Providence VA Medical Center

AUTORES: Daniel J Klionsky1745,1749*, Kotb Abdelmohsen840, Akihisa Abe1237, Md Joynal Abedin1762, Hagai Abeliovich425,
\nAbraham Acevedo Arozena789, Hiroaki Adachi1800, Christopher M Adams1669, Peter D Adams57, Khosrow Adeli1981,
\nPeter J Adhihetty1625, Sharon G Adler700, Galila Agam67, Rajesh Agarwal1587, Manish K Aghi1537, Maria Agnello1826,
\nPatrizia Agostinis664, Patricia V Aguilar1960, Julio Aguirre-Ghiso784,786, Edoardo M Airoldi89,422, Slimane Ait-Si-Ali1376,
\nTakahiko Akematsu2010, Emmanuel T Akporiaye1097, Mohamed Al-Rubeai1394, Guillermo M Albaiceta1294,
\nChris Albanese363, Diego Albani561, Matthew L Albert517, Jesus Aldudo128, Hana Alg€ul1164, Mehrdad Alirezaei1198,
\nIraide Alloza642,888, Alexandru Almasan206, Maylin Almonte-Beceril524, Emad S Alnemri1212, Covadonga Alonso544,
\nNihal Altan-Bonnet848, Dario C Altieri1205, Silvia Alvarez1497, Lydia Alvarez-Erviti1395, Sandro Alves107,
\nGiuseppina Amadoro860, Atsuo Amano930, Consuelo Amantini1554, Santiago Ambrosio1458, Ivano Amelio756,
\nAmal O Amer918, Mohamed Amessou2089, Angelika Amon726, Zhenyi An1538, Frank A Anania291, Stig U Andersen6,
\nUsha P Andley2079, Catherine K Andreadi1690, Nathalie Andrieu-Abadie502, Alberto Anel2027, David K Ann58,
\nShailendra Anoopkumar-Dukie388, Manuela Antonioli832,858, Hiroshi Aoki1791, Nadezda Apostolova2007,
\nSaveria Aquila1500, Katia Aquilano1876, Koichi Araki292, Eli Arama2098, Agustin Aranda456, Jun Araya591,
\nAlexandre Arcaro1472, Esperanza Arias26, Hirokazu Arimoto1225, Aileen R Ariosa1749, Jane L Armstrong1930,
\nThierry Arnould1773, Ivica Arsov2120, Katsuhiko Asanuma675, Valerie Askanas1924, Eric Asselin1867, Ryuichiro Atarashi794,
\nSally S Atherton369, Julie D Atkin713, Laura D Attardi1131, Patrick Auberger1787, Georg Auburger379, Laure Aurelian1727,
\nRiccardo Autelli1992, Laura Avagliano1029,1755, Maria Laura Avantaggiati364, Limor Avrahami1166, Suresh Awale1986,
\nNeelam Azad404, Tiziana Bachetti568, Jonathan M Backer28, Dong-Hun Bae1933, Jae-sung Bae677, Ok-Nam Bae409,
\nSoo Han Bae2117, Eric H Baehrecke1729, Seung-Hoon Baek17, Stephen Baghdiguian1368,
\nAgnieszka Bagniewska-Zadworna2, Hua Bai90, Jie Bai667, Xue-Yuan Bai1133, Yannick Bailly884,
\nKithiganahalli Narayanaswamy Balaji473, Walter Balduini2002, Andrea Ballabio316, Rena Balzan1711, Rajkumar Banerjee239,
\nG abor B anhegyi1052, Haijun Bao2109, Benoit Barbeau1363, Maria D Barrachina2007, Esther Barreiro467, Bonnie Bartel997,
\nAlberto Bartolom e222, Diane C Bassham550, Maria Teresa Bassi1046, Robert C Bast Jr1273, Alakananda Basu1798,
\nMaria Teresa Batista1578, Henri Batoko1336, Maurizio Battino970, Kyle Bauckman2085, Bradley L Baumgarner1909,
\nK Ulrich Bayer1594, Rupert Beale1553, Jean-Fran¸cois Beaulieu1360, George R. Beck Jr48,294, Christoph Becker336,
\nJ David Beckham1595, Pierre-Andr e B edard749, Patrick J Bednarski301, Thomas J Begley1135, Christian Behl1419,
\nChristian Behrends757, Georg MN Behrens406, Kevin E Behrns1627, Eloy Bejarano26, Amine Belaid490,
\nFrancesca Belleudi1041, Giovanni B enard497, Guy Berchem706, Daniele Bergamaschi983, Matteo Bergami1401,
\nBen Berkhout1441, Laura Berliocchi714, Am elie Bernard1749, Monique Bernard1354, Francesca Bernassola1880,
\nAnne Bertolotti791, Amanda S Bess272, S ebastien Besteiro1351, Saverio Bettuzzi1828, Savita Bhalla913,
\nShalmoli Bhattacharyya973, Sujit K Bhutia838, Caroline Biagosch1159, Michele Wolfe Bianchi520,1378,1381,
\nMartine Biard-Piechaczyk210, Viktor Billes298, Claudia Bincoletto1314, Baris Bingol350, Sara W Bird1128, Marc Bitoun1112,
\nIvana Bjedov1258, Craig Blackstone843, Lionel Blanc1183, Guillermo A Blanco1496, Heidi Kiil Blomhoff1812,
\nEmilio Boada-Romero1297, Stefan B€ockler1464, Marianne Boes1423, Kathleen Boesze-Battaglia1835, Lawrence H Boise286,287,
\nAlessandra Bolino2063, Andrea Boman693, Paolo Bonaldo1823, Matteo Bordi897, J€urgen Bosch608, Luis M Botana1308,
\nJoelle Botti1375, German Bou1405, Marina Bouch e1038, Marion Bouchecareilh1331, Marie-Jos ee Boucher1901,
\nMichael E Boulton481, Sebastien G Bouret1926, Patricia Boya133, Micha€el Boyer-Guittaut1345, Peter V Bozhkov1141,
\nNathan Brady374, Vania MM Braga469, Claudio Brancolini1997, Gerhard H Braus353, Jos e M Bravo-San Pedro299,393,508,1374,
\nLisa A Brennan322, Emery H Bresnick2022, Patrick Brest490, Dave Bridges1939, Marie-Agn es Bringer124, Marisa Brini1822,
\nGlauber C Brito1311, Bertha Brodin631, Paul S Brookes1872, Eric J Brown352, Karen Brown1690, Hal E Broxmeyer480,
\nAlain Bruhat486,1339, Patricia Chakur Brum1893, John H Brumell446, Nicola Brunetti-Pierri315,1171,
\nRobert J Bryson-Richardson781, Shilpa Buch1777, Alastair M Buchan1819, Hikmet Budak1022, Dmitry V Bulavin118,505,1789,
\nScott J Bultman1792, Geert Bultynck665, Vladimir Bumbasirevic1470, Yan Burelle1356, Robert E Burke216,217,
