| 1. |
- Okada, Yukinori, et al.
(författare)
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Genetics of rheumatoid arthritis contributes to biology and drug discovery
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 506:7488, s. 376-381
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Tidskriftsartikel (refereegranskat)abstract
- A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)(1). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating similar to 10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2-4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation(5), cis-acting expression quantitative trait loci(6) and pathway analyses(7-9)-as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes-to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.
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| 2. |
- Lalani, T, et al.
(författare)
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Prosthetic valve endocarditis due to coagulase-negative staphylococci: findings from the International Collaboration on Endocarditis Merged Database.
- 2006
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Ingår i: European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology. - : Springer Science and Business Media LLC. - 0934-9723. ; 25:6, s. 365-8
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Tidskriftsartikel (refereegranskat)abstract
- Infective endocarditis due to coagulase-negative staphylococci is increasingly recognized as a difficult-to-treat disease associated with poor outcome. The aim of this report is to describe the characteristics and outcome of patients with prosthetic valve endocarditis (PVE) due to coagulase-negative staphylococci versus those of patients with PVE due to Staphylococcus aureus and viridans streptococci. Patients were identified through the International Collaboration on Endocarditis Merged Database. A total of 54 cases of coagulase-negative staphylococci PVE, 58 cases of S. aureus PVE, and 63 cases of viridans-streptococci-related PVE were available for analysis. There was no difference between the three groups with respect to the type of valve involved or the rate of embolization. However, heart failure was encountered more frequently with coagulase-negative staphylococci (54%) than with either S. aureus (33%; p=0.03) or viridans streptococci (32%; p=0.02). In addition, valvular abscesses complicated 39% of infections due to coagulase-negative staphylococci compared with 22% of those due to S. aureus (p=0.06) and 6% of those due to viridans streptococci (p<0.001). Mortality was highest in patients with S. aureus and coagulase-negative staphylococcal endocarditis (47 and 36%, respectively; p=0.22) and was considerably lower in patients with viridans streptococcal endocarditis (p=0.002 compared to patients with coagulase-negative staphylococcal endocarditis). The results of this analysis demonstrate the aggressive nature of coagulase-negative staphylococcal PVE and the substantially greater morbidity and mortality associated with this infection compared to PVE caused by other pathogens.
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| 3. |
- Barack, Leor, et al.
(författare)
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Black holes, gravitational waves and fundamental physics : a roadmap
- 2019
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Ingår i: Classical and quantum gravity. - : IOP Publishing. - 0264-9381 .- 1361-6382. ; 36:14
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Forskningsöversikt (refereegranskat)abstract
- The grand challenges of contemporary fundamental physics dark matter, dark energy, vacuum energy, inflation and early universe cosmology, singularities and the hierarchy problem all involve gravity as a key component. And of all gravitational phenomena, black holes stand out in their elegant simplicity, while harbouring some of the most remarkable predictions of General Relativity: event horizons, singularities and ergoregions. The hitherto invisible landscape of the gravitational Universe is being unveiled before our eyes: the historical direct detection of gravitational waves by the LIGO-Virgo collaboration marks the dawn of a new era of scientific exploration. Gravitational-wave astronomy will allow us to test models of black hole formation, growth and evolution, as well as models of gravitational-wave generation and propagation. It will provide evidence for event horizons and ergoregions, test the theory of General Relativity itself, and may reveal the existence of new fundamental fields. The synthesis of these results has the potential to radically reshape our understanding of the cosmos and of the laws of Nature. The purpose of this work is to present a concise, yet comprehensive overview of the state of the art in the relevant fields of research, summarize important open problems, and lay out a roadmap for future progress. This write-up is an initiative taken within the framework of the European Action on 'Black holes, Gravitational waves and Fundamental Physics'.
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| 4. |
- Anderson, D J, et al.
(författare)
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Enterococcal prosthetic valve infective endocarditis: report of 45 episodes from the International Collaboration on Endocarditis-merged database.
