Florida College

Purpose The purpose of this paper is to provide a comprehensive, yet concise, overview of the considerations and metrics required for partial least squares structural equation modeling (PLS-SEM) analysis and result reporting. Preliminary considerations are summarized first, including reasons for choosing PLS-SEM, recommended sample size in selected contexts, distributional assumptions, use of secondary data, statistical power and the need for goodness-of-fit testing. Next, the metrics as well as the rules of thumb that should be applied to assess the PLS-SEM results are covered. Besides presenting established PLS-SEM evaluation criteria, the overview includes the following new guidelines: PLSpredict (i.e., a novel approach for assessing a model’s out-of-sample prediction), metrics for model comparisons, and several complementary methods for checking the results’ robustness. Design/methodology/approach This paper provides an overview of previously and recently proposed metrics as well as rules of thumb for evaluating the research results based on the application of PLS-SEM. Findings Most of the previously applied metrics for evaluating PLS-SEM results are still relevant. Nevertheless, scholars need to be knowledgeable about recently proposed metrics (e.g. model comparison criteria) and methods (e.g. endogeneity assessment, latent class analysis and PLSpredict), and when and how to apply them to extend their analyses. Research limitations/implications Methodological developments associated with PLS-SEM are rapidly emerging. The metrics reported in this paper are useful for current applications, but must always be up to date with the latest developments in the PLS-SEM method. Originality/value In light of more recent research and methodological developments in the PLS-SEM domain, guidelines for the method’s use need to be continuously extended and updated. This paper is the most current and comprehensive summary of the PLS-SEM method and the metrics applied to assess its solutions.

BACKGROUND: Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the publication of the American Thyroid Association's guidelines for the management of these disorders was published in 2006, a large amount of new information has become available, prompting a revision of the guidelines. METHODS: Relevant articles through December 2008 were reviewed by the task force and categorized by topic and level of evidence according to a modified schema used by the United States Preventative Services Task Force. RESULTS: The revised guidelines for the management of thyroid nodules include recommendations regarding initial evaluation, clinical and ultrasound criteria for fine-needle aspiration biopsy, interpretation of fine-needle aspiration biopsy results, and management of benign thyroid nodules. Recommendations regarding the initial management of thyroid cancer include those relating to optimal surgical management, radioiodine remnant ablation, and suppression therapy using levothyroxine. Recommendations related to long-term management of differentiated thyroid cancer include those related to surveillance for recurrent disease using ultrasound and serum thyroglobulin as well as those related to management of recurrent and metastatic disease. CONCLUSIONS: We created evidence-based recommendations in response to our appointment as an independent task force by the American Thyroid Association to assist in the clinical management of patients with thyroid nodules and differentiated thyroid cancer. They represent, in our opinion, contemporary optimal care for patients with these disorders.

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,

Allergic rhinitis is a symptomatic disorder of the nose\ninduced after allergen exposure by an IgE-mediated\ninflammation of the membranes lining the nose. It is a\nglobal health problem that causes major illness and disability\nworldwide. Over 600 million patients from all\ncountries, all ethnic groups and of all ages suffer from\nallergic rhinitis. It affects social life, sleep, school and\nwork and its economic impact is substantial.\nRisk factors for allergic rhinitis are well identified.\nIndoor and outdoor allergens as well as occupational\nagents cause rhinitis and other allergic diseases.\nThe role of indoor and outdoor pollution is probably\nvery important, but has yet to be fully understood\nboth for the occurrence of the disease and its manifestations.\nIn 1999, during the Allergic Rhinitis and its Impact on\nAsthma (ARIA) WHO workshop, the expert panel\nproposed a new classification for allergic rhinitis which\nwas subdivided into _intermittent_ or _persistent_ disease.\nThis classification is now validated.\nThe diagnosis of allergic rhinitis is often quite easy, but\nin some cases it may cause problems and many patients\nare still under-diagnosed, often because they do not\nperceive the symptoms of rhinitis as a disease impairing\ntheir social life, school and work.\nThe management of allergic rhinitis is well established\nand the ARIA expert panel based its recommendations\non evidence using an extensive review of the literature\navailable up to December 1999. The statements of\nevidence for the development of these guidelines followed\nWHO rules and were based on those of Shekelle et al.\nA large number of papers have been published since 2000\nand are extensively reviewed in the 2008 Update using\nthe same evidence-based system. Recommendations for\nthe management of allergic rhinitis are similar in both the\nARIA workshop report and the 2008 Update. In the\nfuture, the GRADE approach will be used, but is not yet\navailable.\nAnother important aspect of the ARIA guidelines was\nto consider co-morbidities. Both allergic rhinitis and\nasthma are systemic inflammatory conditions and often\nco-exist in the same patients. In the 2008 Update, these\nlinks have been confirmed.\nTheARIAdocument is not intended to be a standard-ofcare\ndocument for individual countries. It is provided as a\nbasis for physicians, health care professionals and\norganizations involved in the treatment of allergic rhinitis\nand asthma in various countries to facilitate the\ndevelopment of relevant local standard-of-care documents\nfor patients.

