Showing papers by "Karolinska Institutet published in 2012"
TL;DR: Prevalence and severity of health loss were weakly correlated and age-specific prevalence of YLDs increased with age in all regions and has decreased slightly from 1990 to 2010, but population growth and ageing have increased YLD numbers and crude rates over the past two decades.
7,021 citations
TL;DR: The results for 1990 and 2010 supersede all previously published Global Burden of Disease results and highlight the importance of understanding local burden of disease and setting goals and targets for the post-2015 agenda taking such patterns into account.
6,861 citations
Katholieke Universiteit Leuven1, Ghent University2, Karolinska Institutet3, Cairo University4, University of São Paulo5, Cincinnati Children's Hospital Medical Center6, Innsbruck Medical University7, University of Duisburg-Essen8, Tufts University9, University of Aberdeen10, University of California, San Diego11, University College Dublin12, University of the Witwatersrand13, Brown University14, Heidelberg University15, Jikei University School of Medicine16
4,482 citations
Daniel J. Klionsky1, Fábio Camargo Abdalla2, Hagai Abeliovich3, Robert T. Abraham4 +1284 more•Institutions (463)
TL;DR: These guidelines are presented for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes.
Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
4,316 citations
Wellcome Trust Sanger Institute1, Broad Institute2, University of Groningen3, University of Pittsburgh4, Cedars-Sinai Medical Center5, Yale University6, University of Cambridge7, University of Chicago8, Harvard University9, Katholieke Universiteit Leuven10, University of Liège11, King's College London12, Université de Montréal13, New Jersey Institute of Technology14, Cleveland Clinic15, Peninsula College of Medicine and Dentistry16, Université libre de Bruxelles17, Aarhus University18, University of Adelaide19, University of Kiel20, Flinders University21, McGill University22, Ludwig Maximilian University of Munich23, Charité24, Icahn School of Medicine at Mount Sinai25, University of Bonn26, Karolinska Institutet27, Torbay Hospital28, University of Auckland29, Christchurch Hospital30, Imperial College London31, Queen's University32, University of Oslo33, Lithuanian University of Health Sciences34, Emory University35, Casa Sollievo della Sofferenza36, Ghent University37, University of Western Australia38, University of Edinburgh39, Queensland Health40, Newcastle University41, University of Dundee42, University of Manchester43, University of Amsterdam44, University of Maribor45, Royal Hospital for Sick Children46, Guy's and St Thomas' NHS Foundation Trust47, QIMR Berghofer Medical Research Institute48, Norfolk and Norwich University Hospital49, Leiden University50, Technische Universität München51, University of Toronto52, University of Pennsylvania53, Johns Hopkins University54, University of Queensland55
TL;DR: A meta-analysis of Crohn’s disease and ulcerative colitis genome-wide association scans is undertaken, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls.
Abstract: Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.
4,094 citations
Johns Hopkins University1, University of Alabama at Birmingham2, University of Birmingham3, Oklahoma Medical Research Foundation4, Laval University5, University of Manchester6, University College London7, University of California, Los Angeles8, Lund University9, Northwestern University10, Hanyang University11, Dalhousie University12, University of Toronto13, McGill University14, North Shore-LIJ Health System15, Allegheny General Hospital16, University of California, San Diego17, University of Pennsylvania18, Monklands Hospital19, University of the Basque Country20, St Thomas' Hospital21, University of Copenhagen22, New York University23, University of North Carolina at Chapel Hill24, Karolinska Institutet25, SUNY Downstate Medical Center26, University of Manitoba27, Wake Forest University28, University of Louisville29, Emory University30, Istanbul University31, Medical University of South Carolina32, University of Texas Health Science Center at San Antonio33, Cedars-Sinai Medical Center34, University of Maryland, Baltimore35
TL;DR: The Systemic Lupus International Collaborating Clinics (SLICC) group revised and validated the American College of Rheumatology (ACR) systemic lupus erythematosus (SLE) classification criteria in order to improve clinical relevance, meet stringent methodology requirements, and incorporate new knowledge regarding the immunology of SLE.
