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Showing papers by "National Institutes of Health published in 2014"


Journal ArticleDOI
Marie Ng1, Tom P Fleming1, Margaret Robinson1, Blake Thomson1, Nicholas Graetz1, Christopher Margono1, Erin C Mullany1, Stan Biryukov1, Cristiana Abbafati2, Semaw Ferede Abera3, Jerry Abraham4, Niveen M E Abu-Rmeileh, Tom Achoki1, Fadia AlBuhairan5, Zewdie Aderaw Alemu6, Rafael Alfonso1, Mohammed K. Ali7, Raghib Ali8, Nelson Alvis Guzmán9, Walid Ammar, Palwasha Anwari10, Amitava Banerjee11, Simón Barquera, Sanjay Basu12, Derrick A Bennett8, Zulfiqar A Bhutta13, Jed D. Blore14, N Cabral, Ismael Ricardo Campos Nonato, Jung-Chen Chang15, Rajiv Chowdhury16, Karen J. Courville, Michael H. Criqui17, David K. Cundiff, Kaustubh Dabhadkar7, Lalit Dandona18, Lalit Dandona1, Adrian Davis19, Anand Dayama7, Samath D Dharmaratne20, Eric L. Ding21, Adnan M. Durrani22, Alireza Esteghamati23, Farshad Farzadfar23, Derek F J Fay19, Valery L. Feigin24, Abraham D. Flaxman1, Mohammad H. Forouzanfar1, Atsushi Goto, Mark A. Green25, Rajeev Gupta, Nima Hafezi-Nejad23, Graeme J. Hankey26, Heather Harewood, Rasmus Havmoeller27, Simon I. Hay8, Lucia Hernandez, Abdullatif Husseini28, Bulat Idrisov29, Nayu Ikeda, Farhad Islami30, Eiman Jahangir31, Simerjot K. Jassal17, Sun Ha Jee32, Mona Jeffreys33, Jost B. Jonas34, Edmond K. Kabagambe35, Shams Eldin Ali Hassan Khalifa, Andre Pascal Kengne36, Yousef Khader37, Young-Ho Khang38, Daniel Kim39, Ruth W Kimokoti40, Jonas Minet Kinge41, Yoshihiro Kokubo, Soewarta Kosen, Gene F. Kwan42, Taavi Lai, Mall Leinsalu22, Yichong Li, Xiaofeng Liang43, Shiwei Liu43, Giancarlo Logroscino44, Paulo A. Lotufo45, Yuan Qiang Lu21, Jixiang Ma43, Nana Kwaku Mainoo, George A. Mensah22, Tony R. Merriman46, Ali H. Mokdad1, Joanna Moschandreas47, Mohsen Naghavi1, Aliya Naheed48, Devina Nand, K.M. Venkat Narayan7, Erica Leigh Nelson1, Marian L. Neuhouser49, Muhammad Imran Nisar13, Takayoshi Ohkubo50, Samuel Oti, Andrea Pedroza, Dorairaj Prabhakaran, Nobhojit Roy51, Uchechukwu K.A. Sampson35, Hyeyoung Seo, Sadaf G. Sepanlou23, Kenji Shibuya52, Rahman Shiri53, Ivy Shiue54, Gitanjali M Singh21, Jasvinder A. Singh55, Vegard Skirbekk41, Nicolas J. C. Stapelberg56, Lela Sturua57, Bryan L. Sykes58, Martin Tobias1, Bach Xuan Tran59, Leonardo Trasande60, Hideaki Toyoshima, Steven van de Vijver, Tommi Vasankari, J. Lennert Veerman61, Gustavo Velasquez-Melendez62, Vasiliy Victorovich Vlassov63, Stein Emil Vollset41, Stein Emil Vollset64, Theo Vos1, Claire L. Wang65, Xiao Rong Wang66, Elisabete Weiderpass, Andrea Werdecker, Jonathan L. Wright1, Y Claire Yang67, Hiroshi Yatsuya68, Jihyun Yoon, Seok Jun Yoon69, Yong Zhao70, Maigeng Zhou, Shankuan Zhu71, Alan D. Lopez14, Christopher J L Murray1, Emmanuela Gakidou1 
University of Washington1, Sapienza University of Rome2, Mekelle University3, University of Texas at San Antonio4, King Saud bin Abdulaziz University for Health Sciences5, Debre markos University6, Emory University7, University of Oxford8, University of Cartagena9, United Nations Population Fund10, University of Birmingham11, Stanford University12, Aga Khan University13, University of Melbourne14, National Taiwan University15, University of Cambridge16, University of California, San Diego17, Public Health Foundation of India18, Public Health England19, University of Peradeniya20, Harvard University21, National Institutes of Health22, Tehran University of Medical Sciences23, Auckland University of Technology24, University of Sheffield25, University of Western Australia26, Karolinska Institutet27, Birzeit University28, Brandeis University29, American Cancer Society30, Ochsner Medical Center31, Yonsei University32, University of Bristol33, Heidelberg University34, Vanderbilt University35, South African Medical Research Council36, Jordan University of Science and Technology37, New Generation University College38, Northeastern University39, Simmons College40, Norwegian Institute of Public Health41, Boston University42, Chinese Center for Disease Control and Prevention43, University of Bari44, University of São Paulo45, University of Otago46, University of Crete47, International Centre for Diarrhoeal Disease Research, Bangladesh48, Fred Hutchinson Cancer Research Center49, Teikyo University50, Bhabha Atomic Research Centre51, University of Tokyo52, Finnish Institute of Occupational Health53, Heriot-Watt University54, University of Alabama at Birmingham55, Griffith University56, National Center for Disease Control and Public Health57, University of California, Irvine58, Johns Hopkins University59, New York University60, University of Queensland61, Universidade Federal de Minas Gerais62, National Research University – Higher School of Economics63, University of Bergen64, Columbia University65, Shandong University66, University of North Carolina at Chapel Hill67, Fujita Health University68, Korea University69, Chongqing Medical University70, Zhejiang University71
TL;DR: The global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013 is estimated using a spatiotemporal Gaussian process regression model to estimate prevalence with 95% uncertainty intervals (UIs).

