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Showing papers by "Vanderbilt University published in 2013"


Journal ArticleDOI
TL;DR: In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10−8) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.
Abstract: Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10−8) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.

3,726 citations


Journal ArticleDOI
Christopher J L Murray1, Jerry Puthenpurakal Abraham2, Mohammed K. Ali3, Miriam Alvarado1, Charles Atkinson1, Larry M. Baddour4, David Bartels5, Emelia J. Benjamin6, Kavi Bhalla5, Gretchen L. Birbeck7, Ian Bolliger1, Roy Burstein1, Emily Carnahan1, Honglei Chen8, David Chou1, Sumeet S. Chugh9, Aaron Cohen10, K. Ellicott Colson1, Leslie T. Cooper11, William G. Couser12, Michael H. Criqui13, Kaustubh Dabhadkar3, Nabila Dahodwala14, Goodarz Danaei5, Robert P. Dellavalle15, Don C. Des Jarlais16, Daniel Dicker1, Eric L. Ding5, E. Ray Dorsey17, Herbert C. Duber1, Beth E. Ebel12, Rebecca E. Engell1, Majid Ezzati18, David T. Felson6, Mariel M. Finucane5, Seth Flaxman19, Abraham D. Flaxman1, Thomas D. Fleming1, Mohammad H. Forouzanfar1, Greg Freedman1, Michael Freeman1, Sherine E. Gabriel4, Emmanuela Gakidou1, Richard F. Gillum20, Diego Gonzalez-Medina1, Richard A. Gosselin21, Bridget F. Grant8, Hialy R. Gutierrez22, Holly Hagan23, Rasmus Havmoeller9, Rasmus Havmoeller24, Howard J. Hoffman8, Kathryn H. Jacobsen25, Spencer L. James1, Rashmi Jasrasaria1, Sudha Jayaraman5, Nicole E. Johns1, Nicholas J Kassebaum12, Shahab Khatibzadeh5, Lisa M. Knowlton5, Qing Lan, Janet L Leasher26, Stephen S Lim1, John K Lin5, Steven E. Lipshultz27, Stephanie J. London8, Rafael Lozano, Yuan Lu5, Michael F. Macintyre1, Leslie Mallinger1, Mary M. McDermott28, Michele Meltzer29, George A. Mensah8, Catherine Michaud30, Ted R. Miller31, Charles Mock12, Terrie E. Moffitt32, Ali A. Mokdad1, Ali H. Mokdad1, Andrew E. Moran22, Dariush Mozaffarian33, Dariush Mozaffarian5, Tasha B. Murphy1, Mohsen Naghavi1, K.M. Venkat Narayan3, Robert G. Nelson8, Casey Olives12, Saad B. Omer3, Katrina F Ortblad1, Bart Ostro34, Pamela M. Pelizzari35, David Phillips1, C. Arden Pope36, Murugesan Raju37, Dharani Ranganathan1, Homie Razavi, Beate Ritz38, Frederick P. Rivara12, Thomas Roberts1, Ralph L. Sacco27, Joshua A. Salomon5, Uchechukwu K.A. Sampson39, Ella Sanman1, Amir Sapkota40, David C. Schwebel41, Saeid Shahraz42, Kenji Shibuya43, Rupak Shivakoti17, Donald H. Silberberg14, Gitanjali M Singh5, David Singh44, Jasvinder A. Singh41, David A. Sleet, Kyle Steenland3, Mohammad Tavakkoli5, Jennifer A. Taylor45, George D. Thurston23, Jeffrey A. Towbin46, Monica S. Vavilala12, Theo Vos1, Gregory R. Wagner47, Martin A. Weinstock48, Marc G. Weisskopf5, James D. Wilkinson27, Sarah Wulf1, Azadeh Zabetian3, Alan D. Lopez49 
14 Aug 2013-JAMA
TL;DR: To measure the burden of diseases, injuries, and leading risk factors in the United States from 1990 to 2010 and to compare these measurements with those of the 34 countries in the Organisation for Economic Co-operation and Development (OECD), systematic analysis of descriptive epidemiology was used.
Abstract: Importance Understanding the major health problems in the United States and how they are changing over time is critical for informing national health policy. Objectives To measure the burden of diseases, injuries, and leading risk factors in the United States from 1990 to 2010 and to compare these measurements with those of the 34 countries in the Organisation for Economic Co-operation and Development (OECD) countries. Design We used the systematic analysis of descriptive epidemiology of 291 diseases and injuries, 1160 sequelae of these diseases and injuries, and 67 risk factors or clusters of risk factors from 1990 to 2010 for 187 countries developed for the Global Burden of Disease 2010 Study to describe the health status of the United States and to compare US health outcomes with those of 34 OECD countries. Years of life lost due to premature mortality (YLLs) were computed by multiplying the number of deaths at each age by a reference life expectancy at that age. Years lived with disability (YLDs) were calculated by multiplying prevalence (based on systematic reviews) by the disability weight (based on population-based surveys) for each sequela; disability in this study refers to any short- or long-term loss of health. Disability-adjusted life-years (DALYs) were estimated as the sum of YLDs and YLLs. Deaths and DALYs related to risk factors were based on systematic reviews and meta-analyses of exposure data and relative risks for risk-outcome pairs. Healthy life expectancy (HALE) was used to summarize overall population health, accounting for both length of life and levels of ill health experienced at different ages. Results US life expectancy for both sexes combined increased from 75.2 years in 1990 to 78.2 years in 2010; during the same period, HALE increased from 65.8 years to 68.1 years. The diseases and injuries with the largest number of YLLs in 2010 were ischemic heart disease, lung cancer, stroke, chronic obstructive pulmonary disease, and road injury. Age-standardized YLL rates increased for Alzheimer disease, drug use disorders, chronic kidney disease, kidney cancer, and falls. The diseases with the largest number of YLDs in 2010 were low back pain, major depressive disorder, other musculoskeletal disorders, neck pain, and anxiety disorders. As the US population has aged, YLDs have comprised a larger share of DALYs than have YLLs. The leading risk factors related to DALYs were dietary risks, tobacco smoking, high body mass index, high blood pressure, high fasting plasma glucose, physical inactivity, and alcohol use. Among 34 OECD countries between 1990 and 2010, the US rank for the age-standardized death rate changed from 18th to 27th, for the age-standardized YLL rate from 23rd to 28th, for the age-standardized YLD rate from 5th to 6th, for life expectancy at birth from 20th to 27th, and for HALE from 14th to 26th. Conclusions and Relevance From 1990 to 2010, the United States made substantial progress in improving health. Life expectancy at birth and HALE increased, all-cause death rates at all ages decreased, and age-specific rates of years lived with disability remained stable. However, morbidity and chronic disability now account for nearly half of the US health burden, and improvements in population health in the United States have not kept pace with advances in population health in other wealthy nations.

