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Showing papers by "University of London published in 2015"


Journal ArticleDOI
TL;DR: A reporting guideline is described, the Preferred Reporting Items for Systematic reviews and Meta-Analyses for Protocols 2015 (PRISMA-P 2015), which consists of a 17-item checklist intended to facilitate the preparation and reporting of a robust protocol for the systematic review.
Abstract: Systematic reviews should build on a protocol that describes the rationale, hypothesis, and planned methods of the review; few reviews report whether a protocol exists. Detailed, well-described protocols can facilitate the understanding and appraisal of the review methods, as well as the detection of modifications to methods and selective reporting in completed reviews. We describe the development of a reporting guideline, the Preferred Reporting Items for Systematic reviews and Meta-Analyses for Protocols 2015 (PRISMA-P 2015). PRISMA-P consists of a 17-item checklist intended to facilitate the preparation and reporting of a robust protocol for the systematic review. Funders and those commissioning reviews might consider mandating the use of the checklist to facilitate the submission of relevant protocol information in funding applications. Similarly, peer reviewers and editors can use the guidance to gauge the completeness and transparency of a systematic review protocol submitted for publication in a journal or other medium.

14,708 citations


Journal ArticleDOI
02 Jan 2015-BMJ
TL;DR: The PRISMA-P checklist as mentioned in this paper provides 17 items considered to be essential and minimum components of a systematic review or meta-analysis protocol, as well as a model example from an existing published protocol.
Abstract: Protocols of systematic reviews and meta-analyses allow for planning and documentation of review methods, act as a guard against arbitrary decision making during review conduct, enable readers to assess for the presence of selective reporting against completed reviews, and, when made publicly available, reduce duplication of efforts and potentially prompt collaboration. Evidence documenting the existence of selective reporting and excessive duplication of reviews on the same or similar topics is accumulating and many calls have been made in support of the documentation and public availability of review protocols. Several efforts have emerged in recent years to rectify these problems, including development of an international register for prospective reviews (PROSPERO) and launch of the first open access journal dedicated to the exclusive publication of systematic review products, including protocols (BioMed Central's Systematic Reviews). Furthering these efforts and building on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines, an international group of experts has created a guideline to improve the transparency, accuracy, completeness, and frequency of documented systematic review and meta-analysis protocols--PRISMA-P (for protocols) 2015. The PRISMA-P checklist contains 17 items considered to be essential and minimum components of a systematic review or meta-analysis protocol.This PRISMA-P 2015 Explanation and Elaboration paper provides readers with a full understanding of and evidence about the necessity of each item as well as a model example from an existing published protocol. This paper should be read together with the PRISMA-P 2015 statement. Systematic review authors and assessors are strongly encouraged to make use of PRISMA-P when drafting and appraising review protocols.

9,361 citations


Journal ArticleDOI
Mohsen Naghavi1, Haidong Wang1, Rafael Lozano1, Adrian Davis2  +728 moreInstitutions (294)
TL;DR: In the Global Burden of Disease Study 2013 (GBD 2013) as discussed by the authors, the authors used the GBD 2010 methods with some refinements to improve accuracy applied to an updated database of vital registration, survey, and census data.

5,792 citations


Journal ArticleDOI
TL;DR: The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) as discussed by the authors provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution.

5,668 citations


Journal ArticleDOI
Theo Vos1, Ryan M Barber1, Brad Bell1, Amelia Bertozzi-Villa1  +686 moreInstitutions (287)
TL;DR: In the Global Burden of Disease Study 2013 (GBD 2013) as mentioned in this paper, the authors estimated the quantities for acute and chronic diseases and injuries for 188 countries between 1990 and 2013.

