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.
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Lesley Jones1, Jean-Charles Lambert2, Jean-Charles Lambert3, Jean-Charles Lambert4 +205 more•Institutions (71)
TL;DR: Late‐onset Alzheimer's disease (AD) is heritable with 20 genes showing genome‐wide association in the International Genomics of Alzheimer's Project (IGAP), and this work extended these genetic data in a pathway analysis.
Abstract: Background Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. Methods The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response ( P = 3.27 × 10 −12 after multiple testing correction for pathways), regulation of endocytosis ( P = 1.31 × 10 −11 ), cholesterol transport ( P = 2.96 × 10 −9 ), and proteasome-ubiquitin activity ( P = 1.34 × 10 −6 ). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002–.05). Conclusions The immune response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.
178 citations
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Clinical Trial Service Unit1, University of Copenhagen2, University of Cambridge3, Population Health Research Institute4, University of London5, University of Freiburg6, Mie University7, Utrecht University8, University of Ottawa9, University of Pennsylvania10, McGill University Health Centre11, Stanford University12, University of Oxford13, University of Leicester14
TL;DR: A meta-analysis of unpublished datasets suggests that an increase in homocysteine levels is not likely to result in a increase in risk of coronary heart disease.
Abstract: Background: Moderately elevated blood levels of homocysteine are weakly correlated with coronary heart disease (CHD) risk, but causality remains uncertain When folate levels are low, the TT genotype of the common C677T polymorphism (rs1801133) of the methylene tetrahydrofolate reductase gene (MTHFR) appreciably increases homocysteine levels, so ‘‘Mendelian randomization’’ studies using this variant as an instrumental variable could help test causality Methods and Findings: Nineteen unpublished datasets were obtained (total 48,175 CHD cases and 67,961 controls) in which multiple genetic variants had been measured, including MTHFR C677T These datasets did not include measurements of blood homocysteine, but homocysteine levels would be expected to be about 20% higher with TT than with CC genotype in the populations studied In meta-analyses of these unpublished datasets, the case-control CHD odds ratio (OR) and 95% CI comparing TT versus CC homozygotes was 102 (098–107; p=028) overall, and 101 (095–107) in unsupplemented low-folate populations By contrast, in a slightly updated meta-analysis of the 86 published studies (28,617 CHD cases and 41,857 controls), the OR was 115 (109–121), significantly discrepant (p=0001) with the OR in the unpublished datasets Within the meta-analysis of published studies, the OR was 112 (104–121) in the 14 larger studies (those with variance of log OR,005; total 13,119 cases) and 118 (109–128) in the 72 smaller ones (total 15,498 cases) Conclusions: The CI for the overall result from large unpublished datasets shows lifelong moderate homocysteine elevation has little or no effect on CHD The discrepant overall result from previously published studies reflects publication bias or methodological problems Please see later in the article for the Editors’ Summary
178 citations
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Queen Mary University of London1, Medical Research Council2, King's College London3, University of Glasgow4, University of Leicester5, Glenfield Hospital6, University College London7, University of Ioannina8, Imperial College London9, University College Dublin10, St George's, University of London11, University of Cambridge12, University of Dundee13, Centre for Mental Health14, University of Edinburgh15, University of Michigan16, Health Protection Agency17, University Medical Center Groningen18, University of Sassari19, Mount Carmel Health20, University of Milan21, Katholieke Universiteit Leuven22, French Institute of Health and Medical Research23, Paris Descartes University24, University of Tartu25, Tallinn University of Technology26, University of Gothenburg27, University of Oslo28, Lund University29, University of Ottawa30, Clinical Trial Service Unit31, Wellcome Trust Centre for Human Genetics32, John Radcliffe Hospital33, Karolinska University Hospital34, University of Münster35, Wellcome Trust Sanger Institute36, University of London37, GlaxoSmithKline38, AstraZeneca39, Harvard University40, Royal College of Surgeons in Ireland41
TL;DR: An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10(-7) at four further loci and highlighted the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.
Abstract: Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.
178 citations
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TL;DR: The relationship between vascular complications and longitudinal blood counts in a prospective, multicenter cohort of 776 essential thrombocythemia patients was investigated and no association was seen between blood counts at diagnosis and future complications.
172 citations
12 Aug 2020
TL;DR: The reduced number of admissions during this period is likely to have resulted in increases in out-of-hospital deaths and long-term complications of myocardial infarction and missed opportunities to offer secondary prevention treatment for patients with coronary heart disease.
Abstract: BACKGROUND: Several countries affected by the COVID-19 pandemic have reported a substantial drop in the number of patients attending the emergency department with acute coronary syndromes and a reduced number of cardiac procedures. We aimed to understand the scale, nature, and duration of changes to admissions for different types of acute coronary syndrome in England and to evaluate whether in-hospital management of patients has been affected as a result of the COVID-19 pandemic. METHODS: We analysed data on hospital admissions in England for types of acute coronary syndrome from Jan 1, 2019, to May 24, 2020, that were recorded in the Secondary Uses Service Admitted Patient Care database. Admissions were classified as ST-elevation myocardial infarction (STEMI), non-STEMI (NSTEMI), myocardial infarction of unknown type, or other acute coronary syndromes (including unstable angina). We identified revascularisation procedures undertaken during these admissions (ie, coronary angiography without percutaneous coronary intervention [PCI], PCI, and coronary artery bypass graft surgery). We calculated the numbers of weekly admissions and procedures undertaken; percentage reductions in weekly admissions and across subgroups were also calculated, with 95% CIs. FINDINGS: Hospital admissions for acute coronary syndrome declined from mid-February, 2020, falling from a 2019 baseline rate of 3017 admissions per week to 1813 per week by the end of March, 2020, a reduction of 40% (95% CI 37-43). This decline was partly reversed during April and May, 2020, such that by the last week of May, 2020, there were 2522 admissions, representing a 16% (95% CI 13-20) reduction from baseline. During the period of declining admissions, there were reductions in the numbers of admissions for all types of acute coronary syndrome, including both STEMI and NSTEMI, but relative and absolute reductions were larger for NSTEMI, with 1267 admissions per week in 2019 and 733 per week by the end of March, 2020, a percent reduction of 42% (95% CI 38-46). In parallel, reductions were recorded in the number of PCI procedures for patients with both STEMI (438 PCI procedures per week in 2019 vs 346 by the end of March, 2020; percent reduction 21%, 95% CI 12-29) and NSTEMI (383 PCI procedures per week in 2019 vs 240 by the end of March, 2020; percent reduction 37%, 29-45). The median length of stay among patients with acute coronary syndrome fell from 4 days (IQR 2-9) in 2019 to 3 days (1-5) by the end of March, 2020. INTERPRETATION: Compared with the weekly average in 2019, there was a substantial reduction in the weekly numbers of patients with acute coronary syndrome who were admitted to hospital in England by the end of March, 2020, which had been partly reversed by the end of May, 2020. The reduced number of admissions during this period is likely to have resulted in increases in out-of-hospital deaths and long-term complications of myocardial infarction and missed opportunities to offer secondary prevention treatment for patients with coronary heart disease. The full extent of the effect of COVID-19 on the management of patients with acute coronary syndrome will continue to be assessed by updating these analyses. FUNDING: UK Medical Research Council, British Heart Foundation, Public Health England, Health Data Research UK, and the National Institute for Health Research Oxford Biomedical Research Centre.
172 citations
Authors
Showing all 428 results
Name | H-index | Papers | Citations |
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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 |