| 1. |
- Kanai, M, et al.
(författare)
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- 2023
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swepub:Mat__t
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| 2. |
- Niemi, MEK, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 9. |
- Hollestelle, Antoinette, et al.
(författare)
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No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer
- 2016
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Ingår i: Gynecologic Oncology. - : Elsevier BV. - 0090-8258 .- 1095-6859. ; 141:2, s. 386-401
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Tidskriftsartikel (refereegranskat)abstract
- Objective Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3′ UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. Methods Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). Results We found no association with risk of ovarian cancer (OR = 0.99, 95% CI 0.94-1.04, p = 0.74) or breast cancer (OR = 0.98, 95% CI 0.94-1.01, p = 0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR = 1.09, 95% CI 0.97-1.23, p = 0.14, breast cancer HR = 1.04, 95% CI 0.97-1.12, p = 0.27; BRCA2, ovarian cancer HR = 0.89, 95% CI 0.71-1.13, p = 0.34, breast cancer HR = 1.06, 95% CI 0.94-1.19, p = 0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR = 0.94, 95% CI 0.83-1.07, p = 0.38), breast cancer (HR = 0.96, 95% CI 0.87-1.06, p = 0.38), and all other previously-reported associations. Conclusions rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.
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| 10. |
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| 11. |
- Lawrenson, Kate, et al.
(författare)
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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
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| 12. |
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| 14. |
- Pulit, SL, et al.
(författare)
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Loci associated with ischaemic stroke and its subtypes (SiGN): a genome-wide association study.
- 2016
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Ingår i: The Lancet. Neurology. - 1474-4465. ; 15:2, s. 174-84
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Tidskriftsartikel (refereegranskat)abstract
- The discovery of disease-associated loci through genome-wide association studies (GWAS) is the leading genetic approach to the identification of novel biological pathways underlying diseases in humans. Until recently, GWAS in ischaemic stroke have been limited by small sample sizes and have yielded few loci associated with ischaemic stroke. We did a large-scale GWAS to identify additional susceptibility genes for stroke and its subtypes.To identify genetic loci associated with ischaemic stroke, we did a two-stage GWAS. In the first stage, we included 16851 cases with state-of-the-art phenotyping data and 32473 stroke-free controls. Cases were aged 16 to 104 years, recruited between 1989 and 2012, and subtypes of ischaemic stroke were recorded by centrally trained and certified investigators who used the web-based protocol, Causative Classification of Stroke (CCS). We constructed case-control strata by identifying samples that were genotyped on nearly identical arrays and were of similar genetic ancestral background. We cleaned and imputed data by use of dense imputation reference panels generated from whole-genome sequence data. We did genome-wide testing to identify stroke-associated loci within each stratum for each available phenotype, and we combined summary-level results using inverse variance-weighted fixed-effects meta-analysis. In the second stage, we did in-silico lookups of 1372 single nucleotide polymorphisms identified from the first stage GWAS in 20941 cases and 364736 unique stroke-free controls. The ischaemic stroke subtypes of these cases had previously been established with the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification system, in accordance with local standards. Results from the two stages were then jointly analysed in a final meta-analysis.We identified a novel locus (G allele at rs12122341) at 1p13.2 near TSPAN2 that was associated with large artery atherosclerosis-related stroke (first stage odds ratio [OR] 1·21, 95% CI 1·13-1·30, p=4·50×10(-8); joint OR 1·19, 1·12-1·26, p=1·30×10(-9)). Our results also supported robust associations with ischaemic stroke for four other loci that have been reported in previous studies, including PITX2 (first stage OR 1·39, 1·29-1·49, p=3·26×10(-19); joint OR 1·37, 1·30-1·45, p=2·79×10(-32)) and ZFHX3 (first stage OR 1·19, 1·11-1·27, p=2·93×10(-7); joint OR 1·17, 1·11-1·23, p=2·29×10(-10)) for cardioembolic stroke, and HDAC9 (first stage OR 1·29, 1·18-1·42, p=3·50×10(-8); joint OR 1·24, 1·15-1·33, p=4·52×10(-9)) for large artery atherosclerosis stroke. The 12q24 locus near ALDH2, which has previously been associated with all ischaemic stroke but not with any specific subtype, exceeded genome-wide significance in the meta-analysis of small artery stroke (first stage OR 1·20, 1·12-1·28, p=6·82×10(-8); joint OR 1·17, 1·11-1·23, p=2·92×10(-9)). Other loci associated with stroke in previous studies, including NINJ2, were not confirmed.Our results suggest that all ischaemic stroke-related loci previously implicated by GWAS are subtype specific. We identified a novel gene associated with large artery atherosclerosis stroke susceptibility. Follow-up studies will be necessary to establish whether the locus near TSPAN2 can be a target for a novel therapeutic approach to stroke prevention. In view of the subtype-specificity of the associations detected, the rich phenotyping data available in the Stroke Genetics Network (SiGN) are likely to be crucial for further genetic discoveries related to ischaemic stroke.US National Institute of Neurological Disorders and Stroke, National Institutes of Health.
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| 15. |
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| 19. |
- Bellenguez, Celine, et al.
