Royal College of Surgeons in Ireland
UniversityDublin, Ireland
Research output, citation impact, and the most-cited recent papers from Royal College of Surgeons in Ireland (Ireland). Aggregated across the NobleBlocks index of 300M+ scholarly works.
Top-cited papers from Royal College of Surgeons in Ireland
BACKGROUND: Among patients with a proximal vessel occlusion in the anterior circulation, 60 to 80% of patients die within 90 days after stroke onset or do not regain functional independence despite alteplase treatment. We evaluated rapid endovascular treatment in addition to standard care in patients with acute ischemic stroke with a small infarct core, a proximal intracranial arterial occlusion, and moderate-to-good collateral circulation. METHODS: We randomly assigned participants to receive standard care (control group) or standard care plus endovascular treatment with the use of available thrombectomy devices (intervention group). Patients with a proximal intracranial occlusion in the anterior circulation were included up to 12 hours after symptom onset. Patients with a large infarct core or poor collateral circulation on computed tomography (CT) and CT angiography were excluded. Workflow times were measured against predetermined targets. The primary outcome was the score on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) at 90 days. A proportional odds model was used to calculate the common odds ratio as a measure of the likelihood that the intervention would lead to lower scores on the modified Rankin scale than would control care (shift analysis). RESULTS: The trial was stopped early because of efficacy. At 22 centers worldwide, 316 participants were enrolled, of whom 238 received intravenous alteplase (120 in the intervention group and 118 in the control group). In the intervention group, the median time from study CT of the head to first reperfusion was 84 minutes. The rate of functional independence (90-day modified Rankin score of 0 to 2) was increased with the intervention (53.0%, vs. 29.3% in the control group; P<0.001). The primary outcome favored the intervention (common odds ratio, 2.6; 95% confidence interval, 1.7 to 3.8; P<0.001), and the intervention was associated with reduced mortality (10.4%, vs. 19.0% in the control group; P=0.04). Symptomatic intracerebral hemorrhage occurred in 3.6% of participants in intervention group and 2.7% of participants in control group (P=0.75). CONCLUSIONS: Among patients with acute ischemic stroke with a proximal vessel occlusion, a small infarct core, and moderate-to-good collateral circulation, rapid endovascular treatment improved functional outcomes and reduced mortality. (Funded by Covidien and others; ESCAPE ClinicalTrials.gov number, NCT01778335.).
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,
Rhinosinusitis is a significant and increasing health problem which results in a large financial burden on society. This evidence based position paper describes what is known about rhinosinusitis and nasal polyps, offers evidence based recommendations on diagnosis and treatment, and considers how we can make progress with research in this area. Rhinitis and sinusitis usually coexist and are concurrent in most individuals; thus, the correct terminology is now rhinosinusitis. Rhinosinusitis (including nasal polyps) is defined as inflammation of the nose and the paranasal sinuses characterised by two or more symptoms, one of which should be either nasal blockage/obstruction/congestion or nasal discharge (anterior/posterior nasal drip), +/- facial pain/pressure, +/- reduction or loss of smell; and either endoscopic signs of polyps and/or mucopurulent discharge primarily from middle meatus and/or; oedema/mucosal obstruction primarily in middle meatus, and/or CT changes showing mucosal changes within the ostiomeatal complex and/or sinuses. The paper gives different definitions for epidemiology, first line and second line treatment and for research. Furthermore the paper describes the anatomy and (patho)physiology, epidemiology and predisposing factors, inflammatory mechanisms, evidence based diagnosis, medical and surgical treatment in acute and chronic rhinosinusitis and nasal polyposis in adults and children. Evidence based schemes for diagnosis and treatment are given for the first and second line clinicians. Moreover attention is given to complications and socio-economic cost of chronic rhinosinusitis and nasal polyps. Last but not least the relation to the lower airways is discussed.
AIMS: The SCORE project was initiated to develop a risk scoring system for use in the clinical management of cardiovascular risk in European clinical practice. METHODS AND RESULTS: The project assembled a pool of datasets from 12 European cohort studies, mainly carried out in general population settings. There were 20,5178 persons (88,080 women and 11,7098 men) representing 2.7 million person years of follow-up. There were 7934 cardiovascular deaths, of which 5652 were deaths from coronary heart disease. Ten-year risk of fatal cardiovascular disease was calculated using a Weibull model in which age was used as a measure of exposure time to risk rather than as a risk factor. Separate estimation equations were calculated for coronary heart disease and for non-coronary cardiovascular disease. These were calculated for high-risk and low-risk regions of Europe. Two parallel estimation models were developed, one based on total cholesterol and the other on total cholesterol/HDL cholesterol ratio. The risk estimations are displayed graphically in simple risk charts. Predictive value of the risk charts was examined by applying them to persons aged 45-64; areas under ROC curves ranged from 0.71 to 0.84. CONCLUSIONS: The SCORE risk estimation system offers direct estimation of total fatal cardiovascular risk in a format suited to the constraints of clinical practice.