9,180 citations


Journal ArticleDOI
05 Feb 2014-JAMA
TL;DR: Although this guideline provides evidence-based recommendations for the management of high BP and should meet the clinical needs of most patients, these recommendations are not a substitute for clinical judgment, and decisions about care must carefully consider and incorporate the clinical characteristics and circumstances of each individual patient.
Abstract: Hypertension is the most common condition seen in primary care and leads to myocardial infarction, stroke, renal failure, and death if not detected early and treated appropriately. Patients want to be assured that blood pressure (BP) treatment will reduce their disease burden, while clinicians want guidance on hypertension management using the best scientific evidence. This report takes a rigorous, evidence-based approach to recommend treatment thresholds, goals, and medications in the management of hypertension in adults. Evidence was drawn from randomized controlled trials, which represent the gold standard for determining efficacy and effectiveness. Evidence quality and recommendations were graded based on their effect on important outcomes. There is strong evidence to support treating hypertensive persons aged 60 years or older to a BP goal of less than 150/90 mm Hg and hypertensive persons 30 through 59 years of age to a diastolic goal of less than 90 mm Hg; however, there is insufficient evidence in hypertensive persons younger than 60 years for a systolic goal, or in those younger than 30 years for a diastolic goal, so the panel recommends a BP of less than 140/90 mm Hg for those groups based on expert opinion. The same thresholds and goals are recommended for hypertensive adults with diabetes or nondiabetic chronic kidney disease (CKD) as for the general hypertensive population younger than 60 years. There is moderate evidence to support initiating drug treatment with an angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, calcium channel blocker, or thiazide-type diuretic in the nonblack hypertensive population, including those with diabetes. In the black hypertensive population, including those with diabetes, a calcium channel blocker or thiazide-type diuretic is recommended as initial therapy. There is moderate evidence to support initial or add-on antihypertensive therapy with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in persons with CKD to improve kidney outcomes. Although this guideline provides evidence-based recommendations for the management of high BP and should meet the clinical needs of most patients, these recommendations are not a substitute for clinical judgment, and decisions about care must carefully consider and incorporate the clinical characteristics and circumstances of each individual patient.

7,119 citations


Journal ArticleDOI
Stephan Ripke1, Stephan Ripke2, Benjamin M. Neale1, Benjamin M. Neale2  +351 moreInstitutions (102)
24 Jul 2014-Nature
TL;DR: Associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses.
Abstract: Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.

6,809 citations


Journal ArticleDOI
Adam J. Bass1, Vesteinn Thorsson2, Ilya Shmulevich2, Sheila Reynolds2  +254 moreInstitutions (32)
11 Sep 2014-Nature
TL;DR: A comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project is described and a molecular classification dividing gastric cancer into four subtypes is proposed.
Abstract: Gastric cancer was the world’s third leading cause of cancer mortality in 2012, responsible for 723,000 deaths1. The vast majority of gastric cancers are adenocarcinomas, which can be further subdivided into intestinal and diffuse types according to the Lauren classification2. An alternative system, proposed by the World Health Organization, divides gastric cancer into papillary, tubular, mucinous (colloid) and poorly cohesive carcinomas3. These classification systems have little clinical utility, making the development of robust classifiers that can guide patient therapy an urgent priority. The majority of gastric cancers are associated with infectious agents, including the bacterium Helicobacter pylori4 and Epstein–Barr virus (EBV). The distribution of histological subtypes of gastric cancer and the frequencies of H. pylori and EBV associated gastric cancer vary across the globe5. A small minority of gastric cancer cases are associated with germline mutation in E-cadherin (CDH1)6 or mismatch repair genes7 (Lynch syndrome), whereas sporadic mismatch repair-deficient gastric cancers have epigenetic silencing of MLH1 in the context of a CpG island methylator phenotype (CIMP)8. Molecular profiling of gastric cancer has been performed using gene expression or DNA sequencing9–12, but has not led to a clear biologic classification scheme. The goals of this study by The Cancer Genome Atlas (TCGA) were to develop a robust molecular classification of gastric cancer and to identify dysregulated pathways and candidate drivers of distinct classes of gastric cancer.