(författare)
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Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:3, s. 141-328
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Tidskriftsartikel (refereegranskat)abstract
- Genetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 x 10(-11); odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28-1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes.
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| 20. |
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| 21. |
- Fortner, Renée T., et al.
(författare)
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Ovarian cancer risk factors by tumor aggressiveness : An analysis from the Ovarian Cancer Cohort Consortium
- 2019
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 145:1, s. 58-69
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Tidskriftsartikel (refereegranskat)abstract
- Ovarian cancer risk factors differ by histotype; however, within subtype, there is substantial variability in outcomes. We hypothesized that risk factor profiles may influence tumor aggressiveness, defined by time between diagnosis and death, independent of histology. Among 1.3 million women from 21 prospective cohorts, 4,584 invasive epithelial ovarian cancers were identified and classified as highly aggressive (death in <1 year, n = 864), very aggressive (death in 1 to < 3 years, n = 1,390), moderately aggressive (death in 3 to < 5 years, n = 639), and less aggressive (lived 5+ years, n = 1,691). Using competing risks Cox proportional hazards regression, we assessed heterogeneity of associations by tumor aggressiveness for all cases and among serous and endometrioid/clear cell tumors. Associations between parity (phet = 0.01), family history of ovarian cancer (phet = 0.02), body mass index (BMI; phet ≤ 0.04) and smoking (phet < 0.01) and ovarian cancer risk differed by aggressiveness. A first/single pregnancy, relative to nulliparity, was inversely associated with highly aggressive disease (HR: 0.72; 95% CI [0.58-0.88]), no association was observed for subsequent pregnancies (per pregnancy, 0.97 [0.92-1.02]). In contrast, first and subsequent pregnancies were similarly associated with less aggressive disease (0.87 for both). Family history of ovarian cancer was only associated with risk of less aggressive disease (1.94 [1.47-2.55]). High BMI (≥35 vs. 20 to < 25 kg/m2 , 1.93 [1.46-2.56] and current smoking (vs. never, 1.30 [1.07-1.57]) were associated with increased risk of highly aggressive disease. Results were similar within histotypes. Ovarian cancer risk factors may be directly associated with subtypes defined by tumor aggressiveness, rather than through differential effects on histology. Studies to assess biological pathways are warranted.
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| 22. |
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| 23. |
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| 24. |
- Curtis, Bruce A., et al.
(författare)
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Algal genomes reveal evolutionary mosaicism and the fate of nucleomorphs
- 2012
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 492:7427, s. 59-65
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Tidskriftsartikel (refereegranskat)abstract
- Cryptophyte and chlorarachniophyte algae are transitional forms in the widespread secondary endosymbiotic acquisition of photosynthesis by engulfment of eukaryotic algae. Unlike most secondary plastid-bearing algae, miniaturized versions of the endosymbiont nuclei (nucleomorphs) persist in cryptophytes and chlorarachniophytes. To determine why, and to address other fundamental questions about eukaryote-eukaryote endosymbiosis, we sequenced the nuclear genomes of the cryptophyte Guillardia theta and the chlorarachniophyte Bigelowiella natans. Both genomes have >21,000 protein genes and are intron rich, and B. natans exhibits unprecedented alternative splicing for a single-celled organism. Phylogenomic analyses and subcellular targeting predictions reveal extensive genetic and biochemical mosaicism, with both host-and endosymbiont-derived genes servicing the mitochondrion, the host cell cytosol, the plastid and the remnant endosymbiont cytosol of both algae. Mitochondrion-to-nucleus gene transfer still occurs in both organisms but plastid-to-nucleus and nucleomorph-to-nucleus transfers do not, which explains why a small residue of essential genes remains locked in each nucleomorph.
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| 25. |
- Metra, M., et al.
(författare)
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Influence of heart rate, blood pressure, and beta-blocker dose on outcome and the differences in outcome between carvedilol and metoprolol tartrate in patients with chronic heart failure: results from the COMET trial
- 2005
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Ingår i: European heart journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 26:21, s. 2259-68
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: We studied the influence of heart rate (HR), systolic blood pressure (SBP), and beta-blocker dose on outcome in the 2599 out of 3029 patients in Carvedilol Or Metoprolol European Trial (COMET) who were alive and on study drug at 4 months after randomization (time of first visit on maintenance therapy). METHODS AND RESULTS: By multivariable analysis, baseline HR, baseline SBP, and their change after 4 months were not independently related to subsequent outcome. In a multivariable analysis including clinical variables, HR above and SBP below the median value achieved at 4 months predicted subsequent increased mortality [relative risk (RR) for HR>68 b.p.m. 1.333; 95% confidence intervals (CI) 1.152-1.542; P<0.0001 and RR for SBP>120 mmHg 0.78; 95% CI 0.671-0.907; P<0.0013]. Achieving target beta-blocker dose was associated with a better outcome (RR 0.779; 95% CI 0.662-0.916; P<0.0025). The superiority of carvedilol as compared to metoprolol tartrate was maintained in a multivariable model (RR 0.767; 95% CI 0.663-0.887; P=0.0004) and there was no interaction with HR, SBP, or beta-blocker dose. CONCLUSION: Beta-blocker dose, HR, and SBP achieved during beta-blocker therapy have independent prognostic value in heart failure. None of these factors influenced the beneficial effects of carvedilol when compared with metoprolol tartrate at the pre-defined target doses used in COMET.