\nMargit Burmeister1750, Peter B€utikofer1473, Laura Caberlotto1987, Ken Cadwell896, Monika Cahova112, Dongsheng Cai24,
\nJingjing Cai2099, Qian Cai1018, Sara Calatayud2007, Nadine Camougrand1343, Michelangelo Campanella1700,
\nGrant R Campbell1525, Matthew Campbell1249, Silvia Campello556,1876, Robin Candau1769, Isabella Caniggia1983,
\nLavinia Cantoni560, Lizhi Cao116, Allan B Caplan1656, Michele Caraglia1051, Claudio Cardinali1043, Sandra Morais Cardoso1579, Jennifer S Carew208, Laura A Carleton874, Cathleen R Carlin101, Silvia Carloni2002,
\nSven R Carlsson1267, Didac Carmona-Gutierrez1643, Leticia AM Carneiro312, Oliana Carnevali971, Serena Carra1318,
\nAlice Carrier120, Bernadette Carroll900, Caty Casas1324, Josefina Casas1116, Giuliana Cassinelli324, Perrine Castets1462,
\nSusana Castro-Obregon214, Gabriella Cavallini1841, Isabella Ceccherini568, Francesco Cecconi253,555,1884,
\nArthur I Cederbaum459, Valent ın Ce~na199,1281, Simone Cenci1323,2064, Claudia Cerella444, Davide Cervia1996,
\nSilvia Cetrullo1478, Hassan Chaachouay2028, Han-Jung Chae187, Andrei S Chagin634, Chee-Yin Chai626,628,
\nGopal Chakrabarti1502, Georgios Chamilos1601, Edmond YW Chan1142, Matthew TV Chan181, Dhyan Chandra1003,
\nPallavi Chandra548, Chih-Peng Chang818, Raymond Chuen-Chung Chang1653, Ta Yuan Chang345, John C Chatham1434,
\nSaurabh Chatterjee1910, Santosh Chauhan527, Yongsheng Che62, Michael E Cheetham1263, Rajkumar Cheluvappa1783,
\nChun-Jung Chen1153, Gang Chen598,1676, Guang-Chao Chen9, Guoqiang Chen1078, Hongzhuan Chen1077, Jeff W Chen1514,
\nJian-Kang Chen370,371, Min Chen249, Mingzhou Chen2104, Peiwen Chen1823, Qi Chen1674, Quan Chen172,
\nShang-Der Chen138, Si Chen325, Steve S-L Chen10, Wei Chen2125, Wei-Jung Chen829, Wen Qiang Chen979, Wenli Chen1113,
\nXiangmei Chen1133, Yau-Hung Chen1157, Ye-Guang Chen1250, Yin Chen1447, Yingyu Chen953,955, Yongshun Chen2135,
\nYu-Jen Chen712, Yue-Qin Chen1145, Yujie Chen1208, Zhen Chen339, Zhong Chen2123, Alan Cheng1702,
\nChristopher HK Cheng184, Hua Cheng1728, Heesun Cheong814, Sara Cherry1836, Jason Chesney1703,
\nChun Hei Antonio Cheung817, Eric Chevet1359, Hsiang Cheng Chi140, Sung-Gil Chi656, Fulvio Chiacchiera308,
\nHui-Ling Chiang958, Roberto Chiarelli1826, Mario Chiariello235,567,577, Marcello Chieppa835, Lih-Shen Chin290,
\nMario Chiong1285, Gigi NC Chiu878, Dong-Hyung Cho676, Ssang-Goo Cho650, William C Cho982, Yong-Yeon Cho105,
\nYoung-Seok Cho1064, Augustine MK Choi2095, Eui-Ju Choi656, Eun-Kyoung Choi387,400,685, Jayoung Choi1563,
\nMary E Choi2093, Seung-Il Choi2116, Tsui-Fen Chou412, Salem Chouaib395, Divaker Choubey1574, Vinay Choubey1936,
\nKuan-Chih Chow822, Kamal Chowdhury730, Charleen T Chu1856, Tsung-Hsien Chuang827, Taehoon Chun657,
\nHyewon Chung652, Taijoon Chung978, Yuen-Li Chung1194, Yong-Joon Chwae18, Valentina Cianfanelli254,
\nRoberto Ciarcia1775, Iwona A Ciechomska886, Maria Rosa Ciriolo1876, Mara Cirone1042, Sofie Claerhout1694,
\nMichael J Clague1698, Joan Cl aria1457, Peter GH Clarke1687, Robert Clarke361, Emilio Clementi1045,1398, C edric Cleyrat1781,
\nMiriam Cnop1366, Eliana M Coccia574, Tiziana Cocco1459, Patrice Codogno1375, J€orn Coers271, Ezra EW Cohen1533,
\nDavid Colecchia235,567,577, Luisa Coletto25, N uria S Coll123, Emma Colucci-Guyon516, Sergio Comincini1829,
\nMaria Condello578, Katherine L Cook2073, Graham H Coombs1929, Cynthia D Cooper2076, J Mark Cooper1395,
\nIsabelle Coppens601, Maria Tiziana Corasaniti1387, Marco Corazzari485,1884, Ramon Corbalan1566,
\nElisabeth Corcelle-Termeau251, Mario D Cordero1899, Cristina Corral-Ramos1289, Olga Corti507,1109, Andrea Cossarizza1767,
\nPaola Costelli1993, Safia Costes1518, Susan L Cotman721, Ana Coto-Montes946, Sandra Cottet566,1688, Eduardo Couve1301,
\nLori R Covey1015, L Ashley Cowart762, Jeffery S Cox1536, Fraser P Coxon1427, Carolyn B Coyne1846, Mark S Cragg1919,
\nRolf J Craven1679, Tiziana Crepaldi1995, Jose L Crespo1300, Alfredo Criollo1285, Valeria Crippa558, Maria Teresa Cruz1576,
\nAna Maria Cuervo26, Jose M Cuezva1277, Taixing Cui1907, Pedro R Cutillas987, Mark J Czaja27, Maria F Czyzyk-Krzeska1572,
\nRuben K Dagda2068, Uta Dahmen1404, Chunsun Dai800, Wenjie Dai1187, Yun Dai2059, Kevin N Dalby1940,
\nLuisa Dalla Valle1822, Guillaume Dalmasso1340, Marcello D’Amelio557, Markus Damme188, Arlette Darfeuille-Michaud1340,
\nCatherine Dargemont950, Victor M Darley-Usmar1433, Srinivasan Dasarathy205, Biplab Dasgupta202, Srikanta Dash1254,
\nCrispin R Dass242, Hazel Marie Davey8, Lester M Davids1560, David D avila227, Roger J Davis1731, Ted M Dawson604,
\nValina L Dawson606, Paula Daza1898, Jackie de Belleroche470, Paul de Figueiredo1180,1182,
\nRegina Celia Bressan Queiroz de Figueiredo135, Jos e de la Fuente1023, Luisa De Martino1775,
\nAntonella De Matteis1171, Guido RY De Meyer1443, Angelo De Milito631, Mauro De Santi2002,