2,159 citations


Journal ArticleDOI
S. Hong Lee1, Stephan Ripke2, Stephan Ripke3, Benjamin M. Neale3  +402 moreInstitutions (124)
TL;DR: Empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.
Abstract: Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.

2,058 citations


Journal ArticleDOI
TL;DR: This is the largest series reporting mechanisms of acquired resistance to EGFR-TKI therapy and identifies EGFR T790M as the most common mechanism of acquired Resistance, whereas MET amplification, HER2 amplification, and small cell histologic transformation occur less frequently.
Abstract: Purpose: All patients with EGF receptor ( EGFR )–mutant lung cancers eventually develop acquired resistance to EGFR tyrosine kinase inhibitors (TKI). Smaller series have identified various mechanisms of resistance, but systematic evaluation of a large number of patients to definitively establish the frequency of various mechanisms has not been conducted. Experimental Design: Patients with lung adenocarcinomas and acquired resistance to erlotinib or gefitinib enrolled onto a prospective biopsy protocol and underwent a rebiopsy after the development of acquired resistance. Histology was reviewed. Samples underwent genotyping for mutations in EGFR, AKT1, BRAF, ERBB2, KRAS, MEK1, NRAS and PIK3CA , and FISH for MET and HER2 . Results: Adequate tumor samples for molecular analysis were obtained in 155 patients. Ninety-eight had second-site EGFR T790M mutations [63%; 95% confidence interval (CI), 55%–70%] and four had small cell transformation (3%, 95% CI, 0%–6%). MET amplification was seen in 4 of 75 (5%; 95% CI, 1%–13%). HER2 amplification was seen in 3 of 24 (13%; 95% CI, 3%–32%). We did not detect any acquired mutations in PIK3CA, AKT1, BRAF, ERBB2, KRAS, MEK1 , or NRAS (0 of 88, 0%; 95% CI, 0%–4%). Overlap among mechanisms of acquired resistance was seen in 4%. Conclusions: This is the largest series reporting mechanisms of acquired resistance to EGFR-TKI therapy. We identified EGFR T790M as the most common mechanism of acquired resistance, whereas MET amplification, HER2 amplification, and small cell histologic transformation occur less frequently. More comprehensive methods to characterize molecular alterations in this setting are needed to improve our understanding of acquired resistance to EGFR-TKIs. Clin Cancer Res; 19(8); 2240–7. ©2013 AACR .

