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Showing papers by "Virginia Commonwealth University published in 2018"



Journal ArticleDOI
TL;DR: Understanding of pathogenic mechanisms and clinical features of NAFLD is driving progress in therapeutic strategies now in clinical trials and the emerging targets for drug development that involve either single agents or combination therapies intended to arrest or reverse disease progression are discussed.
Abstract: There has been a rise in the prevalence of nonalcoholic fatty liver disease (NAFLD), paralleling a worldwide increase in diabetes and metabolic syndrome. NAFLD, a continuum of liver abnormalities from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), has a variable course but can lead to cirrhosis and liver cancer. Here we review the pathogenic and clinical features of NAFLD, its major comorbidities, clinical progression and risk of complications and in vitro and animal models of NAFLD enabling refinement of therapeutic targets that can accelerate drug development. We also discuss evolving principles of clinical trial design to evaluate drug efficacy and the emerging targets for drug development that involve either single agents or combination therapies intended to arrest or reverse disease progression.

2,004 citations


Journal ArticleDOI
Naomi R. Wray1, Stephan Ripke2, Stephan Ripke3, Stephan Ripke4  +259 moreInstitutions (79)
TL;DR: A genome-wide association meta-analysis of individuals with clinically assessed or self-reported depression identifies 44 independent and significant loci and finds important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia.
Abstract: Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression and imply that a continuous measure of risk underlies the clinical phenotype.

1,898 citations


Journal ArticleDOI
22 Jun 2018-Science
TL;DR: It is demonstrated that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine, and it is shown that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures.
Abstract: 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.

1,357 citations


Journal ArticleDOI
TL;DR: In this paper, the authors performed a prospective trial involving 10,273 women with hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, axillary node-negative breast cancer.
Abstract: Background The recurrence score based on the 21-gene breast cancer assay predicts chemotherapy benefit if it is high and a low risk of recurrence in the absence of chemotherapy if it is low; however, there is uncertainty about the benefit of chemotherapy for most patients, who have a midrange score. Methods We performed a prospective trial involving 10,273 women with hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative, axillary node–negative breast cancer. Of the 9719 eligible patients with follow-up information, 6711 (69%) had a midrange recurrence score of 11 to 25 and were randomly assigned to receive either chemoendocrine therapy or endocrine therapy alone. The trial was designed to show noninferiority of endocrine therapy alone for invasive disease–free survival (defined as freedom from invasive disease recurrence, second primary cancer, or death). Results Endocrine therapy was noninferior to chemoendocrine therapy in the analysis of invasive disease–free surv...

1,337 citations


Journal ArticleDOI
TL;DR: With continued high rates of adult obesity and DM along with an aging population, NAFLD‐related liver disease and mortality will increase in the United States and strategies to slow the growth ofNAFLD cases and therapeutic options are necessary to mitigate disease burden.

1,322 citations


Journal ArticleDOI
TL;DR: An overview of the imaging procedures of the ABCD study is provided, the basis for their selection and preliminary quality assurance and results that provide evidence for the feasibility and age-appropriateness of procedures and generalizability of findings to the existent literature are provided.