Every day thousands of surgical procedures are performed to replace or repair tissue that has been damaged through disease or trauma. The developing field of tissue engineering (TE) aims to regenerate damaged tissues by combining cells from the body with highly porous scaffold biomaterials, which act as templates for tissue regeneration, to guide the growth of new tissue. This article describes the functional requirements, and types, of materials used in developing state of the art of scaffolds for tissue engineering applications. Furthermore, it describes the challenges and where future research and direction is required in this rapidly advancing field.
The Comprehensive Antibiotic Resistance Database (CARD; http://arpcard.mcmaster.ca) is a manually curated resource containing high quality reference data on the molecular basis of antimicrobial resistance (AMR), with an emphasis on the genes, proteins and mutations involved in AMR. CARD is ontologically structured, model centric, and spans the breadth of AMR drug classes and resistance mechanisms, including intrinsic, mutation-driven and acquired resistance. It is built upon the Antibiotic Resistance Ontology (ARO), a custom built, interconnected and hierarchical controlled vocabulary allowing advanced data sharing and organization. Its design allows the development of novel genome analysis tools, such as the Resistance Gene Identifier (RGI) for resistome prediction from raw genome sequence. Recent improvements include extensive curation of additional reference sequences and mutations, development of a unique Model Ontology and accompanying AMR detection models to power sequence analysis, new visualization tools, and expansion of the RGI for detection of emergent AMR threats. CARD curation is updated monthly based on an interplay of manual literature curation, computational text mining, and genome analysis.
, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.
autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
Ulcerative colitis and Crohn's disease are the principal forms of inflammatory bowel disease. Both represent chronic inflammation of the gastrointestinal tract, which displays heterogeneity in inflammatory and symptomatic burden between patients and within individuals over time. Optimal management relies on understanding and tailoring evidence-based interventions by clinicians in partnership with patients. This guideline for management of inflammatory bowel disease in adults over 16 years of age was developed by Stakeholders representing UK physicians (British Society of Gastroenterology), surgeons (Association of Coloproctology of Great Britain and Ireland), specialist nurses (Royal College of Nursing), paediatricians (British Society of Paediatric Gastroenterology, Hepatology and Nutrition), dietitians (British Dietetic Association), radiologists (British Society of Gastrointestinal and Abdominal Radiology), general practitioners (Primary Care Society for Gastroenterology) and patients (Crohn's and Colitis UK). A systematic review of 88 247 publications and a Delphi consensus process involving 81 multidisciplinary clinicians and patients was undertaken to develop 168 evidence- and expert opinion-based recommendations for pharmacological, non-pharmacological and surgical interventions, as well as optimal service delivery in the management of both ulcerative colitis and Crohn's disease. Comprehensive up-to-date guidance is provided regarding indications for, initiation and monitoring of immunosuppressive therapies, nutrition interventions, pre-, peri- and postoperative management, as well as structure and function of the multidisciplinary team and integration between primary and secondary care. Twenty research priorities to inform future clinical management are presented, alongside objective measurement of priority importance, determined by 2379 electronic survey responses from individuals living with ulcerative colitis and Crohn's disease, including patients, their families and friends.