2,027 citations


Journal ArticleDOI
TL;DR: The Baryon Oscillation Spectroscopic Survey (BOSS) as discussed by the authors was designed to measure the scale of baryon acoustic oscillations (BAO) in the clustering of matter over a larger volume than the combined efforts of all previous spectroscopic surveys of large-scale structure.
Abstract: The Baryon Oscillation Spectroscopic Survey (BOSS) is designed to measure the scale of baryon acoustic oscillations (BAO) in the clustering of matter over a larger volume than the combined efforts of all previous spectroscopic surveys of large-scale structure. BOSS uses 1.5 million luminous galaxies as faint as i = 19.9 over 10,000 deg2 to measure BAO to redshifts z < 0.7. Observations of neutral hydrogen in the Lyα forest in more than 150,000 quasar spectra (g < 22) will constrain BAO over the redshift range 2.15 < z < 3.5. Early results from BOSS include the first detection of the large-scale three-dimensional clustering of the Lyα forest and a strong detection from the Data Release 9 data set of the BAO in the clustering of massive galaxies at an effective redshift z = 0.57. We project that BOSS will yield measurements of the angular diameter distance dA to an accuracy of 1.0% at redshifts z = 0.3 and z = 0.57 and measurements of H(z) to 1.8% and 1.7% at the same redshifts. Forecasts for Lyα forest constraints predict a measurement of an overall dilation factor that scales the highly degenerate DA (z) and H –1(z) parameters to an accuracy of 1.9% at z ~ 2.5 when the survey is complete. Here, we provide an overview of the selection of spectroscopic targets, planning of observations, and analysis of data and data quality of BOSS.

1,938 citations


Journal ArticleDOI
TL;DR: A demonstration of strain engineering the band structure in the emergent class of two-dimensional crystals, transition-metal dichalcogenides, with pronounced strain-induced decrease in the photoluminescence intensity of monolayer MoS2 that is indicative of the direct-to-indirect transition of the character of the optical band gap.
Abstract: We report the influence of uniaxial tensile mechanical strain in the range 0–2.2% on the phonon spectra and bandstructures of monolayer and bilayer molybdenum disulfide (MoS2) two-dimensional crystals. First, we employ Raman spectroscopy to observe phonon softening with increased strain, breaking the degeneracy in the E′ Raman mode of MoS2, and extract a Gruneisen parameter of ∼1.06. Second, using photoluminescence spectroscopy we measure a decrease in the optical band gap of MoS2 that is approximately linear with strain, ∼45 meV/% strain for monolayer MoS2 and ∼120 meV/% strain for bilayer MoS2. Third, we observe a pronounced strain-induced decrease in the photoluminescence intensity of monolayer MoS2 that is indicative of the direct-to-indirect transition of the character of the optical band gap of this material at applied strain of ∼1%. These observations constitute a demonstration of strain engineering the band structure in the emergent class of two-dimensional crystals, transition-metal dichalcogenides.