IMPORTANCE: Understanding skin cancer incidence is critical for planning prevention and treatment strategies and allocating medical resources. However, owing to lack of national reporting and previously nonspecific diagnosis classification, accurate measurement of the US incidence of nonmelanoma skin cancer (NMSC) has been difficult. OBJECTIVE: To estimate the incidence of NMSC (keratinocyte carcinomas) in the US population in 2012 and the incidence of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) in the 2012 Medicare fee-for-service population. DESIGN, SETTING, AND PARTICIPANTS: This study analyzes US government administrative data including the Centers for Medicare & Medicaid Services Physicians Claims databases to calculate totals of skin cancer procedures performed for Medicare beneficiaries from 2006 through 2012 and related parameters. The population-based National Ambulatory Medical Care Survey database was used to estimate NMSC-related office visits for 2012. We combined these analyses to estimate totals of new skin cancer diagnoses and affected individuals in the overall US population. MAIN OUTCOMES AND MEASURES: Incidence of NMSC in the US population in 2012 and BCC and SCC in the 2012 Medicare fee-for-service population. RESULTS: The total number of procedures for skin cancer in the Medicare fee-for-service population increased by 13% from 2,048,517 in 2006 to 2,321,058 in 2012. The age-adjusted skin cancer procedure rate per 100,000 beneficiaries increased from 6075 in 2006 to 7320 in 2012. The number of procedures in Medicare beneficiaries specific for NMSC increased by 14% from 1,918,340 in 2006 to 2,191,100 in 2012. The number of persons with at least 1 procedure for NMSC increased by 14% (from 1,177,618 to 1,336,800) from 2006 through 2012. In the 2012 Medicare fee-for-service population, the age-adjusted procedure rate for BCC and SCC were 3280 and 3278 per 100,000 beneficiaries, respectively. The ratio of BCC to SCC treated in Medicare beneficiaries was 1.0. We estimate the total number of NMSCs in the US population in 2012 at 5,434,193 and the total number of persons in the United States treated for NMSC at 3,315,554. CONCLUSIONS AND RELEVANCE: This study is a thorough nationwide estimate of the incidence of NMSC and provides evidence of continued increases in numbers of skin cancer diagnoses and affected patients in the United States. This study also demonstrates equal incidence rates for BCC and SCC in the Medicare population.

