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Showing papers by "University of Leicester published in 2015"


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
Majid Nikpay1, Anuj Goel2, Won H-H.3, Leanne M. Hall4  +164 moreInstitutions (60)
TL;DR: This article conducted a meta-analysis of coronary artery disease (CAD) cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 millions low-frequency (0.005 < MAF < 0.5) variants.
Abstract: Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of ∼185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.

1,839 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.

1,609 citations


Journal ArticleDOI
01 Oct 2015-Nature
TL;DR: In extensively phenotyped cohorts, insights from sequencing whole genomes or exomes of nearly 10,000 individuals from population-based and disease collections are described and population structure and functional annotation of rare and low-frequency variants are described.
Abstract: The contribution of rare and low-frequency variants to human traits is largely unexplored. Here we describe insights from sequencing whole genomes (low read depth, 7×) or exomes (high read depth, 80×) of nearly 10,000 individuals from population-based and disease collections. In extensively phenotyped cohorts we characterize over 24 million novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with levels of triglycerides (APOB), adiponectin (ADIPOQ) and low-density lipoprotein cholesterol (LDLR and RGAG1) from single-marker and rare variant aggregation tests. We describe population structure and functional annotation of rare and low-frequency variants, use the data to estimate the benefits of sequencing for association studies, and summarize lessons from disease-specific collections. Finally, we make available an extensive resource, including individual-level genetic and phenotypic data and web-based tools to facilitate the exploration of association results.

948 citations


Journal ArticleDOI
TL;DR: In this paper, a review examines current understanding of the processes regulating tropospheric ozone at global to local scales from both measurements and models and takes the view that knowledge across the scales is important for dealing with air quality and climate change in a synergistic manner.
Abstract: Ozone holds a certain fascination in atmospheric science. It is ubiquitous in the atmosphere, central to tropospheric oxidation chemistry, yet harmful to human and ecosystem health as well as being an important greenhouse gas. It is not emitted into the atmosphere but is a by-product of the very oxidation chemistry it largely initiates. Much effort is focussed on the reduction of surface levels of ozone owing to its health impacts but recent efforts to achieve reductions in exposure at a country scale have proved difficult to achieve due to increases in background ozone at the zonal hemispheric scale. There is also a growing realisation that the role of ozone as a short-lived climate pollutant could be important in integrated air quality climate-change mitigation. This review examines current understanding of the processes regulating tropospheric ozone at global to local scales from both measurements and models. It takes the view that knowledge across the scales is important for dealing with air quality and climate change in a synergistic manner.

877 citations


Journal ArticleDOI
TL;DR: The data suggest that the risk for MetS is similarly elevated in the diagnostic subgroups of severe mental illness, and routine screening and multidisciplinary management of medical and behavioral conditions is needed in these patients.

815 citations


Journal ArticleDOI
TL;DR: The ability to provide lifesaving treatments for AKI provides a compelling argument to consider therapy forAKI as much of a basic right as it is to give antiretroviral drugs to treat HIV in low-resource regions, especially because care needs only be given for a Published Online March 13, 2015 http://dx.doi.org/10.1016/ S0140-6736(15)60126-X

