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- Mishra, A., et al.
(författare)
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Stroke genetics informs drug discovery and risk prediction across ancestries
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611, s. 115-123
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Tidskriftsartikel (refereegranskat)abstract
- Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
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- Jaworek, T., et al.
(författare)
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Contribution of Common Genetic Variants to Risk of Early-Onset Ischemic Stroke
- 2022
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Ingår i: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 99:16
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objectives Current genome-wide association studies of ischemic stroke have focused primarily on late-onset disease. As a complement to these studies, we sought to identify the contribution of common genetic variants to risk of early-onset ischemic stroke. Methods We performed a meta-analysis of genome-wide association studies of early-onset stroke (EOS), ages 18-59 years, using individual-level data or summary statistics in 16,730 cases and 599,237 nonstroke controls obtained across 48 different studies. We further compared effect sizes at associated loci between EOS and late-onset stroke (LOS) and compared polygenic risk scores (PRS) for venous thromboembolism (VTE) between EOS and LOS. Results We observed genome-wide significant associations of EOS with 2 variants in ABO, a known stroke locus. These variants tag blood subgroups O1 and A1, and the effect sizes of both variants were significantly larger in EOS compared with LOS. The odds ratio (OR) for rs529565, tagging O1, was 0.88 (95% confidence interval [CI]: 0.85-0.91) in EOS vs 0.96 (95% CI: 0.92-1.00) in LOS, and the OR for rs635634, tagging A1, was 1.16 (1.11-1.21) for EOS vs 1.05 (0.99-1.11) in LOS; p-values for interaction = 0.001 and 0.005, respectively. Using PRSs, we observed that greater genetic risk for VTE, another prothrombotic condition, was more strongly associated with EOS compared with LOS (p = 0.008). Discussion The ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with EOS than with LOS, supporting a stronger role of prothrombotic factors in EOS.
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- Bonkhoff, A. K., et al.
(författare)
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Sex-specific lesion pattern of functional outcomes after stroke
- 2022
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Ingår i: Brain Communications. - : Oxford University Press (OUP). - 2632-1297. ; 4:2
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Tidskriftsartikel (refereegranskat)abstract
- Relying on neuroimaging and clinical data of 822 acute stroke patients, Bonkhoff et al. report substantially more detrimental effects of lesions in left-hemispheric posterior circulation regions on functional outcomes in women compared to men. These findings may motivate a sex-specific clinical stroke management to improve outcomes in the longer term. Stroke represents a considerable burden of disease for both men and women. However, a growing body of literature suggests clinically relevant sex differences in the underlying causes, presentations and outcomes of acute ischaemic stroke. In a recent study, we reported sex divergences in lesion topographies: specific to women, acute stroke severity was linked to lesions in the left-hemispheric posterior circulation. We here determined whether these sex-specific brain manifestations also affect long-term outcomes. We relied on 822 acute ischaemic patients [age: 64.7 (15.0) years, 39% women] originating from the multi-centre MRI-GENIE study to model unfavourable outcomes (modified Rankin Scale >2) based on acute neuroimaging data in a Bayesian hierarchical framework. Lesions encompassing bilateral subcortical nuclei and left-lateralized regions in proximity to the insula explained outcomes across men and women (area under the curve = 0.81). A pattern of left-hemispheric posterior circulation brain regions, combining left hippocampus, precuneus, fusiform and lingual gyrus, occipital pole and latero-occipital cortex, showed a substantially higher relevance in explaining functional outcomes in women compared to men [mean difference of Bayesian posterior distributions (men - women) = -0.295 (90% highest posterior density interval = -0.556 to -0.068)]. Once validated in prospective studies, our findings may motivate a sex-specific approach to clinical stroke management and hold the promise of enhancing outcomes on a population level.
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| 5. |
- Soderholm, M., et al.
