| 1. |
- Chauhan, Ganesh, et al.
(författare)
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Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies
- 2016
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Ingår i: The Lancet Neurology. - 1474-4465 .- 1474-4422. ; 15:7, s. 695-707
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Tidskriftsartikel (refereegranskat)abstract
- Background Genetic determinants of stroke, the leading neurological cause of death and disability, are poorly understood and have seldom been explored in the general population. Our aim was to identify additional loci for stroke by doing a meta-analysis of genome-wide association studies. Methods For the discovery sample, we did a genome-wide analysis of common genetic variants associated with incident stroke risk in 18 population-based cohorts comprising 84 961 participants, of whom 4348 had stroke. Stroke diagnosis was ascertained and validated by the study investigators. Mean age at stroke ranged from 45·8 years to 76·4 years, and data collection in the studies took place between 1948 and 2013. We did validation analyses for variants yielding a significant association (at p<5 × 10−6) with all-stroke, ischaemic stroke, cardioembolic ischaemic stroke, or non-cardioembolic ischaemic stroke in the largest available cross-sectional studies (70 804 participants, of whom 19 816 had stroke). Summary-level results of discovery and follow-up stages were combined using inverse-variance weighted fixed-effects meta-analysis, and in-silico lookups were done in stroke subtypes. For genome-wide significant findings (at p<5 × 10−8), we explored associations with additional cerebrovascular phenotypes and did functional experiments using conditional (inducible) deletion of the probable causal gene in mice. We also studied the expression of orthologs of this probable causal gene and its effects on cerebral vasculature in zebrafish mutants. Findings We replicated seven of eight known loci associated with risk for ischaemic stroke, and identified a novel locus at chromosome 6p25 (rs12204590, near FOXF2) associated with risk of all-stroke (odds ratio [OR] 1·08, 95% CI 1·05–1·12, p=1·48 × 10−8; minor allele frequency 21%). The rs12204590 stroke risk allele was also associated with increased MRI-defined burden of white matter hyperintensity—a marker of cerebral small vessel disease—in stroke-free adults (n=21 079; p=0·0025). Consistently, young patients (aged 2–32 years) with segmental deletions of FOXF2 showed an extensive burden of white matter hyperintensity. Deletion of Foxf2 in adult mice resulted in cerebral infarction, reactive gliosis, and microhaemorrhage. The orthologs of FOXF2 in zebrafish (foxf2b and foxf2a) are expressed in brain pericytes and mutant foxf2b−/− cerebral vessels show decreased smooth muscle cell and pericyte coverage. Interpretation We identified common variants near FOXF2 that are associated with increased stroke susceptibility. Epidemiological and experimental data suggest that FOXF2 mediates this association, potentially via differentiation defects of cerebral vascular mural cells. Further expression studies in appropriate human tissues, and further functional experiments with long follow-up periods are needed to fully understand the underlying mechanisms. Funding NIH, NINDS, NHMRC, CIHR, European national research institutions, Fondation Leducq. © 2016 Elsevier Ltd
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| 2. |
- Miro, J M, et al.
(författare)
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Staphylococcus aureus native valve infective endocarditis: report of 566 episodes from the International Collaboration on Endocarditis Merged Database.
- 2005
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Ingår i: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. - : Oxford University Press (OUP). - 1537-6591. ; 41:4, s. 507-14
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Staphylococcus aureus native valve infective endocarditis (SA-NVIE) is not completely understood. The objective of this investigation was to describe the characteristics of a large, international cohort of patients with SA-NVIE. METHODS: The International Collaboration on Endocarditis Merged Database (ICE-MD) is a combination of 7 existing electronic databases from 5 countries that contains data on 2212 cases of definite infective endocarditis (IE). RESULTS: Of patients with native valve IE, 566 patients [corrected] had IE due to S. aureus, and 1074 patients had IE due to pathogens other than S. aureus (non-SA-NVIE). Patients with S. aureus IE were more likely to die (20% vs. 12%; P < .001), to experience an embolic event (61% [corrected] vs. 31%; P < .001), or to have a central nervous system event (21% [corrected] vs. 13%; P < .001) and were less likely to undergo surgery (26% vs. 39%; P < .001) than were patients with non-SA-NVIE. Multivariate analysis of prognostic factors of mortality identified age (odds ratio [OR], 1.4; 95% confidence interval [CI], 1.1-1.7), periannular abscess (OR, 2.4; 95% CI, 1.0 [corrected] -5.6), heart failure (OR, 3.9; 95% CI, 2.3-6.7), and absence of surgical therapy (OR, 2.3; 95% CI, 1.3-4.2) as variables that were independently associated with mortality in patients with SA-NVIE. After adjusting for patient-, pathogen-, and treatment-specific characteristics by multivariate analysis, geographical region was also found to be associated with mortality in patients with SA-NVIE (P < .001). CONCLUSIONS: S. aureus is an important and common cause of IE. The outcome of SA-NVIE is worse than that of non-SA-NVIE. Several clinical parameters are independently associated with mortality for patients with SA-NVIE. The clinical characteristics and outcome of SA-NVIE vary significantly by geographic region, although the reasons for such regional variations in outcomes of SA-NVIE are unknown and are probably multifactorial. A large, prospective, multinational cohort study of patients with IE is now under way to further investigate these observations.
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| 3. |
- Murdoch, David R, et al.
(författare)
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Clinical presentation, etiology, and outcome of infective endocarditis in the 21st century: the International Collaboration on Endocarditis-Prospective Cohort Study.
- 2009
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Ingår i: Archives of internal medicine. - : American Medical Association (AMA). - 1538-3679 .- 0003-9926. ; 169:5, s. 463-73
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: We sought to provide a contemporary picture of the presentation, etiology, and outcome of infective endocarditis (IE) in a large patient cohort from multiple locations worldwide. METHODS: Prospective cohort study of 2781 adults with definite IE who were admitted to 58 hospitals in 25 countries from June 1, 2000, through September 1, 2005. RESULTS: The median age of the cohort was 57.9 (interquartile range, 43.2-71.8) years, and 72.1% had native valve IE. Most patients (77.0%) presented early in the disease (<30 days) with few of the classic clinical hallmarks of IE. Recent health care exposure was found in one-quarter of patients. Staphylococcus aureus was the most common pathogen (31.2%). The mitral (41.1%) and aortic (37.6%) valves were infected most commonly. The following complications were common: stroke (16.9%), embolization other than stroke (22.6%), heart failure (32.3%), and intracardiac abscess (14.4%). Surgical therapy was common (48.2%), and in-hospital mortality remained high (17.7%). Prosthetic valve involvement (odds ratio, 1.47; 95% confidence interval, 1.13-1.90), increasing age (1.30; 1.17-1.46 per 10-year interval), pulmonary edema (1.79; 1.39-2.30), S aureus infection (1.54; 1.14-2.08), coagulase-negative staphylococcal infection (1.50; 1.07-2.10), mitral valve vegetation (1.34; 1.06-1.68), and paravalvular complications (2.25; 1.64-3.09) were associated with an increased risk of in-hospital death, whereas viridans streptococcal infection (0.52; 0.33-0.81) and surgery (0.61; 0.44-0.83) were associated with a decreased risk. CONCLUSIONS: In the early 21st century, IE is more often an acute disease, characterized by a high rate of S aureus infection. Mortality remains relatively high.
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