UNLABELLED: Nonalcoholic steatohepatitis (NASH) is a chronic progressive liver disease that is strongly associated with obesity. Currently, there is no approved therapy for NASH. Weight reduction is typically recommended, but efficacy data are lacking. We performed a randomized controlled trial to examine the effects of lifestyle intervention using a combination of diet, exercise, and behavior modification, with a goal of 7% to 10% weight reduction, on clinical parameters of NASH. The primary outcome measure was the change in NASH histological activity score (NAS) after 48 weeks of intervention. Thirty-one overweight or obese individuals (body mass index [BMI], 25-40 kg/m(2)) with biopsy-proven NASH were randomized in a 2:1 ratio to receive intensive lifestyle intervention (LS) or structured education (control). After 48 weeks of intervention, participants assigned to LS lost an average of 9.3% of their weight versus 0.2% in the control group (P = 0.003). A higher proportion of participants in the LS group had a reduction of NAS of at least 3 points or had posttreatment NAS of 2 or less as compared with the control group (72% versus 30%, P = 0.03). NAS improved significantly in the LS group (from 4.4 to 2.0) in comparison with the control group (from 4.9 to 3.5) (P = 0.05). Percent weight reduction correlated significantly with improvement in NAS (r = 0.497, P = 0.007). Participants who achieved the study weight loss goal (>or=7%), compared with those who lost less than 7%, had significant improvements in steatosis (-1.36 versus -0.41, P < 0.001), lobular inflammation (-0.82 versus -0.24, P = 0.03), ballooning injury (-1.27 versus -0.53, P = 0.03) and NAS (-3.45 versus -1.18, P < 0.001). CONCLUSION: Weight reduction achieved through lifestyle intervention leads to improvements in liver histology in NASH.

CONTEXT: The prevalence of posttraumatic stress disorder (PTSD) is elevated among women who have served in the military, but no prior study has evaluated treatment for PTSD in this population. Prior research suggests that cognitive behavioral therapy is a particularly effective treatment for PTSD. OBJECTIVE: To compare prolonged exposure, a type of cognitive behavioral therapy, with present-centered therapy, a supportive intervention, for the treatment of PTSD. DESIGN, SETTING, AND PARTICIPANTS: A randomized controlled trial of female veterans (n=277) and active-duty personnel (n=7) with PTSD recruited from 9 VA medical centers, 2 VA readjustment counseling centers, and 1 military hospital from August 2002 through October 2005. INTERVENTION: Participants were randomly assigned to receive prolonged exposure (n = 141) or present-centered therapy (n = 143), delivered according to standard protocols in 10 weekly 90-minute sessions. MAIN OUTCOME MEASURES: Posttraumatic stress disorder symptom severity was the primary outcome. Comorbid symptoms, functioning, and quality of life were secondary outcomes. Blinded assessors collected data before and after treatment and at 3- and 6-month follow-up. RESULTS: Women who received prolonged exposure experienced greater reduction of PTSD symptoms relative to women who received present-centered therapy (effect size, 0.27; P = .03). The prolonged exposure group was more likely than the present-centered therapy group to no longer meet PTSD diagnostic criteria (41.0% vs 27.8%; odds ratio, 1.80; 95% confidence interval, 1.10-2.96; P = .01) and achieve total remission (15.2% vs 6.9%; odds ratio, 2.43; 95% confidence interval, 1.10-5.37; P = .01). Effects were consistent over time in longitudinal analyses, although in cross-sectional analyses most differences occurred immediately after treatment. CONCLUSIONS: Prolonged exposure is an effective treatment for PTSD in female veterans and active-duty military personnel. It is feasible to implement prolonged exposure across a range of clinical settings. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00032617.

These clinical practice guidelines are an update of the guidelines published by the Infectious Diseases Society of America (IDSA) in 2009, prior to the 2009 H1N1 influenza pandemic. This document addresses new information regarding diagnostic testing, treatment and chemoprophylaxis with antiviral medications, and issues related to institutional outbreak management for seasonal influenza. It is intended for use by primary care clinicians, obstetricians, emergency medicine providers, hospitalists, laboratorians, and infectious disease specialists, as well as other clinicians managing patients with suspected or laboratory-confirmed influenza. The guidelines consider the care of children and adults, including special populations such as pregnant and postpartum women and immunocompromised patients.

Importance: Frailty is a common geriatric syndrome of significant public health importance, yet there is limited understanding of the risk of frailty development at a population level. Objective: To estimate the global incidence of frailty and prefrailty among community-dwelling adults 60 years or older. Data Sources: MEDLINE, Embase, PsycINFO, Web of Science, CINAHL Plus, and AMED (Allied and Complementary Medicine Database) were searched from inception to January 2019 without language restrictions using combinations of the keywords frailty, older adults, and incidence. The reference lists of eligible studies were hand searched. Study Selection: In the systematic review, 2 authors undertook the search, article screening, and study selection. Cohort studies that reported or had sufficient data to compute incidence of frailty or prefrailty among community-dwelling adults 60 years or older at baseline were eligible. Data Extraction and Synthesis: The methodological quality of included studies was assessed using The Joanna Briggs Institute's Critical Appraisal Checklist for Prevalence and Incidence Studies. Meta-analysis was conducted using a random-effects (DerSimonian and Laird) model. Main Outcomes and Measures: Incidence of frailty (defined as new cases of frailty among robust or prefrail individuals) and incidence of prefrailty (defined as new cases of prefrailty among robust individuals), both over a specified duration. Results: Of 15 176 retrieved references, 46 observational studies involving 120 805 nonfrail (robust or prefrail) participants from 28 countries were included in this systematic review. Among the nonfrail individuals who survived a median follow-up of 3.0 (range, 1.0-11.7) years, 13.6% (13 678 of 100 313) became frail, with the pooled incidence rate being 43.4 (95% CI, 37.3-50.4; I2 = 98.5%) cases per 1000 person-years. The incidence of frailty was significantly higher in prefrail individuals than robust individuals (pooled incidence rates, 62.7 [95% CI, 49.2-79.8; I2 = 97.8%] vs 12.0 [95% CI, 8.2-17.5; I2 = 94.9%] cases per 1000 person-years, respectively; P for difference < .001). Among robust individuals in 21 studies who survived a median follow-up of 2.5 (range, 1.0-10.0) years, 30.9% (9974 of 32 268) became prefrail, with the pooled incidence rate being 150.6 (95% CI, 123.3-184.1; I2 = 98.9%) cases per 1000 person-years. The frailty and prefrailty incidence rates were significantly higher in women than men (frailty: 44.8 [95% CI, 36.7-61.3; I2 = 97.9%] vs 24.3 [95% CI, 19.6-30.1; I2 = 8.94%] cases per 1000 person-years; prefrailty: 173.2 [95% CI, 87.9-341.2; I2 = 99.1%] vs 129.0 [95% CI, 73.8-225.0; I2 = 98.5%] cases per 1000 person-years). The incidence rates varied by diagnostic criteria and country income level. The frailty and prefrailty incidence rates were significantly reduced when accounting for the risk of death. Conclusions and Relevance: Results of this study suggest that community-dwelling older adults are prone to developing frailty. Increased awareness of the factors that confer high risk of frailty in this population subgroup is vital to inform the design of interventions to prevent frailty and to minimize its consequences.

