Institution
Clinical Trial Service Unit
About: Clinical Trial Service Unit is a based out in . It is known for research contribution in the topics: Population & Stroke. The organization has 428 authors who have published 1387 publications receiving 181920 citations.
Papers published on a yearly basis
Papers
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TL;DR: It is suggested that the main driver of benefit may derive from the specific effects of sodium-glucose linked transporter-2 (SGLT2) inhibition on renal sodium and glucose handling, leading to both diuresis and improvements in diabetes-related maladaptive renal arteriolar responses.
Abstract: While the modest reduction in the primary composite outcome of myocardial infarction, stroke or cardiovascular death in the EMPA-REG Outcomes trial was welcome, the 30–40% reductions in heart failure hospitalisation (HFH) and cardiovascular and all-cause deaths in patients treated with empagliflozin were highly impressive and unexpected. In this review, we discuss briefly why cardiovascular endpoint trials for new diabetes agents are required and describe the results of the first four such trials to have reported, as a precursor to understanding why the EMPA-REG Outcomes results came as a surprise. Thereafter, we discuss potential mechanisms that could explain the EMPA-REG Outcomes results, concentrating on non-atherothrombotic effects. We suggest that the main driver of benefit may derive from the specific effects of sodium-glucose linked transporter-2 (SGLT2) inhibition on renal sodium and glucose handling, leading to both diuresis and improvements in diabetes-related maladaptive renal arteriolar responses. These haemodynamic and renal effects are likely to be beneficial in patients with clinical or subclinical cardiac dysfunction. The net result of these processes, we argue, is an improvement in cardiac systolic and diastolic function and, thereby, a lower risk of HFH and sudden cardiac death. We also discuss whether other drugs in this class are likely to show similar cardiovascular benefits. Finally, areas for future research are suggested to better understand the relevant mechanisms and to identify other groups who may benefit from SGLT2 inhibitor therapy.
236 citations
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TL;DR: In this article, a systematic review of studies of iron status and coronary heart disease (CHD) has yielded conflicting results, concluding that published prospective studies do not provide good evidence to support the existence of strong epidemiological associations between IR status and CHD.
Abstract: Background —Studies of iron status and coronary heart disease (CHD) have yielded conflicting results. In a systematic review (“meta-analysis”), we quantitatively assessed epidemiological associations reported in prospective studies.
Methods and Results —Studies were identified by computer-assisted searches of the published literature, scanning of relevant reference lists, hand searching of relevant journals, and discussions with relevant authors. The following was abstracted: size and type of cohort, mean age, mean duration of follow-up, assay methods, degree of adjustment for confounders, and relationship of CHD risk to the baseline assay results. Twelve studies were identified, involving a total of 7800 CHD cases, with several reporting on >1 marker of iron status. For serum ferritin, with 570 CHD cases in 5 studies, comparison of individuals with baseline values ≥200 versus <200 μg/L yielded a combined risk ratio of 1.0 (95% CI, 0.8 to 1.3). For transferrin saturation, with 6194 CHD cases in 5 studies, comparison of individuals in the top third with those in the bottom third of the baseline measurements yielded a combined risk ratio of 0.9 (95% CI, 0.7 to 1.1). Comparisons of individuals in top and bottom thirds of baseline measurements also yielded nonsignificant risk ratios in combined analyses of studies involving total iron-binding capacity (combined risk ratio, 1.0; 95% CI, 0.7 to 1.5), serum iron (0.8; 95% CI, 0.7 to 1.0), and total dietary iron (0.8; 95% CI, 0.7 to 1.1).
Conclusions —Published prospective studies do not provide good evidence to support the existence of strong epidemiological associations between iron status and CHD.
236 citations
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TL;DR: Routinely measured lipid fractions exhibit contrasting associations with the risk of CAD and diabetes, and all 3 lipid traits were associated with a lower risk of type 2 diabetes.