BACKGROUND: Increasing the activity of defective cystic fibrosis transmembrane conductance regulator (CFTR) protein is a potential treatment for cystic fibrosis. METHODS: We conducted a randomized, double-blind, placebo-controlled trial to evaluate ivacaftor (VX-770), a CFTR potentiator, in subjects 12 years of age or older with cystic fibrosis and at least one G551D-CFTR mutation. Subjects were randomly assigned to receive 150 mg of ivacaftor every 12 hours (84 subjects, of whom 83 received at least one dose) or placebo (83, of whom 78 received at least one dose) for 48 weeks. The primary end point was the estimated mean change from baseline through week 24 in the percent of predicted forced expiratory volume in 1 second (FEV(1)). RESULTS: The change from baseline through week 24 in the percent of predicted FEV(1) was greater by 10.6 percentage points in the ivacaftor group than in the placebo group (P<0.001). Effects on pulmonary function were noted by 2 weeks, and a significant treatment effect was maintained through week 48. Subjects receiving ivacaftor were 55% less likely to have a pulmonary exacerbation than were patients receiving placebo, through week 48 (P<0.001). In addition, through week 48, subjects in the ivacaftor group scored 8.6 points higher than did subjects in the placebo group on the respiratory-symptoms domain of the Cystic Fibrosis Questionnaire-revised instrument (a 100-point scale, with higher numbers indicating a lower effect of symptoms on the patient's quality of life) (P<0.001). By 48 weeks, patients treated with ivacaftor had gained, on average, 2.7 kg more weight than had patients receiving placebo (P<0.001). The change from baseline through week 48 in the concentration of sweat chloride, a measure of CFTR activity, with ivacaftor as compared with placebo was -48.1 mmol per liter (P<0.001). The incidence of adverse events was similar with ivacaftor and placebo, with a lower proportion of serious adverse events with ivacaftor than with placebo (24% vs. 42%). CONCLUSIONS: Ivacaftor was associated with improvements in lung function at 2 weeks that were sustained through 48 weeks. Substantial improvements were also observed in the risk of pulmonary exacerbations, patient-reported respiratory symptoms, weight, and concentration of sweat chloride. (Funded by Vertex Pharmaceuticals and others; VX08-770-102 ClinicalTrials.gov number, NCT00909532.).
Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.
UNLABELLED: Recently, there has been an increasing interest in the development and characterization of patient-derived tumor xenograft (PDX) models for cancer research. PDX models mostly retain the principal histologic and genetic characteristics of their donor tumor and remain stable across passages. These models have been shown to be predictive of clinical outcomes and are being used for preclinical drug evaluation, biomarker identification, biologic studies, and personalized medicine strategies. This article summarizes the current state of the art in this field, including methodologic issues, available collections, practical applications, challenges and shortcomings, and future directions, and introduces a European consortium of PDX models. SIGNIFICANCE: PDX models are increasingly used in translational cancer research. These models are useful for drug screening, biomarker development, and the preclinical evaluation of personalized medicine strategies. This review provides a timely overview of the key characteristics of PDX models and a detailed discussion of future directions in the field.
This article updates the guidance published in 2015 for authors submitting papers to British Journal of Pharmacology (Curtis et al., 2015) and is intended to provide the rubric for peer review. Thus, it is directed towards authors, reviewers and editors. Explanations for many of the requirements were outlined previously and are not restated here. The new guidelines are intended to replace those published previously. The guidelines have been simplified for ease of understanding by authors, to make it more straightforward for peer reviewers to check compliance and to facilitate the curation of the journal's efforts to improve standards.
EPOS 2012: European position paper on rhinosinusitis and nasal polyps 2012. A summary for otorhinolaryngologists. no immunosuppressants IV D no nasal saline irrigation Ib, no data in single use D yes for symptomatic relief topical antibiotics no data D no anti-IL-5 no data D unclear phytotherapy no data D no decongestant topical / oral no data in single use D no mucolytics no data D no oral antihistamine in allergic patients no data D no antimycotics -topical Ia (-) ** A(-) no antimycotics -systemic Ib (-)# A(-) $ no anti leukotrienes Ib (-) A(-) no anti-IgE Ib (-) A(-) no * Some of these studies also included patients with CRS with nasal polyps. % short term antibiotics shows one positive and one negative study. Therefore recommendation C. oral antibiotic short term <4 weeks Ib(-) # A(-)* no intravenous antibiotics III(-) ## C(-) ** no # Ib (-): Ib study with a negative outcome.
BACKGROUND: HH-suite is a widely used open source software suite for sensitive sequence similarity searches and protein fold recognition. It is based on pairwise alignment of profile Hidden Markov models (HMMs), which represent multiple sequence alignments of homologous proteins. RESULTS: We developed a single-instruction multiple-data (SIMD) vectorized implementation of the Viterbi algorithm for profile HMM alignment and introduced various other speed-ups. These accelerated the search methods HHsearch by a factor 4 and HHblits by a factor 2 over the previous version 2.0.16. HHblits3 is ∼10× faster than PSI-BLAST and ∼20× faster than HMMER3. Jobs to perform HHsearch and HHblits searches with many query profile HMMs can be parallelized over cores and over cluster servers using OpenMP and message passing interface (MPI). The free, open-source, GPLv3-licensed software is available at https://github.com/soedinglab/hh-suite . CONCLUSION: The added functionalities and increased speed of HHsearch and HHblits should facilitate their use in large-scale protein structure and function prediction, e.g. in metagenomics and genomics projects.