- 2005
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Ingår i: European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology. - : Springer Science and Business Media LLC. - 0934-9723. ; 24:10, s. 665-70
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Tidskriftsartikel (refereegranskat)abstract
- Enterococcal prosthetic valve infective endocarditis (PVE) is an incompletely understood disease. In the present study, patients with enterococcal PVE were compared to patients with enterococcal native valve endocarditis (NVE) and other types of PVE to determine differences in basic clinical characteristics and outcomes using a large multicenter, international database of patients with definite endocarditis. Forty-five of 159 (29%) cases of definite enterococcal endocarditis were PVE. Patients with enterococcal PVE were demographically similar to patients with enterococcal NVE but had more intracardiac abscesses (20% vs. 6%; p=0.009), fewer valve vegetations (51% vs. 79%; p<0.001), and fewer cases of new valvular regurgitation (12% vs. 45%; p=0.01). Patients with either enterococcal PVE or NVE were elderly (median age, 73 vs. 69; p=0.06). Rates of in-hospital mortality, surgical intervention, heart failure, peripheral embolization, and stroke were similar in both groups. Patients with enterococcal PVE were also demographically similar to patients with other types of PVE, but mortality may be lower (14% vs. 26%; p=0.08). Notably, 93% of patients with enterococcal PVE came from European centers, as compared with only 79% of patients with enterococcal NVE (p=0.03). Thus, patients with enterococcal PVE have higher rates of myocardial abscess formation and lower rates of new regurgitation compared to patients with enterococcal NVE, but there are no differences between the groups with regard to surgical or mortality rates. In contrast, though patients with enterococcal PVE and patients with other types of PVE share similar characteristics, mortality is higher in the latter group. Importantly, the prevalence of enterococcal PVE was higher in the European centers in this study.
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| 5. |
- Anguera, Ignasi, et al.
(författare)
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Clinical characteristics and outcome of aortic endocarditis with periannular abscess in the International Collaboration on Endocarditis Merged Database.
- 2005
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Ingår i: The American journal of cardiology. - : Elsevier BV. - 0002-9149. ; 96:7, s. 976-81
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Tidskriftsartikel (refereegranskat)abstract
- The aims of this study were to determine the clinical characteristics and outcome of patients who had definite infective endocarditis (IE) complicated by aortic ring abscess formation that was detected with transesophageal echocardiography (TEE) and to determine the prognostic significance of abscess formation in aortic valve IE. Patients who had aortic valve IE were selected from the International Collaboration on Endocarditis Merged Database (ICE-MD) if they underwent TEE. Among 311 patients who had definite aortic valve IE, 67 (22%) had periannular abscesses. They were more likely to have infection in the setting of a prosthetic valve (40% vs 19%, p <0.001) and coagulase-negative staphylococcal IE (18% vs 6%, p < 0.01) and less likely to have streptococcal IE than were patients who did not develop abscess (28% vs 46%, p = 0.01). Systemic embolization, central nervous system events, and heart failure did not differ between those who developed abscess and those who did not, but power was limited. Patients who had abscess were more likely to undergo surgery (84% vs 36%, p <0.001), and their in-hospital mortality rate was higher (19% vs 11%, p = 0.09). Multivariate analysis of prognostic factors of mortality in aortic IE identified age (odds ratio [OR] 1.6, 95% confidence interval [CI]1.2 to 2.1), Staphylococcus aureus (S. aureus) infection (OR 2.4, 95% CI 1.1 to 5.2), and heart failure (OR 2.9, 95% CI 1.4 to 6.1) as variables that were independently associated with increased risk of death. Periannular abscess formation showed a nonsignificant trend toward an increased risk of death (OR 1.9, 95% CI 0.9 to 3.8). Multivariate analysis of prognostic factors of mortality in complicated aortic IE with abscess formation identified S. aureus infection (OR 6.9, 95% CI 1.6 to 29.4) as independently associated with increased risk of death. In conclusion, in the current era of TEE and high use of surgical treatment, periannular abscess formation in aortic valve IE is not an independent risk factor for mortality. S. aureus infection is an independent prognostic factor for mortality in patients who have abscess formation.
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| 6. |
- Kourany, Wissam M, et al.
(författare)
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Influence of diabetes mellitus on the clinical manifestations and prognosis of infective endocarditis: a report from the International Collaboration on Endocarditis-Merged Database.
- 2006
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Ingår i: Scandinavian journal of infectious diseases. - : Informa UK Limited. - 0036-5548 .- 1651-1980. ; 38:8, s. 613-9
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this investigation was to study the influence of diabetes mellitus (DM) on outcomes of infective endocarditis (IE). Outcomes were compared between 150 diabetic and 905 non-diabetic patients with IE from the International Collaboration on Endocarditis Merged Database. Compared to non-diabetic patients, diabetic patients were older (median age 63 vs 57 y, p<0.001), were more often female (42.0% vs 31.9%, p=0.01), more often had comorbidities (41.5% vs 26.7%, p<0.001), and were more likely to be dialysis dependent (12.7% vs 4.0%, p<0.001). S. aureus was isolated more often (30.7% vs 21.7%, p=0.02), and microorganisms from the viridans Streptococcus group less often (16.7% vs 28.2%, p = 0.001) in the diabetic group. There was no difference with respect to the presence of congestive heart failure, embolism, intra-cardiac abscess, new valvular regurgitation, or valvular vegetation. Diabetic patients underwent surgical intervention less frequently (32.0% vs 44.9%, p = 0.003), and had higher overall in-hospital mortality (30.3% vs 18.6%, p = 0.001). On multivariable analysis, DM was an independent predictor of mortality (odds ratio (OR) = 1.71, 95% confidence interval (CI) 1.08-2.70), especially in male patients, as diabetic males had higher mortality than non-diabetic males (OR 2.18, CI 1.08-4.35). DM is an independent predictor of in-hospital mortality among patients hospitalized with IE.