1,114 citations


Journal ArticleDOI
Ali H. Mokdad1, Katherine Ballestros1, Michelle Echko1, Scott D Glenn1, Helen E Olsen1, Erin C Mullany1, Alexander Lee1, Abdur Rahman Khan2, Alireza Ahmadi3, Alireza Ahmadi4, Alize J. Ferrari1, Alize J. Ferrari5, Alize J. Ferrari6, Amir Kasaeian7, Andrea Werdecker, Austin Carter1, Ben Zipkin1, Benn Sartorius8, Benn Sartorius9, Berrin Serdar10, Bryan L. Sykes11, Christopher Troeger1, Christina Fitzmaurice1, Christina Fitzmaurice12, Colin D. Rehm13, Damian Santomauro1, Damian Santomauro6, Damian Santomauro5, Daniel Kim14, Danny V. Colombara1, David C. Schwebel15, Derrick Tsoi1, Dhaval Kolte16, Elaine O. Nsoesie1, Emma Nichols1, Eyal Oren17, Fiona J Charlson5, Fiona J Charlson1, Fiona J Charlson6, George C Patton18, Gregory A. Roth1, H. Dean Hosgood19, Harvey Whiteford5, Harvey Whiteford6, Harvey Whiteford1, Hmwe H Kyu1, Holly E. Erskine5, Holly E. Erskine6, Holly E. Erskine1, Hsiang Huang20, Ira Martopullo1, Jasvinder A. Singh15, Jean B. Nachega21, Jean B. Nachega22, Jean B. Nachega23, Juan Sanabria24, Juan Sanabria25, Kaja Abbas26, Kanyin Ong1, Karen M. Tabb27, Kristopher J. Krohn1, Leslie Cornaby1, Louisa Degenhardt1, Louisa Degenhardt28, Mark Moses1, Maryam S. Farvid29, Max Griswold1, Michael H. Criqui30, Michelle L. Bell31, Minh Nguyen1, Mitch T Wallin32, Mitch T Wallin33, Mojde Mirarefin1, Mostafa Qorbani, Mustafa Z. Younis34, Nancy Fullman1, Patrick Liu1, Paul S Briant1, Philimon Gona35, Rasmus Havmoller3, Ricky Leung36, Ruth W Kimokoti37, Shahrzad Bazargan-Hejazi38, Shahrzad Bazargan-Hejazi39, Simon I. Hay1, Simon I. Hay40, Simon Yadgir1, Stan Biryukov1, Stein Emil Vollset41, Stein Emil Vollset1, Tahiya Alam1, Tahvi Frank1, Talha Farid2, Ted R. Miller42, Ted R. Miller43, Theo Vos1, Till Bärnighausen29, Till Bärnighausen44, Tsegaye Telwelde Gebrehiwot45, Yuichiro Yano46, Ziyad Al-Aly47, Alem Mehari48, Alexis J. Handal49, Amit Kandel50, Ben Anderson51, Brian J. Biroscak52, Brian J. Biroscak31, Dariush Mozaffarian53, E. Ray Dorsey54, Eric L. Ding29, Eun-Kee Park55, Gregory R. Wagner29, Guoqing Hu56, Honglei Chen57, Jacob E. Sunshine51, Jagdish Khubchandani58, Janet L Leasher59, Janni Leung6, Janni Leung51, Joshua A. Salomon29, Jürgen Unützer51, Leah E. Cahill60, Leah E. Cahill29, Leslie T. Cooper61, Masako Horino, Michael Brauer62, Michael Brauer1, Nicholas J K Breitborde63, Peter J. Hotez64, Roman Topor-Madry65, Roman Topor-Madry66, Samir Soneji67, Saverio Stranges68, Spencer L. James1, Stephen M. Amrock69, Sudha Jayaraman70, Tejas V. Patel, Tomi Akinyemiju15, Vegard Skirbekk71, Vegard Skirbekk41, Yohannes Kinfu72, Zulfiqar A Bhutta73, Jost B. Jonas44, Christopher J L Murray1 
Institute for Health Metrics and Evaluation1, University of Louisville2, Karolinska Institutet3, Kermanshah University of Medical Sciences4, Centre for Mental Health5, University of Queensland6, Tehran University of Medical Sciences7, South African Medical Research Council8, University of KwaZulu-Natal9, University of Colorado Boulder10, University of California, Irvine11, Fred Hutchinson Cancer Research Center12, Montefiore Medical Center13, Northeastern University14, University of Alabama at Birmingham15, Brown University16, San Diego State University17, University of Melbourne18, Albert Einstein College of Medicine19, Cambridge Health Alliance20, University of Cape Town21, University of Pittsburgh22, Johns Hopkins University23, Case Western Reserve University24, Marshall University25, University of London26, University of Illinois at Urbana–Champaign27, National Drug and Alcohol Research Centre28, Harvard University29, University of California, San Diego30, Yale University31, Veterans Health Administration32, Georgetown University33, Jackson State University34, University of Massachusetts Boston35, State University of New York System36, Simmons College37, Charles R. Drew University of Medicine and Science38, University of California, Los Angeles39, University of Oxford40, Norwegian Institute of Public Health41, Curtin University42, Pacific Institute43, Heidelberg University44, Jimma University45, Northwestern University46, Washington University in St. Louis47, Howard University48, University of New Mexico49, University at Buffalo50, University of Washington51, University of South Florida52, Tufts University53, University of Rochester Medical Center54, Kosin University55, Central South University56, Michigan State University57, Ball State University58, Nova Southeastern University59, Dalhousie University60, Mayo Clinic61, University of British Columbia62, Ohio State University63, Baylor University64, Jagiellonian University Medical College65, Wrocław Medical University66, Dartmouth College67, University of Western Ontario68, Oregon Health & Science University69, Virginia Commonwealth University70, Columbia University71, University of Canberra72, Aga Khan University73
10 Apr 2018-JAMA
TL;DR: There are wide differences in the burden of disease at the state level and specific diseases and risk factors, such as drug use disorders, high BMI, poor diet, high fasting plasma glucose level, and alcohol use disorders are increasing and warrant increased attention.
Abstract: Introduction Several studies have measured health outcomes in the United States, but none have provided a comprehensive assessment of patterns of health by state. Objective To use the results of the Global Burden of Disease Study (GBD) to report trends in the burden of diseases, injuries, and risk factors at the state level from 1990 to 2016. Design and Setting A systematic analysis of published studies and available data sources estimates the burden of disease by age, sex, geography, and year. Main Outcomes and Measures Prevalence, incidence, mortality, life expectancy, healthy life expectancy (HALE), years of life lost (YLLs) due to premature mortality, years lived with disability (YLDs), and disability-adjusted life-years (DALYs) for 333 causes and 84 risk factors with 95% uncertainty intervals (UIs) were computed. Results Between 1990 and 2016, overall death rates in the United States declined from 745.2 (95% UI, 740.6 to 749.8) per 100 000 persons to 578.0 (95% UI, 569.4 to 587.1) per 100 000 persons. The probability of death among adults aged 20 to 55 years declined in 31 states and Washington, DC from 1990 to 2016. In 2016, Hawaii had the highest life expectancy at birth (81.3 years) and Mississippi had the lowest (74.7 years), a 6.6-year difference. Minnesota had the highest HALE at birth (70.3 years), and West Virginia had the lowest (63.8 years), a 6.5-year difference. The leading causes of DALYs in the United States for 1990 and 2016 were ischemic heart disease and lung cancer, while the third leading cause in 1990 was low back pain, and the third leading cause in 2016 was chronic obstructive pulmonary disease. Opioid use disorders moved from the 11th leading cause of DALYs in 1990 to the 7th leading cause in 2016, representing a 74.5% (95% UI, 42.8% to 93.9%) change. In 2016, each of the following 6 risks individually accounted for more than 5% of risk-attributable DALYs: tobacco consumption, high body mass index (BMI), poor diet, alcohol and drug use, high fasting plasma glucose, and high blood pressure. Across all US states, the top risk factors in terms of attributable DALYs were due to 1 of the 3 following causes: tobacco consumption (32 states), high BMI (10 states), or alcohol and drug use (8 states). Conclusions and Relevance There are wide differences in the burden of disease at the state level. Specific diseases and risk factors, such as drug use disorders, high BMI, poor diet, high fasting plasma glucose level, and alcohol use disorders are increasing and warrant increased attention. These data can be used to inform national health priorities for research, clinical care, and policy.