The purpose of this study was to determine if ambulatory blood pressure measurement predicted total and cardiovascular mortality over and beyond clinic blood pressure measurement and other cardiovascular risk factors; 5292 untreated hypertensive patients referred to a single blood pressure clinic who had clinic and ambulatory blood pressure measurement at baseline were followed up in a prospective study of mortality outcome. Multiple Cox regression was used to model time to total and cause-specific mortality for ambulatory blood pressure measurement while adjusting for clinic blood pressure measurement and other risk factors at baseline. There were 646 deaths (of which 389 were cardiovascular) during a median follow-up period of 8.4 years. With adjustment for gender, age, risk indices, and clinic blood pressure, higher mean values of ambulatory blood pressure were independent predictors for cardiovascular mortality. The relative hazard ratio for each 10-mm Hg increase in systolic blood pressure was 1.12 (1.06 to 1.18; P<0.001) for daytime and 1.21 (1.15 to 1.27; P<0.001) for nighttime systolic blood pressure. The hazard ratios for each 5-mm Hg increase in diastolic blood pressure were 1.02 (0.99 to 1.07; P=NS) for daytime and 1.09 (1.04 to 1.13; P<0.01) for nighttime diastolic pressures. The hazard ratios for nighttime ambulatory blood pressure remained significant after adjustment for daytime ambulatory blood pressure. These results have 2 important clinical messages: ambulatory measurement of blood pressure is superior to clinic measurement in predicting cardiovascular mortality, and nighttime blood pressure is the most potent predictor of outcome.
Photodynamic therapy (PDT) is now a well-recognized modality for the treatment of cancer. While PDT has developed progressively over the last century, great advances have been observed in the field in recent years. The concept of dual selectivity of PDT agents is now widely accepted due to the relative specificity and selectivity of PDT along with the absence of harmful side effects often encountered with chemotherapy or radiotherapy. Traditionally, porphyrin-based photosensitizers have dominated the PDT field but these first generation photosensitizers have several disadvantages, with poor light absorption and cutaneous photosensitivity being the predominant side effects. As a result, the requirement for new photosensitizers, including second generation porphyrins and porphyrin derivatives as well as third generation photosensitizers has arisen, with the aim of alleviating the problems encountered with first generation porphyrins and improving the efficacy of PDT. The investigation of nonporphyrin photosensitizers for the development of novel PDT agents has been considerably less extensive than porphyrin-based compounds; however, structural modification of nonporphyrin photosensitizers has allowed for manipulation of the photochemotherapeutic properties. The aim of this review is to provide an insight into PDT photosensitizers clinically approved for application in oncology, as well as those which show significant potential in ongoing preclinical studies.
The BJP has been and remains an active advocate of the ARRIVE (Animal Research: Reporting of in vivo Experiments) guidelines (Kilkenny, Browne, Cuthill, Emerson, & Altman, 2010a) that were established by the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) in 2010. The ARRIVE guidelines need no introduction and we will not rehearse the arguments in depth here, other than to restate that the lack of key in vivo experimental details has been identified as a major contributing factor to the poor reproducibility of pre-clinical research. This fact was the primary driver for establishment by the NC3Rs of the first version of the ARRIVE guidelines. ARRIVE provided a 20-point checklist, specifying all of the experimental details (procedures and fixed factors) that should be included in manuscripts for proper reporting of animal research. The guidelines were rapidly endorsed internationally by funding bodies, universities, learned societies and, importantly, Life Science journals. Currently there are 1,046 journals endorsing ARRIVE including BJP, which was one of the original six influential journals that published the guidelines in full in 2010 (Kilkenny, Browne, Cuthill, Emerson, & Altman, 2010b). However, ARRIVE has not had the effect that was originally hoped for, despite this widespread support and endorsement. In 2016 and in 2018 assessments of adherence of articles published in endorsing journals identified a lack of engagement. As an example, one systematic review of reports of studies investigating acute lung injury revealed that, of the items expected for ARRIVE compliance, only 45% of those advised for inclusion in the Methods, and only 29% of those for inclusion in the Results section, were present (Avey et al., 2016). Moreover, formal endorsement of the ARRIVE guidelines by journals did not necessarily improve compliance (Leung, Rousseau-Blass, Beauchamp, & Pang, 2018). Such disappointing reports of outcome triggered a reappraisal of the guidelines led by the NC3Rs who, in 2018, established a new, international Working Group to review and update the ARRIVE guidelines to generate ARRIVE 2.0 (Percie du Sert et al., 2018). As with the team of experts brought together to establish the first iteration of ARRIVE, the Editor in Chief of the BJP is a member of the new team that was assembled. As such, the BJP has been well-placed to influence the content, testing and final publication of both iterations of the guidelines. In 2015, the BJP published an editorial reporting findings from a survey of compliance with ARRIVE in articles published in 2014 in two issues of the journal (McGrath & Lilley, 2015). The results were not as had been