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| 2. |
- Roselli, Carolina, et al.
(författare)
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Multi-ethnic genome-wide association study for atrial fibrillation
- 2018
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:9, s. 1225-1233
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Tidskriftsartikel (refereegranskat)abstract
- Atrial fibrillation (AF) affects more than 33 million individuals worldwide(1) and has a complex heritability(2). We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.
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| 3. |
- Packer, M., et al.
(författare)
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Angiotensin Receptor Neprilysin Inhibition Compared With Enalapril on the Risk of Clinical Progression in Surviving Patients With Heart Failure
- 2015
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Ingår i: Circulation. - 0009-7322. ; 131, s. 54-61
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: -Clinical trials in heart failure have focused on the improvement in symptoms or decreases in the risk of death and other cardiovascular events. Little is known about the effect of drugs on the risk of clinical deterioration in surviving patients. METHODS AND RESULTS: -We compared the angiotensin-neprilysin inhibitor LCZ696 (400 mg daily) with the angiotensinconverting enzyme inhibitor enalapril (20 mg daily) in 8399 patients with heart failure and reduced ejection fraction in a double-blind trial. The analyses focused on prespecified measures of nonfatal clinical deterioration. In comparison with the enalapril group, fewer LCZ696-treated patients required intensification of medical treatment for heart failure (520 versus 604; hazard ratio, 0.84; 95% confidence interval, 0.74-0.94; P=0.003) or an emergency department visit for worsening heart failure (hazard ratio, 0.66; 95% confidence interval, 0.52-0.85; P=0.001). The patients in the LCZ696 group had 23% fewer hospitalizations for worsening heart failure (851 versus 1079; P<0.001) and were less likely to require intensive care (768 versus 879; 18% rate reduction, P=0.005), to receive intravenous positive inotropic agents (31% risk reduction, P<0.001), and to have implantation of a heart failure device or cardiac transplantation (22% risk reduction, P=0.07). The reduction in heart failure hospitalization with LCZ696 was evident within the first 30 days after randomization. Worsening of symptom scores in surviving patients was consistently more common in the enalapril group. LCZ696 led to an early and sustained reduction in biomarkers of myocardial wall stress and injury (N-terminal pro-Btype natriuretic peptide and troponin) versus enalapril. CONCLUSIONS: -Angiotensin-neprilysin inhibition prevents the clinical progression of surviving patients with heart failure more effectively than angiotensin-converting enzyme inhibition. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255.
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| 4. |
- McMurray, J., et al.
(författare)
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A putative placebo analysis of the effects of LCZ696 on clinical outcomes in heart failure
- 2015
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 36:7, s. 434-439
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Although active-controlled trials with renin-angiotensin inhibitors are ethically mandated in heart failure with reduced ejection fraction, clinicians and regulators often want to know how the experimental therapy would perform compared with placebo. The angiotensin receptor-neprilysin inhibitor LCZ696 was compared with enalapril in PARADIGM-HF. We made indirect comparisons of the effects of LCZ696 with putative placebos. METHODS AND RESULTS: We used the treatment-arm of the Studies Of Left Ventricular Dysfunction (SOLVD-T) as the reference trial for comparison of an ACE inhibitor to placebo and the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity-Alternative trial (CHARM-Alternative) as the reference trial for comparison of an ARB to placebo. The hazard ratio of LCZ696 vs. a putative placebo was estimated through the product of the hazard ratio of LCZ696 vs. enalapril (active-control) and that of the historical active-control (enalapril or candesartan) vs. placebo. For the primary composite outcome of cardiovascular death or heart failure hospitalization in PARADIGM-HF, the relative risk reduction with LCZ696 vs. a putative placebo from SOLVD-T was 43% (95%CI 34-50%; P < 0.0001) with similarly large effects on cardiovascular death (34%, 21-44%; P < 0.0001) and heart failure hospitalization (49%, 39-58%; P < 0.0001). For all-cause mortality, the reduction compared with a putative placebo was 28% (95%CI 15-39%; P < 0.0001). Putative placebo analyses based on CHARM-Alternative gave relative risk reductions of 39% (95%CI 27-48%; P < 0.0001) for the composite outcome of cardiovascular death or heart failure hospitalization, 32% (95%CI 16-45%; P < 0.0001) for cardiovascular death, 46% (33-56%; P < 0.0001) for heart failure hospitalization, and 26% (95%CI 11-39%; P < 0.0001) for all-cause mortality. CONCLUSION: These indirect comparisons of LCZ696 with a putative placebo show that the strategy of combined angiotensin receptor blockade and neprilysin inhibition led to striking reductions in cardiovascular and all-cause mortality, as well as heart failure hospitalization. These benefits were obtained even though LCZ696 was added to comprehensive background beta-blocker and mineralocorticoid receptor antagonist therapy.
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| 5. |
- Refsgaard, Jens Christian, et al.
(författare)
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Spatially differentiated regulation : Can it save the Baltic Sea from excessive N-loads?