Moving Average and Autoregressive Processes. Introduction to Fourier Analysis. Spectral Theory and Filtering. Some Large Sample Theory. Estimation of the Mean and Autocorrelations. The Periodogram, Estimated Spectrum. Parameter Estimation. Regression, Trend, and Seasonality. Unit Root and Explosive Time Series. Bibliography. Index.

Reproducible science requires transparent reporting. The ARRIVE guidelines (Animal Research: Reporting of In Vivo Experiments) were originally developed in 2010 to improve the reporting of animal research. They consist of a checklist of information to include in publications describing in vivo experiments to enable others to scrutinise the work adequately, evaluate its methodological rigour and reproduce the methods and results. Despite considerable levels of endorsement by funders and journals over the years, adherence to the guidelines has been inconsistent, and the anticipated improvements in the quality of reporting in animal research publications have not been achieved. Here, we introduce ARRIVE 2.0. The guidelines have been updated and information reorganised to facilitate their use in practice. We used a Delphi exercise to prioritise and divide the items of the guidelines into two sets, the 'ARRIVE Essential 10', which constitutes the minimum requirement, and the 'Recommended Set', which describes the research context. This division facilitates improved reporting of animal research by supporting a stepwise approach to implementation. This helps journal editors and reviewers verify that the most important items are being reported in manuscripts. We have also developed the accompanying Explanation and Elaboration document, which serves (1) to explain the rationale behind each item in the guidelines, (2) to clarify key concepts and (3) to provide illustrative examples. We aim, through these changes, to help ensure that researchers, reviewers and journal editors are better equipped to improve the rigour and transparency of the scientific process and thus reproducibility.

Summary The Mini International Neuropsychiatric Interview (MINI) is a short diagnostic structured interview (DSI) developed in France and the United States to explore 17 disorders according to Diagnostic and Statistical Manual (DSM)-III-R diagnostic criteria. It is fully structured to allow administration by non-specialized interviewers. In order to keep it short it focuses on the existence of current disorders. For each disorder, one or two screening questions rule out the diagnosis when answered negatively. Probes for severity, disability or medically explained symptoms are not explored symptom-by-symptom. Two joint papers present the inter-rater and test-retest reliability of the MINI the validity versus the Composite International Diagnostic Interview (CIDI) (this paper) and the Structured Clinical Interview for DSM-III-R patients (SCID) (joint paper). Three-hundred and forty-six patients (296 psychiatric and 50 non-psychiatric) were administered the MINI and the CIDI ‘gold standard’. Forty two were interviewed by two investigators and 42 interviewed subsequently within two days. Interviewers were trained to use both instruments. The mean duration of the interview was 21 min with the MINI and 92 for corresponding sections of the CIDI. Kappa coefficient, sensitivity and specificity were good or very good for all diagnoses with the exception of generalized anxiety disorder (GAD) (kappa = 0.36), agoraphobia (sensitivity = 0.59) and bulimia (kappa = 0.53). Interrater and test-retest reliability were good. The main reasons for discrepancies were identified. The MINI provided reliable DSM-III-R diagnoses within a short time frame, The study permitted improvements in the formulations for GAD and agoraphobia in the current DSM-IV version of the MINI.

BACKGROUND: Voriconazole is a broad-spectrum triazole that is active against aspergillus species. We conducted a randomized trial to compare voriconazole with amphotericin B for primary therapy of invasive aspergillosis. METHODS: In this randomized, unblinded trial, patients received either intravenous voriconazole (two doses of 6 mg per kilogram of body weight on day 1, then 4 mg per kilogram twice daily for at least seven days) followed by 200 mg orally twice daily or intravenous amphotericin B deoxycholate (1 to 1.5 mg per kilogram per day). Other licensed antifungal treatments were allowed if the initial therapy failed or if the patient had an intolerance to the first drug used. A complete or partial response was considered to be a successful outcome. RESULTS: A total of 144 patients in the voriconazole group and 133 patients in the amphotericin B group with definite or probable aspergillosis received at least one dose of treatment. In most of the patients, the underlying condition was allogeneic hematopoietic-cell transplantation, acute leukemia, or other hematologic diseases. At week 12, there were successful outcomes in 52.8 percent of the patients in the voriconazole group (complete responses in 20.8 percent and partial responses in 31.9 percent) and 31.6 percent of those in the amphotericin B group (complete responses in 16.5 percent and partial responses in 15.0 percent; absolute difference, 21.2 percentage points; 95 percent confidence interval, 10.4 to 32.9). The survival rate at 12 weeks was 70.8 percent in the voriconazole group and 57.9 percent in the amphotericin B group (hazard ratio, 0.59; 95 percent confidence interval, 0.40 to 0.88). Voriconazole-treated patients had significantly fewer severe drug-related adverse events, but transient visual disturbances were common with voriconazole (occurring in 44.8 percent of patients). CONCLUSIONS: In patients with invasive aspergillosis, initial therapy with voriconazole led to better responses and improved survival and resulted in fewer severe side effects than the standard approach of initial therapy with amphotericin B.