BACKGROUND: Previous reports on molecular rapid diagnostic testing (mRDT) do not consistently demonstrate improved clinical outcomes in bloodstream infections (BSIs). This meta-analysis seeks to evaluate the impact of mRDT in improving clinical outcomes in BSIs. METHODS: We searched PubMed, CINAHL, Web of Science, and EMBASE through May 2016 for BSI studies comparing clinical outcomes between mRDT and conventional microbiology methods. RESULTS: Thirty-one studies were included with 5920 patients. The mortality risk was significantly lower with mRDT than with conventional microbiology methods (odds ratio [OR], 0.66; 95% confidence interval [CI], .54-.80), yielding a number needed to treat of 20. The mortality risk was slightly lower with mRDT in studies with antimicrobial stewardship programs (ASPs) (OR, 0.64; 95% CI, .51-.79), and non-ASP studies failed to demonstrate a significant decrease in mortality risk (0.72; .46-1.12). Significant decreases in mortality risk were observed with both gram-positive (OR, 0.73; 95% CI, .55-.97) and gram-negative organisms (0.51; .33-.78) but not yeast (0.90; .49-1.67). Time to effective therapy decreased by a weighted mean difference of -5.03 hours (95% CI, -8.60 to -1.45 hours), and length of stay decreased by -2.48 days (-3.90 to -1.06 days). CONCLUSIONS: For BSIs, mRDT was associated with significant decreases in mortality risk in the presence of a ASP, but not in its absence. mRDT also decreased the time to effective therapy and the length of stay. mRDT should be considered as part of the standard of care in patients with BSIs.

OBJECTIVE: To describe incidence trends for cutaneous T-cell lymphoma (CTCL) in the United States. DESIGN: Population-based study. SETTING: Data were obtained from 13 population-based cancer registries of the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute from 1973 through 2002. PARTICIPANTS: A total of 4783 cases of CTCL were identified for the period 1973 through 2002. MAIN OUTCOME MEASURE: Diagnosis of CTCL. RESULTS: The overall annual age-adjusted incidence of CTCL was 6.4 per million persons. Annual incidence increased by 2.9 x 10(-6) per decade over the study period. Incidence was higher among blacks (9.0 x 10(-6)) than among whites (6.1 x 10(-6)) and was higher among men (8.7 x 10(-6)) than among women (4.6 x 10(-6)). The racial differences in incidence decreased with age, while the sex differences increased with age and decreased over time. Substantial geographic variation in incidence was found. Incidence was correlated with high physician density, high family income, high percentage of population with a bachelor's degree or higher, and high home values. Changes in International Classification of Diseases for Oncology (ICD-O) morphologic definitions have resulted in the redistribution of the cases of CTCL among specific subclassifications. CONCLUSIONS: The continued rise in incidence of CTCL is substantial, and the cause of this increase is unknown. The racial, ethnic, sex, and geographic differences in incidence may be of etiologic importance. Changes in ICD-O definitions have made it difficult to evaluate incidence trends for subclassifications of CTCL such as mycosis fungoides. In addition, these changes resulted in the creation of ambiguous histologic codes, which may have caused coding errors. These errors along with the lack of independent verification are limitations of our study. An epidemiological investigation using population-based data is important to better understand this disorder.

BACKGROUND: Major adverse cardiovascular events (MACE) are increasingly used as composite outcomes in randomized controlled trials (RCTs) and observational studies. However, it is unclear how observational studies most commonly define MACE in the literature when using administrative data. METHODS: We identified peer-reviewed articles published in MEDLINE and EMBASE between January 1, 2010 to October 9, 2020. Studies utilizing administrative data to assess the MACE composite outcome using International Classification of Diseases 9th or 10th Revision diagnosis codes were included. Reviews, abstracts, and studies not providing outcome code definitions were excluded. Data extracted included data source, timeframe, MACE components, code definitions, code positions, and outcome validation. RESULTS: A total of 920 articles were screened, 412 were retained for full-text review, and 58 were included. Only 8.6% (n = 5/58) matched the traditional three-point MACE RCT definition of acute myocardial infarction (AMI), stroke, or cardiovascular death. None matched four-point (+unstable angina) or five-point MACE (+unstable angina and heart failure). The most common MACE components were: AMI and stroke, 15.5% (n = 9/58); AMI, stroke, and all-cause death, 13.8% (n = 8/58); and AMI, stroke and cardiovascular death 8.6% (n = 5/58). Further, 67% (n = 39/58) did not validate outcomes or cite validation studies. Additionally, 70.7% (n = 41/58) did not report code positions of endpoints, 20.7% (n = 12/58) used the primary position, and 8.6% (n = 5/58) used any position. CONCLUSIONS: Components of MACE endpoints and diagnostic codes used varied widely across observational studies. Variability in the MACE definitions used and information reported across observational studies prohibit the comparison, replication, and aggregation of findings. Studies should transparently report the administrative codes used and code positions, as well as utilize validated outcome definitions when possible.