738 citations


Journal ArticleDOI
Damian Smedley1, Syed Haider2, Steffen Durinck3, Luca Pandini4, Paolo Provero4, Paolo Provero5, James E. Allen6, Olivier Arnaiz7, Mohammad Awedh8, Richard Baldock9, Giulia Barbiera4, Philippe Bardou10, Tim Beck11, Andrew Blake, Merideth Bonierbale12, Anthony J. Brookes11, Gabriele Bucci4, Iwan Buetti4, Sarah W. Burge6, Cédric Cabau10, Joseph W. Carlson13, Claude Chelala14, Charalambos Chrysostomou11, Davide Cittaro4, Olivier Collin15, Raul Cordova12, Rosalind J. Cutts14, Erik Dassi16, Alex Di Genova17, Anis Djari10, Anthony Esposito18, Heather Estrella18, Eduardo Eyras19, Eduardo Eyras20, Julio Fernandez-Banet18, Simon A. Forbes1, Robert C. Free11, Takatomo Fujisawa, Emanuela Gadaleta14, Jose Manuel Garcia-Manteiga4, David Goodstein13, Kristian Gray6, José Afonso Guerra-Assunção14, Bernard Haggarty9, Dong Jin Han21, Byung Woo Han21, Todd W. Harris22, Jayson Harshbarger, Robert K. Hastings11, Richard D. Hayes13, Claire Hoede10, Shen Hu23, Zhi-Liang Hu24, Lucie N. Hutchins, Zhengyan Kan18, Hideya Kawaji, Aminah Keliet10, Arnaud Kerhornou6, Sunghoon Kim21, Rhoda Kinsella6, Christophe Klopp10, Lei Kong25, Daniel Lawson6, Dejan Lazarevic4, Ji Hyun Lee21, Thomas Letellier10, Chuan-Yun Li25, Pietro Liò26, Chu Jun Liu25, Jie Luo6, Alejandro Maass17, Jérôme Mariette10, Thomas Maurel6, Stefania Merella4, Azza M. Mohamed8, François Moreews10, Ibounyamine Nabihoudine10, Nelson Ndegwa27, Céline Noirot10, Cristian Perez-Llamas19, Michael Primig28, Alessandro Quattrone16, Hadi Quesneville10, Davide Rambaldi4, James M. Reecy24, Michela Riba4, Steven Rosanoff6, Amna A. Saddiq8, Elisa Salas12, Olivier Sallou15, Rebecca Shepherd1, Reinhard Simon12, Linda Sperling7, William Spooner29, Daniel M. Staines6, Delphine Steinbach10, Kevin R. Stone, Elia Stupka4, Jon W. Teague1, Abu Z. Dayem Ullah14, Jun Wang25, Doreen Ware29, Marie Wong-Erasmus, Ken Youens-Clark29, Amonida Zadissa6, Shi Jian Zhang25, Arek Kasprzyk4, Arek Kasprzyk8 
TL;DR: The latest version of the BioMart Community Portal comes with many new databases that have been created by the ever-growing community and comes with better support and extensibility for data analysis and visualization tools.
Abstract: The BioMart Community Portal (www.biomart.org) is a community-driven effort to provide a unified interface to biomedical databases that are distributed worldwide. The portal provides access to numerous database projects supported by 30 scientific organizations. It includes over 800 different biological datasets spanning genomics, proteomics, model organisms, cancer data, ontology information and more. All resources available through the portal are independently administered and funded by their host organizations. The BioMart data federation technology provides a unified interface to all the available data. The latest version of the portal comes with many new databases that have been created by our ever-growing community. It also comes with better support and extensibility for data analysis and visualization tools. A new addition to our toolbox, the enrichment analysis tool is now accessible through graphical and web service interface. The BioMart community portal averages over one million requests per day. Building on this level of service and the wealth of information that has become available, the BioMart Community Portal has introduced a new, more scalable and cheaper alternative to the large data stores maintained by specialized organizations.

Journal ArticleDOI
18 Aug 2015-JAMA
TL;DR: This randomized, double-blind, placebo-controlled, parallel-group trial with 12-week observational off-drug follow-up period to investigate efficacy and safety of liraglutide vs placebo for weight management in adults with overweight or obesity and type 2 diabetes.
Abstract: Importance Weight loss of 5% to 10% can improve type 2 diabetes and related comorbidities. Few safe, effective weight-management drugs are currently available. Objective To investigate efficacy and safety of liraglutide vs placebo for weight management in adults with overweight or obesity and type 2 diabetes. Design, Setting, and Participants Fifty-six–week randomized (2:1:1), double-blind, placebo-controlled, parallel-group trial with 12-week observational off-drug follow-up period. The study was conducted at 126 sites in 9 countries between June 2011 and January 2013. Of 1361 participants assessed for eligibility, 846 were randomized. Inclusion criteria were body mass index of 27.0 or greater, age 18 years or older, taking 0 to 3 oral hypoglycemic agents (metformin, thiazolidinedione, sulfonylurea) with stable body weight, and glycated hemoglobin level 7.0% to 10.0%. Interventions Once-daily, subcutaneous liraglutide (3.0 mg) (n = 423), liraglutide (1.8 mg) (n = 211), or placebo (n = 212), all as adjunct to 500 kcal/d dietary deficit and increased physical activity (≥150 min/wk). Main Outcomes and Measures Three coprimary end points: relative change in weight, proportion of participants losing 5% or more, or more than 10%, of baseline weight at week 56. Results Baseline weight was 105.7 kg with liraglutide (3.0-mg dose), 105.8 kg with liraglutide (1.8-mg dose), and 106.5 kg with placebo. Weight loss was 6.0% (6.4 kg) with liraglutide (3.0-mg dose), 4.7% (5.0 kg) with liraglutide (1.8-mg dose), and 2.0% (2.2 kg) with placebo (estimated difference for liraglutide [3.0 mg] vs placebo, −4.00% [95% CI, −5.10% to −2.90%]; liraglutide [1.8 mg] vs placebo, −2.71% [95% CI, −4.00% to −1.42%]; P P P P = .006). More gastrointestinal disorders were reported with liraglutide (3.0 mg) vs liraglutide (1.8 mg) and placebo. No pancreatitis was reported. Conclusions and Relevance Among overweight and obese participants with type 2 diabetes, use of subcutaneous liraglutide (3.0 mg) daily, compared with placebo, resulted in weight loss over 56 weeks. Further studies are needed to evaluate longer-term efficacy and safety. Trial Registration clinicaltrials.gov Identifier:NCT01272232


