI); National Heart, Lung and Blood Institute (NHLBI); National Institute of Allergy and Infectious Diseases from NHLBI and NCI [5U10HL069294]; Health Resources and Services Administration (HRSA/DHHS) [HHSH250201200016C]; Office of Naval Research [N00014-15-1-0848, N00014-16-1-2020]; Alexion; *Amgen, Inc. FX The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement 5U24-CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases; Grant/Cooperative Agreement 5U10HL069294 from NHLBI and NCI; contract HHSH250201200016C with Health Resources and Services Administration (HRSA/DHHS); 2 grants N00014-15-1-0848 and N00014-16-1-2020 from the Office of Naval Research; and grants from Alexion; *Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; Astellas Pharma US; AstraZeneca; Be The Match Foundation; *Bluebird Bio, Inc.; *Bristol-Myers Squibb Oncology; *Celgene Corporation; Cellular Dynamics International, Inc.; *Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Gamida Cell Ltd.; Genentech, Inc.; Genzyme Corporation; *Gilead Sciences, Inc.; Health Research, Inc. Roswell Park Cancer Institute; HistoGenetics, Inc.; Incyte Corporation; Janssen Scientific Affairs, LLC; *Jazz Pharmaceuticals, Inc.; Jeff Gordon Children's Foundation; The Leukemia and Lymphoma Society; Medac, GmbH; Medlmmune; The Medical College of Wisconsin; *Merck & Co., Inc.; Mesoblast; MesoScale Diagnostics, Inc.; *Miltenyi Biotec, Inc.; National Marrow Donor Program; Neovii Biotech NA, Inc.; Novartis Pharmaceuticals Corporation; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Otsuka America Pharmaceutical, Inc.; Otsuka Pharmaceutical Co., Ltd. - Japan; PCORI; Perkin Elmer, Inc.; Pfizer, Inc; *Sanofi US; *Seattle Genetics; *Spectrum Pharmaceuticals, Inc.; St. Baldrick's Foundation; *Sunesis Pharmaceuticals, Inc.; Swedish Orphan Biovitrum, Inc.; Takeda Oncology; Telomere Diagnostics, Inc.; University of Minnesota; and *WellPoint, Inc. The views expressed in this article do not reflect the official policy or position of the National Institutes of Health, the Department of the Navy, the Department of Defense, the HRSA, or any other agency of the U.S. Government. *Corporate Members. NR 35 TC 1 Z9 1 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2017 VL 23 IS 2 BP 269 EP 277 DI 10.1016/j.bbmt.2016.11.011 PG 9 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA EJ0JK UT WOS:000392894300011 PM 27864161 ER PT J AU Bandini, J Mitchell, C Epstein-Peterson, ZD Amobi, A Cahill, J Peteet, J Balboni, T Balboni, MJ AF Bandini, Julia Mitchell, Christine Epstein-Peterson, Zachary D. Amobi, Ada Cahill, Jonathan Peteet, John Balboni, Tracy Balboni, Michael J. TI Student and Faculty Reflections of the Hidden Curriculum: How Does the Hidden Curriculum Shape Students' Medical Training and Professionalization? SO AMERICAN JOURNAL OF HOSPICE & PALLIATIVE MEDICINE LA English DT Article DE professionalism; hidden curriculum; medical education; training ID INFORMAL CURRICULUM; EDUCATION AB The hidden curriculum, or the socialization process of medical training, plays a crucial role in the development of physicians, as they navigate the clinical learning environment. The purpose of this qualitative study was to examine medical faculty and students' perceptions of psychological, moral, and spiritual challenges during medical training in caring for critically ill patients. Focus groups were conducted with 25 Harvard Medical School (HMS) students, and interviews were conducted with 8 HMS faculty members. Five major themes emerged as important in shaping students' medical training experiences. First, students and faculty discussed the overall significance of the hidden curriculum in terms of the hierarchy of medicine, behavioral modeling, and the value placed on research versus clinical work. Second, respondents articulated values modeled in medicine. Third, students and faculty reflected on changes in student development during their training, particularly in terms of changes in empathy and compassion. Fourth, respondents discussed challenges faced in medical school including professional clinical education and the psychosocial aspects of medical training. Finally, students and faculty articulated a number of coping mechanisms to mitigate these challenges including reflection, prayer, repression, support systems, creative outlets, exercise, and separation from one's work. The results from this study suggest the significance of the hidden curriculum on medical students throughout their training, as they learn to navigate challenging and emotional experiences. Furthermore, these results emphasize an increased focus toward the effect of the hidden curriculum on students' development in medical school, particularly noting the ways in which self-reflection may benefit students. C1 [Bandini, Julia] Brandeis Univ, Dept Sociol, Waltham, MA USA. [Mitchell, Christine] Harvard Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA USA. [Epstein-Peterson, Zachary D.] Univ Washington, Dept Med, Seattle, WA USA. [Amobi, Ada] Harvard Med Sch Boston, Boston, MA USA. [Cahill, Jonathan] Boston Coll, Dept Theol, Chestnut Hill, MA 02167 USA. [Peteet, John] Harvard Med Sch Boston, Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA USA. [Balboni, Tracy] Harvard Med Sch Boston, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA USA. [Balboni, Michael J.] Harvard Med Sch Boston, Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Dana 1101,450 Brookline Ave, Boston, MA 02115 USA. RP Balboni, MJ (reprint author), Harvard Med Sch Boston, Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Dana 1101,450 Brookline Ave, Boston, MA 02115 USA. EM michael_balboni@dfci.harvard.edu FU Templeton Foundation; University of Chicago Program in Religion and Medicine Faculty Scholars Award FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported in part by a Templeton Foundation Award and a University of Chicago Program in Religion and Medicine Faculty Scholars Award. NR 23 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1049-9091 EI 1938-2715 J9 AM J HOSP PALLIAT ME JI Am. J. Hosp. Palliat. Med. PD FEB PY 2017 VL 34 IS 1 BP 57 EP 63 DI 10.1177/1049909115616359 PG 7 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EJ0BJ UT WOS:000392873300008 PM 26566929 ER PT J AU Maussion, G Cruceanu, C Rosenfeld, JA Bell, SC Jollant, F Szatkiewicz, J Collins, RL Hanscom, C Kolobova, I de Champfleur, NM Blumenthal, I Chiang, C Ota, V Hultman, C O'Dushlaine, C McCarroll, S Alda, M Jacquemont, S Ordulu, Z Marshall, CR Carter, MT Shaffer, LG Sklar, P Girirajan, S Morton, CC Gusella, JF Turecki, G Stavropoulos, DJ Sullivan, PF Scherer, SW Talkowski, ME Ernst, C AF Maussion, Gilles Cruceanu, Cristiana Rosenfeld, Jill A. Bell, Scott C. Jollant, Fabrice Szatkiewicz, Jin Collins, Ryan L. Hanscom, Carrie Kolobova, Ilaria de Champfleur, Nicolas Menjot Blumenthal, Ian Chiang, Colby Ota, Vanessa Hultman, Christina O'Dushlaine, Colm McCarroll, Steve Alda, Martin Jacquemont, Sebastien Ordulu, Zehra Marshall, Christian R. Carter, Melissa T. Shaffer, Lisa G. Sklar, Pamela Girirajan, Santhosh Morton, Cynthia C. Gusella, James F. Turecki, Gustavo Stavropoulos, Dimitri J. Sullivan, Patrick F. Scherer, Stephen W. Talkowski, Michael E. Ernst, Carl TI Implication of LRRC4C and DPP6 in neurodevelopmental disorders SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE autism; sensory processing; LRRC4C; Netrin G; DPP6 ID EXCITATORY SYNAPSE FORMATION; CHROMOSOME REARRANGEMENTS; PROTEIN FAMILY; PTP-SIGMA; EXPRESSION; SCHIZOPHRENIA; GENES; LAR; ASSOCIATION; MUTATIONS AB We performed whole-genome sequencing on an individual from a family with variable psychiatric phenotypes that had a sensory processing disorder, apraxia, and autism. The proband harbored a maternally inherited balanced translocation (46,XY,t(11;14)(p12;p12)mat) that disrupted LRRC4C, a member of the highly specialized netrin G family of axon guidance molecules. The proband also inherited a paternally derived chromosomal inversion that disrupted DPP6, a potassium channel interacting protein. Copy Number (CN) analysis in 14,077 cases with neurodevelopmental disorders and 8,960 control subjects revealed that 60% of cases with exonic deletions in LRRC4C had a second clinically recognizable syndrome associated with variable clinical phenotypes, including 16p11.2, 1q44, and 2q33.1 CN syndromes, suggesting LRRC4C deletion variants may be modifiers of neurodevelopmental disorders. In vitro, functional assessments modeling patient deletions in LRRC4C suggest a negative regulatory role of these exons found in the untranslated region of LRRC4C, which has a single, terminal coding exon. These data suggest that the proband's autism may be due to the inheritance of disruptions in both DPP6 and LRRC4C, and may highlight the importance of the netrin G family and potassium channel interacting molecules in neurodevelopmental disorders. (c) 2016 Wiley Periodicals, Inc. C1 [Maussion, Gilles; Cruceanu, Cristiana; Bell, Scott C.; Jollant, Fabrice; Kolobova, Ilaria; Ota, Vanessa; Turecki, Gustavo; Ernst, Carl] McGill Grp Suicide Studies, Dept Psychiat, Montreal, PQ, Canada. [Cruceanu, Cristiana; Turecki, Gustavo; Ernst, Carl] McGill Univ, Dept Human Genet, Montreal, PQ, Canada. [Rosenfeld, Jill A.; Shaffer, Lisa G.] PerkinElmer Inc, Signature Genom Labs, Spokane, WA USA. [Jollant, Fabrice] Nimes Acad Hosp CHU, Nimes, France. [Szatkiewicz, Jin; Sullivan, Patrick F.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Collins, Ryan L.; Hanscom, Carrie; Blumenthal, Ian; Gusella, James F.; Talkowski, Michael E.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA USA. [Collins, Ryan L.; O'Dushlaine, Colm; McCarroll, Steve; Morton, Cynthia C.; Gusella, James F.; Talkowski, Michael E.] Broad Inst MIT & Harvard, Cambridge, MA USA. [de Champfleur, Nicolas Menjot] Univ Hosp Ctr Montpellier, Dept Neuroradiol, Montpellier, France. [Chiang, Colby] Univ Virginia, Sch Med, Dept Biochem & Mol Genet, Charlottesville, VA USA. [Chiang, Colby] Washington Univ, Sch Med, McDonnell Genome Inst, St Louis, MO USA. [Hultman, Christina] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [McCarroll, Steve; Gusella, James F.] Harvard Med Sch, Dept Genet, Boston, MA USA. [Alda, Martin] Dalhousie Univ, Dept Psychiat Halifax, Halifax, NS, Canada. [Jacquemont, Sebastien] Univ Montreal, Hop St Justine, Dept Pediat, Montreal, PQ, Canada. [Ordulu, Zehra] Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, Boston, MA USA. [Ordulu, Zehra] Harvard Med Sch, Boston, MA USA. [Marshall, Christian R.; Scherer, Stephen W.] Hosp Sick Children, Ctr Appl Genom & Genet & Genome Biol, Toronto, ON, Canada. [Carter, Melissa T.] Childrens Hosp Eastern Ontario, Reg Genet Program, Ottawa, ON, Canada. [Sklar, Pamela] Mt Sinai Hosp, Dept Neurosci Psychiat & Genet & Genome Sci, New York, NY USA. [Girirajan, Santhosh] Penn State Univ, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. [Morton, Cynthia C.] Univ Manchester, Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England. [Scherer, Stephen W.] Univ Toronto, Dept Mol Genet & McLaughlin Ctr, Toronto, ON, Canada. [Talkowski, Michael E.] Harvard Med Sch, Dept Neurol, Boston, MA USA. RP Ernst, C (reprint author), McGill Grp Suicide Studies, Dept Psychiat, Montreal, PQ, Canada.; Ernst, C (reprint author), Douglas Mental Hlth Univ Inst, 6875 LaSalle Blvd,Frank B Common Pavil, Verdun, PQ H4H IR3, Canada. EM carl.ernst@mcgill.ca RI Scherer, Stephen /B-3785-2013 OI Scherer, Stephen /0000-0002-8326-1999 FU Canada Research Chairs program; Scottish Rite Charitable Foundation FX Grant sponsor: Canada Research Chairs program; Grant sponsor: Scottish Rite Charitable Foundation. NR 41 TC 1 Z9 1 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD FEB PY 2017 VL 173 IS 2 BP 395 EP 406 DI 10.1002/ajmg.a.38021 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA EJ4OD UT WOS:000393195800016 PM 27759917 ER PT J AU Ostrow, KL Bergner, AL Blakeley, J Evans, DG Ferner, R Friedman, JM Harris, GJ Jordan, JT Korf, B Langmead, S Leschziner, G Mautner, V Merker, VL Papi, L Plotkin, SR Slopis, JM Smith, MJ Stemmer-Rachamimov, A Yohay, K Belzberg, AJ AF Ostrow, K. L. Bergner, A. L. Blakeley, J. Evans, D. G. Ferner, R. Friedman, J. M. Harris, G. J. Jordan, J. T. Korf, B. Langmead, S. Leschziner, G. Mautner, V. Merker, V. L. Papi, L. Plotkin, S. R. Slopis, J. M. Smith, M. J. Stemmer-Rachamimov, A. Yohay, K. Belzberg, A. J. TI Creation of an international registry to support discovery in schwannomatosis SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE Schwannomatosis; Schwannoma; registry; SMARCB1; LZTR1 ID DIAGNOSTIC-CRITERIA; FAMILIAL SCHWANNOMATOSIS; CLINICAL-FEATURES; NEUROFIBROMATOSIS; UPDATE AB Schwannomatosis is a tumor suppressor syndrome that causes multiple tumors along peripheral nerves. Formal diagnostic criteria were first published in 2005. Variability in clinical presentation and a relative lack of awareness of the syndrome have contributed to difficulty recognizing affected individuals and accurately describing the natural history of the disorder. Many critical questions such as the mutations underlying schwannomatosis, genotype-phenotype correlations, inheritance patterns, pathologic diagnosis of schwannomatosis-associated schwannomas, tumor burden in schwannomatosis, the incidence of malignancy, and the effectiveness of current, or new treatments remain unanswered. A well-curated registry of schwannomatosis patients is needed to facilitate research in field. An international consortium of clinicians and scientists across multiple disciplines with expertise in schwannomatosis was established and charged with the task of designing and populating a schwannomatosis patient registry. The International Schwannomatosis Registry (ISR) was built around key data points that allow confirmation of the diagnosis and identification of potential research subjects to advance research to further the knowledge base for schwannomatosis. A registry with 389 participants enrolled to date has been established. Twenty-three additional subjects are pending review. A formal process has been established for scientific investigators to propose research projects, identify eligible subjects, and seek collaborators from ISR sites. Research collaborations have been created using the information collected by the registry and are currently being conducted. The ISR is a platform from which multiple research endeavors can be launched, facilitating connections between affected individuals interested in participating in research and researchers actively investigating a variety of aspects of schwannomatosis. (c) 2016 Wiley Periodicals, Inc. C1 [Ostrow, K. L.; Bergner, A. L.; Blakeley, J.; Langmead, S.; Belzberg, A. J.] Johns Hopkins Univ, Baltimore, MD USA. [Evans, D. G.; Smith, M. J.] Univ Manchester, Manchester, England. [Ferner, R.; Leschziner, G.] Guys Hosp London, London, England. [Friedman, J. M.] Univ British Columbia, Vancouver, BC, Canada. [Harris, G. J.; Jordan, J. T.; Merker, V. L.; Plotkin, S. R.; Stemmer-Rachamimov, A.] Massachusetts Gen Hosp, Boston, MA USA. [Korf, B.] Univ Alabama Birmingham, Birmingham, AL USA. [Mautner, V.] Univ Hamburg, Hamburg, Germany. [Papi, L.] Univ Florence, Florence, Italy. [Slopis, J. M.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Yohay, K.] Weill Cornell Med Coll, New York, NY USA. RP Belzberg, AJ (reprint author), 600 N Wolfe St,Meyer Bldg 5-181, Baltimore, MD 21287 USA. EM belzbe1@jhmi.edu OI Merker, Vanessa/0000-0002-4542-5227; Evans, Gareth/0000-0002-8482-5784 FU Children's Tumor Foundation FX Grant sponsor: Children's Tumor Foundation. NR 12 TC 2 Z9 2 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD FEB PY 2017 VL 173 IS 2 BP 407 EP 413 DI 10.1002/ajmg.a.38024 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA EJ4OD UT WOS:000393195800017 PM 27759912 ER PT J AU Reilly, DA Hickey, S Glat, P Lineaweaver, WC Goverman, J AF Reilly, Debra Ann Hickey, Sean Glat, Paul Lineaweaver, William C. Goverman, Jeremy TI Clinical Experience Using Dehydrated Human Amnion/Chorion Membrane Allografts for Acute and Reconstructive Burn Care SO ANNALS OF PLASTIC SURGERY LA English DT Article DE amniotic membrane; dehydrated human amnion/chorion membrane; full-thickness burns; partial-thickness burns ID AMNIOTIC MEMBRANE; REPAIR; ULCERS; GRAFT; SKIN AB Amniotic membrane is immunologically privileged and is a reservoir of growth factors and cytokines known to modulate inflammation and enhance the healing process, while also possessing antimicrobial, antifibrosis, and antiscarring properties. These properties establish a strong argument for using amniotic membrane derived products as a treatment for burns. The purpose of this article is to describe the use of commercially available dehydrated human amnion/chorion membrane allografts in patients with partial-thickness and full-thickness burns. C1 [Reilly, Debra Ann] Univ Nebraska Med Ctr, Div Plast Surg, Omaha, NE USA. [Hickey, Sean; Goverman, Jeremy] Massachusetts Gen Hosp, Dept Surg, Sumner Redstone Burn Ctr, Boston, MA 02114 USA. [Glat, Paul] St Christophers Hosp Children, Dept Pediat, Philadelphia, PA 19133 USA. [Lineaweaver, William C.] Joseph M Still Burn & Reconstruct Ctr, Jackson, MS USA. RP Reilly, DA (reprint author), Plast & Reconstruct Surg Acute & Reconstruct Burn, 983335 Nebraska Med Ctr, Omaha, NE 68198 USA. EM dareilly@unmc.edu NR 16 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0148-7043 EI 1536-3708 J9 ANN PLAS SURG JI Ann. Plast. Surg. PD FEB PY 2017 VL 78 SU 1 BP S19 EP S26 DI 10.1097/SAP.0000000000000981 PG 8 WC Surgery SC Surgery GA EI9WL UT WOS:000392860000006 PM 28079552 ER PT J AU Warfield, KL Warren, TK Qiu, XG Wells, J Mire, CE Geisbert, JB Stuthman, KS Garza, NL Van Tongeren, SA Shurtleff, AC Agans, KN Wong, G Callahan, MV Geisbert, TW Klose, B Ramstedt, U Treston, AM AF Warfield, Kelly L. Warren, Travis K. Qiu, Xiangguo Wells, Jay Mire, Chad E. Geisbert, Joan B. Stuthman, Kelly S. Garza, Nicole L. Van Tongeren, Sean A. Shurtleff, Amy C. Agans, Krystle N. Wong, Gary Callahan, Michael V. Geisbert, Thomas W. Klose, Brennan Ramstedt, Urban Treston, Anthony M. TI Assessment of the potential for host-targeted iminosugars UV-4 and UV-5 activity against filovirus infections in vitro and in vivo SO ANTIVIRAL RESEARCH LA English DT Article DE Iminosugar; UV-4B; Ebola virus; Marburg virus; Antiviral; Glucosidase ID IMMUNODEFICIENCY-VIRUS ENTRY; BUTYLDEOXYNOJIRIMYCIN-MEDIATED INHIBITION; ALPHA-GLUCOSIDASE INHIBITORS; MARBURG HEMORRHAGIC-FEVER; VIRAL DIARRHEA VIRUS; N-LINKED GLYCANS; EBOLA-VIRUS; MOUSE MODEL; GLYCOSYLATION; GLYCOPROTEIN AB Iminosugars are host-directed antivirals with broad-spectrum activity. The iminosugar, N-butyl-deoxy-nojirimycin (NB-DNJ or Miglustat (R)), is used in humans for treatment of Gaucher's disease and has mild antiviral properties. More potent analogs of NB-DNJ have been generated and have demonstrated activity against a variety of viruses including flaviviruses, influenza, herpesviruses and filoviruses. In the current study, a panel of analogs based on NB-DNJ was analyzed for activity against Ebola (EBOV) and Marburg viruses (MARV). The antiviral activity of NB-DNJ (UV-1), UV-2, UV-3, UV-4 and UV-5 against both EBOV and MARV was demonstrated in Vero cells. Subsequent studies to examine the activity of UV-4 and UV-5 using rodent models of EBOV and MARV were performed. In vivo efficacy studies provided inconsistent data following treatment with iminosugars using filovirus mouse models. A tolerability study in nonhuman primates demonstrated that UV-4 could be administered at much higher dose levels than rodents. Since UV-4 was active in vitro, had been demonstrated to be active against influenza and dengue in vivo, and was being tested in a Phase 1 clinical trial, a small proof-of-concept nonhuman primate trial was performed to determine whether this antiviral candidate could provide clinical benefit to EBOV-infected individuals. Administration of UV-4B did not provide a clinical or survival benefit to macaques infected with EBOV Makona; however, dosing of animals was not optimal in this study. Efficacy may be improved by thrice daily dosing (e.g. by nasogastric tube feeding) to match the efficacious dosing regimens demonstrated against dengue and influenza viruses. (C) 2016 Elsevier B.V. All rights reserved. C1 [Warfield, Kelly L.; Treston, Anthony M.] Emergent BioSolut, Gaithersburg, MD 20879 USA. [Warren, Travis K.; Wells, Jay; Stuthman, Kelly S.; Garza, Nicole L.; Van Tongeren, Sean A.; Shurtleff, Amy C.] US Army Res Inst Infect Dis USAMRIID, Ft Detrick, MD 21702 USA. [Qiu, Xiangguo; Wong, Gary] Publ Hlth Agcy Canada, Special Pathogens Program, Natl Microbiol Lab, Winnipeg, MB R3E 3R2, Canada. [Mire, Chad E.; Geisbert, Joan B.; Agans, Krystle N.; Geisbert, Thomas W.] Univ Texas Med Branch, Galveston Natl Lab, Galveston, TX 77550 USA. [Wong, Gary] Chinese Acad Sci, CAS Key Lab Pathogen Microbiol & Immunol, Inst Microbiol, Beijing, Peoples R China. [Callahan, Michael V.; Klose, Brennan; Ramstedt, Urban] Unither Virol LLC, Silver Spring, MD 20910 USA. [Callahan, Michael V.] Harvard Med Sch, Massachusetts Gen Hosp, Div Infect Dis, Boston, MA USA. RP Warfield, KL (reprint author), Emergent BioSolut Inc, 400 Profess Dr, Gaithersburg, MD 20879 USA. EM warfieldk@ebsi.com; travis.k.warren.ctr@mail.mil; Xiangguo.qiu@phac-aspc.gc.ca; jay.b.wells.ctr@mail.mil; cmire@utmb.edu; jbgeisbe@utmb.edu; Kelly.s.stuthman.ctr@mail.mil; nicole.l.lackemeyer.ctr@mail.mil; sean.a.vantongeren.ctr@mail.mil; amy.c.shurtleff.ctr@mail.mil; knagans@utmb.edu; garyckwong@hotmail.com; mvcallahan@mgh.harvard.edu; twgeisbe@utmb.edu; brennan.klose@abviro.com; urban_ramstedt@yahoo.com; trestona@ebsi.com FU Emergent BioSolutions; National Institutes of Health [UC7AI094660]; Public Health Agency of Canada FX The studies described here were performed using sponsored research funds from Emergent BioSolutions (formerly Unither Virology, LLC). National Institutes of Health grant number UC7AI094660 provided BSL-4 operations support of the Galveston National Laboratory and were partially supported by Public Health Agency of Canada. NR 43 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 EI 1872-9096 J9 ANTIVIR RES JI Antiviral Res. PD FEB PY 2017 VL 138 BP 22 EP 31 DI 10.1016/j.antiviral.2016.11.019 PG 10 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA EJ1ZE UT WOS:000393008400003 PM 27908828 ER PT J AU Beelontally, R Wilkie, GS Lau, B Goodmaker, CJ Ho, CMK Swanson, CM Deng, XM Wang, JH Gray, NS Davison, AJ Strang, BL AF Beelontally, Rooksarr Wilkie, Gavin S. Lau, Betty Goodmaker, Charles J. Ho, Catherine M. K. Swanson, Chad M. Deng, Xianming Wang, Jinhua Gray, Nathanael S. Davison, Andrew J. Strang, Blair L. TI Identification of compounds with anti-human cytomegalovirus activity that inhibit production of IE2 proteins SO ANTIVIRAL RESEARCH LA English DT Article DE Human cytomegalovirus; Screen; Kinase; Inhibitor; Compound; IE2 ID UL84 PROTEIN; REPLICATION; EXPRESSION; RNA; VIRIONS AB Using a high throughput screening methodology we surveyed a collection of largely uncharacterized validated or suspected kinase inhibitors for anti-human cytomegalovirus (HCMV) activity. From this screen we identified three structurally related 5-aminopyrazine compounds (XMD7-1, -2 and -27) that inhibited HCMV replication in virus yield reduction assays at low micromolar concentrations. Kinase selectivity assays indicated that each compound was a kinase inhibitor capable of inhibiting a range of cellular protein kinases. Western blotting and RNA sequencing demonstrated that treatment of infected cells with XMD7 compounds resulted in a defect in the production of the major HCMV transcriptional transactivator IE2 proteins (IE2-86, IE2-60 and IE2-40) and an overall reduction in transcription from the viral genome. However, production of certain viral proteins was not compromised by treatment with XMD7 compounds. Thus, these novel anti-HCMV compounds likely inhibited transcription from the viral genome and suppressed production of a subset of viral proteins by inhibiting IE2 protein production. (C) 2016 The Authors. Published by Elsevier B.V. C1 [Beelontally, Rooksarr; Goodmaker, Charles J.; Ho, Catherine M. K.; Strang, Blair L.] St Georges Univ London, Inst Infect & Immun, London, England. [Wilkie, Gavin S.; Lau, Betty; Davison, Andrew J.] Univ Glasgow, Ctr Virus Res, MRC, Glasgow, Lanark, Scotland. [Swanson, Chad M.] Kings Coll London, Dept Infect Dis, London, England. [Deng, Xianming; Wang, Jinhua; Gray, Nathanael S.; Strang, Blair L.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA USA. [Deng, Xianming; Wang, Jinhua; Gray, Nathanael S.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Deng, Xianming] Xiamen Univ, State Key Lab Cellular Stress Biol, Innovat Ctr Cell Signaling Network, Sch Life Sci, Xiamen, Peoples R China. RP Strang, BL (reprint author), St Georges Univ London, Inst Infect & Immun, London, England. EM bstrang@sgul.ac.uk OI Swanson, Chad/0000-0002-6650-3634; Lau, Betty/0000-0003-1382-9830 FU National Institutes of Health [R01 AI019838, R01 AI026077]; St George's, University of London; St George's Impact & Innovation Award; PARK/WestFocus Award; Medical Research Council [MC_UU_12014/3] FX We would like to express our thanks to Don Coen for his encouragement during this study and his support of B.L.S. through grants awarded to D.C. from the National Institutes of Health (R01 AI019838 and R01 AI026077). This work was also supported by New Investigator funds from St George's, University of London, a St George's Impact & Innovation Award and a PARK/WestFocus Award (all to B.L.S.) and by Medical Research Council grant MC_UU_12014/3 (to A.J.D.). The funders had no role in experimental design, data collection, data interpretation or the decision to submit the work for publication. NR 20 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 EI 1872-9096 J9 ANTIVIR RES JI Antiviral Res. PD FEB PY 2017 VL 138 BP 61 EP 67 DI 10.1016/j.antiviral.2016.12.006 PG 7 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA EJ1ZE UT WOS:000393008400008 PM 27956134 ER PT J AU Lee, WC Shen, L Catalano, PJ Mickley, LJ Koutrakis, P AF Lee, Wan-Chen Shen, Lu Catalano, Paul J. Mickley, Loretta J. Koutrakis, Petros TI Effects of future temperature change on PM2.5 infiltration in the Greater Boston area SO ATMOSPHERIC ENVIRONMENT LA English DT Article DE Climate change; Indoor-outdoor sulfur ratio; Particle infiltration; Temperature ID AIR CHANGE RATES; RESIDENTIAL INFILTRATION; INDOOR AIR; OUTDOOR; PARTICLES; PARTICULATE; POLLUTION; AMBIENT; FINE; PENETRATION AB Background: Global temperature and the frequency of extreme weather events are projected to increase and affect indoor exposure to outdoor particulate matter (PM); however, no studies have quantitatively examined the effect of climate change on particle infiltration and indoor PM exposure. Obective: To quantify the relationship between future changes in ambient temperature and fine particle (PM2.5) infiltration in the Greater Boston area. Methods: We assembled a large database of outdoor and indoor PM2.5 data from 340 homes, and used the indoor-outdoor sulfur ratio (Sr) as a surrogate for PM2.5 infiltration. We employed linear mixed effects models to examine the relationship between Sr and ambient temperature for all homes in the database and a subgroup of naturally ventilated homes. We used projected temperature data from 1981 to 2000 and 2046-2065 to predict future changes in Sr. Results: The summer-winter difference in Sr was calculated to be 30% and 54% for all homes and in the naturally ventilated subgroup, respectively. The largest future difference in S-r (21%) was linked to differences in prevalence of air conditioning. Furthermore, Sr was predicted to increase by 7% for naturally ventilated homes and 2% for all homes in summer, corresponding to an average increase of 2-3 degrees C in future temperature. Conclusions: We found that increases in future temperature due to climate change will be associated with increased PM2.5 infiltration, particularly in summer. The predicted temperature-related changes in S-r can be used to characterize future health risk due to elevated indoor PM2.5 exposure through increased particle infiltration. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Lee, Wan-Chen] Natl Taiwan Univ, Inst Environm Hlth, Coll Publ Hlth, 17 Xu Zhou Rd, Taipei 100, Taiwan. [Shen, Lu; Mickley, Loretta J.] Harvard Univ, Sch Engn & Appl Sci, 29 Oxford St, Cambridge, MA 02138 USA. [Catalano, Paul J.] Harvard TH Chan Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, 44 Binney St,Dana Farber Canc Inst CLSB 11015, Boston, MA 02115 USA. [Catalano, Paul J.] Harvard TH Chan Sch Publ Hlth, Dept Biostat, 44 Binney St,Dana Farber Canc Inst CLSB 11015, Boston, MA 02115 USA. [Koutrakis, Petros] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, 401 Pk Dr,Landmark Ctr West,Room 410, Boston, MA 02215 USA. RP Lee, WC (reprint author), Natl Taiwan Univ, Inst Environm Hlth, Coll Publ Hlth, 17 Xu Zhou Rd, Taipei 100, Taiwan. EM wanchenlee@ntu.edu.tw FU USEPA grant [RD-83575501, RD-834798] FX This publication was made possible by USEPA grant RD-83575501 and RD-834798. Its contents are solely the responsibility of the grantee and do not necessarily represent the official views of the USEPA. Further, USEPA does not endorse the purchase of any commercial products or services mentioned in the publication. NARR data were provided by NOAA/OAR/ESRL PSD, Boulder, Colorado, from their Web site (http://www.esrl.noaa.gov/psd). NR 32 TC 0 Z9 0 U1 16 U2 16 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1352-2310 EI 1873-2844 J9 ATMOS ENVIRON JI Atmos. Environ. PD FEB PY 2017 VL 150 BP 98 EP 105 DI 10.1016/j.atmosenv.2016.11.027 PG 8 WC Environmental Sciences; Meteorology & Atmospheric Sciences SC Environmental Sciences & Ecology; Meteorology & Atmospheric Sciences GA EI8PU UT WOS:000392770700010 ER PT J AU Wang, YG Huang, YY Wang, Y Lyu, PJ Hamblin, MR AF Wang, Yuguang Huang, Ymg-Ying Wang, Yong Lyu, Peijun Hamblin, Michael R. TI Photobiomodulation of human adipose-derived stem cells using 810 nm and 980 nm lasers operates via different mechanisms of action SO BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS LA English DT Article DE Photobiomodulation; Adipose-derived stem cells; 810 nm; 980 nm; Cytochrome c oxidase; Heat-gated ion channels ID DIFFERENT WAVELENGTHS 660; ANIMAL-MODEL; IN-VITRO; THERAPY; IRRADIATION; WATER; OSTEOBLASTS; MUCOSITIS; MEMBRANE; CHANNEL AB Photobiomodulation (PBM) using red or near-infrared (NIR) light has been used to stimulate the proliferation and differentiation of adipose-derived stem cells. The use of NIR wavelengths such as 810 nm is reasonably well accepted to stimulate mitochondrial activity and ATP production via absorption of photons by cytochrome c oxidase. However, the mechanism of action of 980 nm is less well understood. Here we study the effects of both wavelengths (810 nm and 980 nm) on adipose-derived stem cells in vitro. Both wavelengths showed a biphasic dose response, but 810 nm had a peak dose response at 3 J/cm(2) for stimulation of proliferation at 24 h, while the peak dose for 980 nm was 10-100 times lower at 0.03 or 0.3 J/cm(2). Moreover, 980 nm (but not 810 nm) increased cytosolic calcium while decreasing mitochondrial calcium. The effects of 980 nm could be blocked by calcium channel blockers (capsazepine for TRPV1 and SKF96365 for TRPC channels), which had no effect on 810 nm. To test the hypothesis that the chromophore for 980 nm was intracellular water, which could possibly form a microscopic temperature gradient upon laser irradiation, we added cold medium (4 degrees C) during the light exposure, or pre-incubated the cells at 42 degrees C, both of which abrogated the effect of 980 nm but not 810 nm. We conclude that 980 nm affects temperature-gated calcium ion channels, while 810 nm largely affects mitochondrial cytochrome c oxidase. (C) 2016 Elsevier B.V. All rights reserved. C1 [Wang, Yuguang; Wang, Yong; Lyu, Peijun] Peking Univ, Sch & Hosp Stomatol, Ctr Digital Dent, Beijing, Peoples R China. [Wang, Yuguang; Wang, Yong; Lyu, Peijun] Natl Engn Lab Digital & Mat Technol Stomatol, Beijing, Peoples R China. [Wang, Yuguang; Huang, Ymg-Ying; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Wang, Yuguang; Huang, Ymg-Ying; Hamblin, Michael R.] Harvard Med Sch, Dept Dermatol, Boston, MA 02115 USA. [Hamblin, Michael R.] Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Lyu, PJ (reprint author), Peking Univ, Sch & Hosp Stomatol, Ctr Digital Dent, Beijing, Peoples R China.; Hamblin, MR (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. EM kqlpj@bjmu.edu.cn; hamblin@helix.mgh.harvard.edu OI Hamblin, Michael/0000-0001-6431-4605 FU US NIH [R01AI050875]; Air Force Office of Scientific Research [FA9550-13-1-0068]; US Army Medical Research Acquisition Activity [W81XWH-09-1-0514]; US Army Medical Research and Materiel Command [W81XWH-13-2-0067]; PKUSS [PKUSS20140208]; Ministry of Education [113002A] FX This work was supported by US NIH R01AI050875 and by Air Force Office of Scientific Research grant FA9550-13-1-0068, US Army Medical Research Acquisition Activity grant W81XWH-09-1-0514, and US Army Medical Research and Materiel Command grant W81XWH-13-2-0067. Yuguang Wang was funded by PKUSS grant PKUSS20140208 and Ministry of Education grant 113002A. NR 46 TC 0 Z9 0 U1 8 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-4165 EI 1872-8006 J9 BBA-GEN SUBJECTS JI Biochim. Biophys. Acta-Gen. Subj. PD FEB PY 2017 VL 1861 IS 2 BP 441 EP 449 DI 10.1016/j.bbagen.2016.10.008 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA EI7LU UT WOS:000392680200041 PM 27751953 ER PT J AU Armenian, SH Chemaitilly, W Chen, M Chow, EJ Duncan, CN Jones, LW Pulsipher, MA Remaley, AT Rovo, A Salooja, N Battiwalla, M AF Armenian, Saro H. Chemaitilly, Wassim Chen, Marcus Chow, Eric J. Duncan, Christine N. Jones, Lee W. Pulsipher, Michael A. Remaley, Alan T. Rovo, Alicia Salooja, Nina Battiwalla, Minoo TI National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Cardiovascular Disease and Associated Risk Factors Working Group Report SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE National Institutes of Health consensus; Late effects; Hematopoietic cell transplantation; Cardiovascular disease; Cardiovascular risk factors; Chronic disease; Survivorship ID BONE-MARROW-TRANSPLANTATION; LONG-TERM SURVIVORS; IMPAIRED GLUCOSE-TOLERANCE; AMERICAN-HEART-ASSOCIATION; VERSUS-HOST-DISEASE; VENTRICULAR EJECTION FRACTION; ACUTE LYMPHOBLASTIC-LEUKEMIA; CHILDHOOD-CANCER-SURVIVOR; TOTAL-BODY IRRADIATION; HIGH BLOOD-PRESSURE AB A number of studies have shown that autologous and allogeneic hematopoietic cell transplantation (HCT) contribute to an increased incidence of cardiovascular disease (CVD) and worsening of cardiovascular risk factors that could contribute to further CVD over time. These observations, combined with a notable increase in the number of survivors after HCT in recent years, highlight the need for studies aimed at modifying risk or preventing these outcomes by changing specific approaches and/or post-HCT interventions. To address these issues, the National Heart, Lung and Blood Institute and National Cancer Institute co-sponsored an international initiative on late effects after HCT. This report summarizes the major gaps in knowledge along with detailed recommendations regarding study priorities from the Cardiovascular Disease and Associated Risk Factors Committee, a multidisciplinary panel of international experts. The committee calls for specific studies aimed at understanding and preventing arterial disease and cardiac dysfunction (heart failure, valvular disease, and arrhythmias), as well as decreasing cardiovascular risk factors (hypertension, hyperglycemia, dyslipidemia, and sarcopenic obesity) after HCT. (C) 2017 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved. C1 [Armenian, Saro H.] City Hope Natl Med Ctr, Dept Populat Sci, Duarte, CA USA. [Chemaitilly, Wassim] St Jude Childrens Res Hosp, Pediat Med Dept, 332 N Lauderdale St, Memphis, TN 38105 USA. [Chen, Marcus; Remaley, Alan T.] NHLBI, Cardiovasc & Pulm Branch, Bldg 10, Bethesda, MD 20892 USA. [Chow, Eric J.] Fred Hutchinson Canc Res Ctr, Clin Res & Publ Hlth Sci Div, 1124 Columbia St, Seattle, WA 98104 USA. [Duncan, Christine N.] Dana Farber Canc Inst, Pediat Stem Cell Transplant Ctr, Boston, MA 02115 USA. [Jones, Lee W.] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. [Pulsipher, Michael A.] Childrens Hosp Los Angeles, Childrens Ctr Canc & Blood Dis, Los Angeles, CA 90027 USA. [Rovo, Alicia] Univ Hosp Bern, Dept Hematol, Bern, Switzerland. [Salooja, Nina] Imperial Coll London, Dept Med, London, England. [Battiwalla, Minoo] NHLBI, Hematopoiet Transplantat Sect, Bldg 10, Bethesda, MD 20892 USA. RP Armenian, SH (reprint author), City Hope Natl Med Ctr, Ctr Comprehens Canc, 1500 East Duarte Rd, Duarte, CA 91010 USA. EM sarmenian@coh.org FU National Heart, Lung and Blood Institute (NHLBI); National Cancer Institute (NCI) FX This initiative was sponsored jointly by the National Heart, Lung and Blood Institute (NHLBI) and National Cancer Institute (NCI). NR 108 TC 2 Z9 2 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2017 VL 23 IS 2 BP 201 EP 210 DI 10.1016/j.bbmt.2016.08.019 PG 10 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA EJ0JK UT WOS:000392894300005 PM 27590105 ER PT J AU Cooke, KR Luznik, L Sarantopoulos, S Hakim, FT Jagasia, M Fowler, DH van den Brink, MRM Hansen, JA Parkman, R Miklos, DB Martin, PJ Paczesny, S Vogelsang, G Pavletic, S Ritz, J Schultz, KR Blazar, BR AF Cooke, Kenneth R. Luznik, Leo Sarantopoulos, Stefanie Hakim, Frances T. Jagasia, Madan Fowler, Daniel H. van den Brink, Marcel R. M. Hansen, John A. Parkman, Robertson Miklos, David B. Martin, Paul J. Paczesny, Sophie Vogelsang, Georgia Pavletic, Steven Ritz, Jerome Schultz, Kirk R. Blazar, Bruce R. TI The Biology of Chronic Graft-versus-Host Disease: A Task Force Report from the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Chronic graft-versus-host disease; Blood and marrow transplantation; lmmune mechanisms; Clinical manifestations ID STEM-CELL TRANSPLANTATION; REGULATORY T-CELLS; BONE-MARROW-TRANSPLANTATION; MINOR HISTOCOMPATIBILITY ANTIGENS; BRONCHIOLITIS OBLITERANS SYNDROME; NECROSIS-FACTOR-ALPHA; IDIOPATHIC-PNEUMONIA-SYNDROME; WORKING GROUP-REPORT; NONINFECTIOUS PULMONARY COMPLICATIONS; SYSTEMIC-LUPUS-ERYTHEMATOSUS AB Chronic graft-versus-host disease (GVHD) is the leading cause of late, nonrelapse mortality and disability in allogeneic hematopoietic cell transplantation recipients and a major obstacle to improving outcomes. The biology of chronic GVHD remains enigmatic, but understanding the underpinnings of the immunologic mechanisms responsible for the initiation and progression of disease is fundamental to developing effective prevention and treatment strategies. The goals of this task force review are as follows: Summarize the current state of the science regarding pathogenic mechanisms of chronic GVHD and critical knowledge gaps. Develop Working hypotheses overriding concepts for chronic GVHD development. Define the usefulness of current preclinical models to test working hypotheses and ultimately discover and develop new therapeutic strategies. Identify shortcomings of preclinical models, and define criteria for the creation of additional models to address these limitations. This document is intended as a review of our understanding of chronic GVHD biology and therapies resulting from preclinical studies, and as a platform for developing innovative clinical strategies to prevent and treat chronic GVHD. Published by Elsevier Inc. on behalf of the American Society for Blood and Marrow Transplantation. C1 [Cooke, Kenneth R.; Luznik, Leo; Vogelsang, Georgia] Johns Hopkins Univ Hosp, Dept Oncol, Sidney Kimmel Canc Ctr, Baltimore, MD 21287 USA. [Sarantopoulos, Stefanie] Duke Univ, Div Hematol Malignancies & Cellular Therapy, Dept Immunol, Durham, NC USA. [Sarantopoulos, Stefanie] Duke Univ, Duke Canc Inst, Durham, NC USA. [Hakim, Frances T.; Fowler, Daniel H.; Pavletic, Steven] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Jagasia, Madan] Vanderbilt Univ, Dept Med, Med Ctr, Div Hematol Oncol, Nashville, TN USA. [van den Brink, Marcel R. M.] Mem Sloan Kettering Canc Ctr, Dept Immunol, New York, NY 10021 USA. [van den Brink, Marcel R. M.] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. [Hansen, John A.; Martin, Paul J.] Univ Washington, Dept Med, Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA USA. [Parkman, Robertson] Stanford Univ, Div Pediat Stem Cell Transplantat & Regenerat Med, Palo Alto, CA 94304 USA. [Miklos, David B.] Stanford Univ, Div Blood & Marrow Transplantat, Palo Alto, CA 94304 USA. [Paczesny, Sophie] Indiana Univ Sch Med, Wells Ctr Pediat Res, Dept Pediat, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46202 USA. [Paczesny, Sophie] Indiana Univ Sch Med, Wells Ctr Pediat Res, Dept Immunol, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46202 USA. [Ritz, Jerome] Harvard Med Sch, Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA USA. [Schultz, Kirk R.] Univ British Columbia, Dept Pediat, Michael Cuccione Childhood Canc Res Program, BC Childrens Hosp, Vancouver, BC, Canada. [Blazar, Bruce R.] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN 55455 USA. [Blazar, Bruce R.] Univ Minnesota, Dept Pediat, Div Blood & Marrow Transplantat, Minneapolis, MN 55455 USA. RP Cooke, KR (reprint author), Johns Hopkins Univ Hosp, Dept Oncol, Sidney Kimmel Canc Ctr, Baltimore, MD 21287 USA.; Schultz, KR (reprint author), Univ British Columbia, Dept Pediat, Michael Cuccione Childhood Canc Res Program, BC Childrens Hosp, Vancouver, BC, Canada.; Blazar, BR (reprint author), Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN 55455 USA.; Blazar, BR (reprint author), Univ Minnesota, Dept Pediat, Div Blood & Marrow Transplantat, Minneapolis, MN 55455 USA. EM kcooke5@jhmi.edu; kschultz@mail.ubc.ca; blaza001@umn.edu FU Office of Rare Disease Research, National Center for Advancing Translational Sciences; National Institute of Allergy and Infectious Diseases, Division of Allergy Immunology and Transplantation; National Heart Lung and Blood Institute, Division of Blood Diseases and Resources; Leukemia and Lymphoma Society of America; Meredith A. Cowden Foundation; National Institutes of Health's National Cancer Institute, Center for Cancer Research; Intramural Research Program and Division of Cancer Treatment and Diagnosis; Cancer Therapy Evaluation Program FX This work was supported by the National Institutes of Health's National Cancer Institute, Center for Cancer Research, Intramural Research Program and Division of Cancer Treatment and Diagnosis, Cancer Therapy Evaluation Program; Office of Rare Disease Research, National Center for Advancing Translational Sciences; National Institute of Allergy and Infectious Diseases, Division of Allergy Immunology and Transplantation; National Heart Lung and Blood Institute, Division of Blood Diseases and Resources; the Leukemia and Lymphoma Society of America; and the Meredith A. Cowden Foundation. The opinions expressed here are those of the authors and do not represent the official position of the National Institutes of Health, the National Cancer Institute, or the United States Government. NR 336 TC 0 Z9 0 U1 7 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2017 VL 23 IS 2 BP 211 EP 234 DI 10.1016/j.bbmt.2016.09.023 PG 24 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA EJ0JK UT WOS:000392894300006 PM 27713092 ER PT J AU Cortazar, FB Leaf, DE Owens, CT Laliberte, K Pendergraft, WF Niles, JL AF Cortazar, Frank B. Leaf, David E. Owens, Charles T. Laliberte, Karen Pendergraft, William F., III Niles, John L. TI Combination therapy with rituximab, low-dose cyclophosphamide, and prednisone for idiopathic membranous nephropathy: a case series SO BMC NEPHROLOGY LA English DT Article DE Membranous nephropathy; Cyclophosphamide; Rituximab; Remission ID NEPHROTIC SYNDROME; CONTROLLED-TRIAL; REMISSION; PROGNOSIS; CANCER; GLOMERULONEPHRITIS; METHYLPREDNISOLONE; GRANULOMATOSIS; CHLORAMBUCIL; DEPLETION AB Background: Membranous nephropathy is a common cause of the nephrotic syndrome. Treatment with standard regimens fails to induce complete remission in most patients. We evaluated the efficacy of combination therapy with rituximab, low-dose, oral cyclophosphamide, and an accelerated prednisone taper (RCP) for the treatment of idiopathic membranous nephropathy. Methods: We analyzed 15 consecutive patients with idiopathic membranous nephropathy treated with RCP at Massachusetts General Hospital. Seven patients (47%) received RCP as initial therapy, and the other eight patients (53%) received RCP for relapsing or refractory disease. All patients had at least 1 year of follow-up. The co-primary outcomes were attainment of partial and complete remission. Partial remission was defined as a urinary protein to creatinine ratio (UPCR) < 3 g/g and a 50% reduction from baseline. Complete remission was defined as a UPCR < 0. 3 g/g. Secondary outcomes were serious adverse events and the change in proteinuria, serum creatinine, serum albumin, cholesterol, triglycerides, and immunoglobulin G levels after 1 year of treatment. Results: Over a median follow-up time of 37 (IQR, 34-44) months, 100% of patients achieved partial remission and 93% of patients achieved complete remission at a median time of 2 and 13 months, respectively. After 1 year of treatment, median (IQR) UPCR declined from 8.2 (6.6-11.1) to 0.3 (0.2-0.7) g/g (P < 0.001). Three serious adverse events occurred over 51 patient years. No patients died or progressed to ESKD. Conclusions: Treatment of idiopathic membranous nephropathy with RCP resulted in high rates of complete remission. Larger studies evaluating this regimen are warranted. C1 [Cortazar, Frank B.; Laliberte, Karen; Niles, John L.] Massachusetts Gen Hosp, Vasculitis & Glomerulonephritis Ctr, Div Nephrol, 101 Merrimac St, Boston, MA 02114 USA. [Leaf, David E.] Brigham & Womens Hosp, Div Renal Med, 75 Francis St, Boston, MA 02115 USA. [Owens, Charles T.] Baylor Univ, Med Ctr, Div Nephrol, Dallas, TX USA. [Pendergraft, William F., III] Univ N Carolina, Div Nephrol & Hypertens, Dept Med, Kidney Ctr, Chapel Hill, NC USA. RP Cortazar, FB (reprint author), Massachusetts Gen Hosp, Vasculitis & Glomerulonephritis Ctr, Div Nephrol, 101 Merrimac St, Boston, MA 02114 USA. EM fcortazar@partners.org FU National Institutes of Health [5T32DK007540]; Genentech [G-17505]; National Institute of Diabetes and Digestive Kidney Diseases (NIDDK) [P01-DK058335, 1UM1-DK100845, F32DK097891]; Broad Institute; NIDDK [K23DK106448] FX FBC is supported by National Institutes of Health grant 5T32DK007540 and a fellowship grant from Genentech (G-17505).; WFP3 is supported by grants P01-DK058335, 1UM1-DK100845, and F32DK097891 from the National Institute of Diabetes and Digestive Kidney Diseases (NIDDK) and receives translational research funding from The Broad Institute.; DEL is supported by grant K23DK106448 from the NIDDK. The funding agencies had no role in carrying out the study. NR 32 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2369 J9 BMC NEPHROL JI BMC Nephrol. PD FEB 1 PY 2017 VL 18 AR 44 DI 10.1186/s12882-017-0459-z PG 10 WC Urology & Nephrology SC Urology & Nephrology GA EJ2YG UT WOS:000393076900002 PM 28143416 ER PT J AU Frazer, AL Rubens, S Johnson-Motoyama, M DiPierro, M Fite, PJ AF Frazer, Andrew L. Rubens, Sonia Johnson-Motoyama, Michelle DiPierro, Moneika Fite, Paula J. TI Acculturation Dissonance, Acculturation Strategy, Depressive Symptoms, and Delinquency in Latina/o Adolescents SO CHILD & YOUTH CARE FORUM LA English DT Article DE Acculturation dissonance; Latina/o youth; Acculturation strategy; Youth depression ID AMERICAN-FAMILIES; HISPANIC ADOLESCENTS; CULTURAL ORIENTATION; IMMIGRANT FAMILIES; AFRICAN-AMERICAN; ETHNIC-IDENTITY; MENTAL-HEALTH; LANGUAGE USE; RISK; YOUTH AB Two risk factors for negative outcomes in Latina/o youth are acculturation dissonance (i.e., discrepant family cultural orientations) and the endorsement of an assimilation strategy of acculturation (i.e., valuing dominant mainstream culture over culture of origin). Though these have been uniquely studied as risk factors for maladaptive behaviors among Latina/o youth, their interaction in relation to both externalizing and internalizing symptoms has yet to be fully examined. The present study examined the unique and interactive effects of acculturation dissonance and assimilation on both depressive symptoms and delinquent behaviors among Latina/o adolescents. Participants were 135 Latina/o adolescents (ages 14-20) recruited from a charter high school. Students responded to a paper-and-pencil survey assessing demographic information, acculturation strategy, acculturation dissonance, depressive symptoms, and delinquency. Acculturation dissonance was uniquely associated with depressive symptoms, but interaction effects suggested this association depended on levels of assimilation. At high levels of assimilation, acculturation dissonance was not associated with depressive symptoms, since depressive symptoms were consistently high. In contrast, at low levels of assimilation, acculturation dissonance was positively associated with depressive symptoms. In contrast, acculturation dissonance was uniquely associated with delinquency, and this association did not depend on the level of assimilation. Dissonant cultural orientations within families of Latina/o youth confer risk for negative outcomes across internalizing and externalizing domains. For youth adopting an assimilation strategy of acculturation, risk for depressive symptoms may be increased. Implications of these findings and future directions are discussed. C1 [Frazer, Andrew L.; DiPierro, Moneika; Fite, Paula J.] Univ Kansas, Dole Human Dev Ctr 2006, Clin Child Psychol Program, 1000 Sunnyside Ave, Lawrence, KS 66045 USA. [Rubens, Sonia] Dana Farber Canc Inst, Boston, MA 02115 USA. [Rubens, Sonia] Harvard Med Sch, Boston, MA USA. [Johnson-Motoyama, Michelle] Univ Kansas, Sch Social Welf, Lawrence, KS 66045 USA. [Rubens, Sonia] Univ New Orleans, Dept Psychol, 2000 Lakeshore Dr, New Orleans, LA 70148 USA. RP Frazer, AL (reprint author), Univ Kansas, Dole Human Dev Ctr 2006, Clin Child Psychol Program, 1000 Sunnyside Ave, Lawrence, KS 66045 USA. EM andrew.frazer@ku.edu; slrubens@uno.edu NR 43 TC 0 Z9 0 U1 3 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1053-1890 EI 1573-3319 J9 CHILD YOUTH CARE FOR JI Child Youth Care Forum PD FEB PY 2017 VL 46 IS 1 BP 19 EP 33 DI 10.1007/s10566-016-9367-9 PG 15 WC Psychology, Developmental SC Psychology GA EJ0ZK UT WOS:000392939600002 ER PT J AU Nikiforow, S Li, SL Snow, K Liney, D Kao, GSH Haspel, R Shpall, EJ Glotzbecker, B Sica, RA Armand, P Koreth, J Ho, VT Alyea, EP Ritz, J Soiffer, RJ Antin, JH Dey, B McAfee, S Chen, YB Spitzer, T Avigan, D Cutler, CS Ballen, K AF Nikiforow, Sarah Li, Shuli Snow, Karen Liney, Deborah Kao, Grace Shih-Hui Haspel, Richard Shpall, Elizabeth J. Glotzbecker, Brett Sica, R. Alejandro Armand, Philippe Koreth, John Ho, Vincent T. Alyea, Edwin P., III Ritz, Jerome Soiffer, Robert J. Antin, Joseph H. Dey, Bimal McAfee, Steven Chen, Yi-Bin Spitzer, Thomas Avigan, David Cutler, Corey S. Ballen, Karen TI Lack of impact of umbilical cord blood unit processing techniques on clinical outcomes in adult double cord blood transplant recipients SO CYTOTHERAPY LA English DT Article DE processing; transplantation; umbilical cord blood ID SUSTAINED DONOR ENGRAFTMENT; COMPETING RISK; VIABILITY; INFUSION; BANKING; QUALITY; CRYOPRESERVATION; MALIGNANCIES; ANTIBODIES; DISPARITY AB Background aims. Despite widespread use of umbilical cord blood (UCB) transplantation and distinct practice preferences displayed by individual UCB banks and transplant centers, little information exists on how processing variations affect patient outcomes. Methods. We reviewed 133 adult double UCB transplants performed at a single center: 98 after reduced intensity and 35 after myeloablative conditioning. Processing associated with contributing UCB banks and units was surveyed to identify differences in practice. We analyzed effect of selected variables on clinical outcomes of engraftment, dominance, transplant-related mortality, and survival. Results. Eighty-eight percent of banks queried currently practice red blood cell (RBC) depletion before cryopreservation. This reflects a shift in practice because previously 65% of banks employed RBCreplete processing methods (i.e., cryopreservation or plasma/volume reduction). Neither neutrophil nor platelet engraftment was affected by processing conditions analyzed. RBC depletion was not associated with clinical outcomes, except in 17 recipients of 2 RBC-replete units, where survival was better than that observed in 116 recipients of >= 1 RBC-depleted units (hazard ratio 3.26, P = 0.004). When analyzed by attributes of the dominant unit, RBC depletion, time in storage, bank years in existence, and inventory size did not affect clinical outcomes. Postthaw viability and CD34 dose were factors impacting engraftment. Notably, all RBC-replete units in this cohort were washed in dextran-human serum albumin before infusion. Discussion. These findings support continued utilization of the entire existing pool of cord blood units, despite recent trends in processing, and have important implications for banking resources and UCB selection practices. C1 [Nikiforow, Sarah; Liney, Deborah; Glotzbecker, Brett; Armand, Philippe; Koreth, John; Ho, Vincent T.; Alyea, Edwin P., III; Ritz, Jerome; Soiffer, Robert J.; Antin, Joseph H.; Cutler, Corey S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Nikiforow, Sarah; Haspel, Richard; Glotzbecker, Brett; Armand, Philippe; Koreth, John; Ho, Vincent T.; Alyea, Edwin P., III; Ritz, Jerome; Soiffer, Robert J.; Antin, Joseph H.; Dey, Bimal; McAfee, Steven; Chen, Yi-Bin; Spitzer, Thomas; Avigan, David; Cutler, Corey S.; Ballen, Karen] Harvard Med Sch, Boston, MA USA. [Li, Shuli] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Snow, Karen; Dey, Bimal; McAfee, Steven; Chen, Yi-Bin; Spitzer, Thomas; Ballen, Karen] Massachusetts Gen Hosp, Dept Med Oncol, Boston, MA 02114 USA. [Kao, Grace Shih-Hui] Tufts Med Ctr, Dept Med Oncol, Boston, MA USA. [Haspel, Richard] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA USA. [Shpall, Elizabeth J.] MD Anderson Canc Ctr, Dept Med Oncol, Houston, TX USA. [Sica, R. Alejandro] Univ Illinois, Dept Med Oncol, Chicago, IL USA. [Avigan, David] Beth Israel Deaconess Med Ctr, Med Oncol, Boston, MA USA. RP Nikiforow, S (reprint author), Dana Farber Canc Inst, Div Hematol Malignancies, Dana 168,450 Brookline Ave, Boston, MA 02215 USA. EM sarah_nikiforow@dfci.harvard.edu FU Friends of Dana-Farber; Jock and Bunny Adams Education and Research Endowment; National Heart, Lung, and Blood Institute [U54 HL081030-32] FX SN was supported by Friends of Dana-Farber and the Jock and Bunny Adams Education and Research Endowment. KB and CC were supported in part by National Heart, Lung, and Blood Institute grant U54 HL081030-32. NR 57 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 1465-3249 EI 1477-2566 J9 CYTOTHERAPY JI Cytotherapy PD FEB PY 2017 VL 19 IS 2 BP 272 EP 284 DI 10.1016/j.jcyt.2016.10.016 PG 13 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA EJ0HZ UT WOS:000392890500011 PM 27939176 ER PT J AU Uhlirova, H Tian, PF Kilic, K Thunemann, M Sridhar, VB Bartsch, H Dale, AM Devor, A Saisan, PA AF Uhlirova, Hana Tian, Peifang Kilic, Kivilcim Thunemann, Martin Sridhar, Vishnu B. Bartsch, Hauke Dale, Anders M. Devor, Anna Saisan, Payam A. TI Neurovascular Network Explorer 2.0: A Database of 2-Photon Single-Vessel Diameter Measurements from Mouse SI Cortex in Response To Optogenetic Stimulation SO FRONTIERS IN NEUROINFORMATICS LA English DT Article; Data Paper DE neuroinformatics; graphical user interface; MATLAB; arterioles; blood flow; hemodynamics; cerebrovascular circulation; inhibitory neurons ID BLOOD-FLOW; NEURONAL-ACTIVITY; OXYGEN; TISSUE; SIGNAL C1 [Uhlirova, Hana; Thunemann, Martin; Bartsch, Hauke; Dale, Anders M.; Devor, Anna; Saisan, Payam A.] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA. [Uhlirova, Hana] Brno Univ Technol, Cent European Inst Technol, Brno, Czech Republic. [Uhlirova, Hana] Brno Univ Technol, Fac Mech Engn, Inst Phys Engn, Brno, Czech Republic. [Tian, Peifang; Kilic, Kivilcim; Dale, Anders M.; Devor, Anna; Saisan, Payam A.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Tian, Peifang] John Carroll Univ, Dept Phys, University Hts, OH USA. [Sridhar, Vishnu B.] Univ Calif San Diego, Bioengn Undergrad Program, La Jolla, CA 92093 USA. [Devor, Anna] Harvard Med Sch, Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Uhlirova, H; Devor, A (reprint author), Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA.; Uhlirova, H (reprint author), Brno Univ Technol, Cent European Inst Technol, Brno, Czech Republic.; Uhlirova, H (reprint author), Brno Univ Technol, Fac Mech Engn, Inst Phys Engn, Brno, Czech Republic.; Devor, A (reprint author), Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA.; Devor, A (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. EM huhlirova1@gmail.com; adevor@ucsd.edu FU NIH [NS057198, EB00790, MH111359, S10RR029050]; Ministry of Education, Youth and Sports of the Czech Republic (CEITEC) [LQ1601]; International Headache Society; Scientific and Technological Research Council of Turkey; German Research Foundation [DFG TH2031/1] FX We gratefully acknowledge support from the NIH (NS057198, EB00790, MH111359, and S10RR029050) and the Ministry of Education, Youth and Sports of the Czech Republic (CEITEC 2020, LQ1601). KK was supported by postdoctoral fellowships from the International Headache Society in 2014 and The Scientific and Technological Research Council of Turkey in 2015. MT was supported by postdoctoral fellowship from the German Research Foundation (DFG TH2031/1). NR 15 TC 0 Z9 0 U1 2 U2 2 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5196 J9 FRONT NEUROINFORM JI Front. Neuroinformatics PD FEB 1 PY 2017 VL 11 AR 4 DI 10.3389/fninf.2017.00004 PG 5 WC Mathematical & Computational Biology; Neurosciences SC Mathematical & Computational Biology; Neurosciences & Neurology GA EJ2VD UT WOS:000393068800001 PM 28203155 ER PT J AU Dizon, DS AF Dizon, Don S. TI Neoadjuvant chemotherapy for newly diagnosed ovarian cancer: It's all about selection SO GYNECOLOGIC ONCOLOGY LA English DT Editorial Material ID INTRAPERITONEAL CISPLATIN C1 [Dizon, Don S.] Harvard Med Sch, Massachusetts Gen Hosp Ctr, Dept Med, Gynecol Oncol, Boston, MA 02115 USA. RP Dizon, DS (reprint author), Harvard Med Sch, Massachusetts Gen Hosp Ctr, Dept Med, Gynecol Oncol, Boston, MA 02115 USA. EM ddizon@partners.org NR 9 TC 0 Z9 0 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD FEB PY 2017 VL 144 IS 2 BP 241 EP 242 DI 10.1016/j.ygyno.2016.12.020 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA EJ0FY UT WOS:000392885200005 PM 28062117 ER PT J AU Rodrigues, R Barber, GE Ananthakrishnan, AN AF Rodrigues, Rodrigo Barber, Grant E. Ananthakrishnan, Ashwin N. TI A Comprehensive Study of Costs Associated With Recurrent Clostridium difficile Infection SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article ID TREATMENT STRATEGIES; ECONOMIC BURDEN; DONOR FECES; DISEASE; EPIDEMIOLOGY; HOSPITALS; DIARRHEA; POPULATION; PREVENTION; GUIDELINES AB BACKGROUND. Clostridium difficile infection (CDI) is the most common healthcare-associated infection and is associated with considerable morbidity. Recurrent CDI is a key contributing factor to this morbidity. Despite an estimated 83,000 recurrences annually in the United States, there are few accurate estimates of costs associated with recurrent CDI. OBJECTIVE. We performed this study (1) to identify the health consequences of recurrent CDI including need for repeat hospitalization, intensive care unit (ICU) stay, and surgery; (2) to determine costs associated with recurrent CDI and identify determinants of such costs; and (3) to compare the outcomes and costs of recurrent CDI to those who develop reinfection. METHODS. We identified all patients with confirmed recurrent CDI between January to December 2013 at a single referral center. Healthcare burden associated with recurrence including diagnostic testing, pharmacologic treatment, and inpatient and outpatient healthcare visits were identified in the 12 months following the first recurrence. Total healthcare costs were calculated, and the predictors of high healthcare utilization were identified. RESULTS. Our study population included 98 patients with recurrent CDI. The median interval between the initial infection and recurrence was 37 days. The mean age of the cohort was 67 years, two-thirds were women (62%), and the mean Charlson index was 8.6. During the year following the first recurrence of CDI, each patient underwent a mean of 4.4 stool C. difficile toxin tests and received a mean of 2.5 prescriptions for oral vancomycin (range, 0-6). Most patients (84%) with recurrence had a CDI-related hospitalization, and 6% underwent colectomy. The mean total CDI-associated cost was $34,104 per patient, with hospitalization costs accounting for 68%, surgery 20%, and drug treatment 8% of this cost, respectively. Extrapolating to the United States overall, we estimate an annual cost of $2.8 billion related to recurrent CDI. CONCLUSION. Recurrent CDI is associated with considerable morbidity and cost. C1 [Rodrigues, Rodrigo; Ananthakrishnan, Ashwin N.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Barber, Grant E.; Ananthakrishnan, Ashwin N.] Harvard Med Sch, Boston, MA USA. RP Ananthakrishnan, AN (reprint author), Massachusetts Gen Hosp, 165 Cambridge St,9th Floor, Boston, MA 02114 USA. EM aananthakrishnan@mgh.harvard.edu FU Cubist/Merck FX This study was supported by research funding from Cubist/Merck to Dr Ananthakrishnan. NR 43 TC 0 Z9 0 U1 2 U2 2 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0899-823X EI 1559-6834 J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD FEB PY 2017 VL 38 IS 2 BP 196 EP 202 DI 10.1017/ice.2016.246 PG 7 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA EJ0NT UT WOS:000392907000011 PM 27817758 ER PT J AU Hunter, LL Keefe, DH Feeney, MP Fitzpatrick, DF AF Hunter, Lisa L. Keefe, Douglas H. Feeney, M. Patrick Fitzpatrick, Denis F. TI Pressurized Wideband Acoustic Stapedial Reflex Thresholds: Normal Development and Relationships to Auditory Function in Infants SO JARO-JOURNAL OF THE ASSOCIATION FOR RESEARCH IN OTOLARYNGOLOGY LA English DT Article DE middle ear muscle reflexes; acoustic stapedial reflex; middle ear; development ID TEST-RETEST RELIABILITY; MIDDLE-EAR PRESSURE; OTOACOUSTIC EMISSIONS; NORMAL-HEARING; REFLECTANCE; ADMITTANCE; TYMPANOMETRY; NEWBORN; PERFORMANCE; CHILDREN AB This study analyzed effects of pressurization on wideband acoustic stapedial-muscle reflex (ASR) tests in infants cared for in normal newborn (NN) and neonatal intensive care units (NICU). Effects of hearing-screening outcomes on ASR threshold measurements were also evaluated, and a subsequent longitudinal study established normative threshold ranges over the first year after birth. An initial experiment compared thresholds in newborns measured at ambient pressure in the ear canal and at the tympanometric peak pressure. ASR thresholds for broadband noise were higher for ears that did not pass newborn hearing screening and ASR threshold was 14 dB higher for real-ear compared to coupler conditions. Effects of pressurization were significant for ears that passed screening; thus, ASR testing in infants should be conducted at tympanometric peak pressure. ASR threshold was significantly higher for ears that referred on transient evoked otoacoustic emissions and Auditory Brainstem Response (ABR) screening tests and also for ears with conductive and sensorineural hearing loss diagnosed by ABR. Developmental ASR changes were significant over the first year for both normal and NICU infants. Wideband pressurized ASR thresholds are a clinically relevant measure of newborn hearing screening and diagnostic outcomes. C1 [Hunter, Lisa L.] Cincinnati Childrens Hosp, Med Ctr, Div Audiol, 3333 Burnet Ave, Cincinnati, OH 45213 USA. [Keefe, Douglas H.; Fitzpatrick, Denis F.] Boys Town Natl Res Hosp, 555 N 30th St, Omaha, NE 68131 USA. [Feeney, M. Patrick] Portland VA Med Ctr, Natl Ctr Rehabilitat Auditory Res, 3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. [Feeney, M. Patrick] Oregon Hlth & Sci Univ, Dept Otolaryngol Head & Neck Surg, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. RP Hunter, LL (reprint author), Cincinnati Childrens Hosp, Med Ctr, Div Audiol, 3333 Burnet Ave, Cincinnati, OH 45213 USA. EM lisa.hunter@cchmc.org FU National Institute of Deafness and other Communication Disorders of the National Institutes of Health [R01 DC010202]; ARRA [DC010202-01S1] FX Funding Source Research reported in this publication was supported by the National Institute of Deafness and other Communication Disorders of the National Institutes of Health under Award Number R01 DC010202 and an ARRA supplement (DC010202-01S1). Co-author Keefe is involved in commercializing devices to assess middle-ear function in infants. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The content of this article does not represent the views of the Department of Veterans Affairs or of the United States Government. NR 30 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1525-3961 EI 1438-7573 J9 JARO-J ASSOC RES OTO JI JARO PD FEB PY 2017 VL 18 IS 1 BP 49 EP 63 DI 10.1007/s10162-016-0595-3 PG 15 WC Neurosciences; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA EJ1BY UT WOS:000392946400003 PM 27928634 ER PT J AU Berezina-Greene, MA Guinan, JJ AF Berezina-Greene, Maria A. Guinan, John J., Jr. TI Electrically Evoked Medial Olivocochlear Efferent Effects on Stimulus Frequency Otoacoustic Emissions in Guinea Pigs SO JARO-JOURNAL OF THE ASSOCIATION FOR RESEARCH IN OTOLARYNGOLOGY LA English DT Article DE Medial olivocochlear; SFOAE; Cochlear mechanics; Cochlear irregularities ID NERVE-FIBER RESPONSES; BUNDLE STIMULATION; NEURONS; CAT; HUMANS; NOISE; SIMULATIONS; CHINCHILLAS; PHYSIOLOGY; FEEDBACK AB Stimulus frequency otoacoustic emissions (SFOAEs) are produced by cochlear irregularities reflecting energy from the peak region of the traveling wave (TW). Activation of medial olivocochlear (MOC) efferents reduces cochlear amplification and otoacoustic emissions (OAEs). In other OAEs, MOC activation can produce enhancements. The extent of MOC enhancements of SFOAEs has not been previously studied. In anesthetized guinea pigs, we electrically stimulated MOC fibers and recorded their effects on SFOAEs. MOC stimulation mostly inhibited SFOAEs but sometimes enhanced them. Some enhancements were not near response dips and therefore cannot be explained by a reduction of wavelet cancelations. MOC stimulation always inhibited auditory-nerve compound action potentials showing that cochlear-amplifier gain was not increased. We propose that some SFOAE enhancements arise because shocks excite only a small number of MOC fibers that inhibit a few scattered outer hair cells thereby changing (perhaps increasing) cochlear irregularities and SFOAE amplitudes. Contralateral sound activation is expected to excite approximately one third of MOC efferents and may also change cochlear irregularities. Some papers suggest that large SFOAE components originate far basal of the TW peak, basal of the region that receives cochlear amplification. Using a time-frequency analysis, we separated SFOAEs into components with different latencies. At all SFOAE latencies, most SFOAE components were inhibited by MOC stimulation, but some were enhanced. The MOC inhibition of short-latency SFOAE components is consistent with these components being produced in the cochlear-amplified region near the TW peak. C1 [Berezina-Greene, Maria A.; Guinan, John J., Jr.] Mass Eye & Ear Infirm, Eaton Peabody Lab, 243 Charles St, Boston, MA 02114 USA. [Berezina-Greene, Maria A.; Guinan, John J., Jr.] Harvard MIT HST Speech & Hearing Biosci & Technol, Cambridge, MA USA. [Guinan, John J., Jr.] Harvard Med Sch, Boston, MA USA. RP Guinan, JJ (reprint author), Mass Eye & Ear Infirm, Eaton Peabody Lab, 243 Charles St, Boston, MA 02114 USA. EM jjg@epl.meei.harvard.edu FU NSF GRFP; [RO1 DC000235]; [R01 DC003687]; [T32 DC00038]; [P30 DC005209] FX We thank Drs. C.A. Shera, M.C. Brown, and D.C. Mountain for comments on earlier versions of the manuscript. This work was supported by RO1 DC000235, R01 DC003687, T32 DC00038, P30 DC005209, and a NSF GRFP, and was part of M. B-G's PhD thesis. NR 36 TC 0 Z9 0 U1 3 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1525-3961 EI 1438-7573 J9 JARO-J ASSOC RES OTO JI JARO PD FEB PY 2017 VL 18 IS 1 BP 153 EP 163 DI 10.1007/s10162-016-0593-5 PG 11 WC Neurosciences; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA EJ1BY UT WOS:000392946400009 PM 27798720 ER PT J AU Contrera, KJ Betz, J Deal, J Choi, JS Ayonayon, HN Harris, T Helzner, E Martin, KR Mehta, K Pratt, S Rubin, SM Satterfield, S Yaffe, K Simonsick, EM Lin, FR AF Contrera, Kevin J. Betz, Josh Deal, Jennifer Choi, Janet S. Ayonayon, Hilsa N. Harris, Tamara Helzner, Elizabeth Martin, Kathryn R. Mehta, Kala Pratt, Sheila Rubin, Susan M. Satterfield, Suzanne Yaffe, Kristine Simonsick, Eleanor M. Lin, Frank R. CA Hlth ABC Study TI Association of Hearing Impairment and Anxiety in Older Adults SO JOURNAL OF AGING AND HEALTH LA English DT Article DE hearing; anxiety; mental health; geriatrics ID NUTRITION EXAMINATION SURVEY; OF-THE-LITERATURE; PHYSICAL FUNCTION; BODY-COMPOSITION; NATIONAL-HEALTH; LOSS PREVALENCE; UNITED-STATES; RISK-FACTORS; US ADULTS; DEPRESSION AB Objective: The objective of the study is was investigate the association between hearing impairment and anxiety. Method: We conducted a cross-sectional analysis of 1,732 community-based adults aged 76 to 85 years who participated in the Health Aging and Body Composition (ABC) study. Logistic regression models were adjusted for demographic and cardiovascular risk factors. Hearing impairment was defined by the speech-frequency pure tone average. Anxiety was defined as reporting two symptoms of at least a little or one symptom quite a bit on the three-item Hopkins Symptom Checklist. Results: Compared with individuals with no hearing impairment, the odds of prevalent anxiety were higher among individuals with mild hearing impairment (odds ratio [OR] = 1.32, 95% confidence interval [CI] = [1.01, 1.73]) and moderate or greater hearing impairment (OR = 1.59, 95% CI = [1.14, 2.22]). Hearing aid use was not significantly associated with lower odds of anxiety. Discussion: Hearing impairment is independently associated with greater odds of anxiety symptoms in older adults. C1 [Contrera, Kevin J.; Betz, Josh; Deal, Jennifer; Choi, Janet S.; Pratt, Sheila; Lin, Frank R.] Johns Hopkins Univ, Baltimore, MD USA. [Ayonayon, Hilsa N.; Rubin, Susan M.; Yaffe, Kristine] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Harris, Tamara; Simonsick, Eleanor M.] NIA, Baltimore, MD 21224 USA. [Helzner, Elizabeth] Suny Downstate Med Ctr, Brooklyn, NY 11203 USA. [Martin, Kathryn R.] Sch Med & Dent, Inst Appl Hlth Sci, Aberdeen, Scotland. [Mehta, Kala; Pratt, Sheila] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Satterfield, Suzanne] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. RP Lin, FR (reprint author), Johns Hopkins Univ, Johns Hopkins Ctr Aging & Hlth, 2024 E Monument St,Suite 2-700, Baltimore, MD 21205 USA. EM flin1@jhmi.edu OI Betz, Joshua/0000-0003-4488-9799 FU Eleanor Schwartz Charitable Foundation; Triological Society/American College of Surgeons Clinician Scientist Award; Johns Hopkins Institute for Clinical and Translational Research; National Institutes of Health (NIH) [K23DC011279, TL1 TR001078]; National Institute on Aging (NIA) [R01-AG028050, N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; National Institute of Nursing Research [R01-NR012459]; NIH Intramural Research Program FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This article was supported in part by the Eleanor Schwartz Charitable Foundation; a Triological Society/American College of Surgeons Clinician Scientist Award; the Johns Hopkins Institute for Clinical and Translational Research; the National Institutes of Health (NIH; Grant Numbers K23DC011279, TL1 TR001078); the National Institute on Aging (NIA; Grant Number R01-AG028050, and Contract Numbers N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106); National Institute of Nursing Research (Grant Number R01-NR012459); and the NIH Intramural Research Program. NR 39 TC 0 Z9 0 U1 4 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0898-2643 EI 1552-6887 J9 J AGING HEALTH JI J. Aging Health PD FEB PY 2017 VL 29 IS 1 BP 172 EP 184 DI 10.1177/0898264316634571 PG 13 WC Gerontology; Health Policy & Services SC Geriatrics & Gerontology; Health Care Sciences & Services GA EI9ZR UT WOS:000392868600008 ER PT J AU Thomson, AK Somers, E Powis, RA Shorrock, HK Murphy, K Swoboda, KJ Gillingwater, TH Parson, SH AF Thomson, Alison K. Somers, Eilidh Powis, Rachael A. Shorrock, Hannah K. Murphy, Kelley Swoboda, Kathryn J. Gillingwater, Thomas H. Parson, Simon H. TI Survival of motor neurone protein is required for normal postnatal development of the spleen SO JOURNAL OF ANATOMY LA English DT Article DE SMN; megakaryocytes; patients; immunity; organ pathology ID SPINAL MUSCULAR-ATROPHY; SPLENIC WHITE PULP; MOUSE MODEL; GENE SMN2; B-CELLS; DEFECTS; MICE; MUSCLE; IMPAIRMENT; EXPRESSION AB Spinal muscular atrophy (SMA), traditionally described as a predominantly childhood form of motor neurone disease, is the leading genetic cause of infant mortality. Although motor neurones are undoubtedly the primary affected cell type, the severe infantile form of SMA (Type I SMA) is now widely recognised to represent a multisystem disorder where a variety of organs and systems in the body are also affected. Here, we report that the spleen is disproportionately small in the Taiwanese' murine model of severe SMA (Smn(-/-);SMN2(tg/0)), correlated to low levels of cell proliferation and increased cell death. Spleen lacks its distinctive red appearance and presents with a degenerated capsule and a disorganised fibrotic architecture. Histologically distinct white pulp failed to form and this was reflected in an almost complete absence of B lymphocytes necessary for normal immune function. In addition, megakaryoctyes persisted in the red pulp. However, the vascular density remained unchanged in SMA spleen. Assessment of the spleen in SMA patients with the infantile form of the disease indicated a range of pathologies. We conclude that development of the spleen fails to occur normally in SMA mouse models and human patients. Thus, further analysis of immune function is likely to be required to fully understand the full extent of systemic disease pathology in SMA. C1 [Thomson, Alison K.; Parson, Simon H.] Univ Aberdeen, Inst Med Sci, Foresterhill, Aberdeen AB25 2ZD, Scotland. [Thomson, Alison K.; Somers, Eilidh; Powis, Rachael A.; Shorrock, Hannah K.; Gillingwater, Thomas H.; Parson, Simon H.] Euan MacDonald Ctr Motor Neurone Dis Res, Edinburgh, Midlothian, Scotland. [Somers, Eilidh; Powis, Rachael A.; Shorrock, Hannah K.; Gillingwater, Thomas H.] Univ Edinburgh, Ctr Integrat Physiol, Edinburgh, Midlothian, Scotland. [Murphy, Kelley] Morgan State Univ, Dept Biol, Baltimore, MD 21239 USA. [Swoboda, Kathryn J.] Massachusetts Gen Hosp, Dept Neurol, Ctr Human Genet Res, Boston, MA 02114 USA. RP Parson, SH (reprint author), Univ Aberdeen, Inst Med Sci, Foresterhill, Aberdeen AB25 2ZD, Scotland. EM simon.parson@abdn.ac.uk OI Gillingwater, Thomas/0000-0002-0306-5577 FU Anatomical Society; SMA Trust (UK SMA Research Consortium); Euan MacDonald Centre for Motor Neurone Disease Research; Muscular Dystrophy UK; NICHD [R01-HD054599] FX S.H.P. received an Anatomical Society PhD Studentship award for A.K.T. T.H.G. received an Anatomical Society PhD Studentship award for R.A.P. and funding from the SMA Trust (UK SMA Research Consortium), Euan MacDonald Centre for Motor Neurone Disease Research, and Muscular Dystrophy UK. K.J.S received funding for pathologic studies in human subjects from NICHD grant R01-HD054599. NR 48 TC 3 Z9 3 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-8782 EI 1469-7580 J9 J ANAT JI J. Anat. PD FEB PY 2017 VL 230 IS 2 BP 337 EP 346 DI 10.1111/joa.12546 PG 10 WC Anatomy & Morphology SC Anatomy & Morphology GA EJ4MW UT WOS:000393192400013 PM 27726134 ER PT J AU Labonte, JW Adolf-Bryfogle, J Schief, WR Gray, JJ AF Labonte, Jason W. Adolf-Bryfogle, Jared Schief, William R. Gray, Jeffrey J. TI Residue-Centric Modeling and Design of Saccharide and Glycoconjugate Structures SO JOURNAL OF COMPUTATIONAL CHEMISTRY LA English DT Article DE carbohydrates; docking; glycoproteins; modeling; structure; Rosetta; oligosaccharides; computation; glycoconjugates ID PROTEIN-PROTEIN DOCKING; CAPRI ROUNDS 20-27; FORCE-FIELD; COMPUTATIONAL DESIGN; CARBOHYDRATE DOCKING; STRUCTURE PREDICTION; STATISTICAL-ANALYSIS; ATOMIC-ACCURACY; ROSETTA; REFINEMENT AB The RosettaCarbohydrate framework is a new tool for modeling a wide variety of saccharide and glycoconjugate structures. This report describes the development of the framework and highlights its applications. The framework integrates with established protocols within the Rosetta modeling and design suite, and it handles the vast complexity and variety of carbohydrate molecules, including branching and sugar modifications. To address challenges of sampling and scoring, RosettaCarbohydrate can sample glycosidic bonds, side-chain conformations, and ring forms, and it utilizes a glycan-specific term within its scoring function. Rosetta can work with standard PDB, GLYCAM, and GlycoWorkbench (.gws) file formats. Saccharide residue-specific chemical information is stored internally, permitting glycoengineering and design. Carbohydrate- specific applications described herein include virtual glycosylation, loop-modeling of carbohydrates, and docking of glyco-ligands to antibodies. Benchmarking data are presented and compared to other studies, demonstrating Rosetta's ability to predict glyco-ligand binding. The framework expands the tools available to glycoscientists and engineers. (C) 2016 Wiley Periodicals, Inc. C1 [Labonte, Jason W.; Gray, Jeffrey J.] Johns Hopkins Univ, Dept Biomol & Chem Engn, 3400 N Charles St, Baltimore, MD 21218 USA. [Adolf-Bryfogle, Jared; Schief, William R.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Adolf-Bryfogle, Jared; Schief, William R.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Schief, William R.] MIT, Ragon Inst, Massachusetts Gen Hosp, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Schief, William R.] Harvard Univ, Cambridge, MA 02139 USA. RP Gray, JJ (reprint author), Johns Hopkins Univ, Dept Biomol & Chem Engn, 3400 N Charles St, Baltimore, MD 21218 USA. EM jgray@jhu.edu FU National Institutes of Health [1F32-CA189246-01, R01 GM-078221]; International AIDS Vaccine Initiative Neutralizing Antibody Consortium and Center; CAVD; Ragon Institute of MGH; MIT; Harvard; National Institute of Allergy and Infectious Diseases [R01AI113867]; CHAVI-ID [1UM1AI100663]; [T32AI007244] FX Contract grant sponsor: National Institutes of Health; Contract grant numbers: 1F32-CA189246-01 (to J.W.L.) and R01 GM-078221 (to J.J.G.); Contract grant sponsor: International AIDS Vaccine Initiative Neutralizing Antibody Consortium and Center (to W.R.S.); CAVD funding for the IAVI NAC Center (to W.R.S.); Ragon Institute of MGH, MIT, and Harvard (to W.R.S.); Contract grant sponsor: National Institute of Allergy and Infectious Diseases; Contract grant number: R01AI113867 and CHAVI-ID 1UM1AI100663 (to W.R.S.); Contract grant sponsor: Postdoctoral Training Grant; Contract grant number: T32AI007244 (to J.A.-B.) NR 73 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0192-8651 EI 1096-987X J9 J COMPUT CHEM JI J. Comput. Chem. PD FEB PY 2017 VL 38 IS 5 BP 276 EP 287 DI 10.1002/jcc.24679 PG 12 WC Chemistry, Multidisciplinary SC Chemistry GA EI9UY UT WOS:000392855900003 PM 27900782 ER PT J AU Bhambhvani, P Hage, FG Iskandrian, AE AF Bhambhvani, Pradeep Hage, Fadi G. Iskandrian, Ami E. TI A quick glance at selected topics in this issue SO JOURNAL OF NUCLEAR CARDIOLOGY LA English DT Editorial Material AB "A quick glance at selected topics in this issue" aims to highlight few randomly selected articles and provide a quick review to the readers. C1 [Bhambhvani, Pradeep] Univ Alabama Birmingham, Dept Radiol, Div Mol Imaging & Therapeut, Birmingham, AL 35294 USA. [Hage, Fadi G.; Iskandrian, Ami E.] Univ Alabama Birmingham, Div Cardiovasc Dis, Birmingham, AL 35294 USA. [Hage, Fadi G.] Birmingham Vet Affairs Med Ctr, Cardiol Sect, Birmingham, AL USA. RP Bhambhvani, P (reprint author), Univ Alabama Birmingham, Dept Radiol, Div Mol Imaging & Therapeut, Birmingham, AL 35294 USA. EM pbhambhvani@uabmc.edu OI Hage, Fadi/0000-0002-1397-4942 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1071-3581 EI 1532-6551 J9 J NUCL CARDIOL JI J. Nucl. Cardiol. PD FEB PY 2017 VL 24 IS 1 BP 6 EP 8 DI 10.1007/s12350-016-0742-6 PG 3 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA EJ2RE UT WOS:000393057600003 PM 27995470 ER PT J AU AlJaroudi, WA Hage, FG AF AlJaroudi, Wael A. Hage, Fadi G. TI Cardiovascular disease in the literature: A selection of recent original research papers SO JOURNAL OF NUCLEAR CARDIOLOGY LA English DT Editorial Material C1 [AlJaroudi, Wael A.] Clemenceau Med Ctr, Div Cardiovasc Med, Beirut, Lebanon. [Hage, Fadi G.] Univ Alabama Birmingham, Div Cardiovasc Dis, Dept Med, Lyons Harrison Res Bldg 306,1900 Univ BLVD, Birmingham, AL 35294 USA. [Hage, Fadi G.] Birmingham Vet Affairs Med Ctr, Cardiol Sect, Birmingham, AL USA. RP Hage, FG (reprint author), Univ Alabama Birmingham, Div Cardiovasc Dis, Dept Med, Lyons Harrison Res Bldg 306,1900 Univ BLVD, Birmingham, AL 35294 USA. EM fadihage@uab.edu OI Hage, Fadi/0000-0002-1397-4942 NR 3 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1071-3581 EI 1532-6551 J9 J NUCL CARDIOL JI J. Nucl. Cardiol. PD FEB PY 2017 VL 24 IS 1 BP 12 EP 14 DI 10.1007/s12350-016-0747-1 PG 3 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA EJ2RE UT WOS:000393057600005 PM 27943052 ER PT J AU Lee, PI Cheng, G Alavi, A AF Lee, Pei-Ing Cheng, Gang Alavi, Abass TI The role of serial FDG PET for assessing therapeutic response in patients with cardiac sarcoidosis SO JOURNAL OF NUCLEAR CARDIOLOGY LA English DT Article DE Cardiac sarcoidosis; FDG PET; standardized uptake value; metabolic volume product ID POSITRON-EMISSION-TOMOGRAPHY; MAGNETIC-RESONANCE; DISEASE-ACTIVITY; INVOLVEMENT; IDENTIFICATION; VOLUME; HEART AB The purpose of this study was to determine the feasibility of serial quantitative 2-deoxy-2-[18F]fluoro-D-glucose (FDG) positron emission tomography (PET) to monitor the response of cardiac sarcoidosis to treatment. A total of 38 PET scan intervals (54 PET scans) were obtained in 16 patients with cardiac sarcoidosis who underwent serial FDG PET during treatment. FDG-avid lesions of the heart were interpreted quantitatively using 4 PET parameters: maximum standardized uptake value (SUVmax), partial volume corrected mean standardized uptake value (SUVmean), partial volume corrected metabolic volume product (MVP), and global metabolic volume product (gMVP). Clinical response to treatment (improved, stable, or progressive disease) was evaluated by clinical symptoms, NYHA class, and EKG in all the patients. SUVmax, SUVmean, MVP, and gMVP had significantly decreased value on repeat PET in patients who were either stable or showed clinical improvement between two serial PET scans, while none of them had significant change on repeat PET in patients who were clinically worse. Correlation analysis between PET findings and clinical assessment revealed that the changes of SUVmax and SUVmean on repeat PET were negatively correlated with patient's clinical outcome. Our results indicated that serial FDG PET is feasible to determine the extent of disease activity and to quantitatively assess the response of cardiac sarcoidosis to therapy. C1 [Lee, Pei-Ing] Koo Fdn, Dept Nucl Med, Sun Yat Sen Canc Ctr, Taipei, Taiwan. [Cheng, Gang] Philadelphia VA Med Ctr, Dept Radiol, Philadelphia, PA 19104 USA. [Cheng, Gang; Alavi, Abass] Hosp Univ Penn, Dept Radiol, 3400 Spruce St, Philadelphia, PA 19104 USA. RP Cheng, G (reprint author), Philadelphia VA Med Ctr, Dept Radiol, Philadelphia, PA 19104 USA. EM gangcheng99@yahoo.com; abass.alavi@uphs.upenn.edu NR 32 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1071-3581 EI 1532-6551 J9 J NUCL CARDIOL JI J. Nucl. Cardiol. PD FEB PY 2017 VL 24 IS 1 BP 19 EP 28 DI 10.1007/s12350-016-0682-1 PG 10 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA EJ2RE UT WOS:000393057600008 PM 27813028 ER PT J AU Osborne, MT Hulten, EA Murthy, VL Skali, H Taqueti, VR Dorbala, S DiCarli, MF Blankstein, R AF Osborne, Michael T. Hulten, Edward A. Murthy, Venkatesh L. Skali, Hicham Taqueti, Viviany R. Dorbala, Sharmila DiCarli, Marcelo F. Blankstein, Ron TI Patient preparation for cardiac fluorine-18 fluorodeoxyglucose positron emission tomography imaging of inflammation SO JOURNAL OF NUCLEAR CARDIOLOGY LA English DT Review DE PET imaging; fluorodeoxyglucose (FDG); metabolism; inflammation ID LOW-CARBOHYDRATE-DIET; HIGH-FAT; FDG UPTAKE; SUPPRESSION; SARCOIDOSIS; GLUCOSE; PET/CT; HEART; RESTRICTION; HEPARIN AB Although the number of clinical applications for fluorine-18 fluorodeoxyglucose (F-18-FDG) cardiac positron emission tomography (PET) has continued to grow, there remains a lack of consensus regarding the ideal method of suppressing normal myocardial glucose utilization for image optimization. This review describes various patient preparation protocols that have been used as well as the success rates achieved in different studies. Collectively, the available literature supports using a high-fat, no-carbohydrate diet for at least two meals with a fast of 4-12 hours prior to F-18-FDG PET imaging and suggests that isolated fasting for less than 12 hours and supplementation with food or drink just prior to imaging should be avoided. Each institution should adopt a protocol and continuously monitor its effectiveness with a goal to achieve adequate myocardial suppression in greater than 80% of patients. C1 [Osborne, Michael T.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Osborne, Michael T.; Skali, Hicham; Taqueti, Viviany R.; Dorbala, Sharmila; DiCarli, Marcelo F.; Blankstein, Ron] Harvard Med Sch, Boston, MA 02115 USA. [Osborne, Michael T.; Skali, Hicham; Taqueti, Viviany R.; Dorbala, Sharmila; DiCarli, Marcelo F.; Blankstein, Ron] Brigham & Womens Hosp, Dept Med, Noninvas Cardiovasc Imaging Program, 75 Francis St, Boston, MA 02115 USA. [Osborne, Michael T.; Skali, Hicham; Taqueti, Viviany R.; Dorbala, Sharmila; DiCarli, Marcelo F.; Blankstein, Ron] Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. [Hulten, Edward A.] Walter Reed Natl Mil Med Ctr, Div Med, Serv Cardiol, Bethesda, MD USA. [Hulten, Edward A.