Abstract: Importance Low-density lipoprotein cholesterol (LDL-C) is causally related to coronary artery disease (CAD), but the relevance of high-density lipoprotein cholesterol (HDL-C) and triglycerides (TGs) is uncertain. Lowering of LDL-C levels by statin therapy modestly increases the risk of type 2 diabetes, but it is unknown whether this effect is specific to statins. Objective To investigate the associations of 3 routinely measured lipid fractions with CAD and diabetes through mendelian randomization (MR) using conventional MR and making use of newer approaches, such as multivariate MR and MR-Egger, that address the pleiotropy of genetic instruments where relevant. Design, Setting, and Participants Published data from genome-wide association studies were used to construct genetic instruments and then applied to investigate associations between lipid fractions and the risk of CAD and diabetes using MR approaches that took into account pleiotropy of genetic instruments. The study was conducted from March 12 to December 31, 2015. Main Outcomes and Measures Coronary artery disease and diabetes. Results Genetic instruments composed of 130 single-nucleotide polymorphisms (SNPs) were used for LDL-C (explaining 7.9% of its variance), 140 SNPs for HDL-C (6.6% of variance), and 140 SNPs for TGs (5.9% of variance). A 1-SD genetically instrumented elevation in LDL-C levels (equivalent to 38 mg/dL) and TG levels (equivalent to 89 mg/dL) was associated with higher CAD risk; odds ratios (ORs) were 1.68 (95% CI, 1.51-1.87) for LDL-C and 1.28 (95% CI, 1.13-1.45) for TGs. The corresponding OR for HDL-C (equivalent to a 16-mg/dL increase) was 0.95 (95% CI, 0.85-1.06). All 3 lipid traits were associated with a lower risk of type 2 diabetes. The ORs were 0.79 (95% CI, 0.71-0.88) for LDL-C and 0.83 (95% CI, 0.76-0.90) for HDL-C per 1-SD elevation. For TG, the MR estimates for diabetes were inconsistent, with MR-Egger giving an OR of 0.83 (95%CI, 0.72-0.95) per 1-SD elevation. Conclusions and Relevance Routinely measured lipid fractions exhibit contrasting associations with the risk of CAD and diabetes. Increased LDL-C, HDL-C, and possibly TG levels are associated with a lower risk of diabetes. This information will be relevant to the design of clinical trials of lipid-modifying agents, which should carefully monitor participants for dysglycemia and the incidence of diabetes.
233 citations
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Karolinska Institutet1, Science for Life Laboratory2, University of Oulu3, Baker IDI Heart and Diabetes Institute4, Karolinska University Hospital5, Pfizer6, Mental Health Services7, Translational Genomics Research Institute8, University Medical Center Groningen9, University of Queensland10, Sun Yat-sen University11, Western General Hospital12, University of Tartu13, Broad Institute14, University of Bristol15, Lund University16, Uppsala University17, University of Edinburgh18, Uppsala University Hospital19, Harvard University20, Lancaster University21, University of Split22, University of Cambridge23, University of Gothenburg24, The George Institute for Global Health25, Sunnybrook Health Sciences Centre26, Clinical Trial Service Unit27, Stanford University28
TL;DR: The utility of large-scale mapping of the genetics of the proteome is demonstrated and pQTLs are provided as a resource for future precision studies of circulating proteins in human health.
Abstract: Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
230 citations
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TL;DR: Wider appreciation of the different strengths and weaknesses of these two types of epidemiological study should increase the likelihood that the most reliable evidence available informs decisions about the treatments doctors use--and patients receive--for the management of a wide range of life-threatening conditions.
230 citations
Authors
Showing all 428 results
Name | H-index | Papers | Citations |
---|---|---|---|
Salim Yusuf | 231 | 1439 | 252912 |
Richard Peto | 183 | 683 | 231434 |
Cornelia M. van Duijn | 183 | 1030 | 146009 |
Rory Collins | 162 | 489 | 193407 |
Naveed Sattar | 155 | 1326 | 116368 |
Timothy J. Key | 146 | 808 | 90810 |
John Danesh | 135 | 394 | 100132 |
Andrew J.S. Coats | 127 | 820 | 94490 |
Valerie Beral | 114 | 471 | 53729 |
Mike Clarke | 113 | 1037 | 164328 |
Robert Clarke | 111 | 512 | 90049 |
Robert U. Newton | 109 | 753 | 42527 |
Richard Gray | 109 | 808 | 78580 |
Braxton D. Mitchell | 102 | 558 | 49599 |
Naomi E. Allen | 101 | 364 | 37057 |