| 1. |
- Pulit, S. L., et al.
(författare)
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Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes
- 2018
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Ingår i: Neurology-Genetics. - : Ovid Technologies (Wolters Kluwer Health). - 2376-7839. ; 4:6
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Tidskriftsartikel (refereegranskat)abstract
- Objective We sought to assess whether genetic risk factors for atrial fibrillation (AF) can explain cardioembolic stroke risk. We evaluated genetic correlations between a previous genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors. We observed a strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson r = 0.77 and 0.76, respectively, across SNPs with p < 4.4 x 10(-4) in the previous AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio [OR] per SD = 1.40, p = 1.45 x 10(-48)), explaining similar to 20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per SD = 1.07,p = 0.004), but no other primary stroke subtypes (all p > 0.1). Genetic risk of AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.
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| 4. |
- Marini, S., et al.
(författare)
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Association of Apolipoprotein E With Intracerebral Hemorrhage Risk by Race/Ethnicity A Meta-analysis
- 2019
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Ingår i: Jama Neurology. - : American Medical Association (AMA). - 2168-6149 .- 2168-6157. ; 76:4, s. 480-491
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE Genetic studies of intracerebral hemorrhage (ICH) have focused mainly on white participants, but genetic risk may vary or could be concealed by differing nongenetic coexposures in nonwhite populations. Transethnic analysis of risk may clarify the role of genetics in ICH risk across populations. OBJECTIVE To evaluate associations between established differences in ICH risk by race/ethnicity and the variability in the risks of apolipoprotein E (APOE) epsilon 4 alleles, the most potent genetic risk factor for ICH. DESIGN, SETTING, AND PARTICIPANTS This case-control study of primary ICH meta-analyzed the association of APOE allele status on ICH risk, applying a 2-stage clustering approach based on race/ethnicity and stratified by a contributing study. A propensity score analysis was used to model the association of APOE with the burden of hypertension across race/ethnic groups. Primary ICH cases and controls were collected from 3 hospital- and population-based studies in the United States and 8 in European sites in the International Stroke Genetic Consortium. Participants were enrolled from January 1, 1999, to December 31, 2017. Participants with secondary causes of ICH were excluded from enrollment. Controls were regionally matched within each participating study. MAIN OUTCOMES AND MEASURES Clinical variables were systematically obtained from structured interviews within each site. APOE genotype was centrally determined for all studies. RESULTS In total, 13 124 participants (7153 [54.5%] male with a median [interquartile range] age of 66 [56-76] years) were included. In white participants, APOE epsilon 2 (odds ratio [OR], 1.49; 95% CI, 1.24-1.80; P < .001) and APOE epsilon 4 (OR, 1.51; 95% CI, 1.23-1.85; P < .001) were associated with lobar ICH risk; however, within self-identified Hispanic and black participants, no associations were found. After propensity score matching for hypertension burden, APOE epsilon 4 was associated with lobar ICH risk among Hispanic (OR, 1.14; 95% CI, 1.03-1.28; P = .01) but not in black (OR, 1.02; 95% CI, 0.98-1.07; P = .25) participants. APOE epsilon 2 and epsilon 4 did not show an association with nonlobar ICH risk in any race/ethnicity. CONCLUSIONS AND RELEVANCE APOE epsilon 4 and epsilon 2 alleles appear to affect lobar ICH risk variably by race/ethnicity, associations that are confirmed in white individuals but can be shown in Hispanic individuals only when the excess burden of hypertension is propensity score-matched; further studies are needed to explore the interactions between APOE alleles and environmental exposures that vary by race/ethnicity in representative populations at risk for ICH.
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| 8. |
- Altenburger, R., et al.