4,510 citations


Journal ArticleDOI
TL;DR: This document contains the checklist and explanatory and elaboration information to enhance the use of theRECORD checklist, and examples of good reporting for each RECORD checklist item are also included herein.
Abstract: Routinely collected health data, obtained for administrative and clinical purposes without specific a priori research goals, are increasingly used for research. The rapid evolution and availability of these data have revealed issues not addressed by existing reporting guidelines, such as Strengthening the Reporting of Observational Studies in Epidemiology (STROBE). The REporting of studies Conducted using Observational Routinely collected health Data (RECORD) statement was created to fill these gaps. RECORD was created as an extension to the STROBE statement to address reporting items specific to observational studies using routinely collected health data. RECORD consists of a checklist of 13 items related to the title, abstract, introduction, methods, results, and discussion section of articles, and other information required for inclusion in such research reports. This document contains the checklist and explanatory and elaboration information to enhance the use of the checklist. Examples of good reporting for each RECORD checklist item are also included herein. This document, as well as the accompanying website and message board (http://www.record-statement.org), will enhance the implementation and understanding of RECORD. Through implementation of RECORD, authors, journals editors, and peer reviewers can encourage transparency of research reporting.

2,644 citations


Journal ArticleDOI
TL;DR: The authors' projection results provide concrete examples of how the distribution of child causes of deaths could look in 15-20 years to inform priority setting in the post-2015 era.

2,600 citations


Journal ArticleDOI
TL;DR: The CPRD primary care database is a rich source of health data for research, including data on demographics, symptoms, tests, diagnoses, therapies, health-related behaviours and referrals to secondary care, but researchers must be aware of the complexity of routinely collected electronic health records.
Abstract: The Clinical Practice Research Datalink (CPRD) is an ongoing primary care database of anonymised medical records from general practitioners, with coverage of over 11.3 million patients from 674 practices in the UK. With 4.4 million active (alive, currently registered) patients meeting quality criteria, approximately 6.9% of the UK population are included and patients are broadly representative of the UK general population in terms of age, sex and ethnicity. General practitioners are the gatekeepers of primary care and specialist referrals in the UK. The CPRD primary care database is therefore a rich source of health data for research, including data on demographics, symptoms, tests, diagnoses, therapies, health-related behaviours and referrals to secondary care. For over half of patients, linkage with datasets from secondary care, disease-specific cohorts and mortality records enhance the range of data available for research. The CPRD is very widely used internationally for epidemiological research and has been used to produce over 1000 research studies, published in peer-reviewed journals across a broad range of health outcomes. However, researchers must be aware of the complexity of routinely collected electronic health records, including ways to manage variable completeness, misclassification and development of disease definitions for research.

1,894 citations



Journal ArticleDOI
TL;DR: The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) as mentioned in this paper provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution.

1,656 citations


Journal ArticleDOI
TL;DR: Patterns of the epidemiological transition with a composite indicator of sociodemographic status, which was constructed from income per person, average years of schooling after age 15 years, and the total fertility rate and mean age of the population, were quantified.


Journal ArticleDOI
TL;DR: In this paper, the authors identify three categories of challenges that have to be addressed to maintain and enhance human health in the face of increasingly harmful environmental trends: conceptual and empathy failures (imagination challenges), such as an overreliance on gross domestic product as a measure of human progress, the failure to account for future health and environmental harms over present day gains, and the disproportionate eff ect of those harms on the poor and those in developing nations.