4,583 citations


Journal ArticleDOI
17 Jul 2014-Immunity
TL;DR: A set of standards encompassing three principles-the source of macrophages, definition of the activators, and a consensus collection of markers to describe macrophage activation are described with the goal of unifying experimental standards for diverse experimental scenarios.

4,287 citations


Journal ArticleDOI
01 Jan 2014-Nature
TL;DR: In this paper, the authors report molecular profiling of 230 resected lung adnocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses.
Abstract: Adenocarcinoma of the lung is the leading cause of cancer death worldwide. Here we report molecular profiling of 230 resected lung adenocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. High rates of somatic mutation were seen (mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in female patients, whereas mutations in RBM10 were more common in males. Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumours. DNA and mRNA sequence from the same tumour highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases. MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis.

4,104 citations


Journal ArticleDOI
TL;DR: PLINK as discussed by the authors is a C/C++ toolset for genome-wide association studies (GWAS) and research in population genetics, which has been widely used in the literature.
Abstract: PLINK 1 is a widely used open-source C/C++ toolset for genome-wide association studies (GWAS) and research in population genetics. However, the steady accumulation of data from imputation and whole-genome sequencing studies has exposed a strong need for even faster and more scalable implementations of key functions. In addition, GWAS and population-genetic data now frequently contain probabilistic calls, phase information, and/or multiallelic variants, none of which can be represented by PLINK 1's primary data format. To address these issues, we are developing a second-generation codebase for PLINK. The first major release from this codebase, PLINK 1.9, introduces extensive use of bit-level parallelism, O(sqrt(n))-time/constant-space Hardy-Weinberg equilibrium and Fisher's exact tests, and many other algorithmic improvements. In combination, these changes accelerate most operations by 1-4 orders of magnitude, and allow the program to handle datasets too large to fit in RAM. This will be followed by PLINK 2.0, which will introduce (a) a new data format capable of efficiently representing probabilities, phase, and multiallelic variants, and (b) extensions of many functions to account for the new types of information. The second-generation versions of PLINK will offer dramatic improvements in performance and compatibility. For the first time, users without access to high-end computing resources can perform several essential analyses of the feature-rich and very large genetic datasets coming into use.

3,513 citations


Journal ArticleDOI
TL;DR: Evidence of progressive increases in overall burden, incidence, prevalence, and AF-associated mortality between 1990 and 2010 is provided, with significant public health implications.
Abstract: Background— The global burden of atrial fibrillation (AF) is unknown. Methods and Results— We systematically reviewed population-based studies of AF published from 1980 to 2010 from the 21 Global Burden of Disease regions to estimate global/regional prevalence, incidence, and morbidity and mortality related to AF (DisModMR software). Of 377 potential studies identified, 184 met prespecified eligibility criteria. The estimated number of individuals with AF globally in 2010 was 33.5 million (20.9 million men [95% uncertainty interval (UI), 19.5–22.2 million] and 12.6 million women [95% UI, 12.0–13.7 million]). Burden associated with AF, measured as disability-adjusted life-years, increased by 18.8% (95% UI, 15.8–19.3) in men and 18.9% (95% UI, 15.8–23.5) in women from 1990 to 2010. In 1990, the estimated age-adjusted prevalence rates of AF (per 100 000 population) were 569.5 in men (95% UI, 532.8–612.7) and 359.9 in women (95% UI, 334.7–392.6); the estimated age-adjusted incidence rates were 60.7 per 100 000 person-years in men (95% UI, 49.2–78.5) and 43.8 in women (95% UI, 35.9–55.0). In 2010, the prevalence rates increased to 596.2 (95% UI, 558.4–636.7) in men and 373.1 (95% UI, 347.9–402.2) in women; the incidence rates increased to 77.5 (95% UI, 65.2–95.4) in men and 59.5 (95% UI, 49.9–74.9) in women. Mortality associated with AF was higher in women and increased by 2-fold (95% UI, 2.0–2.2) and 1.9-fold (95% UI, 1.8–2.0) in men and women, respectively, from 1990 to 2010. There was evidence of significant regional heterogeneity in AF estimations and availability of population-based data. Conclusions— These findings provide evidence of progressive increases in overall burden, incidence, prevalence, and AF-associated mortality between 1990 and 2010, with significant public health implications. Systematic, regional surveillance of AF is required to better direct prevention and treatment strategies.