962 citations


Journal ArticleDOI
08 May 2018-JAMA
TL;DR: The USPSTF concludes with moderate certainty that the net benefit of PSA-based screening for prostate cancer in men aged 55 to 69 years is small for some men.
Abstract: Importance In the United States, the lifetime risk of being diagnosed with prostate cancer is approximately 11%, and the lifetime risk of dying of prostate cancer is 2.5%. The median age of death from prostate cancer is 80 years. Many men with prostate cancer never experience symptoms and, without screening, would never know they have the disease. African American men and men with a family history of prostate cancer have an increased risk of prostate cancer compared with other men. Objective To update the 2012 US Preventive Services Task Force (USPSTF) recommendation on prostate-specific antigen (PSA)–based screening for prostate cancer. Evidence Review The USPSTF reviewed the evidence on the benefits and harms of PSA-based screening for prostate cancer and subsequent treatment of screen-detected prostate cancer. The USPSTF also commissioned a review of existing decision analysis models and the overdiagnosis rate of PSA-based screening. The reviews also examined the benefits and harms of PSA-based screening in patient subpopulations at higher risk of prostate cancer, including older men, African American men, and men with a family history of prostate cancer. Findings Adequate evidence from randomized clinical trials shows that PSA-based screening programs in men aged 55 to 69 years may prevent approximately 1.3 deaths from prostate cancer over approximately 13 years per 1000 men screened. Screening programs may also prevent approximately 3 cases of metastatic prostate cancer per 1000 men screened. Potential harms of screening include frequent false-positive results and psychological harms. Harms of prostate cancer treatment include erectile dysfunction, urinary incontinence, and bowel symptoms. About 1 in 5 men who undergo radical prostatectomy develop long-term urinary incontinence, and 2 in 3 men will experience long-term erectile dysfunction. Adequate evidence shows that the harms of screening in men older than 70 years are at least moderate and greater than in younger men because of increased risk of false-positive results, diagnostic harms from biopsies, and harms from treatment. The USPSTF concludes with moderate certainty that the net benefit of PSA-based screening for prostate cancer in men aged 55 to 69 years is small for some men. How each man weighs specific benefits and harms will determine whether the overall net benefit is small. The USPSTF concludes with moderate certainty that the potential benefits of PSA-based screening for prostate cancer in men 70 years and older do not outweigh the expected harms. Conclusions and Recommendation For men aged 55 to 69 years, the decision to undergo periodic PSA-based screening for prostate cancer should be an individual one and should include discussion of the potential benefits and harms of screening with their clinician. Screening offers a small potential benefit of reducing the chance of death from prostate cancer in some men. However, many men will experience potential harms of screening, including false-positive results that require additional testing and possible prostate biopsy; overdiagnosis and overtreatment; and treatment complications, such as incontinence and erectile dysfunction. In determining whether this service is appropriate in individual cases, patients and clinicians should consider the balance of benefits and harms on the basis of family history, race/ethnicity, comorbid medical conditions, patient values about the benefits and harms of screening and treatment-specific outcomes, and other health needs. Clinicians should not screen men who do not express a preference for screening. (C recommendation) The USPSTF recommends against PSA-based screening for prostate cancer in men 70 years and older. (D recommendation)

902 citations


Journal ArticleDOI
Jeanne E. Savage1, Philip R. Jansen2, Philip R. Jansen1, Sven Stringer1, Kyoko Watanabe1, Julien Bryois3, Christiaan de Leeuw1, Mats Nagel, Swapnil Awasthi4, Peter B. Barr5, Jonathan R. I. Coleman6, Katrina L. Grasby7, Anke R. Hammerschlag1, Jakob Kaminski4, Robert Karlsson3, Eva Krapohl8, Max Lam, Marianne Nygaard9, Chandra A. Reynolds10, Joey W. Trampush11, Hannah Young12, Delilah Zabaneh8, Sara Hägg3, Narelle K. Hansell13, Ida K. Karlsson3, Sten Linnarsson3, Grant W. Montgomery13, Grant W. Montgomery7, Ana B. Muñoz-Manchado3, Erin Burke Quinlan8, Gunter Schumann8, Nathan G. Skene3, Nathan G. Skene14, Bradley T. Webb5, Tonya White2, Dan E. Arking15, Dimitrios Avramopoulos15, Robert M. Bilder16, Panos Bitsios17, Katherine E. Burdick18, Katherine E. Burdick19, Katherine E. Burdick20, Tyrone D. Cannon21, Ornit Chiba-Falek, Andrea Christoforou22, Elizabeth T. Cirulli, Eliza Congdon16, Aiden Corvin23, Gail Davies24, Ian J. Deary24, Pamela DeRosse25, Pamela DeRosse26, Dwight Dickinson27, Srdjan Djurovic28, Srdjan Djurovic29, Gary Donohoe30, Emily Drabant Conley, Johan G. Eriksson31, Thomas Espeseth32, Nelson A. Freimer16, Stella G. Giakoumaki17, Ina Giegling33, Michael Gill23, David C. Glahn21, Ahmad R. Hariri34, Alex Hatzimanolis35, Alex Hatzimanolis36, Matthew C. Keller37, Emma Knowles21, Deborah C. Koltai34, Bettina Konte33, Jari Lahti31, Stephanie Le Hellard28, Todd Lencz26, Todd Lencz25, David C. Liewald24, Edythe D. London16, Astri J. Lundervold28, Anil K. Malhotra25, Anil K. Malhotra26, Ingrid Melle28, Ingrid Melle32, Derek W. Morris30, Anna C. Need38, William Ollier39, Aarno Palotie20, Aarno Palotie31, Aarno Palotie40, Antony Payton39, Neil Pendleton41, Russell A. Poldrack42, Katri Räikkönen31, Ivar Reinvang32, Panos Roussos18, Panos Roussos19, Dan Rujescu33, Fred W. Sabb43, Matthew A. Scult34, Olav B. Smeland32, Nikolaos Smyrnis35, Nikolaos Smyrnis36, John M. Starr24, Vidar M. Steen28, Nikos C. Stefanis36, Nikos C. Stefanis35, Richard E. Straub15, Kjetil Sundet32, Henning Tiemeier2, Aristotle N. Voineskos44, Daniel R. Weinberger15, Elisabeth Widen31, Jin Yu, Gonçalo R. Abecasis45, Ole A. Andreassen32, Gerome Breen6, Lene Christiansen9, Birgit Debrabant9, Danielle M. Dick5, Andreas Heinz4, Jens Hjerling-Leffler3, M. Arfan Ikram46, Kenneth S. Kendler5, Nicholas G. Martin7, Sarah E. Medland7, Nancy L. Pedersen3, Robert Plomin8, Tinca J. C. Polderman1, Stephan Ripke47, Stephan Ripke4, Stephan Ripke20, Sophie van der Sluis, Patrick Sullivan3, Patrick Sullivan48, Scott I. Vrieze12, Margaret J. Wright13, Danielle Posthuma1 
TL;DR: A large-scale genetic association study of intelligence identifies 190 new loci and implicates 939 new genes related to neurogenesis, neuron differentiation and synaptic structure, a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.
Abstract: Intelligence is highly heritable1 and a major determinant of human health and well-being2. Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence3-7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.