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Murthy, Venkatesh L.] Univ Michigan, Dept Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. [Murthy, Venkatesh L.] Univ Michigan, Dept Radiol, Div Nucl Med, Ann Arbor, MI 48109 USA. [Murthy, Venkatesh L.] Univ Michigan, Dept Radiol, Div Cardiothorac Imaging, Ann Arbor, MI 48109 USA. RP Osborne, MT (reprint author), Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA.; Osborne, MT (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM mosborne@partners.org; rblankstein@partners.org NR 33 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1071-3581 EI 1532-6551 J9 J NUCL CARDIOL JI J. Nucl. Cardiol. PD FEB PY 2017 VL 24 IS 1 BP 86 EP 99 DI 10.1007/s12350-016-0502-7 PG 14 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA EJ2RE UT WOS:000393057600018 PM 27277502 ER PT J AU Velasco, A Reyes, E Hage, FG AF Velasco, Alejandro Reyes, Eliana Hage, Fadi G. TI Guidelines in review: Comparison of the 2014 ACC/AHA guidelines on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery and the 2014 ESC/ESA guidelines on noncardiac surgery: Cardiovascular assessment and management SO JOURNAL OF NUCLEAR CARDIOLOGY LA English DT Editorial Material ID ASSOCIATION TASK-FORCE; AMERICAN-COLLEGE C1 [Velasco, Alejandro; Hage, Fadi G.] Univ Alabama Birmingham, Div Cardiovasc Dis, Dept Med, Lyons Harrison Res Bldg 306,1900 Univ Blvd, Birmingham, AL 35294 USA. [Reyes, Eliana] Royal Brompton Hosp, London, England. [Reyes, Eliana] Harefield Hosp, London, England. [Hage, Fadi G.] Birmingham Vet Affairs Med Ctr, Cardiol Sect, Birmingham, AL USA. RP Hage, FG (reprint author), Univ Alabama Birmingham, Div Cardiovasc Dis, Dept Med, Lyons Harrison Res Bldg 306,1900 Univ Blvd, Birmingham, AL 35294 USA. EM fadihage@uab.edu NR 5 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1071-3581 EI 1532-6551 J9 J NUCL CARDIOL JI J. Nucl. Cardiol. PD FEB PY 2017 VL 24 IS 1 BP 165 EP 170 DI 10.1007/s12350-016-0643-8 PG 6 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA EJ2RE UT WOS:000393057600033 PM 27549425 ER PT J AU Farag, AA Andrikopoulou, E Iskandrian, AE Germano, G Hage, FG AF Farag, Ayman A. Andrikopoulou, Efstathia Iskandrian, Ami E. Germano, Guido Hage, Fadi G. TI Detection of right ventricular ischemia by SPECT myocardial perfusion imaging SO JOURNAL OF NUCLEAR CARDIOLOGY LA English DT Editorial Material C1 [Farag, Ayman A.; Andrikopoulou, Efstathia; Iskandrian, Ami E.; Hage, Fadi G.] Univ Alabama Birmingham, Dept Med, Div Cardiovasc Dis, Lyons Harrison Res Bldg 306,1720 2nd AVE S, Birmingham, AL 35294 USA. [Hage, Fadi G.] Birmingham Vet Affairs Med Ctr, Cardiol Sect, Birmingham, AL USA. [Germano, Guido] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. RP Hage, FG (reprint author), Univ Alabama Birmingham, Dept Med, Div Cardiovasc Dis, Lyons Harrison Res Bldg 306,1720 2nd AVE S, Birmingham, AL 35294 USA. EM fadihage@uab.edu OI Hage, Fadi/0000-0002-1397-4942 NR 2 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1071-3581 EI 1532-6551 J9 J NUCL CARDIOL JI J. Nucl. Cardiol. PD FEB PY 2017 VL 24 IS 1 BP 317 EP 318 DI 10.1007/s12350-016-0402-x PG 2 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA EJ2RE UT WOS:000393057600059 PM 26818141 ER PT J AU Ko, D Rahman, F Martins, MAP Hylek, EM Ellinor, PT Schnabel, RB Benjamin, EJ Christophersen, IE AF Ko, Darae Rahman, Faisal Martins, Maria A. P. Hylek, Elaine M. Ellinor, Patrick T. Schnabel, Renate B. Benjamin, Emelia J. Christophersen, Ingrid E. TI Atrial fibrillation in women: treatment SO NATURE REVIEWS CARDIOLOGY LA English DT Review ID ACUTE MYOCARDIAL-INFARCTION; GENDER-RELATED DIFFERENCES; RANDOMIZED CONTROLLED-TRIALS; SEX-RELATED DIFFERENCES; ORAL ANTICOAGULANT USE; VITAMIN-K ANTAGONISTS; STABLE INR CONTROL; CATHETER ABLATION; STROKE PREVENTION; ISCHEMIC-STROKE AB Sex-specific differences in the epidemiology, pathophysiology, presentation, prognosis, and treatment of atrial fibrillation (AF) are increasingly recognized. Women with AF generally experience worse symptoms, poorer quality of life, and have higher risk of stroke and death than men with AF. Effective treatment of the arrhythmia in women is critical to reduce the rate of adverse events. We review the current evidence on sex-specific differences in the utilization and outcomes of treatments for AF, including rate-control and rhythm-control strategies, and stroke-prevention therapy. In addition, we provide a critical evaluation of potential disparities and biases in health-care use that might be associated with differences in the outcomes between women and men. We underscore current knowledge gaps that need to be addressed in future studies to improve the management of AF in women. In particular, we suggest several strategies to produce high-quality evidence from randomized clinical trials for women with AF. C1 [Ellinor, Patrick T.; Christophersen, Ingrid E.] Harvard Med Sch, Cardiac Arrhythmia Serv, 55 Fruit St, Boston, MA 02114 USA. [Ellinor, Patrick T.; Christophersen, Ingrid E.] Harvard Med Sch, Cardiovasc Res Ctr, Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. [Ko, Darae; Rahman, Faisal; Hylek, Elaine M.] Boston Univ, Dept Internal Med, Boston Med Ctr, Sch Med, 72 East Concord St, Boston, MA 02118 USA. [Martins, Maria A. P.] Univ Fed Minas Gerais, Dept Prod Farmaceut, Fac Farm, Av Pres Antonio Carlos,6627 Pampulha, BR-31270901 Belo Horizonte, MG, Brazil. [Martins, Maria A. P.; Benjamin, Emelia J.] Boston Univ, 73 Mt Wayte Ave, Framingham, MA 01702 USA. [Martins, Maria A. P.; Benjamin, Emelia J.] NHLBI, Framingham Heart Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA. [Schnabel, Renate B.] Univ Heart Ctr Hamburg, Dept Gen & Intervent Cardiol, Martinistr 52, D-20246 Hamburg, Germany. [Schnabel, Renate B.] DZHK German Ctr Cardiovasc Res, Partner Site Hamburg Kiel Lubeck, D-13347 Berlin, Germany. [Benjamin, Emelia J.] Boston Univ, Boston Med Ctr, Sect Cardiovasc Med, Sch Med, 72 East Concord St, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Boston Med Ctr, Sect Prevent Med, Sch Med, 72 East Concord St, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Dept Epidemiol, Sch Publ Hlth, 715 Albany St, Boston, MA 02118 USA. [Christophersen, Ingrid E.] Baerum Hosp, Vestre Viken Hosp Trust, Dept Med Res, Sogneprest Munthe Kaas Vei 100, N-1346 Gjettum, Norway. RP Christophersen, IE (reprint author), Harvard Med Sch, Cardiac Arrhythmia Serv, 55 Fruit St, Boston, MA 02114 USA.; Christophersen, IE (reprint author), Harvard Med Sch, Cardiovasc Res Ctr, Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM ichristophersen@mgh.harvard.edu FU National Heart, Lung, and Blood Institute award [5T32HL007224-38]; NIH Clinical and Translational Science Award programme [UL1-TR000157]; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Brazilian government programme for postdoctorate degree abroad [200639/2015-3]; NCRR/NIH [U54TR001012, KL2RR025770, TL1RR025769, 1R01HL106029-03]; NIH [2RO1HL092577, 1K24HL105780]; AHA [13EIA14220013]; Fondation Leducq [14CVD01]; European Research Council under the European Union's Horizon research and innovation programme [648131]; German Ministry of Research and Education e:Med Systems Medicine programme [BMBF 0IZX1408A]; Deutsche Forschungsgemeinschaft (German Research Foundation) Emmy Noether Program [SCHN 1149/3-1]; NIH/NHLBI [HHSN2682015000011, N01-HC25195, 2R01HL092577, 1R01HL128914]; Research Council of Norway [240149/F20] FX D.K. is supported by the National Heart, Lung, and Blood Institute award 5T32HL007224-38 and the NIH Clinical and Translational Science Award programme UL1-TR000157. M.A.P.M. is supported by the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Brazilian government programme for postdoctorate degree abroad (grant number 200639/2015-3). E.M.H is supported in part through NCRR/NIH U54TR001012, KL2RR025770, TL1RR025769, and 1R01HL106029-03. P.T. E is supported by grants from the NIH (2RO1HL092577, 1K24HL105780), an Established Investigator Award from the AHA (13EIA14220013), and the Fondation Leducq (14CVD01). R.B.S. is supported by the European Research Council under the European Union's Horizon 2020 research and innovation programme (agreement No 648131), the Junior Research Alliance symAtrial project funded by the German Ministry of Research and Education (BMBF 0IZX1408A) e:Med Systems Medicine programme and by Deutsche Forschungsgemeinschaft (German Research Foundation) Emmy Noether Program SCHN 1149/3-1. E.J.B. is supported in part through NIH/NHLBI HHSN2682015000011, N01-HC25195, 2R01HL092577, and 1R01HL128914. I.E.C. is supported by a mobility grant from the Research Council of Norway (240149/F20). NR 137 TC 0 Z9 0 U1 6 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5002 EI 1759-5010 J9 NAT REV CARDIOL JI Nat. Rev. Cardiol. PD FEB PY 2017 VL 14 IS 2 BP 113 EP 124 DI 10.1038/nrcardio.2016.171 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EJ0KJ UT WOS:000392897000009 PM 27786235 ER PT J AU Sutton, BS Pracht, E Williams, AR Alemi, F Williams, AE Levy, C AF Sutton, Bryce S. Pracht, Etienne Williams, Arthur R. Alemi, Farrokh Williams, Allison E. Levy, Cari TI Budget Impact Analysis of Veterans Affairs Medical Foster Homes versus Community Living Centers SO POPULATION HEALTH MANAGEMENT LA English DT Article ID LONG-TERM-CARE; HOSPITALIZATIONS; PROGRAM; MODELS; COSTS AB The objectives were to determine whether and by what amounts the US Department of Veterans Affairs (VA) use of Medical Foster Homes (MFH) rather than Community Living Centers (CLC) reduced budget impacts to the VA. This was a retrospective, matched, case-control study of veterans residing in MFH or CLC in the VA health care system from 2008 to 2012. Administrative data sets, nearest neighbor matching, generalized linear models, and a secondary analysis were used to capture and analyze budget impacts by veterans who used MFH or CLC exclusively in 2008-2012. Controls of 1483 veterans in CLC were matched to 203 cases of veterans in MFH. Use of MFH instead of CLC reduced budget impacts to the VA by at least $2645 per veteran per month. A secondary analysis of the data using different matching criteria and statistical methods produced similar results, demonstrating the robustness of the estimates of budget impact. When the average out-of-pocket payments made by MFH residents, not made by CLC residents, were included in the analysis, the net reduction of budget impact ranged from $145 to $2814 per veteran per month or a savings of $1740 to $33,768 per veteran per year. Even though outpatient costs of MFH are higher, much of the reduced budget impact of MFH use arises from lower inpatient or hospital costs. Reduced budget impacts on the VA system indicate that expansion of the MFH program may be cost-effective. Implications for further research are suggested. C1 [Sutton, Bryce S.; Williams, Arthur R.] James A Haley Vet Affairs Hosp, CINDRR, Tampa, FL USA. [Pracht, Etienne; Williams, Allison E.] Bay Pines Vet Affairs Med Ctr, Bay Pines, FL USA. [Alemi, Farrokh] Dist Columbia Vet Affairs Med Ctr, Washington, DC USA. [Levy, Cari] Univ Colorado Denver, Dept Med, Denver Vet Affairs Med Ctr, Denver, CO USA. [Williams, Arthur R.; Alemi, Farrokh] George Mason Univ, Dept Hlth Adm & Policy, Fairfax, VA 22030 USA. RP Sutton, BS (reprint author), Ctr Innovat Disabil & Rehabil Res, 8900 Grand Oak Circle 151R, Tampa, FL 33637 USA. EM bryce.sutton@va.gov FU US Department of Veterans Affairs, Office of Geriatrics and Extended Care [3620160] FX The authors received the following financial support: All aspects of this research were supported by appropriation #3620160 from the US Department of Veterans Affairs, Office of Geriatrics and Extended Care. The contents of this paper do not represent the views of the Department of Veterans Affairs or the United States Government. NR 23 TC 0 Z9 0 U1 2 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1942-7891 EI 1942-7905 J9 POPUL HEALTH MANAG JI Popul. Health Manag. PD FEB PY 2017 VL 20 IS 1 BP 48 EP 54 DI 10.1089/pop.2015.0166 PG 7 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EJ0DC UT WOS:000392877800008 PM 27128142 ER PT J AU Rodriguez-Lopez, J Channick, R AF Rodriguez-Lopez, Josanna Channick, Richard TI The Pulmonary Embolism Response Team: What Is the Ideal Model? SO SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Review DE pulmonary embolism; rapid response teams; team-based approach; venous thromboembolism ID SYSTEMS AB Treatment of patients with intermediate- and high-risk pulmonary embolism (PE) is a controversial area. Many therapeutic options exist, and deciding on appropriate treatment can be difficult. In addition, multiple specialties are often involved in the care of PE patients. To better organize the response to serious PE patients, several hospitals and academic centers across the United States, spearheaded by Massachusetts General Hospital, have created pulmonary embolism response teams (PERTs). The goal of a PERT is to have a single multidisciplinary team of experts in thromboembolic disease, who can respond rapidly to patients with acute PE, and offer consultation with the full spectrum of therapeutic options. PERT teams were modeled after rapid response teams and are meant to generate a prompt, patient-specific plan for patients with PE without having to consult multiple individual specialists. C1 [Rodriguez-Lopez, Josanna; Channick, Richard] Harvard Med Sch, Massachusetts Gen Hosp, Pulm Hypertens & Thromboendarterect Program, 55 Fruit St, Boston, MA 02114 USA. RP Rodriguez-Lopez, J (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Pulm Hypertens & Thromboendarterect Program, 55 Fruit St, Boston, MA 02114 USA. EM jrodriguez-lopez@partners.org NR 6 TC 0 Z9 0 U1 0 U2 0 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1069-3424 EI 1098-9048 J9 SEMIN RESP CRIT CARE JI Semin. Respir. Crit. Care Med. PD FEB PY 2017 VL 38 IS 1 BP 51 EP 55 DI 10.1055/s-0036-1597561 PG 5 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA EJ2BM UT WOS:000393014900007 PM 28208198 ER PT J AU Hafner, S Wagner, K Weber, S Groger, M Wepler, M McCook, O Scheuerle, A Stahl, B Huber-Lang, M Jung, B Calzia, E Georgieff, M Moller, P Frick, M Radermacher, P Wagner, F AF Hafner, Sebastian Wagner, Katja Weber, Sandra Groeger, Michael Wepler, Martin McCook, Oscar Scheuerle, Angelika Stahl, Bettina Huber-Lang, Markus Jung, Birgit Calzia, Enrico Georgieff, Michael Moeller, Peter Frick, Manfred Radermacher, Peter Wagner, Florian TI ROLE OF THE PURINERGIC RECEPTOR P2XR4 AFTER BLUNT CHEST TRAUMA IN CIGARETTE SMOKE-EXPOSED MICE SO SHOCK LA English DT Article; Proceedings Paper CT 16th Congress of the European-Shock-Society (ESS) CY SEP 24-26, 2015 CL Cologne, GERMANY SP European Shock Soc DE Blunt chest trauma; cigarette smoke exposure; cytokines; heme oxygenase-1; nitrotyrosine; pulmonary hypertension; purinergic receptors ID INDUCED LUNG INJURY; INDUCED PULMONARY-HYPERTENSION; MECHANICAL VENTILATION; CARBON-MONOXIDE; HEALTHY MICE; INHIBITION; INFLAMMATION; METABOLISM; EMPHYSEMA; SEPSIS AB Both acute and chronic lung injury are associated with up-regulation of the pulmonary expression of the purinergic receptors P2XR4 and P2XR7. Genetic deletion or blockade of P2XR7 attenuated pulmonary hyperinflammation, but simultaneous P2XR4 up-regulation compensated for P2XR7 deletion. Therefore, we tested the hypothesis whether genetic P2XR4 deletion would attenuate the pulmonary inflammatory response and thereby improve organ function after blunt chest trauma in mice with and without pretraumatic cigarette smoke (CS) exposure. After 3 weeks to 4 weeks of exposure to CS, anesthetized wildtype or C2XR4(-/-) mice (n = 32) underwent a blast wave-induced blunt chest trauma followed by 4 h of lung-protective mechanical ventilation, fluid resuscitation, and noradrenaline support to maintain mean arterial pressure >55mm Hg. Hemodynamics, lung mechanics, gas exchange, and acid-base status were measured together with blood and tissue cytokine and chemokine concentrations, heme oxygenase-1, B-cell lymphoma-extra large (Bcl-xL), endogenous nuclear factor-kappa B inhibitor (I kappa B alpha) expression, nitrotyrosine formation, purinergic receptor expression, and histological scoring. Despite a significant increase in the histopathology score in both CS-exposed groups, neither CS exposure nor P2XR4 deletion had any significant effect on post-traumatic pulmonary function and inflammatory response. However, P2XR4 deletion was associated with attenuated impairment of glucose homeostasis and acid-base-status after CS exposure and chest trauma. In conclusion, genetic P2XR4 deletion failed to attenuate the acute post-traumatic pulmonary inflammatory response. The improved glucose homeostasis and acid-base-status after CS exposure in the P2XR4(-/-) group was possibly due to less alveolar hypoxia-induced right ventricular remodeling resulting in preserved liver metabolic capacity. C1 [Hafner, Sebastian; Wagner, Katja; Weber, Sandra; Groeger, Michael; McCook, Oscar; Stahl, Bettina; Calzia, Enrico; Radermacher, Peter; Wagner, Florian] Univ Ulm Klinikum, Inst Anasthesiol Pathophysiol & Verfahrensentwick, Helmholtzstr 8-1, D-89081 Ulm, Germany. [Hafner, Sebastian; Wagner, Katja; Wepler, Martin; Georgieff, Michael; Wagner, Florian] Univ Ulm Klinikum, Anasthesiol Klin, Albert Einstein Allee 23, D-89081 Ulm, Germany. [Wepler, Martin] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Scheuerle, Angelika; Moeller, Peter] Univ Ulm Klinikum, Inst Pathol, Ulm, Germany. [Huber-Lang, Markus] Univ Ulm Klinikum, Klin Unfallchirurg Hand Plast & Wiederherstellung, Ulm, Germany. [Jung, Birgit] Boehringer Ingelheim Pharma GmbH & Co KG, Dept Pulm Res, Biberach, Germany. [Frick, Manfred] Univ Ulm, Inst Allgemeine Physiol, Ulm, Germany. RP Hafner, S (reprint author), Univ Ulm Klinikum, Inst Anasthesiol Pathophysiol & Verfahrensentwick, Helmholtzstr 8-1, D-89081 Ulm, Germany.; Hafner, S (reprint author), Univ Ulm Klinikum, Anasthesiol Klin, Albert Einstein Allee 23, D-89081 Ulm, Germany. EM sebastian.hafner@gmx.de FU Ministry of Science, Research, and Arts of Baden-Wurttemberg [Az: 32-7533.-6-10/15/5]; Deutsche Forschungsgemeinschaft (Collaborative Research Center) [1149] FX This work was supported by a grant from the Ministry of Science, Research, and Arts of Baden-Wurttemberg (Az: 32-7533.-6-10/15/5) to PR and the Deutsche Forschungsgemeinschaft (Collaborative Research Center 1149, projects A05 and B02). NR 35 TC 1 Z9 1 U1 4 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1073-2322 EI 1540-0514 J9 SHOCK JI Shock PD FEB PY 2017 VL 47 IS 2 BP 193 EP 199 DI 10.1097/SHK.0000000000000726 PG 7 WC Critical Care Medicine; Hematology; Surgery; Peripheral Vascular Disease SC General & Internal Medicine; Hematology; Surgery; Cardiovascular System & Cardiology GA EI9FN UT WOS:000392813300010 PM 27559703 ER PT J AU Sebastian, C Mostoslaysky, R AF Sebastian, Carlos Mostoslaysky, Raul TI The Various Metabolic Sources of Histone Acetylation SO TRENDS IN ENDOCRINOLOGY AND METABOLISM LA English DT Editorial Material ID ACETATE; CANCER C1 [Sebastian, Carlos; Mostoslaysky, Raul] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Sebastian, Carlos; Mostoslaysky, Raul] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Mostoslaysky, Raul] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. RP Mostoslaysky, R (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA.; Mostoslaysky, R (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA.; Mostoslaysky, R (reprint author), Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. EM rmostoslaysky@mgh.harvard.edu NR 10 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1043-2760 J9 TRENDS ENDOCRIN MET JI Trends Endocrinol. Metab. PD FEB PY 2017 VL 28 IS 2 BP 85 EP 87 DI 10.1016/j.tem.2016.11.001 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EJ2CW UT WOS:000393018500001 PM 27863854 ER PT J AU Drew, DA Chin, SM Gilpin, KK Parziale, M Pond, E Schuck, MM Stewart, K Flagg, M Rawlings, CA Backman, V Carolan, PJ Chung, DC Colizzo, FP Freedman, M Gala, M Garber, JJ Huttenhower, C Kedrin, D Khalili, H Kwon, DS Markowitz, SD Milne, GL Nishioka, NS Richter, JM Roy, HK Staller, K Wang, M Chan, AT AF Drew, David A. Chin, Samantha M. Gilpin, Katherine K. Parziale, Melanie Pond, Emily Schuck, Madeline M. Stewart, Kathleen Flagg, Meaghan Rawlings, Crystal A. Backman, Vadim Carolan, Peter J. Chung, Daniel C. Colizzo, Francis P., III Freedman, Matthew Gala, Manish Garber, John J. Huttenhower, Curtis Kedrin, Dmitriy Khalili, Hamed Kwon, Douglas S. Markowitz, Sanford D. Milne, Ginger L. Nishioka, Norman S. Richter, James M. Roy, Hemant K. Staller, Kyle Wang, Molin Chan, Andrew T. TI ASPirin Intervention for the REDuction of colorectal cancer risk (ASPIRED): a study protocol for a randomized controlled trial SO TRIALS LA English DT Article DE Aspirin; Colorectal cancer; Biomarker; Chemoprevention ID PROSTAGLANDIN E-2 METABOLITE; WIDE ASSOCIATION SCAN; MAJOR URINARY METABOLITE; BETA-CATENIN; PGE-M; 15-HYDROXYPROSTAGLANDIN DEHYDROGENASE; COLON-CANCER; ANTIINFLAMMATORY DRUGS; MORPHOGENETIC PROTEIN; SUSCEPTIBILITY LOCUS AB Background: Although aspirin is recommended for the prevention of colorectal cancer, the specific individuals for whom the benefits outweigh the risks are not clearly defined. Moreover, the precise mechanisms by which aspirin reduces the risk of cancer are unclear. We recently launched the ASPirin Intervention for the REDuction of colorectal cancer risk (ASPIRED) trial to address these uncertainties. Methods/design: ASPIRED is a prospective, double-blind, multidose, placebo-controlled, biomarker clinical trial of aspirin use in individuals previously diagnosed with colorectal adenoma. Individuals (n = 180) will be randomized in a 1: 1: 1 ratio to low-dose (81 mg/day) or standard-dose (325 mg/day) aspirin or placebo. At two study visits, participants will provide lifestyle, dietary and biometric data in addition to urine, saliva and blood specimens. Stool, grossly normal colorectal mucosal biopsies and cytology brushings will be collected during a flexible sigmoidoscopy without bowel preparation. The study will examine the effect of aspirin on urinary prostaglandin metabolites (PGE-M; primary endpoint), plasma inflammatory markers (macrophage inhibitory cytokine-1 (MIC-1)), colonic expression of transcription factor binding (transcription factor 7-like 2 (TCF7L2)), colonocyte gene expression, including hydroxyprostaglandin dehydrogenase 15-(NAD) (HPGD) and those that encode Wnt signaling proteins, colonic cellular nanocytology and oral and gut microbial composition and function. Discussion: Aspirin may prevent colorectal cancer through multiple, interrelated mechanisms. The ASPIRED trial will scrutinize these pathways and investigate putative mechanistically based risk-stratification biomarkers. C1 [Drew, David A.; Chin, Samantha M.; Gilpin, Katherine K.; Parziale, Melanie; Pond, Emily; Schuck, Madeline M.; Gala, Manish; Khalili, Hamed; Staller, Kyle; Chan, Andrew T.] Massachusetts Gen Hosp, Dept Med, Clin & Translat Epidemiol Unit, Boston, MA 02114 USA. [Drew, David A.; Chin, Samantha M.; Gilpin, Katherine K.; Parziale, Melanie; Pond, Emily; Schuck, Madeline M.; Stewart, Kathleen; Carolan, Peter J.; Chung, Daniel C.; Colizzo, Francis P., III; Gala, Manish; Garber, John J.; Kedrin, Dmitriy; Khalili, Hamed; Nishioka, Norman S.; Richter, James M.; Staller, Kyle; Wang, Molin; Chan, Andrew T.] Harvard Med Sch, Boston, MA 02115 USA. [Drew, David A.; Chin, Samantha M.; Gilpin, Katherine K.; Parziale, Melanie; Pond, Emily; Schuck, Madeline M.; Stewart, Kathleen; Carolan, Peter J.; Chung, Daniel C.; Colizzo, Francis P., III; Gala, Manish; Garber, John J.; Kedrin, Dmitriy; Khalili, Hamed; Nishioka, Norman S.; Richter, James M.; Staller, Kyle; Chan, Andrew T.] Massachusetts Gen Hosp, Dept Med, Div Gastroenterol, Boston, MA 02114 USA. [Flagg, Meaghan; Rawlings, Crystal A.; Kwon, Douglas S.] Ragon Inst MGH MIT & Harvard, Cambridge, MA USA. [Backman, Vadim] Northwestern Univ, McCormick Sch Engn, Evanston, IL USA. [Freedman, Matthew; Chan, Andrew T.] Broad Inst, Cambridge, MA 02142 USA. [Huttenhower, Curtis; Wang, Molin] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Wang, Molin] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Markowitz, Sanford D.] Case Western Reserve Univ, Sch Med, Cleveland, OH USA. [Markowitz, Sanford D.] Univ Hosp Cleveland, Cleveland, OH 44106 USA. [Milne, Ginger L.] Vanderbilt Univ, Div Clin Pharmacol, Eicosanoid Core Lab, 221 Kirkland Hall, Nashville, TN 37235 USA. [Roy, Hemant K.] Boston Med Ctr, Gastroenterol Sect, Boston, MA USA. [Wang, Molin; Chan, Andrew T.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, GRJ-825C, Boston, MA 02114 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Clin & Translat Epidemiol Unit, GRJ-825C, Boston, MA 02114 USA. RP Chan, AT (reprint author), Massachusetts Gen Hosp, Dept Med, Clin & Translat Epidemiol Unit, Boston, MA 02114 USA.; Chan, AT (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Chan, AT (reprint author), Massachusetts Gen Hosp, Dept Med, Div Gastroenterol, Boston, MA 02114 USA.; Chan, AT (reprint author), Broad Inst, Cambridge, MA 02142 USA.; Chan, AT (reprint author), Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA.; Chan, AT (reprint author), Massachusetts Gen Hosp, Div Gastroenterol, GRJ-825C, Boston, MA 02114 USA.; Chan, AT (reprint author), Massachusetts Gen Hosp, Clin & Translat Epidemiol Unit, GRJ-825C, Boston, MA 02114 USA. EM achan@mgh.harvard.edu FU National Institutes of Health - National Cancer Institute [R01 CA137178] FX National Institutes of Health - National Cancer Institute R01 CA137178 awarded to ATC. NR 73 TC 0 Z9 0 U1 4 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6215 J9 TRIALS JI Trials PD FEB 1 PY 2017 VL 18 AR 50 DI 10.1186/s13063-016-1744-z PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EK0LV UT WOS:000393619000001 PM 28143522 ER PT J AU Seagrave, KG Troelsen, A Malchau, H Husted, H Gromov, K AF Seagrave, Kurt G. Troelsen, Anders Malchau, Henrik Husted, Henrik Gromov, Kirill TI Acetabular cup position and risk of dislocation in primary total hip arthroplasty A systematic review of the literature SO Acta Orthopaedica LA English DT Review ID FEMORAL-HEAD SIZE; COMPONENT ORIENTATION; SAFE ZONE; RECURRENT DISLOCATION; POSTERIOR APPROACH; SURGICAL APPROACH; JOINT-REGISTRY; PELVIC TILT; REPLACEMENT; CT AB Background and purpose - Hip dislocation is one of the most common complications following total hip arthroplasty (THA). Several factors that affect dislocation have been identified, including acetabular cup positioning. Optimal values for cup inclination and anteversion are debatable. We performed a systematic review to describe the different methods for measuring cup placement, target zones for cup positioning, and the association between cup positioning and dislocation following primary THA. Methods - A systematic search of literature in the PubMed database was performed (January and February 2016) to identify articles that compared acetabular cup positioning and the risk of dislocation. Surgical approach and methods for measurement of cup angles were also considered. Results - 28 articles were determined to be relevant to our research question. Some articles demonstrated that cup positioning influenced postoperative dislocation whereas others did not. The majority of articles could not identify a statistically significant difference between dislocating and non-dislocating THA with regard to mean angles of cup anteversion and inclination. Most of the articles that assessed cup placement within the Lewinnek safe zone did not show a statistically significant reduction in dislocation rate. Alternative target ranges have been proposed by several authors. Interpretation - The Lewinnek safe zone could not be justified. It is difficult to draw broad conclusions regarding a definitive target zone for cup positioning in THA, due to variability between studies and the likely multifactorial nature of THA dislocation. Future studies comparing cup positioning and dislocation rate should investigate surgical approach separately. Standardized tools for measurement of cup positioning should be implemented to allow comparison between studies. C1 [Seagrave, Kurt G.] Univ New South Wales, Fac Med, Sydney, NSW, Australia. [Seagrave, Kurt G.; Troelsen, Anders; Husted, Henrik; Gromov, Kirill] Univ Copenhagen, Hvidovre Hosp, Dept Orthopaed Surg, Copenhagen, Denmark. [Malchau, Henrik] Massachusetts Gen Hosp, Harris Orthopaed Lab, Boston, MA USA. [Malchau, Henrik] Harvard Med Sch, Dept Orthopaed Surg, Boston, MA USA. RP Gromov, K (reprint author), Univ Copenhagen, Hvidovre Hosp, Dept Orthopaed Surg, Copenhagen, Denmark. EM kirgromov@gmail.com NR 66 TC 0 Z9 0 U1 6 U2 6 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1745-3674 EI 1745-3682 J9 ACTA ORTHOP JI Acta Orthop. PD FEB PY 2017 VL 88 IS 1 BP 10 EP 17 DI 10.1080/17453674.2016.1251255 PG 8 WC Orthopedics SC Orthopedics GA EI8DT UT WOS:000392736200003 PM 27879150 ER PT J AU Kamal, AH Bull, JH Swetz, KM Wolf, SP Shanafelt, TD Myers, ER AF Kamal, Arif H. Bull, Janet H. Swetz, Keith M. Wolf, Steven P. Shanafelt, Tait D. Myers, Evan R. TI Future of the Palliative Care Workforce: Preview to an Impending Crisis SO AMERICAN JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Kamal, Arif H.; Wolf, Steven P.; Myers, Evan R.] Duke Univ, Durham, NC 27708 USA. [Bull, Janet H.] Four Seasons, Flat Rock, NC USA. [Swetz, Keith M.] Univ Alabama Birmingham, Birmingham, AL USA. [Swetz, Keith M.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Shanafelt, Tait D.] Mayo Clin, Rochester, MN USA. OI Swetz, Keith/0000-0001-9893-6517 NR 6 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 EI 1555-7162 J9 AM J MED JI Am. J. Med. PD FEB PY 2017 VL 130 IS 2 BP 113 EP 114 DI 10.1016/j.amjmed.2016.08.046 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA EI6RH UT WOS:000392623200018 PM 27687068 ER PT J AU Dugdale, C Brown, S Davila, C Wolkow, N Fishbein, G Sun, J Barkoudah, E Rawizza, H AF Dugdale, Caitlin Brown, Sarah Davila, Carine Wolkow, Natalie Fishbein, Gregory Sun, Jennifer Barkoudah, Ebrahim Rawizza, Holly TI Out of Sight: Culture-Negative Endocarditis and Endophthalmitis SO AMERICAN JOURNAL OF MEDICINE LA English DT Editorial Material ID CLASSIC WHIPPLES-DISEASE; TROPHERYMA-WHIPPLEI C1 [Dugdale, Caitlin; Rawizza, Holly] Brigham & Womens Hosp, Div Infect Dis, 75 Francis St, Boston, MA 02115 USA. [Brown, Sarah; Barkoudah, Ebrahim] Brigham & Womens Hosp, Dept Internal Med, 75 Francis St, Boston, MA 02115 USA. [Davila, Carine] Univ Calif San Francisco, Med Ctr, Dept Internal Med, San Francisco, CA USA. [Wolkow, Natalie] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. [Fishbein, Gregory] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Sun, Jennifer] Beetham Eye Inst, Joslin Diabet Ctr, Dept Ophthalmol, Boston, MA USA. EM cdugdale@partners.org OI Fishbein, Gregory/0000-0002-3632-5654 FU National Institute of Allergy and Infectious Diseases [T32 AI007433] FX This publication was supported by Grant Number T32 AI007433 from the National Institute of Allergy and Infectious Diseases. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. NR 11 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 EI 1555-7162 J9 AM J MED JI Am. J. Med. PD FEB PY 2017 VL 130 IS 2 BP E51 EP E53 DI 10.1016/j.amjmed.2016.08.029 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA EI6RH UT WOS:000392623200004 PM 27637598 ER PT J AU Misra, D Peloquin, C Kiel, DP Neogi, T Lu, N Zhang, YQ AF Misra, Devyani Peloquin, Christine Kiel, Douglas P. Neogi, Tuhina Lu, Na Zhang, Yuqing TI Intermittent Nitrate Use and Risk of Hip Fracture SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Fracture; Intermittent; Nitrates ID STABLE ANGINA-PECTORIS; NITRIC-OXIDE SYNTHASE; OSTEOBLAST-LIKE CELLS; BONE-RESORPTION; NITROGLYCERIN THERAPY; ORGANIC NITRATES; OSTEOPOROSIS; FLUORIDE; ENDOTHELIUM; VALIDATION AB PURPOSE: Nitrates, commonly used antianginal medications, also have a beneficial effect on bone remodeling and bone density, particularly with intermittent use. However, their effect on fracture risk is not clear. We examined the relation of short-acting nitrate use (proxy for intermittent use) with the risk of hip fracture in a large cohort of older adults with ischemic heart disease. METHODS: Participants aged 60 years or more with ischemic heart disease and without a history of hip fracture from The Health Improvement Network, an electronic medical records database in the United Kingdom, were included. The association of incident (new) use of short-acting nitrate formulations (nitroglycerin sublingual/spray/ointment or isosorbide dinitrate injection/sprays) with incident (new-onset) hip fracture risk was examined by plotting Kaplan-Maier curves and calculating hazard ratios using Cox proportional hazards regression models. Competing risk by death was analyzed in separate analyses. RESULTS: Among 14,451 pairs of matched nitrate users and nonusers (mean age, 72 +/- 7.6 years, 41% women for each cohort), 573 fractures occurred during follow-up (257 nitrate users; 316 nonusers). Hip fracture risk was 33% lower among short-acting nitrate users compared with nonusers (hazard ratio, 0.67; 95% confidence interval, 0.53-0.85; P =.0008). Competing risk analysis by death did not change effect estimates. CONCLUSIONS: In this large population-based cohort of older adults with ischemic heart disease, we found a significant reduction in hip fracture risk with the use of short-acting nitrates (intermittent use). Future studies are warranted given the potential for nitrates to be potent, inexpensive, and readily available antiosteoporotic agents. (C) 2016 Elsevier Inc. All rights reserved. C1 [Misra, Devyani; Peloquin, Christine; Neogi, Tuhina; Lu, Na; Zhang, Yuqing] Boston Univ, Sch Med, Boston, MA 02215 USA. [Kiel, Douglas P.] Beth Israel Deaconess Med Ctr, Dept Med, Hebrew SeniorLife, Inst Aging Res, Boston, MA 02215 USA. [Kiel, Douglas P.] Harvard Med Sch, Boston, MA USA. [Lu, Na] Massachusetts Gen Hosp, Boston, MA 02114 USA. EM demisra@bu.edu FU National Institute of Arthritis and Musculoskeletal and Skin Diseases [P60AR047785]; American College of Rheumatology, Rheumatology Research Foundation investigator award; BU CTSI KL2 scholarship; [1R01AR062506-01A1] FX This investigator-initiated study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases P60AR047785. DM is supported by the American College of Rheumatology, Rheumatology Research Foundation investigator award, and BU CTSI KL2 scholarship. TN is supported by 1R01AR062506-01A1. NR 31 TC 0 Z9 0 U1 5 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 EI 1555-7162 J9 AM J MED JI Am. J. Med. PD FEB PY 2017 VL 130 IS 2 AR 229.e15 DI 10.1016/j.amjmed.2016.09.006 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA EI6RH UT WOS:000392623200038 PM 27720852 ER PT J AU Acierno, R Knapp, R Tuerk, P Gilmore, AK Lejuez, C Ruggiero, K Muzzy, W Egede, L Hernandez-Tejada, MA Foa, EB AF Acierno, Ron Knapp, Rebecca Tuerk, Peter Gilmore, Amanda K. Lejuez, Carl Ruggiero, Kenneth Muzzy, Wendy Egede, Leonard Hernandez-Tejada, Melba A. Foa, Edna B. TI A non-inferiority trial of Prolonged Exposure for posttraumatic stress disorder: In person versus home-based telehealth SO BEHAVIOUR RESEARCH AND THERAPY LA English DT Article DE PTSD; Prolonged exposure; Telehealth; Non-inferiority; RCT ID COGNITIVE PROCESSING THERAPY; MENTAL-HEALTH-SERVICES; COMBAT VETERANS; AFGHANISTAN VETERANS; TELEMENTAL HEALTH; IRAQ; TELEMEDICINE; PTSD; CARE; CLINICIAN AB This is the first randomized controlled trial to evaluate non-inferiority of Prolonged Exposure (PE) delivered via home-based telehealth (HBT) compared to standard in-person (IP) PE. One-hundred thirty two Veterans recruited from a Southeastern Veterans Affairs Medical Center and affiliated University who met criteria for posttraumatic stress disorder (PTSD) were randomized to receive PE via HBT or PE via IP. Results indicated that PE-HBT was non-inferior to PE-IP in terms of reducing PTSD scores at posttreatment, 3 and 6 month follow-up. However, non-inferiority hypotheses for depression were only supported at 6 month follow-up. HBT has great potential to reduce patient burden associated with receiving treatment in terms of travel time, travel cost, lost work, and stigma without sacrificing efficacy. These findings indicate that telehealth treatment delivered directly into patients' homes may dramatically increase the reach of this evidence-based therapy for PTSD without diminishing effectiveness. Published by Elsevier Ltd. C1 [Acierno, Ron; Tuerk, Peter; Ruggiero, Kenneth; Muzzy, Wendy; Egede, Leonard; Hernandez-Tejada, Melba A.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. [Acierno, Ron; Ruggiero, Kenneth; Muzzy, Wendy; Hernandez-Tejada, Melba A.] Med Univ South Carolina, Coll Nursing, Charleston, SC USA. [Knapp, Rebecca] Med Univ South Carolina, Dept Publ Hlth Sci, Charleston, SC USA. [Tuerk, Peter; Gilmore, Amanda K.] Med Univ South Carolina, Dept Psychiat & Behav Sci, Charleston, SC USA. [Lejuez, Carl] Univ Kansas, Coll Liberal Arts & Sci, Lawrence, KS 66045 USA. [Foa, Edna B.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. RP Acierno, R (reprint author), Coll Nursing, 99 Jonathan Lucas St,MSC 160, Charleston, SC 29425 USA. EM acierno@musc.edu FU Department of Veterans Affairs Health Services Research and Development grant [HX00152]; South Carolina Clinical & Translational Research (SCTR) Institute; Medical University of South Carolina through NIH/NCATS Grant [UL1 TR001450]; National Institute of Mental Health [T32 MH18869] FX This research was supported by the Department of Veterans Affairs Health Services Research and Development grant #HX00152 (PI: Acierno) and by the South Carolina Clinical & Translational Research (SCTR) Institute, with an academic home at the Medical University of South Carolina through NIH/NCATS Grant Number UL1 TR001450. Manuscript preparation was partially supported by a grant from the National Institute of Mental Health (T32 MH18869; PIs: Kilpatrick & Danielson). NR 57 TC 0 Z9 0 U1 6 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0005-7967 EI 1873-622X J9 BEHAV RES THER JI Behav. Res. Ther. PD FEB PY 2017 VL 89 BP 57 EP 65 DI 10.1016/j.brat.2016.11.009 PG 9 WC Psychology, Clinical SC Psychology GA EI8SY UT WOS:000392779600007 PM 27894058 ER PT J AU Zhang, PP Andorko, JI Jewell, CM AF Zhang, Peipei Andorko, James I. Jewell, Christopher M. TI Impact of dose, route, and composition on the immunogenicity of immune polyelectrolyte multilayers delivered on gold templates SO BIOTECHNOLOGY AND BIOENGINEERING LA English DT Article DE vaccine; adjuvant; polyelectrolyte multilayer; immunology; nanotechnology; cancer ID DENDRITIC CELLS; TLR AGONISTS; ADJUVANTS; RESPONSES; EFFICACY; SYSTEM; CANCER; BIODISTRIBUTION; NANOPARTICLES; BIOMATERIALS AB Biomaterial vaccines offer new capabilities that can be exploited for both infectious disease and cancer. We recently developed a novel vaccine platform based on self-assembly of immune signals into immune polyelectrolyte multilayers (iPEMs). These iPEM vaccines are electrostatically assembled from peptide antigens and nucleic acid-based toll-like receptor agonists (TLRas) that serve as molecular adjuvants. Gold nanoparticles (AuNPs) coated with iPEMs stimulate effector cytokine secretion in vitro and expand antigen-specific T cells in mice. Here we investigated how the dose, injection route, and choice of molecular adjuvant impacts the ability of iPEMs to generate T cell immunity and anti-tumor response in mice. Three injection routesintradermal, subcutaneous, and intramuscularand three iPEM dosing levels were employed. Intradermal injection induced the most potent antigen-specific T cell responses and, for all routes, the level of response was dose-dependent. We further discovered that these vaccines generate durable memory, indicated by potent, antigen-specific CD8(+) T cell recall responses in mice challenged with vaccine 49 days after a prime-boost immunization regimen. In a common exogenous antigen melanoma model, iPEM vaccines slowed or stopped tumor growth more effectively than equivalent ad-mixed formulations. Further, iPEMs containing CpGa TLR9awere more potent compared with iPEMs containing polyIC, a TLR3a. These findings demonstrate the ability of iPEMs to enhance response to several different classes of vaccine cargos, supporting iPEMs as a simple vaccine platform that mimics attractive features of other nanoparticles using immune signals that can be self-assembled or coated on substrates. Biotechnol. Bioeng. 2017;114: 423-431. (c) 2016 Wiley Periodicals, Inc. C1 [Zhang, Peipei; Jewell, Christopher M.] Univ Maryland, Fischell Dept Bioengn, 2212 Jeong H Kim Engn Bldg,8228 Paint Branch Dr, College Pk, MD 20742 USA. [Andorko, James I.; Jewell, Christopher M.] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. [Jewell, Christopher M.] Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Jewell, Christopher M.] US Dept Vet Affairs, Baltimore, MD 21201 USA. EM cmjewell@umd.edu FU NSF CAREER Award [1351688]; Alliance for Cancer Gene Therapy Young Investigator Award [15051543]; University of Maryland Division of Research (Tier 1); Damon Runyon Foundation [DRR3415]; Melanoma Research Alliance [348963]; NIH Grant [T32 AI089621]; American Association of Pharmaceutical Scientists Foundation FX Contract grant sponsor: NSF CAREER Award; Contract grant number: #1351688; Contract grant sponsor: Alliance for Cancer Gene Therapy Young Investigator Award; Contract grant number: #15051543; Contract grant sponsor: University of Maryland Division of Research (Tier 1); Contract grant sponsor: Damon Runyon Foundation; Contract grant number: #DRR3415; Contract grant sponsor: Melanoma Research Alliance; Contract grant number: #348963; Contract grant sponsor: NIH Grant; Contract grant number: #T32 AI089621; Contract grant sponsor: American Association of Pharmaceutical Scientists Foundation NR 37 TC 1 Z9 1 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-3592 EI 1097-0290 J9 BIOTECHNOL BIOENG JI Biotechnol. Bioeng. PD FEB PY 2017 VL 114 IS 2 BP 423 EP 431 DI 10.1002/bit.26083 PG 9 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA EI5MU UT WOS:000392539800017 PM 27567213 ER PT J AU Pojednic, R Frates, E AF Pojednic, Rachele Frates, Elizabeth TI A parallel curriculum in lifestyle medicine SO Clinical Teacher LA English DT Article ID STUDENTS AB Background: Less than 50 percent of US primary care doctors routinely provide guidance to their patients on lifestyle behaviours such as diet, physical activity or weight control, despite the prediction by the World Health Organization that by 2020, two-thirds of disease worldwide will be the result of poor lifestyle choices. This gap in patient-clinician dialogue is perhaps the result of a lack of structured training in medical school surrounding the components of lifestyle medicine. Context: Although Harvard Medical School does have a required course in nutrition, there are no requirements for the other components of lifestyle medicine, including physical activity, behaviour change and self-care. Innovation: Since 2009 Harvard Medical School has addressed this absence in the curriculum by developing a student-led, faculty member-advised, parallel curriculum in lifestyle medicine. Medical student participants were invited to take part in anonymous questionnaires between 2009 and 2013, which gathered data about personal ability and attitude in counselling patients on lifestyle behaviours, as well as subjective data on the curriculum content and applications to effective medical practice. C1 [Pojednic, Rachele; Frates, Elizabeth] Harvard Med Sch, Joslin Diabet Ctr, Inst Lifestyle Med, 1 Joslin Pl, Boston, MA 02215 USA. RP Pojednic, R (reprint author), Harvard Med Sch, Joslin Diabet Ctr, Inst Lifestyle Med, 1 Joslin Pl, Boston, MA 02215 USA. EM rachele.pojednic@joslin.harvard.edu NR 9 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1743-4971 EI 1743-498X J9 CLIN TEACH JI Clin. Teach. PD FEB PY 2017 VL 14 IS 1 BP 27 EP 31 DI 10.1111/tct.12475 PG 5 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EI8FC UT WOS:000392740100005 PM 26639320 ER PT J AU Koelman, DLH Benkeser, DC Xu, Y Neo, SX Tan, K Katsuno, M Sobue, G Natsume, J Chahin, S Mar, SS Venkatesan, A Chitnis, T Hoganson, GM Yeshokumar, AK Barreras, P Majmudar, B Carone, M Mateen, FJ AF Koelman, D. L. H. Benkeser, D. C. Xu, Y. Neo, S. X. Tan, K. Katsuno, M. Sobue, G. Natsume, J. Chahin, S. Mar, S. S. Venkatesan, A. Chitnis, T. Hoganson, G. M. Yeshokumar, A. K. Barreras, P. Majmudar, B. Carone, M. Mateen, F. J. TI Acute disseminated encephalomyelitis in China, Singapore and Japan: a comparison with the USA SO EUROPEAN JOURNAL OF NEUROLOGY LA English DT Article DE acute disseminated encephalomyelitis; cohort studies; demyelination; international comparison; multiple sclerosis; neuromyelitis optica spectrum disorders ID MULTIPLE-SCLEROSIS; NEUROMYELITIS-OPTICA; CLINICAL-FEATURES; DISORDERS AB Background and purposeEthnicity-related differences in the incidence of acute disseminated encephalomyelitis (ADEM) and other demyelinating diseases including multiple sclerosis and neuromyelitis optica spectrum disorders have been reported. Little is reported on the influence of ethnicity and geographical location in ADEM. MethodsMedical records of patients who presented with ADEM (ICD-9 323.61 and 323.81) at large referral hospitals in China, Singapore and Japan (years 1992-2015) were retrospectively reviewed and data were collected in a centralized database. Presenting features and outcomes of ADEM were compared between this multi-country Asian cohort and a uniformly collected US cohort using risk differences and risk ratios. Both cohorts were standardized to a 35% pediatric population to facilitate the comparison. ResultsThere were 83 Asian patients (48 male, 16 pediatric) followed for a median of 2 (25th-75th percentile 1-10) months. Asian patients exhibited a 26% higher prevalence of spinal cord involvement on magnetic resonance imaging [95% confidence interval (CI) 0-52%; P = 0.05; 63% vs. 37%], a 39% lower prevalence of preceding events (95% CI 12-65%; P < 0.01; 33% vs. 72%) and a 23% lower prevalence of corpus callosum involvement (95% CI 7-39%; P < 0.01; 8% vs. 31%). No difference was observed between the two cohorts in the probability of relapse over the first year after disease onset. ConclusionsIt is hypothesized that the high proportion of Asian patients with spinal cord lesions relates to genetic vulnerability or the higher incidence of neuromyelitis optica spectrum disorders in Asia or could be a spurious association. ADEM presentations most probably vary across geographical settings or ethnicities. C1 [Koelman, D. L. H.; Mateen, F. J.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Koelman, D. L. H.] Univ Amsterdam, Acad Med Ctr, Amsterdam, Netherlands. [Benkeser, D. C.] Univ Calif Berkeley, Grp Biostat, Berkeley, CA 94720 USA. [Xu, Y.] Beijing Union Med Coll Hosp, Dept Neurol, Beijing, Peoples R China. [Neo, S. X.; Tan, K.] Natl Inst Neurosci, Dept Neurol, Singapore, Singapore. [Katsuno, M.; Sobue, G.] Nagoya Univ, Dept Neurol, Grad Sch Med, Nagoya, Aichi, Japan. [Natsume, J.] Nagoya Univ, Grad Sch Med, Dept Dev Disabil Med, Nagoya, Aichi, Japan. [Chahin, S.] Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA. [Mar, S. S.; Hoganson, G. M.; Majmudar, B.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Venkatesan, A.; Yeshokumar, A. K.; Barreras, P.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Chitnis, T.] Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA. [Carone, M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Mateen, F. J.] Harvard Med Sch, Boston, MA USA. [Chitnis, T.] Massachusetts Gen Hosp, Dept Pediat Neurol, Boston, MA 02114 USA. RP Mateen, FJ (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, 165 Cambridge St,627, Boston, MA 02114 USA. EM fmateen@partners.org NR 12 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1351-5101 EI 1468-1331 J9 EUR J NEUROL JI Eur. J. Neurol. PD FEB PY 2017 VL 24 IS 2 BP 391 EP 396 DI 10.1111/ene.13220 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EI9CG UT WOS:000392804300027 PM 28009079 ER PT J AU Pandey, A Khan, H Newman, AB Lakatta, EG Forman, DE Butler, J Berry, JD AF Pandey, Ambarish Khan, Hassan Newman, Anne B. Lakatta, Edward G. Forman, Daniel E. Butler, Javed Berry, Jarett D. TI Arterial Stiffness and Risk of Overall Heart Failure, Heart Failure With Preserved Ejection Fraction, and Heart Failure With Reduced Ejection Fraction The Health ABC Study (Health, Aging, and Body Composition) SO HYPERTENSION LA English DT Article DE arterial stiffness; ejection fraction; heart failure; hypertension; pulse wave velocity ID LEFT-VENTRICULAR HYPERTROPHY; PULSE-WAVE VELOCITY; CARDIOVASCULAR EVENTS; OLDER-ADULTS; DIASTOLIC DYSFUNCTION; DISEASE; ASSOCIATION; ATHEROSCLEROSIS; EXERCISE; POPULATION AB Higher arterial stiffness is associated with increased risk of atherosclerotic events. However, its contribution toward risk of heart failure (HF) and its subtypes, HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF), independent of other risk factors is not well established. In this study, we included Health ABC study (Health, Aging, and Body Composition) participants without prevalent HF who had arterial stiffness measured as carotid-femoral pulse wave velocity (cf-PWV) at baseline (n=2290). Adjusted Cox-proportional hazards models were constructed to determine the association between continuous and data-derived categorical measures (tertiles) of cf-PWV and incidence of HF and its subtypes (HFpEF [ejection fraction >45%] and HFrEF [ejection fraction <= 45%]). We observed 390 HF events (162 HFpEF and 145 HFrEF events) over 11.4 years of follow-up. In adjusted analysis, higher cf-PWV was associated with greater risk of HF after adjustment for age, sex, ethnicity, mean arterial pressure, and heart rate (hazard ratio [95% confidence interval] for cf-PWV tertile 3 versus tertile 1 [ref] =1.35 [1.05-1.73]). However, this association was not significant after additional adjustment for other cardiovascular risk factors (hazard ratio [95% confidence interval], 1.14 [0.88-1.47]). cf-PWV velocity was also not associated with risk of HFpEF and HFrEF after adjustment for potential confounders (most adjusted hazard ratio [95% confidence interval] for cf-PWV tertile 3 versus tertile 1 [ref]: HFpEF, 1.06 [0.72-1.56]; HFrEF, 1.28 [0.83-1.97]). In conclusion, arterial stiffness, as measured by cf-PWV, is not independently associated with risk of HF or its subtypes after adjustment for traditional cardiovascular risk factors. Online Data Supplement C1 [Pandey, Ambarish; Berry, Jarett D.] Univ Texas Southwestern Med Ctr Dallas, Dept Internal Med, Div Cardiol, Dallas, TX USA. [Berry, Jarett D.] Univ Texas Southwestern Med Ctr Dallas, Dept Clin Sci, Dallas, TX USA. [Khan, Hassan] Emory Univ, Sch Med, Dept Internal Med, Atlanta, GA USA. [Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Lakatta, Edward G.] NIA, Lab Cardiovasc Sci, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. [Forman, Daniel E.] Univ Pittsburgh, VA Pittsburgh Healthcare Syst, Sch Med, Sect Geriatr Cardiol,Div Geriatr, Pittsburgh, PA 15260 USA. [Forman, Daniel E.] Univ Pittsburgh, VA Pittsburgh Healthcare Syst, Sch Med, Sect Geriatr Cardiol,Div Cardiol, Pittsburgh, PA 15260 USA. [Butler, Javed] SUNY Stony Brook, Sch Med, Dept Internal Med, Div Cardiol, New York, NY USA. EM jarett.berry@utsouthwestern.edu FU Intramural Research Program of the National Institutes of Health (NIH), National Institute on Aging; National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050]; National Institute of Nursing Research [R01-NR012459] FX This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Institute on Aging. This research was supported by National Institute on Aging (NIA) Contracts N01-AG-6-2101; N01-AG-6-2103; N01-AG-6-2106; NIA grant R01-AG028050, and National Institute of Nursing Research grant R01-NR012459. NR 50 TC 0 Z9 0 U1 5 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0194-911X EI 1524-4563 J9 HYPERTENSION JI Hypertension PD FEB PY 2017 VL 69 IS 2 BP 267 EP + DI 10.1161/HYPERTENSIONAHA.116.08327 PG 12 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EI3QE UT WOS:000392405500011 PM 27993954 ER PT J AU Ascher, SB Scherzer, R Peralta, CA Tien, PC Grunfeld, C Estrella, MM Abraham, A Gustafson, DR Nowicki, M Sharma, A Cohen, MH Butch, AW Young, MA Bennett, MR Shlipak, MG AF Ascher, Simon B. Scherzer, Rebecca Peralta, Carmen A. Tien, Phyllis C. Grunfeld, Carl Estrella, Michelle M. Abraham, Alison Gustafson, Deborah R. Nowicki, Marek Sharma, Anjali Cohen, Mardge H. Butch, Anthony W. Young, Mary A. Bennett, Michael R. Shlipak, Michael G. TI Association of Kidney Function and Early Kidney Injury With Incident Hypertension in HIV-Infected Women SO HYPERTENSION LA English DT Article DE albuminuria; glomerular filtration rate; HIV; hypertension; kidney disease ID ACTIVE ANTIRETROVIRAL THERAPY; GLOMERULAR-FILTRATION-RATE; BLOOD-PRESSURE; GENERAL-POPULATION; FUNCTION DECLINE; DISEASE; ALBUMINURIA; PREVALENCE; RISK; MORTALITY AB Subclinical kidney disease is associated with developing hypertension in the general population, but data are lacking among HIV-infected people. We examined associations of kidney function and injury with incident hypertension in 823 HIV-infected and 267 HIV-uninfected women in the Women's Interagency HIV Study, a multicenter, prospective cohort of HIV-infected and uninfected women in the United States. Baseline kidney biomarkers included estimated glomerular filtration rate using cystatin C, urine albumin-to-creatinine ratio, and 7 urine biomarkers of tubular injury: alpha-1-microglobulin, interleukin-18, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, liver fatty acid-binding protein, N-acetyl-beta-D-glucosaminidase, and alpha 1-acid-glycoprotein. We used multivariable Poisson regression to evaluate associations of kidney biomarkers with incident hypertension, defined as 2 consecutive visits of antihypertensive medication use. During a median follow-up of 9.6 years, 288 HIV-infected women (35%) developed hypertension. Among the HIV-infected women, higher urine albumin-to-creatinine ratio was independently associated with incident hypertension (relative risk = 1.13 per urine albumin-to-creatinine ratio doubling, 95% confidence interval, 1.07-1.20), as was lower estimated glomerular filtration rate (relative risk = 1.10 per 10 mL/min/1.73 m(2) lower estimated glomerular filtration rate; 95% confidence interval, 1.04-1.17). No tubular injury and dysfunction biomarkers were independently associated with incident hypertension in HIV-infected women. In contrast, among the HIV-uninfected women, urine albumin-to-creatinine ratio was not associated with incident hypertension, whereas higher urine interleukin-18, alpha 1-acid-glycoprotein, and N-acetyl-beta-D-glucosaminidase levels were significantly associated with incident hypertension. These findings suggest that early glomerular injury and kidney dysfunction may be involved in the pathogenesis of hypertension in HIV-infected people. The associations of tubular markers with hypertension in HIV-uninfected women should be validated in other studies. Online Data Supplement C1 [Ascher, Simon B.; Scherzer, Rebecca; Peralta, Carmen A.; Tien, Phyllis C.; Grunfeld, Carl; Shlipak, Michael G.] Univ Calif San Francisco, San Francisco VA Med Ctr, Dept Med, Kidney Hlth Res Collaborat, San Francisco, CA 94143 USA. [Peralta, Carmen A.; Tien, Phyllis C.; Grunfeld, Carl; Shlipak, Michael G.] Univ Calif San Francisco, Dept Epidemiol & Biostat, 4150 Clement St,111A1, San Francisco, CA 94121 USA. [Estrella, Michelle M.; Abraham, Alison] Johns Hopkins Sch Med, Dept Med, Baltimore, MD USA. [Gustafson, Deborah R.] Suny Downstate Med Ctr, Dept Med, Brooklyn, NY 11203 USA. [Nowicki, Marek] Univ Southern Calif, Dept Med, Los Angeles, CA USA. [Sharma, Anjali] Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA. [Cohen, Mardge H.] Stroger Hosp, Dept Med, Chicago, IL USA. [Cohen, Mardge H.] Rush Univ, Chicago, IL 60612 USA. [Butch, Anthony W.] UCLA Hlth Syst, Dept Pathol & Lab Med, Los Angeles, CA USA. [Young, Mary A.] Georgetown Univ, Med Ctr, Washington, DC 20007 USA. [Bennett, Michael R.] Cincinnati Childrens Hosp Med Ctr, Div Nephrol & Hypertens, Cincinnati, OH 45229 USA. EM michael.shlipak@ucsf.edu FU National Institute of Allergy and Infectious Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Cancer Institute; National Institute on Drug Abuse; National Institute on Mental Health; National Institute of Dental and Craniofacial Research; National Institute on Alcohol Abuse and Alcoholism; National Institute on Deafness and other Communication Disorders; National Institutes of Health Office of Research on Women's Health; [R01AG034853-08] FX The WIHS (Women's Interagency HIV Study) is funded primarily by the National Institute of Allergy and Infectious Diseases, with additional cofunding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Cancer Institute, the National Institute on Drug Abuse, and the National Institute on Mental Health. Targeted supplemental funding for specific projects is also provided by the National Institute of Dental and Craniofacial Research, the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Deafness and other Communication Disorders, and the National Institutes of Health Office of Research on Women's Health. WIHS data collection is also supported by UL1-TR000004 (UCSF CTSA) and UL1-TR000454 (Atlanta CTSA). MG Shlipak and R Scherzer are funded by R01AG034853-08. NR 46 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0194-911X EI 1524-4563 J9 HYPERTENSION JI Hypertension PD FEB PY 2017 VL 69 IS 2 BP 304 EP + DI 10.1161/HYPERTENSIONAHA.116.08258 PG 18 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EI3QE UT WOS:000392405500015 PM 27993956 ER PT J AU Takayesu, JK Peak, D Stearns, D AF Takayesu, James Kimo Peak, David Stearns, Dana TI Cadaver-based training is superior to simulation training for cricothyrotomy and tube thoracostomy SO INTERNAL AND EMERGENCY MEDICINE LA English DT Article DE Procedures; Competence; Patient care; Patient simulation; Cadaver; Airway management; Graduate medical education; Residency; Emergency medicine ID FRESH-FROZEN CADAVER; EMERGENCY-MEDICINE; REALITY SIMULATOR; AIRWAY MANAGEMENT; SKILLS; COMPETENCE; RESIDENTS; STUDENTS; ACQUISITION; PROGRAM AB Emergency medicine (EM) training mandates that residents be able to competently perform low-frequency critical procedures upon graduation. Simulation is the main method of training in addition to clinical patient care. Access to cadaver-based training is limited due to cost and availability. The relative fidelity and perceived value of cadaver-based simulation training is unknown. This pilot study sought to describe the relative value of cadaver training compared to simulation for cricothyrotomy and tube thoracostomy. To perform a pilot study to assess whether there is a significant difference in fidelity and educational experience of cadaver-based training compared to simulation training. To understand how important this difference is in training residents in low-frequency procedures. Twenty-two senior EM residents (PGY3 and 4) who had completed standard simulation training on cricothyrotomy and tube thoracostomy participated in a formalin-fixed cadaver training program. Participants were surveyed on the relative fidelity of the training using a 100 point visual analogue scale (VAS) with 100 defined as equal to performing the procedure on a real patient. Respondents were also asked to estimate how much the cadaveric training improved the comfort level with performing the procedures on a scale between 0 and 100 %. Open-response feedback was also collected. The response rate was 100 % (22/22). The average fidelity of the cadaver versus simulation training was 79.9 +/- 7.0 vs. 34.7 +/- 13.4 for cricothyrotomy (p < 0.0001) and 86 +/- 8.6 vs. 38.4 +/- 19.3 for tube thoracostomy (p < 0.0001). Improvement in comfort levels performing procedures after the cadaveric training was rated as 78.5 +/- 13.3 for tube thoracostomy and 78.7 +/- 14.3 for cricothyrotomy. All respondents felt this difference in fidelity to be important for procedural training with 21/22 respondents specifically citing the importance of superior landmark and tissue fidelity compared to simulation training. Cadaver-based training provides superior landmark and tissue fidelity compared to simulation training and may be a valuable addition to EM residency training for certain low-frequency procedures. C1 [Takayesu, James Kimo; Peak, David; Stearns, Dana] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. EM jtakayesu@partners.org NR 22 TC 0 Z9 0 U1 3 U2 3 PU SPRINGER-VERLAG ITALIA SRL PI MILAN PA VIA DECEMBRIO, 28, MILAN, 20137, ITALY SN 1828-0447 EI 1970-9366 J9 INTERN EMERG MED JI Intern. Emerg. Med. PD FEB PY 2017 VL 12 IS 1 BP 99 EP 102 DI 10.1007/s11739-016-1439-1 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA EI5BV UT WOS:000392509500013 PM 27021389 ER PT J AU Haas, DA Bozic, KJ DiGioia, AM Song, ZR Kaplan, RS AF Haas, Derek A. Bozic, Kevin J. DiGioia, Anthony M. Song, Zirui Kaplan, Robert S. TI Drivers of the Variation in Prosthetic Implant Purchase Prices for Total Knee and Total Hip Arthroplasties SO JOURNAL OF ARTHROPLASTY LA English DT Article DE costing; cost variation; total knee arthroplasty; total hip arthroplasty; prosthetic implant cost ID PRIVATE INSURERS; OFFICE VISITS AB Background: Previous studies have documented wide variation in health care spending and prices; however, the causes for the variation in supply purchase prices across providers are not well understood. The purpose of this study was to determine the drivers of variation in prosthetic implant purchase prices for primary total knee and hip arthroplasties (TKA and THA, respectively) across providers. Methods: We obtained retrospective data from 27 hospitals on the average prosthetic implant purchase prices for primary TKAs and THAs over the 12 months ending September 30, 2013, as well as data on a range of independent potential explanatory variables. Each hospital performed at least 200 primary total joint arthroplasties per year. The multivariate seemingly unrelated regression approach was used to evaluate the impact of the variables on purchase price for each type of implant. Results: The average purchase price at the hospital at the 90th percentile was 2.1 times higher for TKAs and 1.7 times higher for THAs than that at the hospital at the 10th percentile. The use of a hospital - physician committee for implant vendor selection and negotiation was associated with 17% and 23% lower implant purchase prices (P<.05) for TKAs and THAs, respectively, relative to hospitals that did not have this collaborative approach. Conclusion: The use of a joint hospitalephysician committee is a potential strategy for achieving lower average purchase prices for prosthetic implants. Policies to increase hospitalephysician collaboration may lead to lower average purchase prices in this market. (C) 2016 Elsevier Inc. All rights reserved. C1 [Haas, Derek A.; Kaplan, Robert S.] Harvard Sch Business, Boston, MA USA. [Haas, Derek A.] Avant Garde Hlth, Boston, MA USA. [Bozic, Kevin J.] Univ Texas Austin, Dell Med Sch, Dept Surg & Perioperat Care, Austin, TX 78712 USA. [DiGioia, Anthony M.] Univ Pittsburgh, Magee Womens Hosp, Med Ctr, UPMC, Pittsburgh, PA 15213 USA. [Song, Zirui] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Song, Zirui] Harvard Med Sch, Boston, MA USA. NR 13 TC 0 Z9 0 U1 1 U2 1 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0883-5403 EI 1532-8406 J9 J ARTHROPLASTY JI J. Arthroplast. PD FEB PY 2017 VL 32 IS 2 BP 347 EP + DI 10.1016/j.arth.2016.07.030 PG 7 WC Orthopedics SC Orthopedics GA EI6RM UT WOS:000392623800001 PM 27687807 ER PT J AU Goh, GSH Liow, MHL Bin Abd Razak, HR Tay, DKJ Lo, NN Yeo, SJ AF Goh, Graham Seow-Hng Liow, Ming Han Lincoln Bin Abd Razak, Hamid Rahmatullah Tay, Darren Keng-Jin Lo, Ngai-Nung Yeo, Seng-Jin TI Patient-Reported Outcomes, Quality of Life, and Satisfaction Rates in Young Patients Aged 50 Years or Younger After Total Knee Arthroplasty SO JOURNAL OF ARTHROPLASTY LA English DT Article DE total knee arthroplasty; patient-reported outcome measures; quality of life; satisfaction; young; age 50 ID 55 YEARS OLD; ACTIVE PATIENTS; FOLLOW-UP; TOTAL HIP; REPLACEMENT; OSTEOARTHRITIS; METAANALYSIS; SURVIVAL; JOINT; SURVIVORSHIP AB Background: Recent studies have shown a discrepancy between traditional functional outcomes and patient satisfaction, with some reporting less than 85% satisfaction in older patients undergoing total knee arthroplasty (TKA). As native knee biomechanics are not completely replicated, the resulting functional limitations may cause dissatisfaction in higher-demand individuals. Few studies have recorded patient-reported outcomes, health-related quality of life scores, and patient satisfaction in a young population undergoing TKA. Methods: One hundred thirty-six primary TKAs were performed in 114 patients aged 50 years or younger (mean age, 47.0 years; range, 30-50 years) at a single institution. The main diagnoses were osteoarthritis (85%) and rheumatoid arthritis (10%). Results: The range of motion, Knee Society Score, Oxford Knee Score, and Physical and Mental Component Scores of Short Form-36 increased significantly (P<.001). At 2 years, 85.3% of patients had good/excellent knee scores, 71.3% had good/excellent function scores, 94.9% met the minimal clinically important difference for the Oxford Knee Score, and 84.6% met the minimal clinically important difference for the Physical Component Score. We found that 88.8% of patients were satisfied with their surgeries, whereas 86.8% had their expectations fulfilled. Survivorship using revision as an end point was 97.8% at a mean of 7 years (range, 3-16 years). Conclusion: Patients aged 50 years or younger undergoing TKA can experience significant improvements in their quality of life, have their expectations met, and be satisfied with their surgeries, at rates similar to those of noneage-restricted populations. Surgeons should inform them of these benefits and the potential risk of revision surgery in the future, albeit increasingly shown to be low. (C) 2016 Elsevier Inc. All rights reserved. C1 [Goh, Graham Seow-Hng; Liow, Ming Han Lincoln; Bin Abd Razak, Hamid Rahmatullah; Tay, Darren Keng-Jin; Lo, Ngai-Nung; Yeo, Seng-Jin] Singapore Gen Hosp, Dept Orthopaed Surg, 20 Coll Rd,Level 4, Singapore 169865, Singapore. [Liow, Ming Han Lincoln] Harvard Med Sch, Massachusetts Gen Hosp, Dept Orthopaed, Boston, MA USA. NR 45 TC 0 Z9 0 U1 1 U2 1 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0883-5403 EI 1532-8406 J9 J ARTHROPLASTY JI J. Arthroplast. PD FEB PY 2017 VL 32 IS 2 BP 419 EP 425 DI 10.1016/j.arth.2016.07.043 PG 7 WC Orthopedics SC Orthopedics GA EI6RM UT WOS:000392623800014 PM 27593732 ER PT J AU Spanyer, JM Beaumont, CM Yerasimides, JG AF Spanyer, Jonathon M. Beaumont, Christopher M. Yerasimides, Jonathan G. TI The Extended Direct Anterior Approach for Column Augmentation in the Deficient Pelvis: A Novel Surgical Technique, and Case Series Report SO JOURNAL OF ARTHROPLASTY LA English DT Article DE revision hip arthroplasty; anterior column augmentation; anterior column; augmentation; total hip arthroplasty; deficient pelvis ID TOTAL HIP-ARTHROPLASTY; REVISION; DISCONTINUITY; DEFECTS; RECONSTRUCTION AB Background: Anterior column deficiency of the pelvis may pose a serious threat to the stability of the acetabular component after total hip arthroplasty and, thus, jeopardize the overall success of the procedure. Methods: After Institutional Review Board approval, a retrospective review was undertaken to identify all patients undergoing revision total hip arthroplasty with anterior column augmentation through an extended direct anterior approach. Demographics and surgical details were collected, and subjects were followed for a 2-year minimum period to measure patient outcomes and to evaluate for the stability of construct fixation. A novel surgical procedure description was provided and supplemented with an illustrative case example. Results: At 2 years post augmentation, patients had favorable functional outcomes with radiologic evidence of stable fixation. Conclusion: Proximal extension of the direct anterior approach to the hip can facilitate anterior column access and augmentation to improve stability of the hip reconstruction. This treatment may be an alternative to spanning constructs such as cup-cage constructs and custom implants, affording the potential for long-term biologic fixation. Further investigation into this technique is warranted. (C) 2016 Elsevier Inc. All rights reserved. C1 [Spanyer, Jonathon M.] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [Spanyer, Jonathon M.; Beaumont, Christopher M.; Yerasimides, Jonathan G.] Univ Louisville, Dept Orthopaed Surg, Louisville, KY 40292 USA. [Beaumont, Christopher M.] Univ Louisville, Sch Med, Abell Adm Bldg,323 East Chestnut St, Louisville, KY 40202 USA. [Yerasimides, Jonathan G.] Norton Healthcare, Orthopaed & Hand Ctr, Norton Med Plaza 2, Louisville, KY USA. NR 16 TC 0 Z9 0 U1 2 U2 2 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0883-5403 EI 1532-8406 J9 J ARTHROPLASTY JI J. Arthroplast. PD FEB PY 2017 VL 32 IS 2 BP 515 EP 519 DI 10.1016/j.arth.2016.08.012 PG 5 WC Orthopedics SC Orthopedics GA EI6RM UT WOS:000392623800030 PM 27639306 ER PT J AU Abt, NB McCutcheon, BA Kerezoudis, P Murphy, M Rinaldo, L Fogelson, J Nassr, A Currier, BL Bydon, M AF Abt, Nicholas B. McCutcheon, Brandon A. Kerezoudis, Panagiotis Murphy, Meghan Rinaldo, Lorenzo Fogelson, Jeremy Nassr, Ahmad Currier, Bradford L. Bydon, Mohamad TI Discharge to a rehabilitation facility is associated with decreased 30-day readmission in elective spinal surgery SO JOURNAL OF CLINICAL NEUROSCIENCE LA English DT Article DE Nsqip; Rehabilitation; Spinal surgery; Discharge; Disposition; Readmission ID SURGICAL-TREATMENT; CONTROLLED-TRIAL; CARE; RATES AB The aim of our study was to determine independent predictors of discharge disposition to rehabilitation or skilled care (SC) facilities and investigate whether discharge location is associated with unplanned readmission and/or reoperation rates. All elective spinal surgery patients in a national surgical registry were analyzed using between 2011 and 2012. Multivariable logistic regression analysis was used to assess for predictors of discharge to rehabilitation or SC facilities versus home as well as to determine whether discharge disposition was significantly associated with the 30-day unplanned readmission or reoperation. Of 34,023 elective spinal surgery patients, the distribution of discharge locations was as follows: 30,606 (90.0%) discharged home, 1674 (4.9%) discharged to rehabilitation, and 1743 (5.1%) discharged to SC. Patients discharged home were associated with the lowest complication rate relative to rehabilitation and SC facilities. Following multivariable regression analysis, there was a significant increase in the odds of discharge to rehabilitation associated with age, male gender, current smoking, ASA class three and four, history of diabetes, operative time, total hospital length of stay, preoperative neurologic morbidity and having at least one postoperative morbidity event. Moreover, there were 804 (4.06%) 30-day unplanned readmissions and 822 (2.45%) unplanned reoperations. After risk adjustment, discharge to rehabilitation was independently associated with decreased odds of 30-day unplanned readmission (OR = 0.41; p = 0.008) but not reoperation. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Abt, Nicholas B.] Harvard Med Sch, Dept Otolaryngol Head & Neck Surg, Massachusetts Eye & Ear Infirm, Boston, MA USA. [McCutcheon, Brandon A.; Kerezoudis, Panagiotis; Murphy, Meghan; Rinaldo, Lorenzo; Fogelson, Jeremy; Bydon, Mohamad] Mayo Clin, Dept Neurol Surg, Rochester, MN USA. [McCutcheon, Brandon A.; Kerezoudis, Panagiotis; Murphy, Meghan; Rinaldo, Lorenzo; Bydon, Mohamad] Mayo Clin Neuroinformat Lab, Rochester, MN USA. [Nassr, Ahmad; Currier, Bradford L.] Mayo Clin, Dept Orthoped Surg, Rochester, MN USA. EM Bydon.mohamad@mayo.edu NR 13 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0967-5868 EI 1532-2653 J9 J CLIN NEUROSCI JI J. Clin. Neurosci. PD FEB PY 2017 VL 36 BP 37 EP 42 DI 10.1016/j.jocn.2016.10.029 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EI5WN UT WOS:000392567100007 PM 27810418 ER PT J AU Clark, PA Gaal, JT Strebe, JK Pasch, CA Deming, DA Kuo, JS Robins, HI AF Clark, Paul A. Gaal, Jordan T. Strebe, Joslyn K. Pasch, Cheri A. Deming, Dustin A. Kuo, John S. Robins, H. Ian TI The effects of tumor treating fields and temozolomide in MGMT expressing and non-expressing patient-derived glioblastoma cells SO JOURNAL OF CLINICAL NEUROSCIENCE LA English DT Article DE Cancer stem cells; Glioblastoma; MGMT methylation; Temozolomide; Tumor treating fields ID ALTERNATING ELECTRIC-FIELDS; RANDOMIZED PHASE-III; RECURRENT GLIOBLASTOMA; ADJUVANT TEMOZOLOMIDE; TREATMENT MODALITY; CANCER; CONCOMITANT; THERAPY; CHEMOTHERAPY; RADIOTHERAPY AB A recent Phase 3 study of newly diagnosed glioblastoma (GBM) demonstrated the addition of tumor treating fields (TTFields) to temozolomide (TMZ) after combined radiation/TMZ significantly increased survival and progression free survival. Preliminary data suggested benefit with both methylated and unmethylated O-6-methylguanine-DNA methyl-transferase (MGMT) promoter status. To date, however, there have been no studies to address the potential interactions of TTFields and TMZ. Thus, the effects of TTFields and TMZ were studied in vitro using patient-derived GBM stem-like cells (GSCs) including MGMT expressing (TMZ resistant: 12.1 and 22 GSC) and non-MGMT expressing (TMZ sensitive: 33 and 114 GSC) lines. Dose-response curves were constructed using cell proliferation and sphere-forming assays. Results demonstrated a >= 10-fold increase in TMZ resistance of MGMT-expressing (12.1 GSCs: IC50 = 160 mu M; 22 GSCs: IC50 = 44 mu M) compared to MGMT non-expressing (33 GSCs: IC50 = 1.5 mu M; 114 GSCs: IC50 = 5.2 mu M) lines. TTFields inhibited 12.1 GSC proliferation at all tested doses (50-500 kHz) with an optimal frequency of 200 kHz. At 200 kHz, TTFields inhibited proliferation and tumor sphere formation of both MGMT GSC subtypes at comparable levels (12.1 GSC: 74 +/- 2.9% and 38 +/- 3.2%, respectively; 22 GSC: 61 +/- 11% and 38 +/- 2.6%, respectively; 33 GSC: 56 +/- 9.5% and 60 +/- 7.1%, respectively; 114 GSC: 79 +/- 3.5% and 41 +/- 4.3%, respectively). In combination, TTFields (200 kHz) and TMZ showed an additive anti-neoplastic effect with equal efficacy for TTFields in both cell types (i.e., +/- MGMT expression) with no effect on TMZ resistance. This is the first demonstration of the effects of TTFields on cancer stem cells. The expansion of such studies may have clinical implications. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Clark, Paul A.; Gaal, Jordan T.; Strebe, Joslyn K.; Kuo, John S.] Univ Wisconsin, Dept Neurol Surg, Sch Med & Publ Hlth UWSMPH, Madison, WI USA. [Pasch, Cheri A.; Deming, Dustin A.; Kuo, John S.; Robins, H. Ian] Univ Wisconsin, Carbone Canc Ctr, UWSMPH, Madison, WI USA. [Deming, Dustin A.; Robins, H. Ian] UWSMPH, Dept Med, Div Hematol & Oncol, Madison, WI USA. [Deming, Dustin A.] UWSMPH, Dept Oncol, McArdle Lab Canc Res, Madison, WI USA. [Deming, Dustin A.; Robins, H. Ian] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. [Robins, H. Ian] UWSMPH, Dept Neurol, Madison, WI USA. [Kuo, John S.; Robins, H. Ian] UWSMPH, Dept Human Oncol, Madison, WI USA. EM hirobins@wisc.edu FU National Institutes of Health (NIH) [P30 CA014520]; UW Carbone Cancer pilot grant; Semman Gray Matters Jam; UW (Carbone Cancer Center, Dept. of Medicine, School of Medicine and Public Health); UW (Graduate School through the Wisconsin Alumni Research Foundation); Novocure, Ltd. (Portsmouth, NH); Novocure, Ltd. (New York, NY); NIH [R01CA15880, R01NS75995]; Headrush Brain Tumor Research Professorship; Roger Loff Memorial Fund for GBM Research; Dept. of Neurological Surgery; Katheryn Reader Neuro-Oncology Fund; Steve Bolser Memorial Joggin for Noggin fund FX This research was supported by the National Institutes of Health (NIH) [Grant No. P30 CA014520], UW Carbone Cancer pilot grant, Semman Gray Matters Jam and Steve Bolser Memorial Joggin for Noggin fund. DAD was supported by start-up funds from the UW (Carbone Cancer Center, Dept. of Medicine, School of Medicine and Public Health, and the Graduate School through the Wisconsin Alumni Research Foundation). The in vitro TTFields cell culture equipment was provided by a grant from Novocure, Ltd. (Portsmouth, NH and New York, NY). JSK was partly supported by NIH R01CA15880, R01NS75995, Headrush Brain Tumor Research Professorship, Roger Loff Memorial Fund for GBM Research and the Dept. of Neurological Surgery. HIR was partly supported by the Katheryn Reader Neuro-Oncology Fund. NR 30 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0967-5868 EI 1532-2653 J9 J CLIN NEUROSCI JI J. Clin. Neurosci. PD FEB PY 2017 VL 36 BP 120 EP 124 DI 10.1016/j.jocn.2016.10.042 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EI5WN UT WOS:000392567100023 PM 27865821 ER PT J AU Adams, ZW McClure, EA Gray, KM Danielson, CK Treiber, FA Ruggiero, KJ AF Adams, Zachary W. McClure, Erin A. Gray, Kevin M. Danielson, Carla Kmett Treiber, Frank A. Ruggiero, Kenneth J. TI Mobile devices for the remote acquisition of physiological and behavioral biomarkers in psychiatric clinical research SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Biomarkers; Mobile health; Biosensors; Technology; Ecological momentary assessment; Clinical research ID SUBSTANCE USE DISORDERS; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; CONTINGENCY MANAGEMENT; SMOKING-CESSATION; CIGARETTE-SMOKING; BIPOLAR DISORDER; VOUCHER REINFORCEMENT; PRECISION MEDICINE; HEALTH-CARE; TECHNOLOGY AB Psychiatric disorders are linked to a variety of biological, psychological, and contextual causes and consequences. Laboratory studies have elucidated the importance of several key physiological and behavioral biomarkers in the study of psychiatric disorders, but much less is known about the role of these biomarkers in naturalistic settings. These gaps are largely driven by methodological barriers to assessing biomarker data rapidly, reliably, and frequently outside the clinic or laboratory. Mobile health (mHealth) tools offer new opportunities to study relevant biomarkers in concert with other types of data (e.g., self-reports, global positioning system data). This review provides an overview on the state of this emerging field and describes examples from the literature where mHealth tools have been used to measure a wide array of biomarkers in the context of psychiatric functioning (e.g., psychological stress, anxiety, autism, substance use). We also outline advantages and special considerations for incorporating mHealth tools for remote biomarker measurement into studies of psychiatric illness and treatment and identify several specific opportunities for expanding this promising methodology. Integrating mHealth tools into this area may dramatically improve psychiatric science and facilitate highly personalized clinical care of psychiatric disorders. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Adams, Zachary W.; McClure, Erin A.; Gray, Kevin M.; Danielson, Carla Kmett; Treiber, Frank A.] Med Univ South Carolina, Dept Psychiat & Behav Sci, Coll Med, 67 President St, Charleston, SC USA. [Adams, Zachary W.] Indiana Univ Sch Med, Dept Psychiat, 410 West 10th St, Indianapolis, IN 46202 USA. [Treiber, Frank A.; Ruggiero, Kenneth J.] Med Univ South Carolina, Technol Applicat Ctr Healthful Lifestyles, Coll Nursing, 99 Jonathan Lucas St, Charleston, SC USA. [Ruggiero, Kenneth J.] Ralph H Johnson VA Med Ctr, 109 Bee St, Charleston, SC USA. RP Adams, ZW (reprint author), 410 West 10th St,Suite 2000, Indianapolis, IN 46202 USA. EM zwadams@iu.edu FU National Institutes of Health [K23DA038257, K01DA036739, U01DA031779, K24DA039783, R01DA031285, T32MH018869, I21HX001729, R34MH096907, R01MH107641, R01DK098777, R01HL114957, R21HL118447]; Substance Abuse and Mental Health Services Administration; Veterans Administration; Duke Endowment; National Institutes of Health (NIH grant) [UL1RR029882] FX This work was supported primarily by National Institutes of Health (ZWA, grant number, K23DA038257; EAM, grant number K01DA036739; KMG, grant number U01DA031779; CKD, grant numbers K24DA039783, R01DA031285, and T32MH018869; KJR, grant numbers I21HX001729, R34MH096907, and R01MH107641; and FAT, grant numbers R01DK098777, R01HL114957, and R21HL118447; and NIH grant number UL1RR029882). Additional funding came from the Substance Abuse and Mental Health Services Administration (CKD), Veterans Administration (KJR), and the Duke Endowment (FAT). NR 108 TC 0 Z9 0 U1 9 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 EI 1879-1379 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD FEB PY 2017 VL 85 BP 1 EP 14 DI 10.1016/j.jpsychires.2016.10.019 PG 14 WC Psychiatry SC Psychiatry GA EI8QW UT WOS:000392773600001 ER PT J AU Yule, AM Martelon, M Faraone, SV Carrellas, N Wilens, TE Biederman, J AF Yule, Amy M. Martelon, MaryKate Faraone, Stephen V. Carrellas, Nicholas Wilens, Timothy E. Biederman, Joseph TI Examining the association between attention deficit hyperactivity disorder and substance use disorders: A familial risk analysis SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Familial risk; Substance use disorder; Attention deficit hyperactivity disorder; Co-segregation ID FOLLOW-UP; DEFICIT/HYPERACTIVITY DISORDER; YOUNG-ADULTS; ADOLESCENTS; ALCOHOL; ADHD; TRANSMISSION; DEPENDENCE; CHILDREN; GIRLS AB Objective: The main aim of this study was to use familial risk analysis to examine the association between attention deficit hyperactivity disorder (ADHD) and substance use disorders (SUDs) attending to sex effects and the specificity of alcohol and drug use disorder risks. Methods: Subjects were derived from two longitudinal case-control family studies of probands aged 6 17 years with and without DSM-III-R ADHD of both sexes and their first degree relatives followed from childhood onto young adult years. Cox proportional hazard models were used to estimate rates of ADHD and SUDs (any SUD, alcohol dependence, and drug dependence). Logistic regression was used to test both co-segregation and assortative mating. Results: Our sample included 404 probands (ADHD: 112 boys and 96 girls; Control: 105 boys and 91 girls) and their 1336 relatives. SUDs in probands increased the risk for SUDs in relatives irrespective of ADHD status. The risk for dependence to drug or alcohol in relatives was non-specific. There was evidence that even in the absence of a SUD in the proband, ADHD by itself increased the risk of SUDs in relatives. Proband sex did not moderate the familial relationship between ADHD and SUDs. There was evidence of co-segregation between ADHD and SUD. Conclusions: Findings indicate that various independent pathways are involved in the transmission of SUD in ADHD and that these risks were not moderated by proband sex. ADHD children and siblings should benefit from preventive and early intervention strategies to decrease their elevated risk for developing a SUD. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Yule, Amy M.; Martelon, MaryKate; Carrellas, Nicholas; Wilens, Timothy E.; Biederman, Joseph] Massachusetts Gen Hosp, Div Child Psychiat, Pediat Psychopharmacol Program, Boston, MA 02114 USA. [Yule, Amy M.; Wilens, Timothy E.; Biederman, Joseph] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY 13210 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Neurosci & Physiol, Syracuse, NY 13210 USA. [Faraone, Stephen V.] Univ Bergen, KG Jebsen Ctr Res Neuropsychiat Disorders, Bergen, Norway. RP Yule, AM (reprint author), Massachusetts Gen Hosp, Addict Recovery Management Serv, 151 Merrimac St,6th Floor, Boston, MA 02114 USA. EM ayule@partners.org FU American Academy of Child and Adolescent Psychiatry Pilot Research Award - Lilly USA, LLC; Massachusetts General Hospital Louis V. Gerstner III Research Scholar Award; American Academy of Child and Adolescent Psychiatry Physician Scientist Program in Substance Abuse [K12DA000357-17]; Rhodes; Arbor; Pfizer; Ironshore; Shire; Akili Interactive Labs; CogCubed; Alcobra; VAYA Pharma; NeuroLifeSciences; NACE; Otsuka; McNeil; Janssen; Novartis; Eli Lilly; NIH; Department of Defense, Food & Drug Administration; Lundbeck; Merck; Neurocentria Inc.; PamLab; Shire Pharmaceuticals Inc.; SPRITES; Sunovion; Ingenix; Prophase; Bracket Global; Theravance; Magceutics Inc.; Vaya Pharma/Enzymotec; AACAP; Forest Research Institute; APSARD; ElMindA; Abbott; Alza; AstraZeneca; Boston University; Bristol Myers Squibb; Cambridge University Press; Celltech; Cephalon; Children's Hospital of Southwest Florida/Lee Memorial Health System; Cipher Pharmaceuticals Inc.; Eli Lilly and Co.; Esai; Fundacion Areces (Spain); Forest; Fundacion Dr.Manuel Camelo A.C.; Glaxo; Gliatech; Hastings Center; Juste Pharmaceutical Spain; Medice Pharmaceuticals (Germany); MGH Psychiatry Academy; MMC Pediatric; NARSAD; NIDA; New River; NICHD; NIMH; Noven; Neurosearch; Organon; Pharmacia; Phase V Communications; Physicians Academy; Prechter Foundation; Quantia Communications; Reed Exhibitions; Shionogi Pharma Inc; Spanish Child Psychiatry Association; Stanley Foundation; UCB Pharma Inc.; Veritas; Wyeth FX Amy Yule, MD: Dr. Amy Yule received grant support from the American Academy of Child and Adolescent Psychiatry Pilot Research Award for Junior Faculty supported by Lilly USA, LLC in 2012. She received grant support from the Massachusetts General Hospital Louis V. Gerstner III Research Scholar Award from 2014 to 2016. Dr. Yule is currently receiving funding through the American Academy of Child and Adolescent Psychiatry Physician Scientist Program in Substance Abuse K12DA000357-17.; Stephen Faraone, PhD: In the past year, Dr. Faraone received income, potential income, travel expenses and/or research support from Rhodes, Arbor, Pfizer, Ironshore, Shire, Akili Interactive Labs, CogCubed, Alcobra, VAYA Pharma, NeuroLifeSciences and NACE. With his institution, he has US patent US20130217707 A1 for the use of sodium-hydrogen exchange inhibitors in the treatment of ADHD. In previous years, he received income or research support from: Shire, Alcobra, Otsuka, McNeil, Janssen, Novartis, Pfizer and Eli Lilly. Dr. Faraone receives royalties from books published by Guilford Press: Straight Talk about Your Child's Mental Health, Oxford University Press: Schizophrenia: The Facts and Elsevier: ADHD: Non-Pharmacologic Interventions. He is principal investigator of www.adhdinadults.com.; Timothy Wilens, MD: Dr. Timothy Wilens receives or has received grant support from the following sources: NIH. Dr. Timothy Wilens is or has been a consultant for: Euthymics/Neurovance, NIH(NIDA), Ironshore, Sunovion, TRIS; US National Football League (ERM Associates), U.S. Minor/Major League Baseball; Bay Cove Human Services and Phoenix House (Clinical Services). Dr. Timothy Wilens has a published book: Straight Talk About Psychiatric Medications for Kids (Guilford Press); and co/edited books ADHD in Children and Adults (Cambridge Press), and Massachusetts General Hospital Comprehensive Clinical Psychiatry (Elsevier). Dr. Wilens is co/owner of a copyrighted diagnostic questionnaire (Before School Functioning Questionnaire). Dr. Wilens has a licensing agreement with Ironshore (BSFQ Questionnaire). Dr. Wilens is Chief, Division of Child and Adolescent Psychiatry and (Co) Director of the Center for Addiction Medicine at Massachusetts General Hospital.; Joseph Biederman, MD: Dr. Joseph Biederman is currently receiving research support from the following sources: The Department of Defense, Food & Drug Administration, Lundbeck, Merck, Neurocentria Inc., PamLab, Pfizer, Shire Pharmaceuticals Inc., SPRITES, Sunovion, and NIH. Dr. Biederman's program has received departmental royalties from a copyrighted rating scale used for ADHD diagnoses, paid by Ingenix, Prophase, Shire, Bracket Global, Sunovion, and Theravance; these royalties were paid to the Department of Psychiatry at MGH.; In 2016, Dr. Joseph Biederman received honoraria from the MGH Psychiatry Academy for tuition-funded CME courses, and from Avekshan, Alcobra and AACAP. He has a US Patent Application pending (Provisional Number #61/233,686) through MGH corporate licensing, on a method to prevent stimulant abuse. In 2015, Dr. Joseph Biederman received honoraria from the MGH Psychiatry Academy for tuition-funded CME courses, and from Avekshan. He received research support from Ironshore, Magceutics Inc., and Vaya Pharma/Enzymotec. In 2014, Dr. Joseph Biederman received honoraria from the MGH Psychiatry Academy for tuition-funded CME courses. He received research support from AACAP, Alcobra, Forest Research Institute, and Shire Pharmaceuticals Inc. In 2013, Dr. Joseph Biederman received an honorarium from the MGH Psychiatry Academy for a tuition-funded CME course. He received research support from APSARD, ElMindA, McNeil, and Shire. In previous years, Dr. Joseph Biederman received research support, consultation fees, or speaker's fees for/from the following additional sources: Abbott, Alza, AstraZeneca, Boston University, Bristol Myers Squibb, Cambridge University Press, Celltech, Cephalon, The Children's Hospital of Southwest Florida/Lee Memorial Health System, Cipher Pharmaceuticals Inc., Eli Lilly and Co., Esai, Fundacion Areces (Spain), Forest, Fundacion Dr.Manuel Camelo A.C., Glaxo, Gliatech, Hastings Center, Janssen, Juste Pharmaceutical Spain, McNeil, Medice Pharmaceuticals (Germany), Merck, MGH Psychiatry Academy, MMC Pediatric, NARSAD, NIDA, New River, NICHD, NIMH, Novartis, Noven, Neurosearch, Organon, Otsuka, Pfizer, Pharmacia, Phase V Communications, Physicians Academy, The Prechter Foundation, Quantia Communications, Reed Exhibitions, Shionogi Pharma Inc, Shire, the Spanish Child Psychiatry Association, The Stanley Foundation, UCB Pharma Inc., Veritas, and Wyeth. NR 31 TC 0 Z9 0 U1 6 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 EI 1879-1379 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD FEB PY 2017 VL 85 BP 49 EP 55 DI 10.1016/j.jpsychires.2016.10.018 PG 7 WC Psychiatry SC Psychiatry GA EI8QW UT WOS:000392773600007 PM 27835739 ER PT J AU Atem, FD Qian, J Maye, JE Johnson, KA Betensky, RA AF Atem, Folefac D. Qian, Jing Maye, Jacqueline E. Johnson, Keith A. Betensky, Rebecca A. TI Linear regression with a randomly censored covariate: application to an Alzheimer's study SO JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES C-APPLIED STATISTICS LA English DT Article DE Complete case; Limit of detection; Missing covariate; Multiple imputation ID MATERNAL FAMILY-HISTORY; MULTIPLE IMPUTATION; DETECTION LIMITS; DISEASE; MODELS; DEMENTIA; SUBJECT; ONSET; RISK; TRANSMISSION AB The association between maternal age of onset of dementia and amyloid deposition (measured by in vivo positron emission tomography imaging) in cognitively normal older offspring is of interest. In a regression model for amyloid, special methods are required because of the random right censoring of the covariate of maternal age of onset of dementia. Prior literature has proposed methods to address the problem of censoring due to assay limit of detection, but not random censoring. We propose imputation methods and a survival regression method that do not require parametric assumptions about the distribution of the censored covariate. Existing imputation methods address missing covariates, but not right-censored covariates. In simulation studies, we compare these methods with the simple, but inefficient, complete-case analysis, and with thresholding approaches. We apply the methods to the Alzheimer's study. C1 [Atem, Folefac D.; Betensky, Rebecca A.] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Qian, Jing] Univ Massachusetts, Amherst, MA 01003 USA. [Maye, Jacqueline E.; Johnson, Keith A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Maye, Jacqueline E.] Univ Florida, Gainesville, FL USA. RP Betensky, RA (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Biostat, 655 Huntington Ave, Boston, MA 02115 USA. EM betensky@hsph.harvard.edu FU US National Institutes of Health [5T32NS048005, 5P50AG005134, 5P01AG036694]; Harvard NeuroDiscovery Center FX This work was supported by US National Institutes of Health grants (5T32NS048005, 5P50AG005134 and 5P01AG036694) and the Harvard NeuroDiscovery Center. We thank the Joint Editor, Associate Editor and the referees for their very helpful comments. NR 47 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0035-9254 EI 1467-9876 J9 J R STAT SOC C-APPL JI J. R. Stat. Soc. Ser. C-Appl. Stat. PD FEB PY 2017 VL 66 IS 2 BP 313 EP 328 DI 10.1111/rssc.12164 PG 16 WC Statistics & Probability SC Mathematics GA EI9DO UT WOS:000392807800005 PM 28239197 ER PT J AU Perakakis, N Farr, OM Tuccinardi, D Upadhyay, J Mantzoros, CS AF Perakakis, Nikolaos Farr, Olivia M. Tuccinardi, Dario Upadhyay, Jagriti Mantzoros, Christos S. TI Research advances in metabolism 2016 SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Editorial Material ID POLYCYSTIC-OVARY-SYNDROME; TYPE-1 DIABETES-MELLITUS; FATTY LIVER-DISEASE; GASTRIC-INHIBITORY POLYPEPTIDE; T-CELL-ACTIVATION; SELECTIVE SGLT-2 INHIBITOR; IMPROVES GLYCEMIC CONTROL; GLUCAGON-LIKE PEPTIDE-1; INTIMA-MEDIA THICKNESS; GROWTH-FACTOR 23 C1 [Perakakis, Nikolaos; Farr, Olivia M.; Tuccinardi, Dario; Upadhyay, Jagriti; Mantzoros, Christos S.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Boston, MA 02215 USA. [Upadhyay, Jagriti; Mantzoros, Christos S.] Harvard Med Sch, Boston VA Healthcare Syst, Endocrinol Sect, Boston, MA 02130 USA. EM nperakak@bidmc.harvard.edu OI Farr, Olivia/0000-0002-5182-3432 FU NIH [DK081913] FX This work is also supported in part by NIH DK081913. NR 111 TC 0 Z9 0 U1 1 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0026-0495 EI 1532-8600 J9 METABOLISM JI Metab.-Clin. Exp. PD FEB PY 2017 VL 67 BP 41 EP 53 DI 10.1016/j.metabol.2016.11.001 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EI5YG UT WOS:000392571600005 PM 28081777 ER PT J AU Gong, JJ Munoz, AR Pingali, S Payton-Stewart, F Chan, DE Freeman, JW Ghosh, R Kumar, AP AF Gong, Jingjing Munoz, Amanda R. Pingali, Subramanya Payton-Stewart, Florastina Chan, Daniel E. Freeman, James W. Ghosh, Rita Kumar, Addanki P. TI Downregulation of STAT3/NF-B potentiates gemcitabine activity in pancreatic cancer cells SO MOLECULAR CARCINOGENESIS LA English DT Article DE chemoresistance; pancreatic cancer; nexrutine; gemcitabine; STAT3; NFB ID NF-KAPPA-B; PROSTATE-CANCER; PLUS GEMCITABINE; MUC4 EXPRESSION; NEXRUTINE; BERBERINE; SURVIVAL; EXTRACT; MICROENVIRONMENT; CHEMORESISTANCE AB There is an unmet need to develop new agents or strategies against therapy resistant pancreatic cancer (PanCA). Recent studies from our laboratory showed that STAT3 negatively regulates NF-B and that inhibition of this crosstalk using Nexrutine (R) (Nx) reduces transcriptional activity of COX-2. Inhibition of these molecular interactions impedes pancreatic cancer cell growth as well as reduces fibrosis in a preclinical animal model. Nx is an extract derived from the bark of Phellodendron amurense and has been utilized in traditional Chinese medicine as antidiarrheal, astringent, and anti-inflammatory agent for centuries. We hypothesized that Nx-mediated inhibition of survival molecules like STAT3 and NF-B in pancreatic cancer cells will improve the efficacy of the conventional chemotherapeutic agent, gemcitabine (GEM). Therefore, we explored the utility of Nx, one of its active constituents berberine and its derivatives, to enhance the effects of GEM. Using multiple human pancreatic cancer cells we found that combination treatment with Nx and GEM resulted in significant alterations of proteins in the STAT3/NF-B signaling axis culminating in growth inhibition in a synergistic manner. Furthermore, GEM resistant cells were more sensitive to Nx treatment than their parental GEM-sensitive cells. Interestingly, although berberine, the Nx active component used, and its derivatives were biologically active in GEM sensitive cells they did not potentiate GEM activity when used in combination. Taken together, these results suggest that the natural extract, Nx, but not its active component, berberine, has the potential to improve GEM sensitivity, perhaps by down regulating STAT3/NF-B signaling. (c) 2016 Wiley Periodicals, Inc. C1 [Gong, Jingjing; Ghosh, Rita; Kumar, Addanki P.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, 8403 Floyd Curl Dr, San Antonio, TX 78229 USA. [Munoz, Amanda R.; Ghosh, Rita; Kumar, Addanki P.] Univ Texas Hlth Sci Ctr San Antonio, Dept Urol, 8403 Floyd Curl Dr, San Antonio, TX 78229 USA. [Pingali, Subramanya; Payton-Stewart, Florastina] Xavier Univ Louisiana, Dept Chem, New Orleans, LA USA. [Chan, Daniel E.] Univ Colorado, Div Med Oncol, Aurora, CO USA. [Freeman, James W.] Univ Texas Hlth Sci Ctr San Antonio, Div Med Oncol, 8403 Floyd Curl Dr, San Antonio, TX 78229 USA. [Freeman, James W.; Ghosh, Rita; Kumar, Addanki P.] Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, 8403 Floyd Curl Dr, San Antonio, TX 78229 USA. [Freeman, James W.; Kumar, Addanki P.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Ghosh, Rita; Kumar, Addanki P.] Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, 8403 Floyd Curl Dr, San Antonio, TX 78229 USA. EM kumara3@uthscsa.edu FU Veterans Affairs-Merit Award [I01 BX 000766-01, CPRIT RP 150166]; CTRC at UT Health Science Center San Antonio (UTHSCSA) [2P30 CA 054174-17]; CTRC; NIGMS-BUILD [8UL1GM118967]; RCMI [2G12MD007595-06]; [1R01AT007448] FX Grant sponsor: 1R01AT007448; Grant sponsor: Veterans Affairs-Merit Award; Grant numbers: I01 BX 000766-01; CPRIT RP 150166; Grant sponsor: CTRC at UT Health Science Center San Antonio (UTHSCSA); Grant number: #2P30 CA 054174-17; Grant sponsor: CTRC 40th Anniversary Distinguished Professor of Oncology Endowment; Grant sponsor: NIGMS-BUILD; Grant number: 8UL1GM118967; Grant sponsor: RCMI; Grant number: 2G12MD007595-06 NR 41 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0899-1987 EI 1098-2744 J9 MOL CARCINOGEN JI Mol. Carcinog. PD FEB PY 2017 VL 56 IS 2 BP 402 EP 411 DI 10.1002/mc.22503 PG 10 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA EI5GH UT WOS:000392521800009 PM 27208550 ER PT J AU Massa, ST Osazuwa-Peters, N Christopher, KM Arnold, LD Schootman, M Walker, RJ Varvares, MA AF Massa, Sean T. Osazuwa-Peters, Nosayaba Christopher, Kara M. Arnold, Lauren D. Schootman, Mario Walker, Ronald J. Varvares, Mark A. TI Competing causes of death in the head and neck cancer population SO ORAL ONCOLOGY LA English DT Article DE Head and neck cancer; Survival; Survivorship; Competing mortality; Cancer registry ID SQUAMOUS-CELL CARCINOMA; QUALITY-OF-LIFE; UNITED-STATES; OROPHARYNGEAL CANCER; ORAL-CAVITY; SURVIVAL; COMORBIDITY; MORTALITY; SURVIVORSHIP; DISPARITIES AB Purpose/objectives: The increasing survivorship of head and neck squamous cell carcinoma (HNSCC) comes with a risk of death from other causes, known as competing causes. The demographics of HNSCC are also evolving with increasing incidence of Human Papillomavirus (HPV) associated tumors. This study describes competing causes of death for the HNSCC population compared to the general population and identifies associated risk factors. Methods: Adult patients with first mucosal HNSCC (2004-2011) were identified from the Surveillance, Epidemiology and End Result database. Competing causes of death were compared to reference populations using proportion of deaths and Standardized Mortality Ratios (SMR). A multivariable competing risk survival analysis yielded subdistribution hazard ratios (HR) for competing mortality. Results: Of 64,598 HNSCC patients, 24,602 (38.1%) were deceased including 7142 deaths (29.0%) from competing causes. The most common were cardiovascular disease, lung cancer, and other cancers. All relative mortality rates were elevated, especially liver disease (SMR 38.7; 95% CI: 29.4-49.3), suicide (SMR 37.1; 95% CI: 26.1-48.6), and subsequent primary cancers (SMR 7.5; 95% CI: 6.78-8.32). Demographic and tumor factors independently increased risk of competing mortality, including age (HR per 5 years 1.24; 95% CI: 1.22-1.25), sex (male HR 1.23; 95% CI: 1.16-1.32), race (Black HR 1.17; 95% CI: 1.09-1.26), insurance (uninsured HR 1.28; 95% CI: 1.09-1.50), and marital status (single HR 1.29; 95% CI: 1.21-1.37). Conclusion: Nearly one in three HNSCC patients died from competing causes. When developing long term survivorship regimens for HNSCC patients, clinicians should be familiar with this population's specific risks. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Massa, Sean T.; Osazuwa-Peters, Nosayaba; Walker, Ronald J.] St Louis Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, 3635 Vista Ave, St Louis, MO 63110 USA. [Christopher, Kara M.] St Louis Univ, Sch Med, Ctr Canc, St Louis, MO USA. [Arnold, Lauren D.; Schootman, Mario] St Louis Univ, Dept Epidemiol, Coll Publ Hlth & Social Justice, St Louis, MO 63103 USA. [Varvares, Mark A.] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA USA. EM seanmassa@slu.edu NR 50 TC 0 Z9 0 U1 9 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1368-8375 EI 1879-0593 J9 ORAL ONCOL JI Oral Oncol. PD FEB PY 2017 VL 65 BP 8 EP 15 DI 10.1016/j.oraloncology.2016.12.006 PG 8 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA EI6XO UT WOS:000392641100004 PM 28109473 ER PT J AU Gentile, MS Yip, D Liebsch, NJ Adams, JA Busse, PM Chan, AW AF Gentile, Michelle S. Yip, Darwin Liebsch, Norbert J. Adams, Judith A. Busse, Paul M. Chan, Annie W. TI Definitive proton beam therapy for adenoid cystic carcinoma of the nasopharynx involving the base of skull SO ORAL ONCOLOGY LA English DT Article DE Adenoid cystic carcinoma; Nasopharynx; Minor salivary gland; Proton beam therapy; Base of skull ID CARBON ION THERAPY; RADIATION-THERAPY; NECK; HEAD; RADIOTHERAPY; CISPLATIN; CHEMOTHERAPY; EXPERIENCE; OUTCOMES AB Objectives: Management of unresectable adenocystic carcinoma (ACC) of the nasopharynx is challenging given the high dose required for tumor control while respecting dose constraints. We evaluated long-term outcomes and toxicity in patients with unresectable ACC of the nasopharynx treated with definitive proton beam therapy. Methods: Between 2000 and 2013, 14 patients with ACC of the nasopharynx were treated. Ninety-three percent had T4 disease. All had involvement of the skull base. Seventy-nine percent and 21% of patients underwent biopsy and endoscopic debulking surgery, respectively. Median dose was 73.8 Gy (RBE). Fifty percent of patients received concurrent chemotherapy. Locoregional control and overall survival probabilities were estimated by the Kaplan-Meier method. Treatment toxicity was scored by the Common Terminology Criteria for Adverse Events version 4.0. Results: Median follow-up of surviving patients was 69 months. There were 3 local, 1 regional, and 4 distant failures. Median time of local failures was 69 months (range: 63-161). All local recurrences were within previous high-dose regions. Four patients developed metastatic disease at a median of 30 months (range: 4-64). Five-year overall survival was 59%. The most common cause of death was due to metastatic disease. There was one acute grade 3 toxicity. No patient required gastrostomy tube or hospitalization. Three patients developed grade 3 or higher late toxicity. Two of these patients received combined modality treatment. With 176 months follow-up, no second cancer was observed. Conclusion: Proton beam therapy results in promising local control with acceptable toxicity in patients with unresectable ACC of the nasopharynx. As late recurrence is common, longer follow-up is necessary to confirm our findings. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Gentile, Michelle S.; Yip, Darwin; Liebsch, Norbert J.; Adams, Judith A.; Busse, Paul M.; Chan, Annie W.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA USA. EM awchan@mgh.harvard.edu NR 22 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1368-8375 EI 1879-0593 J9 ORAL ONCOL JI Oral Oncol. PD FEB PY 2017 VL 65 BP 38 EP 44 DI 10.1016/j.oraloncology.2016.11.016 PG 7 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA EI6XO UT WOS:000392641100008 PM 28109466 ER PT J AU Cowan, S Lozano-Calderon, SA Uppot, RN Sajed, D Huang, AJ AF Cowan, Sophie Lozano-Calderon, Santiago A. Uppot, Raul N. Sajed, Dipti Huang, Ambrose J. TI Successful CT guided cryoablation of phosphaturic mesenchymal tumor in the soft tissues causing tumor-induced osteomalacia: a case report SO SKELETAL RADIOLOGY LA English DT Article DE Cryoablation; Phosphaturic mesenchymal tumor; Tumor-induced osteomalacia ID OF-THE-LITERATURE; ONCOGENIC OSTEOMALACIA; RADIOFREQUENCY ABLATION AB We report the case of a 25-year-old male patient with tumor-induced osteomalacia from a 1.8-cm phosphaturic mesenchymal tumor in the right distal thigh, who was treated at our institution with a single session of CT-guided cryoablation in December 2015, which resulted in biochemical and clinical resolution. We present the clinical history, physical examination, biochemistry, functional imaging, anatomic characterization, and follow-up for clinical outcome. The response to treatment was documented in terms of normalization of serum fibroblastic growth factor 23 (FGF23) and phosphorous levels, symptomatic improvement, as well as normalization of bone mineralization on femur radiographs 3 months after the procedure. Although the first-line treatment for phosphaturic mesenchymal tumor-induced osteomalacia is wide surgical excision, CT-guided cryoablation widens the array of treatment options, especially in those patients who decline surgery or who are otherwise poor surgical candidates. C1 [Cowan, Sophie; Huang, Ambrose J.] Massachusetts Gen Hosp, Div Musculoskeletal Imaging & Intervent, Dept Radiol, 55 Fruit St,Yawkey 6E, Boston, MA 02114 USA. [Lozano-Calderon, Santiago A.] Massachusetts Gen Hosp, Div Musculoskeletal Oncol, Dept Orthopaed Surg, 55 Fruit St,Yawkey 3B, Boston, MA 02114 USA. [Uppot, Raul N.] Massachusetts Gen Hosp, Div Intervent Radiol, Dept Radiol, 55 Fruit St,Gray Bigelow 298, Boston, MA 02114 USA. [Sajed, Dipti] Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,Warren 219, Boston, MA 02114 USA. EM ajhuang@mgh.harvard.edu NR 11 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2348 EI 1432-2161 J9 SKELETAL RADIOL JI Skeletal Radiol. PD FEB PY 2017 VL 46 IS 2 BP 273 EP 277 DI 10.1007/s00256-016-2548-7 PG 5 WC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging SC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging GA EI6ZD UT WOS:000392645400022 PM 27921126 ER PT J AU Gebregziabher, M AF Gebregziabher, Mulugeta TI Some comments on "The analysis of multivariate longitudinal data: A review" SO STATISTICAL METHODS IN MEDICAL RESEARCH LA English DT Letter DE hearing loss data; multivariate longitudinal data; shared random effects; separate random effects ID HEARING-LOSS; INFERENCE AB We provide a commentary on The analysis of multivariate longitudinal data: a review by Verbeke etal. The authors provide a comprehensive review of the issues in the analysis of multivariate longitudinal data and use examples to demonstrate the pros and cons of several approaches. In this commentary, we indicate some important omissions in their review paper. C1 [Gebregziabher, Mulugeta] Med Univ South Carolina, Dept Publ Hlth Sci Biostat, 135 Cannon St,MSC 835, Charleston, SC 29425 USA. [Gebregziabher, Mulugeta] Ralph H Johnson Dept Vet Affairs Med Ctr, Hlth Equ & Rural Outreach Innovat Ctr, Charleston, SC USA. RP Gebregziabher, M (reprint author), Med Univ South Carolina, Dept Publ Hlth Sci Biostat, 135 Cannon St,MSC 835, Charleston, SC 29425 USA. EM gebregz@musc.edu OI Gebregziabher, Mulugeta/0000-0002-4826-481X FU National Institutes of Health, National Institute on Deafness and Other Communication Disorders (NIH/NIDCD) [P50 DC000422] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported (in part) by grant P50 DC000422 from the National Institutes of Health, National Institute on Deafness and Other Communication Disorders (NIH/NIDCD). NR 9 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0962-2802 EI 1477-0334 J9 STAT METHODS MED RES JI Stat. Methods Med. Res. PD FEB PY 2017 VL 26 IS 1 BP 108 EP 111 DI 10.1177/0962280214539863 PG 4 WC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Statistics & Probability SC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Mathematics GA EJ1KK UT WOS:000392968900007 PM 25847912 ER PT J AU Ma, YB Zhou, XH AF Ma, Yunbei Zhou, Xiao-Hua TI Treatment selection in a randomized clinical trial via covariate-specific treatment effect curves SO STATISTICAL METHODS IN MEDICAL RESEARCH LA English DT Article DE predictive biomarker; covariate-specific treatment effect curve; time-to-event outcome; pointwise confidence interval; simultaneous confidence interval; varying coefficient ID CONFIDENCE BANDS; SURVIVAL-DATA; COX MODEL; REGRESSION; COEFFICIENTS; SUBSETS AB For time-to-event data in a randomized clinical trial, we proposed two new methods for selecting an optimal treatment for a patient based on the covariate-specific treatment effect curve, which is used to represent the clinical utility of a predictive biomarker. To select an optimal treatment for a patient with a specific biomarker value, we proposed pointwise confidence intervals for each covariate-specific treatment effect curve and the difference between covariate-specific treatment effect curves of two treatments. Furthermore, to select an optimal treatment for a future biomarker-defined subpopulation of patients, we proposed confidence bands for each covariate-specific treatment effect curve and the difference between each pair of covariate-specific treatment effect curve over a fixed interval of biomarker values. We constructed the confidence bands based on a resampling technique. We also conducted simulation studies to evaluate finite-sample properties of the proposed estimation methods. Finally, we illustrated the application of the proposed method in a real-world data set. C1 [Ma, Yunbei] Southwestern Univ Finance & Econ, Sch Stat, Chengdu, Sichuan, Peoples R China. [Zhou, Xiao-Hua] Univ Washington, Dept Biostat, VA Puget Sound Hlth Care Syst, HSR&D Ctr Excellence, Seattle, WA 98195 USA. [Zhou, Xiao-Hua] Peking Univ, Beijing Int Ctr Math Res, Beijing, Peoples R China. RP Zhou, XH (reprint author), Univ Washington, Dept Biostat, VA Puget Sound Hlth Care Syst, HSR&D Ctr Excellence, Seattle, WA 98195 USA. EM azhou@washington.edu FU National Natural Science Foundation of China (NSFC) [11301424]; U.S. Department of Veterans Affairs HSR&D Research Career Scientist Award [RCS 05-196] FX Dr Ma's work was partially supported by the National Natural Science Foundation of China (NSFC) (No. 11301424), and Dr Zhou's work was supported in part by U.S. Department of Veterans Affairs HSR&D Research Career Scientist Award (RCS 05-196). NR 17 TC 0 Z9 0 U1 2 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0962-2802 EI 1477-0334 J9 STAT METHODS MED RES JI Stat. Methods Med. Res. PD FEB PY 2017 VL 26 IS 1 BP 124 EP 141 DI 10.1177/0962280214541724 PG 18 WC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Statistics & Probability SC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Mathematics GA EJ1KK UT WOS:000392968900010 PM 24996899 ER PT J AU Moon, DH Efstathiou, JA Chen, RC AF Moon, Dominic H. Efstathiou, Jason A. Chen, Ronald C. TI What is the best way to radiate the prostate in 2016? SO UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS LA English DT Review DE Prostate cancer; Radiation therapy; Intensity-modulated radiation therapy (IMRT); Image-guided radiation therapy (IGRT); Proton therapy; Hypofractionation; Stereotactic body radiation therapy (SBRT); Brachytherapy ID INTENSITY-MODULATED RADIOTHERAPY; 3-DIMENSIONAL CONFORMAL RADIOTHERAPY; STEREOTACTIC BODY RADIOTHERAPY; EXTERNAL-BEAM RADIOTHERAPY; QUALITY-OF-LIFE; RANDOMIZED CONTROLLED-TRIAL; TREATMENT RELATED MORBIDITY; PATIENT-REPORTED OUTCOMES; DOSE-ESCALATION TRIAL; PROTON THERAPY AB Prostate cancer treatment with definitive radiation therapy (RT) has evolved dramatically in the past 2 decades. From the initial 2-dimensional planning using X-rays, advances in technology led to 3-dimensional conformal RT, which used computerized tomography-based planning. This has allowed delivery of higher doses of radiation to the prostate while reducing dose to the surrounding organs, resulting in improved cancer control. Today, intensity-modulated RT (IMRT) is considered standard, where radiation beams of different shapes and intensities can be delivered from a wide range of angles, thus further decreasing doses to normal organs and likely reducing treatment-related toxicity. In addition, image guidance ascertains the location of the prostate before daily treatment delivery. Brachytherapy is the placement of radioactive seeds directly in the prostate, and has a long track record as a monotherapy for low-risk prostate cancer patients with excellent long-term cancer control and quality of life outcomes. Recent studies including several randomized trials support the use of brachytherapy in combination with external beam RT for higher-risk patients. RT for prostate cancer continues to evolve. Proton therapy has a theoretical advantage over photons as it deposits most of the dose at a prescribed depth with a rapid dose fall-off thereafter; therefore it reduces some doses delivered to the bladder and rectum. Prospective studies have shown the safety and efficacy of proton therapy for prostate cancer, but whether it leads to improved patient outcomes compared to IMRT is unknown. Hypofractionated RT delivers a larger dose of daily radiation compared to conventional IMRT, and thus reduces the overall treatment time and possibly cost. An extreme form of hypofractionation is stereotactic body radiation therapy where highly precise radiation is used and treatment is completed in a total of 4 to 5 sessions. These techniques take advantage of the biological characteristic of prostate cancer, which is more sensitive to larger radiation doses per fraction, and therefore could be more effective than conventional IMRT. Multiple randomized trials have demonstrated noninferiority of moderately hypofractionated RT compared to conventional fractionation. There is also a growing body of data demonstrating the safety and efficacy of stereotactic body radiation therapy for low- and intermediate-risk prostate cancer. (C) 2017 Elsevier Inc. All rights reserved. C1 [Moon, Dominic H.; Chen, Ronald C.] Univ North Carolina Chapel Hill, Dept Radiat Oncol, Chapel Hill, NC 27514 USA. [Efstathiou, Jason A.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA USA. [Chen, Ronald C.] Univ North Carolina Chapel Hill, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27514 USA. EM ronald_chen@med.unc.edu NR 83 TC 0 Z9 0 U1 5 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1078-1439 EI 1873-2496 J9 UROL ONCOL-SEMIN ORI JI Urol. Oncol.-Semin. Orig. Investig. PD FEB PY 2017 VL 35 IS 2 BP 59 EP 68 DI 10.1016/j.urolonc.2016.06.002 PG 10 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA EI6ZC UT WOS:000392645300013 PM 27395453 ER PT J AU Muralidhar, V Nguyen, PL AF Muralidhar, Vinayak Nguyen, Paul L. TI Maximizing resources in the loca ltreatment of prostate cancer: A summaryof cost- effectiveness studies SO UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS LA English DT Review DE Cost-effectiveness; Prostate cancer; Local therapy; Surgery; Radiation; Active surveillance; Watchful waiting ID RADIATION-THERAPY; PROTON-BEAM; GUIDELINES; HEALTH AB Objectives: Prostate cancer is a common diagnosis with several treatment options for the newly diagnosed patient, including radiation, surgery, active surveillance, and watchful waiting. Although tailoring of treatment to individual patient needs is an important goal, the recent passage of the Affordable Care Act has placed renewed interest in cost containment and cost-effectiveness. We sought to conduct a literature review of recent US-based studies to analyze the cost-effectiveness of initial local treatments for localized prostate cancer. Methods: We conducted a systematic literature search through PubMed, the Cost-Effectiveness Analysis Registry, and manual cross-referencing of articles. We identified US-based studies with cost analyses starting in 2005 that studied the cost-effectiveness of initial local treatments for localized prostate cancer (surgery, radiation, or observation). Results: There were eight studies that met our inclusion and exclusion criteria. Most studies took the cost perspective of Medicare, and two studies also considered the societal cost in terms of lost patient time. Most studies also used a Markov model with inputs based on the available literature for the effectiveness and toxicity of the different treatment options. The radiation-focused studies tended to find brachytherapy (BT) or stereotactic body radiation therapy (SBRT) to be more cost-effective than intensity-modulated radiation therapy or proton beam therapy. These findings were primarily based on the lower cost of SBRT or BT with roughly equal efficacy and toxicity. The two studies focused on surgery found surgery to be more cost effective than intensity-modulated radiation therapy, at least for low-risk disease, and one study found BT to be more cost-effective than surgery, and watchful waiting to be the most cost-effective option overall. Conclusion: Cost-effectiveness analysis is important because it helps patients, physicians, and policymakers make quantitatively-based decisions, which balance treatment efficacy, toxicity, and costs. Significant methodological heterogeneity in the studies we found limit the ability to compare their results directly, but most found that for favorable-risk prostate cancer, shorter or simpler treatments tended to be more cost-effective, including no treatment (watchful waiting) in one study. (C) 2017 Elsevier Inc. All rights reserved. C1 [Muralidhar, Vinayak] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA USA. [Nguyen, Paul L.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Nguyen, Paul L.] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA 02115 USA. EM pnguyen@LROC.harvard.edu NR 22 TC 1 Z9 1 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1078-1439 EI 1873-2496 J9 UROL ONCOL-SEMIN ORI JI Urol. Oncol.-Semin. Orig. Investig. PD FEB PY 2017 VL 35 IS 2 BP 76 EP 85 DI 10.1016/j.urolonc.2016.06.003 PG 10 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA EI6ZC UT WOS:000392645300015 PM 27473636 ER PT J AU Topor, DR AhnAllen, CG Mulligan, EA Dickey, CC AF Topor, David R. AhnAllen, Christopher G. Mulligan, Elizabeth A. Dickey, Chandlee C. TI Using Video Recordings of Psychotherapy Sessions in Supervision: Strategies to Reduce Learner Anxiety SO ACADEMIC PSYCHIATRY LA English DT Editorial Material C1 [Topor, David R.; AhnAllen, Christopher G.; Mulligan, Elizabeth A.; Dickey, Chandlee C.] VA Boston Healthcare Syst, Boston, MA 02130 USA. [Topor, David R.; AhnAllen, Christopher G.; Mulligan, Elizabeth A.; Dickey, Chandlee C.] Harvard Med Sch, Boston, MA 02115 USA. RP Topor, DR (reprint author), VA Boston Healthcare Syst, Boston, MA 02130 USA.; Topor, DR (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM David.Topor@va.gov NR 16 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1042-9670 EI 1545-7230 J9 ACAD PSYCHIATR JI Acad. Psych. PD FEB PY 2017 VL 41 IS 1 BP 40 EP 43 DI 10.1007/s40596-016-0605-0 PG 4 WC Education & Educational Research; Psychiatry SC Education & Educational Research; Psychiatry GA EI2KW UT WOS:000392317100009 PM 27558629 ER PT J AU Vestal, HS Sowden, G Nejad, S Stoklosa, J Valcourt, SC Keary, C Caminis, A Huffman, J AF Vestal, Heather S. Sowden, Gillian Nejad, Shamim Stoklosa, Joseph Valcourt, Stephanie C. Keary, Christopher Caminis, Argyro Huffman, Jeff TI Simulation-Based Training for Residents in the Management of Acute Agitation: A Cluster Randomized Controlled Trial SO ACADEMIC PSYCHIATRY LA English DT Article DE Simulation; Agitation; Teaching methods; Psychiatry; Residents ID PSYCHIATRIC-EDUCATION; PERFORMANCE; CHECKLISTS; VIGNETTES; QUALITY AB Objective Simulations are used extensively in medicine to train clinicians to manage high-risk situations. However, to our knowledge, no studies have determined whether this is an effective means of teaching residents to manage acutely agitated patients. This study aimed to determine whether simulation-based training in the management of acute agitation improves resident knowledge and performance, as compared to didactic-based instruction. Methods Following a standard lecture on the management of agitated patients, first-year psychiatry residents were randomized (in clusters of three to four residents) to either the intervention (n = 15) or control arm (n = 11). Residents in the intervention arm then received simulation-based training on the management of acute agitation using a scenario with an agitated standardized patient. Those in the control arm received simulation-based training on a clinical topic unrelated to the management of agitation using a scenario with a non-agitated standardized patient who had suffered a fall. Baseline confidence and knowledge were assessed using pre-intervention self-assessment questionnaires and open-ended clinical case vignettes. Efficacy of the intervention as a teaching tool was assessed with post-intervention open-ended clinical case vignettes and videotaped simulation-based assessment, using a different scenario of an agitated standardized patient. Reults Residents who received the agitation simulation-based training showed significantly greater improvement in knowledge (intervention = 3.0 vs. control = 0.3, p = 0.007, Cohen's d = 1.2) and performance (intervention = 39.6 vs control = 32.5, p = 0.001, Cohen's d = 1.6). Change in self-perceived confidence did not differ significantly between groups. Conclusion In this study, simulation-based training appeared to be more effective at teaching knowledge and skills necessary for the management of acutely agitated patients, as compared to didactic-based instruction alone. Subjective evaluations of confidence in these skills did not improve significantly compared to controls, corroborating the need for using objective outcome measures when assessing simulation-based training. C1 [Vestal, Heather S.; Stoklosa, Joseph; Valcourt, Stephanie C.; Caminis, Argyro] McLean Hosp, Belmont, MA 02178 USA. [Sowden, Gillian] Geisel Sch Med Dartmouth, Hanover, NH USA. [Nejad, Shamim; Keary, Christopher; Huffman, Jeff] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Vestal, HS (reprint author), McLean Hosp, Belmont, MA 02178 USA. EM hvestal@partners.org FU Partners Centers of Expertise in Medical Education FX Grant support was provided by the Partners Centers of Expertise in Medical Education. NR 28 TC 0 Z9 0 U1 5 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1042-9670 EI 1545-7230 J9 ACAD PSYCHIATR JI Acad. Psych. PD FEB PY 2017 VL 41 IS 1 BP 62 EP 67 DI 10.1007/s40596-016-0559-2 PG 6 WC Education & Educational Research; Psychiatry SC Education & Educational Research; Psychiatry GA EI2KW UT WOS:000392317100013 PM 27114243 ER PT J AU Meyer, MJ Dzik, WH Levine, WC AF Meyer, Matthew J. Dzik, Walter H. Levine, Wilton C. TI Fresh-Frozen Plasma: Ordering Patterns and Utilization in the Operating Rooms of a Tertiary Referral Hospital SO ANESTHESIA AND ANALGESIA LA English DT Article ID COAGULATION-FACTOR ACTIVITY; THAWED PLASMA; BLOOD-TRANSFUSION; DECISION-MAKING; STORAGE; 4-DEGREES-C; PARAMETERS AB BACKGROUND: Blood product transfusion is the most commonly performed hospital procedure. Intraoperative blood product utilization varies between institutions and anesthesiologists. In the United States in 2011, nearly 4 million plasma units were transfused. METHODS: A retrospective analysis of intraoperative plasma ordering patterns and utilization (thawing and transfusing) was performed at a tertiary, academic hospital between January 2015 and March 2016. RESULTS: Over 15 months, 46,002 operative procedures were performed. In 1540 of them, plasma was thawed or transfused: 8297 plasma units were thawed and 3306 of those units were transfused. These 3306 plasma units were transfused in 749 cases with a median of 2 plasma units (interquartile range, 2-4) transfused. The percentage of average monthly procedures with plasma thawed and none transfused was 51.3% (confidence interval, 49.0%-53.6%). The cardiac surgery service requested the greatest number of plasma units to be thawed (2143) but only transfused 712 (33.2%) of them. Of all plasma units not transfused, 45% were generated by procedures with 1 to 4 units of plasma thawed; 95.7% of these units were thawed as even integers (ie, 2, 4). CONCLUSIONS: For operative procedures, far more plasma was thawed than was transfused and this practice occurred across surgical specialties and anesthesiologists. Considering the plasma that was not transfused, 45% occurred in procedures with 4 or fewer units of plasma requested suggesting these low-volume requests were a primary source of potential waste. Further studies are needed to examine associations between plasma utilization and clinical outcomes. C1 [Meyer, Matthew J.; Dzik, Walter H.; Levine, Wilton C.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Meyer, MJ (reprint author), 55 Fruit St, Boston, MA 02114 USA. EM matthewjmeyer@gmail.com FU Massachusetts General Hospital Perioperative Services and Blood Transfusion Service FX Thank you to the Massachusetts General Hospital Perioperative Services and Blood Transfusion Service for their tremendous support of our research. Specific thanks to Micah Flynn and Kent Eliason for consistent and rapid data acquisition as well as Evelyn Abayaah for her involvement and general help. NR 21 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD FEB PY 2017 VL 124 IS 2 BP 618 EP 622 DI 10.1213/ANE.0000000000001789 PG 5 WC Anesthesiology SC Anesthesiology GA EI3CB UT WOS:000392366200033 PM 28067700 ER PT J AU Maher, DP Chen, L Mao, JR AF Maher, Dermot P. Chen, Lucy Mao, Jianren TI Intravenous Ketamine infusions for Neuropathic Pain Management: Promising Therapy in Need of Optimization SO ANESTHESIA AND ANALGESIA LA English DT Review ID SPINAL-CORD-INJURY; RECEPTOR ANTAGONIST KETAMINE; REFRACTORY CANCER PAIN; DOUBLE-BLIND; OPEN-LABEL; POSTHERPETIC NEURALGIA; SUBANESTHETIC KETAMINE; RETROSPECTIVE ANALYSIS; PLACEBO; FIBROMYALGIA AB Intravenous ketamine infusions have been used extensively to treat often-intractable neuropathic pain conditions. Because there are many widely divergent ketamine infusion protocols described in the literature, the variation in these protocols presents a challenge for direct comparison of one protocol with another and in discerning an optimal protocol. Careful examination of the published literature suggests that ketamine infusions can be useful to treat neuropathic pain and that certain characteristics of ketamine infusions may be associated with better clinical outcomes. Increased duration of relief from neuropathic pain is associated with (1) higher total infused doses of ketamine; (2) prolonged infusion durations, although the rate of infusion does not appear to be a factor; and (3) coadministration of adjunct medications such as midazolam and/or clonidine that mitigate some of the unpleasant psychomimetic side effects. However, there are few studies designed to optimize ketamine infusion protocols by defining what an effective infusion protocol entails with regard to a respective neuropathic pain condition. Therefore, despite common clinical practice, the current state of the literature leaves the use of ketamine infusions without meaningful guidance from high-quality comparative evidence. The objectives of this topical review are to (1) analyze the available clinical evidence related to ketamine infusion protocols and (2) call for clinical studies to identify optimal ketamine infusion protocols tailored for individual neuropathic pain conditions. The Oxford Center for Evidence Based Medicine classification for levels of evidence was used to stratify the grades of clinical recommendation for each infusion variable studied. C1 [Maher, Dermot P.; Chen, Lucy; Mao, Jianren] Harvard Sch Med, Massachusetts Gen Hosp, Div Pain Med, Boston, MA USA. RP Maher, DP (reprint author), Massachusetts Gen Hosp, Ctr Pain Med, Div Pain Med, Suite 340,15 Parkman St, Boston, MA 02114 USA. EM dpmaher@mgh.harvard.edu FU NIH [DA036564] FX This work is partially supported by NIH R01 grant DA036564. NR 40 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD FEB PY 2017 VL 124 IS 2 BP 661 EP 674 DI 10.1213/ANE.0000000000001787 PG 14 WC Anesthesiology SC Anesthesiology GA EI3CB UT WOS:000392366200038 PM 28067704 ER PT J AU Zeidan, AM Xu, MN Steensma, DP AF Zeidan, Amer M. Xu, Mina Steensma, David P. TI The importance of erythroblast enumeration in myeloid neoplasia SO ANNALS OF HEMATOLOGY LA English DT Letter DE Myelodysplastic syndromes; Blasts; Prognostication C1 [Zeidan, Amer M.] Yale Univ, Sect Hematol, Dept Internal Med, 333 Cedar St,POB 208028, New Haven, CT 06520 USA. [Zeidan, Amer M.] Yale Comprehens Canc Ctr, 333 Cedar St,POB 208028, New Haven, CT 06520 USA. [Xu, Mina] Yale Univ, Dept Pathol, New Haven, CT 06520 USA. [Steensma, David P.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Zeidan, AM (reprint author), Yale Univ, Sect Hematol, Dept Internal Med, 333 Cedar St,POB 208028, New Haven, CT 06520 USA.; Zeidan, AM (reprint author), Yale Comprehens Canc Ctr, 333 Cedar St,POB 208028, New Haven, CT 06520 USA. EM amer.zeidan@yale.edu NR 3 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0939-5555 EI 1432-0584 J9 ANN HEMATOL JI Ann. Hematol. PD FEB PY 2017 VL 96 IS 2 BP 329 EP 330 DI 10.1007/s00277-016-2862-0 PG 2 WC Hematology SC Hematology GA EI2GO UT WOS:000392305100020 PM 27771743 ER PT J AU Schwartz, DM Fong, ZV Warshaw, AL Zinner, MJ Chang, DC AF Schwartz, Dana M. Fong, Zhi Ven Warshaw, Andrew L. Zinner, Michael J. Chang, David C. TI The Hidden Consequences of the Volume Pledge "No Patient Left Behind"? SO ANNALS OF SURGERY LA English DT Editorial Material ID UNITED-STATES; MORTALITY C1 [Schwartz, Dana M.; Fong, Zhi Ven; Warshaw, Andrew L.; Chang, David C.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Boston, MA USA. [Chang, David C.] Massachusetts Gen Hosp, Codman Ctr Clin Effectiveness Surg, Boston, MA 02114 USA. [Zinner, Michael J.] Harvard Med Sch, Brigham & Womens Hosp, Dept Surg, Boston, MA USA. [Zinner, Michael J.] Miami Canc Inst, Miami, FL USA. RP Chang, DC (reprint author), Codman Ctr Clin Effectiveness Surg, Charles River Plaza,Suite 403,165 Cambridge St, Boston, MA 02114 USA. EM dchang8@mgh.harvard.edu NR 8 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD FEB PY 2017 VL 265 IS 2 BP 273 EP 274 DI 10.1097/SLA.0000000000001833 PG 2 WC Surgery SC Surgery GA EI2CW UT WOS:000392295200012 PM 27280503 ER PT J AU Liu, JB Ko, CY AF Liu, Jason B. Ko, Clifford Y. TI Disparities in Rectal Cancer: Moving from Descriptions to Solutions SO ANNALS OF SURGICAL ONCOLOGY LA English DT Editorial Material ID HEALTH; CARE C1 [Liu, Jason B.; Ko, Clifford Y.] Amer Coll Surg, Chicago, IL 60611 USA. [Liu, Jason B.] Univ Chicago Hosp, Dept Surg, Chicago, IL 60637 USA. [Ko, Clifford Y.] Univ Calif Los Angeles, David Geffen Sch Med, VA Greater Los Angeles Healthcare Syst, Dept Surg, Los Angeles, CA 90095 USA. RP Liu, JB (reprint author), Amer Coll Surg, Chicago, IL 60611 USA.; Liu, JB (reprint author), Univ Chicago Hosp, Dept Surg, Chicago, IL 60637 USA. EM jliu@facs.org FU Department of Surgery, University of Chicago Hospitals; American College of Surgeons Clinical Scholar in Residence Program FX JBL is supported by a research fellowship from the Department of Surgery, University of Chicago Hospitals and the American College of Surgeons Clinical Scholar in Residence Program. NR 10 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2017 VL 24 IS 2 BP 299 EP 301 DI 10.1245/s10434-016-5628-y PG 3 WC Oncology; Surgery SC Oncology; Surgery GA EH7BA UT WOS:000391926600001 PM 27743226 ER PT J AU Wapnir, IL Gelber, S Anderson, SJ Mamounas, EP Robidoux, A Martin, M Nortier, JWR Geyer, CE Paterson, AHG Lang, I Price, KN Coates, AS Gelber, RD Rastogi, P Regan, MM Wolmark, N Aebi, S AF Wapnir, Irene L. Gelber, Shari Anderson, Stewart J. Mamounas, Eleftherios P. Robidoux, Andre Martin, Miguel Nortier, Johan W. R. Geyer, Charles E., Jr. Paterson, Alexander H. G. Lang, Istvan Price, Karen N. Coates, Alan S. Gelber, Richard D. Rastogi, Priya Regan, Meredith M. Wolmark, Norman Aebi, Stefan CA CALOR Trial Investigators TI Poor Prognosis After Second Locoregional Recurrences in the CALOR Trial SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID BREAST-TUMOR RECURRENCE; SURGICAL ADJUVANT BREAST; CONSERVATIVE SURGERY; CONSERVING THERAPY; CANCER RECURRENCE; LOCAL RECURRENCE; MASTECTOMY; IRRADIATION; BRACHYTHERAPY; CHEMOTHERAPY AB Isolated locoregional recurrences (ILRRs) of breast cancer confer a significant risk for the development of distant metastasis. Management practices and second ILRR events in the Chemotherapy as Adjuvant for LOcally Recurrent breast cancer (CALOR) trial were investigated. In this study, 162 patients with ILRR were randomly assigned to receive postoperative chemotherapy or no chemotherapy. Descriptive statistics characterize outcomes according to local therapy and the influence of hormone receptor status on subsequent recurrences. Competing risk regression models, Kaplan-Meier estimates, and Cox proportional hazards models were used to evaluate associations between treatment, site of second recurrence, and outcome. The median follow-up period was 4.9 years. Of the 98 patients who received breast-conserving primary surgery 89 had an ipsilateral-breast tumor recurrence. Salvage mastectomy was performed for 73 patients and repeat lumpectomy for 16 patients. Another eight patients had nodal ILRR, and one patient had chest wall ILRR. Among 64 patients whose primary surgery was mastectomy, 52 had chest wall/skin ILRR, and 12 had nodal ILRR. For 15 patients, a second ILRR developed a median of 1.6 years (range 0.08-4.8 years) after ILRR. All second ILRRs occurred for patients with progesterone receptor-negative ILRR. Death occurred for 7 (47 %) of 15 patients with a second ILRR and 19 (51 %) of 37 patients with a distant recurrence. As shown in the multivariable analysis, the significant predictors of survival after either a second ILRR or distant recurrence were chemotherapy for the primary cancer (hazard ratio [HR], 3.55; 95 % confidence interval [CI], 1.15-10.9; p = 0.03) and the interval (continuous) from the primary surgery (HR, 0.87; 95 % CI, 0.75-1.00; p = 0.05). Second ILRRs represented about one third of all recurrence events after ILRR, and all were PR-negative. These second ILRRs and distant metastases portend an unfavorable outcome. C1 [Wapnir, Irene L.] Stanford Univ, Sch Med, Dept Surg, NRG Oncol, Stanford, CA 94305 USA. [Gelber, Shari; Price, Karen N.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, IBCSG Stat Ctr, Boston, MA 02115 USA. [Gelber, Shari; Price, Karen N.] Frontier Sci & Technol Res Fdn Inc, Boston, MA USA. [Anderson, Stewart J.; Wolmark, Norman] NRG Oncol, Pittsburgh, PA USA. [Anderson, Stewart J.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. [Mamounas, Eleftherios P.] NRG Oncol, Orlando, FL USA. [Mamounas, Eleftherios P.] Univ Florida, Hlth Canc Ctr, Orlando Hlth, Orlando, FL USA. [Robidoux, Andre] NRG Oncol, Montreal, PQ, Canada. [Robidoux, Andre] Ctr Hosp Univ Montreal, Montreal, PQ, Canada. [Martin, Miguel] Univ Complutense, Inst Invest SanitariaGregorio Maranon, GEICAM, Madrid, Spain. [Nortier, Johan W. R.] Leids Univ, Dutch Breast Canc Trialists Grp, BOOG, Med Ctr, Leiden, Netherlands. [Geyer, Charles E., Jr.] NRG Oncol, Richmond, VA USA. [Geyer, Charles E., Jr.] Virginia Commonwealth Univ, Massey Canc Ctr, Richmond, VA USA. [Paterson, Alexander H. G.] NRG Oncol, Calgary, AB, Canada. [Paterson, Alexander H. G.] Tom Baker Canc Clin, Calgary, AB, Canada. [Lang, Istvan] IBCSG, Budapest, Hungary. [Lang, Istvan] Natl Inst Oncol, Budapest, Hungary. [Coates, Alan S.] IBCSG, Bern, Switzerland. [Coates, Alan S.] Univ Sydney, Sydney, NSW, Australia. [Gelber, Richard D.] Harvard Med Sch, Harvard TH Chan Sch Publ Hlth, Dept Biostat & Computat Biol, IBCSG Stat Ctr,Dana Farber Canc Inst, Boston, MA USA. [Gelber, Richard D.] Frontier Sci & Technol Res Fdn Inc, Boston, MA USA. [Rastogi, Priya] Univ Pittsburgh, Inst Canc, NRG Oncol, Pittsburgh, PA USA. [Regan, Meredith M.] Harvard Med Sch, Dana Farber Canc Inst, Dept Biostat & Computat Biol, IBCSG Stat Ctr, Boston, MA USA. [Wolmark, Norman] Allegheny Hlth Network Canc Inst, Pittsburgh, PA USA. [Aebi, Stefan] Luzerner Kantonsspital, IBCSG, Luzern, Switzerland. [Aebi, Stefan] Univ Bern, Bern, Switzerland. [Aebi, Stefan] Swiss Grp Clin Canc Res SAKK, Bern, Switzerland. RP Wapnir, IL (reprint author), Stanford Univ, Sch Med, Dept Surg, NRG Oncol, Stanford, CA 94305 USA. EM wapnir@stanford.edu; shari@jimmy.harvard.edu; sja@pitt.edu; terry.mamounas@orlandohealth.com; andre.robidoux.chum@ssss.gouv.qc.ca; mmartin@geicam.org; J.W.R.Nortier@lumc.nl; cegeyer@vcu.edu; alexander.paterson@albertahealthservices.ca; lang@oncol.hu; price@jimmy.harvard.edu; alan.coates@ibcsg.org; gelber@jimmy.harvard.edu; rastogip@upmc.edu; mregan@jimmy.harvard.edu; nwolmark@nsabp.org; stefan.aebi@onkologie.ch RI Aebi, Stefan/F-2004-2010 OI Aebi, Stefan/0000-0002-3383-9449 FU National Cancer Institute, Department of Health and Human Services [U10-CA-180868, U10-CA-189867, U10-CA-180822, U24-CA-75362]; Swiss Group for Clinical Cancer Research (SAKK); Frontier Science and Technology Research Foundation; Australia and New Zealand Breast Cancer Trials Group; Swedish Cancer Society; Cancer Research Switzerland/Oncosuisse; Cancer Association of South Africa; Foundation for Clinical Research of Eastern Switzerland (OSKK); Grupo Espanol de Investigacion en Cancer de Mama (GEICAM); BOOG, the Dutch Breast Cancer Trialists' Group FX The CALOR trial was supported in part by Public Service Grants U10-CA-180868, U10-CA-189867, U10-CA-180822, and U24-CA-75362 from the National Cancer Institute, Department of Health and Human Services. The International Breast Cancer Study Group is supported in part by the Swiss Group for Clinical Cancer Research (SAKK), Frontier Science and Technology Research Foundation, Australia and New Zealand Breast Cancer Trials Group, Swedish Cancer Society, Cancer Research Switzerland/Oncosuisse, Cancer Association of South Africa, Foundation for Clinical Research of Eastern Switzerland (OSKK). Spanish participation was funded by Grupo Espanol de Investigacion en Cancer de Mama (GEICAM), and Dutch participation by BOOG, the Dutch Breast Cancer Trialists' Group. NR 31 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2017 VL 24 IS 2 BP 398 EP 406 DI 10.1245/s10434-016-5571-y PG 9 WC Oncology; Surgery SC Oncology; Surgery GA EH7BA UT WOS:000391926600014 PM 27663567 ER PT J AU Maehara, T Mattoo, H Ohta, M Mahajan, VS Moriyama, M Yamauchi, M Drijvers, J Nakamura, S Stone, JH Pillai, SS AF Maehara, Takashi Mattoo, Hamid Ohta, Miho Mahajan, Vinay S. Moriyama, Masafumi Yamauchi, Masaki Drijvers, Jefte Nakamura, Seiji Stone, John H. Pillai, Shiv S. TI Lesional CD4(+) IFN-gamma(+) cytotoxic T lymphocytes in IgG4-related dacryoadenitis and sialoadenitis SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID REGULATORY IMMUNE-REACTIONS; LABIAL SALIVARY-GLANDS; MIKULICZS-DISEASE; SJOGRENS-SYNDROME; HELPER SUBSETS; PANCREATITIS; TH2; BIOINFORMATICS; CELLS; ATOPY AB Objectives IgG4-related disease (IgG4-RD) is a chronic, systemic, inflammatory condition of unknown aetiology. We have recently described clonally expanded circulating CD4 cytotoxic T lymphocytes (CTLs) in IgG4RD that infiltrate affected tissues where they secrete interleukin (IL)-1 beta and transforming growth factor-beta 1 (TGF-beta 1). In this study, we sought to examine the role of CD4' CTLs in the pathogenesis of IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS) and to determine whether these cells secrete interferon-gamma (IFN-7) at lesional sites. Methods Salivary glands of 25 patients with IgG4-DS, 22 patients with Sj6gren's syndrome (SS), 12 patients with chronic sialoadenitis (CS) and 12 healthy controls were analysed in this study. Gene expression analysis was performed on submandibular glands (SMGs) from five patients with IgG4-DS, three with CS and three healthy controls. Infiltrating CD4 CTLs were examined by quantitative multicolour imaging in tissue samples from 20 patients with IgG4-DS, 22 patients with SS, 9 patients with CS and 9 healthy controls. Results In IgG4-DS tissues, nine genes associated with CD4(+) CTLs were overexpressed. The expression of granzyme A (GZMA) mRNA was significantly higher in samples from patients with IgG4-RD compared with corresponding tissues from SS and healthy controls. Quantitative imaging showed that infiltrating CD4 GZMA(+) CTLs were more abundant in patients with IgG4-DS than in the other groups. The ratio of CD4(+) GZMA(+) CTLs in SMGs from patients with IgG4-DS correlated with serum IgG4 concentrations and the number of affected organs. A large fraction of CD4(+) GZMA(+) CTLs in SMGs from patients with IgG4-DS secreted IFN-gamma Conclusions The pathogenesis of IgG4-DS is associated with tissue infiltration by CD4(+) GZMA t CTLs that secrete IFN-gamma. C1 [Maehara, Takashi; Mattoo, Hamid; Mahajan, Vinay S.; Drijvers, Jefte; Stone, John H.; Pillai, Shiv S.] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [Maehara, Takashi; Ohta, Miho; Moriyama, Masafumi; Yamauchi, Masaki; Nakamura, Seiji] Kyushu Univ, Sect Oral & Maxillofacial Oncol, Div Maxillofacial Diagnost & Surg Sci, Fac Dent Sci, Fukuoka, Japan. [Moriyama, Masafumi] Kyushu Univ, OBT Res Ctr, Fac Dent Sci, Fukuoka, Japan. RP Pillai, SS (reprint author), Ragon Inst MGH MIT & Harvard, 400 Tech Sq, Cambridge, MA 02139 USA. EM pillai@helix.mgh.harvard.edu FU NIH [AI110495, AI113163]; Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers - Japanese Society for the Promotion of Science (JSPS) [S2605] FX This study was funded by grants AI110495 and AI113163 from the NIH and supported by the Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers (S2605) sponsored by the Japanese Society for the Promotion of Science (JSPS). NR 28 TC 2 Z9 2 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD FEB PY 2017 VL 76 IS 2 BP 377 EP 385 DI 10.1136/annrheumdis-2016-209139 PG 9 WC Rheumatology SC Rheumatology GA EI3XT UT WOS:000392426900009 PM 27358392 ER PT J AU Zhang, YQ Lu, N Peloquin, C Dubreuil, M Neogi, T Avina-Zubieta, JA Rai, SK Choi, HK AF Zhang, Yuqing Lu, Na Peloquin, Christine Dubreuil, Maureen Neogi, Tuhina Avina-Zubieta, J. Antonio Rai, Sharan K. Choi, Hyon K. TI Improved survival in rheumatoid arthritis: a general population-based cohort study SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID MORTALITY; RISK; VALIDATION; DATABASE; THERAPY AB Objective Mortality trends of rheumatoid arthritis (RA) are largely unknown over the past decade when new drugs and management strategies have been adopted to effectively treat RA. Methods Using The Health Improvement Network, an electronic medical record database representative of the UK general population, we identified patients with incident RA and up to five individuals without RA matched for age, sex and year of diagnosis between 1999 and 2014. The RA cohort was divided in two subcohorts based on the year of RA diagnosis: the early cohort (1999-2006) and the late cohort (2007-2014). We compared mortality rates, HRs (using a Cox proportional hazard model) and rate differences (using an additive hazard model) between RA and non-RA cohorts adjusting for potential confounders. Results Patients with RA diagnosed between 1999 and 2006 had a considerably higher mortality rate than their comparison cohort (ie, 29.1 vs 18.0 deaths/1 000 person-years), as compared with a moderate difference in patients with RA diagnosed between 2007 and 2014 and their comparison cohort (17.0 vs 12.9 deaths/1000 years). The corresponding absolute mortality rate differences were 9.5 deaths/1000 person-years (95% Cls 7.5 to 11.6) and 3.1 deaths/1 000 person-years (95% Cl 1.5 to 4.6) and the mortality HRs were 1.56 (95% Cl 1.44 to 1.69) and 1.29 (95% Cl 1.17 to 1.42), respectively (both p values for interaction < 0.01). Conclusion This general population-based cohort study indicates that the survival of patients with RA has improved over the past decade to a greater degree than in the general population. Improved management of RA and its associated comorbidities over recent years may be providing a survival benefit. C1 [Zhang, Yuqing; Lu, Na; Peloquin, Christine; Dubreuil, Maureen; Neogi, Tuhina; Choi, Hyon K.] Boston Univ, Sch Med, Clin Epidemiol Res & Training Unit, Boston, MA 02118 USA. [Avina-Zubieta, J. Antonio; Choi, Hyon K.] Univ British Columbia, Arthrit Res Canada, Vancouver, BC, Canada. [Rai, Sharan K.; Choi, Hyon K.] Harvard Med Sch, Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Boston, MA USA. RP Zhang, YQ (reprint author), Boston Univ, Sch Med, Med & Epidemiol, Boston, MA 02118 USA. EM yuqing@bu.edu FU NIH [P60-AR-047785] FX This project was supported in part by the NIH grant P60-AR-047785. NR 27 TC 1 Z9 1 U1 3 U2 3 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD FEB PY 2017 VL 76 IS 2 BP 408 EP 413 DI 10.1136/annrheumdis-2016-209058 PG 6 WC Rheumatology SC Rheumatology GA EI3XT UT WOS:000392426900013 PM 27338777 ER PT J AU Vandenwijngaert, S Swinnen, M Walravens, AS Beerens, M Gillijns, H Caluwe, E Tainsh, RE Nathan, DI Allen, K Brouckaert, P Bartunek, J Scherrer-Crosbie, M Bloch, KD Bloch, DB Janssens, SP Buys, ES AF Vandenwijngaert, Sara Swinnen, Melissa Walravens, Ann-Sophie Beerens, Manu Gillijns, Hilde Caluwe, Ellen Tainsh, Robert E. Nathan, Daniel I. Allen, Kaitlin Brouckaert, Peter Bartunek, Jozef Scherrer-Crosbie, Marielle Bloch, Kenneth D. Bloch, Donald B. Janssens, Stefan P. Buys, Emmanuel S. TI Decreased Soluble Guanylate Cyclase Contributes to Cardiac Dysfunction Induced by Chronic Doxorubicin Treatment in Mice SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Article DE cardiovascular; cardiomyopathy; chemotherapy; doxorubicin; cyclic nucleotides; soluble guanylate cyclase ID NITRIC-OXIDE; INDUCED CARDIOMYOPATHY; HEART-FAILURE; OXIDATIVE STRESS; RADICAL PRODUCTION; HYDROGEN-PEROXIDE; ACTIVATES SERCA; CARDIOTOXICITY; DEXRAZOXANE; ADRIAMYCIN AB Aims: The use of doxorubicin, a potent chemotherapeutic agent, is limited by cardiotoxicity. We tested the hypothesis that decreased soluble guanylate cyclase (sGC) enzyme activity contributes to the development of doxorubicin-induced cardiotoxicity. Results: Doxorubicin administration (20 mg/kg, intraperitoneally [IP]) reduced cardiac sGC activity in wild-type (WT) mice. To investigate whether decreased sGC activity contributes to doxorubicin-induced cardiotoxicity, we studied mice with cardiomyocyte-specific deficiency of the sGC alpha 1-subunit (mice with cardiomyocyte-specific deletion of exon 6 of the sGC alpha 1 allele [sGC alpha 1(-/-CM)]). After 12 weeks of doxorubicin administration (2 mg/kg/week IP), left ventricular (LV) systolic dysfunction was greater in sGC alpha 1(-/-CM) than WT mice. To further assess whether reduced sGC activity plays a pathogenic role in doxorubicin-induced cardiotoxicity, we studied a mouse model in which decreased cardiac sGC activity was induced by cardiomyocyte-specific expression of a dominant negative sGC alpha 1 mutant (DNsGC alpha 1) upon doxycycline removal (Tet-off). After 8 weeks of doxorubicin administration, DNsGC alpha 1(tg/+), but not WT, mice displayed LV systolic dysfunction and dilatation. The difference in cardiac function and remodeling between DNsGC alpha 1(tg/+) and WT mice was even more pronounced after 12 weeks of treatment. Further impairment of cardiac function was attenuated when DNsGC alpha 1 gene expression was inhibited (beginning at 8 weeks of doxorubicin treatment) by administering doxycycline. Furthermore, doxorubicin-associated reactive oxygen species generation was higher in sGC alpha 1-deficient than WT hearts. Innovation and Conclusion: These data demonstrate that a reduction in cardiac sGC activity worsens doxorubicin-induced cardiotoxicity in mice and identify sGC as a potential therapeutic target. Various pharmacological sGC agonists are in clinical development or use and may represent a promising approach to limit doxorubicin-associated cardiotoxicity. C1 [Vandenwijngaert, Sara; Tainsh, Robert E.; Nathan, Daniel I.; Allen, Kaitlin; Bloch, Kenneth D.; Bloch, Donald B.; Buys, Emmanuel S.] Massachusetts Gen Hosp, Res Inst, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St,Thier 511B, Boston, MA 02114 USA. [Vandenwijngaert, Sara; Tainsh, Robert E.; Nathan, Daniel I.; Allen, Kaitlin; Bloch, Kenneth D.; Bloch, Donald B.; Buys, Emmanuel S.] Harvard Med Sch, Anesthesia Ctr Crit Care Res, Boston, MA USA. [Swinnen, Melissa; Walravens, Ann-Sophie; Beerens, Manu; Gillijns, Hilde; Caluwe, Ellen; Bartunek, Jozef; Janssens, Stefan P.] Katholieke Univ Leuven, Dept Cardiovasc Sci, Leuven, Belgium. [Brouckaert, Peter] Univ Ghent, Dept Biomed Mol Biol, Ghent, Belgium. [Brouckaert, Peter] Flanders Inst Biotechnol, Ghent, Belgium. [Bartunek, Jozef] Onze Lieve Vrouw Hosp, Ctr Cardiovasc, Aalst, Belgium. [Scherrer-Crosbie, Marielle; Bloch, Kenneth D.] Massachusetts Gen Hosp, Res Inst, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Scherrer-Crosbie, Marielle; Bloch, Kenneth D.; Bloch, Donald B.] Harvard Med Sch, Boston, MA USA. [Bloch, Donald B.] Massachusetts Gen Hosp, Dept Med, Res Inst, Boston, MA 02114 USA. RP Buys, ES (reprint author), Massachusetts Gen Hosp, Res Inst, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St,Thier 511B, Boston, MA 02114 USA.; Buys, ES (reprint author), Harvard Med Sch, Anesthesia Ctr Crit Care Res, Boston, MA USA. EM ebuys@mgh.harvard.edu FU Belgian American Education Foundation; American Heart Association [10SDG2610313]; Research Grant from KU Leuven [PF10/014]; NIH [R01EY022746, R01DK082971]; FWO-Vlaanderen; UGent-GOA programs; Leducq Foundation FX The authors would like to thank Dr. Cornelius Busch and Dr. Pieter Vermeersch for their help in generating the DNsGC alpha 1tg/+ mice and Dr. David Dichek for providing the alpha MHC-tTA mice. This work was supported by a Postdoctoral Fellowship from the Belgian American Education Foundation (to S.V.), Scientist Development Grant 10SDG2610313 from the American Heart Association (to E.S.B.), Research Grant from KU Leuven (PF10/014, to S.P.J.), NIH grant R01EY022746 (to E.S.B.), grants from the FWO-Vlaanderen and the UGent-GOA programs (to P.B.), NIH Grant R01DK082971 (to K.D.B., D.B.B.), and the Leducq Foundation (to K.D.B., D.B.B.). NR 57 TC 0 Z9 0 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD FEB 1 PY 2017 VL 26 IS 4 BP 153 EP 164 DI 10.1089/ars.2015.6542 PG 12 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA EI2EC UT WOS:000392298500001 PM 27505125 ER PT J AU Moon, Y Cao, Y Zhu, JJ Xu, YY Balkan, W Buys, ES Diaz, F Kerrick, WG Hare, JM Percival, JM AF Moon, Younghye Cao, Yenong Zhu, Jingjing Xu, Yuanyuan Balkan, Wayne Buys, Emmanuel S. Diaz, Francisca Kerrick, W. Glenn Hare, Joshua M. Percival, Justin M. TI GSNOR Deficiency Enhances In Situ Skeletal Muscle Strength, Fatigue Resistance, and RyR1 S-Nitrosylation Without Impacting Mitochondrial Content and Activity SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Article DE nitric oxide; GSNOR; sGC; fatigue; S-nitrosylation; mitochondria ID NITRIC-OXIDE SYNTHASE; DUCHENNE MUSCULAR-DYSTROPHY; MDX MOUSE MODEL; SOLUBLE GUANYLYL CYCLASE; NNOS-KNOCKOUT MICE; RYANODINE RECEPTORS; REDOX REGULATION; RELEASE CHANNEL; COMPLEX-I; NITROSOGLUTATHIONE AB Aim: Nitric oxide (NO) plays important, but incompletely defined roles in skeletal muscle. NO exerts its regulatory effects partly though S-nitrosylation, which is balanced by denitrosylation by enzymes such as S-nitrosoglutathione reductase (GSNOR), whose functions in skeletal muscle remain to be fully deciphered. Results: GSNOR null (GSNOR(-/-)) tibialis anterior (TA) muscles showed normal growth and were stronger and more fatigue resistant than controls in situ. However, GSNOR(-/-) lumbrical muscles showed normal contractility and Ca2+ handling in vitro, suggesting important differences in GSNOR function between muscles or between in vitro and in situ environments. GSNOR(-/-) TA muscles exhibited normal mitochondrial content, and capillary densities, but reduced type IIA fiber content. GSNOR inhibition did not impact mitochondrial respiratory complex I, III, or IV activities. These findings argue that enhanced GSNOR(-/-) TA contractility is not driven by changes in mitochondrial content or activity, fiber type, or blood vessel density. However, loss of GSNOR led to RyR1 hypernitrosylation, which is believed to increase muscle force output under physiological conditions. cGMP synthesis by soluble guanylate cyclase (sGC) was decreased in resting GSNOR(-/-) muscle and was more responsive to agonist (DETANO, BAY 41, and BAY 58) stimulation, suggesting that GSNOR modulates cGMP production in skeletal muscle. Innovation: GSNOR may act as a "brake'' on skeletal muscle contractile performance under physiological conditions by modulating nitrosylation/denitrosylation balance. Conclusions: GSNOR may play important roles in skeletal muscle contractility, RyR1 S-nitrosylation, fiber type specification, and sGC activity. C1 [Moon, Younghye; Cao, Yenong; Zhu, Jingjing; Hare, Joshua M.; Percival, Justin M.] Univ Miami, Miller Sch Med, Dept Mol & Cellular Pharmacol, Miami, FL 33136 USA. [Cao, Yenong; Balkan, Wayne; Hare, Joshua M.] Univ Miami, Miller Sch Med, Interdisciplinary Stem Cell Inst, Miami, FL 33136 USA. [Xu, Yuanyuan; Kerrick, W. Glenn] Univ Miami, Miller Sch Med, Dept Physiol & Biophys, Miami, FL 33136 USA. [Balkan, Wayne; Hare, Joshua M.] Univ Miami, Miller Sch Med, Dept Med, Miami, FL 33136 USA. [Buys, Emmanuel S.] Harvard Med Sch, Massachusetts Gen Hosp Boston, Anesthesia Ctr Crit Care Res, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. [Diaz, Francisca] Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA. RP Percival, JM (reprint author), Univ Miami, Miller Sch Med, Dept Mol & Cellular Pharmacol R 189, POB 016189, Miami, FL 33101 USA. EM j.percival@med.miami.edu FU NIH [1R03AR066805-01, R01HL110737, R01HL107110, R01HL084275, 5UM1HL113460]; Department of Defense [MD140021]; Starr Foundation; Soffer Family Foundation; American Heart Association FX The authors would like to thank Dr. Kimberley Craven for editing services. JP was funded by NIH grant 1R03AR066805-01 and the Department of Defense grant MD140021. JMH was funded by NIH grants R01HL110737, R01HL107110, R01HL084275, and 5UM1HL113460 and grants from the Starr Foundation and the Soffer Family Foundation. YC was funded by a predoctoral fellowship from the American Heart Association. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or DOD. NR 68 TC 0 Z9 0 U1 4 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD FEB 1 PY 2017 VL 26 IS 4 BP 165 EP 181 DI 10.1089/ars.2015.6548 PG 17 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA EI2EC UT WOS:000392298500002 PM 27412893 ER PT J AU Tsai, JN Burnett-Bowie, SM Lee, H Leder, BZ AF Tsai, J. N. Burnett-Bowie, S. M. Lee, H. Leder, B. Z. TI Relationship between bone turnover and density with teriparatide, denosumab or both in women in the DATA study SO BONE LA English DT Article DE Osteoporosis; Bone resorption; Bone turnover markers; Denosumab; Teriparatide; Bone formation ID RANDOMIZED CONTROLLED-TRIAL; POSTMENOPAUSAL OSTEOPOROSIS; SERUM SCLEROSTIN; PARATHYROID-HORMONE; ZOLEDRONIC ACID; EXTENSION; MARKERS; DECLINE; SOST; PTH AB Background: While changes in biochemical markers of bone turnover (BTM) have been reported to predict changes in bone mineral density (BMD), the relationship between changes in BMD and BTMs with combined antiresorptive/anabolic therapy is unknown. Methods: In the DATA study, 94 postmenopausal osteoporotic women (ages 51-91) received either teriparatide 20-mcg SC daily, denosumab 60-mg SC every 6 months, or both for 2 years. Pearson's correlation coefficients (R) were calculated to determine the relationship between baseline and early changes in BTMs (as well as serum sclerostin) and 2-year changes in BMD. Results: In women receiving teriparatide, baseline BTMs did not correlate with 2-year BMD changes though 12-month increases in osteocalcin and P1NP were associated with 2-year increases in spine BMD. In women receiving denosumab, spine and hip BMD gains correlated with both baseline and changes in P1NP and C-telopeptide. In women receiving combined teriparatide/denosumab, while both baseline and decre'ases in P1NP were associated with spine BMD gains, distal radius increases were associated with less CTX suppression. Neither baseline nor changes in serum sclerostin correlated with BMD in any treatment group. Summary and conclusions: In women treated with teriparatide or denosumab, early BTM changes (increases and decreases, respectively) predict 2-year BMD gains, especially at the spine. In women treated with combined teriparatide/denosumab therapy, BMD increases at the distal radius were associated with less suppression of bone turnover. These results suggest that efficacy of combination therapy at cortical sites such as the radius may depend on residual bone remodeling despite RANKL inhibition. (C) 2016 Elsevier Inc. All rights reserved. C1 [Tsai, J. N.; Burnett-Bowie, S. M.; Leder, B. Z.] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Lee, H.] Massachusetts Gen Hosp, Biostat Ctr, Boston, MA 02114 USA. RP Tsai, JN (reprint author), 50 Blossom St,Thier 1051, Boston, MA 02114 USA. EM jntsai@mgh.harvard.edu FU NIH/NIAMS [K23AR068447, K24AR067847]; Eli Lilly and Company; Amgen FX We thank the study volunteers for their participation. This work is supported by NIH/NIAMS grant K23AR068447 (to JNT), NIH/NIAMS grant K24AR067847 (to BZL), Eli Lilly and Company, and Amgen. Eli Lilly and Amgen did not have any role in study design, data analysis, or data interpretation. NR 24 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 EI 1873-2763 J9 BONE JI Bone PD FEB PY 2017 VL 95 BP 20 EP 25 DI 10.1016/j.bone.2016.11.009 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EI0LD UT WOS:000392165100004 PM 27840301 ER PT J AU Bredella, MA Greenblatt, LB Eajazi, A Torriani, M Yu, EW AF Bredella, Miriam A. Greenblatt, Logan B. Eajazi, Alireza Torriani, Martin Yu, Elaine W. TI Effects of Roux-en-Y gastric bypass and sleeve gastrectomy on bone mineral density and marrow adipose tissue SO BONE LA English DT Article DE Bone mineral density (BMD); Quantitative computed tomography (QCT); Dual-energy X-ray absorptiometry; Marrow adipose tissue (MAT); Proton MR spectroscopy; Bariatric surgery ID BARIATRIC SURGERY; CALCIUM-ABSORPTION; ANOREXIA-NERVOSA; MR SPECTROSCOPY; VITAMIN-D; FAT; MASS; QUANTIFICATION; DETERIORATION; METABOLISM AB Bariatric surgery is associated with bone loss but skeletal consequences may differ between Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), the two most commonly performed bariatric procedures. Furthermore, severe weight loss is associated with high marrow adipose tissue (MAT); however, MAT is also increased in visceral adiposity. The purpose of our study was to determine the effects of RYGB and SG on BMD and MAT. We hypothesized that both bariatric procedures would lead to a decrease in BMD and MAT. We studied 21 adults with morbid obesity (mean BMI 44.1 +/- 5.1 kg/m(2)) prior to and 12 months after RYGB (n = 11) and SG (n = 10). All subjects underwent DXA and QCT of the lumbar spine and hip to assess aBMD and vBMD. Visceral (VAT) and subcutaneous (SAT) adipose tissue was quantified at L1-L2. MAT of the lumbar spine and femur was assessed by 1H-MR spectroscopy. Calcitropic hormones and bone turnover markers were determined. At 12 months after surgery, mean weight and abdominal fat loss was similar between the RYGB and SG groups. Mean serum calcium, 25(OH)-vitamin D, and PTH levels were unchanged after surgery and within the normal range in both groups. Bone turnover markers P1NP and CTX increased within both groups and P1NP increased to a greater extent in the RYGB group (p = 0.03). There were significant declines from baseline in spine aBMD and vBMD within the RYGB and SG groups, although the changes were not significantly different between groups (p = 03). Total hip and femoral neck aBMD by DXA decreased to a greater extent in the RYGB than the SG group (p < 0.04) although the change in femoral vBMD by QCT was not significantly different between groups (p > 0.2). MAT content of the lumbar spine and femoral diaphysis did not change from baseline in the RYGB group but increased after SG (p = 0.03). Within the SG group, 12-month change in weight and VAT were positively associated with 12-month change in MAT (p < 0.04), suggesting that subjects with less weight and VAT loss had higher MAT. In conclusion, RYGB and SG are associated with declines in lumbar spine BMD, however, the changes are not significantly different between the groups. RYGB may be associated with greater decline of aBMD at the total hip and femoral neck compared to SG. MAT content increased after SG and this was associated with lower weight and VAT loss. (C) 2016 Elsevier Inc All rights reserved. C1 [Bredella, Miriam A.; Eajazi, Alireza; Torriani, Martin] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Greenblatt, Logan B.; Yu, Elaine W.] Harvard Med Sch, Massachusetts Gen Hosp, Endocrine Unit, Boston, MA USA. RP Yu, EW (reprint author), Massachusetts Gen Hosp, Endocrine Unit, 50 Blossom St,Thier 1051, Boston, MA 02114 USA. EM ewyu@partners.org OI Greenblatt, Logan/0000-0002-8764-8576 FU National Institutes of Health (NIH) [K23 DK093713, R03DK107869]; Nutrition Obesity Research Center at Harvard [P30-DK040561]; [1UL1TR001102] FX We thank the MGH Musculoskeletal Imaging Research Core for the QCT and 1H-MRS measurements, the MGH Bone Density Center for DXA measurements, the Brigham Research Assay Core for batch laboratory testing, and the nursing and dietary staff of the Mallinckrodt General Clinical Research Center for their dedicated care of the study participants. This work was supported by the National Institutes of Health (NIH) Grants K23 DK093713, R03DK107869, and a pilot grant from the Nutrition Obesity Research Center at Harvard (P30-DK040561). The Clinical Research Center was supported by Grant Number 1UL1TR001102. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources, the National Center for Advancing Translational Science or the National Institutes of Health. NR 42 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 8756-3282 EI 1873-2763 J9 BONE JI Bone PD FEB PY 2017 VL 95 BP 85 EP 90 DI 10.1016/j.bone.2016.11.014 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EI0LD UT WOS:000392165100012 PM 27871812 ER PT J AU Brandt, C Zvolensky, MJ Woods, SP Gonzalez, A Safren, SA O'Cleirigh, CM AF Brandt, Charles Zvolensky, Michael J. Woods, Steven P. Gonzalez, Adam Safren, Steven A. O'Cleirigh, Conall M. TI Anxiety symptoms and disorders among adults living with HIV and AIDS: A critical review and integrative synthesis of the empirical literature SO CLINICAL PSYCHOLOGY REVIEW LA English DT Review ID QUALITY-OF-LIFE; IMMUNODEFICIENCY-VIRUS-INFECTION; ACTIVE ANTIRETROVIRAL THERAPY; INJECTING DRUG-USERS; MENTAL-HEALTH; PSYCHIATRIC-DISORDERS; PSYCHOLOGICAL DISTRESS; MEDICATION ADHERENCE; DEPRESSIVE SYMPTOMS; POSITIVE ADULTS AB There are over 35 million people worldwide infected with the Human Immunodeficiency Virus (HIV) and its progression to Acquired Immunodeficiency Syndrome (AIDS; WHO, 2014). With the advent of combined antiretroviral therapy (i.e., CART) in 1996, persons living with HIV/AIDS (PLWHA) now have much longer life expectancies. However, living with HIV remains challenging, as it is associated with a number of significant and recurrent (chronic) stressors including physical pain, side effects of cART, social stigma, and discrimination, among other social stressors. Presumably, as a result of these types of stressors, a disproportionately high number of PLWHA struggle with clinically-significant psychiatric symptoms and disorders. Although much scientific and clinical attention has focused on depressed mood and psychopathology among PLWHA, there has been comparably less focus on anxiety and its disorders. The paucity of work in this area is concerning from a public health perspective, as anxiety symptoms and disorders are the most common class of psychiatric disorders and often maintain a large negative impact on life functioning. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Brandt, Charles; Zvolensky, Michael J.; Woods, Steven P.] Univ Houston, Dept Psychol, 126 Heyne Bldg, Houston, TX 77204 USA. [Zvolensky, Michael J.] Univ Texas MD Anderson Canc Ctr, Dept Behav Sci, 1515 Holcomb Blvd, Houston, TX 77030 USA. [Gonzalez, Adam] SUNY Stony Brook, Dept Psychiat & Behav Sci, 101 Nicolls Rd, Stony Brook, NY USA. [Safren, Steven A.] Univ Miami, Dept Psychol, 5665 Ponce Leon Blvd, Coral Gables, FL 33124 USA. [O'Cleirigh, Conall M.] Massachusetts Gen Hosp, Dept Psychiat, 1 Bowdoin Sq,Suite 701, Boston, MA 02114 USA. RP Brandt, C (reprint author), Univ Houston, Dept Psychol, 126 Heyne Bldg, Houston, TX 77204 USA. EM cpbrandtl@gmail.com OI Brandt, Charles/0000-0001-5003-1196 FU NIAID NIH HHS [P30 AI073961]; NIMH NIH HHS [F31 MH099922] NR 181 TC 0 Z9 0 U1 72 U2 72 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0272-7358 EI 1873-7811 J9 CLIN PSYCHOL REV JI Clin. Psychol. Rev. PD FEB PY 2017 VL 51 BP 164 EP 184 DI 10.1016/j.cpr.2016.11.005 PG 21 WC Psychology, Clinical SC Psychology GA EI5UE UT WOS:000392559500012 PM 27939443 ER PT J AU Kheirkhah, A Satitpitakul, V Hamrah, P Dana, R AF Kheirkhah, Ahmad Satitpitakul, Vannarut Hamrah, Pedram Dana, Reza TI Patients With Dry Eye Disease and Low Subbasal Nerve Density Are at High Risk for Accelerated Corneal Endothelial Cell Loss SO CORNEA LA English DT Article DE corneal endothelium; corneal subbasal nerves; dry eye disease ID VIVO CONFOCAL MICROSCOPY; IN-VIVO; OCULAR SURFACE; KERATITIS; EPITHELIUM; TRANSPLANTATION; POPULATION; SURVIVAL; VIP; AGE AB Purpose: To evaluate changes in corneal endothelial cell density over time in patients with dry eye disease (DED) and to correlate endothelial cell loss with corneal subbasal nerve density. Methods: This retrospective study included 40 eyes of 20 patients with DED. Laser in vivo confocal microscopy had been performed in the central cornea of both eyes at an initial visit and repeated after a mean follow-up of 33.2 +/- 10.2 months. The densities of corneal endothelial cells and subbasal nerves were measured in both visits and compared with 13 eyes of 13 normal age-matched controls. Results: At the initial visit, the DED group had lower densities of corneal endothelial cells (2620 +/- 386 cells/mm(2)) and subbasal nerves (17.8 +/- 7.5 mm/mm(2)) compared with the control group (2861 +/- 292 cells/mm(2) and 22.8 +/- 3.0 mm/mm(2), with P = 0.08 and P = 0.01, respectively). At the end of follow-up, although there was no significant change in subbasal nerve density (16.7 +/- 7.2 mm/mm(2), P = 0.43), the mean corneal endothelial cell density significantly decreased to 2465 +/- 391 cells/mm(2) (P = 0.01), with a mean corneal endothelial cell loss of 2.1 +/- 3.6% per year. The endothelial cell loss showed a statistically significant negative correlation with the initial subbasal nerve density (Rs = -0.55, P = 0.02). Conclusions: Patients with DED have an accelerated corneal endothelial cell loss compared with that reported in the literature for normal aging. Those with lower subbasal nerve density, in particular, are at a higher risk for endothelial cell loss over time. C1 [Kheirkhah, Ahmad; Satitpitakul, Vannarut; Hamrah, Pedram; Dana, Reza] Harvard Med Sch, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Cornea & Refract Surg Serv, Boston, MA USA. [Satitpitakul, Vannarut] Chulalongkorn Univ, Fac Med, Dept Ophthalmol, Bangkok, Thailand. [Satitpitakul, Vannarut] King Chulalongkorn Mem Hosp, Bangkok, Thailand. [Hamrah, Pedram] Tufts Univ, Sch Med, Tufts Med Ctr, Dept Ophthalmol,Cornea Serv, Boston, MA 02111 USA. [Hamrah, Pedram] Tufts Univ, Sch Med, Tufts Med Ctr, Boston Image Reading Ctr, Boston, MA 02111 USA. RP Dana, R (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM Reza_Dana@meei.harvard.edu FU NEI NIH HHS [K24 EY019098] NR 44 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0277-3740 EI 1536-4798 J9 CORNEA JI Cornea PD FEB PY 2017 VL 36 IS 2 BP 196 EP 201 DI 10.1097/ICO.0000000000001057 PG 6 WC Ophthalmology SC Ophthalmology GA EI2AA UT WOS:000392287100015 PM 28060067 ER PT J AU Rapoport, Y Freeman, T Koyama, T Engelhardt, BG Jagasia, M Savani, BN Tran, U Kassim, AA AF Rapoport, Yuna Freeman, Thomas Koyama, Tatsuki Engelhardt, Brian G. Jagasia, Madan Savani, Bipin N. Tran, Uyen Kassim, Adetola A. TI Validation of International Chronic Ocular Graft-Versus-Host Disease (GVHD) Group Diagnostic Criteria as a Chronic Ocular GVHD-Specific Metric SO CORNEA LA English DT Review DE dry eye disease; chronic ocular GVHD; chronic systemic GVHD; allogeneic hematopoietic cell transplantation ID STEM-CELL TRANSPLANTATION; BONE-MARROW-TRANSPLANTATION; QUALITY-OF-LIFE; TEAR OSMOLARITY; DRY EYE; CONSENSUS GROUP; SURFACE; IMPACT AB Purpose: To validate the International Chronic Ocular GVHD Consensus Group (ICCGVHD) diagnostic criteria for chronic ocular chronic graft-versus-host disease (GVHD), by comparing results with comprehensive ophthalmic evaluation after allogeneic hematopoietic stem cell transplantation. Methods: A single-institution retrospective chart review was conducted on patients who underwent hematopoietic stem cell transplantation at Vanderbilt University Medical Center in Nashville, TN, from January 1, 2002, through April 17, 2014. A total of 344 patients were eligible for the study. Data collected include the Schirmer test score, corneal fluorescein staining, Ocular Surface Disease Index, conjunctival injection, and presence or absence of systemic GVHD. The diagnosis of chronic ocular GVHD in each participant and determination of the overall severity score were determined based on the newly proposed ICCGVHD diagnostic criteria and compared with the best clinical practice (BCP) score. Results: Chronic ocular GVHD was diagnosed in 141/344 (41%) participants, of these, 86 (61%) had complete charts. Based on the BCP score, 1.2% had none, 38.4% mild, 47.7% moderate, and 12.8% had severe chronic ocular GVHD. Based on the ICCGVHD, 34.8% had none, 59.3% mild/moderate, and 5.8% had severe chronic ocular GVHD. The clinical diagnostic stages of chronic ocular GVHD by BCP and ICCGVHD criteria had slight agreement (kappa statistic 0.187, with 95% confidence interval 0.049-0.321), with a higher correlation seen in those with severe chronic ocular GVHD. Conclusions: The newly proposed ICCGVHD diagnostic criteria can be used reproducibly for the diagnosis and determination of severity of chronic ocular GVHD. However, larger prospective studies are needed to further validate it. C1 [Rapoport, Yuna; Tran, Uyen] Vanderbilt Univ, Sch Med, Vanderbilt Eye Inst, Nashville, TN 37212 USA. [Rapoport, Yuna] Massachusetts Gen Hosp, Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. [Freeman, Thomas; Engelhardt, Brian G.; Jagasia, Madan; Savani, Bipin N.; Kassim, Adetola A.] Vanderbilt Univ, Sch Med, Dept Med, Div Hematol Oncol, Nashville, TN 37212 USA. [Koyama, Tatsuki] Vanderbilt Univ, Sch Med, Dept Biostat, Nashville, TN 37212 USA. RP Rapoport, Y (reprint author), Massachusetts Gen Hosp, Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM Yuna.rapoport@gmail.com FU Research to Prevent Blindness, Inc, New York, NY FX Supported in part by an unrestricted departmental grant to the Vanderbilt Eye Institute by Research to Prevent Blindness, Inc, New York, NY. NR 28 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0277-3740 EI 1536-4798 J9 CORNEA JI Cornea PD FEB PY 2017 VL 36 IS 2 BP 258 EP 263 DI 10.1097/ICO.0000000000001109 PG 6 WC Ophthalmology SC Ophthalmology GA EI2AA UT WOS:000392287100024 PM 28060078 ER PT J AU Goligher, EC Ely, EW Sulmasy, DP Bakker, J Raphael, J Volandes, AE Patel, BM Payne, K Hosie, A Churchill, L White, DB Downar, J AF Goligher, Ewan C. Ely, E. Wesley Sulmasy, Daniel P. Bakker, Jan Raphael, John Volandes, Angelo E. Patel, Bhavesh M. Payne, Kate Hosie, Annmarie Churchill, Larry White, Douglas B. Downar, James TI Physician-Assisted Suicide and Euthanasia in the ICU: A Dialogue on Core Ethical Issues SO CRITICAL CARE MEDICINE LA English DT Article DE end of life care; ethics; euthanasia; suicide; assisted ID INTENSIVE-CARE-UNIT; OF-LIFE CARE; CONSCIENTIOUS OBJECTIONS; HASTENING DEATH; PALLIATIVE CARE; CRITICALLY III; END; WITHDRAWAL; STATEMENT; DIGNITY AB Objective : Many patients are admitted to the ICU at or near the end of their lives. Consequently, the increasingly common debate regarding physician-assisted suicide and euthanasia holds implications for the practice of critical care medicine. The objective of this article is to explore core ethical issues related to physician assisted suicide and euthanasia from the perspective of health-care professionals and ethicists on both sides of the debate. Synthesis: We identified four issues highlighting the key areas of ethical tension central to evaluating physician-assisted suicide and euthanasia in medical practice: 1) the benefit or harm of death itself, 2) the relationship between physician-assisted suicide and euthanasia and withholding or withdrawing life support, 3) the morality of a physician deliberately causing death, and 4) the management of conscientious objection related to physician-assisted suicide and euthanasia in the critical care setting. We present areas of common ground and important unresolved differences. Conclusions: We reached differing positions on the first three core ethical questions and achieved unanimity on how critical care clinicians should manage conscientious objections related to physician-assisted suicide and euthanasia. The alternative positions presented in this article may serve to promote open and informed dialogue within the critical care community. C1 [Goligher, Ewan C.; Downar, James] Univ Toronto, Interdept Div Crit Care Med, Toronto, ON, Canada. [Goligher, Ewan C.; Downar, James] Univ Hlth Network, Dept Med, Div Respirol, Toronto, ON, Canada. [Goligher, Ewan C.; Downar, James] Mt Sinai Hosp, Toronto, ON, Canada. [Goligher, Ewan C.] Univ Toronto, Dept Physiol, Toronto, ON, Canada. [Ely, E. Wesley] Vanderbilt Univ, Sch Med, Dept Med, Div Allergy Pulm & Crit Care Med, Nashville, TN 37212 USA. [Ely, E. Wesley] Vanderbilt Univ, Sch Med, Dept Med, Ctr Hlth Serv Res, Nashville, TN 37212 USA. [Ely, E. Wesley] Vet Affairs Tennessee Valley Healthcare Syst, GRECC, Nashville, TN 37212 USA. [Sulmasy, Daniel P.] Univ Chicago, Dept Med, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Sulmasy, Daniel P.] Univ Chicago, Divin Sch, Chicago, IL 60637 USA. [Sulmasy, Daniel P.] Univ Chicago, MacLean Ctr Clin Med Eth, Chicago, IL 60637 USA. [Bakker, Jan] Univ Med Ctr, Erasmus MC, Dept Intens Care, Rotterdam, Netherlands. [Bakker, Jan] Columbia Univ, Div Pulm Allergy & Crit Care Med, Med Ctr, New York, NY USA. [Bakker, Jan] Pontificia Univ Catolica Chile, Dept Med Intens, Fac Med, Santiago, Chile. [Raphael, John] St Thomas West Hosp, Dept Pastoral Care, Nashville, TN USA. [Volandes, Angelo E.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Patel, Bhavesh M.] Mayo Clin, Dept Crit Care Med, Phoenix, AZ USA. [Payne, Kate; Churchill, Larry] Vanderbilt Univ, Med Ctr, Ctr Biomed Eth & Soc, Nashville, TN USA. [Payne, Kate] Vanderbilt Univ, Sch Nursing, Nashville, TN 37240 USA. [Hosie, Annmarie] Univ Notre Dame Australia, Sch Nursing, Sydney, NSW, Australia. [Hosie, Annmarie] Univ Technol Sydney, Fac Hlth, Sydney, NSW, Australia. [Downar, James] Univ Pittsburgh, Sch Med, Dept Crit Care Med, Program Eth & Decis Making Crit Illness, Pittsburgh, PA USA. [Downar, James] Univ Toronto, Dept Family & Community Med, Div Palliat Care, Toronto, ON, Canada. RP Ely, EW (reprint author), Vanderbilt Univ, Sch Med, Dept Med, Div Allergy Pulm & Crit Care Med, Nashville, TN 37212 USA.; Ely, EW (reprint author), Vanderbilt Univ, Sch Med, Dept Med, Ctr Hlth Serv Res, Nashville, TN 37212 USA.; Ely, EW (reprint author), Vet Affairs Tennessee Valley Healthcare Syst, GRECC, Nashville, TN 37212 USA. EM wes.ely@vanderbilt.edu OI Hosie, Annmarie/0000-0003-1674-2124 FU National Institutes of Health (NIH); Veterans Affairs (VA); NIH; VA FX Dr. Ely received support for article research from the National Institutes of Health (NIH) and Veterans Affairs (VA) funding and VA awards. His institution received funding from the NIH and VA funding and VA awards: Dr. Payne received funding from Alive Hospice, Ethics Consultant Group, and Northwest Organization of Nurse Executives. Dr. Downar disclosed other (he is a member of the Physician's Advisory Committee of Dying with Dignity Canada, a not-for-profit that worked toward the legalization of assisted death in Canada). The remaining authors have disclosed that they do not have any potential conflicts of interest. NR 32 TC 1 Z9 1 U1 61 U2 61 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD FEB PY 2017 VL 45 IS 2 BP 149 EP 155 DI 10.1097/CCM.0000000000001818 PG 7 WC Critical Care Medicine SC General & Internal Medicine GA EI4LF UT WOS:000392464500001 PM 28098622 ER PT J AU Artis, KA Dyer, E Mohan, V Gold, JA AF Artis, Kathryn A. Dyer, Edward Mohan, Vishnu Gold, Jeffrey A. TI Accuracy of Laboratory Data Communication on ICU Daily Rounds Using an Electronic Health Record SO CRITICAL CARE MEDICINE LA English DT Article DE attending rounds; communication; critical care; electronic health record; intensive care unit ID INTENSIVE-CARE-UNIT; DIAGNOSTIC ERRORS; MEDICAL-RECORD; INFORMATION; MORTALITY; SAFETY; IMPLEMENTATION; PARTICIPATION; SIMULATION; EVENTS AB Objectives: Accurately communicating patient data during daily ICU rounds is critically important since data provide the basis for clinical decision making. Despite its importance, high fidelity data communication during interprofessional ICU rounds is assumed, yet unproven. We created a robust but simple methodology to measure the prevalence of inaccurately communicated (misrepresented) data and to characterize data communication failures by type. We also assessed how commonly the rounding team detected data misrepresentation and whether data communication was impacted by environmental, human, and workflow factors. Design: Direct observation of verbalized laboratory data during daily ICU rounds compared with data within the electronic health record and on presenters' paper prerounding notes. Setting: Twenty-six-bed academic medical ICU with a well-established electronic health record. Subjects: ICU rounds presenter (medical student or resident physician), interprofessional rounding team. Interventions: None. Measurements and Main Results: During 301 observed patient presentations including 4,945 audited laboratory results, present. ers used a paper prerounding tool for 94.3% of presentations but tools contained only 78% of available electronic health record laboratory data. Ninty-six percent of patient presentations included at least one laboratory misrepresentation (mean, 6.3 per patient) and 38.9% of all audited laboratory data were inaccurately communicated. Most misrepresentation events were omissions. Only 7.8% of all laboratory misrepresentations were detected. Conclusion: Despite a structured interprofessional rounding script and a well-established electronic health record, clinician laboratory data retrieval and communication during ICU rounds at our institution was poor, prone to omissions and inaccuracies, yet largely unrecognized by the rounding team. This highlights an important patient safety issue that is likely widely prevalent, yet underrecognized. C1 [Artis, Kathryn A.; Dyer, Edward; Gold, Jeffrey A.] Oregon Hlth & Sci Univ, Dept Med, Div Pulm & Crit Care Med, Portland, OR 97201 USA. [Artis, Kathryn A.] Portland VA Med Ctr, Sect Pulm & Crit Care Med, Div Hosp & Specialty Care, Portland, OR USA. [Mohan, Vishnu] Oregon Hlth & Sci Univ, Dept Med Informat & Clin Epidemiol, Portland, OR 97201 USA. RP Artis, KA (reprint author), Oregon Hlth & Sci Univ, Dept Med, Div Pulm & Crit Care Med, Portland, OR 97201 USA.; Artis, KA (reprint author), Portland VA Med Ctr, Sect Pulm & Crit Care Med, Div Hosp & Specialty Care, Portland, OR USA. EM artisk@ohsu.edu FU Agency for Healthcare Research and Quality (AHRQ) [R18 HS021367]; AHRQ FX Supported, in part, by Agency for Healthcare Research and Quality (AHRQ) R18 HS021367, AHRQ R01.; Dr. Artis disclosed other support from the Agency for Healthcare Research and Quality (AHRQ). Her institution received funding from the AHRQ. Dr. Mohan's institution received funding from the AHRQ. Dr. Gold's institution received funding from the AHRQ. Dr. Dyer has disclosed that he does not have any potential conflicts of interest. NR 37 TC 1 Z9 1 U1 5 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD FEB PY 2017 VL 45 IS 2 BP 179 EP 186 DI 10.1097/CCM.0000000000002060 PG 8 WC Critical Care Medicine SC General & Internal Medicine GA EI4LF UT WOS:000392464500005 PM 27655323 ER PT J AU Jolley, SE Moss, M Needham, DM Caldwell, E Morris, PE Miller, RR Ringwood, N Anders, M Koo, KK Gundel, SE Parry, SM Hough, CL AF Jolley, Sarah Elizabeth Moss, Marc Needham, Dale M. Caldwell, Ellen Morris, Peter E. Miller, Russell R. Ringwood, Nancy Anders, Megan Koo, Karen K. Gundel, Stephanie E. Parry, Selina M. Hough, Catherine L. CA Acute Resp Distress Syndrome TI Point Prevalence Study of Mobilization Practices for Acute Respiratory Failure Patients in the United States SO CRITICAL CARE MEDICINE LA English DT Article DE early mobility; intensive care unit acquired weakness; intensive care unit rehabilitation ID INTENSIVE-CARE-UNIT; ACUTE LUNG INJURY; CRITICALLY-ILL PATIENTS; PHYSICAL-THERAPY; EARLY MOBILITY; CRITICAL ILLNESS; ICU; REHABILITATION; DISABILITY; OUTCOMES AB Objective: Early mobility in mechanically ventilated patients is safe, feasible, and may improve functional outcomes. We sought to determine the prevalence and character of mobility for ICU patients with acute respiratory failure in U.S. ICUs. Design: Two-day cross-sectional point prevalence study. Setting: Forty-two ICUs across 17 Acute Respiratory Distress Syndrome Network hospitals. Patients: Adult patients (>= 18 yr old) with acute respiratory failure requiring mechanical ventilation. Interventions: We defined therapist-provided mobility as the proportion of patient-days with any physical or occupational therapy provided mobility event. Hierarchical regression models were used to identify predictors of out-of-bed mobility. Measurements and Maln Results: Hospitals contributed 770 patient-days of data. Patients received mechanical ventilation on 73% of the patient-days mostly (n = 432; 56%) ventilated via an endotracheal tube. The prevalence of physical therapy/occupational therapy provided mobility was 32% (247/770), with a significantly higher proportion of nonmechanically ventilated patients receiving physical therapy/occupational therapy (48% vs 26%; p <= 0.001). Patients on mechanical ventilation achieved out-of-bed mobility on 16% (n = 90) of the total patient-days. Physical therapy/occupational therapy involvement in mobility events was strongly associated with progression to out-of-bed mobility (odds ratio, 29.1; CI, 15.1-56.3; p <= 0.001). Presence of an endotracheal tube and delirium were negatively associated with out-of-bed mobility. Conclusions: In a cohort of hospitals caring for acute respiratory failure patients, physical therapy/occupational therapy provided mobility was infrequent. Physical therapy/occupational therapy involvement in mobility was strongly predictive of achieving greater mobility levels in patients with respiratory failure. Mechanical ventilation via an endotracheal tube and delirium are important predictors of mobility progression. C1 [Jolley, Sarah Elizabeth] Louisiana State Univ, Hlth Sci Ctr, Dept Med, Sect Pulm & Crit Care Med, New Orleans, LA 70112 USA. [Moss, Marc] Univ Colorado, Dept Med, Div Pulm & Crit Care Med, Boulder, CO 80309 USA. [Needham, Dale M.] Johns Hopkins Univ, Div Pulm & Crit Care Med, Dept Phys Med & Rehabil, Baltimore, MD USA. [Caldwell, Ellen; Gundel, Stephanie E.; Hough, Catherine L.] Univ Washington, Dept Med, Div Pulm & Crit Care Med, Seattle, WA USA. [Morris, Peter E.] Wake Forest Univ, Dept Med, Div Pulm & Crit Care Med, Winston Salem, NC 27109 USA. [Miller, Russell R.] Univ Utah, Dept Med, Div Pulm & Crit Care Med, Intermt Hosp, Salt Lake City, UT 84112 USA. [Ringwood, Nancy] Massachusetts Gen Hosp, Dept Med, Div Pulm & Crit Care Med, Boston, MA 02114 USA. [Anders, Megan] Univ Maryland, Dept Anesthesiol, College Pk, MD 20742 USA. [Koo, Karen K.] Swedish Med Ctr, Seattle, WA USA. [Parry, Selina M.] Univ Melbourne, Dept Physiotherapy, Melbourne, Vic, Australia. RP Jolley, SE (reprint author), Louisiana State Univ, Hlth Sci Ctr, Dept Med, Sect Pulm & Crit Care Med, New Orleans, LA 70112 USA. EM sjolle@lsuhsc.edu OI Parry, Selina/0000-0003-2204-3143; Anders, Megan/0000-0001-5962-4377 FU National Institute of General Medical Sciences of the National Institutes of Health [1 U54 GM104940]; Lyric Pharmaceuticals; National Institutes of Health (NIH); NIH; National Heart, Lung, and Blood Institute (NHLBI); NHLBI; NIH NHLBI FX Supported, in part, by grant 1 U54 GM104940 from the National Institute of General Medical Sciences of the National Institutes of Health which funds the Louisiana Clinical and Translational Science Center (to Dr. Jolley). Dr. Jolley, Dr. Moss, Dr. Needham, Ms. Caldwell, Dr. Morris, Dr. Miller, Dr. Ringwood, Dr. Koo, Dr. Gundel, Dr. Parry, and Dr. Hough on this study received funding for this work (NIH/non-industry). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.; Dr. Jolley received funding from Lyric Pharmaceuticals, received support for article research from the National Institutes of Health (NIH), and disclosed travel for protocol development meeting for Lyric Pharmaceuticals for work unrelated to this article. Dr. Moss received support for article research from the NIH. Dr. Needham received support for article research from the NIH. His institution received funding from the National Heart, Lung, and Blood Institute (NHLBI). Dr. Ringwood received support for article research from the NIH. Her institution received funding from the NHLBI. Dr. Anders disclosed other support. Dr. Hough received support for article research from the NIH. Her institution received funding from the NIH NHLBI. The remaining authors have disclosed that they do not have any potential conflicts of interest. NR 27 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD FEB PY 2017 VL 45 IS 2 BP 205 EP 215 DI 10.1097/CCM.0000000000002058 PG 11 WC Critical Care Medicine SC General & Internal Medicine GA EI4LF UT WOS:000392464500008 PM 27661864 ER PT J AU Villar, J Kacmarek, RM AF Villar, Jesus Kacmarek, Robert M. TI Oxygen: Breath of Life or Kiss of Death SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE hyperoxemia; hyperoxia; mechanical ventilation; outcome ID ARTERIAL HYPEROXIA; ASSOCIATION; THERAPY C1 [Villar, Jesus] Inst Salud Carlos III, CIBER Enfermedades Resp, Madrid, Spain. [Villar, Jesus] Hosp Univ Dr Negrin, Multidisciplinary Organ Dysfunct Evaluat Res Netw, Res Unit, Las Palmas Gran Canaria, Spain. [Kacmarek, Robert M.] Harvard Univ, Massachusetts Gen Hosp, Dept Resp Care, Boston, MA 02115 USA. [Kacmarek, Robert M.] Harvard Univ, Massachusetts Gen Hosp, Dept Anesthesiol, Boston, MA 02115 USA. RP Villar, J (reprint author), Inst Salud Carlos III, CIBER Enfermedades Resp, Madrid, Spain.; Villar, J (reprint author), Hosp Univ Dr Negrin, Multidisciplinary Organ Dysfunct Evaluat Res Netw, Res Unit, Las Palmas Gran Canaria, Spain. FU Institute de Salud Carlos III [CB06/06/1088, PI13/0119]; Asociacion Cientifica Pulmon y Ventilacion Mecanica; Maquet; Venner Medical; Covidien; Venner Medica FX Supported, in part, by Institute de Salud Carlos III (CB06/06/1088, PI13/0119) and Asociacion Cientifica Pulmon y Ventilacion Mecanica. Dr. Villar has received a research grant from Maquet. Dr. Kacmarek has received research grants from Venner Medical and Covidien and is a consultant for Covidien and Orange Med. His institution received funding from Covidien and from Venner Medica. NR 14 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD FEB PY 2017 VL 45 IS 2 BP 368 EP 369 DI 10.1097/CCM.0000000000002113 PG 2 WC Critical Care Medicine SC General & Internal Medicine GA EI4LF UT WOS:000392464500030 PM 28098637 ER PT J AU Rasmusson, AM AF Rasmusson, Ann M. TI The gut peptide neuropeptide Y and post-traumatic stress disorder SO CURRENT OPINION IN ENDOCRINOLOGY DIABETES AND OBESITY LA English DT Review DE ghrelin; irritable bowel syndrome; neuropeptide Y; post-traumatic stress disorder; visceral pain ID CORTICOTROPIN-RELEASING-FACTOR; IRRITABLE-BOWEL-SYNDROME; ALPHA(2C)-ADRENORECEPTOR GENE POLYMORPHISM; ANXIOLYTIC-LIKE ACTION; CHRONIC PAIN; MEMORY CONSOLIDATION; METABOLIC SYNDROME; FACTOR RECEPTORS; TRAUMA EXPOSURE; HORMONE-LEVELS AB Purpose of review This article reviews the role of neuropeptide Y (NPY) in the pathophysiology of post-traumatic stress disorder (PTSD) and gastrointestinal disorders such as irritable bowel syndrome (IBS) with which PTSD is highly comorbid. NPY is low in the cerebrospinal fluid and plasma of male combat veterans with PTSD and correlates negatively with sympathetic nervous system (SNS) hyperreactivity, PTSD symptoms and time to recovery. NPY regulation has not yet been evaluated in women with PTSD. Recent findings NPY levels in bowel tissue are low in IBS with diarrhea (IBS-D) versus IBS with constipation. The density of ghrelin containing cells of the gastric oxyntic mucosa is markedly increased in IBS-D. PTSD-relareleaseted SNS hyperreactivity may interact with this substrate to increase ghrelin , which activates receptors in the lumbosacral spinal cord and basolateral amygdala to increase colonic motility and amygdala hyperreactivity, respectively. Loss of function gene polymorphisms in adrenergic alpha(2)-autoreceptors and increased corticotropin-releasing hormone, as observed in PTSD, are also thought to contribute to IBS-D. Summary Knowledge of shared underlying NPY system-related neurobiological factors that contribute to the comorbidity of PTSD and gastrointestinal disorders may help guide research, development and prescription of targeted and more effective individualized therapeutic interventions. C1 [Rasmusson, Ann M.] US Dept Vet Affairs, Natl Ctr PTSD, Womens Hlth Sci Div, Boston, MA USA. [Rasmusson, Ann M.] VA Boston Healthcare Syst, Boston, MA USA. [Rasmusson, Ann M.] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Rasmusson, AM (reprint author), Boston Univ, Sch Med, Boston, MA 02118 USA. EM ann.rasmusson@va.gov FU National Center for PTSD; Women's Health Science Division; Department of Veterans Affairs; VA Boston Healthcare System FX National Center for PTSD, Women's Health Science Division, Department of Veterans Affairs and VA Boston Healthcare System. NR 90 TC 0 Z9 0 U1 4 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1752-296X EI 1752-2978 J9 CURR OPIN ENDOCRINOL JI Curr. Opin. Endocrinol. Diabetes Obes. PD FEB PY 2017 VL 24 IS 1 BP 3 EP 8 DI 10.1097/MED.0000000000000301 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EI0NS UT WOS:000392171800003 PM 27898588 ER PT J AU Levitsky, LL AF Levitsky, Lynne L. TI Growth, metabolism, genetics, and the environment - Alice was not a scientist SO CURRENT OPINION IN ENDOCRINOLOGY DIABETES AND OBESITY LA English DT Editorial Material C1 [Levitsky, Lynne L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Levitsky, LL (reprint author), Harvard Med Sch, Pediat, 175 Cambridge St,5th Floor, Boston, MA 02114 USA.; Levitsky, LL (reprint author), Massachusetts Gen Hosp, Pediat Endocrinol, 175 Cambridge St,5th Floor, Boston, MA 02114 USA. EM Lynne.Levitsky@mgh.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1752-296X EI 1752-2978 J9 CURR OPIN ENDOCRINOL JI Curr. Opin. Endocrinol. Diabetes Obes. PD FEB PY 2017 VL 24 IS 1 BP 31 EP 32 DI 10.1097/MED.0000000000000304 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EI0NS UT WOS:000392171800007 PM 27870641 ER PT J AU Shoemaker, AH Juppner, H AF Shoemaker, Ashley H. Juppner, Harald TI Nonclassic features of pseudohypoparathyroidism type 1A SO CURRENT OPINION IN ENDOCRINOLOGY DIABETES AND OBESITY LA English DT Review DE Albright Hereditary Osteodystrophy; GNAS; hormone resistance; pseudohypoparathyroidism ID OBSTRUCTIVE SLEEP-APNEA; SPINAL-CORD COMPRESSION; ALBRIGHT HEREDITARY OSTEODYSTROPHY; I PSEUDOHYPOPARATHYROIDISM; NEUROCOGNITIVE FUNCTION; OLFACTORY DYSFUNCTION; INCREASED PREVALENCE; HORMONE RESISTANCE; PDE4D MUTATIONS; OBESE CHILDREN AB Purpose of review To provide readers with a review of contemporary literature describing the evolving understanding of the pseudohypoparathyroidism type 1A (PHP1A) phenotype. Recent findings The classic features of PHP1A include multihormone resistance and the Albright Hereditary Osteodystrophy phenotype (round facies, short stature, subcutaneous ossifications, brachydactyly, and early-onset obesity. Obesity may be because of a decrease in resting energy expenditure because most patients do not report significant hyperphagia. Patients with PHP1A have an increased risk of type 2 diabetes. In addition to brachydactyly and short stature, orthopedic complications can include spinal stenosis and carpal tunnel syndrome. Hearing loss, both sensorineural and conductive, has been reported in PHP1A. In addition, ear-nose-throat findings include decreased olfaction and frequent otitis media requiring tympanostomy tubes. Sleep apnea was shown to be 4.4-fold more common in children with PHP1A compared with other obese children; furthermore, asthma-like symptoms have been reported. These new findings are likely multifactorial and further research is needed to better understand these nonclassic features of PHP1A. Summary Along with the Albright Hereditary Osteodystrophy phenotype and hormone resistance, patients with PHP1A may have additional skeletal, metabolic, ear-nose-throat, and pulmonary complications. Understanding these nonclassic features will help improve clinical care of patients with PHP1A. C1 [Shoemaker, Ashley H.] Vanderbilt Univ, Div Pediat Endocrinol, 221 Kirkland Hall, Nashville, TN 37235 USA. [Juppner, Harald] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Juppner, Harald] Massachusetts Gen Hosp, Pediat Nephrol Unit, Boston, MA 02114 USA. [Juppner, Harald] Harvard Med Sch, Boston, MA USA. RP Shoemaker, AH (reprint author), 2200 Childrens Way,DOT Room 11133, Nashville, TN 37232 USA. EM Ashley.H.Shoemaker@vanderbilt.edu FU NIH from the National Institute of Diabetes, Digestive and Kidney Diseases [K23DK101689, RO1 DK46718] FX This work was supported by the NIH grants K23DK101689 (to A.H.S.) and RO1 DK46718 (to H.J.) from the National Institute of Diabetes, Digestive and Kidney Diseases. NR 71 TC 0 Z9 0 U1 11 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1752-296X EI 1752-2978 J9 CURR OPIN ENDOCRINOL JI Curr. Opin. Endocrinol. Diabetes Obes. PD FEB PY 2017 VL 24 IS 1 BP 33 EP 38 DI 10.1097/MED.0000000000000306 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EI0NS UT WOS:000392171800008 PM 27875418 ER PT J AU Isganaitis, E Suehiro, H Cardona, C AF Isganaitis, Elvira Suehiro, Harumi Cardona, Connie TI Who's your daddy?: paternal inheritance of metabolic disease risk SO CURRENT OPINION IN ENDOCRINOLOGY DIABETES AND OBESITY LA English DT Review DE epigenetics; germ cells; intergenerational; obesity; paternal ID BODY-MASS INDEX; IN-UTERO UNDERNUTRITION; PRIMORDIAL GERM-CELLS; SLOW GROWTH PERIOD; LIFE-STYLE FACTORS; HIGH-FAT DIET; DNA METHYLATION; GENE-EXPRESSION; EPIGENETIC INHERITANCE; GLUCOSE-INTOLERANCE AB Purpose of review Although the importance of optimizing mothers' health prior to conception and during pregnancy is now well accepted, recent data also implicate health and nutritional status of fathers as contributors to chronic disease risk in their progeny. This brief review will highlight recent epidemiological and experimental studies linking paternal overnutrition, undernutrition, and other forms of stress, to metabolic disease in the offspring. Recent findings The past 2 years have brought tremendous insights into the mechanisms by which paternal exposures can contribute to disease susceptibility in the next generation. Recent data, both from humans and experimental models, demonstrate that paternal obesity and undernutrition result in epigenetic reprogramming of male germ cells, notably altered DNA methylation, histone retention, and expression of small noncoding RNAs and transfer RNA fragments. Novel mechanisms have also been identified, such as epididymal transport vesicles, seminal fluid hormones and metabolites, and a unique seminal fluid microbiome. Summary Paternal nutritional and other perturbations are linked to risk of metabolic disease and obesity in offspring. Germ cell-dependent mechanisms have recently been linked to these intergenerational effects. Nongenetic, paternal inheritance of chronic disease has important implications for public health, and may provide novel opportunities for multigenerational disease prevention. C1 [Isganaitis, Elvira; Suehiro, Harumi; Cardona, Connie] Joslin Diabet Ctr, Div Res, One Joslin Pl Room 607, Boston, MA 02215 USA. RP Isganaitis, E (reprint author), Joslin Diabet Ctr, Div Res, One Joslin Pl Room 607, Boston, MA 02215 USA. EM Elvira.Isganaitis@joslin.harvard.edu FU Pediatric Division at Joslin Diabetes Center FX E.I.'s time and effort were supported by the Pediatric Division at Joslin Diabetes Center. NR 92 TC 0 Z9 0 U1 14 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1752-296X EI 1752-2978 J9 CURR OPIN ENDOCRINOL JI Curr. Opin. Endocrinol. Diabetes Obes. PD FEB PY 2017 VL 24 IS 1 BP 47 EP 55 DI 10.1097/MED.0000000000000307 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EI0NS UT WOS:000392171800011 PM 27906710 ER PT J AU Mitchell, DM AF Mitchell, Deborah M. TI Growth in patients with type 1 diabetes SO CURRENT OPINION IN ENDOCRINOLOGY DIABETES AND OBESITY LA English DT Review DE growth; insulin-like growth factor 1; Mauriac syndrome; type 1 diabetes ID LONGITUDINAL BONE-GROWTH; BETA-CELL FUNCTION; GLYCEMIC CONTROL; MAURIAC-SYNDROME; FACTOR-I; ISLET AUTOIMMUNITY; METABOLIC-CONTROL; EXCESS MORTALITY; MINERAL DENSITY; EARLY-CHILDHOOD AB Purpose of review As the incidence of type 1 diabetes (T1DM) continues to rise, complications including impairment of childhood growth remain a major concern. This review provides an overview of alterations in growth patterns before and after the onset of T1DM. Recent findings Recent advances in this field include several prospective investigations of height and weight trajectories in children leading up to the development of islet autoimmunity and T1DM as well as evaluations of larger cohorts of T1DM patients to better assess predictors of altered growth. In addition, genetic and metabolic investigations have improved our understanding of the more rare severe growth impairment of Mauriac Syndrome. Summary Despite advances in medical care of children with T1DM, growth remains suboptimal in this population and likely reflects ongoing metabolic derangement linked with classic microvascular diabetic complications. C1 [Mitchell, Deborah M.] Massachusetts Gen Hosp, Endocrine Unit, 50 Blossom St, Boston, MA 02114 USA. [Mitchell, Deborah M.] Massachusetts Gen Hosp, Pediat Endocrine Unit, Boston, MA 02114 USA. RP Mitchell, DM (reprint author), Massachusetts Gen Hosp, Endocrine Unit, 50 Blossom St, Boston, MA 02114 USA. EM dmmitchell@partners.org OI Mitchell, Deborah/0000-0003-0364-9107 FU NIH [K23DK105350] FX This work was supported by NIH grant K23DK105350. NR 77 TC 0 Z9 0 U1 7 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1752-296X EI 1752-2978 J9 CURR OPIN ENDOCRINOL JI Curr. Opin. Endocrinol. Diabetes Obes. PD FEB PY 2017 VL 24 IS 1 BP 67 EP 72 DI 10.1097/MED.0000000000000310 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EI0NS UT WOS:000392171800013 PM 27898589 ER PT J AU Gootenberg, DB Paer, JM Luevano, JM Kwon, DS AF Gootenberg, David B. Paer, Jeffrey M. Luevano, Jesus-Mario Kwon, Douglas S. TI HIV-associated changes in the enteric microbial community: potential role in loss of homeostasis and development of systemic inflammation SO CURRENT OPINION IN INFECTIOUS DISEASES LA English DT Review DE developing world; HIV; enteric; microbiome; systemic inflammation; virome ID HUMAN-IMMUNODEFICIENCY-VIRUS; T-CELL-ACTIVATION; CLOSTRIDIUM-DIFFICILE INFECTION; COMBINATION ANTIRETROVIRAL THERAPY; ACUTE MYOCARDIAL-INFARCTION; HUMAN GUT MICROBIOTA; IMMUNE ACTIVATION; BOWEL-DISEASE; INTESTINAL MICROBIOTA; GASTROINTESTINAL-TRACT AB Purpose of review Despite HIV therapy advances, average life expectancy in HIV-infected individuals on effective treatment is significantly decreased relative to uninfected persons, largely because of increased incidence of inflammation-related diseases, such as cardiovascular disease and renal dysfunction. The enteric microbial community could potentially cause this inflammation, as HIV-driven destruction of gastrointestinal CD4(+) T cells may disturb the microbiota-mucosal immune system balance, disrupting the stable gut microbiome and leading to further deleterious host outcomes. Recent findings Varied enteric microbiome changes have been reported during HIV infection, but unifying patterns have emerged. Community diversity is decreased, similar to pathologies such as inflammatory bowel disease, obesity, and Clostridium difficile infection. Many taxa frequently enriched in HIV-infected individuals, such as Enterobacteriaceae and Erysipelotrichaceae, have pathogenic potential, whereas depleted taxa, such as Bacteroidaceae and Ruminococcaceae, are more linked with anti-inflammatory properties and maintenance of gut homeostasis. The gut viral community in HIV has been found to contain a greater abundance of pathogenesis-associated Adenoviridae and Anelloviridae. These bacterial and viral changes correlate with increased systemic inflammatory markers, such as serum sCD14, sCD163, and IL-6. Summary Enteric microbial community changes may contribute to chronic HIV pathogenesis, but more investigation is necessary, especially in the developing world population with the greatest HIV burden (Video, Supplemental Digital Content 1, http://links.lww.com/COID/A15, which includes the authors' summary of the importance of the work). C1 [Gootenberg, David B.; Paer, Jeffrey M.; Luevano, Jesus-Mario; Kwon, Douglas S.] Massachusetts Gen Hosp, Ragon Inst MGH MIT & Harvard, Cambridge, MA USA. [Gootenberg, David B.; Luevano, Jesus-Mario; Kwon, Douglas S.] Harvard Med Sch, Boston, MA USA. [Kwon, Douglas S.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. RP Kwon, DS (reprint author), 400 Technol Sq,Room 892, Cambridge, MA 02139 USA. EM dkwon@mgh.harvard.edu FU NIH (NIDDK); NIH (NIAID); Burroughs Wellcome Fund FX Funding received from NIH (NIDDK and NIAID), and the Burroughs Wellcome Fund. NR 208 TC 1 Z9 1 U1 10 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0951-7375 EI 1473-6527 J9 CURR OPIN INFECT DIS JI Curr. Opin. Infect. Dis. PD FEB PY 2017 VL 30 IS 1 BP 31 EP 43 DI 10.1097/QCO.0000000000000341 PG 13 WC Infectious Diseases SC Infectious Diseases GA EI0NN UT WOS:000392171300005 PM 27922852 ER PT J AU Skyler, JS Bakris, GL Bonifacio, E Darsow, T Eckel, RH Groop, L Groop, PH Handelsman, Y Insel, RA Mathieu, C McElvaine, AT Palmer, JP Pugliese, A Schatz, DA Sosenko, JM Wilding, JPH Ratner, RE AF Skyler, Jay S. Bakris, George L. Bonifacio, Ezio Darsow, Tamara Eckel, Robert H. Groop, Leif Groop, Per-Henrik Handelsman, Yehuda Insel, Richard A. Mathieu, Chantal McElvaine, Allison T. Palmer, Jerry P. Pugliese, Alberto Schatz, Desmond A. Sosenko, Jay M. Wilding, John P. H. Ratner, Robert E. TI Differentiation of Diabetes by Pathophysiology, Natural History, and Prognosis SO DIABETES LA English DT Article ID BETA-CELL FUNCTION; TRIAL-TYPE 1; IMPAIRED GLUCOSE-TOLERANCE; PLACEBO-CONTROLLED TRIAL; RANDOMIZED CONTROLLED-TRIAL; COTRANSPORTER 2 INHIBITOR; LIFE-STYLE INTERVENTION; ISLET AUTOIMMUNITY; GLYCEMIC CONTROL; KIDNEY-DISEASE AB The American Diabetes Association, JDRF, the European Association for the Study of Diabetes, and the American Association of Clinical Endocrinologists convened a research symposium, "The Differentiation of Diabetes by Pathophysiology, Natural History and Prognosis" on 10-12 October 2015. International experts in genetics, immunology, metabolism, endocrinology, and systems biology discussed genetic and environmental determinants of type 1 and type 2 diabetes risk and progression, as well as complications. The participants debated how to determine appropriate therapeutic approaches based on disease pathophysiology and stage and defined remaining research gaps hindering a personalized medical approach for diabetes to drive the field to address these gaps. The authors recommend a structure for data stratification to define the phenotypes and genotypes of subtypes of diabetes that will facilitate individualized treatment. C1 [Skyler, Jay S.; Pugliese, Alberto] Univ Miami, Miller Sch Med, Diabet Res Inst, Miami, FL 33136 USA. [Bakris, George L.] Univ Chicago Med, Chicago, IL USA. [Bonifacio, Ezio] Tech Univ Dresden, Dresden, Germany. [Darsow, Tamara; McElvaine, Allison T.; Ratner, Robert E.] Amer Diabet Assoc, Arlington, VA 22202 USA. [Eckel, Robert H.] Univ Colorado, Anschutz Med Campus, Aurora, CO USA. [Groop, Leif] Lund Univ, Skane Univ Hosp, Malmo, Sweden. [Groop, Per-Henrik] Univ Helsinki, Abdominal Ctr Nephrol, Helsinki, Finland. [Groop, Per-Henrik] Helsinki Univ Hosp, Helsinki, Finland. [Groop, Per-Henrik] Folkhalsan Res Ctr, Folkhalsan Inst Genet, Helsinki, Finland. [Groop, Per-Henrik] Baker IDI Heart & Diabet Inst, Melbourne, Vic, Australia. [Handelsman, Yehuda] Metab Inst Amer, Tarzana, CA USA. [Insel, Richard A.] JDRF, New York, NY USA. [Mathieu, Chantal] Katholieke Univ Leuven, Leuven, Belgium. [Palmer, Jerry P.] Univ Washington, Seattle, WA 98195 USA. [Palmer, Jerry P.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Schatz, Desmond A.] Univ Florida, Coll Med, Gainesville, FL USA. [Sosenko, Jay M.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Wilding, John P. H.] Aintree Univ Hosp NHS Fdn Trust, Liverpool, Merseyside, England. RP McElvaine, AT (reprint author), Amer Diabet Assoc, Arlington, VA 22202 USA. EM amcelvaine@diabetes.org RI Wilding, John/A-7106-2008; Bonifacio, Ezio/E-7700-2010 OI Wilding, John/0000-0003-2839-8404; Bonifacio, Ezio/0000-0002-8704-4713 FU Novo Nordisk Inc. FX The authors gratefully acknowledge the Differentiation of Diabetes by Pathophysiology, Natural History and Prognosis research symposium steering committee members and speakers for the excellent presentations, discussions, and contributions to the conference. J.S.S., G.L.B., E.B., R.H.E., L.G., P.-H.G., R.A.I., C.M., J.P.P., A.P., D.A.S., J.M.S., J.P.H.W., and R.E.R. were presenters. Other faculty included Michael Bergman, New York University School of Medicine; Barbara E. Corkey, Boston University School of Medicine; James R. Gavin III, Emory University School of Medicine; Stanley Schwartz, University of Pennsylvania; and Kumar Sharma, University of California at San Diego. The conference was supported in part by an unrestricted educational grant from Novo Nordisk Inc. The sponsor had no influence on the selection of speakers, selection of writing group members, topics or content covered at the conference, or the content of this report. The authors thank Shirley Ash of the American Diabetes Association for assistance with the conference. NR 176 TC 2 Z9 2 U1 26 U2 26 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD FEB PY 2017 VL 66 IS 2 BP 241 EP 255 DI 10.2337/db16-0806 PG 15 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EI7PS UT WOS:000392691000002 PM 27980006 ER PT J AU Najmi, LA Aukrust, I Flannick, J Molnes, J Burtt, N Molven, A Groop, L Altshuler, D Johansson, S Bjorkhaug, L Njolstad, PR AF Najmi, Laeya Abdoli Aukrust, Ingvild Flannick, Jason Molnes, Janne Burtt, Noel Molven, Anders Groop, Leif Altshuler, David Johansson, Stefan Bjorkhaug, Lise Njolstad, Pal Rasmus TI Functional Investigations of HNF1A Identify Rare Variants as Risk Factors for Type 2 Diabetes in the General Population SO DIABETES LA English DT Article ID HEPATOCYTE NUCLEAR FACTOR-1-ALPHA; I ALPHA-GENE; SOUTH INDIAN PATIENTS; LATE-ONSET NIDDM; FACTOR 1-ALPHA; TRANSCRIPTION FACTORS; MODY3 MUTATIONS; HNF1-ALPHA GENE; YOUNG MODY; CLINICAL-DIAGNOSIS AB Variants in HNF1A encoding hepatocyte nuclear factor-la (HNF-1A) are associated with maturity-onset diabetes of the young form 3 (MODY 3) and type 2 diabetes. We investigated whether functional classification of HNF1A rare coding variants can inform models of diabetes risk prediction in the general population by analyzing the effect of 27 HNF1A variants identified in well-phenotyped populations (n = 4,115). Bioinformatics tools classified 11 variants as likely pathogenic and showed no association with diabetes risk (combined minor allele frequency [MAF] 0.22%; odds ratio [OR] 2.02; 95% CI 0.73-5.60; P = 0.18). However, a different set of 11 variants that reduced HNF-1A transcriptional activity to <60% of normal (wild-type) activity was strongly associated with diabetes in the general population (combined MAF 0.22%; OR 5.04; 95% CI 1.99-12.80; P = 0.0007). Our functional investigations indicate that 0.44% of the population carry HNF1A variants that result in a substantially increased risk for developing diabetes. These results suggest that functional characterization of variants within MODY genes may overcome the limitations of bioinformatics tools for the purposes of presymptomatic diabetes risk prediction in the general population. C1 [Najmi, Laeya Abdoli; Aukrust, Ingvild; Molnes, Janne; Molven, Anders; Johansson, Stefan; Bjorkhaug, Lise; Njolstad, Pal Rasmus] Univ Bergen, Dept Clin Sci, KG Jebsen Ctr Diabet Res, Bergen, Norway. [Najmi, Laeya Abdoli; Aukrust, Ingvild; Johansson, Stefan] Haukeland Hosp, Ctr Med Genet & Mol Med, Bergen, Norway. [Najmi, Laeya Abdoli] Univ Bergen, Dept Biomed, Bergen, Norway. [Flannick, Jason; Burtt, Noel; Altshuler, David] Broad Inst Harvard & Massachusetts Inst Technol, Program Med & Populat Genet, Cambridge, MA USA. [Molnes, Janne; Njolstad, Pal Rasmus] Haukeland Hosp, Dept Pediat, Bergen, Norway. [Molven, Anders] Univ Bergen, Dept Clin Med, Gade Lab Pathol, Bergen, Norway. [Molven, Anders] Haukeland Hosp, Dept Pathol, Bergen, Norway. [Groop, Leif] Lund Univ, Dept Clin Sci Diabet & Endocrinol, Clin Res Ctr, Malmo, Sweden. [Altshuler, David] Harvard Med Sch, Dept Genet, Boston, MA USA. [Altshuler, David] Harvard Med Sch, Dept Med, Boston, MA USA. [Altshuler, David] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Altshuler, David] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. [Bjorkhaug, Lise] Bergen Univ Coll, Dept Biomed Lab Sci, Bergen, Norway. RP Bjorkhaug, L; Njolstad, PR (reprint author), Univ Bergen, Dept Clin Sci, KG Jebsen Ctr Diabet Res, Bergen, Norway.; Njolstad, PR (reprint author), Haukeland Hosp, Dept Pediat, Bergen, Norway.; Bjorkhaug, L (reprint author), Bergen Univ Coll, Dept Biomed Lab Sci, Bergen, Norway. EM lise.b.gundersen@hvl.no; pal.njolstad@uib.no OI Gundersen, Lise Bjorkhaug/0000-0002-9695-4559 FU Bergen Medical Research Foundation; KG Jebsen Foundation; University of Bergen; Research Council of Norway; Western Norway Regional Health Authority (Helse Vest); Norwegian Diabetes Foundation; European Research Council FX This work was supported by grants and fellowships from the translational fund of Bergen Medical Research Foundation, KG Jebsen Foundation, University of Bergen, Research Council of Norway, Western Norway Regional Health Authority (Helse Vest), Norwegian Diabetes Foundation, and European Research Council. L.B. and P.R.N. obtained funding. NR 79 TC 0 Z9 0 U1 6 U2 6 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD FEB PY 2017 VL 66 IS 2 BP 335 EP 346 DI 10.2337/db16-0460 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EI7PS UT WOS:000392691000012 PM 27899486 ER PT J AU Romero, JM Hito, R Dejam, A Ballesteros, LS Cobos, CJ Lievano, JO Ciura, VA Barnaure, I Ernst, M Liberato, AP Gonzalez, GR AF Romero, Javier M. Hito, Rania Dejam, Andre Ballesteros, Laia Sero Cobos, Camilo Jaimes Lievano, J. Ortiz Ciura, Viesha A. Barnaure, Isabelle Ernst, Marielle Liberato, Afonso P. Gonzalez, Gilberto R. TI Negative spot sign in primary intracerebral hemorrhage: potential impact in reducing imaging SO EMERGENCY RADIOLOGY LA English DT Article DE Stroke; Intracerebral hemorrhage; CT; Spot sign ID PREDICTS HEMATOMA EXPANSION; CONTRAST EXTRAVASATION; POSTCONTRAST CT AB Intracerebral hemorrhage (ICH) is one of the most devastating and costly diagnoses in the USA. ICH is a common diagnosis, accounting for 10-15 % of all strokes and affecting 20 out of 100,000 people. The CT angiography (CTA) spot sign, or contrast extravasation into the hematoma, is a reliable predictor of hematoma expansion, clinical deterioration, and increased mortality. Multiple studies have demonstrated a high negative predictive value (NPV) for ICH expansion in patients without spot sign. Our aim is to determine the absolute NPV of the spot sign and clinical characteristics of patients who had ICH expansion despite the absence of a spot sign. This information may be helpful in the development of a cost effective imaging protocol of patients with ICH. During a 3-year period, 204 patients with a CTA with primary intracerebral hemorrhage were evaluated for subsequent hematoma expansion during their hospitalization. Patients with intraventricular hemorrhage were excluded. Clinical characteristics and antithrombotic treatment on admission were noted. The number of follow-up NCCT was recorded. Of the resulting 123 patients, 108 had a negative spot sign and 7 of those patients subsequently had significant hematoma expansion, 6 of which were on antithrombotic therapy. The NPV of the CTA spot sign was calculated at 0.93. In patients without antithrombotic therapy, the NPV was 0.98. In summary, the negative predictive value of the CTA spot sign for expansion of ICH, in the absence of antithrombotic therapy and intraventricular hemorrhage (IVH) on admission, is very high. These results have the potential to redirect follow-up imaging protocols and reduce cost. C1 [Romero, Javier M.; Hito, Rania; Ballesteros, Laia Sero; Cobos, Camilo Jaimes; Lievano, J. Ortiz; Ciura, Viesha A.; Barnaure, Isabelle; Liberato, Afonso P.; Gonzalez, Gilberto R.] Massachusetts Gen Hosp, Neuroradiol Div, Dept Radiol, 55 Fruit St, Boston, MA 02114 USA. [Dejam, Andre] Beth Israel Deaconess Med Ctr, Div Cardiol, 330 Brookline Ave, Boston, MA 02215 USA. [Barnaure, Isabelle] Hop Univ Geneve, Serv Neuroradiol, Rue Gabrielle Perret Gentil 4, CH-1205 Geneva, Switzerland. [Ernst, Marielle] Univ Med Ctr Hamburg Eppendorf, Dept Diagnost & Intervent Neuroradiol, Haus Ost 22 Martinistr 52, D-20246 Hamburg, Germany. RP Romero, JM (reprint author), Massachusetts Gen Hosp, Neuroradiol Div, Dept Radiol, 55 Fruit St, Boston, MA 02114 USA. EM jmromero@mgh.harvard.edu NR 19 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1070-3004 EI 1438-1435 J9 EMERG RADIOL JI Emerg. Radiol. PD FEB PY 2017 VL 24 IS 1 BP 1 EP 6 DI 10.1007/s10140-016-1428-8 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EI2GL UT WOS:000392304800001 PM 27553777 ER PT J AU Jha, P Bentley, B Behr, S Yee, J Zagoria, R AF Jha, Priyanka Bentley, Brian Behr, Spencer Yee, Judy Zagoria, Ronald TI Imaging of flank pain: readdressing state-of-the-art SO EMERGENCY RADIOLOGY LA English DT Review DE Renal stone; Low-dose CT; Ultrasound; MRI; Pregnancy; Imaging protocol; STONE score ID DUAL-ENERGY CT; CLINICAL-PREDICTION RULE; COMPUTED-TOMOGRAPHY; DIAGNOSTIC PERFORMANCE; URETERAL CALCULUS; STONE DISEASE; HELICAL CT; DOSE CT; UROLITHIASIS; US AB Pain resulting from renal and ureteral stones is a common cause for patients presenting in the acute setting. Since the late 1990s, computed tomography (CT) has been the initial imaging method of choice to evaluate patients with suspected ureteral stones; however, concerns regarding both radiation dose and cost-effectiveness have prompted investigations into a different imaging algorithm. Studies utilizing ultrasound have provided evidence indicating that it may be a more appropriate first step, with selective use of CT in selected cases, in the diagnostic work-up. Techniques have evolved with low-dose CT, dual-energy CT, and magnetic resonance urography emerging as useful in imaging of renal colic patients. This manuscript reviews the current literature on state-of-the-art imaging for acute flank pain and proposes a new imaging algorithm in the evaluation of patients with acute flank pain and suspected ureteral stones. C1 [Jha, Priyanka; Bentley, Brian; Behr, Spencer; Yee, Judy; Zagoria, Ronald] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, 4150 Clement St,Bldg 200,Rm 2A-166, San Francisco, CA 94121 USA. [Yee, Judy] San Francisco Vet Adm Med Ctr, San Francisco, CA USA. RP Jha, P (reprint author), Univ Calif San Francisco, Dept Radiol & Biomed Imaging, 4150 Clement St,Bldg 200,Rm 2A-166, San Francisco, CA 94121 USA. EM priyanka.jha@ucsf.edu NR 41 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1070-3004 EI 1438-1435 J9 EMERG RADIOL JI Emerg. Radiol. PD FEB PY 2017 VL 24 IS 1 BP 81 EP 86 DI 10.1007/s10140-016-1443-9 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EI2GL UT WOS:000392304800013 PM 27614885 ER PT J AU Richmond, JM Bangari, DS Essien, KI Currimbhoy, SD Groom, JR Pandya, AG Youd, ME Luster, AD Harris, JE AF Richmond, Jillian M. Bangari, Dinesh S. Essien, Kingsley I. Currimbhoy, Sharif D. Groom, Joanna R. Pandya, Amit G. Youd, Michele E. Luster, Andrew D. Harris, John E. TI Keratinocyte-Derived Chemokines Orchestrate T-Cell Positioning in the Epidermis during Vitiligo and May Serve as Biomarkers of Disease SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID IFN-GAMMA; CONTACT HYPERSENSITIVITY; MOUSE MODEL; KAPPA-B; CXCR3; ACTIVATION; EXPRESSION; CXCL10; SKIN; DIFFERENTIATION AB Vitiligo is an autoimmune disease of the skin that results in the destruction of melanocytes and the clinical appearance of white spots. Disease pathogenesis depends on IFN-gamma and IFN-gamma-induced chemokines to promote T-cell recruitment to the epidermis where melanocytes reside. The skin is a complex organ, with a variety of resident cell types. We sought to better define the microenvironment and distinct cellular contributions during autoimmunity in vitiligo, and we found that the epidermis is a chemokine-high niche in both a mouse model and human vitiligo. Analysis of chemokine expression in mouse skin showed that CXCL9 and CXCL10 expression strongly correlate with disease activity, whereas CXCL10 alone correlates with severity, supporting them as potential biomarkers for following disease progression. Further studies in both our mouse model and human patients showed that keratinocytes were the major chemokine producers throughout the course of disease, and functional studies using a conditional signal transducer and activator of transcription (STAT)-1 knockout mouse showed that IFN-gamma signaling in keratinocytes was critical for disease progression and proper autoreactive T-cell homing to the epidermis. In contrast, epidermal immune cell populations including endogenous T cells, Langerhans cells, and gamma delta T cells were not required. These results have important clinical implications, because topical therapies that target IFN-gamma signaling in keratinocytes could be safe and effective new treatments, and skin expression of these chemokines could be used to monitor disease activity and treatment responses. C1 [Richmond, Jillian M.; Essien, Kingsley I.; Harris, John E.] Univ Massachusetts, Sch Med, Dept Med, Div Dermatol, Worcester, MA 01605 USA. [Bangari, Dinesh S.; Youd, Michele E.] Sanofi Genzyme, Framingham, MA USA. [Currimbhoy, Sharif D.; Pandya, Amit G.] Univ Texas Southwestern Med Ctr Dallas, Dallas, TX 75390 USA. [Groom, Joanna R.] Univ Melbourne, Walter & Eliza Hall Inst Med Res, Dept Med Biol Royal Parade 1G, Melbourne, Vic, Australia. [Luster, Andrew D.] Harvard Med Sch, Ctr Immunol & Inflammatory Dis, Div Rheumatol Allergy & Immunol, Massachusetts Gen Hosp, Boston, MA USA. RP Harris, JE (reprint author), Univ Massachusetts, Sch Med, 364 Plantat St,LRB 270C, Worcester, MA 01605 USA. EM john.harris@umassmed.edu FU American Skin Association; National Institute of Arthritis and Musculoskeletal and Skin Diseases part of the National Institutes of Health [AR061437, AR069114]; Kawaja Vitiligo Research Initiative; Vitiligo Research Foundation; Dermatology Foundation Stiefel Scholar Award FX We thank clinic patients (of JEH and AGP) for donating tissue. We thank L. Hennighausen for STAT1-floxed mice, S. Jones for K5-Cre mice, D. Kaplan for Hu-Lang-DTA mice, B.J. Longley for Krt14-Kitl* mice, U. von Andrian for DPEGFP mice, N. Restifo for recombinant vaccinia virus, and A. Rothstein for insightful comments on the manuscript. We thank members of the Harris Lab including P. Agarwal, M. Damiani, M. Frisoli, M. Rashighi, R. Riding, and J. Strassner for technical assistance. This study was supported by a Research Grant and Calder Research Scholar Award from the American Skin Association (to JMR); the National Institute of Arthritis and Musculoskeletal and Skin Diseases, part of the National Institutes of Health, under Award Numbers AR061437 and AR069114; and research grants from the Kawaja Vitiligo Research Initiative, Vitiligo Research Foundation, and Dermatology Foundation Stiefel Scholar Award (to JEH). Flow cytometry and confocal microscopy equipment used for this study is maintained by the UMMS Flow Cytometry Core Facility and Morphology Core Facility, and tissue sectioning and pathology services are maintained by the UMMS DERC Morphology Core. NR 31 TC 1 Z9 1 U1 6 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD FEB PY 2017 VL 137 IS 2 BP 350 EP 358 DI 10.1016/j.jid.2016.09.016 PG 9 WC Dermatology SC Dermatology GA EI4NE UT WOS:000392469700015 PM 27686391 ER PT J AU Friend, TH Jennings, SJ Levine, WC AF Friend, Tynan H. Jennings, Samantha J. Levine, Wilton C. TI Communication Patterns in the Perioperative Environment During Epic Electronic Health Record System Implementation SO JOURNAL OF MEDICAL SYSTEMS LA English DT Article DE Electronic health records; Epic; Vocera; EHR/EMR implementation; Perioperative communication AB In April 2016, Massachusetts General Hospital (MGH) went live with the Epic electronic health records (EHR) system, replacing a variety of EHRs that previously existed in different departments throughout the hospital. At the time of implementation, the Vocera(R) Badge Communication System, a wireless hands-free communication device distributed to perioperative team members, had increased perioperative communication flow and efficiency. As a quality improvement effort to better understand communication patterns during an EHR go-live, we monitored our Vocera call volume and user volume before, during and after our go-live. We noticed that call volume and user volume significantly increased during our immediate go-live period and quickly returned to baseline levels. We also noticed that call volume increased during periods of unplanned EHR downtime long after our immediate go-live period. When planning the implementation of a new EHR, leadership must plan for and support this critical communication need at the time of the go-live and must also be aware of these needs during unplanned downtime. C1 [Friend, Tynan H.; Jennings, Samantha J.; Levine, Wilton C.] Massachusetts Gen Hosp, 55 Fruit St,WHT 400, Boston, MA 02114 USA. RP Friend, TH; Levine, WC (reprint author), Massachusetts Gen Hosp, 55 Fruit St,WHT 400, Boston, MA 02114 USA. EM tfriend@partners.org; wlevine@partners.org NR 8 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0148-5598 EI 1573-689X J9 J MED SYST JI J. Med. Syst. PD FEB PY 2017 VL 41 IS 2 AR 22 DI 10.1007/s10916-016-0674-3 PG 5 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA EI2PM UT WOS:000392329900005 PM 28000116 ER PT J AU Hyoju, SK Morrison, S Gul, S Gharedaghi, MH Mussa, M Najibi, M Economopoulos, KP Hamarneh, SR Hodin, RA AF Hyoju, Sanjiv K. Morrison, Sara Gul, Sarah Gharedaghi, Mohammad Hadi Mussa, Mohamed Najibi, Mehran Economopoulos, Konstantinos P. Hamarneh, Sulaiman R. Hodin, Richard A. TI Intestinal alkaline phosphatase decreases intraperitoneal adhesion formation SO JOURNAL OF SURGICAL RESEARCH LA English DT Article DE Intestinal alkaline phosphatase; Postoperative adhesions; Cytokines ID NECROSIS-FACTOR-ALPHA; PLASMINOGEN-ACTIVATOR INHIBITOR-1; PERITONEAL MESOTHELIAL CELLS; TNF-ALPHA; ATP RELEASE; INFLAMMATION; MORTALITY; ADENOSINE; IMMUNITY; COLITIS AB Background: Damage to the peritoneum initiates an inflammatory response leading to the formation of adhesions, which subsequently cause significant morbidity in some patients. Intestinal alkaline phosphatase (IAP) is a gut enzyme capable of detoxifying various inflammatory mediators such as lipopolysaccharide, lipoteichoic acid, CpG DNA, and adenosine triphosphate. In this study, we aimed to examine the anti-inflammatory effects of IAP on postoperative adhesions in mice. Methods: C57BL/6 mice were subjected to a midline laparotomy and then six musculoperitoneal buttons (MPBs) were created by pinching and ligating the peritoneum and underlying muscle. The buttons were half-excised and E-cauterized, and then cecal abrasion was performed. Five hundred microliters of vehicle with IAP 5000 U or vehicle alone were applied over the peritoneal cavity. In some experiments, the mice were euthanized on the first and second postoperative day (POD), and cytokines analysis was done on the MPB, peritoneal tissue, and peritoneal fluid. In separate experiments, the mice were sacrificed on the 21st POD, and adhesion to each button was scored based on type and tenacity. Results: IAP group mice had significantly lower adhesion scores compared with controls (21.5 +/- 1.7 versus 13.2 +/- 1.3; P = 0.0014, n = 15). MPB from IAP group mice had significantly lower interleukin-1b and tumor necrosis factor-a protein level compared to control mice (105.66 +/- 4.5 versus 69.8 +/- 4.8 versus pg/mg, P = 0.0001; 45.25 +/- 2.8 pg/mg versus 24.88 +/- 4.1 pg/mg; P = 0.0007, n = 10). IAP treatment significantly decreased interleukin-1b and tumor necrosis factor-a mRNA expression in MPB in the first POD (1.14 +/- 0.25 versus 0.33 +/- 0.07; P = 0.0068; 1.33 +/- 0.31 versus 0.33 +/- 0.08; P = 0.0064, n = 10). Conclusions: Application of IAP during laparotomy could represent a novel approach to prevent postoperative adhesions. (C) 2016 Elsevier Inc. All rights reserved. C1 [Hyoju, Sanjiv K.; Morrison, Sara; Gul, Sarah; Gharedaghi, Mohammad Hadi; Mussa, Mohamed; Najibi, Mehran; Economopoulos, Konstantinos P.; Hamarneh, Sulaiman R.; Hodin, Richard A.] Harvard Sch Med, Massachusetts Gen Hosp, Dept Surg, 15 Parkman St, Boston, MA 02114 USA. RP Hodin, RA (reprint author), Harvard Sch Med, Massachusetts Gen Hosp, Dept Surg, 15 Parkman St, Boston, MA 02114 USA. EM RHODIN@mgh.harvard.edu NR 42 TC 0 Z9 0 U1 2 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0022-4804 EI 1095-8673 J9 J SURG RES JI J. Surg. Res. PD FEB PY 2017 VL 208 BP 84 EP 92 DI 10.1016/j.jss.2016.09.006 PG 9 WC Surgery SC Surgery GA EI1CM UT WOS:000392213400010 PM 27993220 ER PT J AU Laflamme, C Galan, JA Ben El Kadhi, K Meant, A Zeledon, C Carreno, S Roux, PP Emery, G AF Laflamme, Carl Galan, Jacob A. Ben El Kadhi, Khaled Meant, Antoine Zeledon, Carlos Carreno, Sebastien Roux, Philippe P. Emery, Gregory TI Proteomics Screen Identifies Class I Rab11 Family Interacting Proteins as Key Regulators of Cytokinesis SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article DE 14-3-3; cell division; cytokinesis; proteomics; vesicular trafficking ID CRYSTAL-STRUCTURE; STRUCTURAL BASIS; CLEAVAGE FURROW; MIDBODY RING; CELL-CYCLE; COMPLEX; PHOSPHORYLATION; KINASE; ACTIN; CYTOSKELETON AB The 14-3-3 protein family orchestrates a complex network of molecular interactions that regulates various biological processes. Owing to their role in regulating the cell cycle and protein trafficking, 14-3-3 proteins are prevalent in human diseases such as cancer, diabetes, and neurodegeneration. 14-3-3 proteins are expressed in all eukaryotic cells, suggesting that they mediate their biological functions through evolutionarily conserved protein interactions. To identify these core 14-3-3 client proteins, we used an affinity-based proteomics approach to characterize and compare the human and Drosophila 14-3-3 interactomes. Using this approach, we identified a group of Rab11 effector proteins, termed class I Rab11 family interacting proteins (Rab11-FIPs), or Rip11 in Drosophila. We found that 14-3-3 binds to Rip11 in a phospho-dependent manner to ensure its proper subcellular distribution during cell division. Our results indicate that Rip11 plays an essential role in the regulation of cytokinesis and that this function requires its association with 14-3-3 but not with Rab11. Together, our results suggest an evolutionarily conserved role for 14-3-3 in controlling Rip11-dependent protein transport during cytokinesis. C1 [Laflamme, Carl; Galan, Jacob A.; Ben El Kadhi, Khaled; Meant, Antoine; Zeledon, Carlos; Carreno, Sebastien; Roux, Philippe P.; Emery, Gregory] Univ Montreal, IRIC, Montreal, PQ, Canada. [Carreno, Sebastien; Roux, Philippe P.; Emery, Gregory] Univ Montreal, Dept Pathol & Cell Biol, Fac Med, Montreal, PQ, Canada. [Laflamme, Carl] Montreal Neurol Inst, McGill Univ, Dept Neurol & Neurosurg, Montreal, PQ, Canada. [Galan, Jacob A.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. RP Roux, PP; Emery, G (reprint author), Univ Montreal, IRIC, Montreal, PQ, Canada.; Roux, PP; Emery, G (reprint author), Univ Montreal, Dept Pathol & Cell Biol, Fac Med, Montreal, PQ, Canada. EM philippe.roux@umontreal.ca; gregory.emery@umontreal.ca OI Roux, Philippe/0000-0002-5962-0250 FU Canadian Institutes of Health Research (CIHR) [MOP133683, MOP123408, MOP114899]; Human Frontier Science Program; Cancer Research Society; NSERC; CIHR; Fonds de la Recherche du Quebec en Sante (FRQS); Fondation Desjardins; Fondation du Grand Defi Pierre Lavoie; FRQS FX This work was supported by Canadian Institutes of Health Research (CIHR) grants MOP133683 (to S.C.), MOP123408 (to P.P.R.), and MOP114899 (to G.E.), a grant from the Human Frontier Science Program (to P.P.R.), a Cancer Research Society grant (to G.E.), and an NSERC grant (to G.E.). S.C. holds a New Investigator Award from the CIHR. P.P.R. holds a Canada Research Chair in Cell Signaling and Proteomics and a Chercheur-Boursier award from the Fonds de la Recherche du Quebec en Sante (FRQS). G.E. holds a Canada Research Chair in Vesicular Trafficking and Cell Signaling. C.L., K.B.E.K., and C.Z. held Ph.D. training awards from the FRQS. K.B.E.K. also held a Ph.D. fellowship from the Fondation Desjardins and a Ph.D. fellowship from the Fondation du Grand Defi Pierre Lavoie. J.A.G. held postdoctoral fellowships from the CIHR and FRQS. NR 49 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD FEB PY 2017 VL 37 IS 3 AR UNSP e00278-16 DI 10.1128/MCB.00278-16 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EI1IX UT WOS:000392231500001 ER PT J AU Freire, MO Devaraj, A Young, A Navarro, JB Downey, JS Chen, C Bakaletz, LO Zadeh, HH Goodman, SD AF Freire, M. O. Devaraj, A. Young, A. Navarro, J. B. Downey, J. S. Chen, C. Bakaletz, L. O. Zadeh, H. H. Goodman, S. D. TI A bacterial-biofilm-induced oral osteolytic infection can be successfully treated by immuno-targeting an extracellular nucleoid-associated protein SO MOLECULAR ORAL MICROBIOLOGY LA English DT Article DE Aggregatibacter actinomycetemcomitans; biofilm; DNABII protein; inflammation; integration host factor ID INTEGRATION HOST FACTOR; NONSURGICAL PERIODONTAL THERAPY; INDUCED PERI-IMPLANTITIS; ACTINOBACILLUS-ACTINOMYCETEMCOMITANS; AGGRESSIVE PERIODONTITIS; SPONTANEOUS PROGRESSION; BACTEROIDES-GINGIVALIS; CLINICAL-PARAMETERS; SUBGINGIVAL PLAQUE; ALVEOLAR BONE AB Periodontal disease exemplifies a chronic and recurrent infection with a necessary biofilm component. Mucosal inflammation is a hallmark response of the host seen in chronic diseases, such as colitis, gingivitis, and periodontitis (and the related disorder peri-implantitis). We have taken advantage of our recently developed rat model of human peri-implantitis that recapitulates osteolysis, the requirement of biofilm formation, and the perpetuation of the bona fide disease state, to test a new therapeutic modality with two novel components. First we used hyperimmune antiserum directed against the DNABII family of proteins, now known to be a critical component of the extracellular matrix of bacterial biofilms. Second we delivered the antiserum as cargo in biodegradable microspheres to the site of the biofilm infection. We demonstrated that delivery of a single dose of anti-DNABII in poly(lactic-co-glycolic acid) (PLGA) microspheres induced significant resolution of experimental peri-implantitis, including marked reduction of inflammation. These data support the continued development of a DNABII protein-targeted therapeutic for peri-implantitis and other chronic inflammatory pathologies of the oral cavity in animals and humans. C1 [Freire, M. O.] Forsyth Inst, Dept Appl Oral Sci, Cambridge, MA USA. [Freire, M. O.] Harvard Sch Dent Med, Dept Infect & Immun, Boston, MA USA. [Devaraj, A.; Navarro, J. B.; Bakaletz, L. O.; Goodman, S. D.] Nationwide Childrens Hosp, Res Inst, Ctr Microbial Pathogenesis, 700 Childrens Dr, Columbus, OH 43205 USA. [Devaraj, A.; Navarro, J. B.; Bakaletz, L. O.; Goodman, S. D.] Ohio State Univ, Coll Med, Columbus, OH 43210 USA. [Young, A.; Downey, J. S.; Chen, C.; Zadeh, H. H.] Univ Southern Calif, Ostrow Sch Dent, Div Periodontol Diagnost Sci & Dent Hyg, Los Angeles, CA USA. [Zadeh, H. H.] Univ Southern Calif, LITE, Los Angeles, CA USA. RP Goodman, SD (reprint author), Nationwide Childrens Hosp, Res Inst, Ctr Microbial Pathogenesis, 700 Childrens Dr, Columbus, OH 43205 USA. EM steven.goodman@nationwidechildrens.org OI Freire, Marcelo/0000-0003-4906-7698 FU NIH [R01DC011818, DE012212]; Ideas Empowered Program, University of Southern California FX This work was supported by NIH grant R01DC011818 to SDG and LOB, NIH grant DE012212 to CC and HZ and Ideas Empowered Program, University of Southern California to SDG. We thank Joseph Jursicek for imaging the histology slides and Lauren Mashburn-Warren for critical reading of the manuscript. NR 76 TC 1 Z9 1 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2041-1006 EI 2041-1014 J9 MOL ORAL MICROBIOL JI Mol. Oral Microbiol. PD FEB PY 2017 VL 32 IS 1 BP 74 EP 88 DI 10.1111/omi.12155 PG 15 WC Dentistry, Oral Surgery & Medicine; Microbiology SC Dentistry, Oral Surgery & Medicine; Microbiology GA EI3YD UT WOS:000392428100006 PM 26931773 ER PT J AU Beyaz, S Kim, JH Pinello, L Xifaras, ME Hu, Y Huang, JL Kerenyi, MA Das, PP Barnitz, RA Herault, A Dogum, R Haining, WN Yilmaz, OH Passegue, E Yuan, GC Orkin, SH Winau, F AF Beyaz, Semir Kim, Ji Hyung Pinello, Luca Xifaras, Michael E. Hu, Yu Huang, Jialiang Kerenyi, Marc A. Das, Partha P. Barnitz, R. Anthony Herault, Aurelie Dogum, Rizkullah Haining, W. Nicholas Yilmaz, Omer H. Passegue, Emmanuelle Yuan, Guo-Cheng Orkin, Stuart H. Winau, Florian TI The histone demethylase UTX regulates the lineage-specific epigenetic program of invariant natural killer T cells SO NATURE IMMUNOLOGY LA English DT Article ID LYSINE 27 DEMETHYLASES; V-ALPHA-14I NKT CELLS; INKT CELLS; SUPER-ENHANCERS; TRANSCRIPTION FACTORS; GENE-EXPRESSION; IFN-GAMMA; CHROMATIN; JMJD3; DIFFERENTIATION AB Invariant natural killer T cells (iNKT cells) are innate-like lymphocytes that protect against infection, autoimmune disease and cancer. However, little is known about the epigenetic regulation of MKT cell development. Here we found that the H3K27me3 histone demethylase UTX was an essential cell-intrinsic factor that controlled an MKT-cell lineage-specific gene-expression program and epigenetic landscape in a demethylase-activity-dependent manner. UTX-deficient iNKT cells exhibited impaired expression of iNKT cell signature genes due to a decrease in activation-associated H3K4me3 marks and an increase in repressive H3K27me3 marks within the promoters occupied by UTX. We found that JunB regulated MKT cell development and that the expression of genes that were targets of both JunB and the MKT cell master transcription factor PLZF was UTX dependent. We identified iNKT cell super-enhancers and demonstrated that UTX-mediated regulation of super-enhancer accessibility was a key mechanism for commitment to the MKT cell lineage. Our findings reveal how UTX regulates the development of iNKT cells through multiple epigenetic mechanisms. C1 [Beyaz, Semir; Kerenyi, Marc A.; Das, Partha P.; Barnitz, R. Anthony; Orkin, Stuart H.] Harvard Med Sch, Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA. [Beyaz, Semir; Kerenyi, Marc A.; Das, Partha P.; Orkin, Stuart H.] Harvard Med Sch, Harvard Stem Cell Inst, Howard Hughes Med Inst, Dept Pediat Oncol,Dana Farber Canc Inst, Boston, MA USA. [Kim, Ji Hyung; Hu, Yu; Winau, Florian] Harvard Med Sch, Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA USA. [Kim, Ji Hyung; Hu, Yu; Winau, Florian] Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA USA. [Pinello, Luca; Huang, Jialiang; Yuan, Guo-Cheng] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Pinello, Luca; Huang, Jialiang; Yuan, Guo-Cheng] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Xifaras, Michael E.; Dogum, Rizkullah; Yilmaz, Omer H.] MIT, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Xifaras, Michael E.; Dogum, Rizkullah; Yilmaz, Omer H.] MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Kerenyi, Marc A.] Boehringer Ingelheim GmbH & Co KG, Dept Pharmacol & Translat Res, Vienna, Austria. [Barnitz, R. Anthony] Broad Inst MIT & Harvard, Dana Farber Canc Inst, Dept Pediat Oncol, Cambridge, MA USA. [Herault, Aurelie; Passegue, Emmanuelle] Univ Calif San Francisco, Eli & Edythe Broad, Ctr Regenerat Med & Stem Cell Res, San Francisco, CA 94143 USA. [Herault, Aurelie; Passegue, Emmanuelle] Univ Calif San Francisco, Div Hematol Oncol, Dept Med, San Francisco, CA 94143 USA. RP Orkin, SH (reprint author), Harvard Med Sch, Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA.; Orkin, SH (reprint author), Harvard Med Sch, Harvard Stem Cell Inst, Howard Hughes Med Inst, Dept Pediat Oncol,Dana Farber Canc Inst, Boston, MA USA.; Winau, F (reprint author), Harvard Med Sch, Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA USA.; Winau, F (reprint author), Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA USA. EM stuart_orkin@dfci.harvard.edu; florian.winau@childrens.harvard.edu OI Hu, Yu/0000-0002-9511-9383; Beyaz, Semir/0000-0003-4730-4012 FU Howard Hughes Medical Institute; US National Institutes of Health [P30DK0492, RO1 AI083426]; Cancer Research Institute Predoctoral Emphasis Pathway in Tumor Immunology; National Research Foundation of Korea [2012R1A6A3A03040248]; National Human Genome Research Institute of the US National Institutes of Health (Career Development Award) [K99HG008399] FX We thank the US National Institutes of Health Tetramer Facility for CD1d-tetramers, the Center for Cancer Computational Biology sequencing facility at the Dana-Farber Cancer Institute for Illumina HiSeq2000 sequencing, the Microarray core facility at the Dana-Farber Cancer Institute Molecular Biology Core Facilities for microarray analysis, and the Dana-Farber Cancer Institute Jimmy Fund FACS core facility for cell sorting. Supported by the Howard Hughes Medical Institute (S.H.O.), the US National Institutes of Health (P30DK0492 to S.H.O., and RO1 AI083426 to F.W.), the Cancer Research Institute Predoctoral Emphasis Pathway in Tumor Immunology (S.B.), the National Research Foundation of Korea (2012R1A6A3A03040248 to J.H.K.) and the National Human Genome Research Institute of the US National Institutes of Health (Career Development Award K99HG008399 to L.P.). NR 50 TC 1 Z9 1 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD FEB PY 2017 VL 18 IS 2 BP 184 EP 195 DI 10.1038/ni.3644 PG 12 WC Immunology SC Immunology GA EI3AE UT WOS:000392360900012 PM 27992400 ER PT J AU Elmer, J Yamane, D Hou, PC Wilcox, SR Bajwa, EK Hess, DR Camargo, CA Greenberg, SM Rosand, J Pallin, DJ Goldstein, JN Takhar, SS AF Elmer, Jonathan Yamane, David Hou, Peter C. Wilcox, Susan R. Bajwa, Ednan K. Hess, Dean R. Camargo, Carlos A., Jr. Greenberg, Steven M. Rosand, Jonathan Pallin, Daniel J. Goldstein, Joshua N. Takhar, Sukhjit S. TI Cost and Utility of Microbiological Cultures Early After Intensive Care Unit Admission for Intracerebral Hemorrhage SO NEUROCRITICAL CARE LA English DT Article DE Intracerebral hemorrhage; Critical illness; Microbiology; Culture; Antimicrobial ID FEVER; DIAGNOSIS; PREVENTION; INFECTION; INJURY AB Fever is common among intensive care unit (ICU) patients. Clinicians may use microbiological cultures to differentiate infectious and aseptic fever. However, their utility depends on the prevalence of infection; and false-positive results might adversely affect patient care. We sought to quantify the cost and utility of microbiological cultures in a cohort of ICU patients with spontaneous intracerebral hemorrhage (ICH). We performed a secondary analysis of a cohort with spontaneous ICH requiring mechanical ventilation. We collected baseline data, measures of systemic inflammation, microbiological culture results for the first 48 h, and daily antibiotic usage. Two physicians adjudicated true-positive and false-positive culture results using standard criteria. We calculated the cost per true-positive result and used logistic regression to test the association between false-positive results with subsequent antibiotic exposure. Overall, 697 subjects were included. A total of 233 subjects had 432 blood cultures obtained, with one true-positive (diagnostic yield 0.1 %, $22,200 per true-positive) and 11 false-positives. True-positive urine cultures (5 %) and sputum cultures (13 %) were more common but so were false-positives (6 and 17 %, respectively). In adjusted analysis, false-positive blood and sputum results were associated with increased antibiotic exposure. The yield of blood cultures early after spontaneous ICH was very low. False-positive results significantly increased the odds of antibiotic exposure. Our results support limiting the use of blood cultures in the first two days after ICU admission for spontaneous ICH. C1 [Elmer, Jonathan] Univ Pittsburgh, Dept Emergency Med, Iroquois Bldg,Suite 400A,3600 Forbes Ave, Pittsburgh, PA 15213 USA. [Elmer, Jonathan] Univ Pittsburgh, Dept Crit Care Med, Iroquois Bldg,Suite 400A,3600 Forbes Ave, Pittsburgh, PA 15213 USA. [Yamane, David] George Washington Univ Hosp, Dept Anesthesiol & Crit Care Med, Washington, DC USA. [Hou, Peter C.; Pallin, Daniel J.; Takhar, Sukhjit S.] Brigham & Womens Hosp, Dept Emergency Med, 75 Francis St, Boston, MA 02115 USA. [Hou, Peter C.] Brigham & Womens Hosp, Surg Intens Care Unit, 75 Francis St, Boston, MA 02115 USA. [Wilcox, Susan R.] Med Univ South Carolina, Div Emergency Med, Charleston, SC USA. [Wilcox, Susan R.] Med Univ South Carolina, Div Pulm Crit Care & Sleep Med, Charleston, SC USA. [Bajwa, Ednan K.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Bajwa, Ednan K.; Hess, Dean R.] Massachusetts Gen Hosp, Pulm & Crit Care Unit, Boston, MA 02114 USA. [Hess, Dean R.] Massachusetts Gen Hosp, Dept Resp Care, Boston, MA 02114 USA. [Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Greenberg, Steven M.; Rosand, Jonathan] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Greenberg, Steven M.; Rosand, Jonathan; Goldstein, Joshua N.] Massachusetts Gen Hosp, Div Neurocrit Care & Emergency Neurol, Boston, MA 02114 USA. [Takhar, Sukhjit S.] Brigham & Womens Hosp, Div Infect Dis, 75 Francis St, Boston, MA 02115 USA. RP Elmer, J (reprint author), Univ Pittsburgh, Dept Emergency Med, Iroquois Bldg,Suite 400A,3600 Forbes Ave, Pittsburgh, PA 15213 USA.; Elmer, J (reprint author), Univ Pittsburgh, Dept Crit Care Med, Iroquois Bldg,Suite 400A,3600 Forbes Ave, Pittsburgh, PA 15213 USA. EM elmerp@upmc.edu FU Emergency Medicine Foundation/Emergency Medicine Resident's Association; Department of Emergency Medicine at Brigham and Women's Hospital; National Institutes of Health [R01NS073344, R01NS059727, 5K23NS059774, 5K12HL109068] FX This work was supported by grants from the Emergency Medicine Foundation/Emergency Medicine Resident's Association, the Department of Emergency Medicine at Brigham and Women's Hospital, and the National Institutes of Health (R01NS073344, R01NS059727, 5K23NS059774 and 5K12HL109068). NR 20 TC 0 Z9 0 U1 1 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1541-6933 EI 1556-0961 J9 NEUROCRIT CARE JI Neurocrit. Care PD FEB PY 2017 VL 26 IS 1 BP 58 EP 63 DI 10.1007/s12028-016-0285-3 PG 6 WC Critical Care Medicine; Clinical Neurology SC General & Internal Medicine; Neurosciences & Neurology GA EI2AI UT WOS:000392287900009 PM 27605253 ER PT J AU Lerner, DP Kim, J Izzy, S AF Lerner, David P. Kim, Jennifer Izzy, Saef TI Neurocritical Care Education During Residency: Opinions (NEURON) Study SO NEUROCRITICAL CARE LA English DT Article ID MEDICINE AB The American Academy of Neurology (AAN) has established a core curriculum of topics for residency training in neurocritical care. At present there is limited data evaluating neurology residency education within the neurological intensive care unit. This study evaluates learner concerns with the neurological intensive care unit. The Communication Committee and Resident & Fellow Taskforce within the Neurocritical Care Society (NCS) developed an online survey that consisted of 20 selection and free-text based questions. The survey was distributed to NCS members and then to neurology residency program directors. Statistical analysis of neurocritical care exposure were completed with t or Fisher exact test with p-value < 0.05 considered significant. A total of 95 individuals from 32 different residency programs (36.5 % response rate) responded to the questionnaire. Most individuals train with neurocritical care attendings, fellows and advanced practitioners and have neurocritical care exposure during multiple years of residency training. 54 % of responders cite improvement in education as a means to improve neurocritical care training. Those that raised concern had no difference in time in the neurocritical care unit (9.4 weeks vs 8.8 weeks), exposure to trained neurointensivists, neurocritical care fellows or advanced providers (p value 0.53, 0.19, 0.83, respectively). There is significant learner concern regarding education within the neurointensive care unit. Although there are educational guidelines and focused neurocritical care educational materials, these alone do not satisfy residents' educational needs. This study demonstrates the need for educational changes, but it does not assess best strategies nor curricular content. C1 [Lerner, David P.; Kim, Jennifer; Izzy, Saef] Harvard Med Sch, Brigham & Womens Hosp, Massachusetts Gen Hosp, 55 Fruit St,WACC 720, Boston, MA 02114 USA. RP Lerner, DP (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Massachusetts Gen Hosp, 55 Fruit St,WACC 720, Boston, MA 02114 USA. EM dplerner@mgh.harvard.edu NR 8 TC 0 Z9 0 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1541-6933 EI 1556-0961 J9 NEUROCRIT CARE JI Neurocrit. Care PD FEB PY 2017 VL 26 IS 1 BP 115 EP 118 DI 10.1007/s12028-016-0315-1 PG 4 WC Critical Care Medicine; Clinical Neurology SC General & Internal Medicine; Neurosciences & Neurology GA EI2AI UT WOS:000392287900017 PM 27619228 ER PT J AU Xing, CH Hayakawa, K Lo, EH AF Xing, Changhong Hayakawa, Kazuhide Lo, Eng H. TI Mechanisms, Imaging, and Therapy in Stroke Recovery SO TRANSLATIONAL STROKE RESEARCH LA English DT Editorial Material ID RANDOMIZED CONTROLLED-TRIAL; ACUTE ISCHEMIC-STROKE; THROMBECTOMY; REPERFUSION; REHABILITATION; STIMULATION; CHALLENGES C1 [Xing, Changhong; Hayakawa, Kazuhide; Lo, Eng H.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol & Neurol, Charlestown, MA 02129 USA. RP Xing, CH (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol & Neurol, Charlestown, MA 02129 USA. EM XING.CHANGHONG@mgh.harvard.edu FU NINDS NIH HHS [R01 NS094392] NR 30 TC 0 Z9 0 U1 3 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1868-4483 EI 1868-601X J9 TRANSL STROKE RES JI Transl. Stroke Res. PD FEB PY 2017 VL 8 IS 1 BP 1 EP 2 DI 10.1007/s12975-016-0503-5 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EI4TQ UT WOS:000392486700001 PM 27714670 ER PT J AU Egawa, N Lok, J Washida, K Arai, K AF Egawa, Naohiro Lok, Josephine Washida, Kazuo Arai, Ken TI Mechanisms of Axonal Damage and Repair after Central Nervous System Injury SO TRANSLATIONAL STROKE RESEARCH LA English DT Article DE Axonal repair; Axonal regeneration; CNS injury ID SPINAL-CORD-INJURY; OLIGODENDROCYTE-MYELIN GLYCOPROTEIN; ISCHEMIC BRAIN-INJURY; FUNCTIONAL RECOVERY; EPIGENETIC REGULATION; PROGENITOR CELLS; DEFICIENT MICE; CNS INJURY; REGENERATION; STROKE AB Central nervous system (CNS) injury initiates spatial and temporal neurodegeneration. Under pathologic conditions, damaged glial cells cannot supply sufficient metabolites to neurons, leading to energy deficiency for neuronal axons. The widespread disruption of cellular membranes causes disturbed intracellular signaling via dysregulated ionic gradients in neurons. Although several deleterious cascades are activated during the acute phase of CNS injury, some compensatory responses may tend to promote axonal repair during the chronic/remodeling phase. Because it may not be easy to block all multifactorial neurodegenerative pathways after CNS injury, supporting or boosting endogenous regenerative mechanisms would be an important therapeutic approach for CNS diseases. In this mini-review, we briefly but broadly introduce basic mechanisms that trigger axonal degeneration and then discuss potential targets for promoting axonal regeneration after CNS injury. C1 [Egawa, Naohiro; Lok, Josephine; Washida, Kazuo; Arai, Ken] Massachusetts Gen Hosp, Dept Radiol, Neuroprotect Res Lab, MGH East 149-2401, Charlestown, MA 02129 USA. [Egawa, Naohiro; Lok, Josephine; Washida, Kazuo; Arai, Ken] Massachusetts Gen Hosp, Dept Neurol, Neuroprotect Res Lab, MGH East 149-2401, Charlestown, MA 02129 USA. [Egawa, Naohiro; Lok, Josephine; Washida, Kazuo; Arai, Ken] Harvard Med Sch, MGH East 149-2401, Charlestown, MA 02129 USA. [Lok, Josephine] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Lok, Josephine] Harvard Med Sch, Boston, MA USA. RP Arai, K (reprint author), Massachusetts Gen Hosp, Dept Radiol, Neuroprotect Res Lab, MGH East 149-2401, Charlestown, MA 02129 USA.; Arai, K (reprint author), Massachusetts Gen Hosp, Dept Neurol, Neuroprotect Res Lab, MGH East 149-2401, Charlestown, MA 02129 USA.; Arai, K (reprint author), Harvard Med Sch, MGH East 149-2401, Charlestown, MA 02129 USA. EM karai@partners.org FU National Institute of Health FX This study is supported by the National Institute of Health (JL and KA). NR 60 TC 0 Z9 0 U1 13 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1868-4483 EI 1868-601X J9 TRANSL STROKE RES JI Transl. Stroke Res. PD FEB PY 2017 VL 8 IS 1 BP 14 EP 21 DI 10.1007/s12975-016-0495-1 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EI4TQ UT WOS:000392486700003 PM 27566737 ER PT J AU Mandeville, ET Ayata, C Zheng, Y Mandeville, JB AF Mandeville, Emiri T. Ayata, Cenk Zheng, Yi Mandeville, Joseph B. TI Translational MR Neuroimaging of Stroke and Recovery SO TRANSLATIONAL STROKE RESEARCH LA English DT Article DE Stroke; Imaging; MRI; PET; Clinical; Experimental ID APPARENT DIFFUSION-COEFFICIENT; TISSUE-PLASMINOGEN ACTIVATOR; EXPERIMENTAL ISCHEMIC-STROKE; FOCAL CEREBRAL-ISCHEMIA; RESTING HUMAN BRAIN; FUNCTIONAL MRI; INTRACEREBRAL HEMORRHAGE; WATER DIFFUSION; NERVOUS-SYSTEM; MOTOR CORTEX AB Multiparametric magnetic resonance imaging (MRI) has become a critical clinical tool for diagnosing focal ischemic stroke severity, staging treatment, and predicting outcome. Imaging during the acute phase focuses on tissue viability in the stroke vicinity, while imaging during recovery requires the evaluation of distributed structural and functional connectivity. Preclinical MRI of experimental stroke models provides validation of non-invasive biomarkers in terms of cellular and molecular mechanisms, while also providing a translational platform for evaluation of prospective therapies. This brief review of translational stroke imaging discusses the acute to chronic imaging transition, the principles underlying common MRI methods employed in stroke research, and the experimental results obtained by clinical and preclinical imaging to determine tissue viability, vascular remodeling, structural connectivity of major white matter tracts, and functional connectivity using task-based and resting-state fMRI during the stroke recovery process. C1 [Mandeville, Emiri T.] Massachusetts Gen Hosp, Neuroprotect Res Lab, Charlestown, MA 02129 USA. [Ayata, Cenk; Zheng, Yi] Massachusetts Gen Hosp, Neurovasc Res Lab, Charlestown, MA USA. [Mandeville, Joseph B.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Mandeville, Emiri T.; Ayata, Cenk; Zheng, Yi; Mandeville, Joseph B.] Massachusetts Gen Hosp, Dept Radiol, Bldg 149 13th St, Charlestown, MA 02129 USA. RP Mandeville, ET (reprint author), Massachusetts Gen Hosp, Neuroprotect Res Lab, Charlestown, MA 02129 USA.; Mandeville, ET (reprint author), Massachusetts Gen Hosp, Dept Radiol, Bldg 149 13th St, Charlestown, MA 02129 USA. EM etm@nmr.mgh.harvard.edu FU National Institutes of Health [P01NS055104] FX This work was funded in part by a grant from the National Institutes of Health (P01NS055104). NR 104 TC 0 Z9 0 U1 6 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1868-4483 EI 1868-601X J9 TRANSL STROKE RES JI Transl. Stroke Res. PD FEB PY 2017 VL 8 IS 1 BP 22 EP 32 DI 10.1007/s12975-016-0497-z PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EI4TQ UT WOS:000392486700004 PM 27578048 ER PT J AU Lim, TC Spector, M AF Lim, Teck Chuan Spector, Myron TI Biomaterials for Enhancing CNS Repair SO TRANSLATIONAL STROKE RESEARCH LA English DT Article DE Scaffolds; Hydrogels; Cell transplantation; Drug and protein delivery; Immunomodulation; Glycomimetics; Matrix architecture; Bioimaging; Temporal control; Endogenous cells and molecules ID SPINAL-CORD-INJURY; NEURAL STEM-CELLS; HYALURONIC-ACID HYDROGEL; FOCAL CEREBRAL-ISCHEMIA; GROWTH-FACTOR DELIVERY; BLOOD-BRAIN-BARRIER; DRUG-DELIVERY; IN-VIVO; ELECTROSPUN SCAFFOLDS; PRECURSOR CELLS AB The health of the central nervous system (CNS) does not only rely on the state of the neural cells but also on how various extracellular components organize cellular behaviors into proper tissue functions. Biomaterials have been valuable in restoring or augmenting the roles of extracellular components in the CNS in the event of injury and disease. In this review, we highlight how biomaterials have been enabling tools in important therapeutic strategies involving cell transplantation and drug/protein delivery. We further discuss advances in biomaterial design and applications that can potentially be translated into the CNS to provide unprecedented benefits. C1 [Lim, Teck Chuan] Inst Bioengn & Nanotechnol, Singapore, Singapore. [Spector, Myron] VA Boston Healthcare Syst, Tissue Engn, Boston, MA USA. [Spector, Myron] Harvard Med Sch, Brigham & Womens Hosp, Dept Orthoped, Boston, MA USA. RP Lim, TC (reprint author), Inst Bioengn & Nanotechnol, Singapore, Singapore. EM tclim@ibn.a-star.edu.sg NR 79 TC 0 Z9 0 U1 8 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1868-4483 EI 1868-601X J9 TRANSL STROKE RES JI Transl. Stroke Res. PD FEB PY 2017 VL 8 IS 1 BP 57 EP 64 DI 10.1007/s12975-016-0470-x PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EI4TQ UT WOS:000392486700007 PM 27251413 ER PT J AU Yao, ZP Wang, LX Wu, XM Zhao, L Chi, CL Guo, L Tong, DX Yang, XY Dong, ZX Deng, RJ Novakovic, VA Thatte, HS Bi, YY Tian, Y Shi, JL Zhou, J Kou, JJ Hu, SS AF Yao, Zhipeng Wang, Lixiu Wu, Xiaoming Zhao, Lu Chi, Chunling Guo, Li Tong, Dongxia Yang, Xiaoyan Dong, Zengxiang Deng, Ruijuan Novakovic, Valerie A. Thatte, Hemant S. Bi, Yayan Tian, Ye Shi, Jialan Zhou, Jin Kou, Junjie Hu, Shaoshan TI Enhanced Procoagulant Activity on Blood Cells after Acute Ischemic Stroke SO TRANSLATIONAL STROKE RESEARCH LA English DT Article DE Acute ischemic stroke; Procoagulant; Phosphatidylserine; Microparticles; Thrombin ID CIRCULATING ENDOTHELIAL MICROPARTICLES; PHOSPHATIDYLSERINE EXPOSURE; THROMBIN GENERATION; ACUTE-PHASE; ACTIVATION; MECHANISMS; PLATELETS; DISEASE; MARKERS AB The role of phosphatidylserine (PS)-mediated procoagulant activity (PCA) in stroke remains unclear. To ascertain this role, early dynamic evolution of PS exposure on blood cells and released microparticles (MPs) and the corresponding PCA were evaluated in patients with acute ischemic stroke (AIS). Flow cytometry analyses revealed that initial levels of PS exposure on erythrocyte, platelet, and leukocyte were 2.40-, 1.36-, and 1.38-fold higher, respectively, in AIS than the risk factor-matched (RF) controls. Concomitantly, total PS+ MPs were increased in AIS (1949 +/- 483/mu l) compared with the RF group (1674 +/- 387/mu l; P = 0.019) and healthy controls (1052 +/- 179/mu l; P < 0.001). Specifically, PS+ erythrocytes gradually increased within 1 week. PS+ platelets and MPs peaked at 24 h and declined at 7 days, while PS+ leukocytes were markedly elevated at 24 h. Further, PS exposure on blood cells and MPs in stroke resulted in shortened clotting time with an accompanying increase in FXa and thrombin formation significantly. Treatment with lactadherin, a PS antagonist, delayed the coagulation time by approximately 20 % and blocked the generation of FXa and thrombin by about 50 %. Furthermore, initial counts of PS+ platelets and platelet MPs significantly correlated with stroke severity. Thrombin generation promoted by platelets and MPs at 12 h was significantly higher in patients with cardioembolism than in patients without. The thrombophilic susceptibility of AIS patients can be partly ascribed to PS exposure on blood cells and the release of MPs. Our studies identify PS exposure as a potentially novel therapeutic target in the treatment of AIS. C1 [Yao, Zhipeng; Wu, Xiaoming; Zhao, Lu; Guo, Li; Tong, Dongxia; Yang, Xiaoyan; Deng, Ruijuan; Shi, Jialan; Zhou, Jin] Harbin Med Univ, Hosp 1, Dept Hematol, 23 Youzheng St, Harbin 150001, Peoples R China. [Wang, Lixiu; Dong, Zengxiang; Bi, Yayan; Tian, Ye] Harbin Med Univ, Hosp 1, Dept Cardiol, Harbin, Peoples R China. [Chi, Chunling] Harbin Med Univ, Hosp 4, Dept Neurol, Harbin, Peoples R China. [Novakovic, Valerie A.] Harvard Med Sch, VA Boston Healthcare Syst, Brigham & Womens Hosp, Dept Res, Boston, MA USA. [Thatte, Hemant S.; Shi, Jialan] Harvard Med Sch, VA Boston Healthcare Syst, Brigham & Womens Hosp, Dept Surg, Boston, MA USA. [Kou, Junjie] Harbin Med Univ, Hosp 2, Dept Cardiol, Harbin, Peoples R China. [Hu, Shaoshan] Harbin Med Univ, Hosp 2, Dept Neurosurg, Harbin, Peoples R China. RP Shi, JL; Zhou, J (reprint author), Harbin Med Univ, Hosp 1, Dept Hematol, 23 Youzheng St, Harbin 150001, Peoples R China.; Shi, JL (reprint author), Harvard Med Sch, VA Boston Healthcare Syst, Brigham & Womens Hosp, Dept Surg, Boston, MA USA.; Kou, JJ (reprint author), Harbin Med Univ, Hosp 2, Dept Cardiol, Harbin, Peoples R China.; Hu, SS (reprint author), Harbin Med Univ, Hosp 2, Dept Neurosurg, Harbin, Peoples R China. EM jialan_shi@hms.harvard.edu; zhoujinyzp@sina.com; koujunjie000@163.com; hushaoshan000@163.com FU National Natural Science Foundation of China [81270588, 81470301, 81670128, 81670298, 61575058]; Natural Science Foundation of Heilongjiang Province [ZD2015020]; Graduate Innovation Fund of Harbin Medical University [YJSCX2015-56HYD] FX This work was supported by grants from the National Natural Science Foundation of China (81270588, 81470301, 81670128, 81670298, and 61575058), Natural Science Foundation of Heilongjiang Province (ZD2015020), and Graduate Innovation Fund of Harbin Medical University (YJSCX2015-56HYD). NR 27 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1868-4483 EI 1868-601X J9 TRANSL STROKE RES JI Transl. Stroke Res. PD FEB PY 2017 VL 8 IS 1 BP 83 EP 91 DI 10.1007/s12975-016-0501-7 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EI4TQ UT WOS:000392486700011 PM 27650774 ER PT J AU Weise, G Posel, C Moller, K Kranz, A Didwischus, N Boltze, J Wagner, DC AF Weise, Gesa Poesel, Claudia Moeller, Karoline Kranz, Alexander Didwischus, Nadine Boltze, Johannes Wagner, Daniel-Christoph TI High-dosage granulocyte colony stimulating factor treatment alters monocyte trafficking to the brain after experimental stroke SO BRAIN BEHAVIOR AND IMMUNITY LA English DT Article DE Cerebral stroke; Granulocyte colony stimulating factor; Inflammation; Monocytes; Leukocyte adhesion ID FOCAL CEREBRAL-ISCHEMIA; G-CSF; INTRACEREBRAL HEMORRHAGE; ENDOTHELIAL-CELLS; BONE-MARROW; CHEMOATTRACTANT PROTEIN-1; EMERGENCY GRANULOPOIESIS; DENDRITIC CELLS; MICE; EXPRESSION AB Ischemic stroke elicits a prompt inflammatory response that is characterized by a well-timed recruitment of peripheral immune cells to the brain. Among these, monocytes play a particularly important, but multifaceted role and have been increasingly recognized to affect stroke outcome. Granulocyte colony stimulating factor (GCSF) is known for its immunosuppressive actions on mononuclear cells, but previous studies in the stroke field were mainly confined to its neuroprotective actions. Herein, we investigated whether GCSF affects post-stroke inflammation in a mouse model of focal brain ischemia by modulating monocyte responses. Treatment with GCSF was controlled by vehicle injection, sham surgery and naive animals. Despite a significant monocytosis, high-dosage GCSF reduced the number of brain-infiltrating monocytes/macrophages four days after stroke. Lower numbers of mononuclear phagocytes in the brain were associated with smaller cerebral edema and improved motor outcome after stroke. GCSF treatment over 72 h, but not 24 h diminished integrin expression on circulating Ly6C+ inflammatory monocytes. In vitro experiments further revealed that GCSF strongly promotes interleukin (IL)-10 secretion by activated mononuclear cells. Blockade of the IL-10 receptor partly reversed GCSF-induced downregulation of integrin surface expression. Overall, our results suggest that high-dosage GCSF mitigates monocyte infiltration after stroke, likely by attenuating integrin-mediated adhesion to the brain endothelium in an IL-10-dependent manner. Lower amounts of mononuclear cells in the brain translate to less severe brain edema and functional impairment and thus support a harmful role of Ly6C+ inflammatory monocytes in the acute stage of stroke. (C) 2016 Elsevier Inc. All rights reserved. C1 [Weise, Gesa; Poesel, Claudia; Moeller, Karoline; Kranz, Alexander; Didwischus, Nadine; Boltze, Johannes; Wagner, Daniel-Christoph] Fraunhofer Inst Cell Therapy & Immunol, Perlickstr 1, D-04103 Leipzig, Germany. [Weise, Gesa] Univ Leipzig, Dept Neurol, Leipzig, Germany. [Didwischus, Nadine] Univ Leipzig, Inst Biol, Human Biol, Leipzig, Germany. [Boltze, Johannes] Univ Lubeck, Fraunhofer Res Inst Marine Biotechnol, Lubeck, Germany. [Boltze, Johannes] Univ Lubeck, Inst Med & Marine Biotechnol, Lubeck, Germany. [Boltze, Johannes] Massachusetts Gen Hosp, Charlestown, MA USA. [Boltze, Johannes] Harvard Med Sch, Stroke & Neurovasc Regulat Lab, Charlestown, MA USA. [Wagner, Daniel-Christoph] Univ Med Ctr Mainz, Inst Pathol, Mainz, Germany. RP Weise, G (reprint author), Fraunhofer Inst Cell Therapy & Immunol, Perlickstr 1, D-04103 Leipzig, Germany. EM gesa.weise@izi.fraunhofer.de NR 64 TC 1 Z9 1 U1 9 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0889-1591 EI 1090-2139 J9 BRAIN BEHAV IMMUN JI Brain Behav. Immun. PD FEB PY 2017 VL 60 BP 15 EP 26 DI 10.1016/j.bbi.2016.08.008 PG 12 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA EH6UA UT WOS:000391908200003 PM 27524669 ER PT J AU O'Donovan, A Ahmadian, AJ Neylan, TC Pacult, MA Edmondson, D Cohen, BE AF O'Donovan, Aoife Ahmadian, Ashkan J. Neylan, Thomas C. Pacult, Mark A. Edmondson, Donald Cohen, Beth E. TI Current posttraumatic stress disorder and exaggerated threat sensitivity associated with elevated inflammation in the Mind Your Heart Study SO BRAIN BEHAVIOR AND IMMUNITY LA English DT Article DE Avoidance; C-reactive protein; Fibrinogen; Inflammation; Posttraumatic stress disorder; Threat reactivity; Threat sensitivity; Trauma; Veterans; White blood cell count ID C-REACTIVE PROTEIN; REPORTED PHYSICAL-ACTIVITY; QUALITY-OF-LIFE; PSYCHOLOGICAL STRESS; DEPRESSIVE SYMPTOMS; CONSTRUCT-VALIDITY; HEALTH BEHAVIORS; PROBLEM DRINKING; PTSD SYMPTOMS; WAR VETERANS AB Objective: Elevated inflammation has been repeatedly observed in posttraumatic stress disorder (PTSD), and it may drive the development of both psychiatric symptoms and physical comorbidities. However, it is not clear if elevated inflammation is a feature of both remitted and current PTSD, and little is known about relationships between specific clusters of PTSD symptoms and inflammation. Exaggerated threat sensitivity, as indexed by threat reactivity and avoidance of perceived threats, may be particularly closely associated with inflammation. Methods: We assessed PTSD symptoms and threat sensitivity using the Clinician Administered PTSD Scale in 735 Veterans Affairs patients (35% current PTSD; 16% remitted PTSD) who participated in the Mind Your Heart Study (mean age = 59 +/- 11; 94% male). High sensitivity C-reactive protein (hsCRP), white blood cell count (WBC), and fibrinogen were used as indices of inflammation. Analysis of covariance models with planned contrasts were used to examine differences in inflammation by PTSD status, adjusting for age, sex, race, kidney function and socioeconomic status. Results: Individuals with current PTSD had significantly higher hsCRP and WBC than patients with no history of PTSD, but there were no significant differences in inflammatory markers between those with remitted versus no history of PTSD. Within patients with current PTSD, higher threat reactivity was independently associated with higher h5CRP (beta = 0.16, p = 0.01) and WBC count (beta = 0.24, <0.001), and higher effortful avoidance was associated with higher fibrinogen (beta = 0.13, p = 0.04). Conclusion: Our data indicate that elevated inflammation may be a feature of current, but not remitted, PTSD. Within patients with PTSD, higher threat reactivity was also associated with elevated inflammation. A better understanding of the relationship between threat sensitivity and inflammation may inform interventions for patients with PTSD. (C) 2016 Elsevier Inc. All rights reserved. C1 [O'Donovan, Aoife; Ahmadian, Ashkan J.; Neylan, Thomas C.; Pacult, Mark A.; Cohen, Beth E.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [O'Donovan, Aoife; Ahmadian, Ashkan J.; Neylan, Thomas C.; Pacult, Mark A.; Cohen, Beth E.] San Francisco VA Med Ctr, 4150 Clement St,116-C, San Francisco, CA 94121 USA. [O'Donovan, Aoife; Ahmadian, Ashkan J.; Neylan, Thomas C.; Pacult, Mark A.; Cohen, Beth E.] Northern Calif Inst Res & Educ, San Francisco, CA USA. [Edmondson, Donald] Columbia Univ, Med Ctr, New York, NY 10027 USA. RP O'Donovan, A (reprint author), San Francisco VA Med Ctr, 4150 Clement St,116-C, San Francisco, CA 94121 USA. EM Aoife.ODonovan@ucsf.edu FU National Heart, Lung, and Blood Institute [K23 HL 094765-0]; Irene Perstein Foundation; American Heart Association Clinical Research Program; University of California, San Francisco; Society in Science - The Branco Weiss Fellowship; [NIH-KL2TR000143]; [NIH-K01MH109871] FX The Mind Your Heart Study is funded by the National Heart, Lung, and Blood Institute (K23 HL 094765-0), the Irene Perstein Foundation, the American Heart Association Clinical Research Program, and Departmental funds from the University of California, San Francisco. Society in Science - The Branco Weiss Fellowship and NIH-KL2TR000143 and NIH-K01MH109871 provided support to AOD. NR 66 TC 0 Z9 0 U1 9 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0889-1591 EI 1090-2139 J9 BRAIN BEHAV IMMUN JI Brain Behav. Immun. PD FEB PY 2017 VL 60 BP 198 EP 205 DI 10.1016/j.bbi.2016.10.014 PG 8 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA EH6UA UT WOS:000391908200022 PM 27765647 ER PT J AU van der Vliet, QMJ Pereira, NRP Janssen, SJ Hornicek, FJ Ferrone, ML Bramer, JAM van Dijk, CN Schwab, JH AF van der Vliet, Q. M. J. Pereira, N. R. Paulino Janssen, S. J. Hornicek, F. J. Ferrone, M. L. Bramer, J. A. M. van Dijk, C. N. Schwab, J. H. TI What Factors are Associated With Quality Of Life, Pain Interference, Anxiety, and Depression in Patients With Metastatic Bone Disease? SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID CANCER-PATIENTS; FUNCTIONAL ASSESSMENT; SPINAL METASTASES; BREAST-CANCER; EORTC QLQ-C30; DEATH ANXIETY; LARGE-SAMPLE; SURVIVAL; POPULATION; PREDICTORS AB It would be helpful for the decision-making process of patients with metastatic bone disease to understand which patients are at risk for worse quality of life (QOL), pain, anxiety, and depression. Normative data, and where these stand compared with general population scores, can be useful to compare and interpret results of similar patients or patient groups, but to our knowledge, there are no such robust data. We wished (1) to assess what factors are independently associated with QOL, pain interference, anxiety, and depression in patients with metastatic bone disease, and (2) to compare these outcomes with general US population values. Between November 2011 and February 2015, 859 patients with metastatic bone disease presented to our orthopaedic oncology clinic; 202 (24%) were included as they completed the EuroQOL-5 Dimension (EQ-5D(TM)), PROMISA (R) Pain Interference, PROMISA (R) Anxiety, and PROMISA (R) Depression questionnaires as part of a quality improvement program. We did not record reasons for not responding and found no differences between survey respondents and nonrespondents in terms of age (63 versus 64 years; p = 0.916), gender (51% men versus 47% men; p = 0.228), and race (91% white versus 88% white; p = 0.306), but survey responders were more likely to be married or living with a partner (72%, versus 62%; p = 0.001). We assessed risk factors for QOL, pain interference, anxiety, and depression using multivariable linear regression analysis. We used the one-sample signed rank test to assess whether scores differed from US population averages drawn from earlier large epidemiologic studies. Younger age (beta regression coefficient [beta], < 0.01; 95% CI, 0.00-0.01; p = 0.041), smoking (beta, -0.12; 95% CI, -0.22 to -0.01; p = 0.026), pathologic fracture (beta, -0.10; 95% CI, -0.18 to -0.02; p = 0.012), and being unemployed (beta, -0.09; 95% CI, -0.17 to -0.02; p = 0.017) were associated with worse QOL. Current smoking status was associated with more pain interference (beta, 6.0; 95% CI, 1.6-11; p = 0.008). Poor-prognosis cancers (beta, 3.8; 95% CI, 0.37-7.2; p = 0.030), and pathologic fracture (beta, 6.3; 95% CI, 2.5-7.2; p = 0.001) were associated with more anxiety. Being single (beta, 5.9; 95% CI, 0.83-11; p = 0.023), and pathologic fracture (beta, 4.4; 95% CI, 0.8-8.0; p = 0.017) were associated with depression. QOL scores (0.68 versus 0.85; p < 0.001), pain interference scores (65 versus 50; p < 0.001), and anxiety scores (53 versus 50; p = 0.011) were worse for patients with bone metastases compared with general US population values, whereas depression scores were comparable (48 versus 50; p = 0.171). Impending pathologic fractures should be treated promptly to prevent deterioration in QOL, anxiety, and depression. Our normative data can be used to compare and interpret results of similar patients or patient groups. Future studies could focus on specific cancers metastasizing to the bone, to further understand which patients are at risk for worse patient-reported outcomes. Level III, prognostic study. C1 [van der Vliet, Q. M. J.; Pereira, N. R. Paulino; Janssen, S. J.; Hornicek, F. J.; Schwab, J. H.] Harvard Med Sch, Massachusetts Gen Hosp, Orthopaed Oncol Serv, Dept Orthopaed Surg, Boston, MA USA. [Ferrone, M. L.] Harvard Med Sch, Brigham & Womens Hosp, Orthopaed Oncol Serv, Dept Orthopaed Surg, Boston, MA USA. [Bramer, J. A. M.; van Dijk, C. N.] Univ Amsterdam, Dept Orthopaed Surg, Acad Med Ctr, Amsterdam, Netherlands. [Pereira, N. R. Paulino] Massachusetts Gen Hosp, Room 3-946,Yawkey Bldg,55 Fruit St, Boston, MA 02114 USA. RP Pereira, NRP (reprint author), Massachusetts Gen Hosp, Room 3-946,Yawkey Bldg,55 Fruit St, Boston, MA 02114 USA. EM nunorui.pp@gmail.com FU Anna Foundation (Oegstgeest, The Netherlands); De Drie Lichten Foundation (Hilversum, The Netherlands); KWF Kankerbestrijding (Amsterdam, The Netherlands); Michael van Vloten Foundation (Rotterdam, The Netherlands) FX One of the authors certifies that he (SJJ), or a member of his or her immediate family, has or may receive payments or benefits, during the study period, an amount of less than USD 10,000 from the Anna Foundation (Oegstgeest, The Netherlands), an amount of less than USD 10,000 from the De Drie Lichten Foundation (Hilversum, The Netherlands), an amount of less than USD 10,000 from the KWF Kankerbestrijding (Amsterdam, The Netherlands), and an amount of less than USD 10,000 from the Michael van Vloten Foundation (Rotterdam, The Netherlands). NR 32 TC 0 Z9 0 U1 11 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X EI 1528-1132 J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD FEB PY 2017 VL 475 IS 2 BP 498 EP 507 DI 10.1007/s11999-016-5118-3 PG 10 WC Orthopedics; Surgery SC Orthopedics; Surgery GA EH7CX UT WOS:000391931600035 PM 27752988 ER PT J AU Yang, YS Marder, SR Green, MF AF Yang, Y. S. Marder, S. R. Green, M. F. TI Repurposing Drugs for Cognition in Schizophrenia SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article AB Currently approved treatments for schizophrenia only minimally affect the cognitive features of the illness that are the most closely related to disability. Hence, there is now considerable effort to repurpose drugs for schizophrenia, and to seek agents that can improve cognition by targeting receptor systems other than the dopaminergic system. The results of these studies have been mixed thus far; however, this continues to be a high-priority area of schizophrenia research and an important unmet need. C1 [Yang, Y. S.; Marder, S. R.; Green, M. F.] VA Greater Los Angeles Healthcare Syst, Mental Illness Res Educ & Clin Ctr VISN22, Los Angeles, CA 90073 USA. [Yang, Y. S.; Marder, S. R.; Green, M. F.