3,443 citations


Journal ArticleDOI
27 Mar 2014-Cell
TL;DR: In high-income countries, overuse of antibiotics, changes in diet, and elimination of constitutive partners, such as nematodes, may have selected for a microbiota that lack the resilience and diversity required to establish balanced immune responses.

3,257 citations



Journal ArticleDOI
TL;DR: Age-related clonal hematopoiesis is a common condition that is associated with increases in the risk of hematologic cancer and in all-cause mortality, with the latter possibly due to an increased risk of cardiovascular disease.
Abstract: Background The incidence of hematologic cancers increases with age. These cancers are associated with recurrent somatic mutations in specific genes. We hypothesized that such mutations would be detectable in the blood of some persons who are not known to have hematologic disorders. Methods We analyzed whole-exome sequencing data from DNA in the peripheral-blood cells of 17,182 persons who were unselected for hematologic phenotypes. We looked for somatic mutations by identifying previously characterized single-nucleotide variants and small insertions or deletions in 160 genes that are recurrently mutated in hematologic cancers. The presence of mutations was analyzed for an association with hematologic phenotypes, survival, and cardiovascular events. Results Detectable somatic mutations were rare in persons younger than 40 years of age but rose appreciably in frequency with age. Among persons 70 to 79 years of age, 80 to 89 years of age, and 90 to 108 years of age, these clonal mutations were observed in 9.5% (219 of 2300 persons), 11.7% (37 of 317), and 18.4% (19 of 103), respectively. The majority of the variants occurred in three genes: DNMT3A, TET2, and ASXL1. The presence of a somatic mutation was associated with an increase in the risk of hematologic cancer (hazard ratio, 11.1; 95% confidence interval [CI], 3.9 to 32.6), an increase in all-cause mortality (hazard ratio, 1.4; 95% CI, 1.1 to 1.8), and increases in the risks of incident coronary heart disease (hazard ratio, 2.0; 95% CI, 1.2 to 3.4) and ischemic stroke (hazard ratio, 2.6; 95% CI, 1.4 to 4.8). Conclusions Age-related clonal hematopoiesis is a common condition that is associated with increases in the risk of hematologic cancer and in all-cause mortality, with the latter possibly due to an increased risk of cardiovascular disease. (Funded by the National Institutes of Health and others.)


Journal ArticleDOI
TL;DR: The Update Committee recommends that HER2 status (HER2 negative or positive) be determined in all patients with invasive breast cancer on the basis of one or more HER2 test results (negative, equivocal, or positive).
Abstract: Purpose To update the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline recommendations for human epidermal growth factor receptor 2 (HER2) testing in breast cancer to improve the accuracy of HER2 testing and its utility as a predictive marker in invasive breast cancer.

Journal ArticleDOI
TL;DR: The mechanism of mitochondrial RIRR highlights the central role of mitochondria-formed ROS, and all of the known ROS-producing sites and their relevance to the mitochondrial ROS production in vivo are discussed.
Abstract: Byproducts of normal mitochondrial metabolism and homeostasis include the buildup of potentially damaging levels of reactive oxygen species (ROS), Ca2+, etc., which must be normalized. Evidence suggests that brief mitochondrial permeability transition pore (mPTP) openings play an important physiological role maintaining healthy mitochondria homeostasis. Adaptive and maladaptive responses to redox stress may involve mitochondrial channels such as mPTP and inner membrane anion channel (IMAC). Their activation causes intra- and intermitochondrial redox-environment changes leading to ROS release. This regenerative cycle of mitochondrial ROS formation and release was named ROS-induced ROS release (RIRR). Brief, reversible mPTP opening-associated ROS release apparently constitutes an adaptive housekeeping function by the timely release from mitochondria of accumulated potentially toxic levels of ROS (and Ca2+). At higher ROS levels, longer mPTP openings may release a ROS burst leading to destruction of mitochondria, and if propagated from mitochondrion to mitochondrion, of the cell itself. The destructive function of RIRR may serve a physiological role by removal of unwanted cells or damaged mitochondria, or cause the pathological elimination of vital and essential mitochondria and cells. The adaptive release of sufficient ROS into the vicinity of mitochondria may also activate local pools of redox-sensitive enzymes involved in protective signaling pathways that limit ischemic damage to mitochondria and cells in that area. Maladaptive mPTP- or IMAC-related RIRR may also be playing a role in aging. Because the mechanism of mitochondrial RIRR highlights the central role of mitochondria-formed ROS, we discuss all of the known ROS-producing sites (shown in vitro) and their relevance to the mitochondrial ROS production in vivo.