800 citations


Journal ArticleDOI
TL;DR: Consensus criteria for classifying tremor disorders were published by the International Parkinson and Movement Disorder Society in 1998 but subsequent advances with regard to essential tremor, tremor associated with dystonia, and other monosymptomatic and indeterminate tremors make a significant revision necessary.
Abstract: Background Consensus criteria for classifying tremor disorders were published by the International Parkinson and Movement Disorder Society in 1998. Subsequent advances with regard to essential tremor, tremor associated with dystonia, and other monosymptomatic and indeterminate tremors make a significant revision necessary. Objectives Convene an international panel of experienced investigators to review the definition and classification of tremor. Methods Computerized MEDLINE searches in January 2013 and 2015 were conducted using a combination of text words and MeSH terms: “tremor”, “tremor disorders”, “essential tremor”, “dystonic tremor”, and “classification” limited to human studies. Agreement was obtained using consensus development methodology during four in-person meetings, two teleconferences, and numerous manuscript reviews. Results Tremor is defined as an involuntary, rhythmic, oscillatory movement of a body part and is classified along two axes: Axis 1—clinical characteristics, including historical features (age at onset, family history, and temporal evolution), tremor characteristics (body distribution, activation condition), associated signs (systemic, neurological), and laboratory tests (electrophysiology, imaging); and Axis 2—etiology (acquired, genetic, or idiopathic). Tremor syndromes, consisting of either isolated tremor or tremor combined with other clinical features, are defined within Axis 1. This classification scheme retains the currently accepted tremor syndromes, including essential tremor, and provides a framework for defining new syndromes. Conclusions This approach should be particularly useful in elucidating isolated tremor syndromes and syndromes consisting of tremor and other signs of uncertain significance. Consistently defined Axis 1 syndromes are needed to facilitate the elucidation of specific etiologies in Axis 2. © 2017 International Parkinson and Movement Disorder Society

Journal ArticleDOI
21 Aug 2018-JAMA
TL;DR: The USPSTF concludes with high certainty that the benefits of screening every 3 years with cytology alone in women aged 21 to 29 years substantially outweigh the harms and screening women younger than 21 years does not provide significant benefit.
Abstract: Importance The number of deaths from cervical cancer in the United States has decreased substantially since the implementation of widespread cervical cancer screening and has declined from 2.8 to 2.3 deaths per 100 000 women from 2000 to 2015. Objective To update the US Preventive Services Task Force (USPSTF) 2012 recommendation on screening for cervical cancer. Evidence Review The USPSTF reviewed the evidence on screening for cervical cancer, with a focus on clinical trials and cohort studies that evaluated screening with high-risk human papillomavirus (hrHPV) testing alone or hrHPV and cytology together (cotesting) compared with cervical cytology alone. The USPSTF also commissioned a decision analysis model to evaluate the age at which to begin and end screening, the optimal interval for screening, the effectiveness of different screening strategies, and related benefits and harms of different screening strategies. Findings Screening with cervical cytology alone, primary hrHPV testing alone, or cotesting can detect high-grade precancerous cervical lesions and cervical cancer. Screening women aged 21 to 65 years substantially reduces cervical cancer incidence and mortality. The harms of screening for cervical cancer in women aged 30 to 65 years are moderate. The USPSTF concludes with high certainty that the benefits of screening every 3 years with cytology alone in women aged 21 to 29 years substantially outweigh the harms. The USPSTF concludes with high certainty that the benefits of screening every 3 years with cytology alone, every 5 years with hrHPV testing alone, or every 5 years with both tests (cotesting) in women aged 30 to 65 years outweigh the harms. Screening women older than 65 years who have had adequate prior screening and women younger than 21 years does not provide significant benefit. Screening women who have had a hysterectomy with removal of the cervix for indications other than a high-grade precancerous lesion or cervical cancer provides no benefit. The USPSTF concludes with moderate to high certainty that screening women older than 65 years who have had adequate prior screening and are not otherwise at high risk for cervical cancer, screening women younger than 21 years, and screening women who have had a hysterectomy with removal of the cervix for indications other than a high-grade precancerous lesion or cervical cancer does not result in a positive net benefit. Conclusions and Recommendation The USPSTF recommends screening for cervical cancer every 3 years with cervical cytology alone in women aged 21 to 29 years. (A recommendation) The USPSTF recommends screening every 3 years with cervical cytology alone, every 5 years with hrHPV testing alone, or every 5 years with hrHPV testing in combination with cytology (cotesting) in women aged 30 to 65 years. (A recommendation) The USPSTF recommends against screening for cervical cancer in women younger than 21 years. (D recommendation) The USPSTF recommends against screening for cervical cancer in women older than 65 years who have had adequate prior screening and are not otherwise at high risk for cervical cancer. (D recommendation) The USPSTF recommends against screening for cervical cancer in women who have had a hysterectomy with removal of the cervix and do not have a history of a high-grade precancerous lesion or cervical cancer. (D recommendation)