1,872 citations


Journal ArticleDOI
TL;DR: The controlled vapour phase synthesis of molybdenum disulphide atomic layers is reported and a fundamental mechanism for the nucleation, growth, and grain boundary formation in its crystalline monolayers is elucidated.
Abstract: Single-layered molybdenum disulphide with a direct bandgap is a promising two-dimensional material that goes beyond graphene for the next generation of nanoelectronics. Here, we report the controlled vapour phase synthesis of molybdenum disulphide atomic layers and elucidate a fundamental mechanism for the nucleation, growth, and grain boundary formation in its crystalline monolayers. Furthermore, a nucleation-controlled strategy is established to systematically promote the formation of large-area, single- and few-layered films. Using high-resolution electron microscopy imaging, the atomic structure and morphology of the grains and their boundaries in the polycrystalline molybdenum disulphide atomic layers are examined, and the primary mechanisms for grain boundary formation are evaluated. Grain boundaries consisting of 5- and 7- member rings are directly observed with atomic resolution, and their energy landscape is investigated via first-principles calculations. The uniformity in thickness, large grain sizes, and excellent electrical performance signify the high quality and scalable synthesis of the molybdenum disulphide atomic layers.

1,645 citations



Journal ArticleDOI
TL;DR: By integrating functional categories derived from centrally and publicly curated databases as well as computational analyses, WebGestalt has significantly increased the coverage of functional categories in various biological contexts, leading to a total of 78 612 functional categories.
Abstract: Functional enrichment analysis is an essential task for the interpretation of gene lists derived from large-scale genetic, transcriptomic and proteomic studies. WebGestalt (WEB-based GEne SeT AnaLysis Toolkit) has become one of the popular software tools in this field since its publication in 2005. For the last 7 years, WebGestalt data holdings have grown substantially to satisfy the requirements of users from different research areas. The current version of WebGestalt supports 8 organisms and 201 gene identifiers from various databases and different technology platforms, making it directly available to the fast growing omics community. Meanwhile, by integrating functional categories derived from centrally and publicly curated databases as well as computational analyses, WebGestalt has significantly increased the coverage of functional categories in various biological contexts including Gene Ontology, pathway, network module, gene-phenotype association, gene-disease association, gene-drug association and chromosomal location, leading to a total of 78 612 functional categories. Finally, new interactive features, such as pathway map, hierarchical network visualization and phenotype ontology visualization have been added to WebGestalt to help users better understand the enrichment results. WebGestalt can be freely accessed through http://www.webgestalt.org or http://bioinfo.vanderbilt.edu/webgestalt/.

1,442 citations



Journal ArticleDOI
12 Sep 2013-Nature
TL;DR: In this paper, a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms and Lennox-Gastaut syndrome (n = 115) was performed.
Abstract: Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox-Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ∼4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 × 10(-3)). Among these are GABRB3, with de novo mutations in four patients, and ALG13, with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 × 10(-10) and P = 7.8 × 10(-12), respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P < 10(-8)), as has been reported previously for autism spectrum disorders.

Journal ArticleDOI
TL;DR: An improved CRISPR/Cas system in zebra fish with custom guide RNAs and a zebrafish codon-optimized Cas9 protein that efficiently targeted a reporter transgene Tg(-5.1mnx1:egfp) and four endogenous loci and five genomic loci, resulting in multiple loss-of-function phenotypes in the same injected fish.
Abstract: A simple and robust method for targeted mutagenesis in zebrafish has long been sought. Previous methods generate monoallelic mutations in the germ line of F0 animals, usually delaying homozygosity for the mutation to the F2 generation. Generation of robust biallelic mutations in the F0 would allow for phenotypic analysis directly in injected animals. Recently the type II prokaryotic clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated proteins (Cas) system has been adapted to serve as a targeted genome mutagenesis tool. Here we report an improved CRISPR/Cas system in zebrafish with custom guide RNAs and a zebrafish codon-optimized Cas9 protein that efficiently targeted a reporter transgene Tg(-5.1mnx1:egfp) and four endogenous loci (tyr, golden, mitfa, and ddx19). Mutagenesis rates reached 75–99%, indicating that most cells contained biallelic mutations. Recessive null-like phenotypes were observed in four of the five targeting cases, supporting high rates of biallelic gene disruption. We also observed efficient germ-line transmission of the Cas9-induced mutations. Finally, five genomic loci can be targeted simultaneously, resulting in multiple loss-of-function phenotypes in the same injected fish. This CRISPR/Cas9 system represents a highly effective and scalable gene knockout method in zebrafish and has the potential for applications in other model organisms.