(författare)
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Future water quality monitoring - Adapting tools to deal with mixtures of pollutants in water resource management
- 2015
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Ingår i: Science of the Total Environment. - : Elsevier BV. - 0048-9697. ; 512, s. 540-551
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Tidskriftsartikel (refereegranskat)abstract
- Environmental quality monitoring of water resources is challenged with providing the basis for safeguarding the environment against adverse biological effects of anthropogenic chemical contamination from diffuse and point sources. While current regulatory efforts focus on monitoring and assessing a few legacy chemicals, many more anthropogenic chemicals can be detected simultaneously in our aquatic resources. However, exposure to chemical mixtures does not necessarily translate into adverse biological effects nor clearly shows whether mitigation measures are needed. Thus, the question which mixtures are present and which have associated combined effects becomes central for defining adequate monitoring and assessment strategies. Here we describe the vision of the international, EU-funded project SOLUTIONS, where three routes are explored to link the occurrence of chemical mixtures at specific sites to the assessment of adverse biological combination effects. First of all, multi-residue target and non-target screening techniques covering a broader range of anticipated chemicals co-occurring in the environment are being developed. By improving sensitivity and detection limits for known bioactive compounds of concern, new analytical chemistry data for multiple components can be obtained and used to characterise priority mixtures. This information on chemical occurrence will be used to predict mixture toxicity and to derive combined effect estimates suitable for advancing environmental quality standards. Secondly, bioanalytical tools will be explored to provide aggregate bioactivity measures integrating all components that produce common (adverse) outcomes even for mixtures of varying compositions. The ambition is to provide comprehensive arrays of effect-based tools and trait-based field observations that link multiple chemical exposures to various environmental protection goals more directly and to provide improved in situ observations for impact assessment of mixtures. Thirdly, effect-directed analysis (EDA) will be applied to identify major drivers of mixture toxicity. Refinements of EDA include the use of statistical approaches with monitoring information for guidance of experimental EDA studies. These three approaches will be explored using case studies at the Danube and Rhine river basins as well as rivers of the Iberian Peninsula. The synthesis of findings will be organised to provide guidance for future solution-oriented environmental monitoring and explore more systematic ways to assess mixture exposures and combination effects in future water quality monitoring. (C) 2015 Elsevier B.V. All rights reserved.
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| 9. |
- 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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| 10. |
- Schmitz, M., et al.
(författare)
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Demonstration of an aggregated biomarker response approach to assess the impact of point and diffuse contaminant sources in feral fish in a small river case study
- 2022
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Ingår i: Science of the Total Environment. - : Elsevier BV. - 0048-9697. ; 804
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Tidskriftsartikel (refereegranskat)abstract
- The assessment of the exposure of aquatic wildlife to complex environmental mixtures of chemicals originating from both point and diffuse sources and evaluating the potential impact thereof constitutes a significant step towards mitigating toxic pressure and the improvement of ecological status. In the current proof-of-concept study, we demonstrate the potential of a novel Aggregated Biomarker Response (ABR) approach involving a comprehensive set of biomarkers to identify complex exposure and impacts on wild brown trout (Salmo trutta fario). Our scenario used a small lowland river in Germany (Holtemme river in the Elbe river catchment) impacted by two wastewater treatment plants (WWTP) and diffuse agricultural runoff as a case study. The trout were col-lected along a pollution gradient (characterised in a parallel study) in the river. Compared to fish from the refer-ence site upstream of the first WWTP, the trout collected downstream of the WWTPs showed a significant increase in micronucleus formation, phase I and II enzyme activities, and oxidative stress parameters in agree-ment with increasing exposure to various chemicals. By integrating single biomarker responses into an aggre-gated biomarker response, the two WWTPs' contribution to the observed toxicity could be clearly differentiated. The ABR results were supported by chemical analyses and whole transcriptome data, which re-vealed alterations of steroid biosynthesis and associated pathways, including an anti-androgenic effect, as some of the key drivers of the observed toxicity. Overall, this combined approach of in situ biomarker responses complemented with molecular pathway analysis allowed for a comprehensive ecotoxicological assessment of fish along the river. This study provides evidence for specific hazard potentials caused by mixtures of agricultural and WWTP derived chemicals at sublethal concentrations. Using aggregated biomarker responses combined with chemical analyses enabled an evidence-based ranking of sites with different degrees of pollution according to toxic stress and observed effects. (c) 2021 Elsevier B.V. All rights reserved.
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| 11. |
- Backhaus, Thomas, 1967, et al.