Journal ArticleDOI
TL;DR: A mathematical expression is derived to compute PrediXcan results using summary data, and the effects of gene expression variation on human phenotypes in 44 GTEx tissues and >100 phenotypes are investigated.
Abstract: Scalable, integrative methods to understand mechanisms that link genetic variants with phenotypes are needed. Here we derive a mathematical expression to compute PrediXcan (a gene mapping approach) results using summary data (S-PrediXcan) and show its accuracy and general robustness to misspecified reference sets. We apply this framework to 44 GTEx tissues and 100+ phenotypes from GWAS and meta-analysis studies, creating a growing public catalog of associations that seeks to capture the effects of gene expression variation on human phenotypes. Replication in an independent cohort is shown. Most of the associations are tissue specific, suggesting context specificity of the trait etiology. Colocalized significant associations in unexpected tissues underscore the need for an agnostic scanning of multiple contexts to improve our ability to detect causal regulatory mechanisms. Monogenic disease genes are enriched among significant associations for related traits, suggesting that smaller alterations of these genes may cause a spectrum of milder phenotypes.

Journal ArticleDOI
15 Mar 2018
TL;DR: SCD is characterized by a remarkable phenotypic complexity; common acute complications are acute pain events, acute chest syndrome and stroke; chronic complications (including chronic kidney disease) can damage all organs.
Abstract: Sickle cell disease (SCD) is a group of inherited disorders caused by mutations in HBB, which encodes haemoglobin subunit β. The incidence is estimated to be between 300,000 and 400,000 neonates globally each year, the majority in sub-Saharan Africa. Haemoglobin molecules that include mutant sickle β-globin subunits can polymerize; erythrocytes that contain mostly haemoglobin polymers assume a sickled form and are prone to haemolysis. Other pathophysiological mechanisms that contribute to the SCD phenotype are vaso-occlusion and activation of the immune system. SCD is characterized by a remarkable phenotypic complexity. Common acute complications are acute pain events, acute chest syndrome and stroke; chronic complications (including chronic kidney disease) can damage all organs. Hydroxycarbamide, blood transfusions and haematopoietic stem cell transplantation can reduce the severity of the disease. Early diagnosis is crucial to improve survival, and universal newborn screening programmes have been implemented in some countries but are challenging in low-income, high-burden settings.

Journal ArticleDOI
Douglas M. Ruderfer1, Stephan Ripke2, Stephan Ripke3, Stephan Ripke4  +628 moreInstitutions (156)
14 Jun 2018-Cell
TL;DR: For the first time, specific loci that distinguish between BD and SCZ are discovered and polygenic components underlying multiple symptom dimensions are identified that point to the utility of genetics to inform symptomology and potential treatment.

Journal ArticleDOI
TL;DR: Adoptive T cell therapy induced complete and durable remission in a patient with refractory metastatic breast cancer, providing proof of principle for this approach in breast cancer therapy.
Abstract: Immunotherapy using either checkpoint blockade or the adoptive transfer of antitumor lymphocytes has shown effectiveness in treating cancers with high levels of somatic mutations—such as melanoma, smoking-induced lung cancers and bladder cancer—with little effect in other common epithelial cancers that have lower mutation rates, such as those arising in the gastrointestinal tract, breast and ovary1–7. Adoptive transfer of autologous lymphocytes that specifically target proteins encoded by somatically mutated genes has mediated substantial objective clinical regressions in patients with metastatic bile duct, colon and cervical cancers8–11. We present a patient with chemorefractory hormone receptor (HR)-positive metastatic breast cancer who was treated with tumor-infiltrating lymphocytes (TILs) reactive against mutant versions of four proteins—SLC3A2, KIAA0368, CADPS2 and CTSB. Adoptive transfer of these mutant-protein-specific TILs in conjunction with interleukin (IL)-2 and checkpoint blockade mediated the complete durable regression of metastatic breast cancer, which is now ongoing for >22 months, and it represents a new immunotherapy approach for the treatment of these patients.