A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R(2) between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases.

BACKGROUND: Thyrotoxicosis has multiple etiologies, manifestations, and potential therapies. Appropriate treatment requires an accurate diagnosis and is influenced by coexisting medical conditions and patient preference. This document describes evidence-based clinical guidelines for the management of thyrotoxicosis that would be useful to generalist and subspecialty physicians and others providing care for patients with this condition. METHODS: The American Thyroid Association (ATA) previously cosponsored guidelines for the management of thyrotoxicosis that were published in 2011. Considerable new literature has been published since then, and the ATA felt updated evidence-based guidelines were needed. The association assembled a task force of expert clinicians who authored this report. They examined relevant literature using a systematic PubMed search supplemented with additional published materials. An evidence-based medicine approach that incorporated the knowledge and experience of the panel was used to update the 2011 text and recommendations. The strength of the recommendations and the quality of evidence supporting them were rated according to the approach recommended by the Grading of Recommendations, Assessment, Development, and Evaluation Group. RESULTS: Clinical topics addressed include the initial evaluation and management of thyrotoxicosis; management of Graves' hyperthyroidism using radioactive iodine, antithyroid drugs, or surgery; management of toxic multinodular goiter or toxic adenoma using radioactive iodine or surgery; Graves' disease in children, adolescents, or pregnant patients; subclinical hyperthyroidism; hyperthyroidism in patients with Graves' orbitopathy; and management of other miscellaneous causes of thyrotoxicosis. New paradigms since publication of the 2011 guidelines are presented for the evaluation of the etiology of thyrotoxicosis, the management of Graves' hyperthyroidism with antithyroid drugs, the management of pregnant hyperthyroid patients, and the preparation of patients for thyroid surgery. The sections on less common causes of thyrotoxicosis have been expanded. CONCLUSIONS: One hundred twenty-four evidence-based recommendations were developed to aid in the care of patients with thyrotoxicosis and to share what the task force believes is current, rational, and optimal medical practice.

Importance: Parkinson disease is the most common form of parkinsonism, a group of neurological disorders with Parkinson disease-like movement problems such as rigidity, slowness, and tremor. More than 6 million individuals worldwide have Parkinson disease. Observations: Diagnosis of Parkinson disease is based on history and examination. History can include prodromal features (eg, rapid eye movement sleep behavior disorder, hyposmia, constipation), characteristic movement difficulty (eg, tremor, stiffness, slowness), and psychological or cognitive problems (eg, cognitive decline, depression, anxiety). Examination typically demonstrates bradykinesia with tremor, rigidity, or both. Dopamine transporter single-photon emission computed tomography can improve the accuracy of diagnosis when the presence of parkinsonism is uncertain. Parkinson disease has multiple disease variants with different prognoses. Individuals with a diffuse malignant subtype (9%-16% of individuals with Parkinson disease) have prominent early motor and nonmotor symptoms, poor response to medication, and faster disease progression. Individuals with mild motor-predominant Parkinson disease (49%-53% of individuals with Parkinson disease) have mild symptoms, a good response to dopaminergic medications (eg, carbidopa-levodopa, dopamine agonists), and slower disease progression. Other individuals have an intermediate subtype. For all patients with Parkinson disease, treatment is symptomatic, focused on improvement in motor (eg, tremor, rigidity, bradykinesia) and nonmotor (eg, constipation, cognition, mood, sleep) signs and symptoms. No disease-modifying pharmacologic treatments are available. Dopamine-based therapies typically help initial motor symptoms. Nonmotor symptoms require nondopaminergic approaches (eg, selective serotonin reuptake inhibitors for psychiatric symptoms, cholinesterase inhibitors for cognition). Rehabilitative therapy and exercise complement pharmacologic treatments. Individuals experiencing complications, such as worsening symptoms and functional impairment when a medication dose wears off ("off periods"), medication-resistant tremor, and dyskinesias, benefit from advanced treatments such as therapy with levodopa-carbidopa enteral suspension or deep brain stimulation. Palliative care is part of Parkinson disease management. Conclusions and Relevance: Parkinson disease is a heterogeneous disease with rapidly and slowly progressive forms. Treatment involves pharmacologic approaches (typically with levodopa preparations prescribed with or without other medications) and nonpharmacologic approaches (such as exercise and physical, occupational, and speech therapies). Approaches such as deep brain stimulation and treatment with levodopa-carbidopa enteral suspension can help individuals with medication-resistant tremor, worsening symptoms when the medication wears off, and dyskinesias.