(författare)
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Assessing the ecological impact of chemical pollution on aquatic ecosystems requires the systematic exploration and evaluation of four lines of evidence
- 2019
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Ingår i: Environmental Sciences Europe. - : Springer Science and Business Media LLC. - 2190-4707 .- 2190-4715. ; 31:1
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the European Water Framework Directive is to ensure good ecological status for all European surface waters. However, although current monitoring strategies aim to identify the presence and magnitude of ecological impacts, they provide little information on the causes of an ecosystem impairment. In fact, approaches to establish causal links between chemical pollution and impacts on the ecological status of exposed aquatic systems are largely lacking or poorly described and established. This is, however, crucial for developing and implementing appropriately targeted water management strategies. In order to identify the role of chemical pollution on the ecological status of an aquatic ecosystem, we suggest to systematically combine four lines of evidence (LOEs) that provide complementary evidence on the presence and potential ecological impact of complex chemical pollution: (1) component-based methods that allow a predictive mixture risk modeling; (2) effect-based methods; (3) in situ tests; (4) field-derived species inventories. These LOEs differ systematically in their specificity for chemical pollution, data demands, resources required and ecological relevance. They complement each other and, in their combination, allow to assess the contribution of chemical pollution pressure to impacts on ecological structure and function. Data from all LOEs are not always available and the information they provide is not necessarily consistent. We therefore propose a systematic, robust and transparent approach to combine the information available for a given study, in order to ensure that consensual conclusions are drawn from a given dataset. This allows to identify critical data gaps and needs for future testing and/or options for targeted and efficient water management.
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| 12. |
- Brack, W., et al.
(författare)
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Effect-based methods are key. The European Collaborative Project SOLUTIONS recommends integrating effect-based methods for diagnosis and monitoring of water quality
- 2019
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Ingår i: Environmental Sciences Europe. - : Springer Science and Business Media LLC. - 2190-4715 .- 2190-4707. ; 31
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Tidskriftsartikel (refereegranskat)abstract
- The present monitoring and assessment of the chemical status of water bodies fail to characterize the likelihood that complex mixtures of chemicals affect water quality. The European Collaborative Project SOLUTIONS suggests that this likelihood can be estimated with effect-based methods (EBMs) complemented by chemical screening and/or impact modeling. These methods should be used to identify the causes of impacted water quality and to develop programs of measures to improve water quality. Along this line of reasoning, effect-based methods are recommended for Water Framework Directive (WFD) monitoring to cover the major modes of action in the universe of environmentally relevant chemicals so as to evaluate improvements of water quality upon implementing the measures. To this end, a minimum battery of bioassays has been recommended including short-term toxicity to algae, Daphnia and fish embryos complemented with in vitro and short-term in vivo tests on mode-of-action specific effects as proxies for long-term toxicity. The likelihood of adverse impacts can be established with effect-based trigger values, which differentiate good from poor water quality in close alignment with Environmental Quality Standards for individual chemicals, while taking into account mixture toxicity. The use of EBMs is suggested in the WFD as one avenue to establish the likelihood of adverse effects due to chemical pollution in European water systems. The present paper has been written as one component of a series of policy briefs to support decisions on water quality monitoring and management under the WFD.
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| 14. |
- Sehgal, B. R., et al.
(författare)
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Assessment of reactor vessel integrity (ARVI)
- 2003
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Ingår i: Nuclear Engineering and Design. - 0029-5493 .- 1872-759X. ; 221:03-jan, s. 23-53
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Tidskriftsartikel (refereegranskat)abstract
- The cost-shared project ARVI (assessment of reactor vessel integrity) involves a total of nine organisations from Europe and USA. The objective of the ARVI Project is to resolve the safety issues that remain unresolved for the melt vessel interaction phase of the in-vessel progression of a severe accident. The work consists of experiments and analysis development. Four tests were performed in the EC-FOREVER Programme, in which failure was achieved in-vessels employing the French pressure vessel steel. The tests were analysed with the commercial code ANSYS-Multiphysics, and the codes SYSTUS+ and PASULA, and quite good agreement was achieved for the failure location. Natural convection experiments in stratified pools have been performed in the SIMECO and the COPO facilities, which showed that much greater heat is transferred downwards for immiscible layers or before layers mix. A model for gap cooling and a set of simplified models for the system codes have been developed. MVITA code calculations have been performed for the Czech and Hungarian VVERs, towards evaluation of the in-vessel melt retention accident management scheme. Tests have been performed at the ULPU facility with organised flow for vessel external cooling. Considerable enhancement of the critical heat flux (CHF) was obtained. The ARVI Project has reached the halfway stage. This paper presents the results obtained thus far from the project.
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