Journal ArticleDOI
TL;DR: Recommendations and guidelines on the evaluation and treatment of severe asthma in children and adults and coordinated research efforts for improved phenotyping will provide safe and effective biomarker-driven approaches to severe asthma therapy are provided.
Abstract: Severe or therapy-resistant asthma is increasingly recognised as a major unmet need. A Task Force, supported by the European Respiratory Society and American Thoracic Society, reviewed the definition and provided recommendations and guidelines on the evaluation and treatment of severe asthma in children and adults. A literature review was performed, followed by discussion by an expert committee according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for development of specific clinical recommendations. When the diagnosis of asthma is confirmed and comorbidities addressed, severe asthma is defined as asthma that requires treatment with high dose inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming “uncontrolled” or that remains “uncontrolled” despite this therapy. Severe asthma is a heterogeneous condition consisting of phenotypes such as eosinophilic asthma. Specific recommendations on the use of sputum eosinophil count and exhaled nitric oxide to guide therapy, as well as treatment with anti-IgE antibody, methotrexate, macrolide antibiotics, antifungal agents and bronchial thermoplasty are provided. Coordinated research efforts for improved phenotyping will provide safe and effective biomarker-driven approaches to severe asthma therapy.

Journal ArticleDOI
TL;DR: A number of recent improvements to theNHGRI Catalog of Published Genome-Wide Association Studies are presented, including novel ways for users to interact with the Catalog and changes to the curation infrastructure.
Abstract: The National Human Genome Research Institute (NHGRI) Catalog of Published Genome-Wide Association Studies (GWAS) Catalog provides a publicly available manually curated collection of published GWAS assaying at least 100000 singlenucleotide polymorphisms (SNPs) and all SNP-trait associations with P <110 5 . The Catalog includes 1751 curated publications of 11912 SNPs. In addition to the SNP-trait association data, the Catalog also publishes a quarterly diagram of all SNP-trait associations mapped to the SNPs’ chromosomal locations. The Catalog can be accessed via a tabular web interface, via a dynamic visualization on the human karyotype, as a downloadable tab-delimited file and as an OWL knowledge base. This article presents a number of recent improvements to the Catalog, including novel ways for users to interact with the Catalog and changes to the curation infrastructure.

Journal ArticleDOI
TL;DR: It is demonstrated that contaminating DNA is ubiquitous in commonly used DNA extraction kits and other laboratory reagents, varies greatly in composition between different kits and kit batches, and that this contamination critically impacts results obtained from samples containing a low microbial biomass.
Abstract: The study of microbial communities has been revolutionised in recent years by the widespread adoption of culture independent analytical techniques such as 16S rRNA gene sequencing and metagenomics. One potential confounder of these sequence-based approaches is the presence of contamination in DNA extraction kits and other laboratory reagents. In this study we demonstrate that contaminating DNA is ubiquitous in commonly used DNA extraction kits and other laboratory reagents, varies greatly in composition between different kits and kit batches, and that this contamination critically impacts results obtained from samples containing a low microbial biomass. Contamination impacts both PCR-based 16S rRNA gene surveys and shotgun metagenomics. We provide an extensive list of potential contaminating genera, and guidelines on how to mitigate the effects of contamination. These results suggest that caution should be advised when applying sequence-based techniques to the study of microbiota present in low biomass environments. Concurrent sequencing of negative control samples is strongly advised.

Journal ArticleDOI
John N. Weinstein1, Rehan Akbani1, Bradley M. Broom1, Wenyi Wang1  +293 moreInstitutions (30)
01 Jan 2014-Nature
TL;DR: Ch Chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far, indicating the future possibility of targeted therapy for chromatin abnormalities.
Abstract: Urothelial carcinoma of the bladder is a common malignancy that causes approximately 150,000 deaths per year worldwide. To date, no molecularly targeted agents have been approved for the disease. As part of The Cancer Genome Atlas project, we report here an integrated analysis of 131 urothelial carcinomas to provide a comprehensive landscape of molecular alterations. There were statistically significant recurrent mutations in 32 genes, including multiple genes involved in cell Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#termsThis paper is distributed under the terms of the Creative Commons. Attribution-Non-Commercial-Share Alike license, and the online version of the paper is freely available to all readers.