The ongoing pilot clinical trial of the BrainGate neural interface system aims in part to assess the feasibility of using neural activity obtained from a small-scale, chronically implanted, intracortical microelectrode array to provide control signals for a neural prosthesis system. Critical questions include how long implanted microelectrodes will record useful neural signals, how reliably those signals can be acquired and decoded, and how effectively they can be used to control various assistive technologies such as computers and robotic assistive devices, or to enable functional electrical stimulation of paralyzed muscles. Here we examined these questions by assessing neural cursor control and BrainGate system characteristics on five consecutive days 1000 days after implant of a 4 × 4 mm array of 100 microelectrodes in the motor cortex of a human with longstanding tetraplegia subsequent to a brainstem stroke. On each of five prospectively-selected days we performed time-amplitude sorting of neuronal spiking activity, trained a population-based Kalman velocity decoding filter combined with a linear discriminant click state classifier, and then assessed closed-loop point-and-click cursor control. The participant performed both an eight-target center-out task and a random target Fitts metric task which was adapted from a human-computer interaction ISO standard used to quantify performance of computer input devices. The neural interface system was further characterized by daily measurement of electrode impedances, unit waveforms and local field potentials. Across the five days, spiking signals were obtained from 41 of 96 electrodes and were successfully decoded to provide neural cursor point-and-click control with a mean task performance of 91.3% ± 0.1% (mean ± s.d.) correct target acquisition. Results across five consecutive days demonstrate that a neural interface system based on an intracortical microelectrode array can provide repeatable, accurate point-and-click control of a computer interface to an individual with tetraplegia 1000 days after implantation of this sensor.

Abstract Speech brain–computer interfaces (BCIs) have the potential to restore rapid communication to people with paralysis by decoding neural activity evoked by attempted speech into text 1,2 or sound 3,4 . Early demonstrations, although promising, have not yet achieved accuracies sufficiently high for communication of unconstrained sentences from a large vocabulary 1–7 . Here we demonstrate a speech-to-text BCI that records spiking activity from intracortical microelectrode arrays. Enabled by these high-resolution recordings, our study participant—who can no longer speak intelligibly owing to amyotrophic lateral sclerosis—achieved a 9.1% word error rate on a 50-word vocabulary (2.7 times fewer errors than the previous state-of-the-art speech BCI 2 ) and a 23.8% word error rate on a 125,000-word vocabulary (the first successful demonstration, to our knowledge, of large-vocabulary decoding). Our participant’s attempted speech was decoded at 62 words per minute, which is 3.4 times as fast as the previous record 8 and begins to approach the speed of natural conversation (160 words per minute 9 ). Finally, we highlight two aspects of the neural code for speech that are encouraging for speech BCIs: spatially intermixed tuning to speech articulators that makes accurate decoding possible from only a small region of cortex, and a detailed articulatory representation of phonemes that persists years after paralysis. These results show a feasible path forward for restoring rapid communication to people with paralysis who can no longer speak.

BACKGROUND: Actinic keratoses (AKs) are established as direct precursors of squamous cell carcinoma (SCC), but there is significant controversy regarding the rate at which AKs progress to SCC. The authors of this report studied a high-risk population to estimate the risk of progression of AK to SCC and to basal cell carcinoma (BCC) and the risk of spontaneous regression of untreated AKs. METHODS: Data were obtained from participants in the Department of Veterans Affairs Topical Tretinoin Chemoprevention Trial. Participants were examined every 6 months for up to 6 years. At each examination, the locations on the face and ears of clinically diagnosed AKs and lesions scheduled for biopsy were marked, and high-resolution digital photographs were taken. These photographs were used later to map and track the presence, absence, or biopsy of each AK across visits. RESULTS: In total, 7784 AKs were identified on the face and ears of 169 participants. The risk of progression of AK to primary SCC (invasive or in situ) was 0.60% at 1 year and 2.57% at 4 years. Approximately 65% of all primary SCCs and 36% of all primary BCCs diagnosed in the study cohort arose in lesions that previously were diagnosed clinically as AKs. The majority of AKs (55%) that were followed clinically were not present at the 1-year follow-up, and the majority (70%) were not present at the 5-year follow-up. CONCLUSIONS: In the current study, the authors quantified the malignant potential of clinically diagnosed AKs for both SCC and BCC, although many did not persist, and the results suggested that AKs may play a greater role in the overall burden of keratinocyte carcinomas than previously documented.