BACKGROUND: Invasive fungal diseases (IFDs) remain important causes of morbidity and mortality. The consensus definitions of the Infectious Diseases Group of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group have been of immense value to researchers who conduct clinical trials of antifungals, assess diagnostic tests, and undertake epidemiologic studies. However, their utility has not extended beyond patients with cancer or recipients of stem cell or solid organ transplants. With newer diagnostic techniques available, it was clear that an update of these definitions was essential. METHODS: To achieve this, 10 working groups looked closely at imaging, laboratory diagnosis, and special populations at risk of IFD. A final version of the manuscript was agreed upon after the groups' findings were presented at a scientific symposium and after a 3-month period for public comment. There were several rounds of discussion before a final version of the manuscript was approved. RESULTS: There is no change in the classifications of "proven," "probable," and "possible" IFD, although the definition of "probable" has been expanded and the scope of the category "possible" has been diminished. The category of proven IFD can apply to any patient, regardless of whether the patient is immunocompromised. The probable and possible categories are proposed for immunocompromised patients only, except for endemic mycoses. CONCLUSIONS: These updated definitions of IFDs should prove applicable in clinical, diagnostic, and epidemiologic research of a broader range of patients at high-risk.

Aspergillus species have emerged as an important cause of life-threatening infections in immunocompromised patients. This expanding population is composed of patients with prolonged neutropenia, advanced HIV infection, and inherited immunodeficiency and patients who have undergone allogeneic hematopoietic stem cell transplantation (HSCT) and/or lung transplantation. This document constitutes the guidelines of the Infectious Diseases Society of America for treatment of aspergillosis and replaces the practice guidelines for Aspergillus published in 2000 The objective of these

We have developed a new technique for proximity-dependent labeling of proteins in eukaryotic cells. Named BioID for proximity-dependent biotin identification, this approach is based on fusion of a promiscuous Escherichia coli biotin protein ligase to a targeting protein. BioID features proximity-dependent biotinylation of proteins that are near-neighbors of the fusion protein. Biotinylated proteins may be isolated by affinity capture and identified by mass spectrometry. We apply BioID to lamin-A (LaA), a well-characterized intermediate filament protein that is a constituent of the nuclear lamina, an important structural element of the nuclear envelope (NE). We identify multiple proteins that associate with and/or are proximate to LaA in vivo. The most abundant of these include known interactors of LaA that are localized to the NE, as well as a new NE-associated protein named SLAP75. Our results suggest BioID is a useful and generally applicable method to screen for both interacting and neighboring proteins in their native cellular environment.