Abstract: Objective The Systemic Lupus International Collaborating Clinics (SLICC) group revised and validated the American College of Rheumatology (ACR) systemic lupus erythematosus (SLE) classification criteria in order to improve clinical relevance, meet stringent methodology requirements, and incorporate new knowledge regarding the immunology of SLE. Methods The classification criteria were derived from a set of 702 expert-rated patient scenarios. Recursive partitioning was used to derive an initial rule that was simplified and refined based on SLICC physician consensus. The SLICC group validated the classification criteria in a new validation sample of 690 new expert-rated patient scenarios. Results Seventeen criteria were identified. In the derivation set, the SLICC classification criteria resulted in fewer misclassifications compared with the current ACR classification criteria (49 versus 70; P = 0.0082) and had greater sensitivity (94% versus 86%; P < 0.0001) and equal specificity (92% versus 93%; P = 0.39). In the validation set, the SLICC classification criteria resulted in fewer misclassifications compared with the current ACR classification criteria (62 versus 74; P = 0.24) and had greater sensitivity (97% versus 83%; P < 0.0001) but lower specificity (84% versus 96%; P < 0.0001). Conclusion The new SLICC classification criteria performed well in a large set of patient scenarios rated by experts. According to the SLICC rule for the classification of SLE, the patient must satisfy at least 4 criteria, including at least one clinical criterion and one immunologic criterion OR the patient must have biopsy-proven lupus nephritis in the presence of antinuclear antibodies or antidouble-stranded DNA antibodies. (Less)
3,609 citations
TL;DR: A deeper understanding of the axes that physiologically connect the gut, liver, muscle, and brain are a prerequisite for optimizing therapeutic strategies to manipulate the gut microbiota to combat disease and improve health.
Abstract: The composition and activity of the gut microbiota codevelop with the host from birth and is subject to a complex interplay that depends on the host genome, nutrition, and life-style. The gut microbiota is involved in the regulation of multiple host metabolic pathways, giving rise to interactive host-microbiota metabolic, signaling, and immune-inflammatory axes that physiologically connect the gut, liver, muscle, and brain. A deeper understanding of these axes is a prerequisite for optimizing therapeutic strategies to manipulate the gut microbiota to combat disease and improve health.
3,509 citations
French Institute of Health and Medical Research1, Institut Gustave Roussy2, University of Paris-Sud3, University of Texas Southwestern Medical Center4, Thomas Jefferson University5, University of Massachusetts Medical School6, Roswell Park Cancer Institute7, Johns Hopkins University School of Medicine8, Penn State Milton S. Hershey Medical Center9, Goethe University Frankfurt10, St. Jude Children's Research Hospital11, University of Zurich12, University College London13, University of Adelaide14, South Australia Pathology15, Ludwig Institute for Cancer Research16, University of Graz17, Istituto Superiore di Sanità18, University of Michigan19, Northwestern University20, University of Rome Tor Vergata21, University of Cambridge22, University of Bern23, Ghent University24, Harvard University25, Karolinska Institutet26, University of Leicester27
TL;DR: A functional classification of cell death subroutines is proposed that applies to both in vitro and in vivo settings and includes extrinsic apoptosis, caspase-dependent or -independent intrinsic programmed cell death, regulated necrosis, autophagic cell death and mitotic catastrophe.
Abstract: In 2009, the Nomenclature Committee on Cell Death (NCCD) proposed a set of recommendations for the definition of distinct cell death morphologies and for the appropriate use of cell death-related terminology, including 'apoptosis', 'necrosis' and 'mitotic catastrophe'. In view of the substantial progress in the biochemical and genetic exploration of cell death, time has come to switch from morphological to molecular definitions of cell death modalities. Here we propose a functional classification of cell death subroutines that applies to both in vitro and in vivo settings and includes extrinsic apoptosis, caspase-dependent or -independent intrinsic apoptosis, regulated necrosis, autophagic cell death and mitotic catastrophe. Moreover, we discuss the utility of expressions indicating additional cell death modalities. On the basis of the new, revised NCCD classification, cell death subroutines are defined by a series of precise, measurable biochemical features.
2,238 citations
Andrew P. Morris1, Benjamin F. Voight2, Benjamin F. Voight3, Tanya M. Teslovich4 +229 more•Institutions (53)
TL;DR: This article conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent, and identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association.
Abstract: To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of additional common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signaling and cell cycle regulation, in diabetes pathogenesis.
1,899 citations
Broad Institute1, Harvard University2, University of Pennsylvania3, National Institutes of Health4, Boston University5, Lund University6, University of Copenhagen7, University of Texas Health Science Center at Houston8, deCODE genetics9, Queen Mary University of London10, University of Lübeck11, University of Leicester12, Glenfield Hospital13, University of Oxford14, University of Cambridge15, University of Ottawa16, University of Iceland17, Population Health Research Institute18, McGill University19, Vanderbilt University20, University of Missouri–Kansas City21, University of Münster22, University of Verona23, Queen's University Belfast24, MedStar Washington Hospital Center25, GlaxoSmithKline26, University of Helsinki27, Karolinska Institutet28, University of Mainz29, Utrecht University30, University of Groningen31, University of Michigan32, United States Department of Agriculture33, Centro Nacional de Investigaciones Cardiovasculares34, University of North Carolina at Chapel Hill35, University of Regensburg36, Katholieke Universiteit Leuven37, University of Edinburgh38, University of Kiel39, University of Leeds40, Aarhus University41, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico42, University of Washington43, Wellcome Trust Sanger Institute44
TL;DR: In this paper, a Mendelian randomisation analysis was performed to compare the effect of HDL cholesterol, LDL cholesterol, and genetic score on risk of myocardial infarction.