Journal ArticleDOI
TL;DR: To facilitate evaluation of the medical importance of each variant, ClinVar aggregates submissions with the same variation/phenotype combination, adds value from other NCBI databases, assigns a distinct accession of the format RCV000000000.0 and reports if there are conflicting clinical interpretations.
Abstract: ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/) provides a freely available archive of reports of relationships among medically important variants and phenotypes. ClinVar accessions submissions reporting human variation, interpretations of the relationship of that variation to human health and the evidence supporting each interpretation. The database is tightly coupled with dbSNP and dbVar, which maintain information about the location of variation on human assemblies. ClinVar is also based on the phenotypic descriptions maintained in MedGen (http://www.ncbi.nlm.nih.gov/medgen). Each ClinVar record represents the submitter, the variation and the phenotype, i.e. the unit that is assigned an accession of the format SCV000000000.0. The submitter can update the submission at any time, in which case a new version is assigned. To facilitate evaluation of the medical importance of each variant, ClinVar aggregates submissions with the same variation/phenotype combination, adds value from other NCBI databases, assigns a distinct accession of the format RCV000000000.0 and reports if there are conflicting clinical interpretations. Data in ClinVar are available in multiple formats, including html, download as XML, VCF or tab-delimited subsets. Data from ClinVar are provided as annotation tracks on genomic RefSeqs and are used in tools such as Variation Reporter (http://www.ncbi.nlm.nih.gov/variation/tools/reporter), which reports what is known about variation based on user-supplied locations.

Journal ArticleDOI
Silvia De Rubeis1, Xin-Xin He2, Arthur P. Goldberg1, Christopher S. Poultney1, Kaitlin E. Samocha3, A. Ercument Cicek2, Yan Kou1, Li Liu2, Menachem Fromer3, Menachem Fromer1, R. Susan Walker4, Tarjinder Singh5, Lambertus Klei6, Jack A. Kosmicki3, Shih-Chen Fu1, Branko Aleksic7, Monica Biscaldi8, Patrick Bolton9, Jessica M. Brownfeld1, Jinlu Cai1, Nicholas G. Campbell10, Angel Carracedo11, Angel Carracedo12, Maria H. Chahrour3, Andreas G. Chiocchetti, Hilary Coon13, Emily L. Crawford10, Lucy Crooks5, Sarah Curran9, Geraldine Dawson14, Eftichia Duketis, Bridget A. Fernandez15, Louise Gallagher16, Evan T. Geller17, Stephen J. Guter18, R. Sean Hill3, R. Sean Hill19, Iuliana Ionita-Laza20, Patricia Jiménez González, Helena Kilpinen, Sabine M. Klauck21, Alexander Kolevzon1, Irene Lee22, Jing Lei2, Terho Lehtimäki, Chiao-Feng Lin17, Avi Ma'ayan1, Christian R. Marshall4, Alison L. McInnes23, Benjamin M. Neale24, Michael John Owen25, Norio Ozaki7, Mara Parellada26, Jeremy R. Parr27, Shaun Purcell1, Kaija Puura, Deepthi Rajagopalan4, Karola Rehnström5, Abraham Reichenberg1, Aniko Sabo28, Michael Sachse, Stephen Sanders29, Chad M. Schafer2, Martin Schulte-Rüther30, David Skuse31, David Skuse22, Christine Stevens24, Peter Szatmari32, Kristiina Tammimies4, Otto Valladares17, Annette Voran33, Li-San Wang17, Lauren A. Weiss29, A. Jeremy Willsey29, Timothy W. Yu3, Timothy W. Yu19, Ryan K. C. Yuen4, Edwin H. Cook18, Christine M. Freitag, Michael Gill16, Christina M. Hultman34, Thomas Lehner35, Aarno Palotie36, Aarno Palotie3, Aarno Palotie24, Gerard D. Schellenberg17, Pamela Sklar1, Matthew W. State29, James S. Sutcliffe10, Christopher A. Walsh19, Christopher A. Walsh3, Stephen W. Scherer4, Michael E. Zwick37, Jeffrey C. Barrett5, David J. Cutler37, Kathryn Roeder2, Bernie Devlin6, Mark J. Daly24, Mark J. Daly3, Joseph D. Buxbaum1 
13 Nov 2014-Nature
TL;DR: Using exome sequencing, it is shown that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate of < 0.05, plus a set of 107 genes strongly enriched for those likely to affect risk (FDR < 0.30).
Abstract: The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers-most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.

Journal ArticleDOI
Nishant Agrawal1, Rehan Akbani1, B. Arman Aksoy1, Adrian Ally1  +239 moreInstitutions (1)
23 Oct 2014-Cell
TL;DR: The genomic landscape of 496 PTCs is described and a reclassification of thyroid cancers into molecular subtypes that better reflect their underlying signaling and differentiation properties is proposed, which has the potential to improve their pathological classification and better inform the management of the disease.