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| 26. |
- Scott, Robert A., et al.
(författare)
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A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease
- 2016
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 8:341
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Tidskriftsartikel (refereegranskat)abstract
- Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.
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| 27. |
- Torp-Pedersen, C., et al.
(författare)
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Effects of metoprolol and carvedilol on preexisting and new on-set diabetes in patients with chronic heart failure {inverted exclamation}V data from the Carvedilol or metoprolol European Trial (COMET)
- 2007
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Ingår i: Heart. - 1468-201X. ; 93:8, s. 968-973
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Tidskriftsartikel (refereegranskat)abstract
- Objective Beta-blocker therapy may worsen glucose metabolism. We studied the development of new onset diabetes in a large cohort of heart failure patients treated with either metoprolol or carvedilol. Design Prospective and retrospective analysis of a controlled clinical trial. Setting Multinational multicenter study Patients 3029 patients with chronic heart failure. Interventions Randomly assigned treatment with carvedilol (n=1511, target dose 50 mg daily) or metoprolol tartrate (n=1518, target dose 100 mg daily). Results Diabetic events (diabetic coma, peripheral gangrene, diabetic foot, de-creased glucose tolerance or hyperglycemia) and new onset diabetes (clinical di-agnosis, repeated high random glucose level or glucose lowering medication) were assessed in 2298 patients without diabetes at baseline. Diabetic events oc-curred in 122/1151 (10.6%) patients in the carvedilol group and 149/1147 (13.0%) patients in the metoprolol group (hazard ratio (HR) 0.78; 95% confi-dence interval (CI) 0.61-0.99, p=0.039). New onset diabetes was diagnosed in 119/1151 (10.4%) versus 145/1147 (12.6%) cases in the carvedilol and metoprolol treatment groups (HR 0.78, CI 0.61-0.998, p=0.048). Patients with diabetes at baseline had an increased mortality, compared to non-diabetics (45.3% versus, 33.9%; HR 1.45, CI 1.28-1.65). Both diabetics and non-diabetics at baseline had a similar reduction in mortality with carvedilol compared to metoprolol (RR 0.85; CI 0.69-1.06 and RR 0.82; CI, 0.71-0.94, respectively). Conclusion This study demonstrates both a high prevalence and incidence of diabetes in patients with heart failure over a course of 5 years. New onset diabe-tes was more likely to occur during treatment with metoprolol than during treat-ment with carvedilol.
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| 28. |
- Di Lenarda, A., et al.
(författare)
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Exchange of beta-blockers in heart failure patients. Experiences from the poststudy phase of COMET (the Carvedilol or Metoprolol European Trial)
- 2005
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Ingår i: European journal of heart failure. - : Wiley. - 1388-9842. ; 7:4, s. 640-9
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The Carvedilol or Metoprolol European Trial (COMET) reported a significant survival benefit for carvedilol, a beta1-, beta2- and alpha1-blocker, vs. metoprolol tartrate, a beta1-selective blocker, in patients with mild-to-severe chronic heart failure (CHF). Patients on treatment with metoprolol might benefit from switching to carvedilol. AIM: To investigate the safety and tolerability of switching beta-blockers in CHF. METHODS: At the end of COMET, the Steering Committee recommended that study medication was stopped without unblinding, and patients were commenced on open-label beta-blockade at a dose equivalent to half the dose of blinded therapy, with subsequent titration to target or maximum tolerated dose. Patients were followed for 30 days. RESULTS: 1321 out of 1440 patients were transitioned to open-label treatment (76.8% to carvedilol). Serious adverse and CHF-related events were respectively 9.4% and 4.7% in those switching from carvedilol to metoprolol and 3.1% and 1.5% in patients switching from metoprolol to carvedilol. Patients who switched from carvedilol to metoprolol showed the highest mortality or hospitalisation rate (12.3%) in comparison with those who switched from metoprolol to carvedilol (3.1%, p<0.001) or who stayed on the same drug (carvedilol: 2.5%, p<0.001; metoprolol: 4.2%, p=0.04). Reducing the initial dose of the second beta-blocker maximised the safety of this strategy. Event rate was higher in patients with more severe heart failure and in those withdrawing from beta-blockade. CONCLUSION: Our data show that switching beta-blockers is a practical, safe and well-tolerated strategy to optimise treatment of CHF. Patients who switched to carvedilol showed the lowest rate of adverse events. A closer clinical monitoring is recommended during transition in high-risk patients.
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| 29. |
- Franke, A., et al.
