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- van de Vegte, Yordi, et al.
(författare)
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Genetic insights into resting heart rate and its role in cardiovascular disease
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke. Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.
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- Perez-Nadales, Elena, et al.
(författare)
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Predictors of mortality in solid organ transplant recipients with bloodstream infections due to carbapenemase-producing Enterobacterales : The impact of cytomegalovirus disease and lymphopenia
- 2020
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Ingår i: American Journal of Transplantation. - : WILEY. - 1600-6135 .- 1600-6143. ; 20:6, s. 1629-1641
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Tidskriftsartikel (refereegranskat)abstract
- Treatment of carbapenemase-producing Enterobacterales bloodstream infections in solid organ transplant recipients is challenging. The objective of this study was to develop a specific score to predict mortality in solid organ transplant recipients with carbapenemase-producing Enterobacterales bloodstream infections. A multinational, retrospective (2004-2016) cohort study (INCREMENT-SOT, ClinicalTrials.gov NCT02852902) was performed. The main outcome variable was 30-day all-cause mortality. The INCREMENT-SOT-CPE score was developed using logistic regression. The global cohort included 216 patients. The final logistic regression model included the following variables: INCREMENT-CPE mortality score >= 8 (8 points), no source control (3 points), inappropriate empirical therapy (2 points), cytomegalovirus disease (7 points), lymphopenia (4 points), and the interaction between INCREMENT-CPE score >= 8 and CMV disease (minus 7 points). This score showed an area under the receiver operating characteristic curve of 0.82 (95% confidence interval [CI] 0.76-0.88) and classified patients into 3 strata: 0-7 (low mortality), 8-11 (high mortality), and 12-17 (very-high mortality). We performed a stratified analysis of the effect of monotherapy vs combination therapy among 165 patients who received appropriate therapy. Monotherapy was associated with higher mortality only in the very-high (adjusted hazard ratio [HR] 2.82, 95% CI 1.13-7.06, P = .03) and high (HR 9.93, 95% CI 2.08-47.40, P = .004) mortality risk strata. A score-based algorithm is provided for therapy guidance.
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- Linder, Astrid, 1959, et al.
(författare)
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VIRTUAL - a European approach to foster the uptake of virtual testing in vehicle safety assessment
- 2020
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Ingår i: Proceedings of 8th Transport Research Arena TRA 2020.
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Konferensbidrag (refereegranskat)abstract
- In the assessment of road user and vehicle occupant safety, physical testing is limited to a few scenarios. To advance transport safety it is vital to include more relevant scenarios. Virtual Testing offers an opportunity to introduce additional test scenarios. The objectives of the VIRTUAL project, described in this paper, include: Identifying impact scenarios relevant for the future, providing tools such as models, guidelines, and a corresponding platform to foster the uptake of virtual testing. The safety of standing passengers on public transport has been reviewed, scenarios for Vulnerable Road User testing have been identified and new seated positions for future vehicles have been described. In addition, a virtual testing platform has been established on which human body models are provided. The platform follows the open access approach, complements other approaches and does not just provide the models, but also guidelines on how to implement new scenarios in test procedures.
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- Rizzi, Maria C., 1987-, et al.
(författare)
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Snabbcykelstråk i planeringen och praktiken : erfarenheter från Sverige, Norge och Danmark
- 2022
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Syftet med studien har varit att ge en övergripande bild av vilka utmaningar, kunskapsluckor och behov som transportaktörer i Sverige, Norge och Danmark möter i hanteringen av snabbcykelstråk. Fokus har varit på hur tjänstemän från dessa tre länder med ansvar eller engagemang i snabbcykelstråk upplever planering, utformning, drift och underhåll samt utvärdering av stråken. I rapporten lyfts områden där det upplevs saknas stöd eller kunskap, samt likheter och skillnader mellan länderna.En webbenkät med efterföljande intervjuer har använts som datainsamlingsmetod. Webbenkäten sändes till 40 personer i Sverige, Norge och Danmark som på olika sätt arbetar med snabbcykelstråk. Svar inkom från 25 personer. Av dessa valdes sju personer ut för att genomföra en efterföljande intervju.Förutsättningarna att arbeta med snabbcykelstråk skiljer sig mellan länderna, till exempel med hänsyn till väghållaransvar och finansieringsmöjligheter, men även inom länderna kan förutsättningar skilja sig. Det tycks finnas ett behov av nationell samordning kring snabbcykelstråk, samtidigt som man inte ville se några ”tvingande regler” kring utformning. I Sverige efterlyser man särskilt en samordning kring skyltning av snabbcykelstråk, något som redan finns i Danmark. Det upplevdes svårare att planera för snabbcykelstråk jämfört med annan cykelinfrastruktur och det finns aspekter av snabbcykelstråk som skiljer sig från annan cykelinfrastruktur, som till exempel högre krav på utformning, underhåll och säkerhet, samt högre krav på samarbete och samordning. Utvärdering av snabbcykelstråken är något man arbetar med lokalt, och det finns ingen sammanställd systematisk kunskap kring de modeller eller metoder som används för utvärdering. Informationsutbyte mellan olika aktörer i Sverige, Norge och Danmark skulle kunna öka kunskapen och ge nya infallsvinklar hur planering och genomförande av snabbcykelvägar kan förbättras.