Abstract: Methods We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20 913 myocardial infarction cases, 95 407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12 482 cases of myocardial infarction and 41 331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol. – ¹³) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with noncarriers. This diff erence in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84–0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88–1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58–0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68–1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45–1·63) was concordant with that from genetic score (OR 2·13, 95% CI 1·69–2·69, p=2×10
1,878 citations
University of Pennsylvania1, The Catholic University of America2, University of London3, University of Southampton4, Carlos III Health Institute5, Karolinska Institutet6, Dublin City University7, Jagiellonian University8, University of Eastern Finland9, University of Basel10, Radboud University Nijmegen11, National and Kapodistrian University of Athens12
TL;DR: In European hospitals, improvement of hospital work environments might be a relatively low cost strategy to improve safety and quality in hospital care and to increase patient satisfaction.
Abstract: Objective To determine whether hospitals with a good organisation of care (such as improved nurse staffing and work environments) can affect patient care and nurse workforce stability in European countries. Design Cross sectional surveys of patients and nurses. Setting Nurses were surveyed in general acute care hospitals (488 in 12 European countries; 617 in the United States); patients were surveyed in 210 European hospitals and 430 US hospitals. Participants 33 659 nurses and 11 318 patients in Europe; 27 509 nurses and more than 120 000 patients in the US. Main outcome measures Nurse outcomes (hospital staffing, work environments, burnout, dissatisfaction, intention to leave job in the next year, patient safety, quality of care), patient outcomes (satisfaction overall and with nursing care, willingness to recommend hospitals). Results The percentage of nurses reporting poor or fair quality of patient care varied substantially by country (from 11% (Ireland) to 47% (Greece)), as did rates for nurses who gave their hospital a poor or failing safety grade (4% (Switzerland) to 18% (Poland)). We found high rates of nurse burnout (10% (Netherlands) to 78% (Greece)), job dissatisfaction (11% (Netherlands) to 56% (Greece)), and intention to leave (14% (US) to 49% (Finland, Greece)). Patients’ high ratings of their hospitals also varied considerably (35% (Spain) to 61% (Finland, Ireland)), as did rates of patients willing to recommend their hospital (53% (Greece) to 78% (Switzerland)). Improved work environments and reduced ratios of patients to nurses were associated with increased care quality and patient satisfaction. In European hospitals, after adjusting for hospital and nurse characteristics, nurses with better work environments were half as likely to report poor or fair care quality (adjusted odds ratio 0.56, 95% confidence interval 0.51 to 0.61) and give their hospitals poor or failing grades on patient safety (0.50, 0.44 to 0.56). Each additional patient per nurse increased the odds of nurses reporting poor or fair quality care (1.11, 1.07 to 1.15) and poor or failing safety grades (1.10, 1.05 to 1.16). Patients in hospitals with better work environments were more likely to rate their hospital highly (1.16, 1.03 to 1.32) and recommend their hospitals (1.20, 1.05 to 1.37), whereas those with higher ratios of patients to nurses were less likely to rate them highly (0.94, 0.91 to 0.97) or recommend them (0.95, 0.91 to 0.98). Results were similar in the US. Nurses and patients agreed on which hospitals provided good care and could be recommended. Conclusions Deficits in hospital care quality were common in all countries. Improvement of hospital work environments might be a relatively low cost strategy to improve safety and quality in hospital care and to increase patient satisfaction.
TL;DR: The strong protective effect of the A673T substitution against Alzheimer’s disease provides proof of principle for the hypothesis that reducing the β-cleavage of APP may protect against the disease.
Abstract: The prevalence of dementia in the Western world in people over the age of 60 has been estimated to be greater than 5%, about two-thirds of which are due to Alzheimer's disease. The age-specific prevalence of Alzheimer's disease nearly doubles every 5 years after age 65, leading to a prevalence of greater than 25% in those over the age of 90 (ref. 3). Here, to search for low-frequency variants in the amyloid-β precursor protein (APP) gene with a significant effect on the risk of Alzheimer's disease, we studied coding variants in APP in a set of whole-genome sequence data from 1,795 Icelanders. We found a coding mutation (A673T) in the APP gene that protects against Alzheimer's disease and cognitive decline in the elderly without Alzheimer's disease. This substitution is adjacent to the aspartyl protease β-site in APP, and results in an approximately 40% reduction in the formation of amyloidogenic peptides in vitro. The strong protective effect of the A673T substitution against Alzheimer's disease provides proof of principle for the hypothesis that reducing the β-cleavage of APP may protect against the disease. Furthermore, as the A673T allele also protects against cognitive decline in the elderly without Alzheimer's disease, the two may be mediated through the same or similar mechanisms.