(författare)
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Status and trends of circumpolar peregrine falcon and gyrfalcon populations
- 2020
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Ingår i: Ambio. - : Springer Science and Business Media LLC. - 0044-7447 .- 1654-7209. ; 49:3, s. 762-783
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Tidskriftsartikel (refereegranskat)abstract
- The peregrine falcon (Falco peregrinus) and the gyrfalcon (Falco rusticolus) are top avian predators of Arctic ecosystems. Although existing monitoring efforts are well established for both species, collaboration of activities among Arctic scientists actively involved in research of large falcons in the Nearctic and Palearctic has been poorly coordinated. Here we provide the first overview of Arctic falcon monitoring sites, present trends for long-term occupancy and productivity, and summarize information describing abundance, distribution, phenology, and health of the two species. We summarize data for 24 falcon monitoring sites across the Arctic, and identify gaps in coverage for eastern Russia, the Arctic Archipelago of Canada, and East Greenland. Our results indicate that peregrine falcon and gyrfalcon populations are generally stable, and assuming that these patterns hold beyond the temporal and spatial extents of the monitoring sites, it is reasonable to suggest that breeding populations at broader scales are similarly stable. We have highlighted several challenges that preclude direct comparisons of Focal Ecosystem Components (FEC) attributes among monitoring sites, and we acknowledge that methodological problems cannot be corrected retrospectively, but could be accounted for in future monitoring. Despite these drawbacks, ample opportunity exists to establish a coordinated monitoring program for Arctic-nesting raptor species that supports CBMP goals.
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| 30. |
- Remme, W. J., et al.
(författare)
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Carvedilol protects better against vascular events than metoprolol in heart failure: results from COMET
- 2007
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Ingår i: Journal of the American College of Cardiology. - 1558-3597. ; 49:9, s. 963-71
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: We explored whether vascular protection by carvedilol could contribute to its superior effects in the treatment of heart failure (HF) compared with metoprolol tartrate in the COMET (Carvedilol Or Metoprolol European Trial) study. BACKGROUND: Full adrenergic blockade by carvedilol and additional (e.g., antioxidative) properties may lead to vascular protection relative to beta-1 blockade alone, and contribute to its efficacy in HF treatment. METHODS: Three thousand twenty-nine patients with HF due to ischemic (51%) or idiopathic cardiomyopathy (44%) were randomized double-blind to carvedilol (n = 1,511) or metoprolol (n = 1,518) and followed for 58 months. Vascular end points were cardiovascular death, stroke, stroke death, myocardial infarction (MI), and unstable angina. RESULTS: The effect of carvedilol on cardiovascular death improved consistently in subgroups with prespecified baseline variables. Myocardial infarctions were reported in 69 carvedilol and 94 metoprolol patients (hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.52 to 0.97, p = 0.03). Cardiovascular death or nonfatal MI combined were reduced by 19% in carvedilol (HR 0.81, 95% CI 0.72 to 0.92, p = 0.0009 vs. metoprolol). Unstable angina was reported as an adverse event in 56 carvedilol and in 77 metoprolol patients (HR 0.71, 95% CI 0.501 to 0.998, p = 0.049). A stroke occurred in 65 carvedilol and 80 metoprolol patients (HR 0.79, 95% CI 0.57 to 1.10). Stroke or MI combined occurred in 130 carvedilol and 168 metoprolol patients (HR 0.75, 95% CI 0.60 to 0.95, p = 0.015), and fatal MI or fatal stroke occurred in 34 carvedilol and in 72 metoprolol patients (HR 0.46, 95% CI 0.31 to 0.69, p = 0.0002). Death after a nonfatal MI or stroke occurred in 61 of 124 carvedilol and in 106 of 160 metoprolol patients (HR 0.66, 95% CI 0.48 to 0.90, p = 0.0086). CONCLUSIONS: Carvedilol improves vascular outcomes better than metoprolol. These results suggest a ubiquitous protective effect of carvedilol against major vascular events.
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| 31. |
- Torp-Pedersen, C., et al.
(författare)
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Effects of metoprolol and carvedilol on cause-specific mortality and morbidity in patients with chronic heart failure--COMET
- 2005
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Ingår i: American heart journal. - 1097-6744. ; 149:2, s. 370-6
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Beta-blockers with different receptor bindings reduce mortality in patients with chronic heart failure. We compared the effects of the beta1-blocker metoprolol tartrate and the beta1-, beta2-, and alpha1-blocker carvedilol. METHODS: In a randomized double-blind design, 3029 patients with chronic congestive heart failure requiring diuretic therapy and with left ventricular dysfunction were randomized to treatment with carvedilol (n = 1511) or metoprolol tartrate (n = 1518) and titrated to target doses of 25 mg of carvedilol twice daily or 50 mg of metoprolol tartrate twice daily. The main outcome measures were total mortality and the combination of mortality or hospitalization for any cause. Secondary end points were cardiovascular death, combinations of morbidity and mortality, New York Heart Association class, worsening of heart failure, hospitalizations, and discontinuation of study therapy. RESULTS: A total of 512 and 600 patients in the carvedilol group and metoprolol group, respectively, died (hazard ratio [HR] 0.83, 95% CI 0.74-0.93, P = .0017). Cardiovascular death was reduced by carvedilol (HR 0.80, 95% CI 0.70-0.90, P = .0004). There were fewer sudden deaths and deaths caused by circulatory failure or by stroke in the carvedilol group. There was no difference in all-cause hospitalizations or in worsening heart failure between treatment groups. The incidence of fatal or nonfatal acute myocardial infarction was significantly lower in the carvedilol group (HR 0.71, 95% CI 0.52-0.97, P = .03). Discontinuations of study therapy were similar in the 2 groups. CONCLUSION: Compared with metoprolol tartrate, carvedilol reduced cardiovascular mortality, sudden death, death caused by circulatory failure, death caused by stroke, as well as fatal and nonfatal myocardial infarctions.