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90095 USA. RP Yang, YS (reprint author), VA Greater Los Angeles Healthcare Syst, Mental Illness Res Educ & Clin Ctr VISN22, Los Angeles, CA 90073 USA.; Yang, YS (reprint author), Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90095 USA. EM ysyang@mednet.ucla.edu FU Amgen; Forum; Neurocrine FX M.G. has been a consultant to: AbbVie, ACADIA, DSP, FORUM, Lundbeck, and Takeda; he is on the Scientific Board of Luc, and has received research support from Amgen and Forum. S.M. has been a consult to and on advisory boards for: Allergan, Takeda, Lundbeck, Otsuka, Neurocrine, and Boeringer Ingelheim, and has received research support from Forum and Neurocrine. Y.Y. has no disclosures to declare. NR 5 TC 2 Z9 2 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2017 VL 101 IS 2 BP 191 EP 193 DI 10.1002/cpt.529 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH7FS UT WOS:000391938900026 PM 27706797 ER PT J AU Ho, MF da Rocha, EL Bongartz, T Ingle, J Goss, P Mushiroda, T Kubo, M Shepherd, L Li, H Wang, L Weinshilboum, R AF Ho, M-F da Rocha, E. Lummertz Bongartz, T. Ingle, J. Goss, P. Mushiroda, T. Kubo, M. Shepherd, L. Li, H. Wang, L. Weinshilboum, R. TI TCL1A IDENTIFICATION AS A NOVEL TRANSCRIPTION FACTOR AND A PHARMACOGENOMIC LINK TO AROMATASE INHIBITOR-INDUCED MUSCULOSKELETAL ADVERSE EVENTS SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 15-18, 2017 CL Washington, DC SP Amer Soc Clin Pharmacol & Therapeut C1 [Ho, M-F; da Rocha, E. Lummertz; Ingle, J.; Li, H.; Wang, L.; Weinshilboum, R.] Mayo Clin, Rochester, MN USA. [Bongartz, T.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Goss, P.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Mushiroda, T.; Kubo, M.] RIKEN Ctr Integrat Med Sci, Yokohama, Kanagawa, Japan. [Shepherd, L.] NCIC Clin Trials Grp, Kingston, ON, Canada. 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 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2017 VL 101 IS S1 MA PWI-001 BP S15 EP S15 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH7EM UT WOS:000391935700038 ER PT J AU Ho, MF da Rocha, EL Bongartz, T Ingle, J Goss, P Mushiroda, T Kubo, M Shepherd, L Li, H Wang, L Weinshilboum, R AF Ho, M-F da Rocha, E. Lummertz Bongartz, T. Ingle, J. Goss, P. Mushiroda, T. Kubo, M. Shepherd, L. Li, H. Wang, L. Weinshilboum, R. TI TCL1A IDENTIFICATION AS A NOVEL TRANSCRIPTION FACTOR AND A PHARMACOGENOMIC LINK TO AROMATASE INHIBITOR-INDUCED MUSCULOSKELETAL ADVERSE EVENTS SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 15-18, 2017 CL Washington, DC SP Amer Soc Clin Pharmacol & Therapeut C1 [Ho, M-F; da Rocha, E. Lummertz; Ingle, J.; Li, H.; Wang, L.; Weinshilboum, R.] Mayo Clin, Rochester, MN USA. [Bongartz, T.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Goss, P.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Mushiroda, T.; Kubo, M.] RIKEN Ctr Integrat Med Sci, Yokohama, Kanagawa, Japan. [Shepherd, L.] NCIC Clin Trials Grp, Kingston, ON, Canada. 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 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2017 VL 101 IS S1 MA PT-026 BP S12 EP S12 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH7EM UT WOS:000391935700027 ER PT J AU Rotroff, DM Marvel, SW Jack, JR Havener, TM Doria, A Shah, HS Mychaleckyi, JC McLeod, HL Buse, JB Wagner, MJ Motsinger-Reif, AA AF Rotroff, D. M. Marvel, S. W. Jack, J. R. Havener, T. M. Doria, A. Shah, H. S. Mychaleckyi, J. C. McLeod, H. L. Buse, J. B. Wagner, M. J. Motsinger-Reif, A. A. CA ACCORD ACCORDion Investigators TI COMMON GENETIC VARIANTS IN NEUROBEACHIN (NBEA) ARE ASSOCIATED WITH METFORMIN DRUG RESPONSE IN INDIVIDUALS WITH TYPE 2 DIABETES IN THE ACCORD CLINICAL TRIAL SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 15-18, 2017 CL Washington, DC SP Amer Soc Clin Pharmacol & Therapeut C1 [Rotroff, D. M.; Marvel, S. W.; Jack, J. R.; Motsinger-Reif, A. A.] North Carolina State Univ, Bioinformat Res Ctr, Raleigh, NC USA. [Havener, T. M.; Wagner, M. J.] Univ North Carolina Chapel Hill, Ctr Pharmacogen & Individualized Therapy, Chapel Hill, NC USA. [Doria, A.; Shah, H. S.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Doria, A.; Shah, H. S.] Harvard Med Sch, Boston, MA USA. [Mychaleckyi, J. C.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [McLeod, H. L.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Buse, J. B.] Univ N Carolina, Sch Med, Div Endocrinol, Chapel Hill, NC USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2017 VL 101 IS S1 MA PWIV-003 BP S96 EP S96 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH7EM UT WOS:000391935700345 ER PT J AU Rotroff, DM Marvel, SW Jack, JR Havener, TM Doria, A Shah, HS Mychaleckyi, JC McLeod, HL Buse, JB Wagner, MJ Motsinger-Reif, AA AF Rotroff, D. M. Marvel, S. W. Jack, J. R. Havener, T. M. Doria, A. Shah, H. S. Mychaleckyi, J. C. McLeod, H. L. Buse, J. B. Wagner, M. J. Motsinger-Reif, A. A. CA ACCORD Investigator ACCORDion Investigator TI COMMON GENETIC VARIANTS IN NEUROBEACHIN (NBEA) ARE ASSOCIATED WITH METFORMIN DRUG RESPONSE IN INDIVIDUALS WITH TYPE 2 DIABETES IN THE ACCORD CLINICAL TRIAL SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 15-18, 2017 CL Washington, DC SP Amer Soc Clin Pharmacol & Therapeut C1 [Rotroff, D. M.; Marvel, S. W.; Jack, J. R.; Motsinger-Reif, A. A.] North Carolina State Univ, Bioinformat Res Ctr, Raleigh, NC USA. [Havener, T. M.; Wagner, M. J.] Univ North Carolina Chapel Hill, Ctr Pharmacogen & Individualized Therapy, Chapel Hill, NC USA. [Doria, A.; Shah, H. S.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Doria, A.; Shah, H. S.] Harvard Med Sch, Boston, MA USA. [Mychaleckyi, J. C.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [McLeod, H. L.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Buse, J. B.] Univ N Carolina, Div Endocrinol, Sch Med, Chapel Hill, NC USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2017 VL 101 IS S1 MA PT-017 BP S9 EP S9 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH7EM UT WOS:000391935700018 ER PT J AU Thompson, BT AF Thompson, B. Taylor TI Acute respiratory distress syndrome in another 50 years: historical footnote or persistent malady? SO CURRENT OPINION IN CRITICAL CARE LA English DT Editorial Material ID SURVIVAL; ARDS C1 [Thompson, B. Taylor] Massachusetts Gen Hosp, Dept Med, Div Pulm & Crit Care Med, 55 Fruit St, Boston, MA 02130 USA. [Thompson, B. Taylor] Harvard Med Sch, Boston, MA USA. RP Thompson, BT (reprint author), Massachusetts Gen Hosp, Dept Med, Div Pulm & Crit Care Med, 55 Fruit St, Boston, MA 02130 USA. EM thompson.taylor@mgh.harvard.edu NR 10 TC 0 Z9 0 U1 4 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1070-5295 EI 1531-7072 J9 CURR OPIN CRIT CARE JI Curr. Opin. Crit. Care PD FEB PY 2017 VL 23 IS 1 BP 1 EP 3 DI 10.1097/MCC.0000000000000383 PG 3 WC Critical Care Medicine SC General & Internal Medicine GA EH7LM UT WOS:000391954500001 PM 27922846 ER PT J AU Shah, FA Girard, TD Yende, S AF Shah, Faraaz Ali Girard, Timothy D. Yende, Sachin TI Limiting sedation for patients with acute respiratory distress syndrome - time to wake up SO CURRENT OPINION IN CRITICAL CARE LA English DT Review DE acute respiratory distress syndrome; outcomes; sedation ID INTENSIVE-CARE-UNIT; CRITICALLY-ILL PATIENTS; MECHANICALLY VENTILATED PATIENTS; RANDOMIZED CONTROLLED-TRIAL; EXTRACORPOREAL MEMBRANE-OXYGENATION; TERM COGNITIVE IMPAIRMENT; ACUTE LUNG INJURY; NEUROMUSCULAR BLOCKING-AGENTS; CONFUSION ASSESSMENT METHOD; BREATHING CONTROLLED-TRIAL AB Purpose of review Critically ill patients with acute respiratory distress syndrome (ARDS) may require sedation in their clinical care. The goals of sedation in ARDS patients are to improve patient comfort and tolerance of supportive and therapeutic measures without contributing to adverse outcomes. This review discusses the current evidence for sedation management in patients with ARDS. Recent findings Deep sedation strategies should be avoided in the care of patients with ARDS because deep sedation has been associated with increased time on mechanical ventilation, longer ICU and hospital length of stay, and higher mortality in critically ill patients. Adoption of protocol-based, light-sedation strategies is preferred and improves patient outcomes. Although the optimal sedative agent for ARDS patients is unclear, benzodiazepines should be avoided because of associations with oversedation, delirium, prolonged ICU and hospital length of stay, and increased mortality. Minimizing sedation in patients with ARDS facilitates early mobilization and early discharge from the ICU, potentially aiding in recovery from critical illness. Strategies to optimize ventilation in ARDS patients, such as low tidal volume ventilation and high positive end-expiratory pressure can be employed without deep sedation; however, deep sedation is required if patients receive neuromuscular blockade, which may benefit some ARDS patients. Knowledge gaps persist as to whether or not prone positioning and extracorporeal membrane oxygenation can be tolerated with light sedation. Summary Current evidence supports the use of protocol-based, light-sedation strategies in critically ill patients with ARDS. Further research into sedation management specifically in ARDS populations is needed. C1 [Shah, Faraaz Ali] Univ Pittsburgh, CRISMA Ctr, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA USA. [Girard, Timothy D.; Yende, Sachin] Univ Pittsburgh, CRISMA Ctr, Dept Crit Care Med, Pittsburgh, PA USA. [Yende, Sachin] VA Pittsburgh Healthcare Syst, Univ Dr C,Room 2A124, Pittsburgh, PA 15240 USA. RP Yende, S (reprint author), VA Pittsburgh Healthcare Syst, Univ Dr C,Room 2A124, Pittsburgh, PA 15240 USA. EM yendes@upmc.edu OI Girard, Timothy/0000-0002-9833-4871 FU National Institutes of Health FX F.A.S., T.D.G., and S.Y. are supported by grants from the National Institutes of Health. NR 83 TC 0 Z9 0 U1 13 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1070-5295 EI 1531-7072 J9 CURR OPIN CRIT CARE JI Curr. Opin. Crit. Care PD FEB PY 2017 VL 23 IS 1 BP 45 EP 51 DI 10.1097/MCC.0000000000000382 PG 7 WC Critical Care Medicine SC General & Internal Medicine GA EH7LM UT WOS:000391954500008 PM 27898439 ER PT J AU Ochando, J Charron, D Baptista, PM Uygun, BE AF Ochando, Jordi Charron, Dominique Baptista, Pedro M. Uygun, Basak E. TI Immune responses to bioengineered organs SO CURRENT OPINION IN ORGAN TRANSPLANTATION LA English DT Review DE allogeneicity; bioengineered organs; extracellular matrix; stem cells ID EMBRYONIC STEM-CELLS; SKELETAL-MUSCLE FIBERS; MULTIPOTENT STEM/PROGENITOR CELLS; FETAL BILIARY TREE; ORTHOTOPIC TRANSPLANTATION; REGENERATIVE MEDICINE; EXTRACELLULAR-MATRIX; ALLOGRAFT-REJECTION; LIVER-CIRRHOSIS; SATELLITE CELLS AB Purpose of review Organ donation in the United States registered 9079 deceased organ donors in 2015. This high percentage of donations allowed organ transplantation in 29 851 recipients. Despite increasing numbers of transplants performed in comparison with previous years, the numbers of patients that are in need for a transplant increase every year at a higher rate. This reveals that the discrepancy between the demand and availability of organs remains fundamental problem in organ transplantation. Recent findings Development of bioengineered organs represents a promising approach to increase the pool of organs for transplantation. The technology involves obtaining complex three-dimensional scaffolds that support cellular activity and functional remodeling though tissue recellularization protocols using progenitor cells. This innovative approach integrates cross-thematic approaches from specific areas of transplant immunology, tissue engineering and stem cell biology, to potentially manufacture an unlimited source of donor organs for transplantation. Summary Although bioengineered organs are thought to escape immune recognition, the potential immune reactivity toward each of its components has not been studied in detail. Here, we summarize the host immune response toward different progenitor cells and discuss the potential implications of using nonself biological scaffolds to develop bioengineered organs. C1 [Ochando, Jordi] Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA. [Charron, Dominique] Univ Paris Diderot, HLA & MED Jean Dausset Lab Network & Transplantex, Hop St Louis, Inserm,U976, Paris, France. [Charron, Dominique] Jiao Tong Univ, Shanghai, Peoples R China. [Baptista, Pedro M.] IIS Aragon, Zaragoza, Spain. [Baptista, Pedro M.] CIBERehd, Zaragoza, Spain. [Uygun, Basak E.] Harvard Med Sch, Shriners Hosp Children, Massachusetts Gen Hosp, Dept Surg,Ctr Engn Med, Boston, MA USA. RP Ochando, J (reprint author), Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA. EM jordi.ochando@mssm.edu FU National Institutes of Health [R00DK088962, H2020-MSCA-IF-2014-660554, ISCIII PI15/00563]; SAF [SAF2013-48834-R/SAF2016-80031-R] FX The work was supported by the National Institutes of Health (R00DK088962) to B.E.U., by H2020-MSCA-IF-2014-660554 and ISCIII PI15/00563 to P.M.B., and SAF SAF2013-48834-R/SAF2016-80031-R to J.O. NR 70 TC 0 Z9 0 U1 13 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1087-2418 EI 1531-7013 J9 CURR OPIN ORGAN TRAN JI Curr. Opin. Organ Transpl. PD FEB PY 2017 VL 22 IS 1 BP 79 EP 85 DI 10.1097/MOT.0000000000000378 PG 7 WC Transplantation SC Transplantation GA EH9NM UT WOS:000392098000011 PM 27926545 ER PT J AU Tritos, NA Chanson, P Jimenez, C King, D Jonsson, PJ Klibanski, A Biller, BMK AF Tritos, Nicholas A. Chanson, Philippe Jimenez, Camilo King, Donna Jonsson, Peter J. Klibanski, Anne Biller, Beverly M. K. TI Effectiveness of first-line pegvisomant monotherapy in acromegaly: an ACROSTUDY analysis SO EUROPEAN JOURNAL OF ENDOCRINOLOGY LA English DT Article ID LONG-TERM TREATMENT; HORMONE-RECEPTOR ANTAGONIST; CLINICAL-PRACTICE; THERAPY; SAFETY; OCTREOTIDE; EFFICACY AB Objective: To examine the effectiveness and safety of primary pegvisomant monotherapy. Design: Retrospective analysis of data extracted from ACROSTUDY (global observational outcomes study of patients with acromegaly treated with pegvisomant). Methods: The earliest time to insulin-like growth factor 1 (IGF-1) normalization on pegvisomant monotherapy was determined. Both the proportion of patients who achieved IGF-1 normalization and the time to IGF-1 normalization on pegvisomant monotherapy were assessed. Results: Eligible patients included 28 subjects on primary medical therapy (PT) and 176 controls on adjunctive pegvisomant therapy treated postoperatively, including 43 who were naive to medical therapy (NMT) and 133 who were previously treated medically and were washed out (WASH). IGF-1 normalization occurred in 76.9% (PT), 85.2% (NMT) and 78.3% (WASH) patients (P = NS). Median times to IGF-1 normalization were 0.5 year (PT), 0.7 year (NMT) and 0.6 year (WASH), P = NS. On survival analysis, the fraction of patients controlled on pegvisomant monotherapy was not different between groups. Higher baseline IGF-1 levels, obtained at study entry, predicted a lower likelihood of IGF-1 normalization on monotherapy (P = 0.012). Safety data include low prevalence of skin rashes, injection site reactions and reversible transaminase elevations. There was one patient (NMT) with a verified increase in tumor size. Conclusions: Pegvisomant monotherapy, administered either as primary medical therapy or as adjunctive therapy according to local practice, led to IGF-1 normalization in > 75% of patients. Pegvisomant monotherapy had a favorable safety profile, consistent with previous observations. Prospective data are needed to further evaluate the role of primary pegvisomant monotherapy in acromegaly. C1 [Tritos, Nicholas A.; Klibanski, Anne; Biller, Beverly M. K.] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Tritos, Nicholas A.; Klibanski, Anne; Biller, Beverly M. K.] Harvard Med Sch, Boston, MA 02115 USA. [Chanson, Philippe] Hop Univ Paris Sud, Hop Bicetre, AP HP, Serv Endocrinol & Malad Reprod, Le Kremlin Bicetre, France. [Chanson, Philippe] Univ Paris Saclay, Fac Med Paris Sud, INSERM, U 1185, Le Kremlin Bicetre, France. [Jimenez, Camilo] Univ Texas MD Anderson Canc Ctr, Endocrine Neoplasia & Hormonal Disorders, Houston, TX USA. [King, Donna] Pfizer Inc, Endocrine Care, Lawrenceville, NJ USA. [Jonsson, Peter J.] Pfizer Hlth AB, Sollentuna, Sweden. RP Tritos, NA (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA.; Tritos, NA (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM ntritos@mgh.harvard.edu FU Pfizer, Inc.; Ipsen; Novartis; Novo Nordisk; Pfizer, Inc; Antisense FX ACROSTUDY is sponsored by Pfizer, Inc. N A T, P C, C J, A K and B M K B were not compensated for their participation in the present study. N A T has received institution-directed research support from Ipsen, Novartis, Novo Nordisk and Pfizer, Inc; P C has received institution-directed research and educational support from Ipsen, Novartis, Antisense and Pfizer, Inc; C J has no conflicts of interest to disclose; D K and P J J are employees of Pfizer, Inc; A K has no conflicts of interest to disclose; B M K B has received institution-directed research support from Novartis and consulting honoraria from Ipsen, Novartis and Pfizer, Inc. NR 24 TC 0 Z9 0 U1 1 U2 1 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0804-4643 EI 1479-683X J9 EUR J ENDOCRINOL JI Eur. J. Endocrinol. PD FEB PY 2017 VL 176 IS 2 BP 213 EP 220 DI 10.1530/EJE-16-0697 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EH7MP UT WOS:000391957400017 PM 27932529 ER PT J AU Gurrera, RJ Mortillaro, G Velamoor, V Caroff, SN AF Gurrera, Ronald J. Mortillaro, Gino Velamoor, Varadaraj Caroff, Stanley N. TI A Validation Study of the International Consensus Diagnostic Criteria for Neuroleptic Malignant Syndrome SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article DE neuroleptic malignant syndrome; antipsychotics; catatonia; diagnosis; interrater agreement; validity AB Background: Neurolepticmalignant syndrome requires prompt recognition for effective management, but there are no established diagnostic criteria. This is the first validation study of recently published international expert consensus (IEC) diagnostic criteria, which include priority points assigned on the basis of the importance of each criterion for making a diagnosis of neuroleptic malignant syndrome. Methods: Data were extracted from 221 archived telephone contact reports of clinician-initiated calls to a national telephone consultation service from 1997 to 2009; each case was given a total priority point score on the basis of the IEC criteria. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, (DSM-IV-TR) research criteria, in original form and modified to accept less than "severe" rigidity, served as the primary diagnostic reference standard. Consultants' diagnostic impressions were used as a secondary reference standard. Receiver operating characteristic curve analysis was used to optimize the priority point cutoff score with respect to the reference standards. Results: Area under the receiver operating characteristic curve ranged from 0.715 (95% confidence interval, 0.645-0.785; P = 1.62 x 10(-7)) for consultant diagnoses to 0.857 (95% confidence interval, 0.808-0.907; P < 5 x 10(-10)) for modified DSM-IV-TR criteria. The latter was associated with 69.6% sensitivity and 90.7% specificity. Conclusions: Agreement was best between IEC criteria with a cutoff score of 74 and modified DSM-IV-TR criteria (sensitivity, 69.6%; specificity, 90.7%); this cutoff score demonstrated the highest agreement in all comparisons. Consultant diagnoses showed much better agreement with modified, compared with original, DSM-IV-TR criteria, suggesting that the DSM-IV-TR criterion of "severe" rigidity may be more restrictive than what most knowledgeable clinicians use in practice. C1 [Gurrera, Ronald J.] VA Boston Healthcare Syst, Boston, MA USA. [Gurrera, Ronald J.; Mortillaro, Gino] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Mortillaro, Gino] Boston Childrens Hosp, Boston, MA USA. [Velamoor, Varadaraj] Univ Western Ontario, Fac Med & Dent, London, ON, Canada. [Caroff, Stanley N.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Gurrera, RJ (reprint author), VA Boston Healthcare Syst, 940 Belmont St 116A, Brockton, MA 02301 USA. EM ronald.gurrera@va.gov NR 11 TC 0 Z9 0 U1 5 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0271-0749 EI 1533-712X J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD FEB PY 2017 VL 37 IS 1 BP 67 EP 71 DI 10.1097/JCP.0000000000000640 PG 5 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA EH5UN UT WOS:000391838500014 PM 28027111 ER PT J AU Lendon, JP AF Lendon, Jessica Penn TI A Decade of Love and Hate: Trajectories of Intergenerational Ambivalence Experienced by Two Cohorts of Older Parents and Adult Children SO JOURNAL OF FAMILY ISSUES LA English DT Article DE dyadic relationship; quality; satisfaction; quantitative; intergenerational; life course; parent-child relations ID AGING PARENTS; LIFE; MOTHERS AB The intergenerational ambivalence paradigm is a critical lens for understanding the complexities of aging families, and researchers have begun to explore the potential changes and implications of ambivalence over the life course. This study is one of few to examine trajectories of ambivalence over 13 years and is the first to include two birth cohorts of reciprocal parent-child dyads. This research uses five waves of the Longitudinal Study of Generations to assess changes in ambivalence and reciprocal influences among 903 parent-child dyads using latent growth models. Primary findings show an overall decline in ambivalence over time with different patterns by generation, cohort/life stage, and gender. Children experienced greater levels of ambivalence than parents. There is a reciprocal influence of ambivalence in parent-child dyads; parents and children have similar trajectories of ambivalence and the older generation of parents' ambivalence exerted influence on the change in their children's ambivalence over time. This study highlights the importance of using longitudinal data and reciprocal dyads in intergenerational research and adds to theory about the important influences of life stages, social contexts, and linked lives on intergenerational ambivalence. C1 [Lendon, Jessica Penn] Vet Affairs Greater Los Angeles Healthcare Syst, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. RP Lendon, JP (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM jessicapenn@gmail.com FU National Institute on Aging [RO1AG07977] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was funded by the National Institute on Aging, Grant No. RO1AG07977. NR 39 TC 0 Z9 0 U1 3 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-513X EI 1552-5481 J9 J FAM ISSUES JI J. Fam. Issues PD FEB PY 2017 VL 38 IS 3 BP 336 EP 357 DI 10.1177/0192513X16634763 PG 22 WC Family Studies SC Family Studies GA EH5GP UT WOS:000391800900003 ER PT J AU Sun, ZH Chen, FF Zhou, XH Zhang, QZ AF Sun, Zhihua Chen, Feifei Zhou, Xiaohua Zhang, Qingzhao TI Improved model checking methods for parametric models with responses missing at random SO JOURNAL OF MULTIVARIATE ANALYSIS LA English DT Article DE Empirical process; High dimensional covariates; Missing at random; Model checking; Projection ID PARTIAL LINEAR-MODEL; SINGLE-INDEX MODELS; OF-FIT TESTS; REGRESSION-MODELS; CONSISTENT TEST; BOOTSTRAP; ADEQUACY AB In this paper, we consider the lack-of-fit test of a parametric model when the response variable is missing at random. The popular imputation and inverse probability weighting methods are first employed to tackle the missing data. Then by employing the projection technique, we propose empirical-process-based testing methods to check the appropriateness of the parametric model. The asymptotic properties of the test statistics are obtained under the null and local alternative hypothetical models. It is shown that the proposed testing methods are consistent, and can detect local alternative hypothetical models converging to the null model at the parametric rate. To determine the critical values, a consistent bootstrap method is proposed, and its asymptotic properties are established. The simulation results show that the tests outperform the existing methods in terms of empirical sizes and powers, especially under the situation with high dimensional covariates. Analysis of a diabetes data set of Pima Indians is carried out to demonstrate the application of the testing procedures. (C) 2016 Elsevier Inc. All rights reserved. C1 [Sun, Zhihua] Univ Chinese Acad Sci, Beijing, Peoples R China. [Sun, Zhihua] Chinese Acad Sci, Key Lab Big Data Min & Knowledge Management, Beijing, Peoples R China. [Chen, Feifei] Renmin Univ China, Sch Stat, Beijing, Peoples R China. [Zhou, Xiaohua] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Zhou, Xiaohua] VA Puget Sound Hlth Care Syst, HSR&D Ctr Excellence, Tacoma, WA USA. [Zhang, Qingzhao] Xiamen Univ, Sch Econ, Xiamen, Peoples R China. [Zhang, Qingzhao] Xiamen Univ, Wang Yanan Inst Studies Econ, Xiamen, Peoples R China. RP Zhang, QZ (reprint author), Xiamen Univ, Sch Econ, Xiamen, Peoples R China.; Zhang, QZ (reprint author), Xiamen Univ, Wang Yanan Inst Studies Econ, Xiamen, Peoples R China. EM zhangqingzhao@amss.ac.cn FU National Natural Science Foundation of China [11571340, 11401561, U1430103, 10901162]; UCAS; Key Laboratory of Big Data Mining and Knowledge Management, Chinese Academy of Sciences FX The author would like to thank the Editor and the reviewer for their careful review and insightful comments that have led to significant improvement of this article. This research was supported by National Natural Science Foundation of China (Grant Nos. 11571340, 11401561, U1430103, 10901162), the President Fund of UCAS and the Open Project of Key Laboratory of Big Data Mining and Knowledge Management, Chinese Academy of Sciences. NR 27 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0047-259X J9 J MULTIVARIATE ANAL JI J. Multivar. Anal. PD FEB PY 2017 VL 154 BP 147 EP 161 DI 10.1016/j.jmva.2016.11.003 PG 15 WC Statistics & Probability SC Mathematics GA EH6TQ UT WOS:000391907200009 ER PT J AU Halpern, JA Shoag, JE Mittal, S Oromendia, C Ballman, KV Hershman, DL Wright, JD Shih, YCT Nguyen, PL Hu, JC AF Halpern, Joshua A. Shoag, Jonathan E. Mittal, Sameer Oromendia, Clara Ballman, Karla V. Hershman, Dawn L. Wright, Jason D. Shih, Ya-Chen Tina Nguyen, Paul L. Hu, Jim C. TI Prognostic Significance of Digital Rectal Examination and Prostate Specific Antigen in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Arm SO JOURNAL OF UROLOGY LA English DT Article DE digital rectal examination; early detection of cancer; prostatic neoplasms; prostate-specific antigen ID UNITED-STATES; PRIMARY-CARE; TRIAL; IMPACT; TRENDS; SERUM; RISK; MEN AB Purpose: The absence of definitive data or explicit guidelines regarding the use of digital rectal examination for prostate cancer screening may lead to confusion for physicians and patients alike. We evaluated the prognostic value of abnormal digital rectal examination and prostate specific antigen following the widespread dissemination of prostate specific antigen testing in the U.S. Materials and Methods: Collectively, men comprising the screening arm of the PLCO cancer screening trial who underwent digital rectal examination screening (35,350) were followed for 314,033 person-years. Adjusted analyses with competing risks regression were performed to assess the association of suspicious (nodularity, induration, asymmetry) digital rectal examination and abnormal prostate specific antigen (4 ng/ml or greater) with the detection of clinically significant prostate cancer, prostate cancer specific mortality and overall mortality. Results: Among all screening encounters with a suspicious digital rectal examination only 15.4% had a concurrently abnormal prostate specific antigen (McNemar's test p < 0.001). During followup there were 1,612 clinically significant prostate cancers detected, 64 prostate cancer specific deaths and 4,600 deaths. On multivariable analysis suspicious digital rectal examination and abnormal prostate specific antigen were associated with a greater risk of clinically significant prostate cancer (HR 2.21, 95% CI 1.99-2.44 vs HR 5.48, 95% CI 5.05-5.96, p < 0.001 and p < 0.001) and prostate cancer specific mortality (HR 2.54, 95% CI 1.41-4.58 vs HR 5.23, 95% CI 3.08-8.88, p = 0.002 and p < 0.001), respectively. Conclusions: In a secondary analysis of a contemporary U.S. cohort, suspicious digital rectal examination and abnormal prostate specific antigen on routine screening were independently associated with clinically significant prostate cancer and prostate cancer specific mortality. However, additional research is needed to optimize screening protocols. C1 [Halpern, Joshua A.; Shoag, Jonathan E.; Mittal, Sameer; Hu, Jim C.] New York Presbyterian Weill Cornell Med, Dept Urol, New York, NY USA. [Oromendia, Clara; Ballman, Karla V.] Weill Cornell Med, Dept Healthcare Policy & Res, New York, NY USA. [Hershman, Dawn L.; Wright, Jason D.] Columbia Univ Coll Phys & Surg, Herbert Irving Comprehens Canc Ctr, 630 W 168th St, New York, NY 10032 USA. [Shih, Ya-Chen Tina] Univ Texas MD Anderson Canc Ctr, Dept Hlth Serv Res, Houston, TX 77030 USA. [Nguyen, Paul L.] Harvard Med Sch, Dana Farber Brigham & Womens Canc Ctr, Dept Radiat Oncol, Boston, MA USA. RP Hu, JC (reprint author), Weill Cornell Med, 525 East 70th St,Starr 900, New York, NY 10065 USA. EM jch9011@med.cornell.edu NR 29 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD FEB PY 2017 VL 197 IS 2 BP 363 EP 368 DI 10.1016/j.juro.2016.08.092 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA EH8YT UT WOS:000392059300035 PM 27569432 ER PT J AU Chang, P Regan, MM Ferrer, M Guedea, F Patil, D Wei, JT Hembroff, LA Michalski, JM Saigal, CS Litwin, MS Hamstra, DA Kaplan, ID Ciezki, JP Klein, EA Kibel, AS Sandler, HM Dunn, RL Crociani, CM Sanda, MG AF Chang, Peter Regan, Meredith M. Ferrer, Montserrat Guedea, Ferran Patil, Dattatraya Wei, John T. Hembroff, Larry A. Michalski, Jeff M. Saigal, Chris S. Litwin, Mark S. Hamstra, Daniel A. Kaplan, Irving D. Ciezki, Jay P. Klein, Eric A. Kibel, Adam S. Sandler, Howard M. Dunn, Rodney L. Crociani, Catrina M. Sanda, Martin G. CA PROST-QA Consortium TI Relief of Urinary Symptom Burden after Primary Prostate Cancer Treatment SO JOURNAL OF UROLOGY LA English DT Article DE prostatic neoplasms; quality of life; outcome assessment (health care); surveys and questionnaires; patient-centered care ID QUALITY-OF-LIFE; RADICAL PROSTATECTOMY; TRACT SYMPTOMS; FOLLOW-UP; BRACHYTHERAPY; OUTCOMES; RADIOTHERAPY; INDEX; PREVALENCE; RADIATION AB Purpose: Harms of prostate cancer treatment on urinary health related quality of life have been thoroughly studied. In this study we evaluated not only the harms but also the potential benefits of prostate cancer treatment in relieving the pretreatment urinary symptom burden. Materials and Methods: In American (1,021) and Spanish (539) multicenter prospective cohorts of men with localized prostate cancer we evaluated the effects of radical prostatectomy, external radiotherapy or brachytherapy in relieving pretreatment urinary symptoms and in inducing urinary symptoms de novo, measured by changes in urinary medication use and patient reported urinary bother. Results: Urinary symptom burden improved in 23% and worsened in 28% of subjects after prostate cancer treatment in the American cohort. Urinary medication use rates before treatment and 2 years after treatment were 15% and 6% with radical prostatectomy, 22% and 26% with external radiotherapy, and 19% and 46% with brachytherapy, respectively. Pretreatment urinary medication use (OR 1.4, 95% CI 1.0-2.0, p = 0.04) and pretreatment moderate lower urinary tract symptoms (OR 2.8, 95% CI 2.2-3.6) predicted prostate cancer treatment associated relief of baseline urinary symptom burden. Subjects with pretreatment lower urinary tract symptoms who underwent radical prostatectomy experienced the greatest relief of pretreatment symptoms (OR 4.3, 95% CI 3.0-6.1), despite the development of deleterious de novo urinary incontinence in some men. The magnitude of pretreatment urinary symptom burden and beneficial effect of cancer treatment on those symptoms were verified in the Spanish cohort. Conclusions: Men with pretreatment lower urinary tract symptoms may experience benefit rather than harm in overall urinary outcome from primary prostate cancer treatment. Practitioners should consider the full spectrum of urinary symptom burden evident before prostate cancer treatment in treatment decisions. C1 [Chang, Peter; Crociani, Catrina M.] Beth Israel Deaconess Med Ctr, Dept Surg, 330 Brookline Ave, Boston, MA 02215 USA. [Kaplan, Irving D.] Beth Israel Deaconess Med Ctr, Dept Radiat Oncol, Boston, MA 02215 USA. [Regan, Meredith M.] Harvard Med Sch, Dept Biostat & Computat Biol, Dana Farber Canc Inst, Boston, MA USA. [Regan, Meredith M.] Harvard Med Sch, Div Urol, Brigham & Womens Hosp, Boston, MA USA. [Kibel, Adam S.] Harvard Med Sch, Boston, MA USA. [Ferrer, Montserrat] Univ Autonoma Barcelona, Res Inst, Hlth Serv Res Unit, Hosp del Mar, Barcelona, Spain. [Ferrer, Montserrat] Univ Autonoma Barcelona, CIBER Epidemiol & Salud Publ, Barcelona, Spain. [Guedea, Ferran] Inst Catala Oncol, Dept Radiat Oncol, Barcelona, Spain. [Wei, John T.; Dunn, Rodney L.] Univ Michigan, Dept Urol, Ann Arbor, MI 48109 USA. [Hembroff, Larry A.] Michigan State Univ, Off Survey Res, Inst Publ Policy & Social Res, E Lansing, MI 48824 USA. [Saigal, Chris S.; Litwin, Mark S.] UCLA Ctr Hlth Sci, Dept Urol, Los Angeles, CA USA. [Litwin, Mark S.] UCLA Ctr Hlth Sci, Dept Hlth Policy & Management, Los Angeles, CA USA. [Sandler, Howard M.] Cedars Sinai Med Ctr, Dept Radiat Oncol, Los Angeles, CA 90048 USA. [Hamstra, Daniel A.] Texas Ctr Proton Therapy, Irving, TX USA. [Ciezki, Jay P.] Cleveland Clin, Dept Radiat Oncol, Cleveland, OH 44106 USA. [Klein, Eric A.] Cleveland Clin, Glickman Urol & Kidney Inst, Cleveland, OH 44106 USA. [Patil, Dattatraya; Sanda, Martin G.] Emory Univ, Sch Med, Dept Urol, Atlanta, GA USA. RP Chang, P (reprint author), Beth Israel Deaconess Med Ctr, Prostate Canc Care Ctr, 330 Brookline Ave,Rabb 440, Boston, MA 02215 USA.; Chang, P (reprint author), Harvard Med Sch, 330 Brookline Ave,Rabb 440, Boston, MA 02215 USA. EM pchang@bidmc.harvard.edu FU National Institutes of Health [R01 CA95662, RC1 CA146596, RC1 EB011001]; Instituto de Salud Carlos III FEDER: Fondo Europeo de Desarrollo Regional [PI13/00412]; Urology Care Foundation Research Scholar Award; Martin and Diane Trust Career Development Chair in Surgery FX The PROST-QA Consortium was supported by National Institutes of Health Grants R01 CA95662, RC1 CA146596 and RC1 EB011001.; The Multicentric Spanish Group of Clinically Localized Prostate Cancer was supported by a grant from Instituto de Salud Carlos III FEDER: Fondo Europeo de Desarrollo Regional (PI13/00412).; Supported by a Urology Care Foundation Research Scholar Award, and the Martin and Diane Trust Career Development Chair in Surgery. NR 29 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD FEB PY 2017 VL 197 IS 2 BP 376 EP 383 DI 10.1016/j.juro.2016.08.101 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA EH8YT UT WOS:000392059300038 PM 27593476 ER PT J AU Mirheydar, H Zhou, T Chang, DC Hsieh, TC AF Mirheydar, H. Zhou, T. Chang, D. C. Hsieh, T. C. TI Re: Reoperation Rates for Penile Prosthetic Surgery Editorial Comment SO JOURNAL OF UROLOGY LA English DT Editorial Material C1 [Mirheydar, H.] Univ Calif San Diego Hlth, Dept Urol, San Diego, CA 92103 USA. Univ Calif San Diego, Sch Med, La Jolla, CA 92093 USA. Harvard Med Sch, Codman Ctr, Massachusetts Gen Hosp, Boston, MA USA. RP Mirheydar, H (reprint author), Univ Calif San Diego Hlth, Dept Urol, San Diego, CA 92103 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD FEB PY 2017 VL 197 IS 2 BP 421 EP 421 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA EH8YT UT WOS:000392059300062 ER PT J AU van Opstal, AM van Rooden, S van Harten, T Ghariq, E Labadie, G Fotiadis, P Gurol, ME Terwindt, GM Wermer, MJH van Buchem, MA Greenberg, SM van der Grond, J AF van Opstal, Anna M. van Rooden, Sanneke van Harten, Thijs Ghariq, Eidrees Labadie, Gerda Fotiadis, Panagiotis Gurol, M. Edip Terwindt, Gisela M. Wermer, Marieke J. H. van Buchem, Mark A. Greenberg, Steven M. van der Grond, Jeroen TI Cerebrovascular function in presymptomatic and symptomatic individuals with hereditary cerebral amyloid angiopathy: a case-control study SO LANCET NEUROLOGY LA English DT Article ID DUTCH TYPE; HEMORRHAGE; DYSFUNCTION; PATHOLOGY; MODEL AB Background Previous work suggests that impairments of cerebrovascular flow or reactivity might be early markers of cerebral amyloid angiopathy (CAA). Hereditary cerebral haemorrhage with amyloidosis Dutch type (HCHWA-D) is a genetic form of CAA that can be diagnosed before the onset of clinical symptoms by DNA testing. We aimed to investigate whether haemodynamic measures are decreased in presymptomatic and symptomatic HCHWA-D mutation carriers compared with healthy controls. Methods In this case-control study, we included presymptomatic and symptomatic HCHWA-D mutation carriers diagnosed through genetic testing and recruited through the HCHWA-D patient association (Katwijk, Netherlands) and the outpatient clinic of the Department of Neurology of the Leiden University Medical Center (Leiden, Netherlands), and healthy controls. We measured regional cerebral blood flow (rCBF) using pseudo-continuous arterial spin labelling. Quantitative flow was measured by phase-contrast magnetic resonance angiography of the cerebropetal vessels. Vascular reactivity was established by measuring changes in blood-oxygen-level-dependent (BOLD) signal after visual stimulation. Data from presymptomatic and symptomatic individuals were compared with healthy controls using mixed-model regression analysis. Findings Between May 15,2012, and December 22,2015, we investigated cross-sectional imaging data from 27 HCHWA-D mutation carriers (12 presymptomatic and 15 symptomatic) and 33 healthy controls. Compared with controls, symptomatic HCHWA-D carriers had significantly decreased cortical grey matter rCBF in the occipital lobe (mean difference -11.1 mL/100 g per min, 95% CI -2.8 to -19.3; uncorrected p=0.010) and decreased flux in the basilar artery (mean difference -0.9 mL/s, 95% CI -1.5 to -0.2; uncorrected p=0.019). However, we noted no changes in rCBF and flux in presymptomatic carriers compared with controls. Vascular reactivity was significantly decreased in the occipital lobe in both presymptomatic (mean BOLD change 1.1% [SD 0.5], mean difference -0.4% change, 95% CI -0.7 to -0.2; p=0.001; mean time to baseline 10.1 s [SD 7.6], mean difference 4.6 s, 95% CI 0.4 to 8.8; p=0.032) and symptomatic carriers (mean BOLD change 0.4% [SD 0.1], mean difference 0.9%, 95% CI -1.1 to -0.6; p<0.0001; mean time to baseline 20.3 s [SD 8.4], mean difference 13.1 s, 95% CI 9.4 to 16.9; p<0.0001) compared with controls; however, the difference in mean time to peak was only significant for symptomatic carriers (mean difference 12.2 s, 95% CI 8.6 to 15.9; p<0.0001). Interpretation Our findings suggest that determination of vascular reactivity might be a useful biomarker for early detection of vascular amyloid pathology in sporadic CAA, and a biomarker of efficacy in future intervention trials. Our data indicate that vascular reactivity measurements might be useful for differential diagnosis in dementia to determine the vascular component. C1 [van Opstal, Anna M.; van Rooden, Sanneke; van Harten, Thijs; Ghariq, Eidrees; Labadie, Gerda; van Buchem, Mark A.; van der Grond, Jeroen] Leiden Univ, Med Ctr, Dept Radiol, NL-2300 RC Leiden, Netherlands. [Terwindt, Gisela M.; Wermer, Marieke J. H.] Leiden Univ, Med Ctr, Dept Neurol, Leiden, Netherlands. [Fotiadis, Panagiotis; Gurol, M. Edip; Greenberg, Steven M.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP van Opstal, AM (reprint author), Leiden Univ, Med Ctr, Dept Radiol, NL-2300 RC Leiden, Netherlands. EM a.m.van_opstal@lumc.nl FU USA National Institutes of Health FX USA National Institutes of Health. NR 21 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 EI 1474-4465 J9 LANCET NEUROL JI Lancet Neurol. PD FEB PY 2017 VL 16 IS 2 BP 115 EP 122 DI 10.1016/S1474-4422(16)30346-5 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA EH6VA UT WOS:000391910800010 PM 27989553 ER PT J AU Sands, SA Harel, BT Savone, M Kelly, K Vijayanathan, V Welch, JG Vrooman, L Silverman, LB Cole, PD AF Sands, Stephen A. Harel, Brian T. Savone, Mirko Kelly, Kara Vijayanathan, Veena Welch, Jennifer Greene Vrooman, Lynda Silverman, Lewis B. Cole, Peter D. TI Feasibility of baseline neurocognitive assessment using Cogstate during the first month of therapy for childhood leukemia SO SUPPORTIVE CARE IN CANCER LA English DT Article DE Neurocognitive; Acute lymphoblastic leukemia; Neurotoxicity; Methotrexate; Late effects; Biomarkers ID ACUTE LYMPHOBLASTIC-LEUKEMIA; LONG-TERM SURVIVORS; CHEMOTHERAPY-ONLY TREATMENT; COGNITIVE IMPAIRMENT; INTRATHECAL METHOTREXATE; CONTEMPORARY TREATMENT; CRANIAL IRRADIATION; CEREBROSPINAL-FLUID; EXECUTIVE FUNCTION; ADULT SURVIVORS AB Neurocognitive impairment is frequently observed among acute lymphoblastic leukemia (ALL) survivors within the domains of intelligence, attention, processing speed, working memory, learning, and memory. However, few have investigated treatment-induced changes in neurocognitive function during the first months of treatment. Additionally, dysfunction during treatment may be preceded by changes in biomarkers measured within cerebrospinal fluid (CSF). Identification of acute declines in neurocognitive function, as well as predictive genotypes or biomarkers, could guide therapeutic trials of protective interventions. This study collects CSF while prospectively assessing neurocognitive functioning (working memory, executive function, learning, processing speed, and attention) of ALL patients using the Cogstate computerized battery at six time points during and after the 2 years of leukemia treatment on a Dana-Farber Cancer Institute ALL Consortium trial. Baseline data collected during the first 3 weeks of induction chemotherapy indicate reliable data as all subjects (N = 34) completed Cogstate baseline testing, while completion and performance checks indicate that 100 % of subjects completed testing and complied with test requirements. The majority (85 %) exhibited normal function compared with age peers. Preliminary analysis of CSF biomarkers (folate, homocysteine, 8-isoprostane, and myelin basic protein) similarly reveals values at baseline within expected normal ranges. The first month of induction therapy for ALL is a reliable baseline for detecting treatment-induced changes in neurocognitive functioning. Consequently, serial data collection might identify subgroups of ALL patients at increased risk for neurocognitive decline, warranting proactive interventions to improve their level of functioning both during treatment and into survivorship. C1 [Sands, Stephen A.; Savone, Mirko; Kelly, Kara] Columbia Univ, Med Ctr, Div Pediat Hematol Oncol & Stem Cell Transplantat, 161 Ft Washington Ave, New York, NY USA. [Sands, Stephen A.] Mem Sloan Kettering Canc Ctr, Div Psychiat & Behav Sci, 641 Lexington Ave 7th Floor, New York, NY 10022 USA. [Harel, Brian T.] Cogstate Inc, 195 Church St, New Haven, CT USA. [Harel, Brian T.] Yale Sch Med, Yale Child Study Ctr, 230 South Frontage Rd, New Haven, CT USA. [Vijayanathan, Veena; Cole, Peter D.] Albert Einstein Coll Med, Dept Pediat, 3415 Bainbridge Ave, Bronx, NY 10467 USA. [Welch, Jennifer Greene] Brown Univ, Dept Pediat, Alpert Med Sch, Div Pediat Hematol Oncol, Providence, RI 02912 USA. [Vrooman, Lynda; Silverman, Lewis B.] Boston Childrens Hosp, Dana Farber Canc Inst, Dept Pediat Oncol, Div Pediat Hematol Oncol, 450 Brookline Ave, Boston, MA USA. RP Sands, SA (reprint author), Columbia Univ, Med Ctr, Div Pediat Hematol Oncol & Stem Cell Transplantat, 161 Ft Washington Ave, New York, NY USA.; Sands, SA (reprint author), Mem Sloan Kettering Canc Ctr, Div Psychiat & Behav Sci, 641 Lexington Ave 7th Floor, New York, NY 10022 USA. EM sandss@mskcc.org FU NIH/NCI [R21-CA187226] FX Patients were enrolled at the following sites: Columbia University Medical Center, New York, NY; The Children's Hospital at Montefiore, Bronx, NY; Dana-Farber Cancer Institute/Boston Children's Hospital, Boston, NY; and Hasbro Children's Hospital, Providence, RI. This work was supported in part by NIH/NCI R21-CA187226. NR 44 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-4355 EI 1433-7339 J9 SUPPORT CARE CANCER JI Support. Care Cancer PD FEB PY 2017 VL 25 IS 2 BP 449 EP 457 DI 10.1007/s00520-016-3422-9 PG 9 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA EH2RN UT WOS:000391615500015 PM 27726029 ER PT J AU Barry, MJ Fowler, FJ O'Leary, MP Bruskewitz, RC Holtgrewe, HL Mebust, WK Cockett, ATK AF Barry, Michael J. Fowler, Floyd J. O'Leary, Michael P. Bruskewitz, Reginald C., Jr. Holtgrewe, H. Logan Mebust, Winston K. Cockett, Abraham T. K. CA Measurement Comm Amer Urol Associa TI THE AMERICAN UROLOGICAL ASSOCIATION SYMPTOM INDEX FOR BENIGN PROSTATIC HYPERPLASIA SO JOURNAL OF UROLOGY LA English DT Article DE prostatic hypertrophy; prostatic diseases; statistics ID TRANSURETHRAL PROSTATECTOMY AB A symptom index for benign prostatic hyperplasia (BPH) was developed and validated by a multidisciplinary measurement committee of the American Urological Association (AUA). Validation studies were conducted involving a total of 210 BPH patients and 108 control subjects. The final AUA symptom index includes 7 questions covering frequency, nocturia, weak urinary stream, hesitancy, intermittence, incomplete emptying and urgency. On revalidation, the index was internally consistent (Cronbach's alpha = 0.86) and the score generated had excellent test-retest reliability (r = 0.92). Scores were highly correlated with subjects' global ratings of the magnitude of their urinary problem (r = 0.65 to 0.72) and powerfully discriminated between BPH and control subjects (receiver operating characteristic area 0.85). Finally, the index was sensitive to change, with preoperative scores decreasing from a mean of 17.6 to 7.1 by 4 weeks after prostatectomy (p<0,001), The AUA symptom index is clinically sensible, reliable, valid and responsive. It is practical for use in practice and for inclusion in research protocols. C1 [Barry, Michael J.] Massachusetts Gen Hosp, Med Practices Evaluat Ctr, Boston, MA 02114 USA. Univ Massachusetts, Harvard Med Sch, Survey Res Ctr, Boston, MA 02125 USA. Tufts Univ, Sch Med, Dept Urol, Boston, MA 02111 USA. Univ Wisconsin, Dept Urol, Madison, WI USA. Johns Hopkins Univ, Baltimore, MD USA. Univ Rochester, Med Ctr, Rochester, NY 14642 USA. Univ Kansas, Med Ctr, Urol Sect, Kansas City, KS 66103 USA. Amer Urol Assoc, Boston, MA USA. RP Barry, MJ (reprint author), Massachusetts Gen Hosp, Med Practices Evaluat Ctr, Boston, MA 02114 USA. FU Patient Outcome Research Team (PORT) Grant from the Center for Medical Effectiveness Research of the Agency for Health Care Policy and Research [HSO 6336]; American Urological Association, Inc. FX Supported by Patient Outcome Research Team (PORT) Grant HSO 6336 from the Center for Medical Effectiveness Research of the Agency for Health Care Policy and Research, and by the American Urological Association, Inc. NR 17 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD FEB PY 2017 VL 197 IS 2 SU S BP S189 EP S197 DI 10.1016/j.juro.2016.10.071 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA EH5XA UT WOS:000391845100044 PM 28012747 ER PT J AU Politano, VA Leadbetter, WF AF Politano, Victor A. Leadbetter, Wyland F. TI AN OPERATIVE TECHNIQUE FOR THE CORRECTION OF VESICOURETERAL REFLUX SO JOURNAL OF UROLOGY LA English DT Article C1 [Politano, Victor A.; Leadbetter, Wyland F.] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. RP Politano, VA (reprint author), Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. NR 0 TC 0 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 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD FEB PY 2017 VL 197 IS 2 SU S BP S94 EP S100 DI 10.1016/j.juro.2016.10.093 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA EH5XA UT WOS:000391845100014 PM 28012771 ER PT J AU Prout, GR AF Prout, George R., Jr. TI INTRACAVITARY BACILLUS CALMETTE-GUERIN IN THE TREATMENT OF SUPERFICIAL BLADDER TUMORS COMMENT SO JOURNAL OF UROLOGY LA English DT Editorial Material C1 [Prout, George R., Jr.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Prout, GR (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD FEB PY 2017 VL 197 IS 2 SU S BP S144 EP S145 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA EH5XA UT WOS:000391845100029 PM 28012769 ER PT J AU Levison, JH Regan, S Khan, I Freedberg, KA AF Levison, Julie H. Regan, Susan Khan, Iman Freedberg, Kenneth A. TI Foreign-born status as a predictor of engagement in HIV care in a large US metropolitan health system SO AIDS CARE-PSYCHOLOGICAL AND SOCIO-MEDICAL ASPECTS OF AIDS/HIV LA English DT Article DE Immigrant health; foreign born; HIV; AIDS; outcomes; linkage to care; engagement in care ID HUMAN-IMMUNODEFICIENCY-VIRUS; ANTIRETROVIRAL THERAPY; UNITED-STATES; HIV-1-INFECTED PATIENTS; INCOME COUNTRIES; MEDICAL-CARE; 1ST YEAR; INFECTION; DIAGNOSIS; RETENTION AB We sought to determine the linkage to and retention in HIV care after HIV diagnosis in foreign-born compared with US-born individuals. From a clinical data registry, we identified 619 patients aged 18 years with a new HIV diagnosis between 2000 and 2012. Timely linkage to care was the proportion of patients with an ICD-9 code for HIV infection (V08 or 042) associated with a primary care or infectious disease physician within 90 days of the index positive HIV test. Retention in HIV care was the presence of an HIV primary care visit in each 6-month period of the 24-month measurement period from the index HIV test. We used Cox regression analysis with adjustment for hypothesized confounders (age, gender, race/ethnicity, substance abuse, year, and location of HIV diagnosis). Foreign-born individuals comprised 36% (225/619) of the cohort. Index CD4 count was 225/mu l (IQR 67-439/mu l) in foreign-born compared with 328/mu l (IQR 121-527/mu l) in US-born individuals (p<.001). The proportion linked to care was 87% (196/225) in foreign-born compared with 77% (302/394) in US-born individuals (p=.002). The adjusted hazard ratio of linkage to HIV care in foreign-born compared with US-born individuals was 1.28 (95% confidence interval [CI], 1.05-1.56). Once linked, there was no difference in retention in care or virologic suppression at 24 months. These results show that despite late presentation to HIV care, foreign-born persons can subsequently engage in HIV care as well as US-born persons. Interventions that promote HIV screening in foreign-born persons are a promising way to improve outcomes in these populations. C1 [Levison, Julie H.; Regan, Susan; Khan, Iman; Freedberg, Kenneth A.] Massachusetts Gen Hosp, Div Gen Internal Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. [Levison, Julie H.; Regan, Susan; Freedberg, Kenneth A.] Harvard Med Sch, Boston, MA USA. [Freedberg, Kenneth A.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Freedberg, Kenneth A.] Massachusetts Gen Hosp, Med Practice Evaluat Ctr, Boston, MA 02114 USA. [Freedberg, Kenneth A.] Harvard Univ, Harvard Univ Ctr AIDS Res, Boston, MA 02115 USA. RP Levison, JH (reprint author), Massachusetts Gen Hosp, Div Gen Internal Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM jlevison@partners.org FU US National Institute of Mental Health [K23 MH100978]; National Institute of Allergy and Infectious Diseases [R01 AI042006]; Harvard University Center for AIDS Research [P30 AI060354]; Harvard Catalyst \ The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health) [KL2 TR001100]; Harvard Medical School Eleanor and Miles Shore 50th Anniversary Award FX The work was supported by the US National Institute of Mental Health [K23 MH100978]; National Institute of Allergy and Infectious Diseases [R01 AI042006]; Harvard University Center for AIDS Research [P30 AI060354]; Harvard Catalyst vertical bar The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award KL2 TR001100; and the Harvard Medical School Eleanor and Miles Shore 50th Anniversary Award. NR 46 TC 0 Z9 0 U1 8 U2 8 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0954-0121 EI 1360-0451 J9 AIDS CARE JI Aids Care-Psychol. Socio-Med. Asp. Aids-Hiv PD FEB PY 2017 VL 29 IS 2 BP 244 EP 251 DI 10.1080/09540121.2016.1210077 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 EF5ZA UT WOS:000390407400016 PM 27469972 ER PT J AU Vogelzang, NJ Fizazi, K Burke, JM De Wit, R Bellmunt, J Hutson, TE Crane, E Berry, WR Doner, K Hainsworth, JD Wiechno, PJ Liu, KJ Waldman, MF Gandhi, A Barton, D Jungnelius, U Fandi, A Sternberg, CN Petrylak, DP AF Vogelzang, Nicholas J. Fizazi, Karim Burke, John M. De Wit, Ronald Bellmunt, Joaquim Hutson, Thomas E. Crane, Edward Berry, William R. Doner, Kevin Hainsworth, John D. Wiechno, Pawel J. Liu, Kejian Waldman, Michelle F. Gandhi, Anita Barton, Debora Jungnelius, Ulf Fandi, Abderrahim Sternberg, Cora N. Petrylak, Daniel P. TI Circulating Tumor Cells in a Phase 3 Study of Docetaxel and Prednisone with or without Lenalidomide in Metastatic Castration-resistant Prostate Cancer SO EUROPEAN UROLOGY LA English DT Article DE Prostate cancer; Metastatic castration-resistant prostate cancer; Circulating tumor cells; Docetaxel; Lenalidomide ID END-POINTS; SURVIVAL; TRIAL; CHEMOTHERAPY; SURROGATE; MEN AB Elevated circulating tumor cell (CTC) blood levels (>= 5 cells/7.5 ml) convey a negative prognosis in metastatic castration-resistant prostate cancer but their prognostic significance in patients receiving chemotherapy is uncertain. The association between CTC counts (at baseline or after treatment), overall survival (OS), and response to docetaxelwith lenalidomidewas evaluated in a 208-patient subset fromtheMAINSAIL trial, which compared docetaxel-prednisone-lenalidomide and docetaxel-prednisoneplacebo inmetastatic castration-resistant prostate cancer patients. Baseline CTCswere < 5 cells/7.5 ml blood in 87 (42%) patients and >= 5 cells/7.5 ml in 121 (58%) patients. Neither tumor response nor prostate-specific antigen response correlated with baseline CTCs. However, CTC count >= 5 cells/7.5 ml was significantly associated with lower OS (hazard ratio: 3.23, p = 0.0028). Increases in CTCs from < 5 cells/7.5 ml to >= 5 cells/7.5 ml after three cycleswere associated with significantly shorter OS (hazard ratio: 5.24, p = 0.025), whereas CTC reductions from >= 5 cells/7.5 ml to >= 5 cells/7.5 ml were associated with the best prognosis (p = 0.003). Patient summary: Our study in metastatic castration-resistant prostate cancer patients treated with docetaxel chemotherapy, with or without lenalidomide, showed that patient survival was best predicted by circulating tumor cell count at the start of treatment. A rising circulating tumor cell count after three cycles of therapy predicted poor survival, while a decline predicted good survival. (C) 2016 European Association of Urology. Published by Elsevier B. V. All rights reserved. C1 [Bellmunt, Joaquim; Crane, Edward; Hainsworth, John D.; Waldman, Michelle F.] US Oncol Res, Houston, TX USA. [Vogelzang, Nicholas J.; De Wit, Ronald; Berry, William R.; Liu, Kejian] Comprehens Canc Centers Nevada, 3730 South Eastern Ave, Las Vegas, NV 89169 USA. [Burke, John M.; Wiechno, Pawel J.; Barton, Debora] Univ Paris Sud, Inst Gustave Roussy, Dept Canc Med, Villejuif, France. [Burke, John M.; Crane, Edward; Liu, Kejian; Barton, Debora] Rocky Mt Canc Ctr, Aurora, CO USA. [Crane, Edward; Berry, William R.; Hainsworth, John D.; Wiechno, Pawel J.] Erasmus MC, Inst Canc, Rotterdam, Netherlands. [Burke, John M.; Hutson, Thomas E.; Doner, Kevin; Waldman, Michelle F.] Univ Hosp Mar IMIM, Barcelona, Spain. [De Wit, Ronald; Hutson, Thomas E.; Wiechno, Pawel J.; Gandhi, Anita] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA USA. [Bellmunt, Joaquim; Crane, Edward] Texas Oncology Baylor Charles A Sammons Canc Ctr, Dallas, TX USA. [Fizazi, Karim; Crane, Edward; Doner, Kevin] Oncol Hematol Care Inc, Cincinnati, OH USA. [Hutson, Thomas E.] US Oncol, Canc Ctr N Carolina, Raleigh, NC USA. [Bellmunt, Joaquim; Berry, William R.; Hainsworth, John D.] Texas Oncol, Austin, TX USA. [Bellmunt, Joaquim; Berry, William R.; Waldman, Michelle F.] Sarah Cannon Res Inst, Nashville, TN USA. [Bellmunt, Joaquim; Berry, William R.; Liu, Kejian] Inst Marii Sklodowskiej, Dept Uro Oncol Ctr Onkol, Warsaw, Poland. [Burke, John M.; Wiechno, Pawel J.; Liu, Kejian] Celgene Corp, Summit, NJ USA. [De Wit, Ronald; Bellmunt, Joaquim; Hutson, Thomas E.] San Camillo & Forlanini Hosp, Dept Med Oncol, Rome, Italy. [Crane, Edward; Berry, William R.; Liu, Kejian] Dept Med Div Oncol, Yale Canc Ctr, New Haven, CT USA. RP Vogelzang, NJ (reprint author), Comprehens Canc Centers Nevada, 3730 South Eastern Ave, Las Vegas, NV 89169 USA. EM Nicholas.Vogelzang@usoncology.com FU Celgene Corporation FX This study was funded by Celgene Corporation. NR 10 TC 2 Z9 2 U1 4 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD FEB PY 2017 VL 71 IS 2 BP 168 EP 171 DI 10.1016/j.eururo.2016.07.051 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA EF8FY UT WOS:000390565700027 PM 27522164 ER PT J AU Wells, JC Stukalin, I Norton, C Srinivas, S Lee, JL Donskov, F Bjarnason, GA Yamamoto, H Beuselinck, B Rini, BI Knox, JJ Agarwal, N Ernst, DS Pal, SK Wood, LA Bamias, A Alva, AS Kanesvaran, R Choueiri, TK Heng, DYC AF Wells, J. Connor Stukalin, Igor Norton, Craig Srinivas, Sandy Lee, Jae Lyun Donskov, Frede Bjarnason, Georg A. Yamamoto, Haru Beuselinck, Benoit Rini, Brian I. Knox, Jennifer J. Agarwal, Neeraj Ernst, D. Scott Pal, Sumanta K. Wood, Lori A. Bamias, Aristotelis Alva, Ajjai S. Kanesvaran, Ravindran Choueiri, Toni K. Heng, Daniel Y. C. TI Third-line Targeted Therapy in Metastatic Renal Cell Carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium SO EUROPEAN UROLOGY LA English DT Article DE Metastatic renal cell carcinoma; Third line therapy; Targeted therapy ID PHASE-3 TRIAL; EVEROLIMUS; CANCER AB Background: The use of third-line targeted therapy (TTT) in metastatic renal cell carcinoma (mRCC) is not well characterized and varies due to the lack of robust data to guide treatment decisions. This study examined the use of third-line therapy in a large international population. Objective: To evaluate the use and efficacy of targeted therapy in a third-line setting. Design, setting, and participants: Twenty-five international cancer centers provided consecutive data on 4824 mRCC patients who were treated with an approved targeted therapy. One thousand and twelve patients (21%) received TTT and were included in the analysis. Outcome measurements and statistical analysis: Patients were analyzed for overall survival (OS) and progression-free survival using Kaplan-Meier curves, and were evaluated for overall response. Cox regression analyses were used to determine the statistical association between OS and the six factors included in the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic model. Subgroup analysis was performed on patients stratified by their IMDC prognostic risk status. Results and limitations: Everolimus was the most prevalent third-line therapy (27.5%), but sunitinib, sorafenib, pazopanib, temsirolimus, and axitinib were all utilized in over >= 9% of patients. Patients receiving any TTT had an OS of 12.4 mo, a progression-free survival of 3.9 mo, and 61.1% of patients experienced an overall response of stable disease or better. Patients not receiving TTT had an OS of 2.1 mo. Patients with favorable-(7.2%) or intermediate-risk (65.3%) disease had the highest OS with TTT, 29.9 mo and 15.5 mo, respectively, while poor-risk (27.5%) patients survived 5.5 mo. Results are limited by the retrospective nature of the study. Conclusions: TTT remains highly heterogeneous. The IMDC prognostic criteria can be used to stratify third-line patients. TTT use in favorable-and intermediate-risk patients was associated with the greatest OS. Patient summary: Patients with favorable-and intermediate-prognostic criteria disease treated with third-line targeted therapy have an associated longer overall survival compared with those with poor risk disease. (C) 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved. C1 [Wells, J. Connor; Stukalin, Igor; Choueiri, Toni K.] Tom Baker Canc Clin, Calgary, AB, Canada. [Wells, J. Connor; Rini, Brian I.; Ernst, D. Scott] Queens Sch Med, Kingston, ON, Canada. [Norton, Craig] Dana Farber Canc Inst, Boston, MA 02115 USA. [Srinivas, Sandy] Stanford Med Ctr, Div Oncol, Stanford, CA USA. [Lee, Jae Lyun] Univ Ulsan, Asan Med Ctr, Coll Med, Seoul, South Korea. [Donskov, Frede] Aarhus Univ Hosp, Dept Oncol, Aarhus, Denmark. [Bjarnason, Georg A.] Univ Toronto, Sunnybrook Odette Canc Ctr, Toronto, ON, Canada. [Beuselinck, Benoit] Univ Texas Southwestern Med Ctr Dallas, Dallas, TX 75390 USA. [Beuselinck, Benoit] Univ Hosp Leuven, Leuven Canc Inst, Dept Gen Med Oncol & Lab Expt Oncol, Leuven, Belgium. [Rini, Brian I.] Cleveland Clin, Taussig Canc Ctr, Cleveland, OH USA. [Knox, Jennifer J.] Univ Toronto, Univ Hlth Network, Dept Med Oncol, Princess Margaret Canc Ctr, Toronto, ON, Canada. [Agarwal, Neeraj] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. [Ernst, D. Scott] London Reg Canc Ctr, London, ON, Canada. [Pal, Sumanta K.] City Hope Comprehens Canc Ctr, Duarte, CA USA. [Wood, Lori A.] Queen Elizabeth 2 Hlth Sci Ctr, Halifax, NS, Canada. [Bamias, Aristotelis] Natl & Kapodistrian Univ, Dept Clin Therapeut, Athens, Greece. [Alva, Ajjai S.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI USA. [Kanesvaran, Ravindran] Natl Canc Ctr Singapore, Singapore, Singapore. RP Heng, DYC (reprint author), Tom Baker Canc Clin, 1331 29 St N W, Calgary, AB T2N 4N2, Canada. EM daniel.heng@albertahealthservices.ca FU Pfizer; Novartis; Bayer; Roche; BMS; AstraZeneca; GSK; Merck; Exilixis; Tracon FX Daniel Y.C. Heng certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Beuselinck: honoraria from Amgen, Pfizer, Janssen and Bayer, is an investigator of the EudraCT: 2011-006085-40/MetaSun trial supported by Pfizer; Agarwal: consultancy to Pfizer, Exelixis, Argos, and Cerulean; Bamias: honoraria, advisory role, and research funding from Pfizer, Novartis, Bayer, Roche, BMS; Rini: consultancy and research funding Pfizer; Kanesvaran: honoraria from Novartis, Pfizer, Bayer; Knox: research support Pfizer, AstraZeneca; Donskov: research funding Novartis, GSK, Pfizer; Choueiri: research funding Pfizer, GSK, Novartis, BMS, Merck, Exilixis, Roche, AstraZeneca, Tracon, and consultancy Pfizer, GSK, Novartis, Merck, Bayer, AstraZeneca; Heng: consultancy Pfizer, Novartis. NR 21 TC 3 Z9 3 U1 7 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD FEB PY 2017 VL 71 IS 2 BP 204 EP 209 DI 10.1016/j.eururo.2016.05.049 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA EF8FY UT WOS:000390565700035 PM 27318422 ER PT J AU Necchi, A Sonpavde, G Lo Vullo, S Giardiello, D Bamias, A Crabb, SJ Harshman, LC Bellmunt, J De Giorgi, U Sternberg, CN Cerbone, L Ladoire, S Wong, YN Yu, EY Chowdhury, S Niegisch, G Srinivas, S Vaishampayan, UN Pal, SK Agarwal, N Alva, A Baniel, J Golshayan, AR Morales-Barrera, R Bowles, DW Milowsky, MI Theodore, C Berthold, DR Daugaard, G Sridhar, SS Powles, T Rosenberg, JE Galsky, MD Mariani, L AF Necchi, Andrea Sonpavde, Guru Lo Vullo, Salvatore Giardiello, Daniele Bamias, Aristotelis Crabb, Simon J. Harshman, Lauren C. Bellmunt, Joaquim De Giorgi, Ugo Sternberg, Cora N. Cerbone, Linda Ladoire, Sylvain Wong, Yu-Ning Yu, Evan Y. Chowdhury, Simon Niegisch, Gunter Srinivas, Sandy Vaishampayan, Ulka N. Pal, Sumanta K. Agarwal, Neeraj Alva, Ajjai Baniel, Jack Golshayan, Ali-Reza Morales-Barrera, Rafael Bowles, Daniel W. Milowsky, Matthew I. Theodore, Christine Berthold, Dominik R. Daugaard, Gedske Sridhar, Srikala S. Powles, Thomas Rosenberg, Jonathan E. Galsky, Matthew D. Mariani, Luigi CA RISC Investigators TI Nomogram-based Prediction of Overall Survival in Patients with Metastatic Urothelial Carcinoma Receiving First-line Platinum-based Chemotherapy: Retrospective International Study of Invasive/Advanced Cancer of the Urothelium (RISC) SO EUROPEAN UROLOGY LA English DT Article DE Urothelial carcinoma; Overall survival; Prognosis; Platinum chemotherapy; Nomogram ID CISPLATIN-BASED CHEMOTHERAPY; TRANSITIONAL-CELL CARCINOMA; THERAPY AB Background: The available prognostic models for overall survival (OS) in patients with metastatic urothelial carcinoma (UC) have been derived from clinical trial populations of cisplatin-treated patients. Objective: To develop a new model based on real-world patients. Design, setting, and participants: Individual patient-level data from 29 centers were collected, including metastatic UC and first-line cisplatin-or carboplatin-based chemotherapy administered between January 2006 and January 2011. Intervention: First-line, platinum-based, combination chemotherapy. Outcome measurements and statistical analysis: The population was randomly split into a development and a validation cohort. Generalized boosted regression modelling was used to screen out irrelevant variables and address multivariable analyses. Two nomograms were built to estimate OS probability, the first based on baseline factors and platinum agent, the second incorporating objective response (OR). The performance of the above nomograms and that of other available models was assessed. We plotted decision curves to evaluate the clinical usefulness of the two nomograms. Results and limitations: A total of 1020 patients were analyzed (development: 687, validation: 333). In a platinum-stratified Cox model, significant variables for OS were performance status (p < 0.001), white blood cell count (p = 0.013), body mass index (p = 0.003), ethnicity (p = 0.012), lung, liver, or bone metastases (p < 0.001), and prior perioperative chemotherapy (p = 0.012). The c-index was 0.660. The distribution of the nomogram scores was associated with OR (p < 0.001), and incorporating OR into the model further improved the c-index in the validation cohort (0.670). Conclusions: We developed and validated two nomograms for OS to be used before and after completion of first-line chemotherapy for metastatic UC. Patient summary: We proposed two models for estimating overall survival of patients with metastatic urothelial carcinoma receiving first-line, platinum-based chemotherapy. These nomograms have been developed on real-world patients who were treated outside of clinical trials and may be used irrespective of the chemotherapeutic platinum agent used. (C) 2016 European Association of Urology. Published by Elsevier B. V. All rights reserved. C1 [Necchi, Andrea; Lo Vullo, Salvatore; Giardiello, Daniele; Mariani, Luigi] Fdn IRCCS Ist Nazl Tumori, Milan, Italy. [Sonpavde, Guru] UAB Comprehens Canc Ctr, Birmingham, AL USA. [Bamias, Aristotelis] Univ Athens, Athens, Greece. [Crabb, Simon J.] Univ Southampton, Southampton, Hants, England. [Harshman, Lauren C.; Bellmunt, Joaquim] Dana Farber Canc Inst, Boston, MA 02115 USA. [De Giorgi, Ugo] IRCCS Ist Sci Romagnolo Studio & Cura Tumori, Meldola, Italy. [Sternberg, Cora N.; Cerbone, Linda] San Camillo Forlanini Hosp, Rome, Italy. [Ladoire, Sylvain] Ctr Georges Francois Leclerc, Dijon, France. [Wong, Yu-Ning] Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Yu, Evan Y.] Univ Washington, Seattle, WA USA. [Chowdhury, Simon] Guys & St Thomas Hosp, London, England. [Niegisch, Gunter] Univ Dusseldorf, Fac Med, Dept Urol, Dusseldorf, Germany. [Srinivas, Sandy] Stanford Univ, Sch Med, Stanford, CA USA. [Vaishampayan, Ulka N.] Karmanos Canc Inst, Detroit, MI USA. [Pal, Sumanta K.] City Hope Comprehens Canc Ctr, Duarte, CA USA. [Agarwal, Neeraj] Univ Utah, Salt Lake City, UT USA. [Alva, Ajjai] Univ Michigan, Ann Arbor, MI 48109 USA. [Baniel, Jack] Rabin Med Ctr, Petah Tiqwa, Israel. [Golshayan, Ali-Reza] Med Univ South Carolina, Charleston, SC 29425 USA. [Morales-Barrera, Rafael] Univ Autonoma Barcelona, Vall Hebron Univ Hosp, Vall Hebron Inst Oncol, Barcelona, Spain. [Bowles, Daniel W.] Eastern Colorado Hlth Care Syst, Denver Vet Affairs Med Ctr, Denver, CO USA. [Milowsky, Matthew I.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27515 USA. [Theodore, Christine] Hop Foch, Suresnes, France. [Berthold, Dominik R.] Ctr Hospitalier Univ Vaudois, Lausanne, Switzerland. [Daugaard, Gedske] Copenhagen Univ Hosp, Rigshosp, Copenhagen, Denmark. [Sridhar, Srikala S.] Univ Hlth Network, Princess Margaret Hosp, Toronto, ON, Canada. [Powles, Thomas] Queen Mary Univ London, Barts Hlth & Royal Free NHS Trust, London, England. [Rosenberg, Jonathan E.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Galsky, Matthew D.] Tisch Canc Inst, Mt Sinai Sch Med, New York, NY USA. RP Necchi, A (reprint author), Fdn IRCCS Ist Nazl Tumori, Dept Med Oncol, Via Giacomo Venezian 1, I-20133 Milan, Italy. EM andrea.necchi@istitutotumori.mi.it RI Mariani, Luigi/C-2580-2017; OI Mariani, Luigi/0000-0001-6208-4084; Lo Vullo, Salvatore/0000-0002-4444-9526; Crabb, Simon/0000-0003-3521-9064 NR 20 TC 0 Z9 0 U1 8 U2 8 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 FEB PY 2017 VL 71 IS 2 BP 281 EP 289 DI 10.1016/j.eururo.2016.09.042 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA EF8FY UT WOS:000390565700047 PM 27726966 ER PT J AU Heist, RS AF Heist, Rebecca S. TI First-Line Systemic Therapy for Non-Small Cell Lung Cancer SO HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA LA English DT Article DE Non-small cell lung cancer; Systemic therapy; First-line ID PHASE-III TRIAL; CISPLATIN PLUS GEMCITABINE; OPEN-LABEL; MAINTENANCE BEVACIZUMAB; CHEMOTHERAPY; PLACEBO; CARBOPLATIN; INDUCTION; ERLOTINIB; CETUXIMAB AB Major advances in the treatment of metastatic non-small cell lung cancer have led to significant incremental improvements in patient outcomes. Platinum-based combination therapy remains the cornerstone of first line therapy. The addition of biologic agents, such as bevacizumab or necitumumab, in selected populations has shown benefit over chemotherapy alone. The advent of maintenance therapy has also improved overall survival outcomes in selected populations of patients. Ongoing studies will further refine optimal treatment in the first-line setting and further advance first-line treatment options. C1 [Heist, Rebecca S.] Massachusetts Gen Hosp, Dept Thorac Oncol, 32 Fruit St,Yawkey 7B, Boston, MA 02114 USA. RP Heist, RS (reprint author), Massachusetts Gen Hosp, Dept Thorac Oncol, 32 Fruit St,Yawkey 7B, Boston, MA 02114 USA. EM rheist@partners.org NR 25 TC 0 Z9 0 U1 4 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-8588 EI 1558-1977 J9 HEMATOL ONCOL CLIN N JI Hematol. Oncol. Clin. North Am. PD FEB PY 2017 VL 31 IS 1 BP 59 EP + DI 10.1016/j.hoc.2016.08.001 PG 13 WC Oncology; Hematology SC Oncology; Hematology GA EG4AC UT WOS:000390984800006 PM 27912834 ER PT J AU Momen-Heravi, F Babic, A Tworoger, SS Zhang, LB Wu, KN Smith-Warner, SA Ogino, S Chan, AT Meyerhardt, J Giovannucci, E Fuchs, C Cho, EY Michaud, DS Stampfer, MJ Yu, YH Kim, D Zhang, XH AF Momen-Heravi, Fatemeh Babic, Ana Tworoger, Shelley S. Zhang, Libin Wu, Kana Smith-Warner, Stephanie A. Ogino, Shuji Chan, Andrew T. Meyerhardt, Jeffrey Giovannucci, Edward Fuchs, Charles Cho, Eunyoung Michaud, Dominique S. Stampfer, Meir J. Yu, Yau-Hua Kim, David Zhang, Xuehong TI Periodontal disease, tooth loss and colorectal cancer risk: Results from the Nurses' Health Study SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE colorectal cancer; periodontal disease; tooth loss; oral health; microbiota ID PANCREATIC-CANCER; LIFE-STYLE; FUSOBACTERIUM-NUCLEATUM; PROSPECTIVE COHORT; FOLLOW-UP; PROFESSIONALS; ASSOCIATION; MICROBIOTA; CARCINOMA; WOMEN AB Periodontal diseases including tooth loss might increase systemic inflammation, lead to immune dysregulation and alter gut microbiota, thereby possibly influencing colorectal carcinogenesis. Few epidemiological studies have examined the association between periodontal diseases and colorectal cancer (CRC) risk. We collected information on the periodontal disease (defined as history of periodontal bone loss) and number of natural teeth in the Nurses' Health Study. A total of 77,443 women were followed since 1992. We used Cox proportional hazard models to calculate multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs) after adjustment for smoking and other known risk factors for CRC. We documented 1,165 incident CRC through 2010. Compared to women with 25-32 teeth, the multivariable HR (95% CI) for CRC for women with <17 teeth was 1.20 (1.04-1.39). With regard to tumor site, the HRs (95% CIs) for the same comparison were 1.23 (1.01-1.51) for proximal colon cancer, 1.03 (0.76-1.38) for distal colon cancer and 1.48 (1.07-2.05) for rectal cancer. In addition, compared to those without periodontal disease, HRs for CRC were 0.91 (95% CI 0.74-1.12) for periodontal disease, and 1.22 (95% CI 0.91-1.63) when limited to moderate to severe periodontal disease. The results were not modified by smoking status, body mass index or alcohol consumption. Women with fewer teeth, possibly moderate or severe periodontal disease, might be at a modest increased risk of developing CRC, suggesting a potential role of oral health in colorectal carcinogenesis. What's new? Periodontal disease does not simply affect the mouth. It is also thought to increase systemic inflammation, trigger immune dysfunction, alter the microbiome and increase the risk of a number of cancers. Might it also increase colorectal cancer (CRC) risk? In this analysis of data from the Nurses' Health Study, the authors found that the risk of developing CRC increased by as much as 48% in women with periodontal disease. Cancer risk increased with the severity of tooth loss. These results suggest that oral health may affect factors involved in colorectal carcinogenesis. C1 [Momen-Heravi, Fatemeh; Tworoger, Shelley S.; Smith-Warner, Stephanie A.; Ogino, Shuji; Giovannucci, Edward; Cho, Eunyoung; Stampfer, Meir J.] Halyard TH Chao Sch Poblic Hlth, Dept Epidemiol, Boston, MA USA. [Momen-Heravi, Fatemeh; Babic, Ana; Tworoger, Shelley S.; Giovannucci, Edward; Stampfer, Meir J.; Zhang, Xuehong] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Momen-Heravi, Fatemeh; Babic, Ana; Tworoger, Shelley S.; Ogino, Shuji; Chan, Andrew T.; Meyerhardt, Jeffrey; Giovannucci, Edward; Fuchs, Charles; Stampfer, Meir J.; Zhang, Xuehong] Harvard Med Sch, Boston, MA USA. [Momen-Heravi, Fatemeh] Columbia Univ, Coll Dent Med, Sect Oral & Diagnost Sci, Div Periodont, New York, NY USA. [Babic, Ana; Ogino, Shuji; Meyerhardt, Jeffrey; Fuchs, Charles] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Zhang, Libin] Univ Massachusetts, Inst Community Inclus, Boston, MA 02125 USA. [Wu, Kana; Smith-Warner, Stephanie A.; Giovannucci, Edward; Stampfer, Meir J.] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Clin & Translat Epidemiol Unit, Boston, MA 02114 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Cho, Eunyoung] Brown Univ, Warren Alpert Med Sch, Dept Dermatol, Providence, RI 02912 USA. [Cho, Eunyoung; Michaud, Dominique S.] Brown Univ, Sch Publ Hlth, Dept Epidemiol, Providence, RI 02912 USA. [Michaud, Dominique S.] Tufts Univ, Sch Med, Dept Publ Hlth & Community Med, Boston, MA 02111 USA. [Yu, Yau-Hua; Kim, David] Harvard Sch Dent Med, Boston, MA USA. RP Zhang, XH (reprint author), Harvard Med Sch, Med, 181 Longwood Ave,Room 453, Boston, MA 02115 USA.; Zhang, XH (reprint author), Brigham & Womens Hosp, 181 Longwood Ave,Room 453, Boston, MA 02115 USA. EM xuehong.zhang@channing.harvard.edu OI Momen-Heravi, Fatemeh/0000-0003-4534-1450 FU National Institutes of Health (NIH) [UM1CA186107, P50CA127003, P01CA87969, R01CA151993, R35CA197735, R01CA137178, K24DK098311, R03CA176717, K07CA188126]; [5T32CA009001-38] FX This work was supported by a grant from the National Institutes of Health (NIH) grants UM1CA186107 (to M.J. Stampfer), P50CA127003 (to C.S. Fuchs), P01CA87969 (to M.J. Stampfer), R01CA151993, R35CA197735 (to S. Ogino), R01CA137178, K24DK098311 (A.T. Chan). R03CA176717, K07CA188126 (to X. Zhang). A. Babic was supported by a training grant (5T32CA009001-38). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. NR 50 TC 0 Z9 0 U1 19 U2 19 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD FEB 1 PY 2017 VL 140 IS 3 BP 646 EP 652 DI 10.1002/ijc.30486 PG 7 WC Oncology SC Oncology GA EG0DY UT WOS:000390702500017 PM 27778343 ER PT J AU Meehan, TM Martinez-Salazar, EL Torriani, M AF Meehan, Timothy M. Martinez-Salazar, Edgar Leonardo Torriani, Martin TI Aftermath of Ankle Inversion Injuries Spectrum of MR Imaging Findings SO MAGNETIC RESONANCE IMAGING CLINICS OF NORTH AMERICA LA English DT Article DE Ankle; Injuries; Sprain; MR imaging; Ligaments ID TIBIOFIBULAR SYNDESMOSIS INJURY; SUPERIOR PERONEAL RETINACULUM; COLLATERAL LIGAMENTS; DELTOID LIGAMENT; IMPINGEMENT SYNDROMES; SURGICAL FINDINGS; ANTERIOR PROCESS; TARSAL SINUS; FOLLOW-UP; ARTHROGRAPHY AB Acute and chronic ankle inversion injuries are a common source of pain and a diagnostic challenge. Several studies have shown a variety of injury patterns after inversion injury both in acute and chronic settings. Although traditional assessment with clinical examination and radiographs is generally accepted for inversion injuries, MR imaging is a useful tool to detect occult injuries and in patients with chronic symptoms. This article examines a range of MR imaging findings that may be present in patients with lateral ankle pain following an acute or chronic inversion injury. C1 [Meehan, Timothy M.; Martinez-Salazar, Edgar Leonardo; Torriani, Martin] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Div Musculoskeletal Imaging & Intervent, 55 Fruit St, Boston, MA 02114 USA. RP Torriani, M (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Musculoskeletal Imaging & Intervent, YAW 6048, 55 Fruit St, Boston, MA 02114 USA. EM mtorriani@mgh.harvard.edu NR 62 TC 0 Z9 0 U1 4 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1064-9689 EI 1557-9786 J9 MAGN RESON IMAGING C JI Magn. Reson. Imaging Clin. N. Am. PD FEB PY 2017 VL 25 IS 1 BP 45 EP + DI 10.1016/j.mric.2016.08.0120 PG 19 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EG5JF UT WOS:000391079400006 PM 27888851 ER PT J AU Bryant, PA Baddley, JW AF Bryant, Paul A. Baddley, John W. TI Opportunistic Infections in Biological Therapy, Risk and Prevention SO RHEUMATIC DISEASE CLINICS OF NORTH AMERICA LA English DT Article DE Opportunistic infection; Biologics; Tuberculosis; Zoster; Histoplasmosis; Pneumocystosis ID NECROSIS-FACTOR ANTAGONISTS; PNEUMOCYSTIS-CARINII-PNEUMONIA; RHEUMATOID-ARTHRITIS PATIENTS; INFLAMMATORY-BOWEL-DISEASE; FACTOR-ALPHA ANTAGONISTS; ANTI-TNF-ALPHA; HERPES-ZOSTER; POSTMARKETING SURVEILLANCE; SERIOUS INFECTION; BRITISH-SOCIETY AB Patients being treated with biological therapies are at increased risk for serious infections, including opportunistic infections. Although more is known about opportunistic infection risk with older biologics, such as antitumor necrosis factor drugs, there is less knowledge of opportunistic infection risk with newer biological therapies. The incidence of certain opportunistic infections (tuberculosis, herpes zoster, pneumo-cystosis) has been rigorously evaluated in large observational studies. However, data are more limited for other infections (histoplasmosis, nontuberculous mycobacteria). Infectious morbidity and mortality may be preventable with screening and prophylaxis in select populations. C1 [Bryant, Paul A.] Univ Alabama Birmingham, Dept Med, Div Infect Dis, 1900 Univ Blvd,229 THT, Birmingham, AL 35294 USA. [Baddley, John W.] Univ Alabama Birmingham, Birmingham VA Med Ctr, Dept Med, Div Infect Dis, 1900 Univ Blvd,229 THT, Birmingham, AL 35294 USA. [Baddley, John W.] Med Serv, 1900 Univ Blvd,229 THT, Birmingham, AL 35294 USA. RP Baddley, JW (reprint author), Univ Alabama Birmingham, Birmingham VA Med Ctr, Dept Med, Div Infect Dis, 1900 Univ Blvd,229 THT, Birmingham, AL 35294 USA.; Baddley, JW (reprint author), Med Serv, 1900 Univ Blvd,229 THT, Birmingham, AL 35294 USA. EM jbaddley@uabmc.edu FU BMS FX P.A. Bryant: none; J.W. Baddley: consulting for Merck, Pfizer. Research grant from BMS. NR 77 TC 0 Z9 0 U1 3 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-857X EI 1558-3163 J9 RHEUM DIS CLIN N AM JI Rheum. Dis. Clin. North Am. PD FEB PY 2017 VL 43 IS 1 BP 27 EP + DI 10.1016/j.rdc.2016.09.005 PG 16 WC Rheumatology SC Rheumatology GA EG3ZP UT WOS:000390983500005 PM 27890172 ER PT J AU Chavarri-Guerra, Y St Louis, J Bukowski, A Soto-Perez-de-Celis, E Liedke, PER Symecko, H Moy, B Higgins, M Finkelstein, DM Goss, PE AF Chavarri-Guerra, Y. St Louis, J. Bukowski, A. Soto-Perez-de-Celis, E. Liedke, P. E. R. Symecko, H. Moy, B. Higgins, M. Finkelstein, D. M. Goss, P. E. TI Real world patterns of care in HER2-overexpressing breast cancer: Results of a survey of TEACH clinical trial investigators in 2011 SO BREAST LA English DT Article DE Breast neoplasm; HER2; Health care disparities; Molecular targeted therapy ID ADJUVANT CHEMOTHERAPY; TRASTUZUMAB AB Background: HER2-overexpressing breast cancer (BC) is common among young patients and poses a public health burden. Adjuvant anti-HER2/neu therapy with trastuzumab reduces the risk of recurrence and improves survival. Methods: A web-based survey was sent to 386 physicians of the "TEACH" trial in 2011 to determine access to HER2/neu testing and treatment patterns for HER2-overexpressing BC. Results: There were 151 responders (39%) from 28 countries. Ninety-seven percent reported HER2/neu expression is routinely measured in their institutions by immunohistochemistry (85%), FISH (80%) and other methods (16%). Twenty percent of responders from Asia reported that the test was not routinely available. Forty-eight percent of participants reported instances when adjuvant HER2-directed therapy was recommended to a patient who eventually did not receive it. Reasons for not receiving trastuzumab was cost (73%, p < 0.0001) in low-and middle-income countries and co-morbidities in high-income countries (43%, p = 0.003). Conclusions: This survey reflects the availability of HER2/neu testing and anti-HER2/neu therapy among physicians who participated in TEACH. A high proportion of women with HER2-overexpressing BC may not receive standard adjuvant therapy due to unavailability of the test and cost of therapy. Despite having some limitations, such as a possible selection bias of participating physicians, variable definitions of access to healthcare among respondents, and changes in trastuzumab availability since 2011, our results demonstrate that access to care and region of practice impact the implementation of cancer treatments. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Chavarri-Guerra, Y.; St Louis, J.; Bukowski, A.; Soto-Perez-de-Celis, E.; Liedke, P. E. R.; Goss, P. E.] Global Canc Inst, Boston, MA 02114 USA. [Chavarri-Guerra, Y.] Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Dept Hematol & Oncol, Mexico City, DF, Mexico. [St Louis, J.; Bukowski, A.; Goss, P. E.] Massachusetts Gen Hosp, Avon Int Breast Canc Program, Ctr Canc, Boston, MA 02114 USA. [Soto-Perez-de-Celis, E.] Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Dept Geriatr, Canc Care Elderly Clin, Mexico City, DF, Mexico. [Liedke, P. E. R.] Hosp Clin Porto Alegre, Dept Clin Oncol, Porto Alegre, RS, Brazil. [Liedke, P. E. R.] Hosp Mae Deus, Mae Deus Canc Inst, Porto Alegre, RS, Brazil. [Symecko, H.; Finkelstein, D. M.] Massachusetts Gen Hosp, Biostat Ctr, Boston, MA 02114 USA. [Moy, B.; Goss, P. E.] Massachusetts Gen Hosp, Ctr Canc, 55 Fruit St,Lawrence House,LRH 302, Boston, MA 02114 USA. [Higgins, M.] Mater Misericordiae Univ Hosp, Dublin, Ireland. RP Goss, PE (reprint author), Massachusetts Gen Hosp, Ctr Canc, 55 Fruit St,Lawrence House,LRH 302, Boston, MA 02114 USA. EM pgoss@mgh.harvard.edu FU Avon Foundation New York FX We would like to thank and acknowledge all of the TEACH investigators who participated in the survey. This work was supported by the Avon Foundation New York. This funding source had no role in the planning or writing of this manuscript. NR 19 TC 0 Z9 0 U1 3 U2 3 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0960-9776 EI 1532-3080 J9 BREAST JI Breast PD FEB PY 2017 VL 31 SI SI BP 197 EP 201 DI 10.1016/j.breast.2016.11.014 PG 5 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA EF8NU UT WOS:000390586600031 PM 27894048 ER PT J AU Cardoso, F Costa, A Senkus, E Aapro, M Andre, F Barrios, CH Bergh, J Bhattacharyya, G Biganzoli, L Cardoso, MJ Carey, L Corneliussen-James, D Curigliano, G Dieras, V El Saghir, N Eniu, A Fallowfield, L Fenech, D Francis, P Gelmon, K Gennari, A Harbeck, N Hudis, C Kaufman, B Krop, I Mayer, M Meijer, H Mertz, S Ohno, S Pagani, O Papadopoulos, E Peccatori, F Pernault-Llorca, F Piccart, MJ Pierga, JY Rugo, H Shockney, L Sledge, G Swain, S Thomssen, C Tutt, A Vorobiof, D Xu, B Norton, L Winer, E AF Cardoso, F. Costa, A. Senkus, E. Aapro, M. Andre, F. Barrios, C. H. Bergh, J. Bhattacharyya, G. Biganzoli, L. Cardoso, M. J. Carey, L. Corneliussen-James, D. Curigliano, G. Dieras, V. El Saghir, N. Eniu, A. Fallowfield, L. Fenech, D. Francis, P. Gelmon, K. Gennari, A. Harbeck, N. Hudis, C. Kaufman, B. Krop, I. Mayer, M. Meijer, H. Mertz, S. Ohno, S. Pagani, O. Papadopoulos, E. Peccatori, F. Pernault-Llorca, F. Piccart, M. J. Pierga, J. Y. Rugo, H. Shockney, L. Sledge, G. Swain, S. Thomssen, C. Tutt, A. Vorobiof, D. Xu, B. Norton, L. Winer, E. TI 3rd ESO-ESMO international consensus guidelines for Advanced Breast Cancer (ABC 3) SO BREAST LA English DT Article ID PROGRESSION-FREE SURVIVAL; PHASE-II TRIAL; OPEN-LABEL; TRASTUZUMAB EMTANSINE; ESTROGEN-RECEPTOR; 1ST-LINE TREATMENT; PHYSICIANS CHOICE; ZOLEDRONIC ACID; BONE METASTASES; PERTUZUMAB P C1 [Cardoso, F.; Aapro, M.] European Sch Oncol, Lisbon, Portugal. [Cardoso, F.] Breast Unit, Champalimaud Clin Ctr, Lisbon, Portugal. [Cardoso, F.; Cardoso, M. J.; El Saghir, N.] European Sch Oncol, Milan, Italy. [Cardoso, M. J.; El Saghir, N.; Eniu, A.] European Sch Oncol, Bellinzona, Switzerland. [Biganzoli, L.; El Saghir, N.; Eniu, A.] Med Univ Gdansk, Dept Radiotherapy & Oncol, Gdansk, Poland. [Cardoso, M. J.; El Saghir, N.; Fenech, D.] Med Univ Gdansk, Dept Radiotherapy & Oncol, Gdansk, Poland. [Bhattacharyya, G.; El Saghir, N.; Francis, P.] Inst Gustave Roussy, Dept Med Oncol, Villejuif, France. [Fallowfield, L.; Gelmon, K.] PUCRS Sch Med, Dept Med, Porto Alegre, RS, Brazil. [Eniu, A.; Fallowfield, L.; Francis, P.; Harbeck, N.] Karolinska Inst, Dept Oncol Radiumhemmet, Stockholm, Sweden. [Dieras, V.; Fallowfield, L.; Gennari, A.; Hudis, C.] Canc Ctr Karolinska, Stockholm, Sweden. [Barrios, C. H.; Dieras, V.; Fallowfield, L.; Harbeck, N.] Karolinska Univ Hosp, Stockholm, Sweden. [Carey, L.; El Saghir, N.; Fallowfield, L.; Harbeck, N.] Fortis Hosp, Dept Med Oncol, Kolkata, India. [Bergh, J.; Curigliano, G.] Hosp Prato, Dept Med Oncol, Prato, Italy. [Andre, F.; Cardoso, M. J.] Breast Unit, Champalimaud Clin Ctr, Lisbon, Portugal. [Eniu, A.; Francis, P.] UNC Lineberger Comprehens Canc Ctr, Dept Hematol & Oncol, Polson, MT USA. [Eniu, A.; Fenech, D.; Francis, P.] METAvivor Res & Support, Annapolis, MD USA. [Bergh, J.] European Inst Oncol, Div Expt Therapeut, Milan, Italy. [Thomssen, C.; Vorobiof, D.] Inst Curie, Dept Med Oncol, Paris, France. [Cardoso, F.; Costa, A.; Senkus, E.] Amer Univ Beirut, NK Basile Canc Inst Breast Ctr Excellence, Beirut, Lebanon. [Cardoso, M. J.; Dieras, V.] Canc Inst Chiricuta, Dept Breast Tumors, Cluj Napoca, Romania. [Barrios, C. H.; Cardoso, M. J.; El Saghir, N.; Francis, P.] Univ Sussex, Brighton & Sussex Med Sch, Brighton, E Sussex, England. [Costa, A.; Senkus, E.; Biganzoli, L.; Dieras, V.; Papadopoulos, E.; Rugo, H.; Thomssen, C.] Europa Donna Malta, Breast Care Support Grp, Mtarfa, Malta. [Peccatori, F.; Pierga, J. Y.; Sledge, G.] Div Canc Med, Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Ohno, S.; Piccart, M. J.; Sledge, G.] Vancouver Canc Ctr, BC Canc Agcy, Vancouver, BC, Canada. [Peccatori, F.; Rugo, H.; Vorobiof, D.] Galliera Hosp, Dept Med Oncol, Genoa, Italy. [Barrios, C. H.; Peccatori, F.; Thomssen, C.] Bustzentrum Univ Munchen, Munich, Germany. [Pagani, O.; Sledge, G.] Mem Sloan Kettering Canc Ctr, Breast Med Serv, New York, NY USA. [Francis, P.; Pagani, O.; Peccatori, F.] Sheba Med Ctr, Tel Hashomer, Israel. [Tutt, A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA. [Pagani, O.; Swain, S.] Adv BC Org, New York, NY USA. [Aapro, M.] Radvoud Univ Med Ctr, Dept Radiat Oncol, Nijmegen, Netherlands. [Piccart, M. J.] Metastat Breast Canc Network US, Inversness, MA USA. [Carey, L.; Curigliano, G.; Peccatori, F.] Canc Inst Hosp, Breast Oncol Ctr, Tokyo, Japan. [Andre, F.; Gelmon, K.; Piccart, M. J.; Pierga, J. Y.] Oncol Inst So Switzerland & Breast Unit So Switze, Bellinzona, Switzerland. [Peccatori, F.] Europa Donna, Nicosia, Cyprus. [Pernault-Llorca, F.; Piccart, M. J.] Jean Perrin Ctr, Ctr Comprehens Canc, Clermont Ferrand, France. [Aapro, M.; Pagani, O.] Univ Libre Bruxelles, Inst Jules Bordet, Dept Med, Brussels, Belgium. [Swain, S.] Inst Curie Univ Paris Descartes, Dept Med Oncol, Paris, France. [Pagani, O.; Swain, S.] UCSF Helen Diller Family Comprehens Canc Ctr, Dept Med, Breast Oncol Program, San Francisco, CA USA. [Andre, F.; Carey, L.] Dept Surg & Oncol, Johns Hopkins Breast Ctr, Baltimore, MD USA. [Pagani, O.; Piccart, M. J.] Indiana Univ Med Ctr, Indianapolis, IN USA. [Andre, F.; Carey, L.; Dieras, V.] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. [Pagani, O.; Piccart, M. J.; Pierga, J. Y.] Martin Luther Univ Halle Wittenberg, Dept Gynaecol, Halle, DE, Germany. RP Cardoso, F (reprint author), Breast Unit, Champalimaud Clin Ctr, Lisbon, Portugal. EM fatimacardoso@fundacaochampalimaud.pt NR 65 TC 1 Z9 1 U1 8 U2 8 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0960-9776 EI 1532-3080 J9 BREAST JI Breast PD FEB PY 2017 VL 31 SI SI BP 244 EP 259 DI 10.1016/j.breast.2016.10.001 PG 16 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA EF8NU UT WOS:000390586600039 PM 27927580 ER PT J AU Bychkovsky, BL Lin, NU AF Bychkovsky, Brittany L. Lin, Nancy U. TI Imaging in the evaluation and follow-up of early and advanced breast cancer: When, why, and how often? SO BREAST LA English DT Article DE Breast cancer; Imaging; Overuse; Utilization; Surveillance; Staging ID EARLY-STAGE; ADJUVANT CHEMOTHERAPY; RANDOMIZED-TRIAL; UNITED-STATES; GUIDELINES; SURVEILLANCE; METAANALYSIS; THERAPY; TESTS; CT AB Imaging in the evaluation and follow-up of patients with early or advanced breast cancer is an important aspect of cancer care. The role of imaging in breast cancer depends on the goal and should only be performed to guide clinical decisions. Imaging is valuable if a finding will change the course of treatment and improve outcomes, whether this is disease-free survival, overall survival or quality-of-life. In the last decade, imaging is often overused in oncology and contributes to rising healthcare costs. In this context, we review the data that supports the appropriate use of imaging for breast cancer patients. We will discuss: 1) the optimal use of staging imaging in both early (Stage 0-II) and locally advanced (Stage III) breast cancer, 2) the role of surveillance imaging to detect recurrent disease in Stage 0-III breast cancer and 3) how patients with metastatic breast cancer should be followed with advanced imaging. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Bychkovsky, Brittany L.; Lin, Nancy U.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Bychkovsky, Brittany L.; Lin, Nancy U.] Harvard Med Sch, Boston, MA USA. RP Bychkovsky, BL (reprint author), Dana Farber Canc Inst, Breast Oncol, Yawkey 12,450 Brookline Ave, Boston, MA 02215 USA. EM Brittany_Bychkovsky@dfci.harvard.edu; Nancy_Lin@dfci.harvard.edu FU Dana-Farber Cancer Institute FX We appreciate the support of Dana-Farber Cancer Institute. NR 54 TC 0 Z9 0 U1 1 U2 1 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0960-9776 EI 1532-3080 J9 BREAST JI Breast PD FEB PY 2017 VL 31 SI SI BP 318 EP 324 DI 10.1016/j.breast.2016.06.017 PG 7 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA EF8NU UT WOS:000390586600049 PM 27422453 ER PT J AU Habib, S Shaikh, OS AF Habib, Shahid Shaikh, Obaid S. TI Drug-Induced Acute Liver Failure SO CLINICS IN LIVER DISEASE LA English DT Article DE Drug hepatotoxicity; Liver failure; Cerebral edema; Encephalopathy; Liver transplantation ID FULMINANT HEPATIC-FAILURE; INTRACRANIAL-PRESSURE MONITORS; ADSORBENT RECIRCULATING SYSTEM; CEREBRAL-BLOOD-FLOW; CONTROLLED-TRIAL; MODERATE HYPOTHERMIA; N-ACETYLCYSTEINE; RENAL-FAILURE; BRAIN EDEMA; LUNG INJURY AB Drug-induced acute liver failure (ALF) disproportionately affects women and nonwhites. It is most frequently caused by antimicrobials and to a lesser extent by complementary and alternative medications, antiepileptics, antimetabolites, nonsteroidals, and statins. Most drug-induced liver injury ALF patients have hepatocellular injury pattern. Cerebral edema and intracranial hypertension are the most serious complications of ALF. Other complications include coagulopathy, sepsis, metabolic derangements, and renal, circulatory, and respiratory dysfunction. Although advances in intensive care have improved outcome, ALF has significant mortality without liver transplantation. Liver-assist devices may provide a bridge to transplant or to spontaneous recovery. C1 [Habib, Shahid] Southern Arizona Vet Affairs Healthcare Syst, Dept Med, 3601 S 6th Ave, Tucson, AZ 85723 USA. [Shaikh, Obaid S.] Vet Affairs Pittsburgh Healthcare Syst, Dept Med, Gastroenterol Sect, Univ Dr C,FU 112, Pittsburgh, PA 15240 USA. [Shaikh, Obaid S.] Univ Pittsburgh, Sch Med, Div Gastroenterol Hepatol & Nutr, 200 Lothrop St, Pittsburgh, PA 15213 USA. RP Shaikh, OS (reprint author), Vet Affairs Pittsburgh Healthcare Syst, Dept Med, Gastroenterol Sect, Univ Dr C,FU 112, Pittsburgh, PA 15240 USA. EM obaid@pitt.edu NR 83 TC 0 Z9 0 U1 16 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 1089-3261 EI 1557-8224 J9 CLIN LIVER DIS JI Clin. Liver Dis. PD FEB PY 2017 VL 21 IS 1 BP 151 EP + DI 10.1016/j.cld.2016.08.003 PG 13 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EG0OA UT WOS:000390730900011 PM 27842769 ER PT J AU Tosti, R Shin, E AF Tosti, Rick Shin, Eon TI Wrist Arthroscopy for Athletic Injuries SO HAND CLINICS LA English DT Article DE Wrist arthroscopy; Wrist injuries; Sports; Athletes ID TRIANGULAR FIBROCARTILAGE COMPLEX; SCAPHOLUNATE LIGAMENT; REPAIR; TEARS; MANAGEMENT; DISSOCIATION; CAPSULODESIS; INSTABILITY; DEBRIDEMENT; FRACTURE AB Management of hand and wrist injuries for athletes often places emphasis on an expeditious return to sport. Arthroscopic techniques have the advantage of directly visualizing joint derangements and correcting them via a minimally invasive approach. This article discusses the evaluation and management of common wrist injuries treated with arthroscopy in athletes, including scapholunate and lunotriquetral injury, triangular fibrocartilage complex tears, hamatolunate impingement, and arthroscopic-assisted reduction of wrist fractures. C1 [Tosti, Rick] Harvard Med Sch, Massachusetts Gen Hosp, Dept Orthopaed Surg, 55 Fruit St, Boston, MA 02114 USA. [Shin, Eon] Thomas Jefferson Univ, Sidney Kimmel Med Coll, Philadelphia Hand Ctr, 834 Chestnut St, Philadelphia, PA 19107 USA. RP Tosti, R (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Orthopaed Surg, 55 Fruit St, Boston, MA 02114 USA. EM rjtosti@gmail.com NR 32 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0749-0712 EI 1558-1969 J9 HAND CLIN JI Hand Clin. PD FEB PY 2017 VL 33 IS 1 BP 107 EP + DI 10.1016/j.hcl.2016.08.005 PG 12 WC Orthopedics SC Orthopedics GA EG0OE UT WOS:000390731300011 PM 27886828 ER PT J AU Jones, JD Scott, JC Calkins, ME Ruparel, K Moore, TM Gur, RC Gur, RE AF Jones, Jason D. Scott, J. Cobb Calkins, Monica E. Ruparel, Kosha Moore, Tyler M. Gur, Ruben C. Gur, Raquel E. TI Correspondence between adolescent and informant reports of substance use: Findings from the Philadelphia Neurodevelopmental Cohort SO ADDICTIVE BEHAVIORS LA English DT Article DE Adolescent substance use; Reporter agreement; Collateral informants; Substance use assessment; Philadelphia Neurodevelopmental Cohort ID PARENTAL AWARENESS; RISK INVOLVEMENT; AGREEMENT; ATTACHMENT; DEPRESSION; BEHAVIOR; ALCOHOL; SAMPLE; ABUSE; CHILD AB Inclusion of collateral informant reports is common in adolescent psychopathology research and clinical assessment, yet few studies have examined agreement on ratings of adolescent substance use or factors that may be associated with reporter agreement. The present study aimed to extend prior work on the correspondence between adolescent and informant reports of adolescent substance use with data from a large (n = 5214), diverse, community-based sample of youth aged 11-17 (mean age = 14.53, SD = 1.98; 52% female). Specifically, we examined: (a) agreement between adolescent and collateral informant reports of adolescent use of alcohol, marijuana, cocaine, inhalants, and stimulants and (b) potential correlates of reporter agreement. Agreement ranged from low (k = 0.007,p = 0.053) for inhalant use to moderate (k = 0.414, p < 0.001) for marijuana use. Disagreements were mainly driven by collateral underestimation of adolescent substance use. Older adolescent age was associated with poorer agreement across all substances (Odds Ratios [ORs] <= 0.80, ps < 0.05) except inhalants (OR = 128, p < 0.001). Reporter agreement on alcohol and marijuana use was lower for male than female adolescents (ORs <= 0.85, ps < 0.05). Adolescent psychopathology was associated with poorer agreement on all substances (ORs <= 0.62, ps < 0.01). For alcohol and marijuana, past year frequency of use was associated with better reporter agreement (ORs >= 1.54, ps < 0.001). For marijuana, older age at first use was related to poorer agreement (OR = 0.81, p = 0.01). Our results suggest that collateral reports of adolescent substance use may be ineffective proxies for adolescent self-reports in community samples, particularly for low base rate substances. Findings also highlight important factors to consider when collecting substance use information from multiple informants. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Jones, Jason D.; Scott, J. Cobb; Calkins, Monica E.; Ruparel, Kosha; Moore, Tyler M.; Gur, Ruben C.; Gur, Raquel E.] Univ Penn, Perelman School Med, Dept Psychiat, Neuropsychiat Sect, 3400 Spruce St,10th Floor Gates Bldg, Philadelphia, PA 19104 USA. [Scott, J. Cobb; Gur, Ruben C.] Philadelphia VA Med Ctr, Mental Illness Res Educ & Clin Ctr VISN4, 3900 Woodland Ave, Philadelphia, PA 19104 USA. RP Jones, JD; Gur, RE (reprint author), 3400 Spruce St,10th Floor,Gates Bldg, Philadelphia, PA 19104 USA. EM jasjones@upenn.edu; raquel@upenn.edu FU NIH [RC2 MH089983, MH089924, K08MH079364, T32MH019112, MH089983]; Dowshen Program for Neuroscience; Department of Veterans Affairs Career Development Award [IK2CX000772] FX This work was supported by the NIH (RC2 MH089983 and MH089924; K08MH079364; T32MH019112; NIDA supplement to MH089983) and the Dowshen Program for Neuroscience. Dr. Scott's participation was supported by a Department of Veterans Affairs Career Development Award (IK2CX000772). We thank the participants of this study, and all the members of the Recruitment, Assessment, and Data Teams whose individual contributions collectively made this work possible. We also thank William G. Iacono for allowing use, modification, and computerization of the University of Minnesota Center for Twin and Family Research substance use measure, and Emily Bach for coding the family history of substance abuse questions. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. NR 30 TC 0 Z9 0 U1 14 U2 14 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 EI 1873-6327 J9 ADDICT BEHAV JI Addict. Behav. PD FEB PY 2017 VL 65 BP 13 EP 18 DI 10.1016/j.addbeh.2016.09.006 PG 6 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA EF1GT UT WOS:000390074000003 PM 27701026 ER PT J AU Andreas, JB O'Farrell, TJ AF Andreas, Jasmina Burdzovic O'Farrell, Timothy J. TI Psychosocial problems in children of women entering substance use disorder treatment: A longitudinal study SO ADDICTIVE BEHAVIORS LA English DT Article DE Maternal SUD; Psychosocial symptoms ID CHILDHOOD PSYCHOPATHOLOGY; PARENTAL ALCOHOLISM; BEHAVIOR PROBLEMS; SYMPTOMATOLOGY; DEPENDENCE; FAMILIES; ABUSE; ASSOCIATIONS; IMPACT; RISK AB Background: While parental substance use disorder (SUD) has been-recognized as a risk factor for child outcomes, past research seldom focused specifically on children whose mothers suffer from alcohol and drug use disorders. Are these children at risk for elevated psychosocial problems, and would such risk be reduced if maternal substance use was reduced? Aims: Children of substance-abusing mothers (COSAM, N = 130) were compared to a demographically matched comparison sample, and examined soon after their mothers entered SUD treatment and in the 18 months after treatment entry. We expected to observe elevated symptomatology among COSAM at baseline assessment, followed by a decreasing trend after maternal treatment in general, and remission in particular. Results: Children's psychosocial problems were assessed through maternal reports on the Pediatric Symptom Checklist. Soon after their mothers entered SUD treatment, COSAM exhibited significantly greater overall. and clinical-level psychosocial problems than the children from the matched comparison sample. However, at the end of the 18-months study period, these two groups no longer differed in terms of problems. Results from the longitudinal growth models revealed reductions in COSAM's overall and clinical-level problems following their mothers' SUD treatment. However, these reductions were similar for all COSAM, regardless of whether their mothers relapsed or remitted. Conclusion: Psychosocial problems were significantly reduced in COSAM following maternal SUD treatment, such that COSAM did-not significantly differ from children from the matched comparison sample by the end of the 18 month study period. Published by Elsevier Ltd. C1 [Andreas, Jasmina Burdzovic] Norwegian Inst Publ Hlth, Oslo, Norway. [O'Farrell, Timothy J.] Harvard Med Sch, Dept Psychiat, VA Boston Healthcare Syst, VAMC-116B1,940 Belmont St, Brockton, MA 02301 USA. RP O'Farrell, TJ (reprint author), Harvard Med Sch, Dept Psychiat, VA Boston Healthcare Syst, VAMC-116B1,940 Belmont St, Brockton, MA 02301 USA. EM timothy_ofarrell@hms.harvard.edu FU National Institute on Alcohol Abuse and Alcoholism (NIAAA) [R01AA12834]; National Institute of Mental Health (NIMH) [T32MH16259]; U.S. Department of Veterans Affairs FX Funding for this study was provided by grant R01AA12834 awarded to the second author from the National Institute on Alcohol Abuse and Alcoholism (NIAAA), by National Institute of Mental Health (NIMH) grant T32MH16259 to support the first author in the Harvard Medical School Clinical Research Training Program, and by the U.S. Department of Veterans Affairs. NIAAA, NIMH and the VA had no role in the study design, collection, analysis or interpretation of the data, writing the manuscript, or the decision to submit the paper for publication. NR 27 TC 0 Z9 0 U1 11 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 EI 1873-6327 J9 ADDICT BEHAV JI Addict. Behav. PD FEB PY 2017 VL 65 BP 193 EP 197 DI 10.1016/j.addbeh.2016.10.015 PG 5 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA EF1GT UT WOS:000390074000030 ER PT J AU Willett, FR Pandarinath, C Jarosiewicz, B Murphy, BA Memberg, WD Blabe, CH Saab, J Walter, BL Sweet, JA Miller, JP Henderson, JM Shenoy, KV Simeral, JD Hochberg, LR Kirsch, RF Ajiboye, AB AF Willett, Francis R. Pandarinath, Chethan Jarosiewicz, Beata Murphy, Brian A. Memberg, William D. Blabe, Christine H. Saab, Jad Walter, Benjamin L. Sweet, Jennifer A. Miller, Jonathan P. Henderson, Jaimie M. Shenoy, Krishna V. Simeral, John D. Hochberg, Leigh R. Kirsch, Robert F. Ajiboye, A. Bolu TI Feedback control policies employed by people using intracortical brain-computer interfaces SO JOURNAL OF NEURAL ENGINEERING LA English DT Article DE brain-computer interface; motor cortex; motor control ID PERFORMANCE NEURAL PROSTHESIS; MACHINE INTERFACES; SENSORIMOTOR CONTROL; REACHING MOVEMENTS; CORTICAL CONTROL; KALMAN FILTER; TETRAPLEGIA; ARM; ADAPTATION; DEVICES AB Objective. When using an intracortical BCI (iBCI), users modulate their neural population activity to move an effector towards a target, stop accurately, and correct for movement errors. We call the rules that govern this modulation a 'feedback control policy'. A better understanding of these policies may inform the design of higher-performing neural decoders. Approach. We studied how three participants in the BrainGate2 pilot clinical trial used an iBCI to control a cursor in a 2D target acquisition task. Participants used a velocity decoder with exponential smoothing dynamics. Through offline analyses, we characterized the users' feedback control policies by modeling their neural activity as a function of cursor state and target position. We also tested whether users could adapt their policy to different decoder dynamics by varying the gain (speed scaling) and temporal smoothing parameters of the iBCI. Main results. We demonstrate that control policy assumptions made in previous studies do not fully describe the policies of our participants. To account for these discrepancies, we propose a new model that captures (1) how the user's neural population activity gradually declines as the cursor approaches the target from afar, then decreases more sharply as the cursor comes into contact with the target, (2) how the user makes constant feedback corrections even when the cursor is on top of the target, and (3) how the user actively accounts for the cursor's current velocity to avoid overshooting the target. Further, we show that users can adapt their control policy to decoder dynamics by attenuating neural modulation when the cursor gain is high and by damping the cursor velocity more strongly when the smoothing dynamics are high. Significance. Our control policy model may help to build better decoders, understand how neural activity varies during active iBCI control, and produce better simulations of closed-loop iBCI movements. C1 [Willett, Francis R.; Murphy, Brian A.; Memberg, William D.; Kirsch, Robert F.; Ajiboye, A. Bolu] Case Western Reserve Univ, Dept Biomed Engn, Cleveland, OH 44106 USA. [Willett, Francis R.; Murphy, Brian A.; Memberg, William D.; Walter, Benjamin L.; Sweet, Jennifer A.; Miller, Jonathan P.; Kirsch, Robert F.; Ajiboye, A. Bolu] FES Ctr Excellence, Louis Stokes Cleveland Dept, Vet Affairs Med Ctr, Rehab R&D Serv, Cleveland, OH USA. [Pandarinath, Chethan; Blabe, Christine H.; Henderson, Jaimie M.] Stanford Univ, Dept Neurosurg, Stanford, CA 94305 USA. [Pandarinath, Chethan; Shenoy, Krishna V.] Stanford Univ, Dept Elect Engn, Stanford, CA 94305 USA. [Pandarinath, Chethan; Henderson, Jaimie M.; Shenoy, Krishna V.] Stanford Univ, Stanford Neurosci Inst, Stanford, CA 94305 USA. [Jarosiewicz, Beata] Brown Univ, Dept Neurosci, Providence, RI 02912 USA. [Jarosiewicz, Beata; Saab, Jad; Simeral, John D.; Hochberg, Leigh R.] Dept Vet Affairs Med Ctr, Rehabil R&D Serv, Ctr Neurorestorat & Neurotechnol, Providence, RI USA. [Jarosiewicz, Beata; Simeral, John D.; Hochberg, Leigh R.] Brown Univ, Brown Inst Brain Sci, Providence, RI 02912 USA. [Saab, Jad; Simeral, John D.; Hochberg, Leigh R.] Brown Univ, Sch Engn, Providence, RI 02912 USA. [Walter, Benjamin L.] Univ Hosp Case Med Ctr, Dept Neurol, Cleveland, OH USA. [Sweet, Jennifer A.; Miller, Jonathan P.] Univ Hosp Case Med Ctr, Dept Neurosurg, Cleveland, OH USA. [Shenoy, Krishna V.] Stanford Univ, Dept Neurobiol, Stanford, CA 94305 USA. [Shenoy, Krishna V.] Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA. [Shenoy, Krishna V.] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA. [Simeral, John D.; Hochberg, Leigh R.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Hochberg, Leigh R.] Harvard Med Sch, Dept Neurol, Boston, MA USA. RP Willett, FR (reprint author), Case Western Reserve Univ, Dept Biomed Engn, Cleveland, OH 44106 USA.; Willett, FR (reprint author), FES Ctr Excellence, Louis Stokes Cleveland Dept, Vet Affairs Med Ctr, Rehab R&D Serv, Cleveland, OH USA. EM frw9@case.edu FU Larry and Pamela Garlick Foundation; National Science Foundation [GRFP DGE-0951783]; National Institutes of Health [1R01HD077220, R01NS066311, R01DC014034, R01DC009899, N01HD53403, N01HD10018]; Rehabilitation Research and Development Service [B6453R]; Samuel and Betsy Reeves Foundation; MGH-Deane Institute for Integrated Research on Atrial Fibrillation and Stroke FX The authors would like to thank participants T6, T7, T8 and their caregivers and families; Brittany Sorice for help with data collection; Daniel Young for informative discussions. This study is funded by the Larry and Pamela Garlick Foundation; National Science Foundation: GRFP DGE-0951783; National Institutes of Health: 1R01HD077220, R01NS066311, R01DC014034, R01DC009899, N01HD53403, N01HD10018; Rehabilitation Research and Development Service: B6453R; Samuel and Betsy Reeves Foundation; MGH-Deane Institute for Integrated Research on Atrial Fibrillation and Stroke. NR 41 TC 0 Z9 0 U1 11 U2 11 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 1741-2560 EI 1741-2552 J9 J NEURAL ENG JI J. Neural Eng. PD FEB PY 2017 VL 14 IS 1 AR 016001 DI 10.1088/1741-2560/14/1/016001 PG 16 WC Engineering, Biomedical; Neurosciences SC Engineering; Neurosciences & Neurology GA EF5HZ UT WOS:000390362600001 PM 27900953 ER PT J AU Schmidt, TP Pennington, DL Cardoos, SL Durazzo, TC Meyerhoff, DJ AF Schmidt, Thomas P. Pennington, David L. Cardoos, Stephanie L. Durazzo, Timothy C. Meyerhoff, Dieter J. TI Neurocognition and inhibitory control in polysubstance use disorders: Comparison with alcohol use disorders and changes with abstinence SO JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY LA English DT Article DE Addiction; Cognition; Impulsivity; Longitudinal; Recovery; Substance use disorders ID CHRONIC CIGARETTE-SMOKING; SUBSTANCE USE DISORDERS; DEPENDENT INDIVIDUALS; COGNITIVE IMPAIRMENTS; EXECUTIVE FUNCTIONS; DRUG-USE; RECOVERY; DEFICITS; DRINKERS; RISK AB Introduction: Intact neurocognition and early cognitive recovery during abstinence are important for substance use treatment outcome. Yet, little is known about them in the largest group of treatment seekers today, individuals with polysubstance use disorders (PSU). This study primarily contrasted PSU and individuals with an alcohol use disorder (AUD) on neurocognitive and inhibitory control measures and, secondarily, measured changes during abstinence in PSU. Method: At one month of abstinence from all substances except tobacco, 36 PSU and 69 AUD completed neurocognitive assessments of executive function, general intelligence, auditory-verbal learning/memory, visuospatial learning/memory/skills, processing speed, working memory, fine motor skills, and cognitive efficiency. The groups were also assessed on inhibitory control measures of self-reported impulsivity, risk-taking, and decision-making. Seventeen PSU repeated the assessments after approximately four months of abstinence. All cross-sectional and longitudinal analyses included smoking status as a possible confound. Results: At baseline, PSU performed significantly worse than AUD on auditory-verbal memory and on an inhibitory control measure of impulsivity. Polysubstance users showed trends to worse performance than AUD on general intelligence, auditory-verbal learning, and a decision-making task. Between one and four months of abstinence, PSU showed significant improvements on several neurocognitive and inhibitory control measures. Conclusions: Polysubstance users exhibit distinct differences in neurocognition and inhibitory control compared to AUD. Between one and four months of abstinence, neurocognition and inhibitory control improve in PSU. This neurocognitive recovery in some domains of abstinent PSU is influenced by smoking status. These results underscore the clinical value of select methods to augment neurocognitive recovery in PSU through appropriate interventions. C1 [Schmidt, Thomas P.; Pennington, David L.; Meyerhoff, Dieter J.] Northern Calif Inst Res & Educ, Dept Radiol, San Francisco, CA USA. [Schmidt, Thomas P.; Pennington, David L.; Cardoos, Stephanie L.; Meyerhoff, Dieter J.] San Francisco VA Med Ctr, Dept Radiol, San Francisco, CA USA. [Pennington, David L.; Cardoos, Stephanie L.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Durazzo, Timothy C.] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. [Durazzo, Timothy C.] Vet Affairs Palo Alto Hlth Care Syst, Dept Psychiat, Palo Alto, CA USA. [Meyerhoff, Dieter J.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. RP Schmidt, TP (reprint author), San Francisco VA Med Ctr, Ctr Imaging Neurodegenerat Dis 114M, 4150 Clement St, San Francisco, CA 94121 USA. EM thomas.schmidt@ucsf.edu FU National Institutes of Health [AA10788, DA25202, DA21436] FX This work was supported by the National Institutes of Health [grant number AA10788 to D.J.M.], [grant number DA25202 to D.J.M.], [grant number DA21436 to T.C.D.], administered by the Northern California Institute for Research and Education; and by the use of resources and facilities at the San Francisco Veterans Administration Medical Center. NR 70 TC 0 Z9 0 U1 14 U2 14 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1380-3395 EI 1744-411X J9 J CLIN EXP NEUROPSYC JI J. Clin. Exp. Neuropsychol. PD FEB PY 2017 VL 39 IS 1 BP 22 EP 34 DI 10.1080/13803395.2016.1196165 PG 13 WC Psychology, Clinical; Clinical Neurology; Psychology SC Psychology; Neurosciences & Neurology GA EE3OH UT WOS:000389499700003 PM 27690739 ER PT J AU Auerbach, S Yaffe, K AF Auerbach, Sanford Yaffe, Kristine TI The link between sleep-disordered breathing and cognition in the elderly New opportunities? SO NEUROLOGY LA English DT Editorial Material ID POSITIVE AIRWAY PRESSURE; OLDER-ADULTS; APNEA; RISK; CPAP C1 [Auerbach, Sanford] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02215 USA. [Auerbach, Sanford] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02215 USA. [Auerbach, Sanford] Boston Univ, Sch Med, Dept Behav Neurosci, Boston, MA 02215 USA. [Auerbach, Sanford] Boston Med Ctr, Sleep Disorders Ctr, Boston, MA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Yaffe, Kristine] San Francisco VA Med Ctr, San Francisco, CA USA. RP Auerbach, S (reprint author), Boston Univ, Sch Med, Dept Neurol, Boston, MA 02215 USA.; Auerbach, S (reprint author), Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02215 USA.; Auerbach, S (reprint author), Boston Univ, Sch Med, Dept Behav Neurosci, Boston, MA 02215 USA.; Auerbach, S (reprint author), Boston Med Ctr, Sleep Disorders Ctr, Boston, MA USA. EM sauerbac@bu.edu NR 11 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD JAN 31 PY 2017 VL 88 IS 5 BP 424 EP 425 DI 10.1212/WNL.0000000000003577 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA EP4HE UT WOS:000397340800006 PM 28039313 ER PT J AU Yaffe, K Freimer, D Chen, HL Asao, K Rosso, A Rubin, S Tranah, G Cummings, S Simonsick, E AF Yaffe, Kristine Freimer, Daniel Chen, Honglei Asao, Keiko Rosso, Andrea Rubin, Susan Tranah, Greg Cummings, Steve Simonsick, Eleanor TI Olfaction and risk of dementia in a biracial cohort of older adults SO NEUROLOGY LA English DT Article ID MILD COGNITIVE IMPAIRMENT; ALZHEIMERS-DISEASE; AFRICAN-AMERICANS; APOLIPOPROTEIN-E; RACIAL DISPARITIES; URBAN-COMMUNITY; IDENTIFICATION; ALLELE; CAUCASIANS; CONVERSION AB Objective: Prior studies indicate that olfactory function may be an early marker for cognitive impairment, but the body of evidence has been largely restricted to white populations. Methods: We studied 2,428 community-dwelling black and white older adults (baseline age 70-79 years) without dementia enrolled in the Health, Aging, and Body Composition (Health ABC) study. Olfaction was measured as odor identification (OI) with the 12-item Cross Cultural Smell Identification Test in year 3. We defined incident dementia over 12 years on the basis of hospitalization records, prescription for dementia medication, or 1.5-SD decline in race-stratified global cognition score. We assessed dementia risk associated with OI score (by tertile) using Cox proportional hazards models. All analyses were stratified by race. Results: Poorer OI in older adults without dementia was associated with increased risk of dementia. After adjustment for demographics, medical comorbidities, and lifestyle characteristics, white participants in the poor or moderate OI tertile had greater risk of dementia (adjusted hazard ratio [HR] 3.34, 95% confidence interval [CI] 2.45-4.54; and HR 1.84, 95% CI 1.33-2.54, respectively) compared to those in the good tertile of function. Among blacks, worse OI was associated with an increased risk of dementia, but the magnitude of the effect was weaker (p for interaction 5 0.04) for the poor OI tertile (adjusted HR 2.03, 95% CI 1.44-2.84) and for the moderate tertile (adjusted HR 1.42, 95% CI 0.97-2.10). There was no interaction between OI and APOE e4 and risk of dementia. Conclusions: While the magnitude of the association was stronger in whites, we found that poor OI was associated with increased risk of dementia among both black and white older adults. C1 [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; Rubin, Susan] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Yaffe, Kristine] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Yaffe, Kristine; Freimer, Daniel] NCIRE Vet Hlth Res Inst, San Francisco, CA 94121 USA. [Chen, Honglei] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Asao, Keiko] Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, Memphis, TN USA. [Rosso, Andrea] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Tranah, Greg; Cummings, Steve] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Simonsick, Eleanor] NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA. RP Yaffe, K (reprint author), Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA.; Yaffe, K (reprint author), Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA.; Yaffe, K (reprint author), Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA.; Yaffe, K (reprint author), San Francisco VA Med Ctr, San Francisco, CA 94121 USA.; Yaffe, K (reprint author), NCIRE Vet Hlth Res Inst, San Francisco, CA 94121 USA. EM kristine.yaffe@ucsf.edu OI Chen, Honglei/0000-0003-3446-7779 FU National Institute on Aging [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050, K24-AG031155]; National Institute of Nursing Research [R01-NR012459]; Intramural Research Program of the NIH, the National Institute of Environmental Health Sciences [Z01-ES101986] FX This research was supported by National Institute on Aging contracts N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050, and K24-AG031155; and National Institute of Nursing Research grant R01-NR012459. The study was supported in part by the Intramural Research Program of the NIH, the National Institute of Environmental Health Sciences (Z01-ES101986). NR 46 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD JAN 31 PY 2017 VL 88 IS 5 BP 456 EP 462 DI 10.1212/WNL.0000000000003558 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA EP4HE UT WOS:000397340800011 PM 28039314 ER PT J AU Dizon, MP Linos, E Arron, ST Hills, NK Chren, MM AF Dizon, Matthew P. Linos, Eleni Arron, Sarah T. Hills, Nancy K. Chren, Mary-Margaret TI Comparing the Quality of Ambulatory Surgical Care for Skin Cancer in a Veterans Affairs Clinic and a Fee-For-Service Practice Using Clinical and Patient-Reported Measures SO PLOS ONE LA English DT Article ID SQUAMOUS-CELL CARCINOMA; MEDICAL-CARE; OF-LIFE; SUNLIGHT EXPOSURE; HEALTH-CARE; RISK; SATISFACTION; PERFORMANCE AB The Institute of Medicine has identified serious deficiencies in the measurement of cancer care quality, including the effects on quality of life and patient experience. Moreover, comparisons of quality in Veterans Affairs Medical Centers (VA) and other sites are timely now that many Veterans can choose where to seek care. To compare quality of ambulatory surgical care for keratinocyte carcinoma (KC) between a VA and fee-for-service (FFS) practice, we used unique clinical and patient-reported data from a comparative effectiveness study. Patients were enrolled in 1999-2000 and followed for a median of 7.2 years. The practices differed in a few process measures (e. g., median time between biopsy and treatment was 7.5 days longer at VA) but there were no substantial or consistent differences in clinical outcomes or a broad range of patient-reported outcomes. For example, 5-year tumor recurrence rates were equally low (3.6% [2.3-5.5] at VA and 3.4% [2.3-5.1] at FFS), and similar proportions of patients reported overall satisfaction at one year (78% at VA and 80% at FFS, P = 0.69). These results suggest that the quality of care for KC can be compared comprehensively in different health care systems, and suggest that quality of care for KC was similar at a VA and FFS setting. C1 [Dizon, Matthew P.; Linos, Eleni; Arron, Sarah T.; Chren, Mary-Margaret] Univ Calif San Francisco, Dept Dermatol, Program Clin Res, San Francisco, CA 94143 USA. [Arron, Sarah T.; Chren, Mary-Margaret] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Hills, Nancy K.] Univ Calif San Francisco, Dept Biostat & Epidemiol, San Francisco, CA 94143 USA. RP Chren, MM (reprint author), Univ Calif San Francisco, Dept Dermatol, Program Clin Res, San Francisco, CA 94143 USA.; Chren, MM (reprint author), San Francisco VA Med Ctr, San Francisco, CA 94121 USA. EM chrenm@ucsf.edu FU University of California, San Francisco Resource Allocation Program for Trainees (RAPtr); University of California, San Francisco Resource Allocation Program (RAP); National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institutes of Health [R01 AR054983, K24 AR052667] FX This study was supported in part by the University of California, San Francisco Resource Allocation Program for Trainees (RAPtr), University of California, San Francisco Resource Allocation Program (RAP), and grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (http://www.niams.nih.gov/), National Institutes of Health (R01 AR054983 and K24 AR052667). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 26 TC 0 Z9 0 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 31 PY 2017 VL 12 IS 1 AR e0171253 DI 10.1371/journal.pone.0171253 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN6QW UT WOS:000396129500054 ER PT J AU Tian, L Bashan, A Shi, DN Liu, YY AF Tian, Liang Bashan, Amir Shi, Da-Ning Liu, Yang-Yu TI Articulation points in complex networks SO NATURE COMMUNICATIONS LA English DT Article ID SCALE-FREE NETWORKS; RANDOM GRAPHS; PERCOLATION; DYNAMICS AB An articulation point in a network is a node whose removal disconnects the network. Those nodes play key roles in ensuring connectivity of many real-world networks, from infrastructure networks to protein interaction networks and terrorist communication networks. Despite their fundamental importance, a general framework of studying articulation points in complex networks is lacking. Here we develop analytical tools to study key issues pertinent to articulation points, such as the expected number of them and the network vulnerability against their removal, in an arbitrary complex network. We find that a greedy articulation point removal process provides us a different perspective on the organizational principles of complex networks. Moreover, this process results in a rich phase diagram with two fundamentally different types of percolation transitions. Our results shed light on the design of more resilient infrastructure networks and the effective destruction of terrorist communication networks. C1 [Tian, Liang; Liu, Yang-Yu] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Tian, Liang; Liu, Yang-Yu] Harvard Med Sch, Boston, MA 02115 USA. [Tian, Liang; Shi, Da-Ning] Nanjing Univ Aeronaut & Astronaut, Coll Sci, Nanjing 210016, Jiangsu, Peoples R China. [Bashan, Amir] Bar Ilan Univ, Dept Phys, IL-5290002 Ramat Gan, Israel. [Liu, Yang-Yu] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. RP Liu, YY (reprint author), Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA.; Liu, YY (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Liu, YY (reprint author), Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. EM yyl@channing.harvard.edu FU John Templeton Foundation [51977]; National Natural Science Foundation of China [11505095, 11374159]; Fundamental Research Funds for the Central Universities of China [NS2014072, NZ2015110] FX We thank Shlomo Havlin, Mehran Kardar, Wei Chen, Endre Csoka, Abhijeet Sonawane, Yandong Xiao, Chuliang Song for valuable discussions. This work was partially supported by the John Templeton Foundation (Award No 51977), National Natural Science Foundation of China (grants nos. 11505095 and 11374159), and the Fundamental Research Funds for the Central Universities of China (grants nos NS2014072 and NZ2015110). NR 46 TC 0 Z9 0 U1 8 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 JAN 31 PY 2017 VL 8 AR 14223 DI 10.1038/ncomms14223 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EJ1EL UT WOS:000392953200001 PM 28139697 ER PT J AU Gao, WH Li, W Xiao, TF Liu, XS Kaelin, WG AF Gao, Wenhua Li, Wei Xiao, Tengfei Liu, Xiaole Shirley Kaelin, William G., Jr. TI Inactivation of the PBRM1 tumor suppressor gene amplifies the HIF-response in VHL-/- clear cell renal carcinoma SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE kidney cancer; chromatin; PBAF; BAF180; hypoxia ID KIDNEY CANCER; SWI/SNF COMPLEX; TARGET; HETEROGENEITY; EVOLUTION; GENOMICS; MUTATION AB Most clear cell renal carcinomas (ccRCCs) are initiated by somatic inactivation of the VHL tumor suppressor gene. The VHL gene product, pVHL, is the substrate recognition unit of an ubiquitin ligase that targets the HIF transcription factor for proteasomal degradation; inappropriate expression of HIF target genes drives renal carcinogenesis. Loss of pVHL is not sufficient, however, to cause ccRCC. Additional cooperating genetic events, including intragenic mutations and copy number alterations, are required. Common examples of the former are loss-of-functionmutations of the PBRM1 and BAP1 tumor suppressor genes, which occur in a mutually exclusive manner in ccRCC and define biologically distinct subsets of ccRCC. PBRM1 encodes the Polybromo-and BRG1-associated factors-containing complex (PBAF) chromatin remodeling complex component BRG1-associated factor 180 (BAF180). Here we identified ccRCC lines whose ability to proliferate in vitro and in vivo is sensitive to wild-type BAF180, but not a tumor-associated BAF180 mutant. Biochemical and functional studies linked growth suppression by BAF180 to its ability to form a canonical PBAF complex containing BRG1 that dampens the HIF transcriptional signature. C1 [Gao, Wenhua; Xiao, Tengfei; Kaelin, William G., Jr.] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Gao, Wenhua; Xiao, Tengfei; Kaelin, William G., Jr.] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA 02115 USA. [Li, Wei; Xiao, Tengfei; Liu, Xiaole Shirley] Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02215 USA. [Li, Wei; Xiao, Tengfei; Liu, Xiaole Shirley] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Li, Wei; Xiao, Tengfei; Liu, Xiaole Shirley] Harvard TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Kaelin, William G., Jr.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Kaelin, WG (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA.; Kaelin, WG (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Boston, MA 02115 USA.; Kaelin, WG (reprint author), Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. EM william_kaelin@dfci.harvard.edu FU NIH; [GM99409] FX We thank members of the W.G.K. laboratory for useful discussions. X.S.L. is supported by Grant GM99409. W.G.K. is a Howard Hughes Medical Institute investigator and is supported by grants from the NIH. NR 30 TC 0 Z9 0 U1 2 U2 2 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 JAN 31 PY 2017 VL 114 IS 5 BP 1027 EP 1032 DI 10.1073/pnas.1619726114 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EJ4OI UT WOS:000393196300074 PM 28082722 ER PT J AU Gupta, N Badeaux, M Liu, YQ Naxerova, K Sgroi, D Munn, LL Jain, RK Garkavtsev, I AF Gupta, Nisha Badeaux, Mark Liu, Yiqian Naxerova, Kamila Sgroi, Dennis Munn, Lance L. Jain, Rakesh K. Garkavtsev, Igor TI Stress granule-associated protein G3BP2 regulates breast tumor initiation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE tumor-initiating cells; breast cancer; G3BP2; stress granule ID CANCER STEM-CELLS; EPITHELIAL-MESENCHYMAL TRANSITION; DRUG-RESISTANCE; NANOG; HETEROGENEITY; QUIESCENCE; PLASTICITY; MARKER; GENE AB Breast tumors contain tumorigenic cancer cells, termed "tumorinitiating cells" (TICs), which are capable of both replenishing themselves and giving rise to populations of nontumorigenic breast cancer cells (non-TICs). However, the molecular mechanisms responsible for breast tumor initiation remain poorly understood. Here we describe a chemical screening strategy to identify small molecules that enhance the effect of chemotherapeutic agents on TIC-enriched breast cancer cells. We identified proteins that interact with the lead compound C108, including the stress granule-associated protein, GTPase-activating protein (SH3 domain)-binding protein 2, G3BP2. G3BP2 regulates breast tumor initiation through the stabilization of Squamous cell carcinoma antigen recognized by T cells 3 (SART3) mRNA, which leads to increased expression of the pluripotency transcription factors Octamer-binding protein 4 (Oct-4) and Nanog Homeobox (Nanog). Our findings suggest that G3BP2 is important for the process of breast cancer initiation. Furthermore, these data suggest a possible connection between stress granule formation and tumor initiation in breast cancer cells. C1 [Gupta, Nisha; Badeaux, Mark; Naxerova, Kamila; Munn, Lance L.; Jain, Rakesh K.; Garkavtsev, Igor] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Labs, Boston, MA 02114 USA. [Gupta, Nisha; Badeaux, Mark; Naxerova, Kamila; Munn, Lance L.; Jain, Rakesh K.; Garkavtsev, Igor] Harvard Med Sch, Boston, MA 02114 USA. [Gupta, Nisha] Vrije Univ Amsterdam, Med Ctr, Dept Physiol, NL-1081 HV Amsterdam, Netherlands. [Liu, Yiqian] Jiangsu Prov Hosp, Dept Oncol, Nanjing 210029, Jiangsu, Peoples R China. [Sgroi, Dennis] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Sgroi, Dennis] Harvard Med Sch, Boston, MA 02114 USA. RP Garkavtsev, I (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Labs, Boston, MA 02114 USA.; Garkavtsev, I (reprint author), Harvard Med Sch, Boston, MA 02114 USA. EM igorg@steele.mgh.harvard.edu OI Naxerova, Kamila/0000-0001-7744-5110 FU NIH [R21CA169616-01A1]; Federal Share Proton Beam Program; Department of Physiology, Vrije Universiteit Amsterdam Medical Center FX We thank past and present members of the Edwin L. Steele laboratory for helpful discussions. This work was supported in part by NIH Grant R21CA169616-01A1 (to I.G.) and the Federal Share Proton Beam Program (I.G. and R.K.J.). N.G. was supported in part by the Department of Physiology, Vrije Universiteit Amsterdam Medical Center. Screening of the chemical library was done by the Small Molecule Screening Core of Roswell Park Cancer Institute. Mass spectrometry analysis was done by the Core Facility of Harvard Medical School. NR 32 TC 0 Z9 0 U1 1 U2 1 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 JAN 31 PY 2017 VL 114 IS 5 BP 1033 EP 1038 DI 10.1073/pnas.1525387114 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EJ4OI UT WOS:000393196300075 PM 28096337 ER PT J AU Urbach, JM Ausubel, FM AF Urbach, Jonathan M. Ausubel, Frederick M. TI The NBS-LRR architectures of plant R-proteins and metazoan NLRs evolved in independent events SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE NLR; R-protein; innate immunity; evolution; NOD-like receptors ID PHYLOGENETIC TREE SELECTION; MULTIPLE SEQUENCE ALIGNMENT; GENE FAMILY; CELL-DEATH; IMMUNITY; ANIMALS; EVOLUTION; ACTIVATION; ORIGIN AB There are intriguing parallels between plants and animals, with respect to the structures of their innate immune receptors, that suggest universal principles of innate immunity. The cytosolic nucleotide binding site-leucine rich repeat (NBS-LRR) resistance proteins of plants (R-proteins) and the so-called NOD-like receptors of animals (NLRs) share a domain architecture that includes a STAND (signal transduction ATPases with numerous domains) family NTPase followed by a series of LRRs, suggesting inheritance from a common ancestor with that architecture. Focusing on the STAND NTPases of plant R-proteins, animal NLRs, and their homologs that represent the NB-ARC (nucleotide-binding adaptor shared by APAF-1, certain R gene products and CED-4) and NACHT (named for NAIP, CIIA, HET-E, and TEP1) subfamilies of the STAND NTPases, we analyzed the phylogenetic distribution of the NBS-LRR domain architecture, usedmaximum-likelihood methods to infer a phylogeny of the NTPase domains of R-proteins, and reconstructed the domain structure of the protein containing the common ancestor of the STAND NTPase domain of R-proteins and NLRs. Our analyses reject monophyly of plant R-proteins and NLRs and suggest that the protein containing the last common ancestor of the STAND NTPases of plant R-proteins and animal NLRs (and, by extension, all NB-ARC and NACHT domains) possessed a domain structure that included a STAND NTPase paired with a series of tetratricopeptide repeats. These analyses reject the hypothesis that the domain architecture of R-proteins and NLRs was inherited from a common ancestor and instead suggest the domain architecture evolved at least twice. It remains unclear whether the NBS-LRR architectures were innovations of plants and animals themselves or were acquired by one or both lineages through horizontal gene transfer. C1 [Urbach, Jonathan M.; Ausubel, Frederick M.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Ausubel, Frederick M.] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. RP Ausubel, FM (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA.; Ausubel, FM (reprint author), Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. EM ausubel@molbio.mgh.harvard.edu FU National Science Foundation [MCB-0519898, IOS-0929226]; National Institutes of Health [R37-GM48707, P30 DK040561] FX We thank Dong Wang and Linda Holland for providing DNA samples; Samuel Church for advice relating to the SOWH analysis; and Sarah Mathews, Noah Whiteman, Slim Sassi, Xuecheng Zhang, and Richard Michelmore for helpful conversations. This work was supported by National Science Foundation Grants MCB-0519898 and IOS-0929226 and National Institutes of Health Grants R37-GM48707 and P30 DK040561. NR 31 TC 0 Z9 0 U1 7 U2 7 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 JAN 31 PY 2017 VL 114 IS 5 BP 1063 EP 1068 DI 10.1073/pnas.1619730114 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EJ4OI UT WOS:000393196300080 PM 28096345 ER PT J AU Bracamonte-Baran, W Florentin, J Zhou, Y Jankowska-Gan, E Haynes, WJ Zhong, WX Brennan, TV Dutta, P Claas, FHJ van Rood, JJ Burlingham, WJ AF Bracamonte-Baran, William Florentin, Jonathan Zhou, Ying Jankowska-Gan, Ewa Haynes, W. John Zhong, Weixiong Brennan, Todd V. Dutta, Partha Claas, Frans H. J. van Rood, Jon J. Burlingham, William J. TI Modification of host dendritic cells by microchimerism-derived extracellular vesicles generates split tolerance SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE dendritic cells; exosomes; split tolerance; T cells; microchimerism ID MATERNAL HLA ANTIGENS; RHEUMATOID-ARTHRITIS; CORD BLOOD; INDUCTION; PATHWAY; MICE; TRANSPLANTATION; SENSITIZATION; MICROCLUSTERS; ALLOANTIGEN AB Maternal microchimerism (MMc) has been associated with development of allospecific transplant tolerance, antitumor immunity, and cross-generational reproductive fitness, but its mode of action is unknown. We found in a murine model that MMc caused exposure to the noninherited maternal antigens in all offspring, but in some, MMc magnitude was enough to cause membrane alloantigen acquisition (mAAQ; "cross-dressing") of host dendritic cells (DCs). Extracellular vesicle (EV)-enriched serum fractions from mAAQ(+), but not from non-mAAQ, mice reproduced the DC cross-dressing phenomenon in vitro. In vivo, mAAQ was associated with increased expression of immune modulators PD-L1 (programmed death-ligand 1) and CD86 by myeloid DCs (mDCs) and decreased presentation of allopeptide+self-MHC complexes, along with increased PD-L1, on plasmacytoid DCs (pDCs). Remarkably, both serum EV-enriched fractions and membrane microdomains containing the acquired MHC alloantigens included CD86, but completely excluded PD-L1. In contrast, EV-enriched fractions and microdomains containing allopeptide+self-MHC did not exclude PD-L1. Adoptive transfer of allospecific transgenic CD4 T cells revealed a "split tolerance" status in mAAQ+ mice: T cells recognizing intact acquired MHC alloantigens proliferated, whereas those responding to allopeptide+self-MHC did not. Using isolated pDCs and mDCs for in vitro culture with allopeptide+self-MHC-specific CD4 T cells, we could replicate their normal activation in non-mAAQ mice, and PD-L1-dependent anergy in mAAQ(+) hosts. We propose that EVs provide a physiologic link between microchimerism and split tolerance, with implications for tumor immunity, transplantation, autoimmunity, and reproductive success. C1 [Bracamonte-Baran, William; Florentin, Jonathan; Zhou, Ying; Jankowska-Gan, Ewa; Haynes, W. John; Burlingham, William J.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Surg, Div Transplantat, Madison, WI 53792 USA. [Florentin, Jonathan; Dutta, Partha] Univ Pittsburgh, Med Ctr, Vasc Med Inst, Pittsburgh, PA 15213 USA. [Zhong, Weixiong] Univ Wisconsin, Dept Pathol & Lab Med, Sch Med & Publ Hlth, Madison, WI 53792 USA. [Zhong, Weixiong] William S Middleton Mem Vet Adm Med Ctr, Pathol & Lab Serv, Madison, WI 53705 USA. [Brennan, Todd V.] Duke Univ, Med Ctr, Dept Surg, Div Abdominal Transplantat, Durham, NC 27710 USA. [Claas, Frans H. J.; van Rood, Jon J.] Leiden Univ, Med Ctr, Dept Immunohaematol & Blood Transfus, NL-2333 ZA Leiden, Netherlands. RP Burlingham, WJ (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, Dept Surg, Div Transplantat, Madison, WI 53792 USA.; van Rood, JJ (reprint author), Leiden Univ, Med Ctr, Dept Immunohaematol & Blood Transfus, NL-2333 ZA Leiden, Netherlands. EM Jon.vanRood@matchis.nl; burlingham@surgery.wisc.edu FU UW Carbone Cancer Center Flow Laboratory (University of Wisconsin Carbone Cancer Center Support Grant) [P30 CA014520]; NIH Grant [2R01-AI066219] FX We thank the WilliamS. Middleton Memorial Veterans Hospital Electron Microscopy Facility for EM assistance; Drs. Gilles Benichou, Jeremy Sullivan, and Dixon Kaufman for helpful suggestions on the manuscript; Dr. Luis Queiroz, Dr. John Verstegen (MOFA-Madison), and the personnel of the UW Carbone Cancer Center Flow Laboratory (University of Wisconsin Carbone Cancer Center Support Grant P30 CA014520) for the technical support on flow cytometry and ImageStream experiments; and Dr. Douglas McNeel for providing the anti-PD-L1 antibody. This project was supported by NIH Grant 2R01-AI066219 (to W.J.B.). NR 38 TC 0 Z9 0 U1 2 U2 2 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 JAN 31 PY 2017 VL 114 IS 5 BP 1099 EP 1104 DI 10.1073/pnas.1618364114 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EJ4OI UT WOS:000393196300086 PM 28096390 ER PT J AU Kalinich, M Bhan, I Kwan, TT Miyamoto, DT Javaid, S LiCausi, JA Milner, JD Hong, X Goyal, L Sil, S Choz, M Ho, U Kapur, R Muzikansky, A Zhang, HD Weitz, DA Sequist, LV Ryan, DP Chung, RT Zhu, AX Isselbacher, KJ Ting, DT Toner, M Maheswaran, S Haber, DA AF Kalinich, Mark Bhan, Irun Kwan, Tanya T. Miyamoto, David T. Javaid, Sarah LiCausi, Joseph A. Milner, John D. Hong, Xin Goyal, Lipika Sil, Srinjoy Choz, Melissa Ho, Uyen Kapur, Ravi Muzikansky, Alona Zhang, Huidan Weitz, David A. Sequist, Lecia V. Ryan, David P. Chung, Raymond T. Zhu, Andrew X. Isselbacher, Kurt J. Ting, David T. Toner, Mehmet Maheswaran, Shyamala Haber, Daniel A. TI An RNA-based signature enables high specificity detection of circulating tumor cells in hepatocellular carcinoma SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE circulating tumor cells; early cancer detection; hepatocellular carcinoma; blood biopsy; predictive modeling ID ALPHA-FETOPROTEIN; CANCER METASTASIS; PERIPHERAL-BLOOD; EXPRESSION; TRIAL AB Circulating tumor cells (CTCs) are shed into the bloodstream by invasive cancers, but the difficulty inherent in identifying these rare cells by microscopy has precluded their routine use in monitoring or screening for cancer. We recently described a high-throughput microfluidic CTC-iChip, which efficiently depletes hematopoietic cells from blood specimens and enriches for CTCs with well-preserved RNA. Application of RNA-based digital PCR to detect CTC-derived signatures may thus enable highly accurate tissue lineage-based cancer detection in blood specimens. As proof of principle, we examined hepatocellular carcinoma (HCC), a cancer that is derived from liver cells bearing a unique gene expression profile. After identifying a digital signature of 10 liver-specific transcripts, we used a cross-validated logistic regression model to identify the presence of HCC-derived CTCs in nine of 16 (56%) untreated patients with HCC versus one of 31 (3%) patients with nonmalignant liver disease at risk for developing HCC (P < 0.0001). Positive CTC scores declined in treated patients: Nine of 32 (28%) patients receiving therapy and only one of 15 (7%) patients who had undergone curative-intent ablation, surgery, or liver transplantation were positive. RNA-based digital CTC scoring was not correlated with the standard HCC serum protein marker alpha fetoprotein (P = 0.57). Modeling the sequential use of these two orthogonal markers for liver cancer screening in patients with high-risk cirrhosis generates positive and negative predictive values of 80% and 86%, respectively. Thus, digital RNA quantitation constitutes a sensitive and specific CTC readout, enabling high-throughput clinical applications, such as noninvasive screening for HCC in populations where viral hepatitis and cirrhosis are prevalent. C1 [Kalinich, Mark; Bhan, Irun; Kwan, Tanya T.; Miyamoto, David T.; Javaid, Sarah; LiCausi, Joseph A.; Hong, Xin; Goyal, Lipika; Sil, Srinjoy; Choz, Melissa; Ho, Uyen; Muzikansky, Alona; Sequist, Lecia V.; Ryan, David P.; Zhu, Andrew X.; Isselbacher, Kurt J.; Ting, David T.; Maheswaran, Shyamala; Haber, Daniel A.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Bhan, Irun; Chung, Raymond T.; Isselbacher, Kurt J.] Harvard Med Sch, Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Miyamoto, David T.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Goyal, Lipika; Sequist, Lecia V.; Ryan, David P.; Zhu, Andrew X.; Ting, David T.; Haber, Daniel A.] Harvard Med Sch, Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. [Kapur, Ravi; Toner, Mehmet] Massachusetts Gen Hosp, Ctr Bioengn Med, Boston, MA 02114 USA. [Kapur, Ravi; Toner, Mehmet] Harvard Med Sch, Boston, MA 02114 USA. [Kapur, Ravi; Toner, Mehmet] Shriners Hosp Children, Boston, MA 02114 USA. [Muzikansky, Alona] Harvard Med Sch, Massachusetts Gen Hosp, Div Biostat, Boston, MA 02114 USA. [Zhang, Huidan; Weitz, David A.] Harvard Univ, Sch Engn & Appl Sci, Dept Phys, Cambridge, MA 02138 USA. [Toner, Mehmet; Maheswaran, Shyamala] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Haber, Daniel A.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Javaid, Sarah] Merck Res Labs, Boston, MA 02114 USA. RP Isselbacher, KJ; Maheswaran, S; Haber, DA (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA.; Isselbacher, KJ (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA.; Haber, DA (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA.; Maheswaran, S (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA.; Haber, DA (reprint author), Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. EM kisselbacher@mgh.harvard.edu; maheswaran@helix.mgh.harvard.edu; dhaber@mgh.harvard.edu OI Ting, David/0000-0002-3261-2322 FU NIH [2R01CA129933, DK078772, T32DK007191]; Howard Hughes Medical Institute; National Foundation for Cancer Research; NIH Quantum Grant [2U01EB012493]; MD/PhD Training Grant [T32GM007753]; Department of Defense; National Science Foundation [DMR-1310266, ECS-0335765]; Harvard Materials Research Science and Engineering Center Grant [DMR-1420570]; Prostate Cancer Foundation FX We thank all of the patients who participated in this study. We also thank the Massachusetts General Hospital (MGH) nurses and clinical research coordinators for their assistance with the study; A. Bardia, R. Sullivan, P. Saylor, and R. Lee for graciously gathering clinical information and patient samples; and L. Libby for invaluable technical support. This work was supported by NIH Grant 2R01CA129933, the Howard Hughes Medical Institute, the National Foundation for Cancer Research (D.A.H.), NIH Quantum Grant 2U01EB012493 (to M.T. and D.A.H.), MD/PhD Training Grant T32GM007753 (to M.K.), NIH Grant DK078772 (to R.T.C.), NIH Grant T32DK007191 (to I.B.), the Department of Defense and Prostate Cancer Foundation (D.T.M.), National Science Foundation Grants DMR-1310266 and ECS-0335765, and Harvard Materials Research Science and Engineering Center Grant DMR-1420570 (to D.A.W.). The MGH has filed for patent protection for the digital CTC detection approach. NR 27 TC 0 Z9 0 U1 11 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 31 PY 2017 VL 114 IS 5 BP 1123 EP 1128 DI 10.1073/pnas.1617032114 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EJ4OI UT WOS:000393196300090 PM 28096363 ER PT J AU Sherman, MH Yu, RT Tseng, TW Sousa, CM Liu, SH Truitt, ML He, NH Ding, N Liddle, C Atkins, AR Leblanc, M Collisson, EA Asara, JM Kimmelman, AC Downes, M Evans, RM AF Sherman, Mara H. Yu, Ruth T. Tseng, Tiffany W. Sousa, Cristovao M. Liu, Sihao Truitt, Morgan L. He, Nanhai Ding, Ning Liddle, Christopher Atkins, Annette R. Leblanc, Mathias Collisson, Eric A. Asara, John M. Kimmelman, Alec C. Downes, Michael Evans, Ronald M. TI Stromal cues regulate the pancreatic cancer epigenome and metabolome SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE pancreatic ductal adenocarcinoma; tumor microenvironment; cancer metabolism; BRD2; histone acetylation ID DUCTAL ADENOCARCINOMA; MICROARRAY DATA; STELLATE CELLS; C-MYC; GENE; PROGRESSION; BROMODOMAIN; MACROPHAGE; MICROENVIRONMENT; INHIBITION AB A fibroinflammatory stromal reaction cooperates with oncogenic signaling to influence pancreatic ductal adenocarcinoma (PDAC) initiation, progression, and therapeutic outcome, yet the mechanistic underpinning of this crosstalk remains poorly understood. Here we show that stromal cues elicit an adaptive response in the cancer cell including the rapid mobilization of a transcriptional network implicated in accelerated growth, along with anabolic changes of an altered metabolome. The close overlap of stroma-induced changes in vitro with those previously shown to be regulated by oncogenic Kras in vivo suggests that oncogenic Kras signaling-a hallmark and key driver of PDAC-is contingent on stromal inputs. Mechanistically, stroma-activated cancer cells show widespread increases in histone acetylation at transcriptionally enhanced genes, implicating the PDAC epigenome as a presumptive point of convergence between these pathways and a potential therapeutic target. Notably, inhibition of the bromodomain and extraterminal (BET) family of epigenetic readers, and of Bromodomain-containing protein 2 (BRD2) in particular, blocks stroma-inducible transcriptional regulation in vitro and tumor progression in vivo. Our work suggests the existence of a molecular "AND-gate" such that tumor activation is the consequence of mutant Kras and stromal cues, providing insight into the role of the tumor microenvironment in the origin and treatment of Ras-driven tumors. C1 [Sherman, Mara H.; Yu, Ruth T.; Tseng, Tiffany W.; Liu, Sihao; Truitt, Morgan L.; He, Nanhai; Ding, Ning; Atkins, Annette R.; Leblanc, Mathias; Downes, Michael; Evans, Ronald M.] Salk Inst Biol Studies, Gene Express Lab, La Jolla, CA 92037 USA. [Sousa, Cristovao M.; Kimmelman, Alec C.] Harvard Med Sch, Dana Farber Canc Inst, Dept Radiat Oncol, Div Genom Stabil & DNA Repair, Boston, MA 02215 USA. [Liddle, Christopher] Univ Sydney, Sydney Med Sch, Westmead Millennium Inst, Storr Liver Ctr, Sydney, NSW 2006, Australia. [Collisson, Eric A.] Univ Calif San Francisco, Dept Med Hematol & Oncol, San Francisco, CA 94143 USA. [Asara, John M.] Beth Israel Deaconess Med Ctr, Dept Med, Div Signal Transduct, Boston, MA 02115 USA. [Kimmelman, Alec C.] NYU, Sch Med, Dept Radiat Oncol, New York, NY 10016 USA. [Evans, Ronald M.] Salk Inst Biol Studies, Howard Hughes Med Inst, La Jolla, CA 92037 USA. [Sherman, Mara H.] Oregon Hlth & Sci Univ, Dept Cell Dev & Canc Biol, Portland, OR 97201 USA. RP Downes, M; Evans, RM (reprint author), Salk Inst Biol Studies, Gene Express Lab, La Jolla, CA 92037 USA. EM downes@salk.edu; evans@salk.edu FU NIH [DK057978, HL105278, DK090962, HL088093, ES010337, CA014195, K99CA188259, R01GM095567]; National Cancer Institute [R01CA15749, R01CA188048, P01CA117969]; ACS Research Scholar Grant [RSG-13-298-01-TBG]; Glenn Foundation for Medical Research; Leona M. and Harry B. Helmsley Charitable Trust Grant [2012-PG-MED002]; Ipsen/Biomeasure; Stand Up to Cancer Dream Team Translational Cancer Research Grant, a Program of the Entertainment Industry Foundation [SU2C-AACR-DT0509]; Lustgarten Foundation FX We thank P. Phojanakong, D. Wang, J. Alvarez, and H. Juguilon for technical assistance; J. Bradner for providing JQ1; and H. Stoppler and the UCSF Helen Diller Family Comprehensive Cancer Center Tissue Core for providing fresh-frozen human PDAC samples. This work was funded by NIH Grants DK057978, HL105278, DK090962, HL088093, ES010337, and CA014195 (to R.M.E.), K99CA188259 (to M.H.S.), and R01GM095567 (to A.C.K.); National Cancer Institute Grants R01CA15749, R01CA188048, and P01CA117969; ACS Research Scholar Grant RSG-13-298-01-TBG; the Glenn Foundation for Medical Research; Leona M. and Harry B. Helmsley Charitable Trust Grant 2012-PG-MED002; and Ipsen/Biomeasure. R.M.E. and M.D. were supported in part by a Stand Up to Cancer Dream Team Translational Cancer Research Grant, a Program of the Entertainment Industry Foundation (SU2C-AACR-DT0509). R.M.E. is an investigator of the Howard Hughes Medical Institute and March of Dimes Chair in Molecular and Developmental Biology at the Salk Institute and is supported by a grant from the Lustgarten Foundation and a gift from the Freeberg Foundation. NR 56 TC 0 Z9 0 U1 6 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 31 PY 2017 VL 114 IS 5 BP 1129 EP 1134 DI 10.1073/pnas.1620164114 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EJ4OI UT WOS:000393196300091 PM 28096419 ER PT J AU Cerqueira, GC Earl, AM Ernst, CM Grad, YH Dekker, JP Feldgarden, M Chapman, SB Reis-Cunha, JL Shea, TP Young, S Zeng, QD Delaney, ML Kim, D Peterson, EM O'Brien, TF Ferraro, MJ Hooper, DC Huang, SS Kirby, JE Onderdonk, AB Birren, BW Hung, DT Cosimi, LA Wortman, JR Murphy, CI Hanage, WP AF Cerqueira, Gustavo C. Earl, Ashlee M. Ernst, Christoph M. Grad, Yonatan H. Dekker, John P. Feldgarden, Michael Chapman, Sinead B. Reis-Cunha, Joao L. Shea, Terrance P. Young, Sarah Zeng, Qiandong Delaney, Mary L. Kim, Diane Peterson, Ellena M. O'Brien, Thomas F. Ferraro, Mary Jane Hooper, David C. Huang, Susan S. Kirby, James E. Onderdonk, Andrew B. Birren, Bruce W. Hung, Deborah T. Cosimi, Lisa A. Wortman, Jennifer R. Murphy, Cheryl I. Hanage, William P. TI Multi-institute analysis of carbapenem resistance reveals remarkable diversity, unexplained mechanisms, and limited clonal outbreaks SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE carbapenem resistance; Enterobacteriaceae; comparative genomics; whole-genome sequencing; molecular evolution ID SEQUENCE TYPE 258; KLEBSIELLA-PNEUMONIAE; MOLECULAR EPIDEMIOLOGY; ESCHERICHIA-COLI; BETA-LACTAMASE; ENTEROBACTERIACEAE; ACQUISITION; PREVENTION; EXPANSION; STRAINS AB Carbapenem-resistant Enterobacteriaceae (CRE) are among the most severe threats to the antibiotic era. Multiple different species can exhibit resistance due to many different mechanisms, and many different mobile elements are capable of transferring resistance between lineages. We prospectively sampled CRE from hospitalized patients from three Boston-area hospitals, together with a collection of CRE from a single California hospital, to define the frequency and characteristics of outbreaks and determine whether there is evidence for transfer of strains within and between hospitals and the frequency with which resistance is transferred between lineages or species. We found eight species exhibiting resistance, with the majority of our sample being the sequence type 258 (ST258) lineage of Klebsiella pneumoniae. There was very little evidence of extensive hospital outbreaks, but a great deal of variation in resistance mechanisms and the genomic backgrounds carrying these mechanisms. Local transmission was evident in clear phylogeographic structure between the samples from the two coasts. The most common resistance mechanisms were KPC (K. pneumoniae carbapenemases) beta-lactamases encoded by bla(KPC2), bla(KPC3), and bla(KPC4), which were transferred between strains and species by seven distinct subgroups of the Tn4401 element. We also found evidence for previously unrecognized resistance mechanisms that produced resistance when transformed into a susceptible genomic background. The extensive variation, together with evidence of transmission beyond limited clonal outbreaks, points to multiple unsampled transmission chains throughout the continuum of care, including asymptomatic carriage and transmission of CRE. This finding suggests that to control this threat, we need an aggressive approach to surveillance and isolation. C1 [Cerqueira, Gustavo C.; Earl, Ashlee M.; Ernst, Christoph M.; Grad, Yonatan H.; Feldgarden, Michael; Chapman, Sinead B.; Reis-Cunha, Joao L.; Shea, Terrance P.; Young, Sarah; Zeng, Qiandong; Birren, Bruce W.; Hung, Deborah T.; Cosimi, Lisa A.; Wortman, Jennifer R.; Murphy, Cheryl I.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Ernst, Christoph M.; Dekker, John P.; Ferraro, Mary Jane; Hooper, David C.; Hung, Deborah T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Grad, Yonatan H.; Hanage, William P.] Harvard TH Chan Sch Publ Hlth, Ctr Communicable Dis Dynam, Boston, MA 02115 USA. [Grad, Yonatan H.; Delaney, Mary L.; O'Brien, Thomas F.; Onderdonk, Andrew B.; Cosimi, Lisa A.] Univ Fed Minas Gerais, Inst Ciencias Biol, BR-31270 Belo Horizonte, MG, Brazil. [Reis-Cunha, Joao L.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Kim, Diane; Huang, Susan S.] Univ Calif Irvine, Sch Med, Div Infect Dis, Irvine, CA 92617 USA. [Peterson, Ellena M.] Univ Calif Irvine, Sch Med, Dept Pathol & Lab Med, Irvine, CA 92617 USA. [Huang, Susan S.] Univ Calif Irvine, Sch Med, Hlth Policy Res Inst, Irvine, CA 92617 USA. [Kirby, James E.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RP Hanage, WP (reprint author), Harvard TH Chan Sch Publ Hlth, Ctr Communicable Dis Dynam, Boston, MA 02115 USA. EM whanage@hsph.harvard.edu FU National Institute of Allergy and Infectious Diseases (NIAID), NIH, Department of Health and Human Services [HHSN272200900018C, U19AI110818]; NIH/NIAID [K08AI104767, R21AI112694, R21AI119114]; Coordination for the Improvement of Higher Education Personnel fellowship [99999.010768/2014-09] FX We thank Kaye D. Evans (School ofMedicine, University of California Irvine) and Jean Spargo (Massachusetts General Hospital) for assistance with isolates. This project has been funded, in whole or in part, with Federal funds from the National Institute of Allergy and Infectious Diseases (NIAID), NIH, Department of Health and Human Services, under Contract HHSN272200900018C and Grant U19AI110818 to the Broad Institute. This work was supported by NIH/NIAID Grant K08AI104767 (to Y.H.G.) and NIH/NIAID Grants R21AI112694 and R21AI119114 (to J.E.K.). J.L.R.-C. was supported by a Coordination for the Improvement of Higher Education Personnel fellowship (Process 99999.010768/2014-09). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. NR 39 TC 0 Z9 0 U1 4 U2 4 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 JAN 31 PY 2017 VL 114 IS 5 BP 1135 EP 1140 DI 10.1073/pnas.1616248114 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EJ4OI UT WOS:000393196300092 PM 28096418 ER PT J AU Ferris, HA Perry, RJ Moreira, GV Shulman, GI Horton, JD Kahn, CR AF Ferris, Heather A. Perry, Rachel J. Moreira, Gabriela V. Shulman, Gerald I. Horton, Jay D. Kahn, C. Ronald TI Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE brain cholesterol metabolism; glial cells; SREBP2; metabolic regulation; glucose oxidation ID MILD COGNITIVE IMPAIRMENT; CENTRAL-NERVOUS-SYSTEM; ALZHEIMERS-DISEASE; INSULIN-RESISTANCE; INTRANASAL INSULIN; LIPID-METABOLISM; TRANSGENIC MICE; ADIPOSE-TISSUE; FATTY-ACIDS; BRAIN AB Cholesterol is important for normal brain function. The brain synthesizes its own cholesterol, presumably in astrocytes. We have previously shown that diabetes results in decreased brain cholesterol synthesis by a reduction in sterol regulatory element-binding protein 2 (SREBP2)-regulated transcription. Here we show that coculture of control astrocytes with neurons enhances neurite outgrowth, and this is reduced with SREBP2 knockdown astrocytes. In vivo, mice with knockout of SREBP2 in astrocytes have impaired brain development and behavioral and motor defects. These mice also have altered energy balance, altered body composition, and a shift in metabolism toward carbohydrate oxidation driven by increased glucose oxidation by the brain. Thus, SREBP2-mediated cholesterol synthesis in astrocytes plays an important role in brain and neuronal development and function, and altered brain cholesterol synthesis may contribute to the interaction between metabolic diseases, such as diabetes and altered brain function. C1 [Ferris, Heather A.; Kahn, C. Ronald] Harvard Med Sch, Joslin Diabet Ctr, Boston, MA 02215 USA. [Perry, Rachel J.; Moreira, Gabriela V.; Shulman, Gerald I.] Yale Univ, Dept Internal Med, New Haven, CT 06520 USA. [Shulman, Gerald I.] Yale Univ, Cellular & Mol Physiol, New Haven, CT 06520 USA. [Shulman, Gerald I.] Yale Univ, Howard Hughes Med Inst, New Haven, CT 06520 USA. [Horton, Jay D.] Univ Texas Southwestern, Dept Mol Genet, Dallas, TX 75390 USA. RP Kahn, CR (reprint author), Harvard Med Sch, Joslin Diabet Ctr, Boston, MA 02215 USA. EM c.ronald.kahn@joslin.harvard.edu FU National Institute of Diabetes, Digestive and Kidney Diseases [5K08DK097293, R01 DK-40936, MMPC DK059635, R37DK031036]; Diabetes Research Center [P30DK036836, P30CA06516] FX We thank Megan Krumpoch and Noelle Castilla-Ojo for animal care. These studies were funded by National Institute of Diabetes, Digestive and Kidney Diseases Grants 5K08DK097293 (to H.A.F.), R01 DK-40936 and MMPC DK059635 (to G.I.S.), and R37DK031036 (to C.R.K.); and Diabetes Research Center Grants P30DK036836 (to the Joslin Diabetes Center) and P30CA06516 (to the Rodent Histopathology Core at Dana-Farber/Harvard Cancer Center). NR 43 TC 0 Z9 0 U1 1 U2 1 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 JAN 31 PY 2017 VL 114 IS 5 BP 1189 EP 1194 DI 10.1073/pnas.1620506114 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EJ4OI UT WOS:000393196300101 PM 28096339 ER PT J AU Tu, SQ Yuan, GC Shao, Z AF Tu, Shiqi Yuan, Guo-Cheng Shao, Zhen TI The PRC2-binding long non-coding RNAs in human and mouse genomes are associated with predictive sequence features SO Scientific Reports LA English DT Article ID EMBRYONIC STEM-CELLS; MARKOV-CHAINS; EPIGENETIC REGULATION; GENE-EXPRESSION; CHROMATIN; PRC2; BINDING; EVOLUTION; PROTEINS; IDENTIFICATION AB Recently, long non-coding RNAs (lncRNAs) have emerged as an important class of molecules involved in many cellular processes. One of their primary functions is to shape epigenetic landscape through interactions with chromatin modifying proteins. However, mechanisms contributing to the specificity of such interactions remain poorly understood. Here we took the human and mouse lncRNAs that were experimentally determined to have physical interactions with Polycomb repressive complex 2 (PRC2), and systematically investigated the sequence features of these lncRNAs by developing a new computational pipeline for sequences composition analysis, in which each sequence is considered as a series of transitions between adjacent nucleotides. Through that, PRC2-binding lncRNAs were found to be associated with a set of distinctive and evolutionarily conserved sequence features, which can be utilized to distinguish them from the others with considerable accuracy. We further identified fragments of PRC2-binding lncRNAs that are enriched with these sequence features, and found they show strong PRC2-binding signals and are more highly conserved across species than the other parts, implying their functional importance. C1 [Tu, Shiqi; Shao, Zhen] Chinese Acad Sci, Key Lab Computat Biol, Collaborat Innovat Ctr Genet & Dev Biol, Max Planck Soc Partner Inst Computat Biol,Shangha, Shanghai 200031, Peoples R China. [Tu, Shiqi] Grad Univ Chinese Acad Sci, Beijing 100049, Peoples R China. [Yuan, Guo-Cheng] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Yuan, Guo-Cheng] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Yuan, Guo-Cheng] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Shao, Z (reprint author), Chinese Acad Sci, Key Lab Computat Biol, Collaborat Innovat Ctr Genet & Dev Biol, Max Planck Soc Partner Inst Computat Biol,Shangha, Shanghai 200031, Peoples R China. EM shaozhen@picb.ac.cn FU Shanghai Pujiang Talent Program [14PJ1410000]; "100-Talent Program" of the Chinese Academy of Science [Y516C11851]; NIH [R01HL119099] FX We gratefully thank Dr. John L. Rinn for assistance with the RIP-chip data, as well as Dr. Stuart H. Orkin, Dr. Weimou Zheng and Dr. Xiaohua Shen for helpful discussion and instruction. We also thank the anonymous reviewers for their valuable suggestions. This work was supported by the Shanghai Pujiang Talent Program (14PJ1410000 to Z.S.) and the "100-Talent Program" (Y516C11851 to Z.S.) of the Chinese Academy of Science. This work was also supported by NIH R01HL119099 (to G.-C.Y.). NR 43 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JAN 31 PY 2017 VL 7 AR 41669 DI 10.1038/srep41669 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EJ3DY UT WOS:000393094000001 PM 28139710 ER PT J AU McCarthy, MI MacArthur, DG AF McCarthy, Mark I. MacArthur, Daniel G. TI Human disease genomics: from variants to biology SO GENOME BIOLOGY LA English DT Editorial Material ID REGULATORY NETWORK; DNA METHYLATION; MORBID GENOME; DISORDERS; GENE; MUTATIONS; INSIGHTS; RARE AB We summarize the remarkable progress that has been made in the identification and functional characterization of DNA sequence variants associated with disease. C1 [McCarthy, Mark I.; MacArthur, Daniel G.] Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Old Rd, Oxford OX3 7LJ, England. [McCarthy, Mark I.] Univ Oxford, Wellcome Trust Ctr Human Genet, Roosevelt Dr, Oxford OX3 7BN, England. [McCarthy, Mark I.] Churchill Hosp, Oxford NIHR Biomed Res Ctr, Old Rd, Oxford OX3 7LJ, England. [MacArthur, Daniel G.] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA. [MacArthur, Daniel G.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. RP McCarthy, MI (reprint author), Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Old Rd, Oxford OX3 7LJ, England.; MacArthur, DG (reprint author), Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. EM mark.mccarthy@drl.ox.ac.uk; danmac@broadinstitute.org FU Pfizer; Eli Lilly; NovoNordisk; Sanofi-Aventis; Boehringer Ingelheim; Astra Zeneca; Janssen; Takeda; Roche; Merck; Abbvie; Servier; Innovative Medicines Initiative; Accelerating Medicines Partnership; Biogen; Eisai FX MIM serves on advisory panels for Pfizer and NovoNordisk; has received honoraria from Pfizer, NovoNordisk, and Eli Lilly; and has received research funding from Pfizer, Eli Lilly, NovoNordisk, Sanofi-Aventis, Boehringer Ingelheim, Astra Zeneca, Janssen, Takeda, Roche, Merck, Abbvie, and Servier as part of precompetitive research initiatives supported by the Innovative Medicines Initiative and the Accelerating Medicines Partnership. DGM is a founder with equity in Goldfinch Biopharma, and has received research funding from Biogen, Merck, Pfizer, and Eisai. NR 20 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1474-760X J9 GENOME BIOL JI Genome Biol. PD JAN 30 PY 2017 VL 18 AR 20 DI 10.1186/s13059-017-1160-z PG 3 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA EL7UV UT WOS:000394827300001 PM 28137298 ER PT J AU Maesako, M Horlacher, J Zoltowska, KM Kastanenka, KV Kara, E Svirsky, S Keller, LJ Li, X Hyman, BT Bacskai, BJ Berezovska, O AF Maesako, Masato Horlacher, Jana Zoltowska, Katarzyna M. Kastanenka, Ksenia V. Kara, Eleanna Svirsky, Sarah Keller, Laura J. Li, Xuejing Hyman, Bradley T. Bacskai, Brian J. Berezovska, Oksana TI Pathogenic PS1 phosphorylation at Ser367 SO ELIFE LA English DT Article ID GAMMA-SECRETASE ACTIVITY; FAMILIAL ALZHEIMERS-DISEASE; AMYLOID PRECURSOR PROTEIN; PRESENILIN MUTATIONS; BETA-PROTEIN; MOUSE MODEL; CONFORMATION; CALCIUM; IDENTIFICATION; STIMULATION AB The high levels of serine (S) and threonine (T) residues within the Presenilin 1 (PS1) N-terminus and in the large hydrophilic loop region suggest that the enzymatic function of PS1/gamma-secretase can be modulated by its phosphorylated and dephosphorylated states. However, the functional outcome of PS1 phosphorylation and its significance for Alzheimers disease (AD) pathogenesis is poorly understood. Here, comprehensive analysis using FRET-based imaging reveals that activity-driven and Protein Kinase A-mediated PS1 phosphorylation at three domains (domain 1: T74, domain 2: S310 and S313, domain 3: S365, S366, and S367), with S367 being critical, is responsible for the PS1 pathogenic closed conformation, and resulting increase in the A beta 42/40 ratio. Moreover, we have established novel imaging assays for monitoring PS1 conformation in vivo, and report that PS1 phosphorylation induces the pathogenic conformational shift in the living mouse brain. These phosphorylation sites represent potential new targets for AD treatment. C1 [Maesako, Masato; Horlacher, Jana; Zoltowska, Katarzyna M.; Kastanenka, Ksenia V.; Kara, Eleanna; Svirsky, Sarah; Keller, Laura J.; Li, Xuejing; Hyman, Bradley T.; Bacskai, Brian J.; Berezovska, Oksana] Harvard Med Sch, Massachusetts Gen Hosp, Alzheimers Dis Res Lab, MassGen Inst Neurodegenerat Dis, Charlestown, MA 02129 USA. [Horlacher, Jana] Univ Ulm, Dept Neurol, Ulm, Germany. RP Berezovska, O (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Alzheimers Dis Res Lab, MassGen Inst Neurodegenerat Dis, Charlestown, MA 02129 USA. EM OBEREZOVSKA@mgh.harvard.edu OI Zoltowska, Katarzyna/0000-0001-5853-3465 FU Kanae Foundation for Promotion of Medical Science [2014-55]; Japan Society for the Promotion of Science; Kyoto University Education and Research Foundation; Studienstiftung des Deutschen Volkes; European Molecular Biology Organization [ATLF-815-20]; European Commission [GA-2013-609409]; NIH Blueprint for Neuroscience Research [AG15379, AG44486] FX Kanae Foundation for Promotion of Medical Science The 43rd Kanae Foreign Study Award, 2014-55 Masato Maesako; Japan Society for the Promotion of Science Postdoctoral Fellowship for Research Abroad Masato Maesako; Kyoto University Education and Research Foundation Postdoctoral Fellowship for Research Abroad Masato Maesako; Studienstiftung des Deutschen Volkes Medical student Scholarship Jana Horlacher; European Molecular Biology Organization ATLF-815-20, Postdoctoral Long Term Fellowship co-funded with Marie Curie Actions of the European Commission Eleanna Kara; European Commission Marie Curie Actions, LTFCOFUND2013, GA-2013-609409 Eleanna Kara; NIH Blueprint for Neuroscience Research AG15379 Oksana Berezovska; NIH Blueprint for Neuroscience Research AG44486 Oksana Berezovska; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 40 TC 0 Z9 0 U1 1 U2 1 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD JAN 30 PY 2017 VL 6 AR e19720 DI 10.7554/eLife.19720 PG 23 WC Biology SC Life Sciences & Biomedicine - Other Topics GA EJ7NL UT WOS:000393408800001 ER PT J AU Cayrol, F Praditsuktavorn, P Fernando, TM Kwiatkowski, N Marullo, R Calvo-Vidal, MN Phillip, J Pera, B Yang, SN Takpradit, K Roman, L Gaudiano, M Crescenzo, R Ruan, J Inghirami, G Zhang, TH Cremaschi, G Gray, NS Cerchietti, L AF Cayrol, Florencia Praditsuktavorn, Pannee Fernando, Tharu M. Kwiatkowski, Nicholas Marullo, Rosella Calvo-Vidal, M. Nieves Phillip, Jude Pera, Benet Yang, Shao Ning Takpradit, Kaipol Roman, Lidia Gaudiano, Marcello Crescenzo, Ramona Ruan, Jia Inghirami, Giorgio Zhang, Tinghu Cremaschi, Graciela Gray, Nathanael S. Cerchietti, Leandro TI THZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitors SO Nature Communications LA English DT Article ID GENE-EXPRESSION; LYMPHOCYTIC-LEUKEMIA; FAMILY PROTEINS; CANCER; ACTIVATION; MUTATIONS; COMBINATION; BORTEZOMIB; STABILITY; MECHANISM AB Peripheral T-cell lymphomas (PTCL) are aggressive diseases with poor response to chemotherapy and dismal survival. Identification of effective strategies to target PTCL biology represents an urgent need. Here we report that PTCL are sensitive to transcription-targeting drugs, and, in particular, to THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7). The STAT-signalling pathway is highly vulnerable to THZ1 even in PTCL cells that carry the activating STAT3 mutation Y640F. In mutant cells, CDK7 inhibition decreases STAT3 chromatin binding and expression of highly transcribed target genes like MYC, PIM1, MCL1, CD30, IL2RA, CDC25A and IL4R. In surviving cells, THZ1 decreases the expression of STAT-regulated anti-apoptotic BH3 family members MCL1 and BCL-XL sensitizing PTCL cells to BH3 mimetic drugs. Accordingly, the combination of THZ1 and the BH3 mimetic obatoclax improves lymphoma growth control in a primary PTCL ex vivo culture and in two STAT3-mutant PTCL xenografts, delineating a potential targeted agent-based therapeutic option for these patients. C1 [Cayrol, Florencia; Praditsuktavorn, Pannee; Fernando, Tharu M.; Marullo, Rosella; Calvo-Vidal, M. Nieves; Phillip, Jude; Pera, Benet; Yang, Shao Ning; Takpradit, Kaipol; Roman, Lidia; Ruan, Jia; Cerchietti, Leandro] Weill Cornell Med, Div Hematol & Oncol, Dept Med, New York, NY 10065 USA. [Cayrol, Florencia; Cremaschi, Graciela] Catholic Univ Argentina UCA, CONICET, Natl Res Council Argentina,Inst Biomed Res BIOMED, Neuroimmunomodulat & Mol Oncol Dept, C1107AFB, Buenos Aires, DF, Argentina. [Kwiatkowski, Nicholas; Zhang, Tinghu; Gray, Nathanael S.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Dept Canc Biol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Gaudiano, Marcello; Crescenzo, Ramona; Inghirami, Giorgio] Weill Cornell Med, Dept Pathol & Lab Med, New York, NY 10065 USA. [Praditsuktavorn, Pannee] Chulabhorn Hosp, Div Hematol, Dept Med, Bangkok 10210, Thailand. [Fernando, Tharu M.] Genencor Inc, Discovery Oncol, San Francisco, CA 94080 USA. RP Cerchietti, L (reprint author), Weill Cornell Med, Div Hematol & Oncol, Dept Med, New York, NY 10065 USA. EM lec2010@med.cornell.edu FU Leukemia and Lymphoma Society TRP award [6491-16]; National Institutes of Health [CA179483-03] FX This work was partially supported by the Leukemia and Lymphoma Society TRP award 6491-16 (to L.C.) and National Institutes of Health CA179483-03 (to N.S.G.). The approved oncology drugs set was provided (to L.C.) at no cost by the Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health (NIH). NR 46 TC 1 Z9 1 U1 4 U2 4 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 JAN 30 PY 2017 VL 8 AR 14290 DI 10.1038/ncomms14290 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI9FA UT WOS:000392811700001 PM 28134252 ER PT J AU Khan, S Amin, FM Holtmannspotter, M Hansen, K Florescu, AM Fakhril-Din, Z Petersen, JF Ghanizada, H Ayata, C Gaist, D Ashina, M AF Khan, Sabrina Amin, Faisal Mohammad Holtmannspotter, Markus Hansen, Klaus Florescu, Anna Maria Fakhril-Din, Zainab Petersen, Julie Falkenberg Ghanizada, Hashmat Ayata, Cenk Gaist, David Ashina, Messoud TI Endovascular thrombectomy and post-procedural headache SO JOURNAL OF HEADACHE AND PAIN LA English DT Article DE EVT; Stroke; Risk; Complications; Migraine ID MIGRAINE; STROKE; ANEURYSMS; RISK AB Background: We investigated the prevalence of post-procedural headache in patients who have undergone thrombectomy for ischemic stroke, and correlated history of migraine with risk of peri-procedural complications. A total of 314 patients underwent thrombectomy at the Danish National Hospital from January 2012 to December 2014. Eligible subjects were phone-interviewed using a purpose-developed semi-structured questionnaire according to the International Classification of Headache Disorders 3, beta version criteria. Findings: Among 96 eligible subjects, there was a significant decrease in migraine (p = 0.022) within the first 3 months after EVT compared to 1 year before treatment, which was further evident at interview time (on average 1.6 years after EVT, p = 0.013). A minority of patients experienced headaches for the first time within 3 months of their EVT (migraine 2, TTH 9), which persisted at interview time for subjects with migraine. Out of 12 subjects with peri-procedural complications, 2 had a history of migraine with aura. Conclusion: Thrombectomy leads to a significant decrease in previously known migraine, and new onset of headache in a small subset of patients. A history of migraine does not appear to predispose to peri-procedural complications. C1 [Khan, Sabrina; Amin, Faisal Mohammad; Florescu, Anna Maria; Fakhril-Din, Zainab; Petersen, Julie Falkenberg; Ghanizada, Hashmat; Ashina, Messoud] Univ Copenhagen, Rigshosp, Dept Neurol, Danish Headache Ctr, Copenhagen, Denmark. [Holtmannspotter, Markus] Univ Copenhagen, Dept Radiol, Rigshosp, Copenhagen, Denmark. [Hansen, Klaus] Univ Copenhagen, Dept Neurol, Rigshosp, Copenhagen, Denmark. [Ayata, Cenk] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Stroke Serv, Charlestown, MA USA. [Ayata, Cenk] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Neurosci Intens Care Unit, Charlestown, MA USA. [Gaist, David] Odense Univ Hosp, Dept Neurol, Odense, Denmark. [Gaist, David] Univ Southern Denmark, Dept Clin Res, Odense, Denmark. RP Ashina, M (reprint author), Univ Copenhagen, Rigshosp, Dept Neurol, Danish Headache Ctr, Copenhagen, Denmark. EM ashina@dadlnet.dk FU Lundbeck Foundation [R155-2014-171]; Novo Nordisk Foundation [NNF11OC1014333]; European Union [602633] FX We thank the Lundbeck Foundation (R155-2014-171), the Novo Nordisk Foundation (NNF11OC1014333), and the European Union's Seventh Framework programme (FP/-EUROHEADPAIN-no.602633). NR 10 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER-VERLAG ITALIA SRL PI MILAN PA VIA DECEMBRIO, 28, MILAN, 20137, ITALY SN 1129-2369 EI 1129-2377 J9 J HEADACHE PAIN JI J. Headache Pain PD JAN 28 PY 2017 VL 18 AR 10 DI 10.1186/s10194-017-0719-0 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EQ0DJ UT WOS:000397741600002 PM 28130625 ER PT J AU El-Khatib, FH Balliro, C Hillard, MA Magyar, KL Ekhlaspour, L Sinha, M Mondesir, D Esmaeili, A Hartigan, C Thompson, MJ Malkani, S Lock, JP Harlan, DM Clinton, P Frank, E Wilson, DM DeSalvo, D Norlander, L Ly, T Buckingham, BA Diner, J Dezube, M Young, LA Goley, A Kirkman, MS Buse, JB Zheng, H Selagamsetty, RR Damiano, ER Russell, SJ AF El-Khatib, Firas H. Balliro, Courtney Hillard, Mallory A. Magyar, Kendra L. Ekhlaspour, Laya Sinha, Manasi Mondesir, Debbie Esmaeili, Aryan Hartigan, Celia Thompson, Michael J. Malkani, Samir Lock, J. Paul Harlan, David M. Clinton, Paula Frank, Eliana Wilson, Darrell M. DeSalvo, Daniel Norlander, Lisa Ly, Trang Buckingham, Bruce A. Diner, Jamie Dezube, Milana Young, Laura A. Goley, April Kirkman, M. Sue Buse, John B. Zheng, Hui Selagamsetty, Rajendranath R. Damiano, Edward R. Russell, Steven J. TI Home use of a bihormonal bionic pancreas versus insulin pump therapy in adults with type 1 diabetes: a multicentre randomised crossover trial SO LANCET LA English DT Article ID EXCHANGE CLINIC REGISTRY; WEARABLE ARTIFICIAL PANCREAS; ESTIMATED AVERAGE GLUCOSE; SEVERE HYPOGLYCEMIA; GLYCEMIC CONTROL; OUTPATIENT; CHILDREN; ADOLESCENTS; KETOACIDOSIS; DELIVERY AB Background The safety and effectiveness of a continuous, day-and-night automated glycaemic control system using insulin and glucagon has not been shown in a free-living, home-use setting. We aimed to assess whether bihormonal bionic pancreas initialised only with body mass can safely reduce mean glycaemia and hypoglycaemia in adults with type 1 diabetes who were living at home and participating in their normal daily routines without restrictions on diet or physical activity. Methods We did a random-order crossover study in volunteers at least 18 years old who had type 1 diabetes and lived within a 30 min drive of four sites in the USA. Participants were randomly assigned (1: 1) in blocks of two using sequentially numbered sealed envelopes to glycaemic regulation with a bihormonal bionic pancreas or usual care (conventional or sensor-augmented insulin pump therapy) first, followed by the opposite intervention. Both study periods were 11 days in length, during which time participants continued all normal activities, including athletics and driving. The bionic pancreas was initialised with only the participant's body mass. Autonomously adaptive dosing algorithms used data from a continuous glucose monitor to control subcutaneous delivery of insulin and glucagon. The coprimary outcomes were the mean glucose concentration and time with continuous glucose monitoring (CGM) glucose concentration less than 3.3 mmol/L, analysed over days 2-11 in participants who completed both periods of the study. This trial is registered with ClinicalTrials.gov,number NCT02092220. Findings We randomly assigned 43 participants between May 6, 2014, and July 3, 2015, 39 of whom completed the study: 20 who were assigned to bionic pancreas first and 19 who were assigned to the comparator first. The mean CGM glucose concentration was 7.8 mmol/L (SD 0.6) in the bionic pancreas period versus 9.0 mmol/L (1.6) in the comparator period (difference 1.1 mmol/L, 95% CI 0.7-1.6; p<0.0001), and the mean time with CGM glucose concentration less than 3.3 mmol/L was 0.6% (0.6) in the bionic pancreas period versus 1.9% (1.7) in the comparator period (difference 1.3%, 95% CI 0.8-1.8; p<0. 