TL;DR: Although it reduced new-onset diabetes, insulin glargine also increased hypoglycemia and modestly increased weight and had a neutral effect on cardiovascular outcomes and cancers.
Abstract: BACKGROUND: The provision of sufficient basal insulin to normalize fasting plasma glucose levels may reduce cardiovascular events, but such a possibility has not been formally tested.
METHODS: We randomly assigned 12,537 people (mean age, 63.5 years) with cardiovascular risk factors plus impaired fasting glucose, impaired glucose tolerance, or type 2 diabetes to receive insulin glargine (with a target fasting blood glucose level of ≤95 mg per deciliter [5.3 mmol per liter]) or standard care and to receive n-3 fatty acids or placebo with the use of a 2-by-2 factorial design. The results of the comparison between insulin glargine and standard care are reported here. The coprimary outcomes were nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes and these events plus revascularization or hospitalization for heart failure. Microvascular outcomes, incident diabetes, hypoglycemia, weight, and cancers were also compared between groups.
RESULTS: The median follow-up was 6.2 years (interquartile range, 5.8 to 6.7). Rates of incident cardiovascular outcomes were similar in the insulin-glargine and standard-care groups: 2.94 and 2.85 per 100 person-years, respectively, for the first coprimary outcome (hazard ratio, 1.02; 95% confidence interval [CI], 0.94 to 1.11; P=0.63) and 5.52 and 5.28 per 100 person-years, respectively, for the second coprimary outcome (hazard ratio, 1.04; 95% CI, 0.97 to 1.11; P=0.27). New diabetes was diagnosed approximately 3 months after therapy was stopped among 30% versus 35% of 1456 participants without baseline diabetes (odds ratio, 0.80; 95% CI, 0.64 to 1.00; P=0.05). Rates of severe hypoglycemia were 1.00 versus 0.31 per 100 person-years. Median weight increased by 1.6 kg in the insulin-glargine group and fell by 0.5 kg in the standard-care group. There was no significant difference in cancers (hazard ratio, 1.00; 95% CI, 0.88 to 1.13; P=0.97).
CONCLUSIONS: When used to target normal fasting plasma glucose levels for more than 6 years, insulin glargine had a neutral effect on cardiovascular outcomes and cancers. Although it reduced new-onset diabetes, insulin glargine also increased hypoglycemia and modestly increased weight. (Funded by Sanofi; ORIGIN ClinicalTrials.gov number, NCT00069784.).
TL;DR: Applying Smart-Seq to circulating tumor cells from melanomas, it is found that although gene expression estimates from single cells have increased noise, hundreds of differentially expressed genes could be identified using few cells per cell type.
Abstract: RNA-Seq of single cells has been limited by biases in transcript coverage and unknown technical variability. Ramskold et al. describe a protocol to reproducibly recover full-length transcripts and use it to quantitatively analyze splice isoforms in single cells.
Martin Luther University of Halle-Wittenberg1, Katholieke Universiteit Leuven2, Eppendorf (Germany)3, The Catholic University of America4, Uppsala University5, Karolinska Institutet6, Leiden University Medical Center7, Hebron University8, Radboud University Nijmegen9, Seconda Università degli Studi di Napoli10, University of São Paulo11, University of Oxford12, Medical University of Vienna13, Autonomous University of Barcelona14, Sheba Medical Center15, Ain Shams University16, Clínica Alemana17, Mount Vernon Hospital18, Bank of Cyprus19, Odense University Hospital20, University of Crete21, Marmara University22, University of Valencia23
TL;DR: This ESMO guideline is recommended to be used as the basis for treatment and management decisions, delivering a clear proposal for diagnostic and treatment measures in each stage of rectal and colon cancer and the individual clinical situations.
TL;DR: This new report presents updated, more accurate, and comprehensive 2010 estimates of annual costs for brain disorders in Europe for 30 European countries.
Abstract: BACKGROUND AND PURPOSE: In 2005, we presented for the first time overall estimates of annual costs for brain disorders (mental and neurologic disorders) in Europe. This new report presents updated, ...