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- Rizzi, Maria C, et al.
(författare)
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The potential of different countermeasures to prevent injuries with high risk of health loss among bicyclists in Sweden
- 2020
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Ingår i: Traffic Injury Prevention. - : Informa UK Limited. - 1538-9588 .- 1538-957X. ; 21:3, s. 215-221
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Tidskriftsartikel (refereegranskat)abstract
- Objective: As bicyclists account for the largest share of serious injuries in Sweden, focus to improve safety for bicyclists is needed. While knowledge about fatal bicycle crashes is rather extensive, the number of studies that have investigated non-fatal injuries is still rather limited. The aim of this study was to estimate the potential of different countermeasures to reduce crashes resulting in injuries with high risk of health-loss among cyclists in Sweden. A further aim was to describe the residual—that is, crashes that were not considered to be addressed by the analyzed countermeasures. Methods: A sample of individuals with specific injury diagnoses was drawn from the Swedish national crash database Strada. A survey form was used to collect additional information about the crash and the health-related outcomes. The potential of countermeasures currently included in the Swedish Safety Performance Indicators, as well as of countermeasures that could be described as “existing but not fully implemented” was assessed. The overall potential of all countermeasures assessed was calculated, giving a grand total without double counting. Cases that were considered not to be addressed by any of the countermeasures included (i.e., the residual crashes) were described in more detail. Results: The current Swedish Safety Performance Indicators that relate to safe cycling addressed 22% of crashes. Improved maintenance by deicing and removal of snow from bicycle infrastructure was found to have the highest potential (8%), followed by improved crashworthiness of passenger cars (5%) and safer bicycle crossings (4%). The potential for existing but not fully implemented safety improvements was 56%. The greatest potential was found for Autonomous Emergency Braking with cyclist detection for passenger cars (12%), followed by studded winter tyres for bicycles (12%), and improved maintenance on non-bicycle infrastructure (11%). In total, taking double counting into consideration, all safety improvements could address 64% of all crashes. Among the residual crashes, the majority (69%) were single bicycle crashes of which most were related to wheel locking during braking and losing balance at low speed or stationary. Conclusions: Compared with fatal crashes that involve a majority of bicycle-car crashes, the crashes leading to health-loss are mostly single bicycle crashes. Therefore, innovation and development of additional countermeasures to improve safety for bicyclists should focus on single bicycle crashes.
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- Salvi, Erika, et al.
(författare)
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Genomewide Association Study Using a High-Density Single Nucleotide Polymorphism Array and Case-Control Design Identifies a Novel Essential Hypertension Susceptibility Locus in the Promoter Region of Endothelial NO Synthase.
- 2012
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Ingår i: Hypertension. - 1524-4563. ; 59:2, s. 248-248
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Tidskriftsartikel (refereegranskat)abstract
- Essential hypertension is a multifactorial disorder and is the main risk factor for renal and cardiovascular complications. The research on the genetics of hypertension has been frustrated by the small predictive value of the discovered genetic variants. The HYPERGENES Project investigated associations between genetic variants and essential hypertension pursuing a 2-stage study by recruiting cases and controls from extensively characterized cohorts recruited over many years in different European regions. The discovery phase consisted of 1865 cases and 1750 controls genotyped with 1M Illumina array. Best hits were followed up in a validation panel of 1385 cases and 1246 controls that were genotyped with a custom array of 14 055 markers. We identified a new hypertension susceptibility locus (rs3918226) in the promoter region of the endothelial NO synthase gene (odds ratio: 1.54 [95% CI: 1.37-1.73]; combined P=2.58 · 10(-13)). A meta-analysis, using other in silico/de novo genotyping data for a total of 21 714 subjects, resulted in an overall odds ratio of 1.34 (95% CI: 1.25-1.44; P=1.032 · 10(-14)). The quantitative analysis on a population-based sample revealed an effect size of 1.91 (95% CI: 0.16-3.66) for systolic and 1.40 (95% CI: 0.25-2.55) for diastolic blood pressure. We identified in silico a potential binding site for ETS transcription factors directly next to rs3918226, suggesting a potential modulation of endothelial NO synthase expression. Biological evidence links endothelial NO synthase with hypertension, because it is a critical mediator of cardiovascular homeostasis and blood pressure control via vascular tone regulation. This finding supports the hypothesis that there may be a causal genetic variation at this locus.
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| 10. |
- Wuttke, Matthias, et al.
(författare)
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A catalog of genetic loci associated with kidney function from analyses of a million individuals
- 2019
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Ingår i: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 51:6, s. 957-972
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Tidskriftsartikel (refereegranskat)abstract
- Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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