Journal ArticleDOI
TL;DR: This review synthesizes the evidence examining teams and teamwork in health care delivery settings in order to characterize the current state of the science and to highlight gaps in which studies can further illuminate the evidence-based understanding of teamwork and collaboration.
Abstract: Few industries match the scale of health care. In the United States alone, an estimated 85% of the population has at least 1 health care encounter annually and at least one quarter of these people experience 4 to 9 encounters annually. A single visit requires collaboration among a multidisciplinary group of clinicians, administrative staff, patients, and their loved ones. Multiple visits often occur across different clinicians working in different organizations. Ineffective care coordination and the underlying suboptimal teamwork processes are a public health issue. Health care delivery systems exemplify complex organizations operating under high stakes in dynamic policy and regulatory environments. The coordination and delivery of safe, high-quality care demands reliable teamwork and collaboration within, as well as across, organizational, disciplinary, technical, and cultural boundaries. In this review, we synthesize the evidence examining teams and teamwork in health care delivery settings in order to characterize the current state of the science and to highlight gaps in which studies can further illuminate our evidence-based understanding of teamwork and collaboration. Specifically, we highlight evidence concerning (a) the relationship between teamwork and multilevel outcomes, (b) effective teamwork behaviors, (c) competencies (i.e., knowledge, skills, and attitudes) underlying effective teamwork in the health professions, (d) teamwork interventions, (e) team performance measurement strategies, and (f) the critical role context plays in shaping teamwork and collaboration in practice. We also distill potential avenues for future research and highlight opportunities to understand the translation, dissemination, and implementation of evidence-based teamwork principles into practice. (PsycINFO Database Record

Journal ArticleDOI
24 Dec 2018
TL;DR: This paper conducted preregistered replications of 28 classic and contemporary published findings, with protocols that were peer reviewed in advance, to examine variation in effect magnitudes across samples and settings, and found that very little heterogeneity was attributable to the order in which the tasks were performed or whether the task were administered in lab versus online.
Abstract: We conducted preregistered replications of 28 classic and contemporary published findings, with protocols that were peer reviewed in advance, to examine variation in effect magnitudes across samples and settings. Each protocol was administered to approximately half of 125 samples that comprised 15,305 participants from 36 countries and territories. Using the conventional criterion of statistical significance (p < .05), we found that 15 (54%) of the replications provided evidence of a statistically significant effect in the same direction as the original finding. With a strict significance criterion (p < .0001), 14 (50%) of the replications still provided such evidence, a reflection of the extremely high-powered design. Seven (25%) of the replications yielded effect sizes larger than the original ones, and 21 (75%) yielded effect sizes smaller than the original ones. The median comparable Cohen’s ds were 0.60 for the original findings and 0.15 for the replications. The effect sizes were small (< 0.20) in 16 of the replications (57%), and 9 effects (32%) were in the direction opposite the direction of the original effect. Across settings, the Q statistic indicated significant heterogeneity in 11 (39%) of the replication effects, and most of those were among the findings with the largest overall effect sizes; only 1 effect that was near zero in the aggregate showed significant heterogeneity according to this measure. Only 1 effect had a tau value greater than .20, an indication of moderate heterogeneity. Eight others had tau values near or slightly above .10, an indication of slight heterogeneity. Moderation tests indicated that very little heterogeneity was attributable to the order in which the tasks were performed or whether the tasks were administered in lab versus online. Exploratory comparisons revealed little heterogeneity between Western, educated, industrialized, rich, and democratic (WEIRD) cultures and less WEIRD cultures (i.e., cultures with relatively high and low WEIRDness scores, respectively). Cumulatively, variability in the observed effect sizes was attributable more to the effect being studied than to the sample or setting in which it was studied.

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TL;DR: The proportion of patients who achieved a pathological complete response in breast and lymph nodes as determined by site pathologists following completion of neoadjuvant therapy was higher in the paclitaxel, carboplatin, and veliparib group than in patients receiving pac litaxel alone.
Abstract: Summary Background Although several randomised trials in patients with triple-negative breast cancer have shown that the addition of carboplatin, with or without poly(ADP-ribose) polymerase (PARP) inhibitors, to neoadjuvant chemotherapy increases the likelihood of achieving a pathological complete response, the use of these therapies in this setting has remained controversial. The BrighTNess trial was designed to assess the addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer. Methods We did a phase 3, randomised, double-blind, placebo-controlled trial (BrighTNess) across 145 sites in 15 countries. Patients aged 18 years and older with previously untreated histologically or cytologically confirmed clinical stage II–III triple-negative breast cancer, who were candidates for potentially curative surgery and had an Eastern Cooperative Oncology Group performance status of 0 or 1, were randomly assigned (2:1:1) by an interactive response technology system via permuted blocks (block size of four) within strata to receive one of three segment 1 regimens: paclitaxel (80 mg/m 2 intravenously weekly for 12 doses) plus carboplatin (area under the curve 6 mg/mL per min, intravenously every 3 weeks, for four cycles) plus veliparib (50 mg orally, twice a day); paclitaxel plus carboplatin plus veliparib placebo (twice a day); or paclitaxel plus carboplatin placebo (every 3 weeks for four cycles) plus veliparib placebo. Following segment 1, all patients were assigned to segment 2 in which they received doxorubicin and cyclophosphamide every 2–3 weeks for four cycles. Randomisation for segment 1 was stratified by germline BRCA mutation status, nodal stage, and planned schedule of doxorubicin and cyclophosphamide administration. The primary endpoint was pathological complete response in breast and lymph nodes as determined by site pathologists following completion of neoadjuvant therapy. Efficacy analyses were done by intention to treat and safety analyses included all patients who received at least one dose of study treatment. These are the first results of an ongoing clinical trial; the data cutoff for the analyses presented was Dec 8, 2016. This study is registered with ClinicalTrials.gov, number NCT02032277. Findings Between April 4, 2014, and March 18, 2016, 634 patients were randomly assigned: 316 to paclitaxel plus carboplatin plus veliparib, 160 to paclitaxel plus carboplatin, and 158 to paclitaxel alone. The proportion of patients who achieved a pathological complete response was higher in the paclitaxel, carboplatin, and veliparib group than in patients receiving paclitaxel alone (168 [53%] of 316 patients vs 49 [31%] of 158, p Interpretation Although the addition of veliparib and carboplatin to paclitaxel followed by doxorubicin and cyclophosphamide improved the proportion of patients with triple-negative breast cancer who achieved a pathological complete response, the addition of veliparib to carboplatin and paclitaxel did not. Increased toxicities with the addition of carboplatin (with or without veliparib) to paclitaxel were manageable and did not substantially affect treatment delivery of paclitaxel followed by doxorubicin and cyclophosphamide. Given the consistent results with previous studies, the addition of carboplatin appears to have a favourable risk to benefit profile and might be considered as a potential component of neoadjuvant chemotherapy for patients with high-risk, triple-negative breast cancer. Funding AbbVie.