Journal ArticleDOI
TL;DR: The M−σ relation as mentioned in this paper signals a global change in the nature of active galactic nuclei feedback, which is confined to the immediate vicinity of a supermassive black hole and can drive away much of the bulge gas as a fast molecular outflow.
Abstract: Active galactic nuclei (AGNs) represent the growth phases of the supermassive black holes in the center of almost every galaxy. Powerful, highly ionized winds, with velocities ∼0.1–0.2c, are a common feature in X-ray spectra of luminous AGNs, offering a plausible physical origin for the well-known connections between the hole and properties of its host. Observability constraints suggest that the winds must be episodic and detectable only for a few percent of their lifetimes. The most powerful wind feedback, establishing the M−σ relation, is probably not directly observable at all. The M−σ relation signals a global change in the nature of AGN feedback. At black hole masses below M−σ, feedback is confined to the immediate vicinity of the hole. At the M−σ mass, it becomes much more energetic and widespread and can drive away much of the bulge gas as a fast molecular outflow.

Journal ArticleDOI
TL;DR: It is concluded that although informal theory is always at work in improvement, practitioners are often not aware of it or do not make it explicit, and the germane issue for improvement practitioners is whether they make explicit the particular theory or theories, informal and formal, they actually use.
Abstract: The role and value of theory in improvement work in healthcare has been seriously underrecognised. We join others in proposing that more informed use of theory can strengthen improvement programmes and facilitate the evaluation of their effectiveness. Many professionals, including improvement practitioners, are unfortunately mystified—and alienated—by theory, which discourages them from using it in their work. In an effort to demystify theory we make the point in this paper that, far from being discretionary or superfluous, theory (‘reason-giving’), both informal and formal, is intimately woven into virtually all human endeavour. We explore the special characteristics of grand, mid-range and programme theory; consider the consequences of misusing theory or failing to use it; review the process of developing and applying programme theory; examine some emerging criteria of ‘good’ theory; and emphasise the value, as well as the challenge, of combining informal experience-based theory with formal, publicly developed theory. We conclude that although informal theory is always at work in improvement, practitioners are often not aware of it or do not make it explicit. The germane issue for improvement practitioners, therefore, is not whether they use theory but whether they make explicit the particular theory or theories, informal and formal, they actually use.

Journal ArticleDOI
TL;DR: Angiotensin-neprilysin inhibition prevents the clinical progression of surviving patients with heart failure more effectively than angiotens in-converting enzyme inhibition.
Abstract: Background—Clinical trials in heart failure have focused on the improvement in symptoms or decreases in the risk of death and other cardiovascular events. Little is known about the effect of drugs ...