<b>Objective</b>&nbsp;To quantify the accuracy and reproducibility of pathologists’ diagnoses of melanocytic skin lesions. <b>Design</b>&nbsp;Observer accuracy and reproducibility study. <b>Setting</b>&nbsp;10 US states. <b>Participants</b>&nbsp;Skin biopsy cases (n=240), grouped into sets of 36 or 48. Pathologists from 10 US states were randomized to independently interpret the same set on two occasions (phases 1 and 2), at least eight months apart. <b>Main outcome measures</b>&nbsp;Pathologists’ interpretations were condensed into five classes: I (eg, nevus or mild atypia); II (eg, moderate atypia); III (eg, severe atypia or melanoma in situ); IV (eg, pathologic stage T1a (pT1a) early invasive melanoma); and V (eg, ≥pT1b invasive melanoma). Reproducibility was assessed by intraobserver and interobserver concordance rates, and accuracy by concordance with three reference diagnoses. <b>Results</b>&nbsp;In phase 1, 187 pathologists completed 8976 independent case interpretations resulting in an average of 10 (SD 4) different diagnostic terms applied to each case. Among pathologists interpreting the same cases in both phases, when pathologists diagnosed a case as class I or class V during phase 1, they gave the same diagnosis in phase 2 for the majority of cases (class I 76.7%; class V 82.6%). However, the intraobserver reproducibility was lower for cases interpreted as class II (35.2%), class III (59.5%), and class IV (63.2%). Average interobserver concordance rates were lower, but with similar trends. Accuracy using a consensus diagnosis of experienced pathologists as reference varied by class: I, 92% (95% confidence interval 90% to 94%); II, 25% (22% to 28%); III, 40% (37% to 44%); IV, 43% (39% to 46%); and V, 72% (69% to 75%). It is estimated that at a population level, 82.8% (81.0% to 84.5%) of melanocytic skin biopsy diagnoses would have their diagnosis verified if reviewed by a consensus reference panel of experienced pathologists, with 8.0% (6.2% to 9.9%) of cases overinterpreted by the initial pathologist and 9.2% (8.8% to 9.6%) underinterpreted. <b>Conclusion</b>&nbsp;Diagnoses spanning moderately dysplastic nevi to early stage invasive melanoma were neither reproducible nor accurate in this large study of pathologists in the USA. Efforts to improve clinical practice should include using a standardized classification system, acknowledging uncertainty in pathology reports, and developing tools such as molecular markers to support pathologists’ visual assessments.

There is an urgent need to identify lifestyle activities that reduce functional decline and dementia associated with population aging. The goals of this article are to review critically the evidence on the benefits associated with formal volunteering among older adults, propose a theoretical model of how volunteering may reduce functional limitations and dementia risk, and offer recommendations for future research. Database searches identified 113 papers on volunteering benefits in older adults, of which 73 were included. Data from descriptive, cross-sectional, and prospective cohort studies, along with 1 randomized controlled trial, most consistently reveal that volunteering is associated with reduced symptoms of depression, better self-reported health, fewer functional limitations, and lower mortality. The extant evidence provides the basis for a model proposing that volunteering increases social, physical, and cognitive activity (to varying degrees depending on characteristics of the volunteer placement) which, through biological and psychological mechanisms, leads to improved functioning; we further propose that these volunteering-related functional improvements should be associated with reduced dementia risk. Recommendations for future research are that studies (a) include more objective measures of psychosocial, physical, and cognitive functioning; (b) integrate qualitative and quantitative methods in prospective study designs; (c) explore further individual differences in the benefits associated with volunteering; (d) include occupational analyses of volunteers' specific jobs in order to identify their social, physical, and cognitive complexity; (e) investigate the independent versus interactive health benefits associated with volunteering relative to engagement in other forms of activity; and (f) examine the relationship between volunteering and dementia risk.

BACKGROUND: Department of Veterans Affairs Cooperative Study 420 is a randomized clinical trial of 2 methods of group psychotherapy for treating posttraumatic stress disorder (PTSD) in male Vietnam veterans. METHODS: Vietnam veterans (360 men) were randomly assigned to receive trauma-focused group psychotherapy or a present-centered comparison treatment that avoided trauma focus. Treatment was provided weekly to groups of 6 members for 30 weeks, followed by 5 monthly booster sessions. Severity of PTSD was the primary outcome. Additional measures were other psychiatric symptoms, functional status, quality of life, physical health, and service utilization. Follow-up assessments were conducted at the end of treatment (7 months) and at the end of the booster sessions (12 months); 325 individuals participated in 1 or both assessments. Additional follow-up for PTSD severity was performed in a subset of participants at 18 and 24 months. RESULTS: Although posttreatment assessments of PTSD severity and other measures were significantly improved from baseline, intention-to-treat analyses found no overall differences between therapy groups on any outcome. Analyses of data from participants who received an adequate dose of treatment suggested that trauma-focused group therapy reduced avoidance and numbing and, possibly, PTSD symptoms. Dropout from treatment was higher in trauma-focused group treatment. Average improvement was modest in both treatments, although approximately 40% of participants showed clinically significant change. CONCLUSIONS: This study did not find a treatment effect for trauma-focused group therapy. The difference between the effectiveness and adequate dose findings suggests the possible value of methods to enhance the delivery of cognitive-behavioral treatments in clinical practice settings.

BACKGROUND: We know little about the degree to which comorbidity, socommonly seen among psychiatric disorders, arises from variation in normal personality. AIMS: To study the degree to which variation in normal personality accounts for the comorbidity of eight common psychiatric and substance use disorders. METHOD: Internalising disorders (major depression, generalised anxiety and panic disorders, phobias), externalising disorders (alcohol and drug dependence, antisocial personality and conduct disorders) and personality dimensions of neuroticism, extraversion and novelty seeking were assessed in 7588 participants from a population-based twin registry. The proportion of comorbidity explained by each personality dimension was calculated using structural equation modelling. RESULTS: Neuroticism accounted for the highest proportion of comorbidity within internalising disorders (20-45%) and between internalising and externalising disorders (19-88%). Variation in neuroticism and novelty seeking each accounted for a modest proportion (10-12% and 7-14%, respectively) of the comorbidity within externalising disorders. Extraversion contributed negligibly. CONCLUSIONS: High neuroticism appears to be a broad vulnerability factor for comorbid psychiatric disorders. Novelty seeking is modestly important for comorbid externalising disorders.