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TL;DR: The largest genome-wide association study to date of DSM-IV-diagnosed AD found loci associated with AD and characterized the relationship between AD and other psychiatric and behavioral outcomes, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.
Abstract: Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case-control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n = 46,568; African, n = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; P = 9.8 × 10-13) and African ancestries (rs2066702; P = 2.2 × 10-9). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit-hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.

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Gail Davies1, Max Lam, Sarah E. Harris1, Joey W. Trampush2  +254 moreInstitutions (79)
TL;DR: In this paper, the authors combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci associated with general cognitive function.
Abstract: General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10-8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.

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TL;DR: Obesity patients presenting with an excess body fat, yet without metabolic abnormalities, should still be viewed as an "at risk" population, and as such should receive advice to change their lifestyle to improve their CRF and to prevent the development of impaired fasting glucose, diabetes mellitus and other CVD risk factors as a form of primary prevention.

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TL;DR: Among premenopausal women with breast cancer, the addition of ovarian suppression to tamoxifen resulted in significantly higher 8‐year rates of both disease‐free and overall survival than tamox ifen alone and the use of exemestane plus ovarian suppression resulted in even higher rates of freedom from recurrence.
Abstract: Background In the Suppression of Ovarian Function Trial (SOFT) and the Tamoxifen and Exemestane Trial (TEXT), the 5-year rates of recurrence of breast cancer were significantly lower among premenopausal women who received the aromatase inhibitor exemestane plus ovarian suppression than among those who received tamoxifen plus ovarian suppression. The addition of ovarian suppression to tamoxifen did not result in significantly lower recurrence rates than those with tamoxifen alone. Here, we report the updated results from the two trials. Methods Premenopausal women were randomly assigned to receive 5 years of tamoxifen, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression in SOFT and to receive tamoxifen plus ovarian suppression or exemestane plus ovarian suppression in TEXT. Randomization was stratified according to the receipt of chemotherapy. Results In SOFT, the 8-year disease-free survival rate was 78.9% with tamoxifen alone, 83.2% with tamoxifen plus ovarian suppression,...

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30 Oct 2018-ACS Nano
TL;DR: Fenton-reaction-acceleratable magnetic nanoparticles, i.e., cisplatin (CDDP)-loaded Fe3O4/Gd2O3 hybrid nanoparticles with conjugation of lactoferrin (LF) and RGD dimer (RGD2), were exploited in this study for FT of orthotopic brain tumors and led to significant inhibition of tumor growth.
Abstract: Cancer is one of the leading causes of morbidity and mortality in the world, but more cancer therapies are needed to complement existing regimens due to problems of existing cancer therapies. Herein, we term ferroptosis therapy (FT) as a form of cancer therapy and hypothesize that the FT efficacy can be significantly improved via accelerating the Fenton reaction by simultaneously increasing the local concentrations of all reactants (Fe2+, Fe3+, and H2O2) in cancer cells. Thus, Fenton-reaction-acceleratable magnetic nanoparticles, i.e., cisplatin (CDDP)-loaded Fe3O4/Gd2O3 hybrid nanoparticles with conjugation of lactoferrin (LF) and RGD dimer (RGD2) (FeGd-HN@Pt@LF/RGD2), were exploited in this study for FT of orthotopic brain tumors. FeGd-HN@Pt@LF/RGD2 nanoparticles were able to cross the blood–brain barrier because of its small size (6.6 nm) and LF-receptor-mediated transcytosis. FeGd-HN@Pt@LF/RGD2 can be internalized into cancer cells by integrin αvβ3-mediated endocytosis and then release Fe2+, Fe3+, and...

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TL;DR: This Review describes how different electron-counting rules can lead to the design of stable clusters, mimicking the chemistry of atoms, and highlights the potential of these "superatoms" as building blocks of cluster-assembled materials.
Abstract: Atomic clusters, consisting of a few to a few thousand atoms, have emerged over the past 40 years as the ultimate nanoparticles, whose structure and properties can be controlled one atom at a time. One of the early motivations in studying clusters was to understand how the properties of matter evolve as a function of size, shape, and composition. Over the past few decades, more than 200 000 papers have been published in this field. These studies have not only led to a considerable understanding of this evolution from clusters to crystals, but also have revealed many unusual size-specific properties that make cluster science an interdisciplinary field on its own, bridging physics, chemistry, materials science, biology, and medicine. More importantly, the possibility of creating a new class of materials, composed of clusters instead of atoms as building blocks, has fueled the hope that one can synthesize materials from the bottom-up with unique and tailored properties. This Review focuses on the properties ...