La Trobe University1, Harvard University2, German Cancer Research Center3, Yale University4, Morehouse School of Medicine5, Autonomous University of Barcelona6, University of Massachusetts Medical School7, Semmelweis University8, Cardiff University9, Ikerbasque10, Karolinska Institutet11, Pohang University of Science and Technology12, Allahabad University13, Ghent University14, University of Melbourne15, London Metropolitan University16, Erasmus University Rotterdam17, University of Mainz18, National University of Singapore19, University of Oslo20, University of Gothenburg21, University of Valencia22, Umeå University23, University of Freiburg24, University of Amsterdam25, Utrecht University26, Johns Hopkins University27, Mayo Clinic28, Ohio State University29, University of Cambridge30, University of Zurich31, Curie Institute32, Michigan State University33, Autonomous University of Madrid34, University of Helsinki35, Aalborg University36, University of Louisville37, Carlos III Health Institute38, Centre national de la recherche scientifique39, Heidelberg University40
TL;DR: Vesiclepedia is a community-annotated compendium of molecular data on extracellular vesicles that aims to provide a single authoritative source for information on vesicle structure and function.
Abstract: Extracellular vesicles (EVs) are membraneous vesicles released by a variety of cells into their microenvironment. Recent studies have elucidated the role of EVs in intercellular communication, pathogenesis, drug, vaccine and gene-vector delivery, and as possible reservoirs of biomarkers. These findings have generated immense interest, along with an exponential increase in molecular data pertaining to EVs. Here, we describe Vesiclepedia, a manually curated compendium of molecular data (lipid, RNA, and protein) identified in different classes of EVs from more than 300 independent studies published over the past several years. Even though databases are indispensable resources for the scientific community, recent studies have shown that more than 50% of the databases are not regularly updated. In addition, more than 20% of the database links are inactive. To prevent such database and link decay, we have initiated a continuous community annotation project with the active involvement of EV researchers. The EV research community can set a gold standard in data sharing with Vesiclepedia, which could evolve as a primary resource for the field.
Harvard University1, University of Queensland2, Johns Hopkins University3, ICF International4, Centre for Mental Health5, Boston University6, University of Sydney7, University of Melbourne8, Imperial College London9, University of New South Wales10, University of California, San Diego11, Emory University12, University of Pennsylvania13, Autonomous University of Barcelona14, University of London15, National Institutes of Health16, French Institute of Health and Medical Research17, Medical Research Council18, Auckland University of Technology19, Federal University of São Paulo20, National Institute of Population and Social Security Research21, Howard University22, Flinders University23, Erasmus University Rotterdam24, King's College London25, Karolinska Institutet26, University of California, San Francisco27, All India Institute of Medical Sciences28, Nova Southeastern University29, University of Miami30, Swansea University31, Tehran University of Medical Sciences32, Queen Mary University of London33, Allen Institute for Brain Science34, University of Cape Town35, Columbia University36, Watford General Hospital37, Centro Studi GISED38, University of Oxford39, Deakin University40, University of British Columbia41, University of Toronto42, Box Hill Hospital43, Vanderbilt University44, University of Washington45, Brandeis University46, University of Tokyo47, The Queen's Medical Center48, Norwegian University of Science and Technology49, China Medical Board50, University of Cambridge51, Royal Cornwall Hospital52, Cedars-Sinai Medical Center53, Shanghai Jiao Tong University54
TL;DR: In this paper, a comprehensive re-estimation of disability weights for the Global Burden of Disease Study 2010 through a large-scale empirical investigation in which judgments about health losses associated with many causes of disease and injury were elicited from the general public in diverse communities through a new, standardised approach.
TL;DR: Methods for point and interval estimation of relative risk for log-linear exposure-response relations in meta-analyses of published ordinal categorical exposure- response data have been proposed and the use of 2 publicly available user-friendly programs (Stata and SAS) to implement meta-analysis for dose-response data is illustrated.
Abstract: Two methods for point and interval estimation of relative risk for log-linear exposure-response relations in meta-analyses of published ordinal categorical exposure-response data have been proposed. The authors compared the results of a meta-analysis of published data using each of the 2 methods with the results that would be obtained if the primary data were available and investigated the circumstances under which the approximations required for valid use of each meta-analytic method break down. They then extended the methods to handle nonlinear exposure-response relations. In the present article, methods are illustrated using studies of the relation between alcohol consumption and colorectal and lung cancer risks from the ongoing Pooling Project of Prospective Studies of Diet and Cancer. In these examples, the differences between the results of a meta-analysis of summarized published data and the pooled analysis of the individual original data were small. However, incorrectly assuming no correlation between relative risk estimates for exposure categories from the same study gave biased confidence intervals for the trend and biased P values for the tests for nonlinearity and between-study heterogeneity when there was strong confounding by other model covariates. The authors illustrate the use of 2 publicly available user-friendly programs (Stata and SAS) to implement meta-analysis for dose-response data.