PREAMBLE The study of NAFLD has intensified significantly, with more than 1400 publications since 2018, when the last American Association for the Study of Liver Diseases (AASLD) Guidance document was published.1 This new AASLD Guidance document reflects many advances in the field pertinent to any practitioner caring for patients with NAFLD and emphasizes advances in noninvasive risk stratification and therapeutics. A separate guideline focused on the management of patients with NAFLD in the context of diabetes has been written jointly by the American Association of Clinical Endocrinology and AASLD.2 Given the significant growth in pediatric NAFLD, it will not be covered here to allow for a more robust discussion of the diagnosis and management of pediatric NAFLD in the upcoming AASLD Pediatric NAFLD Guidance. A “Guidance” differs from a “Guideline” in that it is not bound by the Grading of Recommendations, Assessment Development and Evaluation system. Thus, actionable statements rather than formal recommendations are provided herein. The highest available level of evidence was used to develop these statements, and, where high-level evidence was not available, expert opinion was used to develop guidance statements to inform clinical practice. Key points highlight important concepts relevant to understanding the disease and its management. The most profound advances in NAFLD relevant to clinical practice are in biomarkers and therapeutics. Biomarkers and noninvasive tests (NITs) can be used clinically to either exclude advanced diseases or identify those with a high probability of cirrhosis.3,4 NIT “cut points” vary with the populations studied, underlying disease severity, and clinical setting. Those proposed in this guidance are meant to aid decision-making in the clinic and are not meant to be interpreted in isolation. Identifying patients with “at-risk” NASH (biopsy-proven NASH with stage 2 or higher fibrosis) is a more recent area of interest. Although the definitive diagnosis and staging of NASH remain linked to histology, noninvasive tools can now be used to assess the likelihood of significant fibrosis, predict risk of disease progression and decompensation, make management decisions, and, to some degree, assess response to treatment. There is an ongoing debate over the nomenclature of fatty liver disease, which had not been finalized at the time this guidance was published. At the culmination of a rigorous consensus process, it is intended that any formal change in nomenclature will advance the field without a negative impact on disease awareness, clinical trial endpoints, or the drug development/approval process. Furthermore, it should allow for the emergence of newly recognized disease subtypes to address the impact of disease heterogeneity, including the role of alcohol, on disease progression and response to therapy. Input from patients has been central to all stages of the consensus process to ensure the minimization of nomenclature-related stigma. DEFINITIONS NAFLD is an overarching term that includes all disease grades and stages and refers to a population in which ≥5% of hepatocytes display macrovesicular steatosis in the absence of a readily identified alternative cause of steatosis (eg, medications, starvation, monogenic disorders) in individuals who drink little or no alcohol (defined as < 20 g/d for women and <30 g/d for men). The spectrum of disease includes NAFL, characterized by macrovesicular hepatic steatosis that may be accompanied by mild inflammation, and NASH, which is additionally characterized by the presence of inflammation and cellular injury (ballooning), with or without fibrosis, and finally cirrhosis, which is characterized by bands of fibrous septa leading to the formation of cirrhotic nodules, in which the earlier features of NASH may no longer be fully appreciated on a liver biopsy. UPDATE ON EPIDEMIOLOGY AND NATURAL HISTORY The prevalence of NAFLD and NASH is rising worldwide in parallel with increases in the prevalence of obesity and metabolic comorbid disease (insulin resistance, dyslipidemia, central obesity, and hypertension).5,6 The prevalence of NAFLD in adults is estimated to be 25%–30% in the general population7–9 and varies with the clinical setting, race/ethnicity, and geographic region studied but often remains undiagnosed.10–14 The associated economic burden attributable to NASH is substantial.15–17 The prevalence of NASH in the general population is challenging to determine with certainty; however, NASH was identified in 14% of asymptomatic patients undergoing colon cancer screening.14 This study also highlights that since the publication of a prior prospective prevalence study,18 the prevalence of clinically significant fibrosis (stage 2 or higher fibrosis) has increased >2-fold. This is supported by the projected rise in NAFLD prevalence by 2030, when patients with advanced hepatic fibrosis, defined as bridging fibrosis (F3) or compensated will the projected of the of hepatic decompensation, and to NASH are to to by Although to is the leading for liver in women and those of and is on with alcohol as the leading of disease progression from and that fibrosis and the presence of are the of disease The NASH and the fibrosis it it challenging to the of NASH to fibrosis and in Although fibrosis is the of increased and and are in patients with NAFLD in the absence of fibrosis on patients with NASH and at stage 2 fibrosis to as “at-risk” NASH, a higher risk of and progression is by many as the presence and of comorbid disease, and A of patients in NASH that or or may earlier of with a NAFLD fibrosis progression of stage in those with NASH for those with The diagnosis of cirrhosis, by or is important it clinical management. Those with for as as for and for or of patients with cirrhosis, progression to clinical from to Association disease stage and The most of in patients with NAFLD are disease and by liver The of liver fibrosis identified in patients with NAFLD has been linked to the of and fibrosis and are associated with an risk of and than earlier stages of a prospective study of in those with fibrosis stages was with in those with bridging fibrosis and in those with for hepatic was associated with has been associated with a in in clinical with NASH and fibrosis are at higher risk for and and are to “at-risk” The of fibrosis progression and hepatic vary on disease severity, and comorbid disease and are the most of in patients with NAFLD without advanced from liver disease in patients with advanced AND The presence and of and NASH are by that the and of fatty and and to and metabolic metabolic and in the of (eg, and the formation and of from There is in the role of patients with the of a role in the of NASH, with a higher risk associated with of NAFLD as of the that to the of NASH and its many of which can be are the many where may a role and where important as of fatty the and may also these A disease may be an of to that to without is which and the of NASH the of for patients with of that or NASH that (eg, (eg, (eg, A and fatty hepatic and and inflammation, and metabolic the with on the liver (eg, of growth growth and as that and is in patients with NAFLD and is in the and is characterized by increased of fatty from in the and with the progression of NAFLD to that the and of the of to an and that in response to in The and to in can be by and decisions, all of which in the of The of to the of NASH patients has the of tests and Although in some the and progression of NASH are by and resistance, in disease progression is by been associated with more advanced liver disease and the of in The of of in and in that a role in also been linked to the prevalence and of NAFLD, including 2 which