Importance: End-of-life care costs are high and decedents often experience poor quality of care. Numerous factors influence changes in site of death, health care transitions, and burdensome patterns of care. Objective: To describe changes in site of death and patterns of care among Medicare decedents. Design, Setting, and Participants: Retrospective cohort study among a 20% random sample of 1 361 870 decedents who had Medicare fee-for-service (2000, 2005, 2009, 2011, and 2015) and a 100% sample of 871 845 decedents who had Medicare Advantage (2011 and 2015) and received care at an acute care hospital, at home or in the community, at a hospice inpatient care unit, or at a nursing home. Exposures: Secular changes between 2000 and 2015. Main Outcomes and Measures: Medicare administrative data were used to determine site of death, place of care, health care transitions, which are changes in location of care, and burdensome patterns of care. Burdensome patterns of care were based on health care transitions during the last 3 days of life and multiple hospitalizations for infections or dehydration during the last 120 days of life. Results: The site of death and patterns of care were studied among 1 361 870 decedents who had Medicare fee-for-service (mean [SD] age, 82.8 [8.4] years; 58.7% female) and 871 845 decedents who had Medicare Advantage (mean [SD] age, 82.1 [8.5] years; 54.0% female). Among Medicare fee-for-service decedents, the proportion of deaths that occurred in an acute care hospital decreased from 32.6% (95% CI, 32.4%-32.8%) in 2000 to 19.8% (95% CI, 19.6%-20.0%) in 2015, and deaths in a home or community setting that included assisted living facilities increased from 30.7% (95% CI, 30.6%-30.9%) in 2000 to 40.1% (95% CI, 39.9%-30.3% ) in 2015. Use of the intensive care unit during the last 30 days of life among Medicare fee-for-service decedents increased from 24.3% (95% CI, 24.1%-24.4%) in 2000 and then stabilized between 2009 and 2015 at 29.0% (95% CI, 28.8%-29.2%). Among Medicare fee-for-service decedents, health care transitions during the last 3 days of life increased from 10.3% (95% CI, 10.1%-10.4%) in 2000 to a high of 14.2% (95% CI, 14.0%-14.3%) in 2009 and then decreased to 10.8% (95% CI, 10.6%-10.9%) in 2015. The number of decedents enrolled in Medicare Advantage during the last 90 days of life increased from 358 600 in 2011 to 513 245 in 2015. Among decedents with Medicare Advantage, similar patterns in the rates for site of death, place of care, and health care transitions were observed. Conclusions and Relevance: Among Medicare fee-for-service beneficiaries who died in 2015 compared with 2000, there was a lower likelihood of dying in an acute care hospital, an increase and then stabilization of intensive care unit use during the last month of life, and an increase and then decline in health care transitions during the last 3 days of life.

Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a well-recognized clinical sleep disorder that results in chronically fragmented sleep and recurrent hypoxemia. The primary daytime sequelae of the disorder include patient reports of excessive daytime sleepiness, depression, and attention and concentration problems. It has been well established that OSAHS negatively impacts certain aspects of cognitive functioning. The primary goals of this article are to (1) clarify the pattern of cognitive deficits that are specific to OSAHS; (2) identify the specific cognitive domains that improve with treatment; and (3) elucidate the possible mechanisms of cognitive dysfunction in OSAHS. At the conclusion of the paper, we propose a potential neurofunctional theory to account for the etiology of cognitive deficits in OSAHS. Thirty-seven peer-reviewed articles were selected for this review. In general, findings were equivocal for most cognitive domains. Treatment, however, was noted to improve attention/vigilance in most studies and consistently did not improve constructional abilities or psychomotor functioning. The results are discussed in the context of a neurofunctional theory for the effects of OSAHS on the brain.

Twelve healthy volunteers received oral placebo, 250 mg of caffeine, and 500 mg of caffeine in a randomized, double-blind, single-dose crossover study. Caffeine kinetics were nonlinear, with clearance significantly reduced and elimination half-life prolonged at the 500-mg compared to the 250-mg dose. The lower dose of caffeine produced more favorable subjective effects than the higher dose (elation, peacefulness, pleasantness), whereas unpleasant effects (tension, nervousness, anxiety, excitement, irritability, nausea, palpitations, restlessness) following the 500-mg dose exceeded those of the 250-mg dose. The lower dose of caffeine enhanced performance on the digit symbol substitution test and a tapping speed test compared to placebo; high-dose caffeine produced less performance enhancement than the lower dose. The plasma concentration versus response relationship revealed concentration-dependent increases in anxiety and improvements in cognitive and motor performance at low to intermediate concentrations. Both caffeine doses reduced electroencephalographic amplitude over the 4 Hz to 30 Hz spectrum, as well as in the alpha (8-11 Hz) and beta (12-30 Hz) ranges; however, effects were not dose-dependent. While favorable subjective and performance-enhancing stimulant effects occur at low to intermediate caffeine doses, the unfavorable subjective and somatic effects, as well as performance disruption, from high doses of caffeine may intrinsically limit the doses of caffeine used in the general population.

Beta oscillations (15-29Hz) are among the most prominent signatures of brain activity. Beta power is predictive of healthy and abnormal behaviors, including perception, attention and motor action. In non-averaged signals, beta can emerge as transient high-power 'events'. As such, functionally relevant differences in averaged power across time and trials can reflect changes in event number, power, duration, and/or frequency span. We show that functionally relevant differences in averaged beta power in primary somatosensory neocortex reflect a difference in the number of high-power beta events per trial, i.e. event rate. Further, beta events occurring close to the stimulus were more likely to impair perception. These results are consistent across detection and attention tasks in human magnetoencephalography, and in local field potentials from mice performing a detection task. These results imply that an increased propensity of beta events predicts the failure to effectively transmit information through specific neocortical representations.