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| 7. |
- 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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| 8. |
- Nacos, M.K., et al.
(författare)
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Kenaf xylan – A source of biologically active acidic oligosaccharides
- 2006
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Ingår i: Carbohydrate Polymers. - : Elsevier BV. - 0144-8617 .- 1879-1344. ; 66:1, s. 126-134
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Tidskriftsartikel (refereegranskat)abstract
- Two xylose-rich hemicellulose fractions were obtained from kenaf wood (Hibiscus cannabinus L.) through a series of sequential extractions which dissociated xylans from other cell wall components. These fractions were subsequently used as substrates for the production of biologically active aldouronic acids. Incubation of the xylans with a family 10 Thermoascus aurantiacus endoxylanase resulted in the isolation of an aldotetrauronic acid as the main acidic oligosaccharide in the hydrolysis products. Enzymic hydrolysis with a family 11 Sporotrichum thermophile endoxylanase instead resulted in the isolation of a aldopentauronic acid as the main acidic oligosaccharide. The identity and purity of both xylans and aldouronic acids were assessed with solid-state FT-IR, solid-state and solution 13C NMR spectroscopy.
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| 9. |
- Wang, Andrew, et al.
(författare)
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Contemporary clinical profile and outcome of prosthetic valve endocarditis.
- 2007
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Ingår i: JAMA : the journal of the American Medical Association. - : American Medical Association (AMA). - 1538-3598. ; 297:12, s. 1354-61
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Prosthetic valve endocarditis (PVE) is associated with significant mortality and morbidity. The contemporary clinical profile and outcome of PVE are not well defined. OBJECTIVES: To describe the prevalence, clinical characteristics, and outcome of PVE, with attention to health care-associated infection, and to determine prognostic factors associated with in-hospital mortality. DESIGN, SETTING, AND PARTICIPANTS: Prospective, observational cohort study conducted at 61 medical centers in 28 countries, including 556 patients with definite PVE as defined by Duke University diagnostic criteria who were enrolled in the International Collaboration on Endocarditis-Prospective Cohort Study from June 2000 to August 2005. MAIN OUTCOME MEASURE: In-hospital mortality. RESULTS: Definite PVE was present in 556 (20.1%) of 2670 patients with infective endocarditis. Staphylococcus aureus was the most common causative organism (128 patients [23.0%]), followed by coagulase-negative staphylococci (94 patients [16.9%]). Health care-associated PVE was present in 203 (36.5%) of the overall cohort. Seventy-one percent of health care-associated PVE occurred within the first year of valve implantation, and the majority of cases were diagnosed after the early (60-day) period. Surgery was performed in 272 (48.9%) patients during the index hospitalization. In-hospital death occurred in 127 (22.8%) patients and was predicted by older age, health care-associated infection (62/203 [30.5%]; adjusted odds ratio [OR], 1.62; 95% confidence interval [CI], 1.08-2.44; P = .02), S aureus infection (44/128 [34.4%]; adjusted OR, 1.73; 95% CI, 1.01-2.95; P = .05), and complications of PVE, including heart failure (60/183 [32.8%]; adjusted OR, 2.33; 95% CI, 1.62-3.34; P<.001), stroke (34/101 [33.7%]; adjusted OR, 2.25; 95% CI, 1.25-4.03; P = .007), intracardiac abscess (47/144 [32.6%]; adjusted OR, 1.86; 95% CI, 1.10-3.15; P = .02), and persistent bacteremia (27/49 [55.1%]; adjusted OR, 4.29; 95% CI, 1.99-9.22; P<.001). CONCLUSIONS: Prosthetic valve endocarditis accounts for a high percentage of all cases of infective endocarditis in many regions of the world. Staphylococcus aureus is now the leading cause of PVE. Health care-associated infection significantly influences the clinical characteristics and outcome of PVE. Complications of PVE strongly predict in-hospital mortality, which remains high despite prompt diagnosis and the frequent use of surgical intervention.
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