may a role in and which in a that an that also to in been linked to NASH, fibrosis, and in a for of also been to be A of the of which is the of this to in disease and as to from the and hepatic may also to the NASH of of patients is to understanding of this disease and its The response of the liver to injury includes and of which to injury and as of a hepatic Although of been a in NASH, its role in the of NASH in remains of NASH an to the liver and and with in and disease inflammation, from to disease to the of NAFLD and disease NAFLD NAFLD is linked to and often the of metabolic (insulin resistance, dyslipidemia, central obesity, and metabolic an risk of progression of NASH and The NAFLD and metabolic may also the liver and (eg, the of that fatty and and The presence and of obesity are associated with NAFLD and disease is an important of the role of obesity in NAFLD characterized by increased and a higher risk of resistance, and hepatic fibrosis, of characterized by increased in the or to be which is more and than the of this more and is the of fatty leading to and of a with NAFLD recent and of NAFLD, or for alcohol including of and (eg, features of (eg, features of advanced liver disease (eg, tests with and and or to not as of liver or 2 diabetes 2 diabetes is the most risk for the of NAFLD, fibrosis and Given the central role that in the of and NAFLD, it is not that patients with a higher prevalence of NAFLD from to and a higher risk of NASH with Furthermore, the probability of advanced fibrosis increases with the of Although is for time and time these the and The NAFLD and is in in its NAFLD is associated with a in in the absence of The presence of NAFLD is associated with a to risk of and patients with NAFLD should be for the presence of Furthermore, as liver disease and diabetes more challenging to The role of in the progression of remains with 2 an and injury and liver not this Although NAFLD has also been in patients with its prevalence is than in and it is to metabolic risk (eg, higher is associated with There is a higher of in those with NAFLD the disease with of in disease to in those with The presence of is to metabolic with to the risk of and has been associated with fibrosis the of or the or are of underlying metabolic disease has not been with NAFLD are as to as those without and the are more in patients with NASH can to and and impact it is to this is by the of the patients to cirrhosis, to remain at high risk for the of and to hepatic of in NAFLD should the of to as on risk and risk of with as fatty or should be when with a not are in patients with NAFLD the disease including advanced liver disease, and to a in and in clinical are often patients with are also in the context of compensated and may on and are Although been used in patients with cirrhosis, the risk of be higher in this and more is patients with and high risk undergoing for liver can be with patients with NAFLD and (eg, or a of with fatty or should be used to the risk of may also when are and are is as an to to can be for of to its on should be when are used in with to a higher risk of is associated with and is also associated with more advanced a of has been linked to of and and increased hepatic Given the NAFLD and patients with NAFLD who are or should be for and or should be for those at high is an important cause of in patients with however, the to which NAFLD is A NAFLD and disease, and increased presence and of and the NAFLD and Furthermore, in a studied the of was the all fibrosis however, the of was the management of risk with the of and is to in patients with comorbid as dyslipidemia, and and is to in those at disease A of 20 that NAFLD was associated with a increased prevalence of NAFLD and NASH are also associated with from the NASH a higher prevalence of in patients with advanced fibrosis with fibrosis The to which the liver to the of of associated metabolic disease remains to be are and for risk in patients with NAFLD the disease including compensated on the and of in patients with cirrhosis, with be in patients with high can be and with fatty or with diabetes are at higher risk for NASH and advanced fibrosis and should be for advanced with NAFLD should be for the presence of Key and of is higher patients with NASH and advanced from is a cause of in patients with NAFLD, and to cancer has the to A NAFLD with NAFLD are most with hepatic steatosis on or liver is important to that provided by most are higher than should be in NAFLD, in which a from to in and from to in of patients should for metabolic of alcohol and of of liver disease as as to identify of and advanced liver disease the clinical is (eg, not associated with metabolic or accompanied by or of steatosis or should be of steatosis or can in or an NASH and should be in clinical can also to hepatic steatosis or or disease in those with underlying NAFLD and should be identified Although risk stratification is not in clinical of and NAFLD in the risk for NAFLD, NASH, and advanced 2 to for of hepatic steatosis and Clinical and advanced fibrosis in steatosis on liver (eg, disease on liver disease with to macrovesicular steatosis or of of steatosis and of hepatic to steatosis of of or may not be of metabolic risk and injury injury to of of metabolic of of hepatic of alcohol can be an important to fatty liver disease progression and should be in all can be as mild to 20 and and or and alcohol increases the probability of advanced in patients with obesity or of and alcohol on liver disease and alcohol the risk of liver cirrhosis, and from liver alcohol liver injury and fibrosis progression and should be in patients with a of mild alcohol on the of but in a alcohol (defined as was associated with in steatosis and and of NASH with patients who not alcohol may the risk for and is in to liver with an of on the to impact disease at an The impact of alcohol and on the of patients with NAFLD, alcohol can be a for liver disease and should be on a with clinically significant hepatic fibrosis should from alcohol Key for those patients with alcohol may the of fibrosis progression and hepatic and in patients with to its with obesity and metabolic risk higher of NAFLD been in patients with growth and the role of in the of hepatic the NAFLD and in remains significant NAFLD and or was in a however, a study of patients for a of was associated with a higher of and the of its metabolic growth are important of and and cellular is associated with and increased and can in resistance, and a growth in patients with NAFLD and associated with obesity and cause of is associated with resistance, and dyslipidemia, with a an increased risk for NASH and of in with and NAFLD been and a study of adults with with and liver in NASH with and hepatic steatosis by patients with and NAFLD, a which and increases growth without liver the a in the and NAFLD is linked to in and resistance, but is not for all A of and and A that NAFLD was associated with in but higher in a by The and NAFLD is often by the presence of obesity and resistance, of which are to be associated with can also resistance, and to the of hepatic study in that a level was associated with NAFLD, and the was for and in study including with by and liver histology, the and steatosis when for and obesity, with no to the of liver or in resistance, and a more role of on metabolic risk for NAFLD in but it should be for as it may The role of and in NAFLD is associated with increased liver as as a higher prevalence of NAFLD and advanced The prevalence of NAFLD is higher in with that higher in women are associated with an increased risk of NAFLD Furthermore, is a likelihood of NAFLD in higher of as as an and the of on NAFLD, hepatic in study that to from and are in The associated