Journal ArticleDOI
Jennifer E. Huffman1, Eva Albrecht, Alexander Teumer2, Massimo Mangino3, Karen Kapur, Toby Johnson4, Z. Kutalik, Nicola Pirastu5, Giorgio Pistis6, Lorna M. Lopez1, Toomas Haller7, Perttu Salo8, Anuj Goel9, Man Li10, Toshiko Tanaka8, Abbas Dehghan11, Daniela Ruggiero, Giovanni Malerba12, Albert V. Smith13, Ilja M. Nolte, Laura Portas, Amanda Phipps-Green14, Lora Boteva1, Pau Navarro1, Åsa Johansson15, Andrew A. Hicks16, Ozren Polasek17, Tõnu Esko18, John F. Peden9, Sarah E. Harris1, Federico Murgia, Sarah H. Wild1, Albert Tenesa1, Adrienne Tin10, Evelin Mihailov7, Anne Grotevendt2, Gauti Kjartan Gislason, Josef Coresh10, Pio D'Adamo5, Sheila Ulivi, Peter Vollenweider19, Gérard Waeber19, Susan Campbell1, Ivana Kolcic17, Krista Fisher7, Margus Viigimaa, Jeffrey Metter8, Corrado Masciullo6, Elisabetta Trabetti12, Cristina Bombieri12, Rossella Sorice, Angela Doering, Eva Reischl, Konstantin Strauch20, Albert Hofman11, André G. Uitterlinden11, Melanie Waldenberger, H-Erich Wichmann20, Gail Davies1, Alan J. Gow1, Nicola Dalbeth21, Lisa K. Stamp14, Johannes H. Smit22, Mirna Kirin1, Ramaiah Nagaraja8, Matthias Nauck2, Claudia Schurmann2, Kathrin Budde2, Susan M. Farrington1, Evropi Theodoratou1, Antti Jula8, Veikko Salomaa8, Cinzia Sala6, Christian Hengstenberg23, Michel Burnier19, R Maegi7, Norman Klopp20, Stefan Kloiber24, Sabine Schipf25, Samuli Ripatti26, Stefano Cabras27, Nicole Soranzo28, Georg Homuth2, Teresa Nutile, Patricia B. Munroe4, Nicholas D. Hastie1, Harry Campbell1, Igor Rudan1, Claudia P. Cabrera29, Chris Haley1, Oscar H. Franco11, Tony R. Merriman14, Vilmundur Gudnason13, Mario Pirastu, Brenda W.J.H. Penninx11, Brenda W.J.H. Penninx30, Harold Snieder, Andres Metspalu7, Marina Ciullo, Peter P. Pramstaller16, Cornelia M. van Duijn11, Luigi Ferrucci8, Giovanni Gambaro31, Ian J. Deary1, Malcolm G. Dunlop1, James F. Wilson1, Paolo Gasparini5, Ulf Gyllensten15, Tim D. Spector3, Alan F. Wright1, Caroline Hayward1, Hugh Watkins9, Markus Perola8, Murielle Bochud32, W. H. Linda Kao10, Mark J. Caulfield4, Daniela Toniolo6, Henry Voelzke25, Christian Gieger, Anna Koettgen33, Veronique Vitart1 
26 Mar 2015-PLOS ONE
TL;DR: Interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, and regression-type analyses in a non BMI-stratified overall sample suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum.
Abstract: We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, Pinter= 2.6 x 10-8). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDARADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10-8), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10-8), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10-4). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.


Journal ArticleDOI
TL;DR: The Panel proposes to identify SAMS by symptoms typical of statin myalgia and their temporal association with discontinuation and response to repetitive statin re-challenge, and recommends the use of a maximally tolerated statin dose combined with non-statin lipid-lowering therapies to attain recommended low-density lipoprotein cholesterol targets.
Abstract: Statin-associated muscle symptoms (SAMS) are one of the principal reasons for statin non-adherence and/or discontinuation, contributing to adverse cardiovascular outcomes. This European Atherosclerosis Society (EAS) Consensus Panel overviews current understanding of the pathophysiology of statin-associated myopathy, and provides guidance for diagnosis and management of SAMS. Statin-associated myopathy, with significant elevation of serum creatine kinase (CK), is a rare but serious side effect of statins, affecting 1 per 1000 to 1 per 10 000 people on standard statin doses. Statin-associated muscle symptoms cover a broader range of clinical presentations, usually with normal or minimally elevated CK levels, with a prevalence of 7–29% in registries and observational studies. Preclinical studies show that statins decrease mitochondrial function, attenuate energy production, and alter muscle protein degradation, thereby providing a potential link between statins and muscle symptoms; controlled mechanistic and genetic studies in humans are necessary to further understanding. The Panel proposes to identify SAMS by symptoms typical of statin myalgia (i.e. muscle pain or aching) and their temporal association with discontinuation and response to repetitive statin re-challenge. In people with SAMS, the Panel recommends the use of a maximally tolerated statin dose combined with non-statin lipid-lowering therapies to attain recommended low-density lipoprotein cholesterol targets. The Panel recommends a structured work-up to identify individuals with clinically relevant SAMS generally to at least three different statins, so that they can be offered therapeutic regimens to satisfactorily address their cardiovascular risk. Further research into the underlying pathophysiological mechanisms may offer future therapeutic potential.