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| 32. |
- Torp-Pedersen, C., et al.
(författare)
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The safety of amiodarone in patients with heart failure
- 2007
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Ingår i: J Card Fail. - 1532-8414. ; 13:5, s. 340-5
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Uncertainty persists about the safety and efficacy of amiodarone for the management of heart failure. METHODS AND RESULTS: We randomized 3029 patients with chronic heart failure to receive carvedilol or metoprolol and followed patients for a median of 58 months. One hundred fifty-five of 1466 patients in New York Heart Association (NYHA) Class II and 209 of 1563 in Class III or IV received amiodarone at baseline. Persistence with amiodarone treatment was high and 66% received amiodarone after 4 years. During follow-up, 38.7% and 58.9% of patients receiving amiodarone in NYHA Classes II and III + IV died versus 26.2% and 43.3% not receiving amiodarone (P < .001). This difference was maintained in multivariable analysis (hazard ratio [HR] 1.5, 95% confidence interval [CI] 1.2-1.7, P < .001). The difference was explained by an increased risk of death due to circulatory failure (HR 2.4, CI 1.9-3.1, P < .001) in patients receiving amiodarone. Sudden death was not different (HR 1.07, CI 0.8-1.4, P = .7). The increased risk was similar across NYHA classes with HR of 1.60 (CI 1.2-2.1, P < .001) in NYHA Class II versus 1.58 (CI 1.3-1.9, P < .001) in Classes III + IV. CONCLUSIONS: Treatment with amiodarone was associated with an increased risk of death from circulatory failure independent of functional class.
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| 33. |
- Wentzensen, Nicolas, et al.
(författare)
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Ovarian Cancer Risk Factors by Histologic Subtype : An Analysis From the Ovarian Cancer Cohort Consortium
- 2016
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Ingår i: Journal of Clinical Oncology. - : AMER SOC CLINICAL ONCOLOGY. - 0732-183X .- 1527-7755. ; 34:24, s. 2888-2898
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: An understanding of the etiologic heterogeneity of ovarian cancer is important for improving prevention, early detection, and therapeutic approaches. We evaluated 14 hormonal, reproductive, and lifestyle factors by histologic subtype in the Ovarian Cancer Cohort Consortium (OC3).Patients and Methods: Among 1.3 million women from 21 studies, 5,584 invasive epithelial ovarian cancers were identified (3,378 serous, 606 endometrioid, 331 mucinous, 269 clear cell, 1,000 other). By using competing-risks Cox proportional hazards regression stratified by study and birth year and adjusted for age, parity, and oral contraceptive use, we assessed associations for all invasive cancers by histology. Heterogeneity was evaluated by likelihood ratio test.Results: Most risk factors exhibited significant heterogeneity by histology. Higher parity was most strongly associated with endometrioid (relative risk [RR] per birth, 0.78; 95% CI, 0.74 to 0.83) and clear cell (RR, 0.68; 95% CI, 0.61 to 0.76) carcinomas (P value for heterogeneity [P-het] < .001). Similarly, age at menopause, endometriosis, and tubal ligation were only associated with endometrioid and clear cell tumors (P-het ≤ .01). Family history of breast cancer (P-het = .008) had modest heterogeneity. Smoking was associated with an increased risk of mucinous (RR per 20 pack-years, 1.26; 95% CI, 1.08 to 1.46) but a decreased risk of clear cell (RR, 0.72; 95% CI, 0.55 to 0.94) tumors (P-het = .004). Unsupervised clustering by risk factors separated endometrioid, clear cell, and low-grade serous carcinomas from high-grade serous and mucinous carcinomas.Conclusion: The heterogeneous associations of risk factors with ovarian cancer subtypes emphasize the importance of conducting etiologic studies by ovarian cancer subtypes. Most established risk factors were more strongly associated with nonserous carcinomas, which demonstrate challenges for risk prediction of serous cancers, the most fatal subtype.
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| 34. |
- Cleland, J. G., et al.
(författare)
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A comparison of the effects of carvedilol and metoprolol on well-being, morbidity, and mortality (the "patient journey") in patients with heart failure: a report from the Carvedilol Or Metoprolol European Trial (COMET)
- 2006
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 1558-3597 .- 0735-1097. ; 47:8, s. 1603-11
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: This study was designed to investigate the loss of well-being, in terms of life-years, overall and in patients randomized to metoprolol versus carvedilol in the Carvedilol Or Metoprolol European Trial (COMET). BACKGROUND: The ultimate objectives of treating patients with heart failure are to relieve suffering and prolong life. Although the effect of treatment on mortality is usually described in trials, the effects on patient well-being throughout the trials' courses are rarely reported. METHODS: A total of 3,029 patients randomized in the COMET study were included in the analysis. "Patient journey" was calculated by adjusting days alive and out of hospital over four years using a five-point score completed by the patient every four months, adjusted according to the need for intensification of diuretic therapy. Scores ranged from 0% (dead or hospitalized) to 100% (feeling very well). RESULTS: Over 48 months, 17% of all days were lost through death, 1% through hospitalization, 23% through impaired well-being, and 2% through the need for intensified therapy. Compared with metoprolol, carvedilol was associated with fewer days lost to death, with no increase in days lost due to impaired well-being or days in hospital. The "patient journey" score improved from a mean of 54.8% (SD 26.0) to 57.4% (SD 26.3%) (p < 0.0068). CONCLUSIONS: Despite treatment with beta-blockers, heart failure remains associated with a marked reduction in well-being and survival. Loss of quality-adjusted life-years through death and poor well-being seemed of similar magnitude over four years, and both were much larger than the loss that could be attributed to hospitalization.
