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The Melvin Judkins Young Clinical Investigator Award, named for the pioneer of coronary angiography, recognises meritorious research from early career investigators and promotes careers in cardiovascular radiology.
Role of the Lymphatics in Cardiac Disease.
Cardiovascular diseases remain the largest cause of death worldwide with recent evidence increasingly attributing the development and progression of these diseases to an exacerbated inflammatory response. As a result, significant research is now focused on modifying the immune environment to prevent the disease progression. This in turn has highlighted the lymphatic system in the pathophysiology of cardiovascular diseases owing, in part, to its established function in immune cell surveillance and trafficking. In this review, we highlight the role of the cardiac lymphatic system and its potential as an immunomodulatory therapeutic target in selected cardiovascular diseases.
The effect of sodium-glucose cotransporter-2 inhibitors on inflammatory biomarkers: A meta-analysis of randomized controlled trials.
AIMS: To conduct a meta-analysis of randomized controlled trials (RCTs) to assess the effect of sodium-glucose cotransporter-2 (SGLT2) inhibitors on inflammatory biomarkers. METHODS: Medline, Embase and the Cochrane Library were searched for RCTs investigating the effect of SGLT2 inhibitors on inflammatory biomarkers, adipokine profiles and insulin sensitivity. RESULTS: Thirty-eight RCTs were included (14 967 participants, 63.3% male, mean age 62 ± 8.6 years) with a median (interquartile range) follow-up of 16 (12-24) weeks. Meta-analysis showed that SGLT2 inhibitors significantly improved adiponectin, interleukin-6, tumour necrosis factor receptor-1 (vs. placebo alone: standardized mean difference [SMD] 0.34 [95% confidence interval {CI} 0.23, 0.45], mean difference [MD] -0.85 pg/mL [95% CI -1.32, -0.38], SMD -0.13 [95% CI -0.20, -0.06], respectively), leptin and homeostatic model assessment of insulin resistance index (vs. CONTROL: SMD -0.20 [95% CI -0.33, -0.07], MD -0.83 [95% CI -1.32, -0.33], respectively). There were no significant changes in C-reactive protein (CRP), tumour necrosis factor-α, plasminogen activator inhibitor-1, fibroblast growth factor-21 or monocyte chemoattractant protein-1. CONCLUSIONS: Our analysis shows that SGLT2 inhibitors likely improve adipokine biomarkers and insulin sensitivity, but there is little evidence that SGLT2 inhibitors improve other inflammatory biomarkers including CRP.
Arrhythmogenesis in Fabry Disease.
PURPOSE OF REVIEW: Fabry Disease (FD) is a rare lysosomal storage disorder characterised by multiorgan accumulation of glycosphingolipid due to deficiency in the enzyme α-galactosidase A. Cardiac sphingolipid accumulation triggers various types of arrhythmias, predominantly ventricular arrhythmia, bradyarrhythmia, and atrial fibrillation. Arrhythmia is likely the primary contributor to FD mortality with sudden cardiac death, the most frequent cardiac mode of death. Traditionally FD was seen as a storage cardiomyopathy triggering left ventricular hypertrophy, diastolic dysfunction, and ultimately, systolic dysfunction in advanced disease. The purpose of this review is to outline the current evidence exploring novel mechanisms underlying the arrhythmia substrate. RECENT FINDINGS: There is growing evidence that FD cardiomyopathy is a primary arrhythmic disease with each stage of cardiomyopathy (accumulation, hypertrophy, inflammation, and fibrosis) contributing to the arrhythmia substrate via various intracellular, extracellular, and environmental mechanisms. It is therefore important to understand how these mechanisms contribute to an individual's risk of arrhythmia in FD. In this review, we outline the epidemiology of arrhythmia, pathophysiology of arrhythmogenesis, risk stratification, and cardiac therapy in FD. We explore how advances in conventional cardiac investigations performed in FD patients including 12-lead electrocardiography, transthoracic echocardiography, and cardiac magnetic resonance imaging have enabled early detection of pro-arrhythmic substrate. This has allowed for appropriate risk stratification of FD patients. This paves the way for future work exploring the development of therapeutic initiatives and risk prediction models to reduce the burden of arrhythmia.
Conducting umbrella reviews.