Journal ArticleDOI
TL;DR: The DNA sequence of K. pneumoniae isolates from around the world is determined and it is shown that there is a wide spectrum of diversity, including variation within shared sequences and gain and loss of whole genes, and there is an unrecognized association between the possession of specific gene profiles associated with virulence and antibiotic resistance.
Abstract: Klebsiella pneumoniae is now recognized as an urgent threat to human health because of the emergence of multidrug-resistant strains associated with hospital outbreaks and hypervirulent strains associated with severe community-acquired infections. K. pneumoniae is ubiquitous in the environment and can colonize and infect both plants and animals. However, little is known about the population structure of K. pneumoniae, so it is difficult to recognize or understand the emergence of clinically important clones within this highly genetically diverse species. Here we present a detailed genomic framework for K. pneumoniae based on whole-genome sequencing of more than 300 human and animal isolates spanning four continents. Our data provide genome-wide support for the splitting of K. pneumoniae into three distinct species, KpI (K. pneumoniae), KpII (K. quasipneumoniae), and KpIII (K. variicola). Further, for K. pneumoniae (KpI), the entity most frequently associated with human infection, we show the existence of >150 deeply branching lineages including numerous multidrug-resistant or hypervirulent clones. We show K. pneumoniae has a large accessory genome approaching 30,000 protein-coding genes, including a number of virulence functions that are significantly associated with invasive community-acquired disease in humans. In our dataset, antimicrobial resistance genes were common among human carriage isolates and hospital-acquired infections, which generally lacked the genes associated with invasive disease. The convergence of virulence and resistance genes potentially could lead to the emergence of untreatable invasive K. pneumoniae infections; our data provide the whole-genome framework against which to track the emergence of such threats.

Journal ArticleDOI
TL;DR: Heart failure and peripheral arterial disease are the most common initial manifestations of cardiovascular disease in type 2 diabetes, and the differences between relative risks of different cardiovascular diseases in patients withtype 2 diabetes have implications for clinical risk assessment and trial design.

Journal ArticleDOI
14 Aug 2015-Vaccine
TL;DR: Overall, the results showed that multicomponent and dialogue-based interventions were most effective and identified strategies should be carefully tailored according to the target population, their reasons for hesitancy, and the specific context.

Journal ArticleDOI
TL;DR: The results of this interim analysis indicate that rVSV-ZEBOV might be highly efficacious and safe in preventing Ebola virus disease, and is most likely effective at the population level when delivered during an Ebola virus Disease outbreak via a ring vaccination strategy.

Journal ArticleDOI
TL;DR: Azithromycin is effective for the management of uncomplicated typhoid fever and may serve as an alternative oral drug in areas where fluoroquinolone resistance is common and ciprofloxacin susceptibility breakpoints were lowered to account for accumulating clinical, microbiologic, and pharmacokinetic-pharmacodynamic data.
Abstract: Salmonella enterica infections are common causes of bloodstream infection in low-resource areas, where they may be difficult to distinguish from other febrile illnesses and may be associated with a high case fatality ratio. Microbiologic culture of blood or bone marrow remains the mainstay of laboratory diagnosis. Antimicrobial resistance has emerged in Salmonella enterica, initially to the traditional first-line drugs chloramphenicol, ampicillin, and trimethoprim-sulfamethoxazole. Decreased fluoroquinolone susceptibility and then fluoroquinolone resistance have developed in association with chromosomal mutations in the quinolone resistance-determining region of genes encoding DNA gyrase and topoisomerase IV and also by plasmid-mediated resistance mechanisms. Resistance to extended-spectrum cephalosporins has occurred more often in nontyphoidal than in typhoidal Salmonella strains. Azithromycin is effective for the management of uncomplicated typhoid fever and may serve as an alternative oral drug in areas where fluoroquinolone resistance is common. In 2013, CLSI lowered the ciprofloxacin susceptibility breakpoints to account for accumulating clinical, microbiologic, and pharmacokinetic-pharmacodynamic data suggesting that revision was needed for contemporary invasive Salmonella infections. Newly established CLSI guidelines for azithromycin and Salmonella enterica serovar Typhi were published in CLSI document M100 in 2015.