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| 35. |
- Cleland, J. G., et al.
(författare)
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A description of the clinical characteristics at baseline of patients recruited into the Carvedilol or Metoprolol European Trial (COMET)
- 2004
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Ingår i: Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy. - 0920-3206. ; 18:2, s. 139-52
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: The COMET trial was a prospective, double-blind, randomised trial comparing carvedilol, a comprehensive adrenergic receptor antagonist, with metoprolol, a beta-1-selective agent in patients with heart failure and left ventricular systolic dysfunction. The trial showed a reduction in mortality with carvedilol that was consistent across subgroups. The purpose of this report is to describe in greater detail the heterogeneity of this population at baseline with particular reference to the impact of symptomatic severity, age and gender on patient characteristics. METHODS: A descriptive report using data entered in the COMET study data-base. RESULTS: The characteristics of the population studied were similar to those reported in previous trials of beta-blockers. Almost all patients were receiving diuretics and ACE inhibitors with few patients taking angiotensin receptor blockers. As expected, older patients had more co-morbidity. Older patients and women reported worse symptoms and poorer well-being despite similar ventricular dimensions and systolic dysfunction. NT-proBNP was higher in patients with more severe symptoms and older patients but not in women, although differences in NT-proBNP may have been confounded by differences in renal function. CONCLUSION: Age and gender, as well as the severity of cardiac dysfunction, appear to have an important effect on the severity of heart failure symptoms and patient 'well-being'. This could have important implications for the relationship between symptoms and prognosis and therefore the way in which patients are selected for clinical trials and the goals of treatment. This will be the subject of further analyses.
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| 36. |
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| 37. |
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| 38. |
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| 39. |
- Komajda, M., et al.
(författare)
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The impact of new onset anaemia on morbidity and mortality in chronic heart failure: results from COMET
- 2006
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Ingår i: European heart journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 27:12, s. 1440-6
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Anaemia is a common comorbidity in chronic heart failure (CHF). The predictors of new onset anaemia (NOA) and its long-term prognostic value, particularly in patients treated with beta-blockers, are not known. METHODS AND RESULTS: In COMET, 3029 patients with CHF in NYHA II-IV and EF <35% were randomized to carvedilol or metoprolol tartrate and were followed for an average of 58 months. Plasma haemoglobin (Hb) concentrations were measured at a central laboratory at randomization, at four monthly intervals for the first year and annually thereafter. According to WHO criteria, anaemia was defined when Hb measured <13 g/dL for men and <12 g/dL for women. We considered anaemia to be severe when Hb <11.5 g/dL for men and <10.5 g/dL for women. The baseline mean Hb was 14.2 +/- 1.5 g/dL (n = 2996) and 15.9% of patients had anaemia (males, 16.0%; females, 15.2%). At baseline, severe anaemia was found in 3.3% of patients (males, 3.6%; females, 2.0%). During the study, all-cause mortality (RR 1.47) death or hospitalization (RR 1.28), and heart failure hospitalization (RR 1.43, all P < 0.0001) were higher in anaemic when compared with non-anaemic patients. In patients without anaemia at baseline, at the end of the study, the cumulative frequency of NOA was 28.1% in males and 27.0% in females. NOA increased over time from 14.2% at year 1 to 27.5% at year 5. Predictors of NOA were: higher age, diuretic dose, creatinine (all P < 0.0001), higher serum potassium, lower serum sodium, body mass index, and use of aldosterone antagonists, carvedilol, and digitalis (all P < 0.03). Treatment with carvedilol (vs. metoprolol tartrate) was associated with a 24% increased risk to develop NOA (P = 0.0047), but not severe anaemia (P = 0.18). Patients with a Hb decrease of >3 g/dL (RR 3.37, P < 0.0001) or of 2.0-3.0 g/dL (RR 1.47, P = 0.011) from baseline had an increased subsequent mortality when compared with patients having Hb increases of 0-1.0 g/dL. CONCLUSION: In stable ambulatory CHF patients, development of NOA is frequent and can be predicted by a set of clinical variables. Decreases in Hb over time relate to future increased morbidity and mortality.
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| 40. |
- Mittal, S., et al.