increased to the and progression of NAFLD, has not been of in and population a to in the prevalence of NAFLD and an increased risk of women with that is the of disease in a study of women with NAFLD was associated with the of and advanced fibrosis for and this study not for resistance, which may the NAFLD is more in with but not of is as by clinical or this should be Key Although and may be associated with hepatic role on the and progression of and fibrosis remains to be can in women with which with obesity and can NAFLD and more disease in this NAFLD Although NAFLD is associated with obesity, it can also in or in are with or and the prevalence of NAFLD in individuals varies from in the to as high as in with with NAFLD increased metabolic and and in the may also to NAFLD in a significant role in this but the to NAFLD individuals with NAFLD are more of or which is in by a higher prevalence of the in the which to NASH and fibrosis but is more in individuals with NAFLD with patients who or had but is not as it not can also a role and should be in patients of NAFLD in patients without obesity can be clinically may not be for patients with NAFLD, but and in this may be of populations at increased risk for advanced liver disease is to identify and those with clinically significant fibrosis (stage in as those with obesity with metabolic a of or significant alcohol also separate discussion on the role of may identify those with asymptomatic but clinically significant of patients for that may hepatic of is important of with NASH a higher risk of advanced Furthermore, the risk of NAFLD and advanced fibrosis may be of risk and recommendations are in for advanced fibrosis in populations of advanced fibrosis, obesity NAFLD in context of alcohol of a with to 2 diabetes of advanced fibrosis in population should NAFLD be in and practice most NAFLD is asymptomatic or associated with often patients The prevalence of advanced disease is in than in and the to is context to NAFLD on the of metabolic risk or identified as fatty liver by in the absence of of hepatic steatosis disease, disease, alcohol should risk The of this risk is to identify patients who are not to advanced fibrosis to the negative of in in advanced fibrosis, patients in can be in patients with metabolic risk those with or should more risk with patients with and advanced hepatic fibrosis a from available clinical and may be and allow for the of as progression to or decompensation, the of may be robust in patients with more are available, it is that the for in patients with will for the of patients at risk for or with NAFLD practice with steatosis on or for is a clinical of NAFLD, as those with metabolic risk or in liver should with a prevalence of advanced fibrosis, as in the setting, the is on advanced fibrosis a with a high negative the is patients can be in the and without 2 diabetes and metabolic risk can be with or 2 or more metabolic risk are at higher risk for disease and more (eg, should be patients than a of should be has in those should be in those with increased metabolic risk or liver should not be used in patients with a should be or Liver or the for risk stratification in a to should 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risk stratification in the and practice The in the is the of patients with “at-risk” NASH or advanced patients and may from tools as or can be used to risk patients in been or not of clinical Liver should be when is as may with or and or features a diagnosis of advanced or (eg, or when is in liver for NAFLD is not patients with hepatic steatosis or clinically NAFLD on the presence of obesity and metabolic risk should risk with as those with obesity, of cirrhosis, or more than mild alcohol should be for advanced patients with or 2 or more metabolic risk evidence of hepatic risk with should be with NASH are at the highest risk for and for and for with advanced NASH or should be to a for are in patients with advanced liver disease to NASH and should not be used in to exclude the presence of NASH with clinically significant of patients with NASH should be increased risk and for advanced hepatic Key with “at-risk” NASH with at stage 2 fibrosis) are at increased risk of and AND NAFLD Although liver remains the for the and staging of NASH, it has important to and liver for and staging of NASH are not in clinical practice and should be for clinical biomarkers are as tools for more an important of liver of noninvasive biomarkers in with the and of will the diagnosis of patients with clinically disease and response to without the for liver and of hepatic steatosis Although used in clinical for of in those with and a of steatosis The absence of steatosis on not exclude the presence of NASH or the presence of fibrosis, can be when cirrhotic liver is identified or it evidence of (eg, the of hepatic the in with a of hepatic steatosis but not or in liver is an and for liver that is used in clinical role in clinical practice is it is used in Although is to in the diagnosis as as the of liver this is by and the of not a of liver fibrosis in patients with or NAFLD Clinical and fibrosis biomarkers from clinical can of the presence of advanced fibrosis been (eg, NAFLD however, is the most is a and and in its to identify patients with a probability of advanced of and also been associated with and in a change in from risk to risk to high risk may be used to assess clinical Although is to fibrosis as the and to advanced fibrosis, is as a for general and on its and The is a of in of and of patients with NAFLD at increased risk of progression to and clinical The is for clinical as a in the and fibrosis tests may be as risk when is not available for the noninvasive of NAFLD to clinical context of of hepatic steatosis with steatosis can as advanced fibrosis for ≥5% spectrum of to assess of “at-risk” NASH in the of and patients with at stage 2 fibrosis with of advanced fibrosis not in and individuals who high probability not in with obesity 2 to a to a of points not points not with advanced fibrosis, of of or for and for cirrhosis, is associated with increased risk of hepatic patients with by is associated with cirrhosis, but for is by has a for diagnosis of and is 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clinical is a for or when are patients with cirrhosis, by risk of hepatic and The of that with the stage of fibrosis is by is of the Liver by may also be to assess the risk of of and associated with risk of hepatic or that the for by and are but the are provided of these with a of and that associated with and risk of over of a in liver is associated with a higher risk of as as Although more are NIT in patients with may be as for in response to study for the of “at-risk” NASH and biomarkers are study for the of NASH, but these not the level of clinical evidence for in clinical practice. of biomarkers including and and and and biomarkers are in for “at-risk” as may also be for the of “at-risk” an of the this in not been and over remains to be that clinical with liver that may be of are The is a from liver and by and for the of “at-risk” with study on and a with has been to be to A with has been linked to increased risk of hepatic decompensation, and a negative with has a negative for a risk of hepatic A from and is also to identify “at-risk” as a on and may be but of over the over to be and the of in on the context of Although can hepatic it is not as a to identify hepatic steatosis to the NAFLD as a may be used to identify can additionally is or may be used to exclude advanced Key liver and can predict an increased risk of hepatic and AND of NAFLD should of of and staging of fibrosis assess these with a should be at in but in and are also the spectrum of