0001). The mean nausea score on the Visual Analogue Scale (score 0-10) was greater during the bionic pancreas period (0.52 [SD 0.83]) than in the comparator period (0.05 [0.17]; difference 0.47, 95% CI 0.21-0.73; p=0.0024). Body mass and laboratory parameters did not differ between periods. There were no serious or unexpected adverse events in the bionic pancreas period of the study. Interpretation Relative to conventional and sensor-augmented insulin pump therapy, the bihormonal bionic pancreas, initialised only with participant weight, was able to achieve superior glycaemic regulation without the need for carbohydrate counting. Larger and longer studies are needed to establish the long-term benefits and risks of automated glycaemic management with a bihormonal bionic pancreas. C1 [El-Khatib, Firas H.; Selagamsetty, Rajendranath R.; Damiano, Edward R.] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [Balliro, Courtney; Hillard, Mallory A.; Magyar, Kendra L.; Ekhlaspour, Laya; Sinha, Manasi; Mondesir, Debbie; Esmaeili, Aryan; Russell, Steven J.] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. [Balliro, Courtney; Hillard, Mallory A.; Magyar, Kendra L.; Ekhlaspour, Laya; Sinha, Manasi; Mondesir, Debbie; Esmaeili, Aryan; Russell, Steven J.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Zheng, Hui] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Hartigan, Celia; Thompson, Michael J.; Malkani, Samir; Lock, J. Paul; Harlan, David M.] Univ Massachusetts, Sch Med, Ctr Clin & Translat Sci, Worcester, MA USA. [Hartigan, Celia; Thompson, Michael J.; Malkani, Samir; Lock, J. Paul; Harlan, David M.] Univ Massachusetts, Sch Med, Diabet Ctr Excellence, Worcester, MA USA. [Clinton, Paula; Frank, Eliana; Wilson, Darrell M.; DeSalvo, Daniel; Norlander, Lisa; Ly, Trang; Buckingham, Bruce A.] Stanford Univ, Sch Med, Div Pediat Endocrinol & Diabet, Palo Alto, CA 94304 USA. [Diner, Jamie; Dezube, Milana; Young, Laura A.; Goley, April; Kirkman, M. Sue; Buse, John B.] Univ North Carolina Chapel Hill, Diabet Care Ctr, Sch Med, Chapel Hill, NC USA. RP Russell, SJ (reprint author), Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. EM sjrussell@mgh.harvard.edu FU National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health; National Center for Advancing Translational Sciences FX National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, and National Center for Advancing Translational Sciences. NR 45 TC 0 Z9 0 U1 7 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD JAN 28 PY 2017 VL 389 IS 10067 BP 369 EP 380 DI 10.1016/S0140-6736(16)32567-3 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA EI9CK UT WOS:000392804700034 PM 28007348 ER PT J AU Battaglini, L Casco, C Isaacs, BR Bridges, D Ganis, G AF Battaglini, Luca Casco, Clara Isaacs, Bethany Rose Bridges, David Ganis, Giorgio TI Electrophysiological correlates of motion extrapolation: An investigation on the CNV SO NEUROPSYCHOLOGIA LA English DT Article DE Motion extrapolation; CNV; Time to contact ID VISUAL-MOTION; PREDICTION-MOTION; NEURAL MECHANISMS; EYE-MOVEMENTS; TIME; MEMORY; AREA; PERCEPTION; TARGET; SPEED AB Motion extrapolation (ME), the ability to estimate the current position of moving objects hidden by an occluder, is critical to interact with a dynamic environment. In a typical paradigm, participants estimate time to contact (ITC) by pressing a button when they estimate the occluded moving target reaches a certain cue. Research using this paradigm has shown that motion adaptation of the occluded area produces a shift in the TTC estimate (Gilden et al., 1995). We examined the effect of motion adaptation on the contingent negative variation (CNV), a frontal electrophysiological component (Tecce, 1972) that could reflect the activity of an accumulator (Buhusi and Meek, 2005) for time processing. We predicted that longer ITC estimates due to previous visual motion adaptation would result in a larger CNV because the accumulator can collect more time units. Results showed that motion adaptation actually modulates the CNV, but the CNV amplitude did not correlate with TTC duration, falsifying the accumulator hypothesis. We suggest that motion adaptation interferes with the remembered speed (stored during the visible part of the trajectory) that may be used as input by higher cognitive function to guide the temporal update of target position, regardless of the ITC estimate. C1 [Battaglini, Luca; Casco, Clara] Univ Padua, Dept Gen Psychol, I-35100 Padua, Italy. [Isaacs, Bethany Rose; Bridges, David; Ganis, Giorgio] Univ Plymouth, Cognit Inst, Sch Psychol, Plymouth, Devon, England. [Isaacs, Bethany Rose] Univ Amsterdam, Sch Psychol, NL-1012 WX Amsterdam, Netherlands. [Isaacs, Bethany Rose] Maastricht Univ, Sch Psychol, NL-6200 MD Maastricht, Netherlands. [Ganis, Giorgio] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. RP Battaglini, L (reprint author), Univ Padua, Dept Gen Psychol, I-35100 Padua, Italy. EM luca.battaglini@unipd.it NR 58 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3932 EI 1873-3514 J9 NEUROPSYCHOLOGIA JI Neuropsychologia PD JAN 27 PY 2017 VL 95 BP 86 EP 93 DI 10.1016/j.neuropsychologia.2016.12.019 PG 8 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA EK1YO UT WOS:000393723900008 PM 27986635 ER PT J AU Khazaeinezhad, R Kassani, SH Paulson, B Jeong, H Gwak, J Rotermund, F Yeom, DI Oh, K AF Khazaeinezhad, Reza Kassani, Sahar Hosseinzadeh Paulson, Bjorn Jeong, Hwanseong Gwak, Jiyoon Rotermund, Fabian Yeom, Dong-Il Oh, Kyunghwan TI Ultrafast nonlinear optical properties of thin-solid DNA film and their application as a saturable absorber in femtosecond mode-locked fiber laser SO SCIENTIFIC REPORTS LA English DT Article ID NORMAL DISPERSION REGIMES; ELECTRON-BLOCKING LAYER; LIGHT-EMITTING-DIODES; DEOXYRIBONUCLEIC-ACID; REFRACTIVE-INDEX; NUCLEIC-ACIDS; MOLECULAR-STRUCTURE; ABSORPTION EDGES; URBACHS RULE; PHOTONICS AB A new extraordinary application of deoxyribonucleic acid (DNA) thin-solid-film was experimentally explored in the field of ultrafast nonlinear photonics. Optical transmission was investigated in both linear and nonlinear regimes for two types of DNA thin-solid-films made from DNA in aqueous solution and DNA-cetyltrimethylammonium chloride (CTMA) in an organic solvent. Z-scan measurements revealed a high third-order nonlinearity with n(2) exceeding 10(-9) at a wavelength of 1570 nm, for a nonlinarity about five orders of magnitude larger than that of silica. We also demonstrated ultrafast saturable absorption (SA) with a modulation depth of 0.43%. DNA thin solid films were successfully deposited on a side-polished optical fiber, providing an efficient evanescent wave interaction. We built an organic-inorganic hybrid all-fiber ring laser using DNA film as an ultrafast SA and using Erbium-doped fiber as an efficient optical gain medium. Stable transform-limited femtosecond soliton pulses were generated with full width half maxima of 417 fs for DNA and 323 fs for DNA-CTMA thin-solid-film SAs. The average output power was 4.20 mW for DNA and 5.46 mW for DNA-CTMA. Detailed conditions for DNA solid film preparation, dispersion control in the laser cavity and subsequent characteristics of soliton pulses are discussed, to confirm unique nonlinear optical applications of DNA thin-solid-film. C1 [Khazaeinezhad, Reza; Kassani, Sahar Hosseinzadeh; Paulson, Bjorn; Oh, Kyunghwan] Yonsei Univ, Inst Phys & Appl Phys, Photon Device Phys Lab, Seoul 120749, South Korea. [Khazaeinezhad, Reza; Kassani, Sahar Hosseinzadeh] Harvard Med Sch, Boston, MA 02115 USA. [Khazaeinezhad, Reza; Kassani, Sahar Hosseinzadeh] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Jeong, Hwanseong; Gwak, Jiyoon; Rotermund, Fabian; Yeom, Dong-Il] Ajou Univ, Dept Phys & Energy Syst Res, Suwon 443749, South Korea. [Rotermund, Fabian] Korea Adv Inst Sci & Technol, Dept Phys, Daejeon 34141, South Korea. RP Oh, K (reprint author), Yonsei Univ, Inst Phys & Appl Phys, Photon Device Phys Lab, Seoul 120749, South Korea.; Rotermund, F; Yeom, DI (reprint author), Ajou Univ, Dept Phys & Energy Syst Res, Suwon 443749, South Korea.; Rotermund, F (reprint author), Korea Adv Inst Sci & Technol, Dept Phys, Daejeon 34141, South Korea. EM rotermund@kaist.ac.kr; diyeom@ajou.ac.kr; koh@yonsei.ac.kr FU Institute of Physics and Applied Physics, Yonsei University; ICT R&D Program of MSIP/IITP [2014-044-014-002]; Nano Material Technology Development Program through NRF - MSIP [NRF-2012M3A7B4049800]; NRF of Korea [NRF-2016R1A2B20122 81, 2011-0027920, NRF-2016R1A2A1A05005381, 2011-0017494] FX This work was supported in part by Institute of Physics and Applied Physics, Yonsei University, in part by ICT R&D Program of MSIP/IITP (2014-044-014-002), in part by Nano Material Technology Development Program through NRF funded by the MSIP (NRF-2012M3A7B4049800). H. Jeong and D.-I. Yeom have been supported by NRF of Korea (NRF-2016R1A2B20122 81, 2011-0027920). J. Gwak and F. Rotermund acknowledge supports from NRF of Korea (NRF-2016R1A2A1A05005381, 2011-0017494). NR 76 TC 0 Z9 0 U1 10 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JAN 27 PY 2017 VL 7 AR 41480 DI 10.1038/srep41480 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EJ4CU UT WOS:000393164500001 PM 28128340 ER PT J AU Kim, S De Jonghe, J Kulesa, AB Feldman, D Vatanen, T Bhattacharyya, RP Berdy, B Gomez, J Nolan, J Epstein, S Blainey, PC AF Kim, Soohong De Jonghe, Joachim Kulesa, Anthony B. Feldman, David Vatanen, Tommi Bhattacharyya, Roby P. Berdy, Brittany Gomez, James Nolan, Jill Epstein, Slava Blainey, Paul C. TI High-throughput automated microfluidic sample preparation for accurate microbial genomics SO Nature Communications LA English DT Article ID GENERATION SEQUENCING LIBRARIES; PSEUDOMONAS-AERUGINOSA; DNA; RESISTANCE; SUSCEPTIBILITY; TRANSPOSITION; DIVERSITY; CHROMATIN; PATHOGEN; BACTERIA AB Low-cost shotgun DNA sequencing is transforming the microbial sciences. Sequencing instruments are so effective that sample preparation is now the key limiting factor. Here, we introduce a microfluidic sample preparation platform that integrates the key steps in cells to sequence library sample preparation for up to 96 samples and reduces DNA input requirements 100-fold while maintaining or improving data quality. The general-purpose microarchitecture we demonstrate supports workflows with arbitrary numbers of reaction and clean-up or capture steps. By reducing the sample quantity requirements, we enabled low- input (similar to 10,000 cells) whole-genome shotgun (WGS) sequencing of Mycobacterium tuberculosis and soil micro-colonies with superior results. We also leveraged the enhanced throughput to sequence similar to 400 clinical Pseudomonas aeruginosa libraries and demonstrate excellent single-nucleotide polymorphism detection performance that explained phenotypically observed antibiotic resistance. Fully-integrated lab-on-chip sample preparation overcomes technical barriers to enable broader deployment of genomics across many basic research and translational applications. C1 [Kim, Soohong; De Jonghe, Joachim; Kulesa, Anthony B.; Feldman, David; Vatanen, Tommi; Bhattacharyya, Roby P.; Gomez, James; Nolan, Jill; Blainey, Paul C.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Kim, Soohong; Kulesa, Anthony B.; Blainey, Paul C.] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [De Jonghe, Joachim] Univ Cambridge, Dept Biochem, Cambridge CB2 1GA, England. [Feldman, David] MIT, Dept Phys, Cambridge, MA 02139 USA. [Vatanen, Tommi] Aalto Univ, Sch Sci, Dept Comp Sci, Espoo 02150, Finland. [Bhattacharyya, Roby P.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Berdy, Brittany; Epstein, Slava] Northeastern Univ, Dept Biol, Boston, MA 02115 USA. RP Blainey, PC (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.; Blainey, PC (reprint author), MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM pblainey@broadinstitute.org FU Burroughs Welcome Fund via Career Award at the Scientific Interface; Broad Institute Startup Funds; Department of Energy Joint Genome Institute; National Science Foundation Postdoctoral Fellowship in Biology [1308852] FX We thank Dr Yonatan Grad, Dr Deb Hung, Dr Ashlee Earl, Dr Christopher Desjardins, Dr Robert Lintner, Mr Bruce Walker, Mr Terrance Shea, Ms Sheila Fisher, Dr Niall Lennon, Dr Stacy Gabriel and members of the Blainey Lab for helpful discussions. The indexing barcodes were provided by the Broad Institute Genomics Platform. We also thank Dr Lynn Bry at Brigham and Women's Hospital regarding sample collection and helpful discussions. This work was supported by the Burroughs Welcome Fund via a Career Award at the Scientific Interface to PCB, Broad Institute Startup Funds and an Emerging Technologies Opportunity Program award from the Department of Energy Joint Genome Institute. S.K. was supported by the National Science Foundation Postdoctoral Fellowship in Biology 1308852. NR 51 TC 0 Z9 0 U1 18 U2 18 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JAN 27 PY 2017 VL 8 AR 13919 DI 10.1038/ncomms13919 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI8FK UT WOS:000392741000001 PM 28128213 ER PT J AU Abramson, JS AF Abramson, Jeremy S. TI Recurrent mutations and targeted therapy in FL SO BLOOD LA English DT Editorial Material ID FOLLICULAR LYMPHOMA; IBRUTINIB C1 [Abramson, Jeremy S.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. RP Abramson, JS (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. NR 10 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JAN 26 PY 2017 VL 129 IS 4 BP 402 EP 403 DI 10.1182/blood-2016-12-753145 PG 2 WC Hematology SC Hematology GA EO2MU UT WOS:000396531400004 PM 28126956 ER PT J AU Canali, S Zumbrennen-Bullough, KB Core, AB Wang, CY Nairz, M Bouley, R Swirski, FK Babitt, JL AF Canali, Susanna Zumbrennen-Bullough, Kimberly B. Core, Amanda B. Wang, Chia-Yu Nairz, Manfred Bouley, Richard Swirski, Filip K. Babitt, Jodie L. TI Endothelial cells produce bone morphogenetic protein 6 required for iron homeostasis in mice SO BLOOD LA English DT Article ID JUVENILE HEMOCHROMATOSIS; HEPCIDIN EXPRESSION; TARGETED DISRUPTION; MOUSE-LIVER; IN-VIVO; OVERLOAD; HEMOJUVELIN; BMP6; DELETION; HEPATOCYTES AB Bone morphogenetic protein 6 (BMP6) signaling in hepatocytes is a central transcriptional regulator of the iron hormone hepcidin that controls systemic iron balance. How iron levels are sensed to regulate hepcidin production is not known, but local induction of liver BMP6 expression by iron is proposed to have a critical role. To identify the cellular source of BMP6 responsible for hepcidin and iron homeostasis regulation, we generated mice with tissue-specific ablation ofBmp6in different liver cell populations and evaluated their iron phenotype. Efficiency and specificity of Cre-mediated recombination was assessed by using Cre-reporter mice, polymerase chain reaction of genomic DNA, and quantitation of Bmp6 messenger RNA expression from isolated liver cell populations. Localization of the BMP co-receptor hemojuvelin was visualized by immunofluorescence microscopy. Analysis of the Bmp6 conditional knockout mice revealed that liver endothelial cells (ECs) expressed Bmp6, whereas resident liver macrophages (Kupffer cells) and hepatocytes did not. Loss of Bmp6 in ECs recapitulated the hemochromatosis phenotype of global Bmp6 knockout mice, whereas hepatocyte and macrophage Bmp6 conditional knockout mice exhibited no iron phenotype. Hemojuvelin was localized on the hepatocyte sinusoidalmembrane immediately adjacent to Bmp6-producing sinusoidal ECs. Together, these data demonstrate that ECs are the predominantsource ofBMP6in the liver andsupport amodel inwhichECBMP6 has paracrine actionson hepatocytehemojuvelin to regulate hepcidin transcription and maintain systemic iron homeostasis. C1 [Canali, Susanna; Zumbrennen-Bullough, Kimberly B.; Core, Amanda B.; Wang, Chia-Yu; Bouley, Richard; Babitt, Jodie L.] Harvard Med Sch, Program Membrane Biol, Div Nephrol, Program Anemia Signaling Res, Boston, MA USA. [Canali, Susanna; Zumbrennen-Bullough, Kimberly B.; Core, Amanda B.; Wang, Chia-Yu; Nairz, Manfred; Bouley, Richard; Swirski, Filip K.; Babitt, Jodie L.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA USA. RP Babitt, JL (reprint author), Massachusetts Gen Hosp, 185 Cambridge St,CPZN 8208, Boston, MA 02114 USA. EM babitt.jodie@mgh.harvard.edu FU National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases [RO1-DK087727, T32 DK007540]; Howard Goodman Fellowship Award from the Massachusetts General Hospital; NIH [S10 RR031563]; Boston Area Diabetes and Endocrinology Research Center [DK57521]; Massachusetts General Hospital Center for the Study of Inflammatory Bowel Disease [DK43351] FX This work was supported by National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases grants RO1-DK087727 (J.L.B.) and T32 DK007540 (K.B.Z.B. and A.B.C.), and a Howard Goodman Fellowship Award from the Massachusetts General Hospital (J.L.B.). NIH Shared Instrumentation Grant S10 RR031563 funded the purchase of the Nikon A1R confocal confocal laser scanning microscope. The Boston Area Diabetes and Endocrinology Research Center (DK57521) and the Massachusetts General Hospital Center for the Study of Inflammatory Bowel Disease (DK43351) provided additional support for the Program in Membrane Biology Microscopy Core. NR 44 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JAN 26 PY 2017 VL 129 IS 4 BP 405 EP 414 DI 10.1182/blood-2016-06-721571 PG 10 WC Hematology SC Hematology GA EO2MU UT WOS:000396531400006 PM 27864295 ER PT J AU Li, H Mar, BG Zhang, H Puram, RV Vazquez, F Weir, BA Hahn, WC Ebert, B Pellman, D AF Li, Hubo Mar, Brenton G. Zhang, Huadi Puram, Rishi V. Vazquez, Francisca Weir, Barbara A. Hahn, William C. Ebert, Benjamin Pellman, David TI The EMT regulator ZEB2 is a novel dependency of human and murine acute myeloid leukemia SO BLOOD LA English DT Article ID DIFFERENTIAL EXPRESSION; CANCER DEVELOPMENT; MLL-AF9 LEUKEMIA; AML PATIENTS; STEM-CELLS; E-CADHERIN; GENE; IDENTIFICATION; DEGRADATION; MAINTENANCE AB Acute myeloid leukemia (AML) is a heterogeneous disease with complex molecular pathophysiology. To systematically characterize AML's genetic dependencies, we conducted genome-scale short hairpin RNA screens in 17 AML cell lines and analyzed dependencies relative to parallel screens in 199 cell lines of other cancer types. We identified 353 genes specifically required for AML cell proliferation. To validate the in vivo relevance of genetic dependencies observed in human cell lines, we performed a secondary screen in a syngeneic murine AML model driven by the MLL-AF9 oncogenic fusion protein. Integrating the results of these interference RNA screens and additional gene expression data, we identified the transcription factor ZEB2 as a novel AML dependency. ZEB2 depletion impaired the proliferation of both human and mouse AML cells and resulted in aberrant differentiation of human AML cells. Mechanistically, we showed that ZEB2 transcriptionally represses genes that regulate myeloid differentiation, including genes involved in cell adhesion and migration. In addition, we found that epigenetic silencing of the miR-200 family microRNAs affects ZEB2 expression. Our results extend the role of ZEB2 beyond regulating epithelial-mesenchymal transition (EMT) and establish ZEB2 as a novel regulator of AML proliferation and differentiation. C1 [Li, Hubo; Zhang, Huadi; Pellman, David] Howard Hughes Med Inst, Chevy Chase, MD USA. [Li, Hubo; Zhang, Huadi; Pellman, David] Boston Childrens Hosp, Dept Pediat Oncol, Dana Farber Canc Inst, Boston, MA USA. [Li, Hubo; Zhang, Huadi; Pellman, David] Boston Childrens Hosp, Pediat Hematol Oncol, Boston, MA USA. [Li, Hubo; Zhang, Huadi; Pellman, David] Harvard Med Sch, Dept Cell Biol, Boston, MA 02215 USA. [Mar, Brenton G.; Puram, Rishi V.; Hahn, William C.; Ebert, Benjamin] Harvard Med Sch, Div Hematol, Dept Med, Brigham & Womens Hosp, Boston, MA 02215 USA. [Mar, Brenton G.; Puram, Rishi V.; Vazquez, Francisca; Weir, Barbara A.; Hahn, William C.; Ebert, Benjamin] Broad Inst MIT & Harvard, Cambridge, MA USA. RP Pellman, D (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Howard Hughes Med Inst, 450 Brookline Ave, Boston, MA 02215 USA.; Pellman, D (reprint author), Harvard Med Sch, Childrens Hosp, 450 Brookline Ave, Boston, MA 02215 USA. EM david_pellman@dfci.harvard.edu OI Mar, Brenton/0000-0002-3857-9324 FU National Institutes of Health (NIH) National Cancer Institute [U01CA176058, P01CA066996, K08 CA184419]; NIH National Heart, Lung, and Blood Institute [R01 HL082945]; NIH National Institute of General Medical Sciences [R01 GM083299]; St. Baldrick's Foundation Scholar grant; Alex's Lemonade Stand Foundation Young Investigator grant; Project Achilles Consortium FX This work is supported by National Institutes of Health (NIH) National Cancer Institute grants U01CA176058 (W.C.H.), P01CA066996 (B.E.), and K08 CA184419 (B.G.M.); NIH National Heart, Lung, and Blood Institute grant R01 HL082945 (B.E.); NIH National Institute of General Medical Sciences grant R01 GM083299 (D.P.); St. Baldrick's Foundation Scholar grant and Alex's Lemonade Stand Foundation Young Investigator grant (B.G.M.); and by the Project Achilles Consortium. D.P. is a Howard Hughes Medical Institute Investigator. NR 53 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JAN 26 PY 2017 VL 129 IS 4 BP 497 EP 508 DI 10.1182/blood-2016-05-714493 PG 12 WC Hematology SC Hematology GA EO2MU UT WOS:000396531400015 PM 27756750 ER PT J AU Singh, JA Dohm, M Choong, PF AF Singh, Jasvinder A. Dohm, Michael Choong, Peter F. TI Consensus on draft OMERACT core domains for clinical trials of Total Joint Replacement outcome by orthopaedic surgeons: a report from the International consensus on outcome measures in TJR trials (I-COMiTT) group SO BMC MUSCULOSKELETAL DISORDERS LA English DT Article DE OMERACT; Core domain; Clinical trails; Total Joint Arthroplasty; TJR ID KNEE ARTHROPLASTY; MEASUREMENT SETS; FILTER 2.0; HIP AB Background: There are no core outcome domain or measurement sets for Total Joint Replacement (TJR) clinical trials. Our objective was to achieve an International consensus by orthopaedic surgeons on the OMERACT core domain/area set for TJR clinical trials. Methods: We conducted surveys of two orthopaedic surgeon cohorts, which included (1) the leadership of international orthopaedic societies and surgeons (IOS; cohort 1), and (2) the members of the American Academy of Orthopaedic Surgeons' Outcome Special Interest Group (AAOS-Outcome SIG), and/or the Outcome Research Interest Group of the Orthopaedic Research Society (ORS; cohort 2). Participants rated OMERACT-endorsed preliminary core area set for TJR clinical trials on a 1 to 9 scale, indicating 1-3 as domain of limited importance, 4-6 being important, but not critical, and 7-9 being critical. Results: Eighteen survey participants from the IOS group and 69 participants from the AAOS-Outcome SIG/ORS groups completed the survey questionnaire. The median (interquartile range [IQR]) scores were seven or higher for all six proposed preliminary core areas/domains across both groups, IOS and AAOS-Outcome SIG/ORS, respectively: pain, 8 [8, 9] and 8 [7, 9]; function, 8 [8, 8] and 8 [7, 9]; patient satisfaction, 8 [7, 9] and 8 [7, 8]; revision surgery, 7 [6, 9] and 8 [6, 8]; adverse events, 7 [5, 8] and 7 [6, 9]; and death, 7 [7, 9] and 8 [5, 9]. Respective median scores were lower for two additional optional domains: patient participation, 6.5 [5, 7] and 6 [5, 8]; and cost, 6 [5, 7] and 6 [5, 7]. Conclusions: This study showed that two independent surveys dervied from three groups of orthopaedic surgeons with international representation endorsed a preliminary/draft OMERACT core domain/area set for Joint Replacement clinical trials. C1 [Singh, Jasvinder A.] Univ Alabama Birmingham, Birmingham, AL 35294 USA. [Singh, Jasvinder A.] Birmingham Vet Affairs Med Ctr, Birmingham, AL 35233 USA. [Dohm, Michael] Univ Arizona, Dept Orthopaed Surg, Tucson, AZ USA. [Choong, Peter F.] Univ Melbourne, Dept Surg, Melbourne, Vic, Australia. [Choong, Peter F.] St Vincents Hosp, Dept Surg, Melbourne, Vic, Australia. RP Singh, JA (reprint author), Univ Alabama Birmingham, Birmingham, AL 35294 USA.; Singh, JA (reprint author), Birmingham Vet Affairs Med Ctr, Birmingham, AL 35233 USA. EM jasvinder.md@gmail.com NR 11 TC 1 Z9 1 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2474 J9 BMC MUSCULOSKEL DIS JI BMC Musculoskelet. Disord. PD JAN 26 PY 2017 VL 18 AR 45 DI 10.1186/s12891-017-1409-4 PG 8 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA EM3DN UT WOS:000395194800003 PM 28125985 ER PT J AU Imielinski, M Guo, GW Meyerson, M AF Imielinski, Marcin Guo, Guangwu Meyerson, Matthew TI Insertions and Deletions Target Lineage-Defining Genes in Human Cancers SO CELL LA English DT Article ID TERT PROMOTER MUTATIONS; CELL LUNG-CANCER; HUMAN GENOME; SOMATIC MUTATIONS; POLY(A) SIGNALS; NEVER-SMOKERS; LANDSCAPE; MELANOMA; TRANSCRIPTION; SIGNATURES AB Certain cell types function as factories, secreting large quantities of one or more proteins that are central to the physiology of the respective organ. Examples include surfactant proteins in lung alveoli, albumin in liver parenchyma, and lipase in the stomach lining. Whole-genome sequencing analysis of lung adenocarcinomas revealed noncoding somatic mutational hotspots near VMP1/MIR21 and indel hotspots in surfactant protein genes (SFTPA1, SFTPB, and SFTPC). Extrapolation to other solid cancers demonstrated highly recurrent and tumor-type-specific indel hotspots targeting the noncoding regions of highly expressed genes defining certain secretory cellular lineages: albumin (ALB) in liver carcinoma, gastric lipase (LIPF) in stomach carcinoma, and thyroglobulin (TG) in thyroid carcinoma. The sequence contexts of indels targeting lineage-defining genes were significantly enriched in the AATAATD DNA motif and specific chromatin contexts, including H3K27ac and H3K36me3. Our findings illuminate a prevalent and hitherto unrecognized mutational process linking cellular lineage and cancer. C1 [Imielinski, Marcin] Weill Cornell Med, Dept Pathol & Lab Med, Englander Inst Precis Med, Inst Computat Biomed, New York, NY 10065 USA. [Imielinski, Marcin] Weill Cornell Med, Meyer Canc Ctr, New York, NY 10065 USA. [Imielinski, Marcin] New York Genome Ctr, New York, NY 10013 USA. [Guo, Guangwu; Meyerson, Matthew] Broad Inst Harvard & MIT, Canc Program, Cambridge, MA 02142 USA. [Guo, Guangwu; Meyerson, Matthew] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Meyerson, Matthew] Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02215 USA. RP Imielinski, M (reprint author), Weill Cornell Med, Dept Pathol & Lab Med, Englander Inst Precis Med, Inst Computat Biomed, New York, NY 10065 USA.; Imielinski, M (reprint author), Weill Cornell Med, Meyer Canc Ctr, New York, NY 10065 USA.; Imielinski, M (reprint author), New York Genome Ctr, New York, NY 10013 USA.; Meyerson, M (reprint author), Broad Inst Harvard & MIT, Canc Program, Cambridge, MA 02142 USA.; Meyerson, M (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA.; Meyerson, M (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02215 USA. EM mai9037@med.cornell.edu; matthew_meyerson@dfci.harvard.edu FU National Cancer Institute as part of The Cancer Genome Atlas project [U24CA126546, U24CA143867, U24CA143845, U24CA126544, U24CA143883]; Department of Defense [W81XWH-12-1-0269]; American Cancer Society Research Professor Award; National Cancer Institute [R35CA197568]; Burroughs- Wellcome Career Award FX The authors would like to thank Aruna Ramachandran for helpful comments and careful editing during manuscript preparation, Leslie Gaffney for help with graphical design of figures, and Jeanie Joe for meticulous proofreading. The authors would also like to thank Korbinian Strimmer for correspondence regarding p value randomization and Heng Li for providing details of his universal mask. The authors thank Yoichiro Mitsuishi and Joshua Francis for helpful discussions. M. I. is supported by a Burroughs- Wellcome Career Award for Medical Scientists. This work was supported by grants from the National Cancer Institute as part of The Cancer Genome Atlas project: U24CA126546, U24CA143867, U24CA143845, U24CA126544, and U24CA143883. This work was also funded by the Department of Defense W81XWH-12-1-0269 (M.M.), the American Cancer Society Research Professor Award (M.M.), and the National Cancer Institute R35CA197568 (M.M.). NR 73 TC 1 Z9 1 U1 1 U2 1 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 JAN 26 PY 2017 VL 168 IS 3 BP 460 EP + DI 10.1016/j.cell.2016.12.025 PG 27 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EN8KP UT WOS:000396249600014 PM 28089356 ER PT J AU Cholera, R Pence, BW Bengtson, AM Crane, HM Christopoulos, K Cole, SR Fredericksen, R Gaynes, BN Heine, A Mathews, WC Mimiaga, MJ Moore, R Napravnik, S O'Clerigh, C Safren, S Mugavero, MJ AF Cholera, Rushina Pence, Brian W. Bengtson, Angela M. Crane, Heidi M. Christopoulos, Katerina Cole, Steven R. Fredericksen, Rob Gaynes, Bradley N. Heine, Amy Mathews, W. Christopher Mimiaga, Matthew J. Moore, Richard Napravnik, Sonia O'Clerigh, Conall Safren, Steven Mugavero, Michael J. TI Mind the Gap: Gaps in Antidepressant Treatment, Treatment Adjustments, and Outcomes among Patients in Routine HIV Care in a Multisite US Clinical Cohort SO PLOS ONE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; UNITED-STATES; PSYCHIATRIC-DISORDERS; INFECTED INDIVIDUALS; DEPRESSIVE SYMPTOMS; PREVALENCE; METAANALYSIS; MANAGEMENT; HEALTH; MEDICATION AB Background Depression affects 20-30% of HIV-infected patients and is associated with worse HIV outcomes. Although effective depression treatment is available, depression is largely untreated or undertreated in this population. Methods We quantified gaps in antidepressant treatment, treatment adjustments, and outcomes among US patients in routine HIV care in the nationally distributed CNICS observational clinical cohort. This cohort combines detailed clinical data with regular, self-reported depressive severity assessments (Patient Health Questionnaire-9, PHQ-9). We considered whether participants with likely depression received antidepressants, whether participants on antidepressants with persistently high depressive symptoms received timely dose adjustments, and whether participants achieved depression remission. We considered a cross-sectional analysis (6,219 participants in care in 2011-2012) and a prospective analysis (2,936 participants newly initiating CNICS care when PHQ-9 screening was active). Results The cross-sectional sample was 87% male, 53% Caucasian, 25% African American, and 18% Hispanic; the prospective sample was similar. In both samples, 39-44% had likely depression, with 44-60% of those receiving antidepressants. Of participants receiving antidepressants, 20-26% experienced persistently high depressive symptoms; only a small minority of those received antidepressant dose adjustments. Overall, 35-40% of participants on antidepressants achieved full depression remission. Remission among participants with persistently high depressive symptoms was rare regardless of dose adjustments. Conclusions In this large, diverse cohort of US patients engaged in routine HIV care, we observed large gaps in antidepressant treatment, timely dose adjustment to address persistently high depressive symptoms, and antidepressant treatment outcomes. These results highlight the importance of more effective pharmacologic depression treatment models for HIV-infected patients. C1 [Cholera, Rushina] Univ North Carolina Chapel Hill, UNC Sch Med, Chapel Hill, NC USA. [Pence, Brian W.; Bengtson, Angela M.; Cole, Steven R.; Napravnik, Sonia] Univ North Carolina Chapel Hill, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27599 USA. [Crane, Heidi M.; Fredericksen, Rob] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [Christopoulos, Katerina] Univ Calif San Francisco, San Francisco Gen Hosp, HIV AIDS Div, San Francisco, CA USA. [Gaynes, Bradley N.] Univ North Carolina Chapel Hill, Sch Med, Dept Psychiat, Chapel Hill, NC USA. [Heine, Amy; Napravnik, Sonia] Univ North Carolina Chapel Hill, Sch Med, Dept Med, Div Infect Dis, Chapel Hill, NC USA. [Mathews, W. Christopher] Univ Calif San Diego, Sch Med, Dept Med, San Diego, CA 92103 USA. [Mimiaga, Matthew J.; O'Clerigh, Conall] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA USA. [Mimiaga, Matthew J.; O'Clerigh, Conall] Fenway Hlth, Fenway Inst, Boston, MA USA. [Mimiaga, Matthew J.] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Moore, Richard] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Safren, Steven] Univ Miami, Dept Psychol, Miami, FL USA. [Mugavero, Michael J.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Mugavero, Michael J.] Univ Alabama Birmingham, UAB Ctr AIDS Res, Birmingham, AL USA. RP Pence, BW (reprint author), Univ North Carolina Chapel Hill, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27599 USA. EM bpence@unc.edu FU National Institute of Mental Health (NIMH), National Institutes of Health (NIH), Bethesda, MD, USA [R01 MH100970]; NIH [R24 AI067039]; Centers for AIDS Research at UNC; UAB, NIH-funded programs [P30 AI50410, P30 AI027767]; NIMH [F30-MH096664, K24MH094214]; Center for AIDS Research at Harvard University, an NIH [P30AI060354] FX Funding/Support: This work was supported by grant R01 MH100970 of the National Institute of Mental Health (NIMH), National Institutes of Health (NIH), Bethesda, MD, USA. Support for the study was also provided by the NIH-funded CFAR Network of Integrated Clinical Systems (R24 AI067039) and by the Centers for AIDS Research at UNC and UAB, NIH-funded programs (P30 AI50410; P30 AI027767). RC was supported by grant F30-MH096664 of NIMH. SS, CO, and M.J. Mimiaga were supported by the Center for AIDS Research at Harvard University, an NIH-funded program (P30AI060354). SS was also supported by grant K24MH094214 of NIMH. Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIMH orthe NIH. NR 38 TC 0 Z9 0 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 26 PY 2017 VL 12 IS 1 AR e0166435 DI 10.1371/journal.pone.0166435 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN7IT UT WOS:000396176100155 PM 28125593 ER PT J AU Patel, B Ismahil, MA Hamid, T Bansal, SS Prabhu, SD AF Patel, Bindiya Ismahil, Mohamed Ameen Hamid, Tariq Bansal, Shyam S. Prabhu, Sumanth D. TI Mononuclear Phagocytes Are Dispensable for Cardiac Remodeling in Established Pressure-Overload Heart Failure SO PLOS ONE LA English DT Article ID DENDRITIC CELLS; MYOCARDIAL-INFARCTION; GENE-EXPRESSION; STEADY-STATE; MACROPHAGES; INFLAMMATION; MONOCYTES; MICE; CARDIOMYOPATHY; IDENTIFICATION AB Background Although cardiac and splenic mononuclear phagocytes (MPs), i.e., monocytes, macrophages and dendritic cells (DCs), are key contributors to cardiac remodeling after myocardial infarction, their role in pressure-overload remodeling is unclear. We tested the hypothesis that these immune cells are required for the progression of remodeling in pressure-overload heart failure (HF), and that MP depletion would ameliorate remodeling. Methods and Results C57BL/6 mice were subjected to transverse aortic constriction (TAC) or sham operation, and assessed for alterations in MPs. As compared with sham, TAC mice exhibited expansion of circulating LyC6(hi) monocytes and pro-inflammatory CD206(-) cardiac macrophages early (1 w) after pressure-overload, prior to significant hypertrophy and systolic dysfunction, with subsequent resolution during chronic HF. In contrast, classical DCs were expanded in the heart in a biphasic manner, with peaks both early, analogous to macrophages, and late (8 w), during established HF. There was no significant expansion of circulating DCs, or Ly6C(+) monocytes and DCs in the spleen. Periodic systemic MP depletion from 2 to 16 w after TAC in macrophage Fas-induced apoptosis (MaFIA) transgenic mice did not alter cardiac remodeling progression, nor did splenectomy in mice with established HF after TAC. Lastly, adoptive transfer of splenocytes from TAC HF mice into naive recipients did not induce immediate or long-term cardiac dysfunction in recipient mice. Conclusions Mononuclear phagocytes populations expand in a phasic manner in the heart during pressure-overload. However, they are dispensable for the progression of remodeling and failure once significant hypertrophy is evident and blood monocytosis has normalized. C1 [Patel, Bindiya; Ismahil, Mohamed Ameen; Hamid, Tariq; Bansal, Shyam S.; Prabhu, Sumanth D.] Univ Alabama Birmingham, Div Cardiovasc Dis, Birmingham, AL 35294 USA. [Patel, Bindiya; Ismahil, Mohamed Ameen; Hamid, Tariq; Bansal, Shyam S.; Prabhu, Sumanth D.] Univ Alabama Birmingham, Comprehens Cardiovasc Ctr, Birmingham, AL 35233 USA. [Prabhu, Sumanth D.] Birmingham VA Med Ctr, Med Serv, Birmingham, AL 35233 USA. RP Prabhu, SD (reprint author), Univ Alabama Birmingham, Div Cardiovasc Dis, Birmingham, AL 35294 USA.; Prabhu, SD (reprint author), Univ Alabama Birmingham, Comprehens Cardiovasc Ctr, Birmingham, AL 35233 USA.; Prabhu, SD (reprint author), Birmingham VA Med Ctr, Med Serv, Birmingham, AL 35233 USA. EM sprabhu@uab.edu FU National Institutes of Health [1R01HL125735]; VA Merit Award [I01BX002706] FX This work was supported by National Institutes of Health grant 1R01HL125735 and a VA Merit Award I01BX002706 (both to SDP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 1 Z9 1 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 26 PY 2017 VL 12 IS 1 AR e0170781 DI 10.1371/journal.pone.0170781 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN7IT UT WOS:000396176100052 PM 28125666 ER PT J AU Szema, AM Forsyth, E Ying, B Hamidi, SA Chen, JJ Hwang, S Li, JC Dwyer, DS Ramiro-Diaz, JM Giermakowska, W Bosc, LVG AF Szema, Anthony M. Forsyth, Edward Ying, Benjamin Hamidi, Sayyed A. Chen, John J. Hwang, Sonya Li, Jonathan C. Dwyer, Debra Sabatini Ramiro-Diaz, Juan M. Giermakowska, Wieslawa Bosc, Laura V. Gonzalez TI NFATc3 and VIP in Idiopathic Pulmonary Fibrosis and Chronic Obstructive Pulmonary Disease SO PLOS ONE LA English DT Article ID VASOACTIVE-INTESTINAL-PEPTIDE; ACTIVATED T-CELLS; CHRONIC HYPOXIA; ARTERIAL-HYPERTENSION; NUCLEAR FACTOR; SMOOTH-MUSCLE; UP-REGULATION; COPD; ANGIOGENESIS; INHIBITION AB Idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) are both debilitating lung diseases which can lead to hypoxemia and pulmonary hypertension (PH). Nuclear Factor of Activated T-cells (NFAT) is a transcription factor implicated in the etiology of vascular remodeling in hypoxic PH. We have previously shown that mice lacking the ability to generate Vasoactive Intestinal Peptide (VIP) develop spontaneous PH, pulmonary arterial remodeling and lung inflammation. Inhibition of NFAT attenuated PH in these mice suggesting a connection between NFAT and VIP. To test the hypotheses that: 1) VIP inhibits NFAT isoform c3 (NFATc3) activity in pulmonary vascular smooth muscle cells; 2) lung NFATc3 activation is associated with disease severity in IPF and COPD patients, and 3) VIP and NFATc3 expression correlate in lung tissue from IPF and COPD patients. NFAT activity was determined in isolated pulmonary arteries from NFAT-luciferase reporter mice. The% of nuclei with NFAT nuclear accumulation was determined in primary human pulmonary artery smooth muscle cell (PASMC) cultures; in lung airway epithelia and smooth muscle and pulmonary endothelia and smooth muscle from IPF and COPD patients; and in PASMC from mouse lung sections by fluorescence microscopy. Both NFAT and VIP mRNA levels were measured in lungs from IPF and COPD patients. Empirical strategies applied to test hypotheses regarding VIP, NFATc3 expression and activity, and disease type and severity. This study shows a significant negative correlation between NFAT isoform c3 protein expression levels in PASMC, activity of NFATc3 in pulmonary endothelial cells,expression and activity of NFATc3 in bronchial epithelial cells and lung function in IPF patients, supporting the concept that NFATc3 is activated in the early stages of IPF. We further show that there is a significant positive correlation between NFATc3 mRNA expression and VIP RNA expression only in lungs from IPF patients. In addition, we found that VIP inhibits NFAT nuclear translocation in primary human pulmonary artery smooth muscle cells (PASMC). Early activation of NFATc3 in IPF patients may contribute to disease progression and the increase in VIP expression could be a protective compensatory mechanism. C1 [Szema, Anthony M.; Dwyer, Debra Sabatini] SUNY Stony Brook, Coll Engn & Appl Sci, Dept Technol & Soc, Stony Brook, NY 11794 USA. [Szema, Anthony M.] John T Mather Mem Hosp, Stony Brook Med SUNY, Stony Brook Internal Med Residency Program, Port Jefferson, NY USA. [Szema, Anthony M.] Hofstra Univ, Dept Occupat Med Epidemiol & Prevent Med, Hofstra Northwell Sch Med, Hempstead, NY 11550 USA. [Szema, Anthony M.] Hofstra Univ, Dept Occupat Med Epidemiol & Prevent Med, Hofstra Northwell Sch Med, Manhasset, NY USA. [Szema, Anthony M.; Li, Jonathan C.] Three Village Allergy & Asthma PLLC, South Setauket, NY USA. [Szema, Anthony M.] Columbia Univ, Child Psychiat Epidemiol Grp, New York, NY USA. [Forsyth, Edward; Ying, Benjamin] SUNY Stony Brook, Sch Med, MD Scholarly Recognit Program, Stony Brook, NY 11794 USA. [Hamidi, Sayyed A.] Bronx Vet Affairs Med Ctr, Internal Med Residency Program, Dept Internal Med, Bronx, NY USA. [Chen, John J.] Univ Hawaii, Biostat & Data Management Core, John A Burns Sch Med, Honolulu, HI 96822 USA. [Hwang, Sonya] SUNY Stony Brook, Sch Med, Dept Pathol, Stony Brook, NY 11794 USA. [Ramiro-Diaz, Juan M.; Giermakowska, Wieslawa; Bosc, Laura V. Gonzalez] Univ New Mexico, Hlth Sci Ctr, Dept Cell Biol & Physiol, Albuquerque, NM 87131 USA. RP Bosc, LVG (reprint author), Univ New Mexico, Hlth Sci Ctr, Dept Cell Biol & Physiol, Albuquerque, NM 87131 USA. EM lgonzalezbosc@salud.unm.edu FU NIH Lung Tissue Research Consortium (LTRC) [08-99-0002]; NIH [R01 HL088151-05]; Three Village Allergy Asthma, PLLC FX NIH Lung Tissue Research Consortium (LTRC) concept sheet number 08-99-0002. "Gene deficiency of Vasoactive Intestinal Peptide in COPD patients with pulmonary artery hypertension" to Anthony Szema, M.D (PI). NIH R01 HL088151-05 "NFATc3 in Chronic Pulmonary Hypertension" to Laura Gonzalez Bosc, Ph.D (PI). Three Village Allergy & Asthma, PLLC provided support in the form of salaries only for A.M.S., but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of this author are articulated in the 'author contributions' section. NR 39 TC 0 Z9 0 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 26 PY 2017 VL 12 IS 1 AR e0170606 DI 10.1371/journal.pone.0170606 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN7IT UT WOS:000396176100088 PM 28125639 ER PT J AU Martin-Gayo, E Cronin, J Hickman, T Ouyang, ZY Lindqvist, M Kolb, KE zur Wiesch, JS Cubas, R Porichis, F Shalek, AK van Lunzen, J Haddad, EK Walker, BD Kaufmann, DE Lichterfeld, M Yu, XG AF Martin-Gayo, Enrique Cronin, Jacqueline Hickman, Taylor Ouyang, Zhengyu Lindqvist, Madelene Kolb, Kellie E. zur Wiesch, Julian Schulze Cubas, Rafael Porichis, Filippos Shalek, Alex K. van Lunzen, Jan Haddad, Elias K. Walker, Bruce D. Kaufmann, Daniel E. Lichterfeld, Mathias Yu, Xu G. TI Circulating CXCR5(+)CXCR3(+)PD-1(lo) Tfh-like cells in HIV-1 controllers with neutralizing antibody breadth SO JCI INSIGHT LA English DT Article ID FOLLICULAR HELPER-CELL; CD4 T-CELLS; RNA-SEQ DATA; DENDRITIC CELLS; BCL6 EXPRESSION; B-CELLS; DIFFERENTIATION; INFECTION; RESPONSES; SUBSET AB HIV-1-specific broadly neutralizing antibodies (bnAbs) typically develop in individuals with continuous high-level viral replication and increased immune activation, conditions that cannot be reproduced during prophylactic immunization. Understanding mechanisms supporting bnAb development in the absence of high-level viremia may be important for designing bnAb-inducing immunogens. Here, we show that the breadth of neutralizing antibody responses in HIV-1 controllers was associated with a relative enrichment of circulating CXCR5(+)CXCR3(+)PD-1(lo) CD4(+) T cells. These CXCR3(+)PD-1(lo) Tfh-like cells were preferentially induced in vitro by functionally superior dendritic cells from controller neutralizers, and able to secrete IL-21 and support B cells. In addition, these CXCR3(+)PD-1(lo) Tfh-like cells contained higher proportions of stem cell-like memory T cells, and upon antigenic stimulation differentiated into PD-1(hi) Tfh-like cells in a Notch-dependent manner. Together, these data suggest that CXCR5(+)CXCR3(+)PD-1(lo) cells represent a dendritic cell-primed precursor cell population for PD-1(hi) Tfh-like cells that may contribute to the generation of bnAbs in the absence of high-level viremia. C1 [Martin-Gayo, Enrique; Cronin, Jacqueline; Hickman, Taylor; Ouyang, Zhengyu; Lindqvist, Madelene; Kolb, Kellie E.; Porichis, Filippos; Shalek, Alex K.; Walker, Bruce D.; Kaufmann, Daniel E.; Lichterfeld, Mathias; Yu, Xu G.] Ragon Inst MGH MIT & Harvard, Cambridge, MA USA. [Lindqvist, Madelene; Walker, Bruce D.; Kaufmann, Daniel E.] Duke Univ, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, Durham, NC USA. [Kolb, Kellie E.; Shalek, Alex K.] MIT, IMES, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [zur Wiesch, Julian Schulze; van Lunzen, Jan] Univ Med Ctr Hamburg, Hamburg, Germany. [Cubas, Rafael] Vaccine & Gene Therapy Inst Florida, Port St Lucie, FL USA. [Haddad, Elias K.] Drexel Univ, Div Infect Dis & HIV Med, Philadelphia, PA 19104 USA. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Kaufmann, Daniel E.] Univ Montreal, CHUM, Res Ctr, Montreal, PQ, Canada. [Lichterfeld, Mathias] Brigham & Womens Hosp, Infect Dis Div, 75 Francis St, Boston, MA 02115 USA. [Lichterfeld, Mathias] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Yu, XG (reprint author), Massachusetts Gen Hosp, Ragon Inst MGH MIT & Harvard, 400 Technol Sq, Cambridge, MA 02139 USA. EM xyu@mgh.harvard.edu FU NIH [AI078799, AI089339, HL121890, AI098484, HL126554, AI116228, AI087452, AI098487, AI106468, AI106482]; Searle Scholars Foundation; Beckman Young Investigator Program; NIH New Innovator Award [DP2 OD020839]; Quebec Health Research Fund (FRQS) FX This work was supported by the NIH (grants AI078799, AI089339, HL121890, AI098484, HL126554, AI116228 and AI087452 to XGY; AI098487 and AI106468 to M Lichterfeld). PBMC sample collection was supported by the Bill and Melinda Gates Foundation (OPP 1066973), the Mark and Lisa Schwartz Foundation, the Ragon Institute of MGH, MIT and Harvard, and the International HIV Controller Consortium. AKS was supported by the Searle Scholars Foundation, the Beckman Young Investigator Program, and an NIH New Innovator Award (DP2 OD020839). DEK is supported by a Research Scholar Career Award of the Quebec Health Research Fund (FRQS). Lymph node sample collection was supported by NIH Scripps CHAVI-ID (1UM1-AI100663 to BDW and DEK); tonsil sample collection was supported by NIH grant AI106482 to EKH. NR 59 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD JAN 26 PY 2017 VL 2 IS 2 AR e89574 DI 10.1172/jci.insight.89574 PG 17 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EK0BT UT WOS:000393592200008 PM 28138558 ER PT J AU Surolia, R Li, FJ Wang, Z Li, HS Liu, G Zhou, Y Luckhardt, T Bae, S Liu, RM Rangarajan, S de Andrade, J Thannickal, VJ Antony, VB AF Surolia, Ranu Li, Fu Jun Wang, Zheng Li, Huashi Liu, Gang Zhou, Yong Luckhardt, Tracy Bae, Sejong Liu, Rui-ming Rangarajan, Sunad de Andrade, Joao Thannickal, Victor J. Antony, Veena B. TI 3D pulmospheres serve as a personalized and predictive multicellular model for assessment of antifibrotic drugs SO JCI INSIGHT LA English DT Article ID IDIOPATHIC PULMONARY-FIBROSIS; INVASIVE FIBROBLAST PHENOTYPE; FORCED VITAL CAPACITY; MODERATE IMPAIRMENT; LUNG FIBROBLASTS; PIRFENIDONE; NINTEDANIB; MYOFIBROBLASTS; INHIBITION; CRYOBIOPSY AB Idiopathic pulmonary fibrosis (IPF) is a fatal progressive fibrotic lung disease characterized by the presence of invasive myofibroblasts in the lung. Currently, there are only two FDA-approved drugs (pirfenidone and nintedanib) for the treatment of IPF. There are no defined criteria to guide specific drug therapy. New methodologies are needed not only to predict personalized drug therapy, but also to screen novel molecules that are on the horizon for treatment of IPF. We have developed a model system that exploits the invasive phenotype of IPF lung tissue. This ex vivo 3D model uses lung tissue from patients to develop pulmospheres. Pulmospheres are 3D spheroids composed of cells derived exclusively from primary lung biopsies and inclusive of lung cell types reflective of those in situ, in the patient. We tested the pulmospheres of 20 subjects with IPF and 9 control subjects to evaluate the responsiveness of individual patients to antifibrotic drugs. Clinical parameters and outcomes were also followed in the same patients. Our results suggest that pulmospheres simulate the microenvironment in the lung and serve as a personalized and predictive model for assessing responsiveness to antifibrotic drugs in patients with IPF. C1 [Surolia, Ranu; Li, Fu Jun; Wang, Zheng; Li, Huashi; Liu, Gang; Zhou, Yong; Luckhardt, Tracy; Liu, Rui-ming; Rangarajan, Sunad; de Andrade, Joao; Thannickal, Victor J.; Antony, Veena B.] Univ Alabama Birmingham, Div Pulm Allergy & Crit Care Med, Birmingham, AL USA. [Bae, Sejong] Univ Alabama Birmingham, Dept Med, Div Prevent Med, Birmingham, AL 35294 USA. [de Andrade, Joao; Thannickal, Victor J.] Birmingham VA Med Ctr, Birmingham, AL USA. RP Antony, VB (reprint author), 1530 3rd Ave So,THT 422, Birmingham, AL 35294 USA. EM vantony@uabmc.edu FU NIH [P01 HL114470] FX This work was supported by NIH grant P01 HL114470 (to VJT and VBA). NR 42 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD JAN 26 PY 2017 VL 2 IS 2 AR e91377 DI 10.1172/jci.insight.91377 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EK0BT UT WOS:000393592200015 PM 28138565 ER PT J AU Togel, F Valerius, MT Freedman, BS Latrino, R Grinstein, M Bonventre, JV AF Togel, Florian Valerius, M. Todd Freedman, Benjamin S. Latrino, Rossella Grinstein, Mor Bonventre, Joseph V. TI Repair after nephron ablation reveals limitations of neonatal neonephrogenesis SO JCI INSIGHT LA English DT Article ID COMPENSATORY RENAL GROWTH; KIDNEY DEVELOPMENT; GLOMERULAR NUMBER; BIRTH-WEIGHT; STEM-CELLS; MAMMALIAN KIDNEY; PROGENITOR CELLS; HYPERTENSION; NEPHROGENESIS; REGENERATION AB The neonatal mouse kidney retains nephron progenitor cells in a nephrogenic zone for 3 days after birth. We evaluated whether de novo nephrogenesis can be induced postnatally beyond 3 days. Given the long-term implications of nephron number for kidney health, it would be useful to enhance nephrogenesis in the neonate. We induced nephron reduction by cryoinjury with or without contralateral nephrectomy during the neonatal period or after 1 week of age. There was no detectable compensatory de novo nephrogenesis, as determined by glomerular counting and lineage tracing. Contralateral nephrectomy resulted in additional adaptive healing, with little or no fibrosis, but did not also stimulate de novo nephrogenesis. In contrast, injury initiated at 1 week of age led to healing with fibrosis. Thus, despite the presence of progenitor cells and ongoing nephron maturation in the newborn mouse kidney, de novo nephrogenesis is not inducible by acute nephron reduction. This indicates that additional nephron progenitors cannot be recruited after birth despite partial renal ablation providing a reparative stimulus and suggests that nephron number in the mouse is predetermined at birth. C1 [Togel, Florian; Valerius, M. Todd; Freedman, Benjamin S.; Latrino, Rossella; Bonventre, Joseph V.] Harvard Med Sch, Dept Med, Brigham & Womens Hosp, Renal Div, Boston, MA USA. [Valerius, M. Todd; Bonventre, Joseph V.] Harvard Stem Cell Inst, Cambridge, MA USA. [Grinstein, Mor] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Grinstein, Mor] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Freedman, Benjamin S.] Univ Washington, Sch Med, Div Nephrol, Kidney Res Inst, Seattle, WA USA. [Freedman, Benjamin S.] Univ Washington, Sch Med, Dept Med, Inst Stem Cell & Regenerat Med, Seattle, WA 98195 USA. Univ Vita Salute San Raffaele, IRCCS San Raffaele Sci Inst, Milan, Italy. RP Valerius, MT; Bonventre, JV (reprint author), Harvard Inst Med, 4 Blackfan Circle, Boston, MA 02115 USA. EM mtvalerius@research.bwh.harvard.edu OI Valerius, M. Todd/0000-0001-8143-9231 FU NIH [R01DK072381, R37DK039773, T32DK007527, K01DK102826, F32DK092036]; Harvard Stem Cell Institute; NIH sub award [U01DK107350] FX This work was supported by NIH grants R01DK072381 and R37DK039773 (to JVB), T32DK007527 (to FT), and K01DK102826 and F32DK092036 (to BSF) and the Harvard Stem Cell Institute and U01DK107350 (NIH sub award) (to MTV). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. NR 45 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD JAN 26 PY 2017 VL 2 IS 2 AR e88848 DI 10.1172/jci.insight.88848 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EK0BT UT WOS:000393592200005 PM 28138555 ER PT J AU Choueiri, TK Motzer, RJ AF Choueiri, Toni K. Motzer, Robert J. TI Systemic Therapy for Metastatic Renal-Cell Carcinoma SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID PHASE-III TRIAL; INTERFERON-ALPHA; TARGETED THERAPY; OPEN-LABEL; DOUBLE-BLIND; CYTOREDUCTIVE NEPHRECTOMY; DATABASE CONSORTIUM; RANDOMIZED-TRIAL; BONE METASTASES; EVEROLIMUS AB Until recently, there was a dearth of effective systemic therapies for kidney cancer. The incidence of the disease steadily increased from 1975 through 2008 and leveled off after 2008.(1-3) Currently, it is among the 10 most frequently diagnosed cancers in men and women in the United States, with more than an estimated 62,000 new cases in 2016.(4) The prognosis has historically been poor, with current 5-year survival rates of 74% overall, decreasing to 53% among patients with locoregional (stage III) disease and 8% among patients with metastatic disease. 1,3 Kidney cancer is a disease of the middle-aged and elderly: 91% of patients receive a diagnosis at 45 years of age or older, and 48% receive a diagnosis at 65 years of age or older. (1) Renal-cell carcinoma, the most common form of kidney cancer, occurs in 90% of cases and is nearly twice as common in men as in women. (3) The 5-year survival rate among patients with kidney cancer increased from 57% in 1987-1989 to 74% in 2006-2012(1); this increase was attributable in part to a higher proportion of indolent and low-stage tumors identified using improved early-detection techniques. (5) Still, one third of patients with kidney cancer present with regional or distant metastases, (1) and of patients with localized renal-cell carcinoma treated with nephrectomy with curative intent, approximately one quarter have relapses in distant sites. (6-8) Distant metastases occur most often in the lungs, lymph nodes, liver, bone, and brain. (9) Although more than 14,000 patients die from kidney cancer each year,(4) we have seen considerable progress in the systemic treatment of metastatic renal-cell carcinoma in the past 20 years.(10) Researchers have achieved a better understanding of the pathogenesis of the most common type of renal-cell carcinoma, clear-cell renal-cell carcinoma. This understanding has led to new agents, expanded treatment options, and increased rates of survival. C1 [Choueiri, Toni K.] Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Boston, MA 02115 USA. [Motzer, Robert J.] Mem Sloan Kettering Canc Ctr, Dept Med, Genitourinary Oncol Serv, 1275 York Ave, New York, NY 10021 USA. RP Choueiri, TK (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA.; Motzer, RJ (reprint author), Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10065 USA. EM toni_choueiri@dfci.harvard.edu; motzerr@mskcc.org FU Pfizer; Exelixis; Novartis; Merck; Bristol-Myers Squibb; Roche; AstraZeneca; Bayer; Eisai; Peloton Therapeutics; Prometheus Laboratories; Foundation Medicine; Calithera; Cerulean Pharma FX Dr. Choueiri reports receiving fees for consulting and serving on advisory boards from Pfizer, Exelixis, Novartis, Merck, Bristol-Myers Squibb, Roche, AstraZeneca, Bayer, Eisai, Peloton Therapeutics, Prometheus Laboratories, Foundation Medicine, Calithera, and Cerulean Pharma and clinical-trial support to his hospital from Exelixis, TRACON Pharmaceuticals, GlaxoSmithKline, Peloton Therapeutics, Celldex Therapeutics, Pfizer, Novartis, Merck, Bristol-Myers Squibb, Roche, Agensys, and AstraZeneca; and Dr. Motzer, receiving consulting fees from Pfizer, Exelixis, Eisai, Novartis, Pharmacyclics, and Acceleron Pharma and clinical-trial support to his hospital from Pfizer, Eisai, Novartis, Bristol-Myers Squibb, Genentech/Roche, and GlaxoSmithKline. No other potential conflict of interest relevant to this article was reported. NR 95 TC 0 Z9 0 U1 5 U2 5 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 JAN 26 PY 2017 VL 376 IS 4 BP 354 EP 366 DI 10.1056/NEJMra1601333 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA EJ3KR UT WOS:000393111600010 PM 28121507 ER PT J AU Plichta, JK Hughes, K AF Plichta, Jennifer K. Hughes, Kevin TI Radiation-Induced Angiosarcoma after Breast-Cancer Treatment SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Plichta, Jennifer K.] Duke Univ, Durham, NC 27708 USA. [Hughes, Kevin] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Plichta, JK (reprint author), Duke Univ, Durham, NC 27708 USA. EM jennifer.plichta@duke.edu NR 0 TC 0 Z9 0 U1 1 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 26 PY 2017 VL 376 IS 4 BP 367 EP 367 DI 10.1056/NEJMicm1516482 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA EJ3KR UT WOS:000393111600011 PM 28121510 ER PT J AU Samuels, MA Gonzalez, RG Makadzange, AT Hedley-Whyte, ET AF Samuels, Martin A. Gonzalez, R. Gilberto Makadzange, Azure T. Hedley-Whyte, E. Tessa TI Case 3-2017: A 62-Year-Old Man with Cardiac Sarcoidosis and New Diplopia and Weakness SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID GRANULOMATOUS AMEBIC ENCEPHALITIS; ACANTHAMOEBA; PATIENT; INFECTION; MILTEFOSINE C1 [Samuels, Martin A.] Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA. [Gonzalez, R. Gilberto] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Makadzange, Azure T.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Hedley-Whyte, E. Tessa] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Samuels, Martin A.] Harvard Med Sch, Dept Neurol, Boston, MA 02115 USA. [Gonzalez, R. Gilberto] Harvard Med Sch, Dept Radiol, Boston, MA USA. [Makadzange, Azure T.] Harvard Med Sch, Dept Med, Boston, MA USA. [Hedley-Whyte, E. Tessa] Harvard Med Sch, Dept Pathol, Boston, MA USA. RP Samuels, MA (reprint author), Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA.; Samuels, MA (reprint author), Harvard Med Sch, Dept Neurol, Boston, MA 02115 USA. FU GlaxoSmithKline; Janssen Pharmaceuticals FX Dr. Hedley-Whyte reports holding stock in Becton Dickinson; and Dr. Makadzange, receiving consulting fees from GlaxoSmithKline and lecture fees from Janssen Pharmaceuticals, as well as nonfinancial support from Roche Diagnostics and Becton Dickinson. No other potential conflict of interest relevant to this article was reported. NR 18 TC 0 Z9 0 U1 1 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 26 PY 2017 VL 376 IS 4 BP 368 EP 379 DI 10.1056/NEJMcpc1610713 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA EJ3KR UT WOS:000393111600012 PM 28121502 ER PT J AU Chatterton, Z Hartley, BJ Seok, MH Mendelev, N Chen, S Milekic, M Rosoklija, G Stankov, A Trencevsja-Ivanovska, I Brennand, K Ge, YC Dwork, AJ Haghighi, F AF Chatterton, Zac Hartley, Brigham J. Seok, Man-Ho Mendelev, Natalia Chen, Sean Milekic, Maria Rosoklija, Gorazd Stankov, Aleksandar Trencevsja-Ivanovska, Iskra Brennand, Kristen Ge, Yongchao Dwork, Andrew J. Haghighi, Fatemeh TI In utero exposure to maternal smoking is associated with DNA methylation alterations and reduced neuronal content in the developing fetal brain SO EPIGENETICS & CHROMATIN LA English DT Article DE Brain; DNA methylation; Epigenetics; Fetal; Neuron; Nicotine; Neurodevelopment; Prenatal; Smoking; Tobacco ID NICOTINE EXPOSURE; OXIDATIVE STRESS; SUCCINATE-DEHYDROGENASE; PROMOTER METHYLATION; INDUSTRIAL-CHEMICALS; PRENATAL EXPOSURE; PREGNANCY; SCHIZOPHRENIA; CHILDREN; TISSUE AB Background: Intrauterine exposure to maternal smoking is linked to impaired executive function and behavioral problems in the offspring. Maternal smoking is associated with reduced fetal brain growth and smaller volume of cortical gray matter in childhood, indicating that prenatal exposure to tobacco may impact cortical development and manifest as behavioral problems. Cellular development is mediated by changes in epigenetic modifications such as DNA methylation, which can be affected by exposure to tobacco. Results: In this study, we sought to ascertain how maternal smoking during pregnancy affects global DNA methylation profiles of the developing dorsolateral prefrontal cortex (DLPFC) during the second trimester of gestation. When DLPFC methylation profiles (assayed via Illumina, HM450) of smoking-exposed and unexposed fetuses were compared, no differentially methylated regions (DMRs) passed the false discovery correction (FDR = 0.05). However, the most significant DMRs were hypomethylated CpG Islands within the promoter regions of GNA15 and SDHAP3 of smoking-exposed fetuses. Interestingly, the developmental up-regulation of SDHAP3 mRNA was delayed in smoking-exposed fetuses. Interaction analysis between gestational age and smoking exposure identified significant DMRs annotated to SYCE3, C21orf56/LSS, SPAG1 and RNU12/POLDIP3 that passed FDR. Furthermore, utilizing established methods to estimate cell proportions by DNA methylation, we found that exposed DLPFC samples contained a lower proportion of neurons in samples from fetuses exposed to maternal smoking. We also show through in vitro experiments that nicotine impedes the differentiation of neurons independent of cell death. Conclusions: We found evidence that intrauterine smoking exposure alters the developmental patterning of DNA methylation and gene expression and is associated with reduced mature neuronal content, effects that are likely driven by nicotine. C1 [Chatterton, Zac; Hartley, Brigham J.; Seok, Man-Ho; Mendelev, Natalia; Chen, Sean; Brennand, Kristen; Haghighi, Fatemeh] Icahn Sch Med Mt Sinai, Friedman Brain Inst, 1425 Madison Ave, New York, NY 10029 USA. [Chatterton, Zac; Hartley, Brigham J.; Seok, Man-Ho; Mendelev, Natalia; Chen, Sean; Brennand, Kristen; Haghighi, Fatemeh] Icahn Sch Med Mt Sinai, Dept Neurosci, 1425 Madison Ave,Floor 10,Room 10-70D, New York, NY 10029 USA. [Hartley, Brigham J.; Seok, Man-Ho; Brennand, Kristen] Icahn Sch Med Mt Sinai, Dept Psychiat, 1425 Madison Ave, New York, NY 10029 USA. [Ge, Yongchao] Icahn Sch Med Mt Sinai, Dept Neurol, 1425 Madison Ave, New York, NY 10029 USA. [Milekic, Maria; Rosoklija, Gorazd; Dwork, Andrew J.] Columbia Univ, Dept Psychiat, New York, NY 10032 USA. [Dwork, Andrew J.] Columbia Univ, Dept Pathol & Cell Biol, New York, NY 10032 USA. [Chatterton, Zac; Mendelev, Natalia; Chen, Sean; Haghighi, Fatemeh] James J Peters VA Med Ctr, Med Epigenet, Bronx, NY 10468 USA. [Rosoklija, Gorazd; Dwork, Andrew J.] Macedonian Acad Sci & Arts, Skopje, Macedonia. [Rosoklija, Gorazd; Stankov, Aleksandar] Sch Med, Skopje, Macedonia. [Trencevsja-Ivanovska, Iskra] Psychiat Hosp Skopje, Skopje, Macedonia. RP Haghighi, F (reprint author), Icahn Sch Med Mt Sinai, Dept Neurosci, 1425 Madison Ave,Floor 10,Room 10-70D, New York, NY 10029 USA. EM fatemeh.haghighi@mssm.edu FU National Institute of Health (NIH) [R01MH094774]; NIDA T32 training grant in Drug Abuse Research from the NIH, USA; Brain and Behavior Research Foundation; NIH [R01 MH101454, R01 MH106056]; New York Stem Cell Foundation; Office of Research Infrastructure of the National Institutes of Health [S10OD018522] FX The Haghighi Laboratory is supported by the National Institute of Health (NIH) Grant R01MH094774. ZC is supported by a NIDA T32 training grant in Drug Abuse Research from the NIH, USA. Kristen J. Brennand is a New York Stem Cell Foundation-Robertson Investigator. The Brennand Laboratory is supported by the Brain and Behavior Research Foundation, NIH Grants R01 MH101454 and R01 MH106056, and the New York Stem Cell Foundation. Research reported in this paper was supported by the Office of Research Infrastructure of the National Institutes of Health under award number S10OD018522. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 78 TC 0 Z9 0 U1 13 U2 13 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-8935 J9 EPIGENET CHROMATIN JI Epigenetics Chromatin PD JAN 26 PY 2017 VL 10 AR 4 DI 10.1186/s13072-017-0111-y PG 11 WC Genetics & Heredity SC Genetics & Heredity GA EI7HV UT WOS:000392669300001 PM 28149327 ER PT J AU Okubo, M Gibo, K Hagiwara, Y Nakayama, Y Hasegawa, K AF Okubo, Masashi Gibo, Koichiro Hagiwara, Yusuke Nakayama, Yukiko Hasegawa, Kohei CA Japanese Emergency Med Network Inv TI The effectiveness of rapid sequence intubation (RSI) versus non-RSI in emergency department: an analysis of multicenter prospective observational study SO INTERNATIONAL JOURNAL OF EMERGENCY MEDICINE LA English DT Article DE Airway management; Intubation; Rapid sequence intubation; Intubation success; Complications of intubation; Resuscitation; Emergency department ID AIRWAY MANAGEMENT; ENDOTRACHEAL INTUBATION; TRACHEAL INTUBATION; ADVERSE EVENTS; SUCCESS RATE; ASSOCIATION; CARE AB Background: Although rapid sequence intubation (RSI) is the method of choice in emergency department (ED) airway management, data to support the use of RSI remain scarce. We sought to compare the effectiveness of airway management between RSI and non-RSI (intubation with sedative agents only or without medications) in the ED. Methods: Secondary analysis of the data from a multicenter prospective observational registry at 13 Japanese EDs. All non-cardiac-arrest patients who underwent intubation with RSI or non-RSI were included for the analysis. Outcomes of interest were the success rate of intubation and intubation-related complications. Results: Of 2365 eligible patients, 761 (32%) underwent intubations with RSI and 1,604 (68%) with non-RSI. Intubations with RSI had a higher success rate on the first attempt compared to those with non-RSI (73 vs. 63%; P < 0.0001). By contrast, the complication rates did not differ significantly between RSI and non-RSI groups (12 vs. 13%; P = 0.59). After adjusting for age, sex, estimated weight, principal indication, device, specialties and training level of the intubator, and clustering of patients within EDs, intubation with RSI was associated with a significantly higher success rate on the first attempt (OR, 2.3; 95% CI, 1.8-2.9; P < 0.0001) while that with RSI was not associated with the risk of complications (OR, 0.9; 95% CI, 0.6-1.2; P = 0.31). Conclusions: In this large multicenter study of ED airway management, we found that intubation with RSI was independently associated with a higher success rate on the first attempt but not with the risk of complications. C1 [Okubo, Masashi] Univ Pittsburgh, Dept Emergency Med, Iroquois Bldg Suite 400 A,3600 Forbes Ave, Pittsburgh, PA 15261 USA. [Gibo, Koichiro] Kurume Univ, Biostat Ctr, 67 Asahimachi, Kurume, Fukuoka 8300011, Japan. [Hagiwara, Yusuke] Tokyo Metropolitan Childrens Med Ctr, Dept Pediat Emergency & Crit Care Med, 2-8-29 Musashidai, Fuchu, Tokyo 1838561, Japan. [Nakayama, Yukiko] Okinawa Prefectural Chubu Hosp, Dept Emergency Med, 281 Miyazato, Okinawa 9042293, Japan. [Hasegawa, Kohei] Massachusetts Gen Hosp, Dept Emergency Med, 55 Fruit St, Boston, MA 02114 USA. RP Okubo, M (reprint author), Univ Pittsburgh, Dept Emergency Med, Iroquois Bldg Suite 400 A,3600 Forbes Ave, Pittsburgh, PA 15261 USA. EM masashiokubo914@gmail.com FU St. Luke's Life Science Institute; Harvard Affiliated Emergency Medicine Residency (PI, Hasegawa) FX This study was supported by a grant from St. Luke's Life Science Institute and a grant from Harvard Affiliated Emergency Medicine Residency (PI, Hasegawa). The sponsors of this study have no involvement in the study design, in the collection, analysis, and interpretation of data, in the writing of the manuscript, and in the decision to submit the manuscript for publication. NR 25 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 1865-1372 EI 1865-1380 J9 INT J EMERG MED JI Int. J. Emergency Medicine PD JAN 25 PY 2017 VL 10 IS 1 AR 1 DI 10.1186/s12245-017-0129-8 PG 9 WC Emergency Medicine SC Emergency Medicine GA EO3XX UT WOS:000396629300001 PM 28124199 ER PT J AU Hulten, EA Bittencourt, MS Preston, R Singh, A Romagnolli, C Ghoshhajra, B Shah, R Abbasi, S Abbara, S Nasir, K Blaha, M Hoffmann, U Di Carli, MF Blankstein, R AF Hulten, Edward A. Bittencourt, Marcio Sommer Preston, Ryan Singh, Avinainder Romagnolli, Carla Ghoshhajra, Brian Shah, Ravi Abbasi, Siddique Abbara, Suhny Nasir, Khurram Blaha, Michael Hoffmann, Udo Di Carli, Marcelo F. Blankstein, Ron TI Obesity, metabolic syndrome and cardiovascular prognosis: from the Partners coronary computed tomography angiography registry SO CARDIOVASCULAR DIABETOLOGY LA English DT Article DE Obesity; Metabolic syndrome; Coronary computed tomography angiography; Coronary artery disease; Prognosis; Cohort ID BODY-MASS INDEX; ALL-CAUSE MORTALITY; ARTERY-DISEASE; CT ANGIOGRAPHY; CARDIOMETABOLIC RISK; WAIST CIRCUMFERENCE; SUBCLINICAL ATHEROSCLEROSIS; INTERNATIONAL MULTICENTER; ABDOMINAL OBESITY; AMERICAN-COLLEGE AB Objective: To investigate the relationship among body mass index (BMI), cardiometabolic risk and coronary artery disease (CAD) among patients undergoing coronary computed tomography angiography (CTA). Methods: Retrospective cohort study of 1118 patients, who underwent coronary CTA at two centers from September 2004 to October 2011. Coronary CTA were categorized as normal, nonobstructive CAD (< 50%), or obstructive CAD (>= 50%) in addition to segment involvement (SIS) and stenosis scores. Extensive CAD was defined as SIS > 4. Association of BMI with cardiovascular prognosis was evaluated using multivariable fractional polynomial models. Results: Mean age of the cohort was 57 +/- 13 years with median follow-up of 3.2 years. Increasing BMI was associated with MetS (OR 1.28 per 1 kg/m(2), p < 0.001) and burden of CAD on a univariable basis, but not after multivariable adjustment. Prognosis demonstrated a J-shaped relationship with BMI. For BMI from 20-39.9 kg/m(2), after adjustment for age, gender, and smoking, MetS (HR 2.23, p = 0.009) was more strongly associated with adverse events. Conclusions: Compared to normal BMI, there was an increased burden of CAD for BMI > 25 kg/m(2). Within each BMI category, metabolically unhealthy patients had greater extent of CAD, as measured by CCTA, compared to metabolically healthy patients. C1 [Hulten, Edward A.; Bittencourt, Marcio Sommer; Singh, Avinainder; Abbasi, Siddique; Di Carli, Marcelo F.; Blankstein, Ron] Harvard Med Sch, Brigham & Womens Hosp, Dept Med & Radiol, Non Invas Cardiovasc Imaging Program, Boston, MA USA. [Hulten, Edward A.] Walter Reed Natl Mil Med Ctr & Uniformed Serv Uni, Div Med, Serv Cardiol, Bethesda, MD USA. [Romagnolli, Carla] Univ Sao Paulo, Univ Hosp, Ctr Clin & Epidemiol Res, Sao Paulo, Brazil. [Preston, Ryan] Walter Reed Natl Mil Med Ctr, Div Med, Bethesda, MD USA. [Ghoshhajra, Brian] Uniformed Serv Univ Hlth Sci, Bethesda, MD USA. [Shah, Ravi] Harvard Med Sch, Massachusetts Gen Hosp, Div Cardiac Imaging, Dept Radiol, Boston, MA USA. [Abbara, Suhny] Beth Israel Deaconess Med Ctr, Div Cardiol, Dept Med, Boston, MA USA. [Nasir, Khurram] Harvard Med Sch, Boston, MA USA. [Blaha, Michael] UT S western Med Ctr, Cardiothorac Imaging Div, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. [Singh, Avinainder; Abbasi, Siddique] Ctr Wellness & Prevent Res, Baptist Hlth S Florida, Miami, FL USA. [Blankstein, Ron] Johns Hopkins Ciccarone Ctr Prevent Heart Dis, Baltimore, MD USA. [Blankstein, Ron] Brigham & Womens Hosp, Cardiovasc Div, 75 Francis St, Boston, MA 02115 USA. RP Blankstein, R (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Dept Med & Radiol, Non Invas Cardiovasc Imaging Program, Boston, MA USA.; Blankstein, R (reprint author), Johns Hopkins Ciccarone Ctr Prevent Heart Dis, Baltimore, MD USA.; Blankstein, R (reprint author), Brigham & Womens Hosp, Cardiovasc Div, 75 Francis St, Boston, MA 02115 USA. EM rblankstein@partners.org NR 50 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2840 J9 CARDIOVASC DIABETOL JI Cardiovasc. Diabetol. PD JAN 25 PY 2017 VL 16 AR 14 DI 10.1186/s12933-017-0496-8 PG 11 WC Cardiac & Cardiovascular Systems; Endocrinology & Metabolism SC Cardiovascular System & Cardiology; Endocrinology & Metabolism GA EL7UH UT WOS:000394825600001 PM 28122619 ER PT J AU Zheng, XQ Zhang, NQ Wu, HJ Wu, H AF Zheng, Xiaoqi Zhang, Naiqian Wu, Hua-Jun Wu, Hao TI Estimating and accounting for tumor purity in the analysis of DNA methylation data from cancer studies SO GENOME BIOLOGY LA English DT Article DE DNA methylation; Tumor purity; Differential methylation; Cancer epigenomics ID SURROGATE VARIABLE ANALYSIS; EPIGENOME-WIDE ASSOCIATION; DIFFERENTIAL METHYLATION; GENE-EXPRESSION; ARRAY DATA; BIOMARKERS; DECONVOLUTION; HETEROGENEITY; MICROARRAY; SEPARATION AB We present a set of statistical methods for the analysis of DNA methylation microarray data, which account for tumor purity. These methods are an extension of our previously developed method for purity estimation; our updated method is flexible, efficient, and does not require data from reference samples or matched normal controls. We also present a method for incorporating purity information for differential methylation analysis. In addition, we propose a control-free differential methylation calling method when normal controls are not available. Extensive analyses of TCGA data demonstrate that our methods provide accurate results. All methods are implemented in InfiniumPurify. C1 [Zheng, Xiaoqi] Shanghai Normal Univ, Dept Math, Shanghai 200234, Peoples R China. [Zhang, Naiqian] Weifang Univ, Dept Math, Weifang 261061, Shandong, Peoples R China. [Wu, Hua-Jun] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Wu, Hua-Jun] Harvard Sch Publ Hlth, Boston, MA 02215 USA. [Wu, Hao] Emory Univ, Rollins Sch Publ Hlth, Dept Biostat & Bioinformat, 1518 Clifton Rd, Atlanta, GA 30322 USA. RP Zheng, XQ (reprint author), Shanghai Normal Univ, Dept Math, Shanghai 200234, Peoples R China.; Wu, H (reprint author), Emory Univ, Rollins Sch Publ Hlth, Dept Biostat & Bioinformat, 1518 Clifton Rd, Atlanta, GA 30322 USA. EM xqzheng@shnu.edu.cn; hao.wu@emory.edu FU National Natural Science Foundation of China [61572327, 31601079]; National Institute of General Medical Sciences [R01GM122083] FX This project was supported by the National Natural Science Foundation of China (61572327 to XZ, 31601079 to NZ) and National Institute of General Medical Sciences (R01GM122083 to HW). NR 60 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1474-760X J9 GENOME BIOL JI Genome Biol. PD JAN 25 PY 2017 VL 18 AR 17 DI 10.1186/s13059-016-1143-5 PG 14 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA EL7UT UT WOS:000394827000002 PM 28122605 ER PT J AU Hainsworth, AH Allan, SM Boltze, J Cunningham, C Farris, C Head, E Ihara, M Isaacs, JD Kalaria, RN Oberstein, SAMJL Moss, MB Nitzsche, B Rosenberg, GA Rutten, JW Salkovic-Petrisic, M Troen, AM AF Hainsworth, Atticus H. Allan, Stuart M. Boltze, Johannes Cunningham, Catriona Farris, Chad Head, Elizabeth Ihara, Masafumi Isaacs, Jeremy D. Kalaria, Raj N. Oberstein, Saskia A. M. J. Lesnik Moss, Mark B. Nitzsche, Bjoern Rosenberg, Gary A. Rutten, Julie W. Salkovic-Petrisic, Melita Troen, Aron M. TI Translational models for vascular cognitive impairment: a review including larger species SO BMC MEDICINE LA English DT Review DE Vascular dementia; Vascular cognitive impairment; VCID; Experimental models; In vivo models; Translational models ID CEREBRAL AMYLOID ANGIOPATHY; SMALL VESSEL DISEASE; AUTOSOMAL-DOMINANT ARTERIOPATHY; NEAR-INFRARED SPECTROSCOPY; MONKEYS MACACA-MULATTA; CANINE SENILE PLAQUES; LARGE ANIMAL-MODEL; STROKE-PRONE RATS; WHITE-MATTER; MOUSE MODEL AB Background: Disease models are useful for prospective studies of pathology, identification of molecular and cellular mechanisms, pre-clinical testing of interventions, and validation of clinical biomarkers. Here, we review animal models relevant to vascular cognitive impairment (VCI). A synopsis of each model was initially presented by expert practitioners. Synopses were refined by the authors, and subsequently by the scientific committee of a recent conference (International Conference on Vascular Dementia 2015). Only peer-reviewed sources were cited. Methods: We included models that mimic VCI-related brain lesions (white matter hypoperfusion injury, focal ischaemia, cerebral amyloid angiopathy) or reproduce VCI risk factors (old age, hypertension, hyperhomocysteinemia, high-salt/high-fat diet) or reproduce genetic causes of VCI (CADASIL-causing Notch3 mutations). Conclusions: We concluded that (1) translational models may reflect a VCI-relevant pathological process, while not fully replicating a human disease spectrum; (2) rodent models of VCI are limited by paucity of white matter; and (3) further translational models, and improved cognitive testing instruments, are required. C1 [Hainsworth, Atticus H.; Isaacs, Jeremy D.] St Georges Univ, Clin Neurosci J OB Mol & Clin Sci Res Inst, Cranmer Terrace, London SW17 0RE, England. [Hainsworth, Atticus H.; Isaacs, Jeremy D.] St Georges Univ Hosp NHS Fdn Trust, Dept Neurol, London, England. [Allan, Stuart M.; Cunningham, Catriona] Univ Manchester, Fac Biol Med & Hlth, Manchester M13 9PT, Lancs, England. [Boltze, Johannes] Univ Lubeck, Dept Translat Med & Cell Technol, Lubeck, Germany. [Boltze, Johannes] Massachusetts Gen Hosp, Neurovasc Res Lab, Charlestown, MA USA. [Boltze, Johannes] Harvard Med Sch, Charlestown, MA USA. [Farris, Chad; Moss, Mark B.] Boston Univ, Sch Med, Dept Anat & Neurobiol, Boston, MA 02215 USA. [Farris, Chad; Moss, Mark B.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Head, Elizabeth] Univ Kentucky, Sanders Brown Ctr Aging, Dept Pharmacol & Nutr Sci, Lexington, KY 40536 USA. [Ihara, Masafumi] Natl Cerebral & Cardiovasc Ctr, Dept Stroke & Cerebrovasc Dis, Osaka, Japan. [Kalaria, Raj N.] Newcastle Univ, Inst Neurosci, Newcastle Upon Tyne, Tyne & Wear, England. [Oberstein, Saskia A. M. J. Lesnik; Rutten, Julie W.] Leiden Univ, Med Ctr, Dept Clin Genet, Leiden, Netherlands. [Nitzsche, Bjoern] Fraunhofer Inst Cell Therapy & Immunol, Leipzig, Germany. [Nitzsche, Bjoern] Univ Leipzig, Clin Nucl Med, Leipzig, Germany. [Nitzsche, Bjoern] Univ Leipzig, Fac Vet Med, Inst Anat, Leipzig, Germany. [Rosenberg, Gary A.] Univ New Mexico, Hlth Sci Ctr, Dept Neurol, Albuquerque, NM 87131 USA. [Salkovic-Petrisic, Melita] Univ Zagreb, Sch Med, Croatian Inst Brain Res, Dept Pharmacol, Zagreb, Croatia. [Troen, Aron M.] Hebrew Univ Jerusalem, Inst Biochem Food & Nutr Sci, Rehovot, Israel. [Rutten, Julie W.] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. RP Hainsworth, AH (reprint author), St Georges Univ, Clin Neurosci J OB Mol & Clin Sci Res Inst, Cranmer Terrace, London SW17 0RE, England.; Hainsworth, AH (reprint author), St Georges Univ Hosp NHS Fdn Trust, Dept Neurol, London, England. EM ahainsworth@sgul.ac.uk FU Alzheimer's Drug Discovery Foundation (ADDF) [20140901]; Alzheimer's Society UK [PG146/151]; Alzheimer's Research UK [PPG2014A-8]; British Heart Foundation (UK); EPSRC (UK); MRC (UK) Centre for Doctoral Training in Regenerative Medicine [EP/L014904/1]; Israel Science Foundation (ISF) [1353/11] FX AHH gratefully acknowledges funding from Alzheimer's Drug Discovery Foundation (ADDF grant no. 20140901), Alzheimer's Society UK (PG146/151) and Alzheimer's Research UK (PPG2014A-8). SMA received research funding from the British Heart Foundation and EPSRC (UK). CC is funded by the MRC (UK) Centre for Doctoral Training in Regenerative Medicine (grant no. EP/L014904/1). AMT was supported in this work by Israel Science Foundation (ISF) Grant 1353/11. NR 140 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7015 J9 BMC MED JI BMC Med. PD JAN 25 PY 2017 VL 15 AR 16 DI 10.1186/s12916-017-0793-9 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA EN3RQ UT WOS:000395926000001 PM 28118831 ER PT J AU Triplette, M Attia, EF Akgun, KM Hoo, GWS Freiberg, MS Butt, AA Wongtrakool, C Goetz, MB Brown, ST Graber, CJ Huang, L Crothers, K AF Triplette, Matthew Attia, Engi F. Akgun, Kathleen M. Hoo, Guy W. Soo Freiberg, Matthew S. Butt, Adeel A. Wongtrakool, Cherry Goetz, Matthew Bidwell Brown, Sheldon T. Graber, Christopher J. Huang, Laurence Crothers, Kristina TI A Low Peripheral Blood CD4/CD8 Ratio Is Associated with Pulmonary Emphysema in HIV SO PLOS ONE LA English DT Article ID SPIROMETRY REFERENCE VALUES; OBSTRUCTIVE LUNG-DISEASES; T-CELL-ACTIVATION; ANTIRETROVIRAL THERAPY; DIFFUSING-CAPACITY; IMMUNOLOGICAL RECOVERY; LYMPHOCYTE SUBSETS; INFECTED PATIENTS; CD4CD8 RATIO; ADULTS AB Objectives The prevalence of emphysema is higher among HIV-infected (HIV+) individuals compared to HIV-uninfected persons. While greater tobacco use contributes, HIV-related effects on immunity likely confer additional risk. Low peripheral blood CD4+ to CD8+ T-lymphocyte (CD4/CD8) ratio may reflect chronic inflammation in HIV and may be a marker of chronic lung disease in this population. Therefore, we sought to determine whether the CD4/CD8 ratio was associated with chronic obstructive pulmonary disease (COPD), particularly the emphysema subtype, in a cohort of HIV+ subjects. Methods We performed a cross-sectional analysis of 190 HIV+ subjects enrolled in the Examinations of HIV Associated Lung Emphysema (EXHALE) study. Subjects underwent baseline laboratory assessments, pulmonary function testing and chest computed tomography (CT) analyzed for emphysema severity and distribution. We determined the association between CD4/CD8 ratio and emphysema, and the association between CD4/CD8 ratio and pulmonary function markers of COPD. Results Mild or greater emphysema (> 10% lung involvement) was present in 31% of subjects. Low CD4/CD8 ratio was associated with > 10% emphysema in multivariable models, adjusting for risk factors including smoking, current and nadir CD4 count and HIV RNA level. Those with CD4/CD8 ratio < 0.4 had 6.3 (1.1-39) times the odds of > 10% emphysema compared to those with a ratio > 1.0 in fully adjusted models. A low CD4/CD8 ratio was also associated with reduced diffusion capacity (DLCO). Conclusions A low CD4/CD8 ratio was associated with emphysema and low DLCO in HIV+ subjects, independent of other risk factors and clinical markers of HIV. The CD4/CD8 ratio may be a useful, clinically available, marker for risk of emphysema in HIV+ subjects in the antiretroviral therapy (ART) era. C1 [Triplette, Matthew; Attia, Engi F.; Crothers, Kristina] Univ Washington, Dept Med, Seattle, WA 98105 USA. [Akgun, Kathleen M.] Vet Affairs Connecticut Healthcare Syst, Dept Med, New Haven, CT USA. [Akgun, Kathleen M.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. [Hoo, Guy W. Soo; Goetz, Matthew Bidwell; Graber, Christopher J.] Vet Affairs Greater Los Angeles Healthcare Syst, Dept Med, Los Angeles, CA USA. [Hoo, Guy W. Soo; Goetz, Matthew Bidwell; Graber, Christopher J.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Freiberg, Matthew S.] Vanderbilt Univ, Dept Med, Nashville, TN USA. [Butt, Adeel A.] Weill Cornell Med Coll, Dept Med, New York, NY USA. [Butt, Adeel A.] Hamad Healthcare Qual Inst & Med Corp, Doha, Qatar. [Wongtrakool, Cherry] Atlanta Vet Affairs Med Ctr, Dept Med, Atlanta, GA USA. [Wongtrakool, Cherry] Emory Univ, Sch Med, Dept Med, Atlanta, GA USA. [Brown, Sheldon T.] James J Peters Vet Affairs Med Ctr, Dept Med, New York, NY USA. [Brown, Sheldon T.] Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA. [Huang, Laurence] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. RP Triplette, M (reprint author), Univ Washington, Dept Med, Seattle, WA 98105 USA. EM mtrip@uw.edu FU National Heart, Lung, and Blood Institute (NHLBI) at the National Institutes of Health (NIH) [R01 HL090342, 5R01HL126536, T32 HL007287-37, K24 HL087713]; National Institute on Alcohol Abuse and Alcoholism at NIH [U01 AA013566] FX This work was supported by the National Heart, Lung, and Blood Institute (NHLBI) at the National Institutes of Health (NIH) [R01 HL090342 and 5R01HL126536 to Dr. Crothers, T32 HL007287-37 supporting Dr. Triplette under Drs. Robb Glenny and J. Randall Curtis, K24 HL087713 to Dr. Huang] and the National Institute on Alcohol Abuse and Alcoholism at NIH [U01 AA013566]. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 0 Z9 0 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 25 PY 2017 VL 12 IS 1 AR e0170857 DI 10.1371/journal.pone.0170857 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN7FK UT WOS:000396167300008 PM 28122034 ER PT J AU Vijayan, S Lepage, KQ Kopell, NJ Cash, SS AF Vijayan, Sujith Lepage, Kyle Q. Kopell, Nancy J. Cash, Sydney S. TI Frontal beta-theta network during REM sleep SO ELIFE LA English DT Article ID EYE-MOVEMENT SLEEP; SLOW-WAVE SLEEP; ANTERIOR CINGULATE CORTEX; SURFACE-BASED ANALYSIS; CEREBRAL-BLOOD-FLOW; MOTOR AREAS; EMOTIONAL MEMORY; RHESUS-MONKEY; PREFRONTAL CORTEX; HUMAN HIPPOCAMPUS AB We lack detailed knowledge about the spatio-temporal physiological signatures of REM sleep, especially in humans. By analyzing intracranial electrode data from humans, we demonstrate for the first time that there are prominent beta (15-35 Hz) and theta (4-8 Hz) oscillations in both the anterior cingulate cortex (ACC) and the DLPFC during REM sleep. We further show that these theta and beta activities in the ACC and the DLPFC, two relatively distant but reciprocally connected regions, are coherent. These findings suggest that, counter to current prevailing thought, the DLPFC is active during REM sleep and likely interacting with other areas. Since the DLPFC and the ACC are implicated in memory and emotional regulation, and the ACC has motor areas and is thought to be important for error detection, the dialogue between these two areas could play a role in the regulation of emotions and in procedural motor and emotional memory consolidation. C1 [Vijayan, Sujith; Lepage, Kyle Q.; Kopell, Nancy J.