Journal ArticleDOI
18 Dec 2013-PLOS ONE
TL;DR: A 20-year-old HIV-positive adult on ART in the U.S. or Canada is expected to live into their early 70 s, a life expectancy approaching that of the general population.
Abstract: Background: Combination antiretroviral therapy (ART) has significantly increased survival among HIV-positive adults in the United States (U.S.) and Canada, but gains in life expectancy for this region have not been well characterized. We aim to estimate temporal changes in life expectancy among HIV-positive adults on ART from 2000–2007 in the U.S. and Canada.

Journal ArticleDOI
01 Sep 2013-Stroke
TL;DR: A multidisciplinary panel of neurointerventionalists, neuroradiologists, and stroke neurologists with extensive experience in neuroimaging and IAT, convened at the “Consensus Meeting on Revascularization Grading Following Endovascular Therapy” with the goal of addressing heterogeneity in cerebral angiographic revascularization grading.
Abstract: See related article, p 2509 Intra-arterial therapy (IAT) for acute ischemic stroke (AIS) has dramatically evolved during the past decade to include aspiration and stent-retriever devices. Recent randomized controlled trials have demonstrated the superior revascularization efficacy of stent-retrievers compared with the first-generation Merci device.1,2 Additionally, the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) 2, the Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE), and the Interventional Management of Stroke (IMS) III trials have confirmed the importance of early revascularization for achieving better clinical outcome.3–5 Despite these data, the current heterogeneity in cerebral angiographic revascularization grading (CARG) poses a major obstacle to further advances in stroke therapy. To date, several CARG scales have been used to measure the success of IAT.6–14 Even when the same scale is used in different studies, it is applied using varying operational criteria, which further confounds the interpretation of this key metric.10 The lack of a uniform grading approach limits comparison of revascularization rates across clinical trials and hinders the translation of promising, early phase angiographic results into proven, clinically effective treatments.6–14 For these reasons, it is critical that CARG scales be standardized and end points for successful revascularization be refined.6 This will lead to a greater understanding of the aspects of revascularization that are strongly predictive of clinical response. The optimal grading scale must demonstrate (1) a strong correlation with clinical outcome, (2) simplicity and feasibility of scale interpretation while ensuring characterization of relevant angiographic findings, and (3) high inter-rater reproducibility. To address these issues, a multidisciplinary panel of neurointerventionalists, neuroradiologists, and stroke neurologists with extensive experience in neuroimaging and IAT, convened at the “Consensus Meeting on Revascularization Grading Following Endovascular Therapy” with the goal …

Journal ArticleDOI
25 Apr 2013-Nature
TL;DR: It is shown that increased salt concentrations found locally under physiological conditions in vivo markedly boost the induction of murine and human TH17 cells, which display a highly pathogenic and stable phenotype characterized by the upregulation of the pro-inflammatory cytokines GM-CSF, TNF-α and IL-2.
Abstract: There has been a marked increase in the incidence of autoimmune diseases in the past half-century. Although the underlying genetic basis of this class of diseases has recently been elucidated, implicating predominantly immune-response genes, changes in environmental factors must ultimately be driving this increase. The newly identified population of interleukin (IL)-17-producing CD4(+) helper T cells (TH17 cells) has a pivotal role in autoimmune diseases. Pathogenic IL-23-dependent TH17 cells have been shown to be critical for the development of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, and genetic risk factors associated with multiple sclerosis are related to the IL-23-TH17 pathway. However, little is known about the environmental factors that directly influence TH17 cells. Here we show that increased salt (sodium chloride, NaCl) concentrations found locally under physiological conditions in vivo markedly boost the induction of murine and human TH17 cells. High-salt conditions activate the p38/MAPK pathway involving nuclear factor of activated T cells 5 (NFAT5; also called TONEBP) and serum/glucocorticoid-regulated kinase 1 (SGK1) during cytokine-induced TH17 polarization. Gene silencing or chemical inhibition of p38/MAPK, NFAT5 or SGK1 abrogates the high-salt-induced TH17 cell development. The TH17 cells generated under high-salt conditions display a highly pathogenic and stable phenotype characterized by the upregulation of the pro-inflammatory cytokines GM-CSF, TNF-α and IL-2. Moreover, mice fed with a high-salt diet develop a more severe form of EAE, in line with augmented central nervous system infiltrating and peripherally induced antigen-specific TH17 cells. Thus, increased dietary salt intake might represent an environmental risk factor for the development of autoimmune diseases through the induction of pathogenic TH17 cells.