Journal ArticleDOI
TL;DR: Gaining more insights and knowledge into this complex network of host‐pathogen interaction will identify novel target sites of intervention to successfully clear infection at a time of rapidly emerging multi‐resistance of M. tuberculosis against conventional antibiotics.
Abstract: Macrophages and neutrophils play a decisive role in host responses to intracellular bacteria including the agent of tuberculosis (TB), Mycobacterium tuberculosis as they represent the forefront of innate immune defense against bacterial invaders. At the same time, these phagocytes are also primary targets of intracellular bacteria to be abused as host cells. Their efficacy to contain and eliminate intracellular M. tuberculosis decides whether a patient initially becomes infected or not. However, when the infection becomes chronic or even latent (as in the case of TB) despite development of specific immune activation, phagocytes have also important effector functions. Macrophages have evolved a myriad of defense strategies to combat infection with intracellular bacteria such as M. tuberculosis. These include induction of toxic anti-microbial effectors such as nitric oxide and reactive oxygen intermediates, the stimulation of microbe intoxication mechanisms via acidification or metal accumulation in the phagolysosome, the restriction of the microbe's access to essential nutrients such as iron, fatty acids, or amino acids, the production of anti-microbial peptides and cytokines, along with induction of autophagy and efferocytosis to eliminate the pathogen. On the other hand, M. tuberculosis, as a prime example of a well-adapted facultative intracellular bacterium, has learned during evolution to counter-balance the host's immune defense strategies to secure survival or multiplication within this otherwise hostile environment. This review provides an overview of innate immune defense of macrophages directed against intracellular bacteria with a focus on M. tuberculosis. Gaining more insights and knowledge into this complex network of host-pathogen interaction will identify novel target sites of intervention to successfully clear infection at a time of rapidly emerging multi-resistance of M. tuberculosis against conventional antibiotics.

Journal ArticleDOI
TL;DR: Among patients at high risk for bleeding who underwent PCI, a polymer-free umirolimus-coated stent was superior to a bare-metal stent with respect to the primary safety and efficacy end points when used with a 1-month course of dual antiplatelet therapy.
Abstract: BACKGROUND Patients at high risk for bleeding who undergo percutaneous coronary intervention (PCI) often receive bare-metal stents followed by 1 month of dual antiplatelet therapy. We studied a polymer-free and carrier-free drug-coated stent that transfers umirolimus (also known as biolimus A9), a highly lipophilic sirolimus analogue, into the vessel wall over a period of 1 month. METHODS In a randomized, double-blind trial, we compared the drug-coated stent with a very similar bare-metal stent in patients with a high risk of bleeding who underwent PCI. All patients received 1 month of dual antiplatelet therapy. The primary safety end point, tested for both noninferiority and superiority, was a composite of cardiac death, myocardial infarction, or stent thrombosis. The primary efficacy end point was clinically driven target-lesion revascularization. RESULTS We enrolled 2466 patients. At 390 days, the primary safety end point had occurred in 112 patients (9.4%) in the drug-coated–stent group and in 154 patients (12.9%) in the bare-metal–stent group (risk difference, −3.6 percentage points; 95% confi dence interval [CI], −6.1 to −1.0; hazard ratio, 0.71; 95% CI, 0.56 to 0.91; P<0.001 for noninferiority and P = 0.005 for superiority). During the same time period, clinically driven target-lesion revascularization was needed in 59 patients (5.1%) in the drug-coated–stent group and in 113 patients (9.8%) in the bare-metal–stent group (risk difference, −4.8 percentage points; 95% CI, −6.9 to −2.6; hazard ratio, 0.50; 95% CI, 0.37 to 0.69; P<0.001). CONCLUSIONS Among patients at high risk for bleeding who underwent PCI, a polymer-free umirolimus-coated stent was superior to a bare-metal stent with respect to the primary safety and efficacy end points when used with a 1-month course of dual antiplatelet therapy. (Funded by Biosensors Europe; LEADERS FREE ClinicalTrials .gov number, NCT01623180.)