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.

Peer Reviewed

The tumor microenvironment of colorectal carcinoma is a complex community of genomically altered cancer cells, nonneoplastic cells, and a diverse collection of microorganisms. Each of these components may contribute to carcinogenesis; however, the role of the microbiota is the least well understood. We have characterized the composition of the microbiota in colorectal carcinoma using whole genome sequences from nine tumor/normal pairs. Fusobacterium sequences were enriched in carcinomas, confirmed by quantitative PCR and 16S rDNA sequence analysis of 95 carcinoma/normal DNA pairs, while the Bacteroidetes and Firmicutes phyla were depleted in tumors. Fusobacteria were also visualized within colorectal tumors using FISH. These findings reveal alterations in the colorectal cancer microbiota; however, the precise role of Fusobacteria in colorectal carcinoma pathogenesis requires further investigation.

Intracellular current administration evokes rapid, graded, and bidirectional mechanical responses of isolated outer hair cells from the mammalian inner ear. The cells become shorter in response to depolarizing and longer in response to hyperpolarizing currents in the synaptic end of the cell. The cells respond with either an increase or decrease in length to transcellular alternating current stimulation. The direction of the movement with transcellular stimuli appears to be frequency dependent. Iontophoretic application of acetylcholine to the synaptic end of the cell decreases its length. The microarchitecture of the organ of Corti permits length changes of outer hair cells in a manner that could significantly influence the mechanics of the cochlear partition and thereby contribute to the exquisite sensitivity of mammalian hearing.

OBJECTIVE: To investigate the concurrent validity and reliability of the Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID), a short structured diagnostic interview for DSM-IV and ICD-10 psychiatric disorders in children and adolescents. METHOD: Participants were 226 children and adolescents (190 outpatients and 36 controls) aged 6 to 17 years. To assess the concurrent validity of the MINI-KID, participants were administered the MINI-KID and the Schedule for Affective Disorders and Schizophrenia for School Aged Children-Present and Lifetime Version (K-SADS-PL) by blinded interviewers in a counterbalanced order on the same day. Participants also completed a self-rated measure of disability. In addition, interrater (n = 57) and test-retest (n = 83) reliability data (retest interval, 1-5 days) were collected, and agreement between the parent version of the MINI-KID and the standard MINI-KID (n = 140) was assessed. Data were collected between March 2004 and January 2008. RESULTS: Substantial to excellent MINI-KID to K-SADS-PL concordance was found for syndromal diagnoses of any mood disorder, any anxiety disorder, any substance use disorder, any ADHD or behavioral disorder, and any eating disorder (area under curve [AUC] = 0.81-0.96, kappa = 0.56-0.87). Results were more variable for psychotic disorder (AUC = 0.94, kappa = 0.41). Sensitivity was substantial (0.61-1.00) for 15/20 individual DSM-IV disorders. Specificity was excellent (0.81-1.00) for 18 disorders and substantial (> 0.73) for the remaining 2. The MINI-KID identified a median of 3 disorders per subject compared to 2 on the K-SADS-PL and took two-thirds less time to administer (34 vs 103 minutes). Interrater and test-retest kappas were substantial to almost perfect (0.64-1.00) for all individual MINI-KID disorders except dysthymia. Concordance of the parent version (MINI-KID-P) with the standard MINI-KID was good. CONCLUSIONS: The MINI-KID generates reliable and valid psychiatric diagnoses for children and adolescents and does so in a third of the time as the K-SADS-PL.