hoped for, as was also evident from assessments elsewhere, and revealed scope for improving compliance in respect of both the design of the (animal) experiments and the description of experimental procedures. To help remedy this problem, a checklist was developed that provided an aide memoire of the details of the animals and research procedures that should be reported in manuscripts submitted to the journal. A further editorial focussed on experimental design and data analysis (Curtis et al., 2018) for all types of experimental data published in the journal, including those emanating from experiments with animals, was also published. A key issue with many of the studies reported in BJP prior to this related to inadequate experimental design and inappropriate statistical analysis. At the same time, the Instructions to Authors were revised, to include the new rubric, and the editorial scrutiny of these aspects of the peer review process was tightened up. As a further prompt, in 2016, authors were required to make a Declaration as part of the submission process, to confirm that their manuscript was ARRIVE compliant. In addition to these measures, two new 'specialist' editors were appointed: a Design & Analysis Advisor and a Consulting Editor in ARRIVE Guidelines and Animal Welfare. The brief of the latter was to monitor ARRIVE compliance in BJP publications and to assist Senior Editors with their appraisal of manuscripts. All these changes still remain in place with the addition of a Consulting Editor in Statistical Analysis to ensure that the research reports match BJP criteria and so qualify for publication. ARRIVE 2.0 together with an 'Explanation and Elaboration' document was loaded onto the NC3Rs website in July 2019 as a preprint (i.e., before peer review (Percie du Sert et al., 2019)), and is now published in full in PLOS Biology (Percie du Sert et al., 2020), with simultaneous publication in several international journals, including this issue of the BJP (Percie du Sert et al., 2020). In preparation for the publication of the new guidelines we conducted surveys assessing compliance to ARRIVE in the BJP over 4 years, the results of which can be seen in Table 1. These data together with the July 2019 preprint of ARRIVE 2.0 were discussed extensively by the Senior Editorial Board of the BJP in December 2019. This editorial explains the ensuing changes in the journal's editorial policy as a result of those discussions and how they relate to ARRIVE 2.0. The principle of full disclosure lies at the heart of what we expect from authors wishing to publish in the BJP and in support of this principle is the absence of a word restriction for the Methods section. Judging from articles surveyed, between July 2014 and October 2019, most authors are conscientious about compliance with our 'Instructions to Authors' in respect of confirming ethical approval of the research, specifying the source, species and strain of animals and the inclusion of a statement on the translational relevance of the research study (Table 1). However, a general observation is that, although many manuscripts include lengthy details of the molecular biological or biochemical techniques that were used in the study, when experiments involved the use of animals, both the design of experiments and the description of the experimental procedures are often inadequately detailed making reproducibility challenging. Reporting of the method for killing animals has improved over the years but is still inconsistent, despite the need for manuscripts to be clear about when and how animals were killed. Information on housing and husbandry is often provided but, again, the level of detail is highly variable. Important elements, such as stocking density, configuration of group-housed animals (in respect of littermates, genotypes, or randomised mixed-caging, for example) provision of food (including, ideally, the composition of the laboratory diet) and water and environmental enrichment are not always disclosed, despite increasing recognition that these factors can affect the research findings (Finney et al., 2020; Reardon, 2016). The poor reporting of the provision of analgesia in the surgical context is particularly worrying. Of course, a lack of any mention of analgesia in the manuscript does not mean that none was provided; there could also be a strong scientific justification for withholding analgesia in some experiments. However, that did not apply to any of the manuscripts that were reviewed: in all those cases, analgesia could and should have been provided. Two options were considered by the Senior Editorial Board in December 2019: (i) endorse ARRIVE 2.0 guidelines and adopt them verbatim as official BJP policy or (ii) endorse ARRIVE 2.0 but devise our own reporting policy, which would be particularly relevant for pharmacologists. In considering the results of our surveys and the content of the ARRIVE 2.0 preprint, the Board decided on the latter approach. Authors should be reassured that nothing major has changed in practice. This journal has always taken inspiration from ARRIVE, while adopting a 'bespoke' approach to the reporting of the types of animal research carried out by pharmacologists. Authors should also note that requirements in respect of experimental design and analysis in articles published in BJP have not changed at all and can be found at: https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/bph.14153 (Curtis et al., 2018). That said, we strongly advise authors to use the NC3Rs Experimental Design Assistant (https://www.nc3rs.org.uk/experimental-design-assistant-eda) (Percie du Sert et al., 2017) when planning the experimental design and the data analysis of their work. The most striking change in the updated ARRIVE guidelines is the subdivision of the