Journal ArticleDOI
Colm O'Dushlaine1, Lizzy Rossin1, Phil Lee2, Laramie E. Duncan2  +401 moreInstitutions (115)
TL;DR: It is indicated that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders.
Abstract: Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders.

Journal ArticleDOI
TL;DR: Remote ischemic preconditioning did not improve clinical outcomes in patients undergoing elective on-pump CABG with or without valve surgery and there were no significant between-group differences in either adverse events or the secondary end points of perioperative myocardial injury.
Abstract: BackgroundWhether remote ischemic preconditioning (transient ischemia and reperfusion of the arm) can improve clinical outcomes in patients undergoing coronary-artery bypass graft (CABG) surgery is not known. We investigated this question in a randomized trial. MethodsWe conducted a multicenter, sham-controlled trial involving adults at increased surgical risk who were undergoing on-pump CABG (with or without valve surgery) with blood cardioplegia. After anesthesia induction and before surgical incision, patients were randomly assigned to remote ischemic preconditioning (four 5-minute inflations and deflations of a standard blood-pressure cuff on the upper arm) or sham conditioning (control group). Anesthetic management and perioperative care were not standardized. The combined primary end point was death from cardiovascular causes, nonfatal myocardial infarction, coronary revascularization, or stroke, assessed 12 months after randomization. ResultsWe enrolled a total of 1612 patients (811 in the control ...

Journal ArticleDOI
TL;DR: It is demonstrated that triglyceride-related pathways have a causal effect on the risk of coronary heart disease independent of the effects of low-density lipoprotein cholesterol and high-density lipid fractions.
Abstract: A conventional Mendelian randomization analysis assesses the causal effect of a risk factor on an outcome by using genetic variants that are solely associated with the risk factor of interest as instrumental variables. However, in some cases, such as the case of triglyceride level as a risk factor for cardiovascular disease, it may be difficult to find a relevant genetic variant that is not also associated with related risk factors, such as other lipid fractions. Such a variant is known as pleiotropic. In this paper, we propose an extension of Mendelian randomization that uses multiple genetic variants associated with several measured risk factors to simultaneously estimate the causal effect of each of the risk factors on the outcome. This “multivariable Mendelian randomization” approach is similar to the simultaneous assessment of several treatments in a factorial randomized trial. In this paper, methods for estimating the causal effects are presented and compared using real and simulated data, and the assumptions necessary for a valid multivariable Mendelian randomization analysis are discussed. Subject to these assumptions, we demonstrate that triglyceride-related pathways have a causal effect on the risk of coronary heart disease independent of the effects of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol.

Journal ArticleDOI
TL;DR: The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.
Abstract: AIMS: To investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization. METHODS AND RESULTS: We developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a prior meta-analysis (threshold P < 2 × 10(-6)); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P ≤ 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestricted allele score (48 SNPs) was associated with CHD (OR: 0.53; 95% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95% CI: 1.24, 2.11 and 1.61; 95% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95% CI: 0.59, 1.75). CONCLUSION: The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.

Journal ArticleDOI
TL;DR: In this article, the authors reviewed evidence for interventions to reduce the prevalence and incidence of violence against women and girls, and found that women-centred, advocacy, and home-visitation programs can reduce a woman's risk of further victimisation, with less conclusive evidence for the preventive effect of programmes for perpetrators.