TL;DR: Unique molecular identifiers (UMIs), which make each molecule in a population distinct, are applied to genome-scale human karyotyping and mRNA sequencing in Drosophila melanogaster to improve accuracy of almost any next-generation sequencing method.
Abstract: Unique molecular identifiers (UMIs) associate distinct sequences with every DNA or RNA molecule and can be counted after amplification to quantify molecules in the original sample. Using UMIs, the authors obtain a digital karyotype of an individual with Down's syndrome and quantify mRNA in Drosophila melanogaster cells.
TL;DR: It is shown that the vascular defects in Apoe-deficient and APOE4-expressing mice precede neuronal dysfunction and can initiate neurodegenerative changes, which suggest that CypA is a key target for treating APoe4-mediated neurovascular injury and the resulting neuronal Dysfunction and degeneration.
Abstract: Human apolipoprotein E has three isoforms: APOE2, APOE3 and APOE4. APOE4 is a major genetic risk factor for Alzheimer's disease and is associated with Down's syndrome dementia and poor neurological outcome after traumatic brain injury and haemorrhage. Neurovascular dysfunction is present in normal APOE4 carriers and individuals with APOE4-associated disorders. In mice, lack of Apoe leads to blood-brain barrier (BBB) breakdown, whereas APOE4 increases BBB susceptibility to injury. How APOE genotype affects brain microcirculation remains elusive. Using different APOE transgenic mice, including mice with ablation and/or inhibition of cyclophilin A (CypA), here we show that expression of APOE4 and lack of murine Apoe, but not APOE2 and APOE3, leads to BBB breakdown by activating a proinflammatory CypA-nuclear factor-κB-matrix-metalloproteinase-9 pathway in pericytes. This, in turn, leads to neuronal uptake of multiple blood-derived neurotoxic proteins, and microvascular and cerebral blood flow reductions. We show that the vascular defects in Apoe-deficient and APOE4-expressing mice precede neuronal dysfunction and can initiate neurodegenerative changes. Astrocyte-secreted APOE3, but not APOE4, suppressed the CypA-nuclear factor-κB-matrix-metalloproteinase-9 pathway in pericytes through a lipoprotein receptor. Our data suggest that CypA is a key target for treating APOE4-mediated neurovascular injury and the resulting neuronal dysfunction and degeneration.
TL;DR: Several independent risk factors (prior ICH, myocardial infarction, vascular disease, and renal failure) predict ischaemic stroke and/or the composite thromboembolism endpoint in AF, but thyroid disease was not an independent risk factor for stroke.
Abstract: Aims The impact of some risk factors for stroke and bleeding, and the value of stroke and bleeding risk scores, in atrial fibrillation (AF), has been debated, as clinical trial cohorts have not adequately tested these. Our objective was to investigate risk factors for stroke and bleeding in AF, and application of the new CHA2DS2-VASc and HAS-BLED schemes for stroke and bleeding risk assessments, respectively.
Methods and results We used the Swedish Atrial Fibrillation cohort study, a nationwide cohort study of 182 678 subjects with a diagnosis of AF at any Swedish hospital between 1 July 2005 and 31 December 2008, who were prospectively followed for an average of 1.5 years (260 000 years at risk). With the use of the National Swedish Drug Registry, all patients who used an oral anticoagulant anytime during follow-up were identified. Most of the analyses were made on a subset of 90 490 patients who never used anticoagulants. Risk factors for stroke, the composite thromboembolism endpoint (stroke, TIA, or systemic embolism), and bleeding, and the performance of published stroke and bleeding risk stratification schemes were investigated. On multivariable analysis, significant associations were found between the following ‘new’ risk factors and thromboembolic events; peripheral artery disease [hazard ratio (HR) 1.22 (95% CI 1.12–1.32)], ‘vascular disease’ [HR 1.14 (1.06–1.23)], prior myocardial infarction [HR 1.09 (1.03–1.15)], and female gender [HR 1.17 (1.11–1.22)]. Previous embolic events, intracranial haemorrhage (ICH), hypertension, diabetes, and renal failure were other independent predictors of the composite thromboembolism endpoint, while thyroid disease (or hyperthyroidism) was not an independent stroke risk factor. C-statistics for the composite thromboembolic endpoint with the CHADS2 and CHA2DS2-VASc schemes were 0.66 (0.65–0.66) and 0.67 (0.67–0.68), respectively. On multivariable analysis, age, prior ischaemic stroke or thromboembolism, prior major bleeding events, and hypertension were significant predictors of ICH and major bleeding. Heart failure, diabetes, renal failure, liver disease, anaemia or platelet/coagulation defect, alcohol abuse, and cancer were other significant predictors for major bleeding, but not ICH. The ability for predicting ICH and major bleeding with both bleeding risk schemes (HEMORR2HAGES, HAS-BLED) were similar, with c-statistics of ∼0.6.