original checklist into two tables/checklists: the 'Essential 10' and the 'Recommended set'. The former focuses mainly on aspects of the experimental design that are essential for reducing bias (subjective or systematic), whereas the latter deals with points that pertain to the factors that authors are advised to disclose in order to enable others to replicate the experiment. Our current guidelines for experimental design and statistical analysis address many of the 'Essential 10', and for our modified approach we concentrate on many of the items in the 'Recommended set'. Our updated'BJP Declaration of Transparency and Scientific Rigour: Checklist for Animal Experimentation' is shown in Table 2, along with indicators of how each element connects with ARRIVE 2.0. These amendments do not challenge the importance of either version of ARRIVE. On the contrary, we strongly recommend that all authors read ARRIVE 2.0 (Percie du Sert, Hurst, et al., 2020) and familiarise themselves with the complementary 'Explanation and Elaboration' document (Percie du Sert et al., 2020). Essential 8 Essential 9 Recommended Recommended 12 Recommended 14 Recommended 15 Recommended 16 In terms of the details that should be included in every manuscript submitted to the BJP, the new checklist for reporting animal research will consist of the following six mandatory elements (see also Table 2): Details of the source, species, strain, sex, age and/or weight range of the animals used in the study must be given. A comprehensive account of the experimental procedure with particular attention to the use of any pharmacologically active agents at any stage of the study, including: anaesthesia, analgesia, antibiotics or any veterinary treatment administered for welfare purposes. Authors should also confirm that, for all surgical procedures, precautions to ensure aseptic conditions were applied throughout. Details of post-surgical analgesia and care of the animals should be provided, as should any procedures for monitoring the animals during post-operative recovery: e.g., the frequency and duration of the observations, temperature control etc. If analgesia cannot be given, this needs to be justified scientifically. A statement to confirm that the animals were killed by an individual trained to do this procedure, together with a description of how and when animals are killed, must also be included. In this context, authors should bear in mind that only certain methods for humane killing are permitted in the UK (and other countries governed by Directive 2010/63/EU) and these are stringently regulated. As a consequence, it might not be possible to consider a manuscript for publication in this journal if euthanasia has been carried out using a procedure that is regarded as unacceptable in the UK.One notable change to our policy is that whenever welfare assessments, or other precautions, were necessary during any stage of the research, these must now be reported, together with a clear definition of humane end-points. We acknowledge that these aspects of experimental conduct may well be implemented routinely in individual laboratories but, hitherto, they have not been perceived as an essential aspect of the research report. We want authors to include this information, as a matter of course, not least because other researchers in the field would find it important and helpful. Full details of the specific animal model that was used and the scientific justification for the choice of that model in the context of achieving the research objectives should be provided. This aspect of the report can be challenging, but we hope to encourage authors to be conservative and realistic when claiming to have used an animal 'model' of a complex human disorder (see next section). A statement to confirm that the research reported in the manuscript obtained local ethical approval is essential. BJP seeks to publish research on animals that conforms to standards upheld in the UK. Some elements should always be included, for example: type of housing, type of cage (open or individually ventilated) stocking density, food and water provision, bedding material, environmental enrichment, lighting regimen. For fish, details of the tank and the number of fish in each one should be included. Information on other elements should be included if they are crucial for the study or if they could affect the experimental results: e.g., the time of day the study took place, nature of handling/capture. The configuration of animals within cages should also be specified for instance, mixed or separate housing of genetically-altered/wildtypes or disease-susceptible/normal animals should be provided. Any welfare-related assessments, measurements and interventions that were carried out before, during, or after the study, especially if these were intended to ameliorate or limit the harms to the animals (e.g., humane end-points) must be reported. Another change is that both ARRIVE 2.0 and our revised BJP Declaration have removed the obligation to report any advance in the 3Rs (Replacement, Reduction and Refinement) that has emerged from the research. This is partly because compliance with this has been negligible. Nevertheless, the BJP Senior Editorial Board recognises the importance of the 3Rs as part of the ethical framework for all research that uses animals and so we encourage authors to include this information whenever their findings have made a useful contribution to any of the 3Rs. The ARRIVE 2.0 guidelines are certainly viewed as an important step in helping to address the problem of poor reproducibility and translation of research findings in the biomedical sciences. However, successful translation also depends on a sound rationale for the research. So far, the attempts to improve reproducibility have somewhat overshadowed