Journal ArticleDOI
Ron Do1, Ron Do2, Nathan O. Stitziel3, Hong-Hee Won2, Hong-Hee Won1, Anders Berg Jørgensen4, Stefano Duga5, Pier Angelica Merlini, Adam Kiezun1, Martin Farrall6, Anuj Goel6, Or Zuk1, Illaria Guella5, Rosanna Asselta5, Leslie A. Lange7, Gina M. Peloso1, Gina M. Peloso2, Paul L. Auer8, Domenico Girelli9, Nicola Martinelli9, Deborah N. Farlow1, Mark A. DePristo1, Robert Roberts10, Alex Stewart10, Danish Saleheen11, John Danesh11, Stephen E. Epstein12, Suthesh Sivapalaratnam13, G. Kees Hovingh13, John J.P. Kastelein13, Nilesh J. Samani14, Heribert Schunkert15, Jeanette Erdmann16, Svati H. Shah17, William E. Kraus17, Robert W. Davies10, Majid Nikpay10, Christopher T. Johansen18, Jian Wang18, Robert A. Hegele18, Eliana Hechter1, Winfried März19, Winfried März20, Winfried März21, Marcus E. Kleber21, Jie Huang, Andrew D. Johnson22, Mingyao Li23, Greg L. Burke24, Myron D. Gross25, Yongmei Liu26, Themistocles L. Assimes27, Gerardo Heiss7, Ethan M. Lange7, Aaron R. Folsom25, Herman A. Taylor28, Oliviero Olivieri9, Anders Hamsten29, Robert Clarke6, Dermot F. Reilly30, Wu Yin30, Manuel A. Rivas6, Peter Donnelly6, Jacques E. Rossouw22, Bruce M. Psaty31, Bruce M. Psaty32, David M. Herrington26, James G. Wilson28, Stephen S. Rich33, Michael J. Bamshad31, Russell P. Tracy34, L. Adrienne Cupples35, Daniel J. Rader23, Muredach P. Reilly23, John A. Spertus36, Sharon Cresci3, Jaana Hartiala37, W.H. Wilson Tang38, Stanley L. Hazen38, Hooman Allayee37, Alexander P. Reiner31, Alexander P. Reiner8, Christopher S. Carlson8, Charles Kooperberg8, Rebecca D. Jackson39, Eric Boerwinkle40, Eric S. Lander1, Stephen M. Schwartz8, Stephen M. Schwartz31, David S. Siscovick31, Ruth McPherson10, Anne Tybjærg-Hansen4, Gonçalo R. Abecasis41, Hugh Watkins6, Deborah A. Nickerson31, Diego Ardissino, Shamil R. Sunyaev2, Shamil R. Sunyaev1, Christopher J. O'Donnell, David Altshuler1, David Altshuler2, Stacey Gabriel1, Sekar Kathiresan1, Sekar Kathiresan2 
05 Feb 2015-Nature
TL;DR: Kathiresan et al. as mentioned in this paper used exome sequencing of nearly 10,000 people to identify alleles associated with early-onset myocardial infarction; mutations in low-density lipoprotein receptor (LDLR) or apolipoprotein A-V (APOA5) were associated with disease risk.
Abstract: Exome sequence analysis of nearly 10,000 people was carried out to identify alleles associated with early-onset myocardial infarction; mutations in low-density lipoprotein receptor (LDLR) or apolipoprotein A-V (APOA5) were associated with disease risk, identifying the key roles of low-density lipoprotein cholesterol and metabolism of triglyceride-rich lipoproteins. Sekar Kathiresan and colleagues use exome sequencing of nearly 10,000 people to probe the contribution of multiple rare mutations within a gene to risk for myocardial infarction at a population level. They find that mutations in low-density lipoprotein receptor (LDLR) or apolipoprotein A-V (APOA5) are associated with disease risk. When compared with non-carriers, LDLR mutation carriers had higher plasma levels of LDL cholesterol, whereas APOA5 mutation carriers had higher plasma levels of triglycerides. As well as confirming that APOA5 is a myocardial infarction gene, this work informs the design and conduct of rare-variant association studies for complex diseases. Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance1,2. When MI occurs early in life, genetic inheritance is a major component to risk1. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families3,4,5,6,7,8, whereas common variants at more than 45 loci have been associated with MI risk in the population9,10,11,12,13,14,15. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol16. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl−1. At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase15,17 and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.

Journal ArticleDOI
TL;DR: The amount of carbon stored in peats exceeds that stored in vegetation and is similar in size to the current atmospheric carbon pool as mentioned in this paper, which is a threat to many peat-rich biomes and has the potential to disturb these carbon stocks.
Abstract: The amount of carbon stored in peats exceeds that stored in vegetation A synthesis of the literature suggests that smouldering fires in peatlands could become more common as the climate warms, and release old carbon to the air Globally, the amount of carbon stored in peats exceeds that stored in vegetation and is similar in size to the current atmospheric carbon pool Fire is a threat to many peat-rich biomes and has the potential to disturb these carbon stocks Peat fires are dominated by smouldering combustion, which is ignited more readily than flaming combustion and can persist in wet conditions In undisturbed peatlands, most of the peat carbon stock typically is protected from smouldering, and resistance to fire has led to a build-up of peat carbon storage in boreal and tropical regions over long timescales But drying as a result of climate change and human activity lowers the water table in peatlands and increases the frequency and extent of peat fires The combustion of deep peat affects older soil carbon that has not been part of the active carbon cycle for centuries to millennia, and thus will dictate the importance of peat fire emissions to the carbon cycle and feedbacks to the climate

Journal ArticleDOI
TL;DR: Differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index and the transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models.
Abstract: Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the 'transcriptomic age' of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts.