Conclusion Several independent risk factors (prior ICH, myocardial infarction, vascular disease, and renal failure) predict ischaemic stroke and/or the composite thromboembolism endpoint in AF, but thyroid disease (or hyperthyroidism) was not an independent risk factor for stroke. There is a better performance for CHA2DS2-VASc over CHADS2 schemes for the composite thromboembolism endpoint. While both tested bleeding risk schemes have similar predictive value, the HAS-BLED score has the advantage of simplicity.
University of Cambridge1, Medical Research Council2, University of Glasgow3, Pasteur Institute4, University of Groningen5, The Heart Research Institute6, University of California, San Diego7, Boston University8, University of Gothenburg9, German Cancer Research Center10, University College London11, University of Oxford12, Ludwig Maximilian University of Munich13, University of Vermont14, University of Bristol15, VU University Amsterdam16, Lund University17, University of Minnesota18, University of Edinburgh19, Cardiff University20, Harvard University21, Istituto Superiore di Sanità22, Centers for Disease Control and Prevention23, Erasmus University Rotterdam24, Memorial Hospital of South Bend25, Karolinska Institutet26, Osaka University27, University of Copenhagen28, Innsbruck Medical University29, Kyushu University30, University of Ulm31, Wageningen University and Research Centre32, University of Pittsburgh33, University of London34, National Institute for Health and Welfare35, Istanbul University36, Harokopio University37, University of Washington38, University of Hawaii at Manoa39, University of Eastern Finland40, Analytical Services41, Columbia University42, Maastricht University43, University of Oulu44, Merck & Co.45, Yeshiva University46, Umeå University47, Leiden University48, St George's, University of London49, University of Sydney50, University of Iceland51
TL;DR: It is estimated that under current treatment guidelines, assessment of the CRP or fibrinogen level in people at intermediate risk for a cardiovascular event could help prevent one additional event over a period of 10 years for every 400 to 500 people screened.
Abstract: Background There is debate about the value of assessing levels of C-reactive protein (CRP) and other biomarkers of inflammation for the prediction of first cardiovascular events. Methods We analyzed data from 52 prospective studies that included 246,669 participants without a history of cardiovascular disease to investigate the value of adding CRP or fibrinogen levels to conventional risk factors for the prediction of cardiovascular risk. We calculated measures of discrimination and reclassification during follow-up and modeled the clinical implications of initiation of statin therapy after the assessment of CRP or fibrinogen. Results The addition of information on high-density lipoprotein cholesterol to a prognostic model for cardiovascular disease that included age, sex, smoking status, blood pressure, history of diabetes, and total cholesterol level increased the C-index, a measure of risk discrimination, by 0.0050. The further addition to this model of information on CRP or fibrinogen increased the C-index by 0.0039 and 0.0027, respectively (P = 20%) (P = 20% and for those with certain other risk factors, such as diabetes, irrespective of their 10-year predicted risk), additional targeted assessment of CRP or fibrinogen levels in the 13,199 remaining participants at intermediate risk could help prevent approximately 30 additional cardiovascular events over the course of 10 years. Conclusions In a study of people without known cardiovascular disease, we estimated that under current treatment guidelines, assessment of the CRP or fibrinogen level in people at intermediate risk for a cardiovascular event could help prevent one additional event over a period of 10 years for every 400 to 500 people screened. (Funded by the British Heart Foundation and others.)
TL;DR: In healthy male blood donors there is important variation in the methylation profiles of whole blood, mononuclear cells, granulocytes, and cells from seven selected purified lineages, indicating that whole blood methylation results might be unintelligible.
Abstract: Methylation of cytosines at CpG sites is a common epigenetic DNA modification that can be measured by a large number of methods, now even in a genome-wide manner for hundreds of thousands of sites. The application of DNA methylation analysis is becoming widely popular in complex disorders, for example, to understand part of the “missing heritability”. The DNA samples most readily available for methylation studies are derived from whole blood. However, blood consists of many functionally and developmentally distinct cell populations in varying proportions. We studied whether such variation might affect the interpretation of methylation studies based on whole blood DNA. We found in healthy male blood donors there is important variation in the methylation profiles of whole blood, mononuclear cells, granulocytes, and cells from seven selected purified lineages. CpG methylation between mononuclear cells and granulocytes differed for 22% of the 8252 probes covering the selected 343 genes implicated in immune-related disorders by genome-wide association studies, and at least one probe was differentially methylated for 85% of the genes, indicating that whole blood methylation results might be unintelligible. For individual genes, even if the overall methylation patterns might appear similar, a few CpG sites in the regulatory regions may have opposite methylation patterns (i.e., hypo/hyper) in the main blood cell types. We conclude that interpretation of whole blood methylation profiles should be performed with great caution and for any differences implicated in a disorder, the differences resulting from varying proportions of white blood cell types should be considered.