the growing scepticism about the validity of 'animal models' of some human disorders. In many cases, the creation of an animal model in order to carry out experiments, which would not be permitted in humans, is an entirely reasonable objective. That would be the case for human disorders that have an established link with a single genetic abnormality, such as cystic fibrosis, Down syndrome and hypertrophic cardiomyopathy. Even in cases where a specific genetic mutation is a common, but not invariable, cause of the disorder (e.g., Fragile X syndrome, amyotrophic lateral sclerosis), it is still reasonable to back-translate the mutation to create an animal model to investigate the underlying biological abnormalities and potential treatments. Few people would argue that those research findings are not instructive or that the description of the animal as a 'model' of the human disorder is scientifically unjustified. Even when there is no such clear causal link, it is valid to describe an animal as a 'model' when it expresses an abnormality that is convincingly analogous to the diagnostic biomarker(s) in humans. Examples of these would include: neoplasia, Cushing's/Addison's disease, diabetes, skin pigmentation diseases, myasthenia gravis. Even though treatment strategies that are effective in the animals often do not translate into humans, it is still reasonable to regard them as 'models' of the human condition and such research has contributed a great deal to our understanding of the illnesses. It is far more difficult to be confident about the validity of animal models of complex, multifactorial human illnesses, which can comprise a mixture of any of several pathological, physiological and behavioural abnormalities, which can be primary or secondary features of the illness. These would include conditions such as: hypertension, heart failure, renal failure, metabolic syndrome, neurological and psychiatric disorders. In all these cases, the profile and/or severity of the underlying problems can differ substantially from patient to patient, but still meet the criteria for the same broad clinical diagnosis. In such cases, we hope to encourage authors to be more cautious about claims that their 'animal model' is analogous to the human condition. This is especially important for 'models' that are based on evidence from procedures that are normally used as drug screens to predict therapeutic efficacy in humans (see, for example: Stanford, 2017). In such cases, authors should justify their assumption that the abnormality that is being evaluated in the baseline condition (i.e, with no experimental intervention such as drug treatment or genetic alteration) is a valid model of the human illness or a particular aspects of that illness. On the other hand, we want to discourage non-committal descriptions such as 'cirrhosis-like', 'epilepsy-like' or 'autism-like', or vague terms, such as 'asthma' instead of 'respiratory allergy'. Instead, our aim is to encourage authors to be precise about the extent to which aspect(s) of the human disorder are expressed in the animal model, and also to acknowledge its limitations. Where these questions have been very well analysed for any particular model, it is appropriate for authors to cite the relevant literature explaining why the animal model is appropriate. We believe this is timely advice because there is burgeoning interest in research of 'endophenotypes' in which a specific aspect of an animal's normal/abnormal physiology or behaviour can be mapped onto an underlying genetic mutation or physiological system (e.g., neuronal network, or other physiological feedback loop) – and which are often not confined to a single human disorder. This approach further acknowledges that some human illnesses are better regarded as assemblies of endophenotypes, rather than unitary disorders. Obviously, the definition of an endophenotype also needs scrupulous validation, but this change of mindset will be essential for successful progress in stratified and personalised medicine. A final point, addressed only indirectly by ARRIVE 2.0, concerns the validity of some research procedures that are used to produce the 'model' (see: Stanford, 2020). Examples include some experimental interventions to induce end-stage heart failure, or the use of environmental stressors that are intended to alter the physiology and/or behaviour of the animals. Examples include the use of environmental stressors, such as electric shocks or a series of unpredictable stressors that change from day to day, sometimes for several weeks. In most cases, the individual stressors are mild and can arguably be regarded as analogous to challenges faced by some humans and which impair their mental health, but this is not always the case. Some of these experiments involve prolonged bouts of stressors, which would be regarded as severe, especially when their cumulative harm is taken into account. In such cases, the BJP will require authors to provide assurance that the severity and duration of the aversive stimuli was the minimum required to meet the scientific objectives of the study, particularly when using a series of unpredictable stressors, for instance. Also, in order to underpin the validity of such animal 'models', authors should include a statement to clarify the ways in which the aversive stimuli used in the research are relevant to the manifestation of the disorder of interest, which is being modelled in the animals. In response to the publication of the revised ARRIVE guidelines (ARRIVE 2.0), the Senior Editorial Board of this journal has revised the policy on reporting of animal research. The primary principle remains the same as before, which is to encourage full disclosure of all relevant information and to expect to see evidence for high standards