Journal ArticleDOI
TL;DR: A meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, and identified 29,807 SNPs for further genotyping suggests that more than 1,000 additional loci are involved in breast cancer susceptibility.
Abstract: Breast cancer is the most common cancer among women Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ∼9% of the familial risk of the disease We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC) The SNPs were genotyped as part of a collaborative genotyping experiment involving four consortia (Collaborative Oncological Gene-environment Study, COGS) and used a custom Illumina iSelect genotyping array, iCOGS, comprising more than 200,000 SNPs We identified SNPs at 41 new breast cancer susceptibility loci at genome-wide significance (P < 5 × 10(-8)) Further analyses suggest that more than 1,000 additional loci are involved in breast cancer susceptibility


Journal ArticleDOI
TL;DR: Regulation of iron metabolism in the setting of infection is discussed and strategies used by human pathogens to overcome iron-withholding defenses are delineated.

Journal ArticleDOI
TL;DR: This article addresses GRADE's approach to determining the direction and strength of a recommendation, which describes the balance of desirable and undesirable outcomes of interest among alternative management strategies depending on four domains, namely estimates of effect for desirable and desirable outcomes ofinterest, confidence in the estimates ofEffect, estimates of values and preferences, and resource use.

Journal ArticleDOI
TL;DR: In this article, an expanded literature review showed that CYP2C19 loss-of-function alleles confer increased risks for serious adverse cardiovascular (CV) events among clopidogrel-treated patients with acute coronary syndromes (ACSs) undergoing percutaneous coronary intervention (PCI).
Abstract: Cytochrome P450 (CYP)2C19 catalyzes the bioactivation of the antiplatelet prodrug clopidogrel, and CYP2C19 loss-of-function alleles impair formation of active metabolites, resulting in reduced platelet inhibition. In addition, CYP2C19 loss-of-function alleles confer increased risks for serious adverse cardiovascular (CV) events among clopidogrel-treated patients with acute coronary syndromes (ACSs) undergoing percutaneous coronary intervention (PCI). Guideline updates include emphasis on appropriate indication for CYP2C19 genotype–directed antiplatelet therapy, refined recommendations for specific CYP2C19 alleles, and additional evidence from an expanded literature review (updates at http://www.pharmgkb.org).

Journal ArticleDOI
TL;DR: The first large-scale application of the phenome-wide association study (PheWAS) paradigm within electronic medical records (EMRs) is reported, an unbiased approach to replication and discovery that interrogates relationships between targeted genotypes and multiple phenotypes in EMR-based cohorts.
Abstract: Candidate gene and genome-wide association studies (GWAS) have identified genetic variants that modulate risk for human disease; many of these associations require further study to replicate the results. Here we report the first large-scale application of the phenome-wide association study (PheWAS) paradigm within electronic medical records (EMRs), an unbiased approach to replication and discovery that interrogates relationships between targeted genotypes and multiple phenotypes. We scanned for associations between 3,144 single-nucleotide polymorphisms (previously implicated by GWAS as mediators of human traits) and 1,358 EMR-derived phenotypes in 13,835 individuals of European ancestry. This PheWAS replicated 66% (51/77) of sufficiently powered prior GWAS associations and revealed 63 potentially pleiotropic associations with P < 4.6 × 10⁻⁶ (false discovery rate < 0.1); the strongest of these novel associations were replicated in an independent cohort (n = 7,406). These findings validate PheWAS as a tool to allow unbiased interrogation across multiple phenotypes in EMR-based cohorts and to enhance analysis of the genomic basis of human disease.

Journal ArticleDOI
TL;DR: It is shown that planar graphene/h-BN heterostructures can be formed by growing graphene in lithographically patterned h-BN atomic layers and that the technique can be used to fabricate two-dimensional devices, such as a split closed-loop resonator that works as a bandpass filter.
Abstract: By growing graphene in patterned hexagonal boron nitride layers, planar heterostructures can be fabricated and used to create two-dimensional devices.