TL;DR: Evidence for brain maintenance at different levels is discussed: cellular, neurochemical, gray- and white-matter integrity, and systems-level activation patterns, and it is argued that it constitutes the primary determinant of successful memory aging.
University College London1, University of Cambridge2, University of Cologne3, Leiden University4, Utrecht University5, National Institutes of Health6, University of Pennsylvania7, University of Glasgow8, University of Edinburgh9, Mayo Clinic10, University of London11, University of Bristol12, Cardiff University13, University of Oxford14, University of Ioannina15, University of Hamburg16, Lithuanian University of Health Sciences17, Jagiellonian University18, Russian Academy19, Karolinska Institutet20, Memorial Hospital of South Bend21, University of Groningen22, MedStar Washington Hospital Center23, Swansea University24, Brown University25, University of Iowa26, Harvard University27, University of Exeter28, University of North Carolina at Chapel Hill29, Boston University30, Medical Research Council31, University of California, San Diego32, University of Mississippi33, Fred Hutchinson Cancer Research Center34
TL;DR: IL6R blockade could provide a novel therapeutic approach to prevention of coronary heart disease that warrants testing in suitably powered randomised trials and could help to validate and prioritise novel drug targets or to repurpose existing agents and targets for new therapeutic uses.
TL;DR: The evidence indicates that intravenous rt-PA increased the proportion of patients who were alive with favourable outcome and alive and independent at final follow-up, which strengthens previous evidence to treat patients as early as possible after acute ischaemic stroke, although some patients might benefit up to 6 h after stroke.
Utrecht University1, Imperial College London2, Karolinska Institutet3, Vytautas Magnus University4, Flemish Institute for Technological Research5, University of Hasselt6, National and Kapodistrian University of Athens7, University of California, Berkeley8, University of Basel9, Swiss Tropical and Public Health Institute10, National Institutes of Health11, University of Manchester12, Norwegian Institute of Public Health13, University of Duisburg-Essen14, ARPA-E15, University of Washington16
TL;DR: Careful selection of monitoring sites, examination of influential observations and skewed variable distributions were essential for developing stable LUR models, which are used to estimate air pollution concentrations at the home addresses of participants in the health studies involved in ESCAPE.
Abstract: Land Use Regression (LUR) models have been used increasingly for modeling small-scale spatial variation in air pollution concentrations and estimating individual exposure for participants of cohort studies. Within the ESCAPE project, concentrations of PM(2.5), PM(2.5) absorbance, PM(10), and PM(coarse) were measured in 20 European study areas at 20 sites per area. GIS-derived predictor variables (e.g., traffic intensity, population, and land-use) were evaluated to model spatial variation of annual average concentrations for each study area. The median model explained variance (R(2)) was 71% for PM(2.5) (range across study areas 35-94%). Model R(2) was higher for PM(2.5) absorbance (median 89%, range 56-97%) and lower for PM(coarse) (median 68%, range 32- 81%). Models included between two and five predictor variables, with various traffic indicators as the most common predictors. Lower R(2) was related to small concentration variability or limited availability of predictor variables, especially traffic intensity. Cross validation R(2) results were on average 8-11% lower than model R(2). Careful selection of monitoring sites, examination of influential observations and skewed variable distributions were essential for developing stable LUR models. The final LUR models are used to estimate air pollution concentrations at the home addresses of participants in the health studies involved in ESCAPE.
University of Helsinki1, Finnish Institute of Occupational Health2, University College London3, University of Edinburgh4, Karolinska Institutet5, RMIT University6, Stockholm University7, Federal Institute for Occupational Safety and Health8, Université libre de Bruxelles9, Ghent University10, University of Düsseldorf11, University of Bristol12, French Institute of Health and Medical Research13, Mid Sweden University14, Queen's University Belfast15, Umeå University16, University of Copenhagen17, University of Turku18, Turku University Hospital19, Uppsala University20
TL;DR: The findings suggest that prevention of workplace stress might decrease disease incidence; however, this strategy would have a much smaller effect than would tackling of standard risk factors, such as smoking.
TL;DR: Based on the evidence available for each item of the multimodal perioperative-care pathway, the Enhanced Recovery After Surgery (ERAS) Society, International Association for Surgical Metabolism and Nutrition (IASMEN) and European Society for Clinical Nutrition and Metabolicism (ESPEN) present a comprehensive evidence-based consensus review of peri operative care for colonic surgery.