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TL;DR: A GWAS of lifetime cannabis use reveals new risk loci, shows that cannabis use has genetic overlap with smoking and alcohol use, and indicates that the likelihood of initiating cannabis use is causally influenced by schizophrenia.
Abstract: Cannabis use is a heritable trait that has been associated with adverse mental health outcomes. In the largest genome-wide association study (GWAS) for lifetime cannabis use to date (N = 184,765), we identified eight genome-wide significant independent single nucleotide polymorphisms in six regions. All measured genetic variants combined explained 11% of the variance. Gene-based tests revealed 35 significant genes in 16 regions, and S-PrediXcan analyses showed that 21 genes had different expression levels for cannabis users versus nonusers. The strongest finding across the different analyses was CADM2, which has been associated with substance use and risk-taking. Significant genetic correlations were found with 14 of 25 tested substance use and mental health-related traits, including smoking, alcohol use, schizophrenia and risk-taking. Mendelian randomization analysis showed evidence for a causal positive influence of schizophrenia risk on cannabis use. Overall, our study provides new insights into the etiology of cannabis use and its relation with mental health.

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TL;DR: The results demonstrate genetic influences on the development of PTSD, identify shared genetic risk between PTSD and other psychiatric disorders and highlight the importance of multiethnic/racial samples.
Abstract: The Psychiatric Genomics Consortium-Posttraumatic Stress Disorder group (PGC-PTSD) combined genome-wide case–control molecular genetic data across 11 multiethnic studies to quantify PTSD heritability, to examine potential shared genetic risk with schizophrenia, bipolar disorder, and major depressive disorder and to identify risk loci for PTSD. Examining 20 730 individuals, we report a molecular genetics-based heritability estimate (h2SNP) for European-American females of 29% that is similar to h2SNP for schizophrenia and is substantially higher than h2SNP in European-American males (estimate not distinguishable from zero). We found strong evidence of overlapping genetic risk between PTSD and schizophrenia along with more modest evidence of overlap with bipolar and major depressive disorder. No single-nucleotide polymorphisms (SNPs) exceeded genome-wide significance in the transethnic (overall) meta-analysis and we do not replicate previously reported associations. Still, SNP-level summary statistics made available here afford the best-available molecular genetic index of PTSD—for both European- and African-American individuals—and can be used in polygenic risk prediction and genetic correlation studies of diverse phenotypes. Publication of summary statistics for ∼10 000 African Americans contributes to the broader goal of increased ancestral diversity in genomic data resources. In sum, the results demonstrate genetic influences on the development of PTSD, identify shared genetic risk between PTSD and other psychiatric disorders and highlight the importance of multiethnic/racial samples. As has been the case with schizophrenia and other complex genetic disorders, larger sample sizes are needed to identify specific risk loci.

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TL;DR: Treatment with subcutaneously administered pegbelfermin for 16 weeks was generally well tolerated and significantly reduced hepatic fat fraction in patients with non-alcoholic steatohepatitis, and the full planned sample size was not needed.

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TL;DR: Among children and adults with sickle cell anemia, the median number of pain crises over 48 weeks was lower among those who received oral therapy with l‐glutamine, administered alone or with hydroxyurea, than amongThose who received placebo, with or without hydroxyUREa.
Abstract: Background Oxidative stress contributes to the complex pathophysiology of sickle cell disease. Oral therapy with pharmaceutical-grade l-glutamine (USAN, glutamine) has been shown to increa...

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26 Jun 2018-JAMA
TL;DR: The USPSTF found that the evidence is inadequate to assess the effectiveness of drug therapies in reducing subsequent fracture rates in men without previous fractures, and recommends screening for osteoporosis with bone measurement testing to prevent osteooporotic fractures in women 65 years and older.
Abstract: Importance By 2020, approximately 12.3 million individuals in the United States older than 50 years are expected to have osteoporosis. Osteoporotic fractures, particularly hip fractures, are associated with limitations in ambulation, chronic pain and disability, loss of independence, and decreased quality of life, and 21% to 30% of patients who experience a hip fracture die within 1 year. The prevalence of primary osteoporosis (ie, osteoporosis without underlying disease) increases with age and differs by race/ethnicity. With the aging of the US population, the potential preventable burden is likely to increase in future years. Objective To update the 2011 US Preventive Services Task Force (USPSTF) recommendation on screening for osteoporosis. Evidence review The USPSTF reviewed the evidence on screening for and treatment of osteoporotic fractures in men and women, as well as risk assessment tools, screening intervals, and efficacy of screening and treatment in subgroups. The screening population was postmenopausal women and older men with no known previous osteoporotic fractures and no known comorbid conditions or medication use associated with secondary osteoporosis. Findings The USPSTF found convincing evidence that bone measurement tests are accurate for detecting osteoporosis and predicting osteoporotic fractures in women and men. The USPSTF found adequate evidence that clinical risk assessment tools are moderately accurate in identifying risk of osteoporosis and osteoporotic fractures. The USPSTF found convincing evidence that drug therapies reduce subsequent fracture rates in postmenopausal women. The USPSTF found that the evidence is inadequate to assess the effectiveness of drug therapies in reducing subsequent fracture rates in men without previous fractures. Conclusions and recommendation The USPSTF recommends screening for osteoporosis with bone measurement testing to prevent osteoporotic fractures in women 65 years and older. (B recommendation) The USPSTF recommends screening for osteoporosis with bone measurement testing to prevent osteoporotic fractures in postmenopausal women younger than 65 years at increased risk of osteoporosis, as determined by a formal clinical risk assessment tool. (B recommendation) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for osteoporosis to prevent osteoporotic fractures in men. (I statement).