Journal ArticleDOI
Emanuele Di Angelantonio1, Stephen Kaptoge1, David Wormser1, Peter Willeit1, Adam S. Butterworth1, Narinder Bansal1, Linda M. O’Keeffe1, Pei Gao1, Angela M. Wood1, Stephen Burgess1, Daniel F. Freitag1, Lisa Pennells1, Sanne A.E. Peters2, Carole L. Hart3, Lise Lund Håheim4, Richard F. Gillum5, Børge G. Nordestgaard6, Bruce M. Psaty7, Bu B. Yeap8, Matthew Knuiman8, Paul J. Nietert9, Jussi Kauhanen10, Jukka T. Salonen11, Lewis H. Kuller12, Leon A. Simons13, Yvonne T. van der Schouw2, Elizabeth Barrett-Connor14, Randi Selmer15, Carlos J. Crespo16, Beatriz L. Rodriguez17, W. M. Monique Verschuren, Veikko Salomaa18, Kurt Svärdsudd19, Pim van der Harst20, Cecilia Björkelund21, Lars Wilhelmsen21, Robert B. Wallace22, Hermann Brenner23, Philippe Amouyel24, Elizabeth L M Barr25, Hiroyasu Iso26, Altan Onat27, Maurizio Trevisan28, Ralph B. D'Agostino29, Cyrus Cooper30, Cyrus Cooper31, Maryam Kavousi32, Lennart Welin, Ronan Roussel33, Ronan Roussel34, Frank B. Hu35, Shinichi Sato, Karina W. Davidson36, Barbara V. Howard37, Maarten J.G. Leening32, Annika Rosengren21, Marcus Dörr38, Dorly J. H. Deeg39, Stefan Kiechl, Coen D.A. Stehouwer40, Aulikki Nissinen18, Simona Giampaoli41, Chiara Donfrancesco41, Daan Kromhout42, Jackie F. Price43, Annette Peters, Tom W. Meade44, Edoardo Casiglia45, Debbie A Lawlor46, John Gallacher47, Dorothea Nagel48, Oscar H. Franco32, Gerd Assmann, Gilles R. Dagenais, J. Wouter Jukema49, Johan Sundström19, Mark Woodward50, Eric J. Brunner51, Kay-Tee Khaw1, Nicholas J. Wareham52, Eric A. Whitsel53, Inger Njølstad54, Bo Hedblad55, Sylvia Wassertheil-Smoller56, Gunnar Engström55, Wayne D. Rosamond53, Elizabeth Selvin57, Naveed Sattar3, Simon G. Thompson1, John Danesh1 
University of Cambridge1, Utrecht University2, University of Glasgow3, University of Oslo4, Howard University5, Copenhagen University Hospital6, University of Washington7, University of Western Australia8, Medical University of South Carolina9, University of Eastern Finland10, Analytical Services11, University of Pittsburgh12, University of New South Wales13, University of California, San Diego14, Norwegian Institute of Public Health15, Portland State University16, University of Hawaii17, National Institutes of Health18, Uppsala University19, University Medical Center Groningen20, University of Gothenburg21, University of Iowa22, German Cancer Research Center23, Pasteur Institute24, Baker IDI Heart and Diabetes Institute25, Osaka University26, Istanbul University27, City College of New York28, Boston University29, University of Oxford30, University of Southampton31, Erasmus University Rotterdam32, Paris Diderot University33, French Institute of Health and Medical Research34, Harvard University35, Columbia University Medical Center36, MedStar Health37, Greifswald University Hospital38, VU University Amsterdam39, Maastricht University Medical Centre40, Istituto Superiore di Sanità41, Wageningen University and Research Centre42, University of Edinburgh43, University of London44, University of Padua45, University of Bristol46, Cardiff University47, Ludwig Maximilian University of Munich48, Leiden University Medical Center49, University of Sydney50, University College London51, Medical Research Council52, University of North Carolina at Chapel Hill53, University of Tromsø54, Lund University55, Albert Einstein College of Medicine56, Johns Hopkins University57
07 Jul 2015-JAMA
TL;DR: Because any combination of these conditions was associated with multiplicative mortality risk, life expectancy was substantially lower in people with multimorbidity.
Abstract: IMPORTANCE: The prevalence of cardiometabolic multimorbidity is increasing. OBJECTIVE: To estimate reductions in life expectancy associated with cardiometabolic multimorbidity. DESIGN, SETTING, AND PARTICIPANTS: Age- and sex-adjusted mortality rates and hazard ratios (HRs) were calculated using individual participant data from the Emerging Risk Factors Collaboration (689,300 participants; 91 cohorts; years of baseline surveys: 1960-2007; latest mortality follow-up: April 2013; 128,843 deaths). The HRs from the Emerging Risk Factors Collaboration were compared with those from the UK Biobank (499,808 participants; years of baseline surveys: 2006-2010; latest mortality follow-up: November 2013; 7995 deaths). Cumulative survival was estimated by applying calculated age-specific HRs for mortality to contemporary US age-specific death rates. EXPOSURES: A history of 2 or more of the following: diabetes mellitus, stroke, myocardial infarction (MI). MAIN OUTCOMES AND MEASURES: All-cause mortality and estimated reductions in life expectancy. RESULTS: In participants in the Emerging Risk Factors Collaboration without a history of diabetes, stroke, or MI at baseline (reference group), the all-cause mortality rate adjusted to the age of 60 years was 6.8 per 1000 person-years. Mortality rates per 1000 person-years were 15.6 in participants with a history of diabetes, 16.1 in those with stroke, 16.8 in those with MI, 32.0 in those with both diabetes and MI, 32.5 in those with both diabetes and stroke, 32.8 in those with both stroke and MI, and 59.5 in those with diabetes, stroke, and MI. Compared with the reference group, the HRs for all-cause mortality were 1.9 (95% CI, 1.8-2.0) in participants with a history of diabetes, 2.1 (95% CI, 2.0-2.2) in those with stroke, 2.0 (95% CI, 1.9-2.2) in those with MI, 3.7 (95% CI, 3.3-4.1) in those with both diabetes and MI, 3.8 (95% CI, 3.5-4.2) in those with both diabetes and stroke, 3.5 (95% CI, 3.1-4.0) in those with both stroke and MI, and 6.9 (95% CI, 5.7-8.3) in those with diabetes, stroke, and MI. The HRs from the Emerging Risk Factors Collaboration were similar to those from the more recently recruited UK Biobank. The HRs were little changed after further adjustment for markers of established intermediate pathways (eg, levels of lipids and blood pressure) and lifestyle factors (eg, smoking, diet). At the age of 60 years, a history of any 2 of these conditions was associated with 12 years of reduced life expectancy and a history of all 3 of these conditions was associated with 15 years of reduced life expectancy. CONCLUSIONS AND RELEVANCE: Mortality associated with a history of diabetes, stroke, or MI was similar for each condition. Because any combination of these conditions was associated with multiplicative mortality risk, life expectancy was substantially lower in people with multimorbidity.