In this article, Lazaros Belbasis and colleagues explain the rationale for umbrella reviews and the key steps involved in conducting an umbrella review, using a working example.
Introduction to Epidemiological Studies.
The basic epidemiological study designs are cross-sectional, case-control, and cohort studies. Cross-sectional studies provide a snapshot of a population by determining both exposures and outcomes at one time point. Cohort studies identify the study groups based on the exposure and, then, the researchers follow up study participants to measure outcomes. Case-control studies identify the study groups based on the outcome, and the researchers retrospectively collect the exposure of interest. The present chapter discusses the basic concepts, the advantages, and disadvantages of epidemiological study designs and their systematic biases, including selection bias, information bias, and confounding.
Environmental Risk Factors and Amyotrophic Lateral Sclerosis: An Umbrella Review and Critical Assessment of Current Evidence from Systematic Reviews and Meta-Analyses of Observational Studies.
BACKGROUND: The pathogenesis of amyotrophic lateral sclerosis (ALS) involves both environmental and genetic factors. Our study aimed at summarising the environmental risk factors for ALS, assessing the evidence for diverse biases, and pinpointing risk factors with high epidemiological credibility. METHODS: We searched PubMed from inception to August 20, 2015, to identify systematic reviews and meta-analyses of observational studies examining associations between environmental factors and ALS. For each meta-analysis, we estimated the summary effect size by the use of random-effects and fixed-effects models, the 95% CI, the 95% prediction interval (PI), and the between-study heterogeneity. We assessed the evidence of small-study effects and excess significance bias. RESULTS: Sixteen unique meta-analyses of different risk factors and ALS were considered. Of them, 5 were statistically significant at p < 0.001 under the random-effects model. Only one factor presented robust evidence for a convincing association. This association pertained to chronic occupational exposure to lead (random-effects OR 1.81, 95% CI 1.39-2.35). CONCLUSIONS: A small number of published meta-analyses on environmental factors and risk of ALS was identified, a phenomenon that could be attributed to the challenges in studying a rare neurological disease. More observational studies with adequate sample size and study design are needed to clarify the environmental component of ALS pathogenesis.
Non-genetic risk factors for cutaneous melanoma and keratinocyte skin cancers: An umbrella review of meta-analyses.
BACKGROUND: Skin cancers have a complex disease mechanism, involving both genetic and non-genetic risk factors. Numerous meta-analyses have been published claiming statistically significant associations between non-genetic risk factors and skin cancers without applying a thorough methodological assessment. OBJECTIVE: The present study maps the literature on the non-genetic risk factors of skin cancers, assesses the presence of statistical biases and identifies the associations with robust evidence. METHODS: We searched PubMed up to January 20, 2016 to identify systematic reviews and meta-analyses of observational studies that examined associations between non-genetic factors and skin cancers. For each meta-analysis, we estimated the summary effect size by random-effects and fixed-effects models, the 95% confidence interval and the 95% prediction interval. We also assessed the between-study heterogeneity (I2 metric), evidence for small-study effects and excess significance bias. RESULTS: Forty-four eligible papers were identified and included a total of 85 associations. Twenty-one associations were significant at P<10-6. Fifty-two associations had large or very large heterogeneity. Evidence for small-study effects and excess significance bias was found in fifteen and thirteen associations, respectively. Overall, thirteen associations (actinic keratosis, serum vitamin D, sunburns, and hair color for basal cell carcinoma and density of freckles, eye color, hair color, history of melanoma, skin type, sunburns, premalignant skin lesions, common and atypical nevi for melanoma) presented high level of credibility. CONCLUSION: The majority of meta-analyses on non-genetic risk factors for skin cancers suffered from large between-study heterogeneity and small-study effects or excess significance bias. The associations with convincing and highly suggestive evidence were mainly focused on skin photosensitivity and phenotypic characteristics.
Radiotherapy for prevention of heterotopic ossification of the elbow: a systematic review of the literature.