Book ChapterDOI
01 Jan 2013
TL;DR: In this paper, the authors present the state-of-the-art and identify research challenges when developing, deploying and managing self-adaptive software systems, focusing on four essential topics of selfadaptation: design space for selfadaptive solutions, software engineering processes, from centralized to decentralized control, and practical run-time verification & validation.
Abstract: The goal of this roadmap paper is to summarize the state-of-the-art and identify research challenges when developing, deploying and managing self-adaptive software systems. Instead of dealing with a wide range of topics associated with the field, we focus on four essential topics of self-adaptation: design space for self-adaptive solutions, software engineering processes for self-adaptive systems, from centralized to decentralized control, and practical run-time verification & validation for self-adaptive systems. For each topic, we present an overview, suggest future directions, and focus on selected challenges. This paper complements and extends a previous roadmap on software engineering for self-adaptive systems published in 2009 covering a different set of topics, and reflecting in part on the previous paper. This roadmap is one of the many results of the Dagstuhl Seminar 10431 on Software Engineering for Self-Adaptive Systems, which took place in October 2010.

Journal ArticleDOI
TL;DR: An extended model of the SEIPS, SEIPS 2.0 is a new human factors/ergonomics framework for studying and improving health and healthcare that describes how sociotechnical systems shape health-related work done by professionals and non-professionals, independently and collaboratively.
Abstract: Healthcare practitioners, patient safety leaders, educators and researchers increasingly recognise the value of human factors/ergonomics and make use of the discipline's person-centred models of sociotechnical systems. This paper first reviews one of the most widely used healthcare human factors systems models, the Systems Engineering Initiative for Patient Safety (SEIPS) model, and then introduces an extended model, 'SEIPS 2.0'. SEIPS 2.0 incorporates three novel concepts into the original model: configuration, engagement and adaptation. The concept of configuration highlights the dynamic, hierarchical and interactive properties of sociotechnical systems, making it possible to depict how health-related performance is shaped at 'a moment in time'. Engagement conveys that various individuals and teams can perform health-related activities separately and collaboratively. Engaged individuals often include patients, family caregivers and other non-professionals. Adaptation is introduced as a feedback mechanism that explains how dynamic systems evolve in planned and unplanned ways. Key implications and future directions for human factors research in healthcare are discussed.

Journal ArticleDOI
TL;DR: This guideline is intended for any clinician involved in managing children, aged 6 months to 12 years, with tympanostomy tubes or being considered for tympAnostomy tube insertion in any care setting, as an intervention for otitis media of any type.
Abstract: ObjectiveInsertion of tympanostomy tubes is the most common ambulatory surgery performed on children in the United States. Tympanostomy tubes are most often inserted because of persistent middle ea...

Journal ArticleDOI
TL;DR: Men treated for localized prostate cancer commonly had declines in all functional domains during 15 years of follow-up, and no significant relative differences in disease-specific functional outcomes were observed among men undergoing prostatectomy or radiotherapy.
Abstract: Background The purpose of this analysis was to compare long-term urinary, bowel, and sexual function after radical prostatectomy or external-beam radiation therapy. Methods The Prostate Cancer Outcomes Study (PCOS) enrolled 3533 men in whom prostate cancer had been diagnosed in 1994 or 1995. The current cohort comprised 1655 men in whom localized prostate cancer had been diagnosed between the ages of 55 and 74 years and who had undergone either surgery (1164 men) or radiotherapy (491 men). Functional status was assessed at baseline and at 2, 5, and 15 years after diagnosis. We used multivariable propensity scoring to compare functional outcomes according to treatment. Results Patients undergoing prostatectomy were more likely to have urinary incontinence than were those undergoing radiotherapy at 2 years (odds ratio, 6.22; 95% confidence interval [CI], 1.92 to 20.29) and 5 years (odds ratio, 5.10; 95% CI, 2.29 to 11.36). However, no significant between-group difference in the odds of urinary incontinence ...