of animal welfare. It is important to remember that this is not simply for the benefit of the animals. High standards of experimental design, reporting and animal welfare are crucial if the research is to be reproducible and translatable. In that context, we encourage authors to read Drummond and Vowler (2013). The BJP has, for some time, taken the view that the prevailing standards expected by the regulatory framework in the UK should be reflected in the journal's publications. For example, studies of proprietary tobacco products are not permitted in the UK and the BJP will not publish them. Similarly, death as an endpoint, in non-regulatory studies would not normally be acceptable (with the exception of studies of anti-cancer and certain antimicrobial drugs, for example), but when current regulatory guidelines still mandate mortality endpoints, we expect humane endpoints to be described fully and implemented. Some experiments that involve procedures that would be regarded as 'severe' but can, nonetheless, be scientifically justified. However, the justification for some such procedures might not be clear. In most of these cases, a discussion between the editor(s) and the authors would seek to confirm whether or not there was a robust justification for using such procedures, or humane endpoints, regardless of any local ethical approval for the study. If this turns out to be the case, the manuscript may be published. Finally, raising the standard of research reporting will certainly help to improve reproducibility but, to improve translation will also require a more realistic, evidence-based appraisal of the validity of the experimental procedures and research 'models'. To that end, we want to encourage authors to consider the extent to which the models they have investigated really do offer insight into the causes, pathology and treatment of multifactorial human disorders. In cases where there is any doubt, authors should be assured that more modest objectives and clarity about the specific features of the disorder that have been 'modelled' would attract even more confidence and scientific merit. The authors declare no conflicts of interest.
BACKGROUND: It is uncertain how best to screen pregnant women for the presence of fetal Down's syndrome: to perform first-trimester screening, to perform second-trimester screening, or to use strategies incorporating measurements in both trimesters. METHODS: Women with singleton pregnancies underwent first-trimester combined screening (measurement of nuchal translucency, pregnancy-associated plasma protein A [PAPP-A], and the free beta subunit of human chorionic gonadotropin at 10 weeks 3 days through 13 weeks 6 days of gestation) and second-trimester quadruple screening (measurement of alpha-fetoprotein, total human chorionic gonadotropin, unconjugated estriol, and inhibin A at 15 through 18 weeks of gestation). We compared the results of stepwise sequential screening (risk results provided after each test), fully integrated screening (single risk result provided), and serum integrated screening (identical to fully integrated screening, but without nuchal translucency). RESULTS: First-trimester screening was performed in 38,167 patients; 117 had a fetus with Down's syndrome. At a 5 percent false positive rate, the rates of detection of Down's syndrome were as follows: with first-trimester combined screening, 87 percent, 85 percent, and 82 percent for measurements performed at 11, 12, and 13 weeks, respectively; with second-trimester quadruple screening, 81 percent; with stepwise sequential screening, 95 percent; with serum integrated screening, 88 percent; and with fully integrated screening with first-trimester measurements performed at 11 weeks, 96 percent. Paired comparisons found significant differences between the tests, except for the comparison between serum integrated screening and combined screening. CONCLUSIONS: First-trimester combined screening at 11 weeks of gestation is better than second-trimester quadruple screening but at 13 weeks has results similar to second-trimester quadruple screening. Both stepwise sequential screening and fully integrated screening have high rates of detection of Down's syndrome, with low false positive rates.
BACKGROUND: The Timed Up and Go test (TUG) is a commonly used screening tool to assist clinicians to identify patients at risk of falling. The purpose of this systematic review and meta-analysis is to determine the overall predictive value of the TUG in community-dwelling older adults. METHODS: A literature search was performed to identify all studies that validated the TUG test. The methodological quality of the selected studies was assessed using the QUADAS-2 tool, a validated tool for the quality assessment of diagnostic accuracy studies. A TUG score of ≥13.5 seconds was used to identify individuals at higher risk of falling. All included studies were combined using a bivariate random effects model to generate pooled estimates of sensitivity and specificity at ≥13.5 seconds. Heterogeneity was assessed using the variance of logit transformed sensitivity and specificity. RESULTS: Twenty-five studies were included in the systematic review and 10 studies were included in meta-analysis. The TUG test was found to be more useful at ruling in rather than ruling out falls in individuals classified as high risk (>13.5 sec), with a higher pooled specificity (0.74, 95% CI 0.52-0.88) than sensitivity (0.31, 95% CI 0.13-0.57). Logistic regression analysis indicated that the TUG score is not a significant predictor of falls (OR = 1.01, 95% CI 1.00-1.02, p = 0.05). CONCLUSION: The Timed Up and Go test has limited ability to predict falls in community dwelling elderly and should not be used in isolation to identify individuals at high risk of falls in this setting.