BACKGROUND: Heterotopic ossification is a pathological process characterized by abnormal formation of bone in nonskeletal tissue. Radiotherapy for heterotopic ossification of the elbow is questionable because of possible adverse effects. METHODS: A systematic review of the literature was conducted in MEDLINE, Scopus, ISI Web of Science, National Institute for Health and Clinical Excellence, National Guideline Clearinghouse, System for Information on Grey Literature in Europe, ClinicalTrials.gov, Cochrane Central Register of Clinical Trials, and Cochrane Database of Systematic Reviews up to April 2012. All published articles assessing interventions including radiotherapy for prevention of heterotopic ossification in the elbow of adult patients were considered. Information was recorded by the first two authors, and disagreements in interpretation were resolved by consensus. RESULTS: In total, 27 studies using radiotherapy for elbow heterotopic ossification were identified (1 randomized clinical trial, 1 case-control study, and 25 case reports and case series) in the literature. Most of them used a single dose of 7.0 Gy. The randomized clinical trial was stopped early because of severe adverse effects (pseudarthrosis) caused by radiation. The case-control study showed that radiotherapy did not effectively prevent recurrence of heterotopic ossification. The case reports and case series mentioned only sparse adverse events. CONCLUSION: The use of radiation therapy for prevention of heterotopic ossification of the elbow is supported by weak evidence.
Tobacco Smoking and Risk for Pulmonary Fibrosis: A Prospective Cohort Study From the UK Biobank.
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease of unknown origin. A limited number of small studies show an effect of tobacco smoking on risk of IPF, but second-hand smoking has not been examined. RESEARCH QUESTION: Are smoking-related exposures associated with risk of IPF and does interaction between them exist? STUDY DESIGN AND METHODS: We designed a prospective cohort study using UK Biobank data, including 437,453 nonrelated men and women of White ethnic background (40-69 years of age at baseline). We assessed the effect of tobacco smoking-related exposures on risk for IPF using Cox regression adjusted for age, sex, Townsend deprivation index, and home area population density. We also examined potential additive and multiplicative interaction between these exposures. Multiple imputation with chained equations was used to address missing data. RESULTS: We identified 802 incident IPF cases. We showed an association between smoking status (hazard ratio [HR], 2.12; 95% CI, 1.81-2.47), and maternal smoking (HR, 1.38; 95% CI, 1.18-1.62) with risk of IPF. In ever smokers, a dose-response relationship was observed between pack-years of smoking and risk of IPF (HR per 1-pack-year increase, 1.013; 95% CI, 1.009-1.016). Furthermore, an additive and multiplicative interaction was observed between maternal smoking and smoking status, with a relative excess risk due to interaction of 1.00 (95% CI, 0.45-1.54) and a ratio of HRs of 1.50 (95% CI, 1.05-2.14). INTERPRETATION: Active and maternal tobacco smoking have an independent detrimental effect on risk of IPF and work synergistically. Also, intensity of smoking presents a dose-response association with IPF, strengthening the hypothesis for a potentially causal association.
Elucidating the environmental risk factors for rheumatic diseases: An umbrella review of meta-analyses.
AIMS: Although rheumatic diseases constitute a leading cause of disability, the environmental risk factors for these diseases are not clarified. In the present study, we aim to systematically appraise the epidemiological credibility of the environmental risk factors for rheumatic diseases. METHODS: We systematically searched PubMed to capture meta-analyses of observational studies on environmental risk factors for the most prevalent rheumatic diseases. For each association, we estimated the summary effect size estimate, the 95% confidence and prediction intervals, and the I2 metric. We further examined the presence of small-study effects and excess significance bias. RESULTS: Overall, we identified 30 eligible papers describing 42 associations. Thirty-three associations were statistically significant at P
Environmental factors and risk of multiple sclerosis: Findings from meta-analyses and Mendelian randomization studies.
Multiple sclerosis (MS) is a chronic demyelinating disease that is associated with permanent disability and low quality of life. Development of MS is attributed to a combination of genetic and environmental factors. Genome-wide association studies revealed more than 200 variants that are associated with risk of MS. An umbrella review showed that smoking, history of infectious mononucleosis, and anti-Epstein-Barr virus nuclear antigen (anti-EBNA) immunoglobulin G (IgG) seropositivity are credible risk factors of MS. In the present narrative review, we updated our published umbrella review, showing that body mass index in childhood and adolescence and anti-viral capsid antigen (anti-VCA) IgG seropositivity are additional credible risk factors of MS. In addition, we discuss the findings from Mendelian randomization studies, which present evidence for a potential causal role of serum vitamin D and adulthood body mass index on risk of MS. Finally, we discuss the potential limitations of meta-analyses, umbrella reviews, and Mendelian randomization studies in the search for risk factors of MS.