Journal ArticleDOI
TL;DR: As marijuana use becomes legal in some states, the dominant public opinion is that marijuana is a harmless source of mood alteration, but enough information is available to cause concern.
Abstract: As marijuana use becomes legal in some states, the dominant public opinion is that marijuana is a harmless source of mood alteration. Although the harms associated with marijuana use have not been well studied, enough information is available to cause concern.

Journal ArticleDOI
10 Apr 2014-Nature
TL;DR: A brain-wide, cellular-level, mesoscale connectome for the mouse, using enhanced green fluorescent protein-expressing adeno-associated viral vectors to trace axonal projections from defined regions and cell types, and high-throughput serial two-photon tomography to image the EGFP-labelled axons throughout the brain.
Abstract: Comprehensive knowledge of the brain's wiring diagram is fundamental for understanding how the nervous system processes information at both local and global scales. However, with the singular exception of the C. elegans microscale connectome, there are no complete connectivity data sets in other species. Here we report a brain-wide, cellular-level, mesoscale connectome for the mouse. The Allen Mouse Brain Connectivity Atlas uses enhanced green fluorescent protein (EGFP)-expressing adeno-associated viral vectors to trace axonal projections from defined regions and cell types, and high-throughput serial two-photon tomography to image the EGFP-labelled axons throughout the brain. This systematic and standardized approach allows spatial registration of individual experiments into a common three dimensional (3D) reference space, resulting in a whole-brain connectivity matrix. A computational model yields insights into connectional strength distribution, symmetry and other network properties. Virtual tractography illustrates 3D topography among interconnected regions. Cortico-thalamic pathway analysis demonstrates segregation and integration of parallel pathways. The Allen Mouse Brain Connectivity Atlas is a freely available, foundational resource for structural and functional investigations into the neural circuits that support behavioural and cognitive processes in health and disease.

Journal ArticleDOI
TL;DR: Applications in Theranostics Guanying Chen,*,†,‡ Hailong Qiu,*,‡ and Xiaoyuan Chen.
Abstract: Applications in Theranostics Guanying Chen,*,†,‡ Hailong Qiu,†,‡ Paras N. Prasad,*,‡,§ and Xiaoyuan Chen* †School of Chemical Engineering and Technology, Harbin Institute of Technology, Harbin, Heilongjiang 150001, China ‡Department of Chemistry and the Institute for Lasers, Photonics, and Biophotonics, University at Buffalo, State University of New York, Buffalo, New York 14260, United States Department of Chemistry, Korea University, Seoul 136-701, Korea Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland 20892-2281, United States

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TL;DR: In patients with heart failure and a preserved ejection fraction, treatment with spironolactone did not significantly reduce the incidence of the primary composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure.
Abstract: Background Mineralocorticoid-receptor antagonists improve the prognosis for patients with heart failure and a reduced left ventricular ejection fraction. We evaluated the effects of spironolactone in patients with heart failure and a preserved left ventricular ejection fraction. Methods In this randomized, double-blind trial, we assigned 3445 patients with symptomatic heart failure and a left ventricular ejection fraction of 45% or more to receive either spironolactone (15 to 45 mg daily) or placebo. The primary outcome was a composite of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure. Results With a mean follow-up of 3.3 years, the primary outcome occurred in 320 of 1722 patients in the spironolactone group (18.6%) and 351 of 1723 patients in the placebo group (20.4%) (hazard ratio, 0.89; 95% confidence interval [CI], 0.77 to 1.04; P = 0.14). Of the components of the primary outcome, only hospitalization for heart failure had a significantly lower incidence in the spironolactone group than in the placebo group (206 patients [12.0%] vs. 245 patients [14.2%]; hazard ratio, 0.83; 95% CI, 0.69 to 0.99, P = 0.04). Neither total deaths nor hospitalizations for any reason were significantly reduced by spironolactone. Treatment with spiron olactone was associated with increased serum creatinine levels and a doubling of the rate of hyperkalemia (18.7%, vs. 9.1% in the placebo group) but reduced hypokalemia. With frequent monitoring, there were no significant differences in the incidence of serious adverse events, a serum creatinine level of 3.0 mg per deciliter (265 μmol per liter) or higher, or dialysis. Conclusions In patients with heart failure and a preserved ejection fraction, treatment with spironolactone did not significantly reduce the incidence of the primary composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure. (Funded by the National Heart, Lung, and Blood Institute; TOPCAT ClinicalTrials.gov number, NCT00094302.)