- 2019
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Ingår i: Ambio. - : SPRINGER. - 0044-7447 .- 1654-7209. ; 48:11, s. 1278-1289
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Tidskriftsartikel (refereegranskat)abstract
- The Baltic Sea Action Plan and the EU Water Framework Directive both require substantial additional reductions of nutrient loads (N and P) to the marine environment. Focusing on nitrogen, we present a widely applicable concept for spatially differentiated regulation, exploiting the large spatial variations in the natural removal of nitrate in groundwater and surface water. By targeting mitigation measures towards areas where nature's own capacity for removal is low, spatially differentiated regulation can be more cost-effective than the traditional uniform regulation. We present a methodology for upscaling local modelling results on targeted measures at field scale to Baltic Sea drainage basin scale. The paper assesses the potential gain and discusses key challenges related to implementation of spatially differentiated regulation, including the need for more scientific knowledge, handling of uncertainties, practical constraints related to agricultural practice and introduction of co-governance regimes.
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| 6. |
- Marroquin, I., et al.
(författare)
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MULTI-PARTICLE EMISSION FROM Ar-31 AT ISOLDE
- 2016
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Ingår i: Acta Physica Polonica, Series B.. - 1509-5770 .- 0587-4254. ; 47:3, s. 747-754
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Tidskriftsartikel (refereegranskat)abstract
- A multi-particle decay experiment was successfully performed at the ISOLDE Decay Station. In this new permanent station, devoted to beta-decay studies, the novel MAGISOL Si-Plugin Chamber was installed to study the exotic decay modes of the proton drip-line nucleus Ar-31. The motivation was to search for beta 3p and beta 3p gamma channels, as well as to provide information on resonances in S-30 and P-29 relevant for the astrophysical rp-process. Description of the experimental set-up and preliminary results are presented.
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| 7. |
- Nielsen, Jonas B., et al.
(författare)
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Genome-wide Study of Atrial Fibrillation Identifies Seven Risk Loci and Highlights Biological Pathways and Regulatory Elements Involved in Cardiac Development
- 2018
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 102:1, s. 103-115
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Tidskriftsartikel (refereegranskat)abstract
- Atrial fibrillation (AF) is a common cardiac arrhythmia and a major risk factor for stroke, heart failure, and premature death. The pathogenesis of AF remains poorly understood, which contributes to the current lack of highly effective treatments. To understand the genetic variation and biology underlying AF, we undertook a genome-wide association study (GWAS) of 6,337 AF individuals and 61,607 AF-free individuals from Norway, including replication in an additional 30,679 AF individuals and 278,895 AF-free individuals. Through genotyping and dense imputation mapping from whole-genome sequencing, we tested almost nine million genetic variants across the genome and identified seven risk loci, including two novel loci. One novel locus (lead single-nucleotide variant [SNV] rs12614435; p = 6.76 × 10−18) comprised intronic and several highly correlated missense variants situated in the I-, A-, and M-bands of titin, which is the largest protein in humans and responsible for the passive elasticity of heart and skeletal muscle. The other novel locus (lead SNV rs56202902; p = 1.54 × 10−11) covered a large, gene-dense chromosome 1 region that has previously been linked to cardiac conduction. Pathway and functional enrichment analyses suggested that many AF-associated genetic variants act through a mechanism of impaired muscle cell differentiation and tissue formation during fetal heart development.
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| 8. |
- Ordell Sundelin, M., et al.
(författare)
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The transferability of the minimal invasive surgeon’s skills to open surgery
- 2022
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Ingår i: Scandinavian Journal of Urology. - : Medical Journals Sweden AB. - 2168-1805 .- 2168-1813. ; 56:2, s. 131-136
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Tidskriftsartikel (refereegranskat)abstract
- Background: Robot-assisted laparoscopic surgery has gained popularity, which has contributed to a decrease in the number of open procedures. Hence a growing concern regarding the ability of laparoscopically trained surgeons to perform open surgery (e.g. due to bleeding complications) has been raised. The aim of the study was to investigate the ability of conversion to open surgery following exclusively robotic or laparoscopic training. Methods: Thirty-six medical students were randomized into three groups: Open surgery, laparoscopy, and robot-assisted laparoscopy. All underwent intensive simulation training in the allocated surgical modality. Subsequently, all study subjects performed an open bowel anastomosis in a pig model where anastomoses were tested for resistance to pressure and leak as a surrogate marker of surgical quality. Results: The primary endpoint was the surgical quality of an open surgery model assessed as, leak pressure, which was 80.01 ± 36.16 mmHg in the laparoscopic training group, 106.57 ± 23.03 mmHg in the robotic training group, and 133.65 ± 18.32 mmHg in the open surgery training group (mean, SD). We found that there were no significant differences between the open surgery training group and the robotic training group whereas a significant difference was found when comparing laparoscopic and open surgery training groups in favor of open procedure training (p < 0.001). Conclusion: In a surrogate open surgery model based on bowel anastomosis, we found that skills acquired through practice on robotic simulation platforms were not significantly worse when compared to skills acquired through training in open surgery, whereas skills acquired from laparoscopic training were significantly poorer when compared to open surgery practice. © 2022 Acta Chirurgica Scandinavica Society.
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