Systematic evaluation of the associations between environmental risk factors and dementia: An umbrella review of systematic reviews and meta-analyses.
INTRODUCTION: Dementia is a heterogeneous neurodegenerative disease, whose etiology results from a complex interplay between environmental and genetic factors. METHODS: We searched PubMed to identify meta-analyses of observational studies that examined associations between nongenetic factors and dementia. We estimated the summary effect size using random-effects and fixed-effects model, the 95% CI, and the 95% prediction interval. We assessed the between-study heterogeneity (I-square), evidence of small-study effects, and excess significance. RESULTS: A total of 76 unique associations were examined. By applying standardized criteria, seven associations presented convincing evidence. These associations pertained to benzodiazepines use, depression at any age, late-life depression, and frequency of social contacts for all types of dementia; late-life depression for Alzheimer's disease; and type 2 diabetes mellitus for vascular dementia and Alzheimer's disease. DISCUSSION: Several risk factors present substantial evidence for association with dementia and should be assessed as potential targets for interventions, but these associations may not necessarily be causal.
Environmental factors, serum biomarkers and risk of atrial fibrillation: an exposure-wide umbrella review of meta-analyses.
Atrial fibrillation (AF) is the most common cardiac arrhythmia. We designed an umbrella review to systematically assess the epidemiological credibility of the associations of non-genetic factors with risk of AF. We searched PubMed and EMBASE from inception to December 31, 2018 to identify systematic reviews and meta-analyses of observational studies for the association of non-genetic factors with risk of AF. For each meta-analysis, we used the random-effects model, and we estimated the 95% confidence and prediction intervals. We also assessed between-study heterogeneity, small-study effects and excess significance bias. We identified 34 eligible papers that examined 51 associations of 42 unique non-genetic factors with risk of AF. Eighteen associations remained statistically significant at P value 30 units vs.
Risk factors and peripheral biomarkers for schizophrenia spectrum disorders: an umbrella review of meta-analyses.
OBJECTIVE: This study aimed to systematically appraise the meta-analyses of observational studies on risk factors and peripheral biomarkers for schizophrenia spectrum disorders. METHODS: We conducted an umbrella review to capture all meta-analyses and Mendelian randomization studies that examined associations between non-genetic risk factors and schizophrenia spectrum disorders. For each eligible meta-analysis, we estimated the summary effect size estimate, its 95% confidence and prediction intervals and the I2 metric. Additionally, evidence for small-study effects and excess significance bias was assessed. RESULTS: Overall, we found 41 eligible papers including 98 associations. Sixty-two associations had a nominally significant (P-value <0.05) effect. Seventy-two of the associations exhibited large or very large between-study heterogeneity, while 13 associations had evidence for small-study effects. Excess significance bias was found in 18 associations. Only five factors (childhood adversities, cannabis use, history of obstetric complications, stressful events during adulthood, and serum folate level) showed robust evidence. CONCLUSION: Despite identifying 98 associations, there is only robust evidence to suggest that cannabis use, exposure to stressful events during childhood and adulthood, history of obstetric complications, and low serum folate level confer a higher risk for developing schizophrenia spectrum disorders. The evidence on peripheral biomarkers for schizophrenia spectrum disorders remains limited.
Environmental risk factors and Parkinson's disease: An umbrella review of meta-analyses.