Journal ArticleDOI
TL;DR: In this article, the boundary of the Anthropocene geological time interval as an epoch is defined as the time of the first nuclear bomb explosion, on July 16th 1945 at Alamogordo, New Mexico; additional bombs were detonated at the average rate of one every 9.6 days until 1988 with attendant worldwide fallout easily identifiable in the chemostratigraphic record.

Journal ArticleDOI
TL;DR: This work proposes an alternative approach to be used when only summary genetic data are available or data on gene‐phenotype and gene‐outcome come from different subjects, and investigates the presence of pleiotropy in the between‐instrument heterogeneity Q test in a meta‐analysis of MR Wald estimates.
Abstract: Mendelian randomisation (MR) estimates causal effects of modifiable phenotypes on an outcome by using genetic variants as instrumental variables, but its validity relies on the assumption of no pleiotropy, that is, genes influence the outcome only through the given phenotype. Excluding pleiotropy is difficult, but the use of multiple instruments can indirectly address the issue: if all genes represent valid instruments, their MR estimates should vary only by chance. The Sargan test detects pleiotropy when individual phenotype, outcome and genotype data are measured in the same subjects. We propose an alternative approach to be used when only summary genetic data are available or data on gene-phenotype and gene-outcome come from different subjects. The presence of pleiotropy is investigated using the between-instrument heterogeneity Q test (together with the I(2) index) in a meta-analysis of MR Wald estimates, derived separately from each instrument. For a continuous outcome, we evaluate the approach through simulations and illustrate it using published data. For the scenario where all data come from the same subjects, we compare it with the Sargan test. The Q test tends to be conservative in small samples. Its power increases with the degree of pleiotropy and the sample size, as does the precision of the I(2) index, in which case results are similar to those of the Sargan test. In MR studies with large sample sizes based on summary data, the between-instrument Q test represents a useful tool to explore the presence of heterogeneity due to pleiotropy or other causes.

Journal ArticleDOI
TL;DR: This review compared interventions tailored to address the identified determinants of practice with either no intervention or interventions not tailored to the determinants to determine whether tailored intervention strategies are effective in improving professional practice and healthcare outcomes.
Abstract: Background Tailored intervention strategies are frequently recommended among approaches to the implementation of improvement in health professional performance. Attempts to change the behaviour of health professionals may be impeded by a variety of different barriers, obstacles, or factors (which we collectively refer to as determinants of practice). Change may be more likely if implementation strategies are specifically chosen to address these determinants. Objectives To determine whether tailored intervention strategies are effective in improving professional practice and healthcare outcomes. We compared interventions tailored to address the identified determinants of practice with either no intervention or interventions not tailored to the determinants. Search methods We conducted searches of The Cochrane Library, MEDLINE, EMBASE, PubMed, CINAHL, and the British Nursing Index to May 2014. We conducted a final search in December 2014 (in MEDLINE only) for more recently published trials. We conducted searches of the metaRegister of Controlled Trials (mRCT) in March 2013. We also handsearched two journals. Selection criteria Cluster-randomised controlled trials (RCTs) of interventions tailored to address prospectively identified determinants of practice, which reported objectively measured professional practice or healthcare outcomes, and where at least one group received an intervention designed to address prospectively identified determinants of practice. Data collection and analysis Two review authors independently assessed quality and extracted data. We undertook qualitative and quantitative analyses, the quantitative analysis including two elements: we carried out 1) meta-regression analyses to compare interventions tailored to address identified determinants with either no interventions or an intervention(s) not tailored to the determinants, and 2) heterogeneity analyses to investigate sources of differences in the effectiveness of interventions. These included the effects of: risk of bias, use of a theory when developing the intervention, whether adjustment was made for local factors, and number of domains addressed with the determinants identified. Main results We added nine studies to this review to bring the total number of included studies to 32 comparing an intervention tailored to address identified determinants of practice to no intervention or an intervention(s) not tailored to the determinants. The outcome was implementation of recommended practice, e.g. clinical practice guideline recommendations. Fifteen studies provided enough data to be included in the quantitative analysis. The pooled odds ratio was 1.56 (95% confidence interval (CI) 1.27 to 1.93, P value < 0.001). The 17 studies not included in the meta-analysis had findings showing variable effectiveness consistent with the findings of the meta-regression. Authors' conclusions Despite the increase in the number of new studies identified, our overall finding is similar to that of the previous review. Tailored implementation can be effective, but the effect is variable and tends to be small to moderate. The number of studies remains small and more research is needed, including trials comparing tailored interventions to no or other interventions, but also studies to develop and investigate the components of tailoring (identification of the most important determinants, selecting interventions to address the determinants). Currently available studies have used different methods to identify determinants of practice and different approaches to selecting interventions to address the determinants. It is not yet clear how best to tailor interventions and therefore not clear what the effect of an optimally tailored intervention would be.