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Vijayan, Sujith; Cash, Sydney S.] Harvard Med Sch, Dept Neurol, Boston, MA 02115 USA. [Vijayan, Sujith; Cash, Sydney S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Vijayan, S (reprint author), Boston Univ, Dept Math & Stat, Boston, MA 02215 USA.; Vijayan, S (reprint author), Harvard Med Sch, Dept Neurol, Boston, MA 02115 USA.; Vijayan, S (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM svijayan9@gmail.com FU National Science Foundation [DMS-1042134]; Office of Naval Research [N00014-13-1-0672] FX National Science Foundation DMS-1042134 Sujith Vijayan Kyle Q Lepage Nancy J Kopell; Office of Naval Research N00014-13-1-0672 Sydney S Cash NR 79 TC 0 Z9 0 U1 4 U2 4 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD JAN 25 PY 2017 VL 6 AR e18894 DI 10.7554/eLife.18894 PG 19 WC Biology SC Life Sciences & Biomedicine - Other Topics GA EJ7OZ UT WOS:000393413300001 ER PT J AU Jacobsen, JC Erdin, S Chiang, C Hanscom, C Handley, RR Barker, DD Stortchevoi, A Blumenthal, I Reid, SJ Snell, RG MacDonald, ME Morton, AJ Ernst, C Gusella, JF Talkowski, ME AF Jacobsen, Jessie C. Erdin, Serkan Chiang, Colby Hanscom, Carrie Handley, Renee R. Barker, Douglas D. Stortchevoi, Alex Blumenthal, Ian Reid, Suzanne J. Snell, Russell G. MacDonald, Marcy E. Morton, A. Jennifer Ernst, Carl Gusella, James F. Talkowski, Michael E. TI Potential molecular consequences of transgene integration: The R6/2 mouse example SO SCIENTIFIC REPORTS LA English DT Article ID KNOCK-IN MOUSE; HUNTINGTONS-DISEASE; CAG REPEAT; LONGITUDINAL ANALYSIS; BEHAVIORAL-PHENOTYPE; QUALITY-CONTROL; MICE; GENE; OPTIMIZATION; GENOMICS AB Integration of exogenous DNA into a host genome represents an important route to generate animal and cellular models for exploration into human disease and therapeutic development. In most models, little is known concerning structural integrity of the transgene, precise site of integration, or its impact on the host genome. We previously used whole-genome and targeted sequencing approaches to reconstruct transgene structure and integration sites in models of Huntington's disease, revealing complex structural rearrangements that can result from transgenesis. Here, we demonstrate in the R6/2 mouse, a widely used Huntington's disease model, that integration of a rearranged transgene with coincident deletion of 5,444 bp of host genome within the gene Gm12695 has striking molecular consequences. Gm12695, the function of which is unknown, is normally expressed at negligible levels in mouse brain, but transgene integration has resulted in cortical expression of a partial fragment (exons 8-11) 3' to the transgene integration site in R6/2. This transcript shows significant expression among the extensive network of differentially expressed genes associated with this model, including synaptic transmission, cell signalling and transcription. These data illustrate the value of sequence-level resolution of transgene insertions and transcription analysis to inform phenotypic characterization of transgenic models utilized in therapeutic research. C1 [Jacobsen, Jessie C.; Handley, Renee R.; Reid, Suzanne J.; Snell, Russell G.] Univ Auckland, Sch Biol Sci, Ctr Brain Res, Auckland 1010, New Zealand. [Erdin, Serkan; Chiang, Colby; Hanscom, Carrie; Barker, Douglas D.; Stortchevoi, Alex; Blumenthal, Ian; MacDonald, Marcy E.; Gusella, James F.; Talkowski, Michael E.] Massachusetts Gen Hosp, Mol Neurogenet Unit, Ctr Human Genet Res, Boston, MA 02114 USA. [Erdin, Serkan; MacDonald, Marcy E.; Gusella, James F.; Talkowski, Michael E.] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02143 USA. [Chiang, Colby] Washington Univ, McDonnell Genome Inst, Sch Med, St Louis, MO 63108 USA. [MacDonald, Marcy E.; Talkowski, Michael E.] Harvard Med Sch, Dept Neurol, Boston, MA 02115 USA. [Morton, A. Jennifer] Univ Cambridge, Dept Physiol Dev & Neurosci, Downing St, Cambridge CB2 3DY, England. [Ernst, Carl] McGill Univ, Dept Psychiat, Quebec City, ON H4H 1R3, Canada. [Gusella, James F.] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Talkowski, Michael E.] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Ctr Human Genet Res, Boston, MA 02114 USA. RP Jacobsen, JC (reprint author), Univ Auckland, Sch Biol Sci, Ctr Brain Res, Auckland 1010, New Zealand.; Talkowski, ME (reprint author), Massachusetts Gen Hosp, Mol Neurogenet Unit, Ctr Human Genet Res, Boston, MA 02114 USA.; Talkowski, ME (reprint author), Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02143 USA.; Talkowski, ME (reprint author), Harvard Med Sch, Dept Neurol, Boston, MA 02115 USA.; Talkowski, ME (reprint author), Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Ctr Human Genet Res, Boston, MA 02114 USA. EM j.jacobsen@auckland.ac.nz; talkowski@chgr.mgh.harvard.edu RI Erdin, Serkan/B-4988-2008 OI Erdin, Serkan/0000-0001-6587-2625 FU National Institutes of Health [HD065286, MH095867, GM061354]; CHDI Inc.; NARSAD; Natural Science and Engineering Research Council of Canada; Neurological Foundation of New Zealand; Canada Research Chairs program FX The authors wish to thank Kristine Boxen of the Genomics Centre, Auckland Science Analytical Services, The University of Auckland, Auckland, New Zealand for assistance with Sanger sequencing services. This work was supported by the National Institutes of Health HD065286 (JFG), MH095867 (MET), GM061354 (MET, JFG), CHDI Inc. (JFG, AJM), NARSAD (MET), the Canada Research Chairs program and a grant from the Natural Science and Engineering Research Council of Canada (CE), and the Neurological Foundation of New Zealand (JJ). NR 37 TC 0 Z9 0 U1 5 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JAN 25 PY 2017 VL 7 AR 41120 DI 10.1038/srep41120 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI7GI UT WOS:000392665400001 PM 28120936 ER PT J AU Cosgrove, D Harold, D Mothersill, O Anney, R Hill, MJ Bray, NJ Blokland, G Petryshen, T Richards, A Mantripragada, K Owen, M O'Donovan, MC Gill, M Corvin, A Morris, DW Donohoe, G AF Cosgrove, D. Harold, D. Mothersill, O. Anney, R. Hill, M. J. Bray, N. J. Blokland, G. Petryshen, T. Richards, A. Mantripragada, K. Owen, M. O'Donovan, M. C. Gill, M. Corvin, A. Morris, D. W. Donohoe, G. CA Wellcome Trust Case Control TI MiR-137-derived polygenic risk: effects on cognitive performance in patients with schizophrenia and controls SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID CYTOARCHITECTONIC MAPS; HEALTHY-INDIVIDUALS; BIPOLAR DISORDER; BRAIN STRUCTURE; WORKING-MEMORY; GENE ZNF804A; VARIANT; MIR137; MIR-137; SUSCEPTIBILITY AB Variants at microRNA-137 (MIR137), one of the most strongly associated schizophrenia risk loci identified to date, have been associated with poorer cognitive performance. As microRNA-137 is known to regulate the expression of similar to 1900 other genes, including several that are independently associated with schizophrenia, we tested whether this gene set was also associated with variation in cognitive performance. Our analysis was based on an empirically derived list of genes whose expression was altered by manipulation of MIR137 expression. This list was cross-referenced with genome-wide schizophrenia association data to construct individual polygenic scores. We then tested, in a sample of 808 patients and 192 controls, whether these risk scores were associated with altered performance on cognitive functions known to be affected in schizophrenia. A subgroup of healthy participants also underwent functional imaging during memory (n = 108) and face processing tasks (n = 83). Increased polygenic risk within the empirically derived miR-137 regulated gene score was associated with significantly lower performance on intelligence quotient, working memory and episodic memory. These effects were observed most clearly at a polygenic threshold of P = 0.05, although significant results were observed at all three thresholds analyzed. This association was found independently for the gene set as a whole, excluding the schizophrenia-associated MIR137 SNP itself. Analysis of the spatial working memory fMRI task further suggested that increased risk score (thresholded at P= 10(-5)) was significantly associated with increased activation of the right inferior occipital gyrus. In conclusion, these data are consistent with emerging evidence that MIR137 associated risk for schizophrenia may relate to its broader downstream genetic effects. C1 [Cosgrove, D.; Mothersill, O.; Morris, D. W.; Donohoe, G.] Natl Univ Ireland, Cognit Genet & Cognit Therapy Grp, Sch Psychol, Galway H91 EV56, Ireland. [Cosgrove, D.; Mothersill, O.; Morris, D. W.; Donohoe, G.] Natl Univ Ireland, Discipline Biochem, Ctr Neuroimaging & Cognit Genom, Galway, Ireland. [Harold, D.; Anney, R.; Gill, M.; Corvin, A.] Trinity Coll Dublin, Inst Mol Med, Dept Psychiat, Neuropsychiat Genet Res Grp, Dublin, Ireland. [Anney, R.; Hill, M. J.; Bray, N. J.] Cardiff Univ, Inst Psychol Med & Clin Neurosci, Cardiff, S Glam, Wales. [Blokland, G.; Petryshen, T.] Massachusetts Gen Hosp, Dept Psychiat, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Blokland, G.; Petryshen, T.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Blokland, G.; Petryshen, T.] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Blokland, G.; Petryshen, T.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Richards, A.; Mantripragada, K.; Owen, M.; O'Donovan, M. C.] Cardiff Univ, MRC, Ctr Neuropsychiat Genet & Genom, Cardiff, S Glam, Wales. RP Donohoe, G (reprint author), Natl Univ Ireland, Cognit Genet & Cognit Therapy Grp, Sch Psychol, Galway H91 EV56, Ireland. EM gary.donohoe@nuigalway.ie FU Science Foundation Ireland (SFI) [12.IP.1359, 08/IN.1/B1916]; Wellcome Trust Case Control Consortium [085475/B/08/Z, 085475/Z/08/Z]; Wellcome Trust [072894/Z/03/Z, 090532/Z/09/Z, 075491/Z/04/B] FX We thank all patients and their support staff, and all healthy volunteers for participating in the data collection on which this manuscript is based. Recruitment and genotyping was supported by Science Foundation Ireland (SFI) (grants 12.IP.1359 and 08/IN.1/B1916) and the Wellcome Trust Case Control Consortium 2 project (grants 085475/B/08/Z and 085475/Z/08/Z) and the Wellcome Trust ( grants 072894/Z/03/Z, 090532/Z/09/Z, and 075491/Z/04/B). NR 53 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD JAN 24 PY 2017 VL 7 AR e1012 DI 10.1038/tp.2016.286 PG 9 WC Psychiatry SC Psychiatry GA EO1IV UT WOS:000396452900006 PM 28117840 ER PT J AU Beck, RW Riddlesworth, T Ruedy, K Ahmann, A Bergenstal, R Haller, S Kollman, C Kruger, D McGill, JB Polonsky, W Toschi, E Wolpert, H Price, D AF Beck, Roy W. Riddlesworth, Tonya Ruedy, Katrina Ahmann, Andrew Bergenstal, Richard Haller, Stacie Kollman, Craig Kruger, Davida McGill, Janet B. Polonsky, William Toschi, Elena Wolpert, Howard Price, David CA DIAMOND Study Grp TI Effect of Continuous Glucose Monitoring on Glycemic Control in Adults With Type 1 Diabetes Using Insulin Injections The DIAMOND Randomized Clinical Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID HYPOGLYCEMIC EVENTS; PUMP THERAPY; MANAGEMENT; IMPACT AB IMPORTANCE Previous clinical trials showing the benefit of continuous glucose monitoring (CGM) in the management of type 1 diabetes predominantly have included adults using insulin pumps, even though the majority of adults with type 1 diabetes administer insulin by injection. OBJECTIVE To determine the effectiveness of CGM in adults with type 1 diabetes treated with insulin injections. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial conducted between October 2014 and May 2016 at 24 endocrinology practices in the United States that included 158 adults with type 1 diabetes who were using multiple daily insulin injections and had hemoglobin A(1c) (HbA(1c)) levels of 7.5% to 9.9%. INTERVENTIONS Random assignment 2: 1 to CGM (n = 105) or usual care (control group; n = 53). MAIN OUTCOMES AND MEASURES Primary outcome measure was the difference in change in central-laboratory-measured HbA(1c) level from baseline to 24 weeks. There were 18 secondary or exploratory end points, of which 15 are reported in this article, including duration of hypoglycemia at less than 70 mg/dL, measured with CGM for 7 days at 12 and 24 weeks. RESULTS Among the 158 randomized participants (mean age, 48 years [SD, 13]; 44% women; mean baseline HbA1c level, 8.6% [SD, 0.6%]; and median diabetes duration, 19 years [interquartile range, 10-31 years]), 155 (98%) completed the study. In the CGM group, 93% used CGM 6 d/wk or more in month 6. Mean HbA(1c) reduction from baseline was 1.1% at 12 weeks and 1.0% at 24 weeks in the CGM group and 0.5% and 0.4%, respectively, in the control group (repeated-measures model P < .001). At 24 weeks, the adjusted treatment-group difference in mean change in HbA1c level from baseline was -0.6% (95% CI, -0.8% to -0.3%; P < .001). Median duration of hypoglycemia at less than <70 mg/dL was 43 min/d (IQR, 27-69) in the CGM group vs 80 min/d (IQR, 36-111) in the control group (P = .002). Severe hypoglycemia events occurred in 2 participants in each group. CONCLUSIONS AND RELEVANCE Among adults with type 1 diabetes who used multiple daily insulin injections, the use of CGM compared with usual care resulted in a greater decrease in HbA(1c) level during 24 weeks. Further research is needed to assess longer-term effectiveness, as well as clinical outcomes and adverse effects. C1 [Beck, Roy W.; Riddlesworth, Tonya; Ruedy, Katrina; Kollman, Craig] Jaeb Ctr Hlth Res, 15310 Amberly Dr,Ste 350, Tampa, FL 33647 USA. [Ahmann, Andrew] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Bergenstal, Richard] Int Diabet Ctr, Pk Nicollet Inst, St Louis Pk, MN USA. [Haller, Stacie] Diabet & Glandular Dis Clin, San Antonio, TX USA. [Kruger, Davida] Henry Ford Med Ctr, Div Endocrinol, Detroit, MI USA. [McGill, Janet B.] Washington Univ, St Louis, MO USA. [Polonsky, William] Behav Diabet Inst, San Diego, CA USA. [Toschi, Elena; Wolpert, Howard] Joslin Diabet Ctr, Boston, MA 02215 USA. [Price, David] Dexcom Inc, San Diego, CA USA. RP Beck, RW (reprint author), Jaeb Ctr Hlth Res, 15310 Amberly Dr,Ste 350, Tampa, FL 33647 USA. EM rbeck@jaeb.org FU Dexcom Inc FX Dexcom Inc provided funding for the trial to each investigator's institution. NR 22 TC 5 Z9 5 U1 7 U2 7 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 JAN 24 PY 2017 VL 317 IS 4 BP 371 EP 378 DI 10.1001/jama.2016.19975 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA EI5BW UT WOS:000392509600019 PM 28118453 ER PT J AU Silverman, MG Im, K Sabatine, MS AF Silverman, Michael G. Im, Kyungah Sabatine, Marc S. TI Interventions to Lower Low-Density Lipoprotein Cholesterol and Cardiovascular Risk Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Silverman, Michael G.; Im, Kyungah; Sabatine, Marc S.] Brigham & Womens Hosp, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. RP Sabatine, MS (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Div Cardiovasc Med, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. EM msabatine@partners.org FU Abbott Laboratories; Amgen; AstraZeneca; Critical Diagnostics; Daiichi-Sankyo; Eisai; GlaxoSmithKline; Intarcia; Janssen Research Development; Merck; Pfizer; Roche Diagnostics; Sanofi-Aventis; Takeda; Gilead; Poxel; Novartis; Medimmune; CVS Caremark; Alnylam; Ionis FX The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Sabatine reported receiving grants through his institution from Abbott Laboratories, Amgen, AstraZeneca, Critical Diagnostics, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen Research Development, Merck, Pfizer, Roche Diagnostics, Sanofi-Aventis, Takeda, Gilead, Poxel, Novartis, and Medimmune; and personal fees from Amgen, AstraZeneca, Intarcia, Merck, CVS Caremark, Alnylam, and Ionis. No other disclosures were reported. NR 5 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JAN 24 PY 2017 VL 317 IS 4 BP 440 EP 440 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA EI5BW UT WOS:000392509600028 PM 28118447 ER PT J AU Kelleher, RJ Shen, J AF Kelleher, Raymond J., III Shen, Jie TI Presenilin-1 mutations and Alzheimer's disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID GAMMA-SECRETASE ACTIVITY; AMYLOID HYPOTHESIS; IN-VIVO; ONSET; MICE; NEURODEGENERATION; MECHANISM; PLAQUES C1 [Kelleher, Raymond J., III] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Human Genet Res, Dept Neurol, Boston, MA 02114 USA. [Kelleher, Raymond J., III; Shen, Jie] Harvard Med Sch, Program Neurosci, Boston, MA 02115 USA. [Shen, Jie] Harvard Med Sch, Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. RP Shen, J (reprint author), Harvard Med Sch, Program Neurosci, Boston, MA 02115 USA.; Shen, J (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. EM jshen@rics.bwh.harvard.edu FU NIH [R01NS041783, R01NS042818, R01NS075346]; MetLife Foundation FX This work was supported by NIH Grants R01NS041783 and R01NS042818 (to J.S.) and R01NS075346 (to R.J.K.), and an award from the MetLife Foundation (to J.S.). NR 20 TC 0 Z9 0 U1 9 U2 9 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 JAN 24 PY 2017 VL 114 IS 4 BP 629 EP 631 DI 10.1073/pnas.1619574114 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI6HV UT WOS:000392597000030 PM 28082723 ER PT J AU Sanderson, NSR Zimmermann, M Eilinger, L Gubser, C Schaeren-Wiemers, N Lindberg, RLP Dougan, SK Ploegh, HL Kappos, L Derfuss, T AF Sanderson, Nicholas S. R. Zimmermann, Maria Eilinger, Luca Gubser, Celine Schaeren-Wiemers, Nicole Lindberg, Raija L. P. Dougan, Stephanie K. Ploegh, Hidde L. Kappos, Ludwig Derfuss, Tobias TI Cocapture of cognate and bystander antigens can activate autoreactive B cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE tolerance; autoantibodies; antigen capture; antigen presentation; influenza ID TRANSGENIC MICE; INFLUENZA-VIRUS; T-CELLS; RECEPTOR; DETERMINANT; FATE; HELP AB Autoantibodies against myelin oligodendrocyte glycoprotein (MOG) are associated with autoimmune central nervous system diseases like acute disseminated encephalomyelitis (ADEM). For ADEM, it is speculated that a preceding infection is the trigger of the autoimmune response, but the mechanism connecting the infection to the production of MOG antibodies remains a mystery. We reasoned that the ability of B cells to capture cognate antigen from cell membranes, along with small quantities of coexpressed "bystander" antigens, might enable B-cell escape from tolerance. We tested this hypothesis using influenza hemagglutinin as a model viral antigen and transgenic, MOG-specific B cells. Using flow cytometry and live and fixed cell microscopy, we show that MOG-specific B cells take up large amounts of MOG from cell membranes. Uptake of the antigen from the membrane leads to a strong activation of the capturing B cell. When influenza hemagglutinin is also present in the membrane of the target cell, it can be cocaptured with MOG by MOG-specific B cells via the B-cell receptor. Hemagglutinin and MOG are both presented to T cells, which in turn are activated and proliferate. As a consequence, MOG-specific B cells get help from hemagglutinin-specific T cells to produce anti-MOG antibodies. In vivo, the transfer of MOG-specific B cells into recipient mice after the cocapture of MOG and hemagglutinin leads to the production of class-switched anti-MOG antibodies, dependent on the presence of hemagglutinin-specific T cells. This mechanism offers a link between infection and autoimmunity. C1 [Sanderson, Nicholas S. R.; Zimmermann, Maria; Eilinger, Luca; Gubser, Celine; Schaeren-Wiemers, Nicole; Lindberg, Raija L. P.; Kappos, Ludwig; Derfuss, Tobias] Univ Basel, Univ Basel Hosp, Dept Biomed, CH-4031 Basel, Switzerland. [Dougan, Stephanie K.; Ploegh, Hidde L.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Kappos, Ludwig; Derfuss, Tobias] Univ Basel, Univ Basel Hosp, Dept Med, Clin Neurol, CH-4031 Basel, Switzerland. [Kappos, Ludwig] Univ Basel, Univ Basel Hosp, Dept Clin Res, CH-4031 Basel, Switzerland. [Kappos, Ludwig] Univ Basel, Univ Basel Hosp, Dept Biomed Engn, CH-4031 Basel, Switzerland. [Dougan, Stephanie K.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Ploegh, Hidde L.] Boston Childrens Hosp, 1 Blackfan Circle, Boston, MA 02115 USA. RP Sanderson, NSR; Derfuss, T (reprint author), Univ Basel, Univ Basel Hosp, Dept Biomed, CH-4031 Basel, Switzerland.; Derfuss, T (reprint author), Univ Basel, Univ Basel Hosp, Dept Med, Clin Neurol, CH-4031 Basel, Switzerland. EM nicholas.sanderson@unibas.ch; tobias.derfuss@usb.ch FU Swiss National Science Foundation Grants [310030_149966]; MUAM award from the Medical Faculty of the University of Basel FX We thank D. Merkler, A.- K. Probstel, E. Palmer, G. Krishnamoorthy, J. Lunemann, and I. Tsunoda for advice and A. Sylvain, T. Peyer, A.-C. Lecourt, and the staff of the microscopy and flow cytometry core facilities of the DBM for technical help. Funding was provided from Swiss National Science Foundation Grants 310030_149966 and an MUAM award from the Medical Faculty of the University of Basel. NR 25 TC 0 Z9 0 U1 1 U2 1 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 JAN 24 PY 2017 VL 114 IS 4 BP 734 EP 739 DI 10.1073/pnas.1614472114 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI6HV UT WOS:000392597000049 PM 28057865 ER PT J AU Bublik, DR Bursac, S Sheffer, M Orsolic, I Shalit, T Tarcic, O Kotler, E Mouhadeb, O Hoffman, Y Fuchs, G Levin, Y Volarevic, S Oren, M AF Bublik, Debora R. Bursac, Sladana Sheffer, Michal Orsolic, Ines Shalit, Tali Tarcic, Ohad Kotler, Eran Mouhadeb, Odelia Hoffman, Yonit Fuchs, Gilad Levin, Yishai Volarevic, Sinisa Oren, Moshe TI Regulatory module involving FGF13, miR-504, and p53 regulates ribosomal biogenesis and supports cancer cell survival SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE proteostasis; p53; miR-504; FGF13; ribosomal biogenesis ID FACTOR HOMOLOGOUS FACTORS; FIBROBLAST GROWTH-FACTORS; DATA-INDEPENDENT ANALYSIS; TUMOR-SUPPRESSOR; HOST GENES; INTRONIC MICRORNAS; MULTIPLE-MYELOMA; RNA-SYNTHESIS; IN-VIVO; EXPRESSION AB The microRNA miR-504 targets TP53 mRNA encoding the p53 tumor suppressor. miR-504 resides within the fibroblast growth factor 13 (FGF13) gene, which is overexpressed in various cancers. We report that the FGF13 locus, comprising FGF13 and miR-504, is transcriptionally repressed by p53, defining an additional negative feedback loop in the p53 network. Furthermore, we show that FGF13 1A is a nucleolar protein that represses ribosomal RNA transcription and attenuates protein synthesis. Importantly, in cancer cells expressing high levels of FGF13, the depletion of FGF13 elicits increased proteostasis stress, associated with the accumulation of reactive oxygen species and apoptosis. Notably, stepwise neoplastic transformation is accompanied by a gradual increase in FGF13 expression and increased dependence on FGF13 for survival ("nononcogene addiction"). Moreover, FGF13 overexpression enables cells to cope more effectively with the stress elicited by oncogenic Ras protein. We propose that, in cells in which activated oncogenes drive excessive protein synthesis, FGF13 may favor survival by maintaining translation rates at a level compatible with the protein qualitycontrol capacity of the cell. Thus, FGF13 may serve as an enabler, allowing cancer cells to evade proteostasis stress triggered by oncogene activation. C1 [Bublik, Debora R.; Tarcic, Ohad; Kotler, Eran; Mouhadeb, Odelia; Hoffman, Yonit; Fuchs, Gilad; Oren, Moshe] Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel. [Bursac, Sladana; Orsolic, Ines; Volarevic, Sinisa] Univ Rijeka, Sch Med, Dept Mol Med & Biotechnol, Rijeka 51000, Croatia. [Sheffer, Michal] Weizmann Inst Sci, Dept Phys Complex Syst, IL-76100 Rehovot, Israel. [Shalit, Tali; Levin, Yishai] Weizmann Inst Sci, Nancy & Stephen Grand Israel Natl Ctr Personalize, Botton Inst Prot Profiling, IL-76100 Rehovot, Israel. [Sheffer, Michal] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA 02115 USA. [Mouhadeb, Odelia] Tel Aviv Univ, Sackler Fac Med, Tel Aviv Sourasky Med Ctr, Res Ctr Digest Tract & Liver Dis, IL-69978 Ramat Aviv, Israel. RP Oren, M (reprint author), Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel. EM moshe.oren@weizmann.ac.il FU Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; Israel Science Foundation [1779/11]; Robert Bosch Stiftung Foundation; German-Israeli Foundation for Scientific Research; Moross Integrated Cancer Center; Estate of John Hunter; Croatian Science Foundation FX We thank Lior Golomb for help with confocal microscopy, Varda Rotter for the WI-38 transformation series, and Eytan Domany for fruitful discussions. This work was supported in part by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, Center of Excellence Grant 1779/11 from the Israel Science Foundation, the Robert Bosch Stiftung Foundation, the German-Israeli Foundation for Scientific Research, the Moross Integrated Cancer Center, and the Estate of John Hunter. S.V.'s contribution was partially supported by the Croatian Science Foundation. M.O. holds the Andre Lwoff chair in molecular biology. NR 71 TC 1 Z9 1 U1 1 U2 1 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 JAN 24 PY 2017 VL 114 IS 4 BP E496 EP E505 DI 10.1073/pnas.1614876114 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI6HV UT WOS:000392597000007 PM 27994142 ER PT J AU Kastanenka, KV Hou, SS Shakerdge, N Logan, R Feng, D Wegmann, S Chopra, V Hawkes, JM Chen, XQ Bacskai, BJ AF Kastanenka, Ksenia V. Hou, Steven S. Shakerdge, Naomi Logan, Robert Feng, Danielle Wegmann, Susanne Chopra, Vanita Hawkes, Jonathan M. Chen, Xiqun Bacskai, Brian J. TI Optogenetic Restoration of Disrupted Slow Oscillations Halts Amyloid Deposition and Restores Calcium Homeostasis in an Animal Model of Alzheimer's Disease SO PLOS ONE LA English DT Article ID IN-VIVO; SYNAPSE LOSS; MOUSE MODEL; COGNITIVE IMPAIRMENT; NEOCORTICAL NEURONS; BETA-PLAQUES; SLEEP; MEMORY; ACTIVATION; PROTEIN AB Slow oscillations are important for consolidation of memory during sleep, and Alzheimer's disease (AD) patients experience memory disturbances. Thus, we examined slow oscillation activity in an animal model of AD. APP mice exhibit aberrant slow oscillation activity. Aberrant inhibitory activity within the cortical circuit was responsible for slow oscillation dysfunction, since topical application of GABA restored slow oscillations in APP mice. In addition, light activation of channelrhodopsin-2 (ChR2) expressed in excitatory cortical neurons restored slow oscillations by synchronizing neuronal activity. Driving slow oscillation activity with ChR2 halted amyloid plaque deposition and prevented calcium overload associated with this pathology. Thus, targeting slow oscillatory activity in AD patients might prevent neurodegenerative phenotypes and slow disease progression. C1 [Kastanenka, Ksenia V.; Bacskai, Brian J.] Massachusetts Gen Hosp, MassGeneral Inst Neurodegenerat Dis, Dept Neurol, Charlestown, MA 02129 USA. Harvard Med Sch, Charlestown, MA USA. RP Bacskai, BJ (reprint author), Massachusetts Gen Hosp, MassGeneral Inst Neurodegenerat Dis, Dept Neurol, Charlestown, MA 02129 USA. EM kkastanenka@mgh.harvard.edu; bbacskai@mgh.harvard.edu FU NIBIB NIH HHS [R01 EB000768] NR 47 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 23 PY 2017 VL 12 IS 1 AR e70275 DI 10.1371/journal.pone.0170275 PG 25 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN6QR UT WOS:000396129000031 PM 28114405 ER PT J AU Hosios, AM Vander Heiden, MG AF Hosios, Aaron M. Vander Heiden, Matthew G. TI Endothelial Cells Get beta-ox-ed In to Support Lymphangiogenesis SO DEVELOPMENTAL CELL LA English DT Editorial Material ID ACETATE; CANCER AB Acetyl-CoA has diverse fates in metabolism and can be derived from a variety of nutrients. In a recent study published in Nature, Wong et at. (2016) show that endothelial cells oxidize fatty acids to produce acetyl-CoA for epigenetic modifications critical to lymphangiogenesis. C1 [Hosios, Aaron M.; Vander Heiden, Matthew G.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Hosios, Aaron M.; Vander Heiden, Matthew G.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Vander Heiden, Matthew G.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Vander Heiden, MG (reprint author), MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA.; Vander Heiden, MG (reprint author), MIT, Dept Biol, Cambridge, MA 02139 USA.; Vander Heiden, MG (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM mvh@mit.edu NR 8 TC 0 Z9 0 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 EI 1878-1551 J9 DEV CELL JI Dev. Cell PD JAN 23 PY 2017 VL 40 IS 2 BP 118 EP 119 DI 10.1016/j.devcel.2017.01.004 PG 2 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA EJ0LH UT WOS:000392899700003 PM 28118598 ER PT J AU Gao, JJ Chang, MT Johnsen, HC Gao, SP Sylvester, BE Sumer, SO Zhang, HX Solit, DB Taylor, BS Schultz, N Sander, C AF Gao, Jianjiong Chang, Matthew T. Johnsen, Hannah C. Gao, Sizhi Paul Sylvester, Brooke E. Sumer, Selcuk Onur Zhang, Hongxin Solit, David B. Taylor, Barry S. Schultz, Nikolaus Sander, Chris TI 3D clusters of somatic mutations in cancer reveal numerous rare mutations as functional targets SO GENOME MEDICINE LA English DT Article DE Cancer genomics; Driver mutations; Protein structures; Precision medicine ID PROTEIN-STRUCTURE; HOTSPOT MUTATION; GENOMICS; VEMURAFENIB; INHIBITION; RESISTANCE; DISCOVERY; VARIANTS; MELANOMA; DIVERSE AB Many mutations in cancer are of unknown functional significance. Standard methods use statistically significant recurrence of mutations in tumor samples as an indicator of functional impact. We extend such analyses into the long tail of rare mutations by considering recurrence of mutations in clusters of spatially close residues in protein structures. Analyzing 10,000 tumor exomes, we identify more than 3000 rarely mutated residues in proteins as potentially functional and experimentally validate several in RAC1 and MAP2K1. These potential driver mutations (web resources: 3dhotspots.org and cBioPortal.org) can extend the scope of genomically informed clinical trials and of personalized choice of therapy. C1 [Gao, Jianjiong; Sumer, Selcuk Onur; Zhang, Hongxin; Solit, David B.; Taylor, Barry S.; Schultz, Nikolaus] Mem Sloan Kettering Canc Ctr, Marie Josee & Henry R Kravis Ctr Mol Oncol, 1275 York Ave, New York, NY 10021 USA. [Chang, Matthew T.; Johnsen, Hannah C.; Gao, Sizhi Paul; Sylvester, Brooke E.; Solit, David B.; Taylor, Barry S.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA. [Chang, Matthew T.; Taylor, Barry S.; Schultz, Nikolaus] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, 1275 York Ave, New York, NY 10021 USA. [Chang, Matthew T.] Univ Calif San Francisco, Dept Bioengn, San Francisco, CA 94143 USA. [Chang, Matthew T.] Univ Calif San Francisco, Dept Therapeut Sci, San Francisco, CA 94143 USA. [Johnsen, Hannah C.] Mem Sloan Kettering Canc Ctr, Louis V Gerstner Jr Grad Sch Biomed Sci, 1275 York Ave, New York, NY 10021 USA. [Solit, David B.] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. [Solit, David B.] Cornell Univ, Weill Cornell Med Coll, New York, NY 10021 USA. [Sander, Chris] Harvard Med Sch, Dept Cell Biol, Boston, MA USA. [Sander, Chris] Dana Farber Canc Inst, cBio Ctr, Boston, MA 02115 USA. [Sander, Chris] Mem Sloan Kettering Canc Ctr, Computat Biol Program, 1275 York Ave, New York, NY 10021 USA. RP Gao, JJ (reprint author), Mem Sloan Kettering Canc Ctr, Marie Josee & Henry R Kravis Ctr Mol Oncol, 1275 York Ave, New York, NY 10021 USA. EM jgao@cbio.mskcc.org FU NIH Core Grant [P30 CA008748]; NCI funding of the TCGA Genome Data Analysis Center [U24 CA143840]; Marie-Josee and Henry R. Kravis Center for Molecular Oncology; Sontag Foundation; Cycle for Survival; Robertson Foundation; Prostate Cancer Foundation FX This work was supported by an NIH Core Grant (P30 CA008748), NCI funding of the TCGA Genome Data Analysis Center (U24 CA143840), the Marie-Josee and Henry R. Kravis Center for Molecular Oncology, the Sontag Foundation and Cycle for Survival (BST), as well as the Robertson Foundation and the Prostate Cancer Foundation (NS and BST). NR 45 TC 1 Z9 1 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-994X J9 GENOME MED JI Genome Med. PD JAN 23 PY 2017 VL 9 AR 4 DI 10.1186/s13073-016-0393-x PG 13 WC Genetics & Heredity SC Genetics & Heredity GA EI4IF UT WOS:000392455700001 PM 28115009 ER PT J AU Sheets, L AF Sheets, Lavinia TI Excessive activation of ionotropic glutamate receptors induces apoptotic hair-cell death independent of afferent and efferent innervation SO SCIENTIFIC REPORTS LA English DT Article ID TRANSIENT COCHLEAR ISCHEMIA; KAINIC ACID EXCITOTOXICITY; NEWBORN RAT COCHLEA; SYNAPTIC-TRANSMISSION; CONGENITAL DEAFNESS; KAINATE RECEPTORS; AUDITORY NEURONS; NMDA RECEPTORS; AMPA RECEPTORS; ZEBRAFISH AB Accumulation of excess glutamate plays a central role in eliciting the pathological events that follow intensely loud noise exposures and ischemia-reperfusion injury. Glutamate excitotoxicity has been characterized in cochlear nerve terminals, but much less is known about whether excess glutamate signaling also contributes to pathological changes in sensory hair cells. I therefore examined whether glutamate excitotoxicity damages hair cells in zebrafish larvae exposed to drugs that mimic excitotoxic trauma. Exposure to ionotropic glutamate receptor (iGluR) agonists, kainic acid (KA) or N-methyl-D- aspartate (NMDA), contributed to significant, progressive hair cell loss in zebrafish lateral-line organs. To examine whether hair-cell loss was a secondary effect of excitotoxic damage to innervating neurons, I exposed neurog1 alpha morphants-fish whose hair-cell organs are devoid of afferent and efferent innervation-to KA or NMDA. Significant, dose-dependent hair-cell loss occurred in neurog1a morphants exposed to either agonist, and the loss was comparable to wild-type siblings. A survey of iGluR gene expression revealed AMPA-, Kainate-, and NMDA-type subunits are expressed in zebrafish hair cells. Finally, hair cells exposed to KA or NMDA appear to undergo apoptotic cell death. Cumulatively, these data reveal that excess glutamate signaling through iGluRs induces hair-cell death independent of damage to postsynaptic terminals. C1 [Sheets, Lavinia] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Sheets, Lavinia] Harvard Med Sch, Dept Otolaryngol, Boston, MA 02115 USA. RP Sheets, L (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA.; Sheets, L (reprint author), Harvard Med Sch, Dept Otolaryngol, Boston, MA 02115 USA. EM Lavinia_Sheets@meei.harvard.edu FU National Institutes of Health [R01DC012838]; Amelia Peabody Charitable Fund FX I am grateful to Bill Sewell for his support of this project and critical reading of the manuscript. I also thank Maris Handley and the HSCI-CRM Flow Cytometry Core Facility at MGH. This study was supported by National Institutes of Health Grant R01DC012838 (William Sewell) and the Amelia Peabody Charitable Fund (LS). NR 72 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JAN 23 PY 2017 VL 7 AR 41102 DI 10.1038/srep41102 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI4LU UT WOS:000392466000001 PM 28112265 ER PT J AU Ananthakrishnan, AN AF Ananthakrishnan, Ashwin N. TI Filgotinib for Crohn's disease-expanding treatment options SO LANCET LA English DT Editorial Material ID DOSE INTENSIFICATION; TOFACITINIB C1 [Ananthakrishnan, Ashwin N.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Ananthakrishnan, Ashwin N.] Harvard Med Sch, Boston, MA 02114 USA. RP Ananthakrishnan, AN (reprint author), Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA.; Ananthakrishnan, AN (reprint author), Harvard Med Sch, Boston, MA 02114 USA. EM aananthakrishnan@mgh.harvard.edu FU Merck; Takeda; Exact Sciences; Amgen; US National Institutes of Health [K23 DK097142] FX I have received consultancy fees from: AbbVie unrelated to the current work (served on scientific advisory boards to define unmet needs in delivery of inflammatory bowel disease care); Merck (to identify burden and treatment of recurrent Clostridium difficile infection); Takeda (as a member of a Crohn's and colitis focus group to advance research and clinical care in inflammatory bowel disease); and Exact Sciences (to optimise use of faecal DNA testing for colon cancer screening). I have received research funding from Merck (to define costs associated with recurrent Clostridium difficile infection) and Amgen (to identify predictors of response to biological therapy). I am supported by funding from the US National Institutes of Health (K23 DK097142). NR 13 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD JAN 21 PY 2017 VL 389 IS 10066 BP 228 EP 229 DI 10.1016/S0140-6736(16)32538-7 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA EI9BC UT WOS:000392801200005 PM 27988141 ER PT J AU Petibon, Y Guehl, NJ Reese, TG Ebrahimi, B Normandin, MD Shoup, TM Alpert, NM El Fakhri, G Ouyang, JS AF Petibon, Yoann Guehl, Nicolas J. Reese, Timothy G. Ebrahimi, Behzad Normandin, Marc D. Shoup, Timothy M. Alpert, Nathaniel M. El Fakhri, Georges Ouyang, Jinsong TI Impact of motion and partial volume effects correction on PET myocardial perfusion imaging using simultaneous PET-MR SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE PET-MR; motion correction; partial volume correction; myocardial perfusion ID POSITRON-EMISSION-TOMOGRAPHY; CORONARY-ARTERY-DISEASE; FLURPIRIDAZ F 18; BLOOD-FLOW; ITERATIVE RECONSTRUCTION; BRAIN PET; IMAGES; MODEL; HETEROGENEITY; ATTENUATION AB PET is an established modality for myocardial perfusion imaging (MPI) which enables quantification of absolute myocardial blood flow (MBF) using dynamic imaging and kinetic modeling. However, heart motion and partial volume effects (PVE) significantly limit the spatial resolution and quantitative accuracy of PET MPI. Simultaneous PET-MR offers a solution to the motion problem in PET by enabling MR-based motion correction of PET data. The aim of this study was to develop a motion and PVE correction methodology for PET MPI using simultaneous PET-MR, and to assess its impact on both static and dynamic PET MPI using F-18-Flurpiridaz, a novel F-18-labeled perfusion tracer. Two dynamic F-18-Flurpiridaz MPI scans were performed on healthy pigs using a PET-MR scanner. Cardiac motion was tracked using a dedicated tagged-MRI (tMR) sequence. Motion fields were estimated using non-rigid registration of tMR images and used to calculate motion-dependent attenuation maps. Motion correction of PET data was achieved by incorporating tMR-based motion fields and motion-dependent attenuation coefficients into image reconstruction. Dynamic and static PET datasets were created for each scan. Each dataset was reconstructed as (i) Ungated, (ii) Gated (end-diastolic phase), and (iii) Motion-Corrected (MoCo), each without and with point spread function (PSF) modeling for PVE correction. Myocardium-to-blood concentration ratios (MBR) and apparent wall thickness were calculated to assess image quality for static MPI. For dynamic MPI, segment-and voxel-wise MBF values were estimated by non-linear fitting of a 2-tissue compartment model to tissue time-activity-curves. MoCo and Gating respectively decreased mean apparent wall thickness by 15.1% and 14.4% and increased MBR by 20.3% and 13.6% compared to Ungated images (P < 0.01). Combined motion and PSF correction (MoCo-PSF) yielded 30.9% (15.7%) lower wall thickness and 82.2% (20.5%) higher MBR compared to Ungated data reconstructed without (with) PSF modeling (P < 0.01). For dynamic PET, mean MBF across all segments were comparable for MoCo (0.72 +/- 0.21 ml/min/ml) and Gating (0.69 +/- 0.18 ml/min/ml). Ungated data yielded significantly lower mean MBF (0.59 +/- 0.16 ml/min/ml). Mean MBF for MoCo-PSF was 0.80 +/- 0.22 ml/min/ml, which was 37.9% (25.0%) higher than that obtained from Ungated data without (with) PSF correction (P < 0.01). The developed methodology holds promise to improve the image quality and sensitivity of PET MPI studies performed using PET-MR. C1 [Petibon, Yoann; Guehl, Nicolas J.; Ebrahimi, Behzad; Normandin, Marc D.; Shoup, Timothy M.; Alpert, Nathaniel M.; El Fakhri, Georges; Ouyang, Jinsong] Massachusetts Gen Hosp, Dept Radiol, Gordon Ctr Med Imaging, Boston, MA 02114 USA. [Petibon, Yoann; Reese, Timothy G.; Ebrahimi, Behzad; Normandin, Marc D.; Shoup, Timothy M.; Alpert, Nathaniel M.; El Fakhri, Georges; Ouyang, Jinsong] Harvard Med Sch, Dept Radiol, Boston, MA 02115 USA. [Reese, Timothy G.] Massachusetts Gen Hosp, Dept Radiol, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP El Fakhri, G; Ouyang, JS (reprint author), Massachusetts Gen Hosp, Dept Radiol, Gordon Ctr Med Imaging, Boston, MA 02114 USA.; El Fakhri, G; Ouyang, JS (reprint author), Harvard Med Sch, Dept Radiol, Boston, MA 02115 USA. EM elfakhri@pet.mgh.harvard.edu; ouyang.jinsong@mgh.harvard.edu FU NIH [R01-HL118261] FX The authors would like to thank Julia-Ann Scotton and Victoria Douglas for their help during the animal experiments. This work was supported by NIH R01-HL118261. NR 51 TC 0 Z9 0 U1 6 U2 6 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 EI 1361-6560 J9 PHYS MED BIOL JI Phys. Med. Biol. PD JAN 21 PY 2017 VL 62 IS 2 BP 326 EP 343 DI 10.1088/1361-6560/aa5087 PG 18 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA EH2YN UT WOS:000391634700001 PM 27997375 ER PT J AU Lin, YT Clasie, B Lu, HM Flanz, J Shen, T Jee, KW AF Lin, Yuting Clasie, Benjamin Lu, Hsiao-Ming Flanz, Jacob Shen, Tim Jee, Kyung-Wook TI Impacts of gantry angle dependent scanning beam properties on proton PBS treatment SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE proton therapy; pencil beam scanning; patient specific QA; log files ID DELIVERY; THERAPY; FILES AB While proton beam models in treatment planning systems are generally assumed invariant with respect to the beam deliveries at different gantry angles. Physical properties of scanning pencil beams can change. The gantry angle dependent properties include the delivered charge to the monitor unit chamber, the spot position and the spot shape. The aim of this study is to investigate the extent of the changes and their dosimetric impacts using historical pencil beam scanning (PBS) treatment data. Online beam delivery records at the time of the patient-specific qualify assurance were retrospectively collected for a total of 34 PBS fields from 28 patients treated at our institution. For each field, proton beam properties at two different gantry angles (the planned and zero gantry angles) were extracted by a newly-developed machine log analysis method and used to reconstruct the delivered dose distributions in the cubic water phantom geometry. The reconstructed doses at the two different angles and a planar dose measurement by a 2D ion-chamber array were compared and the dosimetric impacts of the gantry angle dependency were accessed by a 3D gamma-index analysis. In addition, the pencil beam spot size was independently characterized as a function of the gantry angle and the beam energy. The dosimetric effects of the perturbed beam shape were also investigated. Comparisons of spot-by-spot beam positions between both gantry angles show a mean deviation of 0.4 and 0.7 mm and a standard deviation of 0.3 and 0.6 mm for x and y directions, respectively. The delivered giga-protons per spot show a percent mean difference and a standard deviation of 0.01% and 0.3%, respectively, from each planned spot weight. These small deviations lead to an excellent agreement in dose comparisons with an average. passing rate of 99.1%. When each calculation for both planned and zero gantry angles was compared to the measurement, a high correlation in. values was also observed, also indicating the dosimetric differences are small when a field is delivered at different gantry angles. Utilizing the online beam delivery records, the gantry angle dependencies of the PBS beam delivery were assessed and quantified. The study confirms the variations of the physical properties to be sufficiently small within the clinical tolerances without taking into account the gantry angle variation. C1 [Lin, Yuting; Clasie, Benjamin; Lu, Hsiao-Ming; Flanz, Jacob; Shen, Tim; Jee, Kyung-Wook] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Lin, Yuting; Clasie, Benjamin; Lu, Hsiao-Ming; Flanz, Jacob; Shen, Tim; Jee, Kyung-Wook] Harvard Med Sch, Boston, MA 02115 USA. [Lin, Yuting] Duke Univ, Med Ctr, Dept Radiat Oncol, Durham, NC USA. RP Clasie, B (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA.; Clasie, B (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM bclasie@partners.org FU Federal Share of program [C06 CA059267]; Medical Physics Residency Program at Harvard Medical School FX The project was supported by the Federal Share of program income earned by Massachusetts General Hospital on C06 CA059267, Proton Therapy Research and Treatment Center. We thank the Medical Physics Residency Program at Harvard Medical School for generous support to Yuting Lin. NR 23 TC 0 Z9 0 U1 4 U2 4 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 EI 1361-6560 J9 PHYS MED BIOL JI Phys. Med. Biol. PD JAN 21 PY 2017 VL 62 IS 2 BP 344 EP 357 DI 10.1088/1361-6560/aa5084 PG 14 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA EH2YN UT WOS:000391634700002 ER PT J AU Kwong, RY Petersen, SE Schulz-Menger, J Arai, AE Bingham, SE Chen, YC Choi, YL Cury, RC Ferreira, VM Flamm, SD Steel, K Bandettini, WP Martin, ET Nallamshetty, L Neubauer, S Raman, SV Schelbert, EB Valeti, US Cao, JJ Reichek, N Young, AA Fexon, L Pivovarov, M Ferrari, VA Simonetti, OP AF Kwong, Raymond Y. Petersen, Steffen E. Schulz-Menger, Jeanette Arai, Andrew E. Bingham, Scott E. Chen, Yucheng Choi, Yuna L. Cury, Ricardo C. Ferreira, Vanessa M. Flamm, Scott D. Steel, Kevin Bandettini, W. Patricia Martin, Edward T. Nallamshetty, Leelakrishna Neubauer, Stefan Raman, Subha V. Schelbert, Erik B. Valeti, Uma S. Cao, Jie Jane Reichek, Nathaniel Young, Alistair A. Fexon, Lyuba Pivovarov, Misha Ferrari, Victor A. Simonetti, Orlando P. CA Global Cardiovas Magnetic Resonan TI The global cardiovascular magnetic resonance registry (GCMR) of the society for cardiovascular magnetic resonance (SCMR): its goals, rationale, data infrastructure, and current developments SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article DE Registry; Cardiovascular magnetic resonance; Imaging; Patient management; Therapeutic implications ID ACUTE ADVERSE-REACTIONS; EUROCMR REGISTRY; CONTRAST AGENTS; CMR PROTOCOLS; EXPERIENCE; UPDATE AB Background: With multifaceted imaging capabilities, cardiovascular magnetic resonance (CMR) is playing a progressively increasing role in the management of various cardiac conditions. A global registry that harmonizes data from international centers, with participation policies that aim to be open and inclusive of all CMR programs, can support future evidence-based growth in CMR. Methods: The Global CMR Registry (GCMR) was established in 2013 under the auspices of the Society for Cardiovascular Magnetic Resonance (SCMR). The GCMR team has developed a web-based data infrastructure, data use policy and participation agreement, data-harmonizing methods, and site-training tools based on results from an international survey of CMR programs. Results: At present, 17 CMR programs have established a legal agreement to participate in GCMR, amongst them 10 have contributed CMR data, totaling 62,456 studies. There is currently a predominance of CMR centers with more than 10 years of experience (65%), and the majority are located in the United States (63%). The most common clinical indications for CMR have included assessment of cardiomyopathy (21%), myocardial viability (16%), stress CMR perfusion for chest pain syndromes (16%), and evaluation of etiology of arrhythmias or planning of electrophysiological studies (15%) with assessment of cardiomyopathy representing the most rapidly growing indication in the past decade. Most CMR studies involved the use of gadolinium-based contrast media (95%). Conclusions: We present the goals, mission and vision, infrastructure, preliminary results, and challenges of the GCMR. C1 [Kwong, Raymond Y.; Choi, Yuna L.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, Boston, MA 02115 USA. [Kwong, Raymond Y.] Harvard Med Sch, 75 Francis St, Boston, MA 02115 USA. [Petersen, Steffen E.] William Harvey Res Inst, London, England. [Schulz-Menger, Jeanette] Charite, Berlin, Germany. [Arai, Andrew E.; Bandettini, W. Patricia] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Bingham, Scott E.] Revere Hlth, Provo, UT USA. [Chen, Yucheng] West China Hosp, Chengdu, Peoples R China. [Cury, Ricardo C.] Miami Cardiac & Vasc Inst, Miami, FL USA. [Ferreira, Vanessa M.; Neubauer, Stefan] Univ Oxford, Oxford, England. [Flamm, Scott D.] Cleveland Clin, Cleveland, OH 44106 USA. [Steel, Kevin] San Antonio Mil Med Ctr, San Antonio, TX USA. [Martin, Edward T.] Oklahoma Heart Inst, Tulsa, OK USA. [Nallamshetty, Leelakrishna] Univ S Florida, Miami, FL USA. [Raman, Subha V.] Ohio State Univ, Wexner Med Ctr, Cleveland, OH USA. [Schelbert, Erik B.] Univ Pittsburgh, Pittsburgh, PA USA. [Valeti, Uma S.] Univ Minnesota, Minneapolis, MN 55455 USA. [Cao, Jie Jane; Reichek, Nathaniel] St Francis Hosp, New York, NY USA. [Young, Alistair A.] Univ Auckland, Auckland, New Zealand. [Fexon, Lyuba; Pivovarov, Misha] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ferrari, Victor A.] Univ Penn, Philadelphia, PA 19104 USA. [Simonetti, Orlando P.] Ohio State Univ, Columbus, OH 43210 USA. RP Kwong, RY (reprint author), Brigham & Womens Hosp, Dept Med, Div Cardiovasc, Boston, MA 02115 USA.; Kwong, RY (reprint author), Harvard Med Sch, 75 Francis St, Boston, MA 02115 USA. EM rykwong@partners.org FU SCMR [SCMR_GRANT_001] FX GCMR received seed funding from SCMR (SCMR_GRANT_001) for the development and maintenance of GCMR websites and database infrastructure. NR 9 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 EI 1532-429X J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD JAN 20 PY 2017 VL 19 AR 23 DI 10.1186/s12968-016-0321-7 PG 11 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA EM7FN UT WOS:000395477000001 ER PT J AU Kwong, TC Nouizi, F Lin, YT Cho, J Zhu, Y Sampathkumaran, U Gulsen, G AF Kwong, Tiffany C. Nouizi, Farouk Lin, Yuting Cho, Jaedu Zhu, Yue Sampathkumaran, Uma Gulsen, Gultekin TI Experimental evaluation of the resolution and quantitative accuracy of temperature-modulated fluorescence tomography SO APPLIED OPTICS LA English DT Article ID DIFFUSE OPTICAL TOMOGRAPHY; REGULARIZATION; INFORMATION AB Previously, we reported on the spatial resolution and quantitative accuracy of temperature-modulated fluorescence tomography (TM-FT) using simulation studies. TM-FT is a novel fully integrated multimodality imaging technique that combines fluorescence diffuse optical tomography (FT) with focused ultrasound. Utilizing unique thermo-reversible fluorescent nanocapsules (ThermoDots), TM-FT provides high-resolution cross-sectional fluorescence images in thick tissue (up to 6 cm). Focused ultrasound and temperature-sensitive ThermoDots are combined to provide accurate localization of these fluorescent probes and functional a priori information to constrain the conventional FT reconstruction algorithm. Our previous simulation studies evaluated the performance of TM-FT using synthetic phantoms with multiple fluorescence targets of various sizes located at different depths. In this follow-up work, we perform experimental studies to evaluate the performance of this hybrid imaging system, in particular, the effect of size, depth, and concentration of the fluorescence target. While FT alone is unable to accurately locate and resolve the fluorophore target in many cases, TM-FT is able to resolve the size and concentration of the ThermoDots within a thick turbid medium with high accuracy for all cases. The maximum error in the recovered ThermoDots concentration and target sizes with TM-FT are 12% and 25%, respectively. (C) 2017 Optical Society of America C1 [Kwong, Tiffany C.; Nouizi, Farouk; Lin, Yuting; Cho, Jaedu; Gulsen, Gultekin] Univ Calif Irvine, Dept Radiol Sci, Tu & Yuen Ctr Funct Oncoimaging, Irvine, CA 92697 USA. [Lin, Yuting] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02144 USA. [Lin, Yuting] Harvard Med Sch, Boston, MA 02144 USA. [Zhu, Yue; Sampathkumaran, Uma] InnoSense LLC, Torrance, CA 90505 USA. RP Kwong, TC (reprint author), Univ Calif Irvine, Dept Radiol Sci, Tu & Yuen Ctr Funct Oncoimaging, Irvine, CA 92697 USA. EM tckwong@uci.edu FU National Institutes of Health (NIH) [P30CA062203, 1F31CA171915-01A1, R01EB008716, R33 CA120175, SBIR HHSN261201300068C]; UCI Eugene Cota-Robles Fellowship; Fulbright Commission FX National Institutes of Health (NIH) (P30CA062203, 1F31CA171915-01A1, R01EB008716, R33 CA120175, SBIR HHSN261201300068C); UCI Eugene Cota-Robles Fellowship; Fulbright Commission (Visiting Scholar). NR 21 TC 0 Z9 0 U1 2 U2 2 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1559-128X EI 2155-3165 J9 APPL OPTICS JI Appl. Optics PD JAN 20 PY 2017 VL 56 IS 3 BP 521 EP 529 DI 10.1364/AO.56.000521 PG 9 WC Optics SC Optics GA EJ6SA UT WOS:000393347900054 PM 28157909 ER PT J AU Beheshti, A Vanderburg, C McDonald, JT Ramkumar, C Kadungure, T Zhang, H Gartenhaus, RB Evens, AM AF Beheshti, Afshin Vanderburg, Charles McDonald, J. Tyson Ramkumar, Charusheila Kadungure, Tatenda Zhang, Hong Gartenhaus, Ronald B. Evens, Andrew M. TI A Circulating microRNA Signature Predicts Age-Based Development of Lymphoma SO PLOS ONE LA English DT Article ID B-CELL LYMPHOMA; REAL-TIME PCR; DOWN-REGULATION; CANCER; THERAPY; PATHOGENESIS; EXPRESSION; DIAGNOSIS; SURVIVAL; REVEALS AB Extensive epidemiological data have demonstrated an exponential rise in the incidence of non-Hodgkin lymphoma (NHL) that is associated with increasing age. The molecular etiology of this remains largely unknown, which impacts the effectiveness of treatment for patients. We proposed that age-dependent circulating microRNA (miRNA) signatures in the host influence diffuse large B cell lymphoma (DLBCL) development. Our objective was to examine tumor development in an age-based DLBCL system using an inventive systems biology approach. We harnessed a novel murine model of spontaneous DLBCL initiation (Smurf2-deficient) at two age groups: 3 and 15 months old. All Smurf2-deficient mice develop visible DLBCL tumor starting at 15 months of age. Total miRNA was isolated from serum, bone marrow and spleen and were collected for all age groups for Smurf2-deficient mice and age-matched wild-type C57BL/6 mice. Using systems biology techniques, we identified a list of 10 circulating miRNAs being regulated in both the spleen and bone marrow that were present in DLBCL forming mice starting at 3 months of age that were not present in the control mice. Furthermore, this miRNA signature was found to occur circulating in the blood and it strongly impacted JUN and MYC oncogenic signaling. In addition, quantification of the miRNA signature was performed via Droplet Digital PCR technology. It was discovered that a key miRNA signature circulates throughout a host prior to the formation of a tumor starting at 3 months old, which becomes further modulated by age and yielded calculation of a ` carcinogenic risk score'. This novel age-based circulating miRNA signature may potentially be leveraged as a DLBCL risk profile at a young age to predict future lymphoma development or disease progression as well as for potential innovative miRNA-based targeted therapeutic strategies in lymphoma. C1 [Beheshti, Afshin; Evens, Andrew M.] Tufts Med Ctr, Mol Oncol Res Inst, Div Hematol Oncol, Boston, MA 02111 USA. [Vanderburg, Charles] Massachusetts Gen Hosp, Harvard NeuroDiscovery Ctr, Boston, MA USA. [McDonald, J. Tyson] Hampton Univ, Canc Res Ctr, Hampton, VA 23668 USA. [Ramkumar, Charusheila; Kadungure, Tatenda; Zhang, Hong] Univ Massachusetts, Sch Med, Dept Cell Biol & Dev, Worcester, MA 01605 USA. [Gartenhaus, Ronald B.] Univ Maryland, Marlene & Stewart Greenebaum Canc Ctr, Dept Med, Baltimore, MD 21201 USA. EM AEvens@tuftsmedicalcenter.org FU [R01 CA164311] FX This research was supported in part by R01 CA164311. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. There was no additional external funding received for this study. NR 65 TC 0 Z9 0 U1 7 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 JAN 20 PY 2017 VL 12 IS 1 AR e0170521 DI 10.1371/journal.pone.0170521 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI3QC UT WOS:000392405300153 PM 28107482 ER PT J AU de Vries, PS Sabater-Lleal, M Chasman, DI Trompet, S Ahluwalia, TS Teumer, A Kleber, ME Chen, MH Wang, JJ Attia, JR Marioni, RE Steri, M Weng, LC Pool, R Grossmann, V Brody, JA Venturini, C Tanaka, T Rose, LM Oldmeadow, C Mazur, J Basu, S Franberg, M Yang, Q Ligthart, S Hottenga, JJ Rumley, A Mulas, A de Craen, AJM Grotevendt, A Taylor, KD Delgado, GE Kifley, A Lopez, LM Berentzen, TL Mangino, M Bandinelli, S Morrison, AC Hamsten, A Tofler, G de Maat, MPM Draisma, HHM Lowe, GD Zoledziewska, M Sattar, N Lackner, KJ Volker, U McKnight, B Huang, J Holliday, EG McEvoy, MA Starr, JM Hysi, PG Hernandez, DG Guan, WH Rivadeneira, F McArdle, WL Slagboom, PE Zeller, T Psaty, BM Uitterlinden, AG de Geus, EJC Stott, DJ Binder, H Hofman, A Franco, OH Rotter, JI Ferrucci, L Spector, TD Deary, IJ Marz, W Greinacher, A Wild, PS Cucca, F Boomsma, DI Watkins, H Tang, WH Ridker, PM Jukema, JW Scott, RJ Mitchell, P Hansen, T O'Donnell, CJ Smith, NL Strachan, DP Dehghan, A AF de Vries, Paul S. Sabater-Lleal, Maria Chasman, Daniel I. Trompet, Stella Ahluwalia, Tarunveer S. Teumer, Alexander Kleber, Marcus E. Chen, Ming-Huei Wang, Jie Jin Attia, John R. Marioni, Riccardo E. Steri, Maristella Weng, Lu-Chen Pool, Rene Grossmann, Vera Brody, Jennifer A. Venturini, Cristina Tanaka, Toshiko Rose, Lynda M. Oldmeadow, Christopher Mazur, Johanna Basu, Saonli Franberg, Mattias Yang, Qiong Ligthart, Symen Hottenga, Jouke J. Rumley, Ann Mulas, Antonella de Craen, Anton J. M. Grotevendt, Anne Taylor, Kent D. Delgado, Graciela E. Kifley, Annette Lopez, Lorna M. Berentzen, Tina L. Mangino, Massimo Bandinelli, Stefania Morrison, Alanna C. Hamsten, Anders Tofler, Geoffrey de Maat, Moniek P. M. Draisma, Harmen H. M. Lowe, Gordon D. Zoledziewska, Magdalena Sattar, Naveed Lackner, Karl J. Voelker, Uwe McKnight, Barbara Huang, Jie Holliday, Elizabeth G. McEvoy, Mark A. Starr, John M. Hysi, Pirro G. Hernandez, Dena G. Guan, Weihua Rivadeneira, Fernando McArdle, Wendy L. Slagboom, P. Eline Zeller, Tanja Psaty, Bruce M. Uitterlinden, Andre G. de Geus, Eco J. C. Stott, David J. Binder, Harald Hofman, Albert Franco, Oscar H. Rotter, Jerome I. Ferrucci, Luigi Spector, Tim D. Deary, Ian J. Maerz, Winfried Greinacher, Andreas Wild, Philipp S. Cucca, Francesco Boomsma, Dorret I. Watkins, Hugh Tang, Weihong Ridker, Paul M. Jukema, Jan W. Scott, Rodney J. Mitchell, Paul Hansen, Torben O'Donnell, Christopher J. Smith, Nicholas L. Strachan, David P. Dehghan, Abbas TI Comparison of HapMap and 1000 Genomes Reference Panels in a Large-Scale Genome-Wide Association Study SO PLOS ONE LA English DT Article ID CARDIOVASCULAR-DISEASE; SUSCEPTIBILITY LOCI; GENETIC-VARIANTS; COMMON VARIANTS; METAANALYSIS; CONSORTIUM; IMPUTATION; PRESSURE; INSIGHTS; BIOLOGY AB An increasing number of genome-wide association (GWA) studies are now using the higher resolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectation that 1000G imputation will lead to the discovery of additional associated loci when compared to HapMap imputation. In order to assess the improvement of 1000G over HapMap imputation in identifying associated loci, we compared the results of GWA studies of circulating fibrinogen based on the two reference panels. Using both HapMap and 1000G imputation we performed a meta-analysis of 22 studies comprising the same 91,953 individuals. We identified six additional signals using 1000G imputation, while 29 loci were associated using both HapMap and 1000G imputation. One locus identified using HapMap imputation was not significant using 1000G imputation. The genome-wide significance threshold of 5x10(-8) is based on the number of independent statistical tests using HapMap imputation, and 1000G imputation may lead to further independent tests that should be corrected for. When using a stricter Bonferroni correction for the 1000G GWA study (P-value < 2.5x10(-8)), the number of loci significant only using HapMap imputation increased to 4 while the number of loci significant only using 1000G decreased to 5. In conclusion, 1000G imputation enabled the identification of 20% more loci than HapMap imputation, although the advantage of 1000G imputation became less clear when a stricter Bonferroni correction was used. More generally, our results provide insights that are applicable to the implementation of other dense reference panels that are under development. C1 [de Vries, Paul S.; Ligthart, Symen; Morrison, Alanna C.; Rivadeneira, Fernando; Uitterlinden, Andre G.; Hofman, Albert; Franco, Oscar H.; Dehghan, Abbas] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [de Vries, Paul S.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Sabater-Lleal, Maria; Franberg, Mattias; Hamsten, Anders] Karolinska Inst, Dept Med, Cardiovasc Med Unit, Stockholm, Sweden. [Chasman, Daniel I.; Rose, Lynda M.; Ridker, Paul M.] Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. [Chasman, Daniel I.; Ridker, Paul M.] Harvard Med Sch, Boston, MA USA. [Trompet, Stella; Jukema, Jan W.] Leiden Univ, Dept Cardiol, Med Ctr, Leiden, Netherlands. [Trompet, Stella; de Craen, Anton J. M.] Leiden Univ, Dept Gerontol & Geriatr, Med Ctr, Leiden, Netherlands. [Ahluwalia, Tarunveer S.] Steno Diabet Ctr Copenhagen, Gentofte, Denmark. [Ahluwalia, Tarunveer S.] Univ Copenhagen, Fac Hlth & Med Sci, Sect Metab Genet, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark. [Teumer, Alexander] Univ Med Greifswald, Inst Community Med, Greifswald, Germany. [Kleber, Marcus E.; Delgado, Graciela E.; Maerz, Winfried] Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Mannheim, Germany. [Chen, Ming-Huei] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Chen, Ming-Huei; Yang, Qiong; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Populat Sci Branch, Div Intramural Res,NIH, Framingham, MA USA. [Wang, Jie Jin; Kifley, Annette; Mitchell, Paul] Univ Sydney, Dept Ophthalmol, Ctr Vis Res, Sydney, NSW, Australia. [Wang, Jie Jin; Kifley, Annette; Mitchell, Paul] Univ Sydney, Westmead Inst Med Res, Sydney, NSW, Australia. [Attia, John R.; Oldmeadow, Christopher] Univ Newcastle, Hunter Med Res Inst, Publ Hlth Stream, Newcastle, NSW, Australia. [Attia, John R.; Oldmeadow, Christopher; McEvoy, Mark A.] Univ Newcastle, Sch Med & Publ Hlth, Newcastle, NSW, Australia. [Marioni, Riccardo E.; Lopez, Lorna M.; Starr, John M.; Deary, Ian J.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland. [Marioni, Riccardo E.] Univ Edinburgh, Ctr Genom & Expt Med, Edinburgh, Midlothian, Scotland. [Marioni, Riccardo E.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia. [Steri, Maristella; Mulas, Antonella; Zoledziewska, Magdalena; Cucca, Francesco] CNR, Ist Ric Genet & Biomed, Cagliari, Italy. [Weng, Lu-Chen; Tang, Weihong] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Pool, Rene; Hottenga, Jouke J.; Draisma, Harmen H. M.; de Geus, Eco J. C.; Boomsma, Dorret I.] Vrije Univ Amsterdam, Netherlands Twin Register, Dept Biol Psychol, Amsterdam, Netherlands. [Pool, Rene; de Geus, Eco J. C.] Vrije Univ Amsterdam, EMGO Inst, Amsterdam, Netherlands. [Pool, Rene; de Geus, Eco J. C.] Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands. [Grossmann, Vera] Johannes Gutenberg Univ Mainz, Univ Med Ctr, CTH, Mainz, Germany. [Brody, Jennifer A.] Univ Washington, Dept Med, Seattle, WA USA. [Venturini, Cristina] UCL, Div Infect & Immunol, London, England. [Venturini, Cristina; Mangino, Massimo; Hysi, Pirro G.; Spector, Tim D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England. [Tanaka, Toshiko; Ferrucci, Luigi] NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA. [Mazur, Johanna] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Inst Med Biostat Epidemiol & Informat, Mainz, Germany. [Basu, Saonli; Guan, Weihua] Univ Minnesota, Div Biostat, Minneapolis, MN USA. [Franberg, Mattias] Stockholm Univ, Dept Numer Anal & Comp Sci, Stockholm, Sweden. [Yang, Qiong] Boston Univ, Dept Biostat, Sch Publ Hlth, Boston, MA USA. [Rumley, Ann] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. [Grotevendt, Anne] Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany. [Taylor, Kent D.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA. [Taylor, Kent D.] Harbor UCLA Med Ctr, Dept Pediat, Div Genom Outcomes, Torrance, CA 90509 USA. [Lopez, Lorna M.] Beaumont Hosp, Royal Coll Surg Ireland, Dept Psychiat, Educ & Res Ctr, Dublin, Ireland. [Lopez, Lorna M.] Univ Coll Dublin, UCD Conway Inst, Ctr Proteome Res, Dublin, Ireland. [Berentzen, Tina L.] Bispebjerg & Frederiksberg Hosp, Inst Prevent Med, Copenhagen, Denmark. [Mangino, Massimo] Guys & St Thomas Fdn Trust, NIHR Biomed Res Ctr, London, England. [Bandinelli, Stefania] ASF, Geriatr Unit, Florence, Italy. [Tofler, Geoffrey] Univ Sydney, Royal North Shore Hosp, Sydney, NSW, Australia. [de Maat, Moniek P. M.] Erasmus MC, Dept Hematol, Rotterdam, Netherlands. [Draisma, Harmen H. M.] Neurosci Campus Amsterdam, Amsterdam, Netherlands. [Lowe, Gordon D.] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. [Sattar, Naveed] Fac Med, BHF Glasgow Cardiovasc Res Ctr, Glasgow, Lanark, Scotland. [Lackner, Karl J.] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Inst Clin Chem & Lab Med, Mainz, Germany. [Voelker, Uwe] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany. [McKnight, Barbara] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Huang, Jie] Wellcome Trust Sanger Inst, Dept Human Genet, Cambridge, England. [Holliday, Elizabeth G.] Univ Newcastle, Hunter Med Res Inst, Publ Hlth Stream, Newcastle, NSW, Australia. [Holliday, Elizabeth G.] Univ Newcastle, Sch Med & Publ Hlth, Newcastle, NSW, Australia. [Starr, John M.] Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh, Midlothian, Scotland. [Hernandez, Dena G.] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [McArdle, Wendy L.] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. [Slagboom, P. Eline] Leiden Univ, Dept Mol Epidemiol, Med Ctr, Leiden, Netherlands. [Zeller, Tanja] Univ Med Ctr Hamburg Eppendorf, Univ Heart Ctr, Dept Gen & Intervent Cardiol, Hamburg, Germany. [Zeller, Tanja] German Ctr Cardiovascular Res DZHK, Partner Site Hamburg, Hamburg, Germany. [Psaty, Bruce M.] Univ Washington, Dept Med Epidemiol & Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.; Smith, Nicholas L.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Stott, David J.] Univ Glasgow, Fac Med, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. [Binder, Harald] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Inst Med Biostat Epidemiol & Informat, Mainz, Germany. [Hofman, Albert] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MS USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Los Angeles BioMed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Pediat, Div Genom Outcomes, Torrance, CA 90509 USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Med, Torrance, CA 90509 USA. [Deary, Ian J.] Univ Edinburgh, Dept Psychol, Edinburgh, Midlothian, Scotland. [Maerz, Winfried] Synlab Holding Deutschland GmbH, Synlab Acad, Mannheim, Germany. [Maerz, Winfried] Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria. [Greinacher, Andreas] Univ Med Greifswald, Inst Immunol & Transfus Med, Greifswald, Germany. [Wild, Philipp S.] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Ctr Cardiol, Prevent Cardiol & Prevent Med, Mainz, Germany. [Wild, Philipp S.] Johannes Gutenberg Univ Mainz, Univ Med Ctr, CTH, Mainz, Germany. [Wild, Philipp S.] German Ctr Cardiovasc Res DZHK, Partner Site RhineMain, Mainz, Germany. [Watkins, Hugh] Univ Oxford, Wellcome Trust Ctr Human Genet, Radcliffe Dept Med, Dept Cardiovasc Med, Oxford, England. [Jukema, Jan W.] Durrer Ctr Cardiogenet Res, Amsterdam, Netherlands. [Jukema, Jan W.] Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands. [Scott, Rodney J.] Univ Newcastle, Hunter Med Res Inst, Informat Based Med Program, Newcastle, NSW, Australia. [Scott, Rodney J.] Univ Newcastle, Sch Biomed Sci & Pharm, Newcastle, NSW, Australia. [Hansen, Torben] Univ Copenhagen, Fac Hlth & Med Sci, Sect Metab Genet, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Smith, Nicholas L.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Smith, Nicholas L.] Dept Vet Affairs, Off Res & Dev, Seattle Epidemiol Res & Informat Ctr, Seattle, WA USA. [Strachan, David P.] St Georges Univ London, Populat Hlth Res Inst, London, England. [Dehghan, Abbas] Imperial Coll London, Dept Epidemiol & Biostat, London, England. RP Dehghan, A (reprint author), Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.; Dehghan, A (reprint author), Imperial Coll London, Dept Epidemiol & Biostat, London, England. EM a.dehghan@imperial.ac.uk RI Wang, Jie Jin/P-1499-2014; OI Wang, Jie Jin/0000-0001-9491-4898; Watkins, Hugh/0000-0002-5287-9016; Sabater Lleal, Maria/0000-0002-0128-379X; Ahluwalia, Tarunveer Singh/0000-0002-7464-3354 FU Steno Diabetes Center; Synlab Holding Deutschland GmbH; National Heart, Lung, and Blood Institute [R01HL105756, HL043851, HL080467]; National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694]; National Human Genome Research Institute [U01HG004402]; National Institutes of Health [HHSN268200625226C, UL1RR025005]; NIH Roadmap for Medical Research; NHLBI [R01HL105756, HL0597367, HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, U01HL080295, R01HL087652, R01HL103612, R01HL120393]; Medical Research Council [G0000934]; Wellcome Trust [068545/Z/02, 076113/B/04/Z, 079895, 075491/Z/04]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institute of Allergy and Infectious Diseases (NIAID); National Human Genome Research Institute (NHGRI); National Institute of Child Health and Human Development (NICHD); Juvenile Diabetes Research Foundation International (JDRF); Juvenile Diabetes Research Foundation International; National Institute for Health Research Cambridge Biomedical Research Centre; European Commission Framework Programme 6 [018996]; French Ministry of Research; Australian National Health & Medical Research Council, Canberra Australia [974159, 211069, 457349, 512423, 475604, 529912, 529923]; Wellcome Trust, UK; National Institute on Aging (NIA) [R01AG023629]; National Center for Advancing Translational Sciences, CTSI [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) [DK063491]; National Heart, Lung, and Blood Institute's (NHLBI's) Framingham Heart Study [N01-HC-25195]; Affymetrix, Inc. [N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine; Boston Medical Center; National Institute of Diabetes and Digestive and Kidney Diseases [K24 DK080140]; National Institute on Aging; National Institute for Neurological Disorders and Stroke [R01 AG033193, NS017950]; GENDINOB; government of Rhineland-Palatinate [AZ 961-386261/733]; Johannes Gutenberg-University of Mainz; Boehringer Ingelheim; PHILIPS Medical Systems; Federal Ministry of Education and Research (BMBF) [01EO1003]; Italian Ministry of Health [ICS110.1/RF97.71]; U.S. National Institute on Aging [263 MD 9164, 263 MD 821336]; Intramural Research Program of the NIH, National Institute on Aging; Biotechnology and Biological Sciences Research Council (BBSRC) [BB/F019394/1]; Age UK; BBSRC; MRC; 6th Framework Program (integrated project Bloodomics) [LSHM-CT-2004-503485]; 7th Framework Program (Atheroremo) of the European Union [201668]; RiskyCAD of the European Union [305739]; INTERREG IV Oberrhein Program [A28]; European Regional Development Fund (ERDF); Wissenschaftsoffensive TMO; Netherlands Organization for Scientific Research (NWO); MagW/ZonMW [904-61-090, 985-10-002, 904-61-193, 480-04-004, 400-05-717, Addiction-31160008, Middelgroot-911-09-032, Spinozapremie 56-464-14192]; Center for Medical Systems Biology (CSMB, NWO Genomics); NBIC/BioAssist/RK [2008.024]; Biobanking and Biomolecular Resources Research Infrastructure (BBMRI -NL) [184.021.007]; European Community's Seventh Framework Program (FP7); National Institutes of Health (NIH) [R01D0042157-01A, MH081802, 1RC2 MH089951]; Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health; NWO; European Community Sixth Framework Program [LSHM-CT- 2007-037273]; AstraZeneca; British Heart Foundation; Swedish Research Council; Knut and Alice Wallenberg Foundation; Swedish Heart-Lung Foundation [20130399]; Torsten and Ragnar Soderberg Foundation; Strategic Cardiovascular and Diabetes Programs of Karolinska Institutet; Stockholm County Council; Foundation for Strategic Research; BHF Centre of Research Excellence, Oxford; Ake Wiberg foundation; Tore Nilssons foundation; Magnus Bergvall Foundation; Foundation for Old Servants; European Union's Seventh Framework Programme (FP7) [HEALTH-F2-2009-223004]; Netherlands Consortium of Healthy Aging [NGI: 05060810]; Scottish Executive Chief Scientist Office, Health Services Research Committee [CZG/4/306]; Netherlands Organisation of Scientific Research NWO Investments [175.010.2005.011, 911-03-012]; Research Institute for Diseases in the Elderly (RIDE2) [014-93-015]; Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) [050-060-810]; Erasmus Medical Center; Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission (DG XII); Municipality of Rotterdam; NWO grant (veni) [916.12.154]; EUR Fellowship; NIA [NO1-AG-12109]; Sardinian Autonomous Region [cRP3-154]; Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012]; Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg - West Pomerania; Siemens Healthcare, Erlangen, Germany; Federal State of Mecklenburg West Pomerania; Leibniz Supercomputing Centre of the Bavarian Academy of Sciences and Humanities (HLRB) [h1231]; Ministry of Cultural Affairs of the Federal State of Mecklenburg - West Pomerania [03IS2061A]; European Community's Seventh Framework Programme (FP7); National Institute for Health Research (NIHR) Clinical Research Facility at Guy's & St Thomas' NHS Foundation Trust; NIHR Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust; King's College London; ERC Advanced Principal Investigator award; National Cancer Institute [CA047988]; Donald W. Reynolds Foundation; Fondation Leducq; Amgen; [U01 DK062418] FX Steno Diabetes Center and Synlab Holding Deutschland GmbH provided support in the form of salaries for authors T.S.A. and W.M. respectively, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section. Infrastructure for the CHARGE Consortium is supported in part by the National Heart, Lung, and Blood Institute grant R01HL105756. ARIC is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute (NHLBI) contracts HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C, R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. LITE is supported by HL0597367 from the NHLBI. B58C acknowledges use of phenotype and genotype data from the British 1958 Birth Cohort DNA collection, funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02. Genotyping for the B58C-WTCCC subset was funded by the Wellcome Trust grant 076113/B/04/Z. The B58C-T1DGC genotyping utilized resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Human Genome Research Institute (NHGRI), National Institute of Child Health and Human Development (NICHD), and Juvenile Diabetes Research Foundation International (JDRF) and supported by U01 DK062418. B58C-T1DGC GWAS data were deposited by the Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research (CIMR), University of Cambridge, which is funded by Juvenile Diabetes Research Foundation International, the Wellcome Trust and the National Institute for Health Research Cambridge Biomedical Research Centre; the CIMR is in receipt of a Wellcome Trust Strategic Award (079895). The B58C-GABRIEL genotyping was supported by a contract from the European Commission Framework Programme 6 (018996) and grants from the French Ministry of Research. The BMES has been supported by the Australian National Health & Medical Research Council, Canberra Australia (Grant Numbers 974159, 211069, 457349, 512423, 475604, 529912, and the funding for Centre for Clinical Research Excellence in Translational Clinical Research in Eye Diseases, CCRE in TCR-Eye, grant ID 529923); In addition, funding by the Wellcome Trust, UK (to A Viswanathan, P McGuffin, P Mitchell, F Topouzis, P Foster) has supported the genotyping costs of the entire BMES population. This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA).; The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The FHS was partially supported by the National Heart, Lung, and Blood Institute's (NHLBI's) Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (Contract No. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Partial investigator support was provided by the National Institute of Diabetes and Digestive and Kidney Diseases K24 DK080140 (JB Meigs), the National Institute on Aging and National Institute for Neurological Disorders and Stroke R01 AG033193, NS017950 (S Seshadri). The GOYA Male study was conducted as part of the activities of the Gene-diet Interactions in Obesity project (GENDINOB, www.gendinob.dk) and the MRC centre for Causal Analyses in Translational Epidemiology (MRC CAiTE). We thank the staff of the Copenhagen City Heart Study for their skillful examination of the study subjects in collection of baseline and follow-up data. Tarunveer Singh Ahluwalia received his Postdoctoral Research funding from GENDINOB project and acknowledges the same. The Gutenberg Health Study is funded through the government of Rhineland-Palatinate ("Stiftung Rheinland-Pfalz fur Innovation", contract AZ 961-386261/733), the research programs "Wissen schafft Zukunft" and "Center for Translational Vascular Biology (CTVB)" of the Johannes Gutenberg-University of Mainz, and its contract with Boehringer Ingelheim and PHILIPS Medical Systems, including an unrestricted grant for the Gutenberg Health Study. VG, PSW are funded by the Federal Ministry of Education and Research (BMBF 01EO1003). The InCHIANTI study baseline (1998-2000) was supported as a "targeted project" (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the U.S. National Institute on Aging (Contracts: 263 MD 9164 and 263 MD 821336); This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. The whole genome association study in LBC1936 and LBC1921 was funded by the Biotechnology and Biological Sciences Research Council (BBSRC; Ref. BB/F019394/1). The LBC1936 research was supported by Age UK. The LBC1921 data collection was funded by the BBSRC. The work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology (MR/K026992/1), part of the cross council Lifelong Health and Wellbeing Initiative. Funding from the BBSRC, and MRC is gratefully acknowledged. LURIC has received funding from the 6th Framework Program (integrated project Bloodomics, grant LSHM-CT-2004-503485) and from the 7th Framework Program (Atheroremo, grant agreement number 201668 and RiskyCAD, grant agreement number 305739) of the European Union as well as from the INTERREG IV Oberrhein Program (Project A28, Genetic mechanisms of cardiovascular diseases) with support from the European Regional Development Fund (ERDF) and the Wissenschaftsoffensive TMO.; NTR: Funding was obtained from the Netherlands Organization for Scientific Research (NWO) and MagW/ZonMW grants 904-61-090, 985-10-002, 904-61-193,480-04-004, 400-05-717, Addiction-31160008, Middelgroot-911-09-032, Spinozapremie 56-464-14192, Center for Medical Systems Biology (CSMB, NWO Genomics), NBIC/BioAssist/RK(2008.024), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI -NL, 184.021.007). VU University's Institute for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam (NCA); the European Science Foundation (ESF, EU/QLRT-2001-01254), the European Community's Seventh Framework Program (FP7/2007-2013), ENGAGE (HEALTH-F4-2007-201413); the European Science Council (ERC Advanced, 230374), Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06), the Avera Institute, Sioux Falls, South Dakota (USA) and the National Institutes of Health (NIH, R01D0042157-01A, MH081802, Grand Opportunity grants 1RC2 MH089951). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health. Computing was supported by BiG Grid, the Dutch e-Science Grid, which is financially supported by NWO. PROCARDIS was supported by the European Community Sixth Framework Program (LSHM-CT- 2007-037273), AstraZeneca, the British Heart Foundation, the Wellcome Trust (Contract No. 075491/Z/04), the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Swedish Heart-Lung Foundation, the Torsten and Ragnar Soderberg Foundation, the Strategic Cardiovascular and Diabetes Programs of Karolinska Institutet and Stockholm County Council, the Foundation for Strategic Research and the Stockholm County Council. Jemma C Hopewell and Robert Clarke acknowledge support from the BHF Centre of Research Excellence, Oxford. M.Sabater-Lleal is supported by the Swedish Heart-Lung Foundation (20130399), and acknowledges funding from Ake Wiberg and Tore Nilssons foundations. B.Sennblad acknowledges funding from the Magnus Bergvall Foundation and the Foundation for Old Servants. PROSPER received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement no HEALTH-F2-2009-223004. For a part of the genotyping we received funding from the Netherlands Consortium of Healthy Aging (NGI: 05060810). Measurement of serum fibrinogen was supported by a grant from the Scottish Executive Chief Scientist Office, Health Services Research Committee grant number CZG/4/306. Prof. Dr. J.W. Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (2001 D 032). The generation and management of GWAS genotype data for the Rotterdam Study is supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project nr. 050-060-810. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. Abbas Dehghan is supported by NWO grant (veni, 916.12.154) and the EUR Fellowship.; The SardiNIA ("ProgeNIA") team was supported by Contract NO1-AG-12109 from the NIA. This research was supported by the Intramural Research Program of the NIH, National Institute on Aging, by Sardinian Autonomous Region (L.R. no. 7/2009) grant cRP3-154, and by grant FaReBio2011 "Farmaci e Reti Biotecnologiche di Qualita". SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg - West Pomerania. Genome- wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg West Pomerania. Computing resources have been made available by the Leibniz Supercomputing Centre of the Bavarian Academy of Sciences and Humanities (HLRB project h1231). The University of Greifswald is a member of the 'Center of Knowledge Interchange' program of the Siemens AG and the Cache Campus program of the InterSystems GmbH. This work is also part of the research project Greifswald Approach to Individualized Medicine (GANI_MED). The GANI_MED consortium is funded by the Federal Ministry of Education and Research and the Ministry of Cultural Affairs of the Federal State of Mecklenburg - West Pomerania (03IS2061A). TwinsUK. The study was funded by the Wellcome Trust; European Community's Seventh Framework Programme (FP7/2007-2013). The study also receives support from the National Institute for Health Research (NIHR) Clinical Research Facility at Guy's & St Thomas' NHS Foundation Trust and NIHR Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. Tim Spector is an NIHR senior Investigator and is holder of an ERC Advanced Principal Investigator award. SNP Genotyping was performed by The Wellcome Trust Sanger Institute and National Eye Institute via NIH/CIDR. The WGHS is supported by HL043851 and HL080467 from the National Heart, Lung, and Blood Institute and CA047988 from the National Cancer Institute, the Donald W. Reynolds Foundation and the Fondation Leducq, with collaborative scientific support and funding for genotyping provided by Amgen. NR 52 TC 0 Z9 0 U1 5 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 20 PY 2017 VL 12 IS 1 AR e0167742 DI 10.1371/journal.pone.0167742 PG 22 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI3QC UT WOS:000392405300006 PM 28107422 ER PT J AU Jin, Y Kong, J AF Jin, Yu Kong, Jian TI Transcutaneous Vagus Nerve Stimulation: A Promising Method for Treatment of Autism Spectrum Disorders SO FRONTIERS IN NEUROSCIENCE LA English DT Article DE Autism Spectrum Disorder; transcutaneous electric nerve stimulation; ear; vagus nerve; transcutaneous vagus nerve stimulation; Non-invasive vagus nerve stimulation ID TREATMENT-RESISTANT DEPRESSION; PARTIAL SEIZURES; POLYVAGAL THEORY; EPILEPSY; BRAIN; CONNECTIVITY; CHILDREN; THERAPY; SAFETY; TOLERABILITY AB Transcutaneous Vagus Nerve Stimulation (tVNS) on the auricular branch of the vagus nerve has been receiving attention due to its therapeutic potential for neuropsychiatric disorders. Although the mechanism of tVNS is not yet completely understood, studies have demonstrated the potential role of vagal afferent nerve stimulation in the regulation of mood and visceral state associated with social communication. In addition, a growing body of evidence shows that tVNS can activate the brain regions associated with Autism Spectrum Disorder (ASD), trigger neuroimmune modulation and produce treatment effects for comorbid disorders of ASD such as epilepsy and depression. We thus hypothesize that tVNS may be a promising treatment for ASD, not only for comorbid epilepsy and depression, but also for the core symptoms of ASD. The goal of this manuscript is to summarize the findings and rationales for applying tVNS to treat ASD and propose potential parameters for tVNS treatment of ASD. C1 [Jin, Yu] Sun Yat Sen Univ, Sch Publ Hlth, Dept Maternal & Child Hlth, Guangzhou, Guangdong, Peoples R China. [Jin, Yu; Kong, Jian] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA USA. RP Jin, Y (reprint author), Sun Yat Sen Univ, Sch Publ Hlth, Dept Maternal & Child Hlth, Guangzhou, Guangdong, Peoples R China.; Jin, Y (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA USA. EM jinyu@mail.sysu.edu.cn FU National Natural Science Foundation of China [81171293]; China Scholarship [201506385026]; NIH/CCIH [R01AT006364, R01AT008563, R21AT008707, R61 AT009310, P01 AT006663] FX YJ was supported by National Natural Science Foundation of China (81171293) and China Scholarship (201506385026), JK was supported by R01AT006364, R01AT008563, R21AT008707, R61 AT009310, and P01 AT006663 from NIH/CCIH. NR 69 TC 0 Z9 0 U1 7 U2 7 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-453X J9 FRONT NEUROSCI-SWITZ JI Front. Neurosci. PD JAN 20 PY 2017 VL 10 AR 609 DI 10.3389/fnins.2016.00609 PG 7 WC Neurosciences SC Neurosciences & Neurology GA EI3LO UT WOS:000392392400001 ER PT J AU Istvan, ES Mallari, JP Corey, VC Dharia, NV Marshall, GR Winzeler, EA Goldberg, DE AF Istvan, Eva S. Mallari, Jeremy P. Corey, Victoria C. Dharia, Neekesh V. Marshall, Garland R. Winzeler, Elizabeth A. Goldberg, Daniel E. TI Esterase mutation is a mechanism of resistance to antimalarial compounds SO NATURE COMMUNICATIONS LA English DT Article ID PLASMODIUM-FALCIPARUM; MALARIA PARASITES; INHIBITOR; PROTEASE; VACUOLE; GENE AB Pepstatin is a potent peptidyl inhibitor of various malarial aspartic proteases, and also has parasiticidal activity. Activity of pepstatin against cultured Plasmodium falciparum is highly variable depending on the commercial source. Here we identify a minor contaminant (pepstatin butyl ester) as the active anti-parasitic principle. We synthesize a series of derivatives and characterize an analogue (pepstatin hexyl ester) with low nanomolar activity. By selecting resistant parasite mutants, we find that a parasite esterase, PfPARE (P. falciparum Prodrug Activation and Resistance Esterase) is required for activation of esterified pepstatin. Parasites with esterase mutations are resistant to pepstatin esters and to an open source antimalarial compound, MMV011438. Recombinant PfPARE hydrolyses pepstatin esters and de-esterifies MMV011438. We conclude that (1) pepstatin is a potent but poorly bioavailable antimalarial; (2) PfPARE is a functional esterase that is capable of activating prodrugs; (3) Mutations in PfPARE constitute a mechanism of antimalarial resistance. C1 [Istvan, Eva S.; Mallari, Jeremy P.; Goldberg, Daniel E.] Washington Univ, Sch Med, Div Infect Dis, Dept Med, St Louis, MO 63110 USA. [Istvan, Eva S.; Mallari, Jeremy P.; Goldberg, Daniel E.] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA. [Corey, Victoria C.; Dharia, Neekesh V.; Winzeler, Elizabeth A.] Univ Calif San Diego, Sch Med, Dept Pediat, La Jolla, CA 92093 USA. [Marshall, Garland R.] Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA. [Mallari, Jeremy P.] Calif State Univ San Bernardino, Dept Chem & Biochem, San Bernardino, CA 92407 USA. [Dharia, Neekesh V.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Dharia, Neekesh V.] Boston Childrens Hosp, Boston, MA 02215 USA. RP Goldberg, DE (reprint author), Washington Univ, Sch Med, Div Infect Dis, Dept Med, St Louis, MO 63110 USA.; Goldberg, DE (reprint author), Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA. EM dgoldberg@wustl.edu FU National Institutes of Health\National Institute of General Medical Sciences [8P41GM103422]; NIH [R01 AI112508, R01 AI103058]; Gates Foundation [OPP 1054480] FX This study made use of the NIH/NIGMS Biomedical Mass Spectrometry Resource at Washington University in St Louis, MO, which is supported by National Institutes of Health\National Institute of General Medical Sciences Grant # 8P41GM103422. Financial support came from NIH R01 AI112508 (Goldberg), NIH R01 AI103058 (Winzeler) and Gates Foundation Grant OPP 1054480 (Winzeler, Goldberg). We are grateful for the help of Dr Fong Fu-Hsu and Dr Henry Rohrs (Washington University, Saint Louis) with the mass spectrometry experiments. We thank Hagai Ginsburg, Hebrew University, for microbial pepstatin and Audrey R. Odom for the HAD1 antibody. Sha Sha Lu developed the pepstatin esterification protocol in our laboratory and Cindy Choy purified the first preparation of PBE. NR 26 TC 0 Z9 0 U1 6 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JAN 20 PY 2017 VL 8 AR 14240 DI 10.1038/ncomms14240 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI5NP UT WOS:000392541900001 PM 28106035 ER EF