BACKGROUND: Parkinson's disease is a neurological disorder with complex pathogenesis implicating both environmental and genetic factors. We aimed to summarise the environmental risk factors that have been studied for potential association with Parkinson's disease, assess the presence of diverse biases, and identify the risk factors with the strongest support. METHODS: We searched PubMed from inception to September 18, 2015, to identify systematic reviews and meta-analyses of observational studies that examined associations between environmental factors and Parkinson's disease. For each meta-analysis we estimated the summary effect size by random-effects and fixed-effects models, the 95% confidence interval and the 95% prediction interval. We estimated the between-study heterogeneity expressed by I(2), evidence of small-study effects and evidence of excess significance bias. RESULTS: Overall, 75 unique meta-analyses on different risk factors for Parkinson's disease were examined, covering diverse biomarkers, dietary factors, drugs, medical history or comorbid diseases, exposure to toxic environmental agents and habits. 21 of 75 meta-analyses had results that were significant at p < 0.001 by random-effects. Evidence for an association was convincing (more than 1000 cases, p < 10(-6) by random-effects, not large heterogeneity, 95% prediction interval excluding the null value and absence of hints for small-study effects and excess significance bias) for constipation, and physical activity. CONCLUSION: Many environmental factors have substantial evidence of association with Parkinson's disease, but several, perhaps most, of them may reflect reverse causation, residual confounding, information bias, sponsor conflicts or other caveats.
Birth weight in relation to health and disease in later life: an umbrella review of systematic reviews and meta-analyses.
BACKGROUND: Birth weight, a marker of the intrauterine environment, has been extensively studied in epidemiological research in relation to subsequent health and disease. Although numerous meta-analyses have been published examining the association between birth weight and subsequent health-related outcomes, the epidemiological credibility of these associations has not been thoroughly assessed. The objective of this study is to map the diverse health outcomes associated with birth weight and evaluate the credibility and presence of biases in the reported associations. METHODS: An umbrella review was performed to identify systematic reviews and meta-analyses of observational studies investigating the association between birth weight and subsequent health outcomes and traits. For each association, we estimated the summary effect size by random-effects and fixed-effects models, the 95 % confidence interval, and the 95 % prediction interval. We also assessed the between-study heterogeneity, evidence for small-study effects and excess significance bias. We further applied standardized methodological criteria to evaluate the epidemiological credibility of the statistically significant associations. RESULTS: Thirty-nine articles including 78 associations between birth weight and diverse outcomes met the eligibility criteria. A wide range of health outcomes has been studied, ranging from anthropometry and metabolic diseases, cardiovascular diseases and cardiovascular risk factors, various cancers, respiratory diseases and allergies, musculoskeletal traits and perinatal outcomes. Forty-seven of 78 associations presented a nominally significant summary effect and 21 associations remained statistically significant at P
Mapping and systematic appraisal of umbrella reviews in epidemiological research: a protocol for a meta-epidemiological study.
INTRODUCTION: Umbrella review is one of the terms used to describe an overview of systematic reviews. During the last years, a rapid increase in the number of umbrella reviews on epidemiological studies has been observed, but there is no systematic assessment of their methodological and reporting characteristics. Our study aims to fill this gap by performing a systematic mapping of umbrella reviews in epidemiological research. METHODS: We will perform a meta-epidemiological study including a systematic review in MEDLINE and EMBASE to identify all the umbrella reviews that focused on systematic reviews of epidemiological studies and were published from inception until December 31, 2022. We will consider eligible any research article which was designed as an umbrella review and summarized systematic reviews and meta-analyses of epidemiological studies. From each eligible article, we will extract information about the research topic, the methodological characteristics, and the reporting characteristics. We will examine whether the umbrella reviews assessed the strength of the available evidence and the rigor of the included systematic reviews. We will also examine whether these characteristics change across time. DISCUSSION: Our study will systematically appraise the methodological and reporting characteristics of published umbrella reviews in epidemiological literature. The findings of our study can be used to improve the design and conduct of future umbrella reviews, to derive a standardized set of reporting and methodological guidelines for umbrella reviews, and to allow further meta-epidemiological work. SYSTEMATIC REVIEW REGISTRATION: osf.io/sxzc6.
Reproducibility of prediction models in health services research.
The field of health services research studies the health care system by examining outcomes relevant to patients and clinicians but also health economists and policy makers. Such outcomes often include health care spending, and utilization of care services. Building accurate prediction models using reproducible research practices for health services research is important for evidence-based decision making. Several systematic reviews have summarized prediction models for outcomes relevant to health services research, but these systematic reviews do not present a thorough assessment of reproducibility and research quality of the prediction modelling studies. In the present commentary, we discuss how recent advances in prediction modelling in other medical fields can be applied to health services research. We also describe the current status of prediction modelling in health services research, and we summarize available methodological guidance for the development, update, external validation and systematic appraisal of prediction models.