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Andrew R. Wood1, Tõnu Esko2, Jian Yang3, Sailaja Vedantam4  +441 moreInstitutions (132)
TL;DR: This article identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height, and all common variants together captured 60% of heritability.
Abstract: Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

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TL;DR: This evidence-based guideline recommends minimally invasive adrenalectomy for most pheochromocytomas with open resection for most paragangliomas and suggests personalized management with evaluation and treatment by multidisciplinary teams with appropriate expertise to ensure favorable outcomes.
Abstract: Objective: The aim was to formulate clinical practice guidelines for pheochromocytoma and paraganglioma (PPGL). Participants: The Task Force included a chair selected by the Endocrine Society Clinical Guidelines Subcommittee (CGS), seven experts in the field, and a methodologist. The authors received no corporate funding or remuneration. Evidence: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. The Task Force reviewed primary evidence and commissioned two additional systematic reviews. Consensus Process: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of the Endocrine Society, European Society of Endocrinology, and Americal Association for Clinical Chemistry reviewed drafts of the guidelines. Conclusions: The Task Force recommends that initial biochemical testing for PPGLs shou...

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TL;DR: Prolonged courses of artemisinin-based combination therapies are currently efficacious in areas where standard 3-day treatments are failing, and the incidence of pretreatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission.
Abstract: BACKGROUND: Artemisinin resistance in Plasmodium falciparum has emerged in Southeast Asia and now poses a threat to the control and elimination of malaria. Mapping the geographic extent of resistance is essential for planning containment and elimination strategies. METHODS: Between May 2011 and April 2013, we enrolled 1241 adults and children with acute, uncomplicated falciparum malaria in an open-label trial at 15 sites in 10 countries (7 in Asia and 3 in Africa). Patients received artesunate, administered orally at a daily dose of either 2 mg per kilogram of body weight per day or 4 mg per kilogram, for 3 days, followed by a standard 3-day course of artemisinin-based combination therapy. Parasite counts in peripheral-blood samples were measured every 6 hours, and the parasite clearance half-lives were determined. RESULTS: The median parasite clearance half-lives ranged from 1.9 hours in the Democratic Republic of Congo to 7.0 hours at the Thailand-Cambodia border. Slowly clearing infections (parasite clearance half-life >5 hours), strongly associated with single point mutations in the "propeller" region of the P. falciparum kelch protein gene on chromosome 13 (kelch13), were detected throughout mainland Southeast Asia from southern Vietnam to central Myanmar. The incidence of pretreatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission. In western Cambodia, where artemisinin-based combination therapies are failing, the 6-day course of antimalarial therapy was associated with a cure rate of 97.7% (95% confidence interval, 90.9 to 99.4) at 42 days. CONCLUSIONS: Artemisinin resistance to P. falciparum, which is now prevalent across mainland Southeast Asia, is associated with mutations in kelch13. Prolonged courses of artemisinin-based combination therapies are currently efficacious in areas where standard 3-day treatments are failing. (Funded by the U.K. Department of International Development and others; ClinicalTrials.gov number, NCT01350856.).

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TL;DR: To prevent a striking rise in resistance in low-income and middle-income countries with large populations and to preserve antibiotic efficacy worldwide, programmes that promote rational use through coordinated efforts by the international community should be a priority.
Abstract: Summary Background Antibiotic drug consumption is a major driver of antibiotic resistance. Variations in antibiotic resistance across countries are attributable, in part, to different volumes and patterns for antibiotic consumption. We aimed to assess variations in consumption to assist monitoring of the rise of resistance and development of rational-use policies and to provide a baseline for future assessment. Methods With use of sales data for retail and hospital pharmacies from the IMS Health MIDAS database, we reviewed trends for consumption of standard units of antibiotics between 2000 and 2010 for 71 countries. We used compound annual growth rates to assess temporal differences in consumption for each country and Fourier series and regression methods to assess seasonal differences in consumption in 63 of the countries. Findings Between 2000 and 2010, consumption of antibiotic drugs increased by 35% (from 52 057 163 835 standard units to 70 440 786 553). Brazil, Russia, India, China, and South Africa accounted for 76% of this increase. In most countries, antibiotic consumption varied significantly with season. There was increased consumption of carbapenems (45%) and polymixins (13%), two last-resort classes of antibiotic drugs. Interpretation The rise of antibiotic consumption and the increase in use of last-resort antibiotic drugs raises serious concerns for public health. Appropriate use of antibiotics in developing countries should be encouraged. However, to prevent a striking rise in resistance in low-income and middle-income countries with large populations and to preserve antibiotic efficacy worldwide, programmes that promote rational use through coordinated efforts by the international community should be a priority. Funding US Department of Homeland Security, Bill & Melinda Gates Foundation, US National Institutes of Health, Princeton Grand Challenges Program.

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27 Feb 2014-Cell
TL;DR: In this article, the crystal structure of the CRISPR-associated endonuclease Cas9 in complex with sgRNA and its target DNA at 2.5-A resolution was reported.