(författare)
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The World-wide Randomized Antibiotic Envelope Infection Prevention (WRAP-IT) trial: Long-term follow-up
- 2020
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Ingår i: Heart Rhythm. - : Elsevier BV. - 1547-5271. ; 17:7, s. 1115-1122
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Tidskriftsartikel (refereegranskat)abstract
- Background: The World-wide Randomized Antibiotic Envelope Infection Prevention trial reported a 40% reduction in major cardiac implantable electronic device (CIED) infections within 12 months of the procedure with the use of an antibacterial-eluting envelope (TYRX Absorbable Antibacterial Envelope, Medtronic, Mounds View, MN). Objective: The purpose of this report was to describe the longer-term (>12 months) envelope effects on infection reduction and complications. Methods: All trial patients who underwent CIED replacement, upgrade, revision, or initial cardiac resynchronization therapy – defibrillator implantation received standard-of-care infection prophylaxis and were randomized in a 1:1 ratio to receive the envelope or not. CIED infection incidence and procedure and system-related complications were characterized through all follow-up (36 months) by using Cox proportional hazards regression modeling. Results: In total, 6800 patients received their intended randomized treatment (3371 envelope; 3429 control; mean follow-up period 21.0 ± 8.3 months). Major CIED-related infections occurred in 32 envelope patients and 51 control patients (Kaplan-Meier [KM] estimate 1.3% vs 1.9%; hazard ratio [HR] 0.64; 95% confidence interval [CI] 0.41–0.99; P = .046). Any CIED-related infection occurred in 57 envelope patients and 84 control patients (KM estimate 2.1% vs 2.8%; HR 0.69; 95% CI 0.49–0.97; P = .030). System- or procedure-related complications occurred in 235 envelope patients and 252 control patients (KM estimate 8.0% vs 8.2%; HR 0.95; 95% CI 0.79–1.13; P < .001 for noninferiority); the most common were lead dislodgment (1.1%), device lead damage (0.5%), and implant site hematoma (0.4%). Implant site pain occurred less frequently in the envelope group (0.1% vs 0.4%; P = .067). There were no (0.0%) reports of allergic reactions to the components of the envelope (mesh, polymer, or antibiotics). Conclusion: The effects of the TYRX envelope on the reduction of the risk of CIED infection are sustained beyond the first year postprocedure, without an increased risk of complications. © 2020 The Authors
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| 41. |
- O'Connor, A., et al.
(författare)
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Plasma phospho-tau181 in presymptomatic and symptomatic familial Alzheimer's disease: a longitudinal cohort study
- 2021
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 26, s. 5967-5976
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Tidskriftsartikel (refereegranskat)abstract
- Blood biomarkers have great potential to advance clinical care and accelerate trials in Alzheimer's disease (AD). Plasma phospho-tau181 (p-tau181) is a promising blood biomarker however, it is unknown if levels increase in presymptomatic AD. Therefore, we investigated the timing of p-tau181 changes using 153 blood samples from 70 individuals in a longitudinal study of familial AD (FAD). Plasma p-tau181 was measured, using an in-house single molecule array assay. We compared p-tau181 between symptomatic carriers, presymptomatic carriers, and non-carriers, adjusting for age and sex. We examined the relationship between p-tau181 and neurofilament light and estimated years to/from symptom onset (EYO), as well as years to/from actual onset in a symptomatic subgroup. In addition, we studied associations between p-tau181 and clinical severity, as well testing for differences between genetic subgroups. Twenty-four were presymptomatic carriers (mean baseline EYO -9.6 years) while 27 were non-carriers. Compared with non-carriers, plasma p-tau181 concentration was higher in both symptomatic (p < 0.001) and presymptomatic mutation carriers (p < 0.001). Plasma p-tau181 showed considerable intra-individual variability but individual values discriminated symptomatic (AUC 0.93 [95% CI 0.85-0.98]) and presymptomatic (EYO >= -7 years) (AUC 0.86 [95% CI 0.72-0.94]) carriers from non-carriers of the same age and sex. From a fitted model there was evidence (p = 0.050) that p-tau181 concentrations were higher in mutation carriers than non-carriers from 16 years prior to estimated symptom onset. Our finding that plasma p-tau181 concentration is increased in symptomatic and presymptomatic FAD suggests potential utility as an easily accessible biomarker of AD pathology.
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| 42. |
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| 43. |
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| 44. |
- Vazir, A, et al.
(författare)
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Resolution of central sleep apnoea following implantation of a left ventricular assist device.
- 2010
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Ingår i: International Journal of Cardiology. - : Elsevier BV. - 0167-5273 .- 1874-1754. ; 4:138, s. 317-319
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Tidskriftsartikel (refereegranskat)abstract
- Central sleep apnoea (CSA) occurs in up to 40% of patients with chronic heart failure (CHF). It is thought to be a consequence of CHF and is associated with an accelerated decline in cardiac function, and increased morbidity and mortality. The optimal treatment of CSA remains unclear. Resolution of CSA has been reported after cardiac transplantation. We report the first case of resolution of CSA 10 months following implantation of a permanent Jarviktrade mark 2000 left ventricular assist device (LVAD). The correction of CSA after implantation of the LVAD was associated with improvements in symptoms, exercise capacity, renal function, and increased arterial carbon dioxide levels at rest during wakefulness and also reduction in brain natriuretic peptide.
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| 45. |
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| 46. |
- Beynnon, Bruce D, et al.
(författare)
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Rehabilitation After Anterior Cruciate Ligament Reconstruction: A Prospective, Randomized, Double-Blind Comparison of Programs Administered Over 2 Different Time Intervals.