Journal ArticleDOI
TL;DR: This review has organised the literature by the unit of analysis and the comparison method used to identify change, significantly reducing the conceptual overlap present in previous reviews giving a succinct nomenclature with which to understand and apply change detection workflows.

Journal ArticleDOI
TL;DR: HIIT appears effective at improving metabolic health, particularly in those at risk of or with type 2 diabetes, particularly during training ≥2 weeks and following continuous training.
Abstract: The aim of this meta-analysis was to quantify the effects of high-intensity interval training (HIIT) on markers of glucose regulation and insulin resistance compared with control conditions (CON) or continuous training (CT). Databases were searched for HIIT interventions based upon the inclusion criteria: training ≥2 weeks, adult participants and outcome measurements that included insulin resistance, fasting glucose, HbA1c or fasting insulin. Dual interventions and participants with type 1 diabetes were excluded. Fifty studies were included. There was a reduction in insulin resistance following HIIT compared with both CON and CT (HIIT vs. CON: standardized mean difference [SMD] = -0.49, confidence intervals [CIs] -0.87 to -0.12, P = 0.009; CT: SMD = -0.35, -0.68 to -0.02, P = 0.036). Compared with CON, HbA1c decreased by 0.19% (-0.36 to -0.03, P = 0.021) and body weight decreased by 1.3 kg (-1.9 to -0.7, P < 0.001). There were no statistically significant differences between groups in other outcomes overall. However, participants at risk of or with type 2 diabetes experienced reductions in fasting glucose (-0.92 mmol L(-1), -1.22 to -0.62, P < 0.001) compared with CON. HIIT appears effective at improving metabolic health, particularly in those at risk of or with type 2 diabetes. Larger randomized controlled trials of longer duration than those included in this meta-analysis are required to confirm these results.

Journal ArticleDOI
TL;DR: The Matchmaker Exchange (MME) was launched to provide a robust and systematic approach to rare disease gene discovery through the creation of a federated network connecting databases of genotypes and rare phenotypes using a common application programming interface (API).
Abstract: There are few better examples of the need for data sharing than in the rare disease community, where patients, physicians, and researchers must search for "the needle in a haystack" to uncover rare, novel causes of disease within the genome. Impeding the pace of discovery has been the existence of many small siloed datasets within individual research or clinical laboratory databases and/or disease-specific organizations, hoping for serendipitous occasions when two distant investigators happen to learn they have a rare phenotype in common and can "match" these cases to build evidence for causality. However, serendipity has never proven to be a reliable or scalable approach in science. As such, the Matchmaker Exchange (MME) was launched to provide a robust and systematic approach to rare disease gene discovery through the creation of a federated network connecting databases of genotypes and rare phenotypes using a common application programming interface (API). The core building blocks of the MME have been defined and assembled. Three MME services have now been connected through the API and are available for community use. Additional databases that support internal matching are anticipated to join the MME network as it continues to grow.

Journal ArticleDOI
23 Jan 2015-Science
TL;DR: In this paper, the authors report detection of background levels of atmospheric methane of mean value 0.69 ± 0.25 ppbv at the 95% confidence interval (CI).
Abstract: Reports of plumes or patches of methane in the Martian atmosphere that vary over monthly timescales have defied explanation to date. From in situ measurements made over a 20-month period by the Tunable Laser Spectrometer (TLS) of the Sample Analysis at Mars (SAM) instrument suite on Curiosity at Gale Crater, we report detection of background levels of atmospheric methane of mean value 0.69 ± 0.25 ppbv at the 95% confidence interval (CI). This abundance is lower than model estimates of ultraviolet (UV) degradation of accreted interplanetary dust particles (IDP’s) or carbonaceous chondrite material. Additionally, in four sequential measurements spanning a 60-sol period, we observed elevated levels of methane of 7.2 ± 2.1 (95% CI) ppbv implying that Mars is episodically producing methane from an additional unknown source.