Journal ArticleDOI
Lars G. Fritsche1, Lars G. Fritsche2, Wei Chen2, Wei Chen3  +182 moreInstitutions (60)
TL;DR: A collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry, identifies 19 loci associated at P < 5 × 10−8, which show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis.
Abstract: Age-related macular degeneration (AMD) is a common cause of blindness in older individuals To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry We identified 19 loci associated at P < 5 × 10(-8) These loci show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis Our results include seven loci with associations reaching P < 5 × 10(-8) for the first time, near the genes COL8A1-FILIP1L, IER3-DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9 and B3GALTL A genetic risk score combining SNP genotypes from all loci showed similar ability to distinguish cases and controls in all samples examined Our findings provide new directions for biological, genetic and therapeutic studies of AMD

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TL;DR: A general review of the steps leading to biofilm formation on surfaces and within eukaryotic cells is provided, highlighting several medically important pathogens, and recent advances on novel strategies aimed at biofilm prevention and/or dissolution are discussed.
Abstract: Biofilm formation constitutes an alternative lifestyle in which microorganisms adopt a multicellular behavior that facilitates and/or prolongs survival in diverse environmental niches. Biofilms form on biotic and abiotic surfaces both in the environment and in the healthcare setting. In hospital wards, the formation of biofilms on vents and medical equipment enables pathogens to persist as reservoirs that can readily spread to patients. Inside the host, biofilms allow pathogens to subvert innate immune defenses and are thus associated with long-term persistence. Here we provide a general review of the steps leading to biofilm formation on surfaces and within eukaryotic cells, highlighting several medically important pathogens, and discuss recent advances on novel strategies aimed at biofilm prevention and/or dissolution.

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TL;DR: A consensus document is presented that proposes a standardized case definition and diagnostic guidelines for evaluation of adults and children with suspected encephalitis and will serve as a practical aid to clinicians evaluating patients with suspectedEncephalitis.
Abstract: Background Encephalitis continues to result in substantial morbidity and mortality worldwide. Advances in diagnosis and management have been limited, in part, by a lack of consensus on case definitions, standardized diagnostic approaches, and priorities for research. Methods In March 2012, the International Encephalitis Consortium, a committee begun in 2010 with members worldwide, held a meeting in Atlanta to discuss recent advances in encephalitis and to set priorities for future study. Results We present a consensus document that proposes a standardized case definition and diagnostic guidelines for evaluation of adults and children with suspected encephalitis. In addition, areas of research priority, including host genetics and selected emerging infections, are discussed. Conclusions We anticipate that this document, representing a synthesis of our discussions and supported by literature, will serve as a practical aid to clinicians evaluating patients with suspected encephalitis and will identify key areas and approaches to advance our knowledge of encephalitis.

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30 May 2013-Nature
TL;DR: The complete atomic HIV-1 capsid model provides a platform for further studies of capsid function and for targeted pharmacological intervention and the cryo-electron-microscopy structures enable modelling by large-scale molecular dynamics simulation, resulting in all-atom models for the hexamer-of- hexamer and pentamer- of-hexamer elements.
Abstract: Retroviral capsid proteins are conserved structurally but assemble into different morphologies. The mature human immunodeficiency virus-1 (HIV-1) capsid is best described by a 'fullerene cone' model, in which hexamers of the capsid protein are linked to form a hexagonal surface lattice that is closed by incorporating 12 capsid-protein pentamers. HIV-1 capsid protein contains an amino-terminal domain (NTD) comprising seven α-helices and a β-hairpin, a carboxy-terminal domain (CTD) comprising four α-helices, and a flexible linker with a 310-helix connecting the two structural domains. Structures of the capsid-protein assembly units have been determined by X-ray crystallography; however, structural information regarding the assembled capsid and the contacts between the assembly units is incomplete. Here we report the cryo-electron microscopy structure of a tubular HIV-1 capsid-protein assembly at 8 A resolution and the three-dimensional structure of a native HIV-1 core by cryo-electron tomography. The structure of the tubular assembly shows, at the three-fold interface, a three-helix bundle with critical hydrophobic interactions. Mutagenesis studies confirm that hydrophobic residues in the centre of the three-helix bundle are crucial for capsid assembly and stability, and for viral infectivity. The cryo-electron-microscopy structures enable modelling by large-scale molecular dynamics simulation, resulting in all-atom models for the hexamer-of-hexamer and pentamer-of-hexamer elements as well as for the entire capsid. Incorporation of pentamers results in closer trimer contacts and induces acute surface curvature. The complete atomic HIV-1 capsid model provides a platform for further studies of capsid function and for targeted pharmacological intervention.