- 2005
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Ingår i: The American journal of sports medicine. - : SAGE Publications. - 1552-3365 .- 0363-5465. ; 33:3, s. 347-359
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Tidskriftsartikel (refereegranskat)abstract
- There are adverse effects associated with immobilization of the knee after anterior cruciate ligament reconstruction, yet very little is known about how much activity will promote adequate rehabilitation without permanently elongating the graft, producing graft failure, or creating damage to articular cartilage. Hypothesis Rehabilitation with either an accelerated or nonaccelerated program produces no difference in anterior-posterior knee laxity, clinical assessment, patient satisfaction, functional performance, and the synovial fluid biomarkers of articular cartilage metabolism. Study Design Randomized controlled clinical trial; Level of evidence, 1. Methods Twenty-five patients who tore their anterior cruciate ligament were enrolled and underwent anterior cruciate ligament reconstruction. Patients were randomized to accelerated rehabilitation or nonaccelerated rehabilitation. At the time of surgery and 3, 6, 12, and 24 months later, measurements of anterior-posterior knee laxity, clinical assessment, patient satisfaction, functional performance, and cartilage metabolism were completed. Results At the 2-year follow-up, there was no difference in the increase of anterior knee laxity relative to the baseline values that were obtained immediately after surgery between the 2 groups (2.2-mm vs 1.8-mm increase relative to the normal knee). The groups were similar in terms of clinical assessment, patient satisfaction, activity level, function, and response of the bio-markers. After 1 year of healing, synthesis of collagen and turnover of aggrecan remained elevated in both groups. Conclusion Anterior cruciate ligament reconstruction with a bone-patellar tendon-bone graft followed by either accelerated or nonaccelerated rehabilitation produces the same increase of anterior knee laxity. Both programs had the same effect in terms of clinical assessment, patient satisfaction, functional performance, and the biomarkers of articular cartilage metabolism. There is concern that the cartilage biomarkers remained elevated for an extended period.
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| 47. |
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| 48. |
- Diller, Gerhard-Paul, et al.
(författare)
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Exercise intolerance in adult congenital heart disease : comparative severity, correlates, and prognostic implication.
- 2005
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Ingår i: Circulation. - 0009-7322 .- 1524-4539. ; 112:6, s. 828-35
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Although some patients with adult congenital heart disease (ACHD) report limitations in exercise capacity, we hypothesized that depressed exercise capacity may be more widespread than superficially evident during clinical consultation and could be a means of assessing risk.METHODS AND RESULTS: Cardiopulmonary exercise testing was performed in 335 consecutive ACHD patients (age, 33+/-13 years), 40 non-congenital heart failure patients (age, 58+/-15 years), and 11 young (age, 29+/-5 years) and 12 older (age, 59+/-9 years) healthy subjects. Peak oxygen consumption (peak VO2) was reduced in ACHD patients compared with healthy subjects of similar age (21.7+/-8.5 versus 45.1+/-8.6; P<0.001). No significant difference in peak VO2 was found between ACHD and heart failure patients of corresponding NYHA class (P=NS for each NYHA class). Within ACHD subgroups, peak VO2 gradually declined from aortic coarctation (28.7+/-10.4) to Eisenmenger (11.5+/-3.6) patients (P<0.001). Multivariable correlates of peak VO2 were peak heart rate (r=0.33), forced expiratory volume (r=0.33), pulmonary hypertension (r=-0.26), gender (r=-0.23), and body mass index (r=-0.19). After a median follow-up of 10 months, 62 patients (18.5%) were hospitalized or had died. On multivariable Cox analysis, peak VO2 predicted hospitalization or death (hazard ratio, 0.937; P=0.01) and was related to the frequency and duration of hospitalization (P=0.01 for each).CONCLUSIONS: Exercise capacity is depressed in ACHD patients (even in allegedly asymptomatic patients) on a par with chronic heart failure subjects. Lack of heart rate response to exercise, pulmonary arterial hypertension, and impaired pulmonary function are important correlates of exercise capacity, as is underlying cardiac anatomy. Poor exercise capacity identifies ACHD patients at risk for hospitalization or death.
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| 49. |
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| 50. |
- Fognini, A., et al.
(författare)
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Dephasing Free Photon Entanglement with a Quantum Dot
- 2019
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Ingår i: ACS Photonics. - : American Chemical Society (ACS). - 2330-4022. ; 6:7, s. 1656-1663
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Tidskriftsartikel (refereegranskat)abstract
- Generation of photon pairs from quantum dots with near-unity entanglement fidelity has been a long-standing scientific challenge. It is generally thought that the nuclear spins limit the entanglement fidelity through spin flip dephasing processes. However, this assumption lacks experimental support. Here, we show two-photon entanglement with negligible dephasing from an indium rich single quantum dot comprising a nuclear spin of 9/2 when excited quasi-resonantly. This finding is based on a significantly close match between our entanglement measurements and our model that assumes no dephasing and takes into account the detection system's timing jitter and dark counts. We suggest that neglecting the detection system is responsible for the degradation of the measured entanglement fidelity in the past and not the nuclear spins. Therefore, the key to unity entanglement from quantum dots comprises a resonant excitation scheme and a detection system with ultralow timing jitter and dark counts.
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