Journal ArticleDOI
TL;DR: The most recent advances in the understanding of the molecular underpinnings of miRNA-mediated repression are discussed and the multitude of regulatory mechanisms that modulate miRNA function are highlighted.
Abstract: Since their discovery 20 years ago, miRNAs have attracted much attention from all areas of biology. These short (∼22 nt) non-coding RNA molecules are highly conserved in evolution and are present in nearly all eukaryotes. They have critical roles in virtually every cellular process, particularly determination of cell fate in development and regulation of the cell cycle. Although it has long been known that miRNAs bind to mRNAs to trigger translational repression and degradation, there had been much debate regarding their precise mode of action. It is now believed that translational control is the primary event, only later followed by mRNA destabilisation. This review will discuss the most recent advances in our understanding of the molecular underpinnings of miRNA-mediated repression. Moreover, we highlight the multitude of regulatory mechanisms that modulate miRNA function.

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26 Mar 2015-Heart
TL;DR: There is potential for miRNAs to complement existing risk prediction models and act as valuable markers of post-AMI prognosis, and promising preclinical studies suggest that they could be useful in treating disorders ranging from heart failure to dyslipidaemia, although several challenges related to specificity and targeted delivery remain to be overcome.
Abstract: MicroRNAs (miRNAs) are small, non-coding, RNA molecules approximately 22 nucleotides in length which act as post-transcriptional regulators of gene expression. Individual miRNAs have been shown to regulate the expression of multiple genes. Conversely, the expression of individual genes can be regulated by multiple miRNAs. Consequently, since their discovery just over 20 years ago, miRNAs have been identified as key regulators of complex biological processes linked to multiple cardiovascular pathologies, including left ventricular hypertrophy, ischaemic heart disease, heart failure, hypertension and arrhythmias. Furthermore, since the finding that miRNAs are present in the circulation, they have been investigated as novel biomarkers, especially in the context of acute myocardial infarction (AMI) and heart failure. While there is little convincing evidence that miRNAs can outperform traditional biomarkers, such as cardiac troponins, in the diagnosis of AMI, there is potential for miRNAs to complement existing risk prediction models and act as valuable markers of post-AMI prognosis. Encouragingly, the concept of miRNA-based therapeutics is developing, with synthetic antagonists of miRNAs (antagomiRs) currently in phase II trials for the treatment of chronic hepatitis C virus infection. In the cardiovascular field, promising preclinical studies suggest that they could be useful in treating disorders ranging from heart failure to dyslipidaemia, although several challenges related to specificity and targeted delivery remain to be overcome. Through this review, we provide clinicians with a brief overview of the ever-expanding world of miRNAs.

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TL;DR: The ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up for malignant pleural mesothelioma show clear trends in survival and morbidity and recommend a 6-month to 12-monthFollow-up period for diagnosis and treatment.

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TL;DR: This work describes a strategy that combines gene expression profiling of large numbers of single cells with data analysis based on diffusion maps for dimensionality reduction and network synthesis from state transition graphs to generate a computationally executable transcriptional regulatory network model of blood development.
Abstract: Reconstruction of the molecular pathways controlling organ development has been hampered by a lack of methods to resolve embryonic progenitor cells Here we describe a strategy to address this problem that combines gene expression profiling of large numbers of single cells with data analysis based on diffusion maps for dimensionality reduction and network synthesis from state transition graphs Applying the approach to hematopoietic development in the mouse embryo, we map the progression of mesoderm toward blood using single-cell gene expression analysis of 3,934 cells with blood-forming potential captured at four time points between E70 and E85 Transitions between individual cellular states are then used as input to develop a single-cell network synthesis toolkit to generate a computationally executable transcriptional regulatory network model of blood development Several model predictions concerning the roles of Sox and Hox factors are validated experimentally Our results demonstrate that single-cell analysis of a developing organ coupled with computational approaches can reveal the transcriptional programs that underpin organogenesis