Journal ArticleDOI
TL;DR: Boys were less sedentary and more active than girls at all ages, and overweight/obese participants were less active than their normal weight counterparts from age seven onwards.
Abstract: Physical activity and sedentary behaviour in youth have been reported to vary by sex, age, weight status and country. However, supporting data are often self-reported and/or do not encompass a wide range of ages or geographical locations. This study aimed to describe objectively-measured physical activity and sedentary time patterns in youth. The International Children’s Accelerometry Database (ICAD) consists of ActiGraph accelerometer data from 20 studies in ten countries, processed using common data reduction procedures. Analyses were conducted on 27,637 participants (2.8–18.4 years) who provided at least three days of valid accelerometer data. Linear regression was used to examine associations between age, sex, weight status, country and physical activity outcomes. Boys were less sedentary and more active than girls at all ages. After 5 years of age there was an average cross-sectional decrease of 4.2 % in total physical activity with each additional year of age, due mainly to lower levels of light-intensity physical activity and greater time spent sedentary. Physical activity did not differ by weight status in the youngest children, but from age seven onwards, overweight/obese participants were less active than their normal weight counterparts. Physical activity varied between samples from different countries, with a 15–20 % difference between the highest and lowest countries at age 9–10 and a 26–28 % difference at age 12–13. Physical activity differed between samples from different countries, but the associations between demographic characteristics and physical activity were consistently observed. Further research is needed to explore environmental and sociocultural explanations for these differences.