(författare)
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Genome-wide association meta-analysis of functional outcome after ischemic stroke
- 2019
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Ingår i: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 92:12
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Tidskriftsartikel (refereegranskat)abstract
- Objective To discover common genetic variants associated with poststroke outcomes using a genome-wide association (GWA) study. Methods The study comprised 6,165 patients with ischemic stroke from 12 studies in Europe, the United States, and Australia included in the GISCOME (Genetics of Ischaemic Stroke Functional Outcome) network. The primary outcome was modified Rankin Scale score after 60 to 190 days, evaluated as 2 dichotomous variables (0-2 vs 3-6 and 0-1 vs 2-6) and subsequently as an ordinal variable. GWA analyses were performed in each study independently and results were meta-analyzed. Analyses were adjusted for age, sex, stroke severity (baseline NIH Stroke Scale score), and ancestry. The significance level was p < 5 x 10(-8). Results We identified one genetic variant associated with functional outcome with genome-wide significance (modified Rankin Scale scores 0-2 vs 3-6, p = 5.3 x 10(-9)). This intronic variant (rs1842681) in the LOC105372028 gene is a previously reported trans-expression quantitative trait locus for PPP1R21, which encodes a regulatory subunit of protein phosphatase 1. This ubiquitous phosphatase is implicated in brain functions such as brain plasticity. Several variants detected in this study demonstrated suggestive association with outcome (p < 10(-5)), some of which are within or near genes with experimental evidence of influence on ischemic stroke volume and/or brain recovery (e.g., NTN4, TEK, and PTCH1). Conclusions In this large GWA study on functional outcome after ischemic stroke, we report one significant variant and several variants with suggestive association to outcome 3 months after stroke onset with plausible mechanistic links to poststroke recovery. Future replication studies and exploration of potential functional mechanisms for identified genetic variants are warranted.
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- Busch, K., et al.
(författare)
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Sick leave and disability pension in patients with chronic hepatitis C compared with a matched general population: a nationwide register study
- 2020
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Ingår i: BMJ Open. - : BMJ. - 2044-6055. ; 10:9
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Tidskriftsartikel (refereegranskat)abstract
- Objective The objective of this study was to evaluate sick leave and disability pension in patients with chronic hepatitis C virus (HCV) infection as compared with a matched general population cohort. Design Retrospective register study. Setting Nationwide in Sweden. Participants This register-based study used the Swedish National Patient Register to identify working-age patients with HCV in 2012 (n=32 021) who were diagnosed between 1999 and 2007 (n=19 362). Sick leave and disability pension data were retrieved from Statistics Sweden (1994-2012), with up to five matched individuals from the general population. Primary and secondary outcome measures The primary outcome was workdays lost due to sick leave episodes (>14 days) and disability pension overall. The secondary outcome was workdays lost per subgroup of patients with chronic HCV. Results In 2012, 14% of the HCV patients had >= 1 registered sick leave episode compared with 10% in the matched comparator cohort. For disability pension benefits, results were 30% versus 8%, respectively. Overall, in 2012, 57% of patients with HCV did not have any registered workdays lost, whereas 30% were absent >= 360 days compared with 83% and 9% in the matched cohort, respectively. The mean total number of annual workdays lost in 2012 was 126 days in the HCV patient cohort compared with 40 days in the matched general population comparator cohort. Annual days lost increased from a mean of 86 days 5 years before diagnosis to 136 days during the year of diagnosis. Conclusions These results show that Swedish HCV patients used more sick days and have a higher frequency of disability pension compared with a comparator cohort from the general Swedish population. Whether earlier diagnosis of HCV and treatment might impact work absence in Sweden warrants further investigation.
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| 15. |
- Qvarford, M, et al.
(författare)
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Photoemission and x-ray absorption study of superconducting and semiconducting Ba1-xKxBiO3 single crystals
- 1996
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Ingår i: Physical Review B Condensed Matter. - 0163-1829 .- 1095-3795. ; 54:9, s. 6700-6707
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Tidskriftsartikel (refereegranskat)abstract
- Semiconducting Ba0.9K0.1BiO3 and superconducting Ba0.6K0.4BiO3 single crystals cleaved in situ have been studied by core level and valence band photoelectron spectroscopy and O K edge x-ray absorption spectroscopy. It was found that the general shape of the valence band spectrum agrees with the shape predicted by band structure calculations, but the intensity near the Fermi level, was lower in the experimental spectrum as compared to the calculated. The O K edge spectra showed that the metallic phase is not related to the presence of doping inducted O 2p holes. This property of Ba1-xKxBiO3 shows that the semiconductor-metal transition of this system is of a different nature than that of the hole doped cuprate high-T-c superconductors. The core level photoemission spectra of the cations showed a small asymmetry for Ba0.9K0.1BiO3. Corresponding spectra for Ba0.6K0.4BiO3 showed a larger asymmetry resulting in a resolved high binding energy shoulder in the Bi 4f spectrum. The origin of this feature is discussed.
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| 20. |
- Tsegaye, T., et al.
(författare)
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Experimental demonstration of three mutually orthogonal polarization states of entangled photons
- 2000
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Ingår i: Physical Review Letters. - 0031-9007 .- 1079-7114. ; 85:24, s. 5013-5017
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Tidskriftsartikel (refereegranskat)abstract
- Linearly polarized classical light can be expressed in a vertical and a horizontal component. Geometrically rotating vertically polarized light by 90 degrees will convert it to the orthogonal horizontal polarization. We have experimentally generated a two-photon state of light which evolves into an orthogonal state upon geometrical rotation by 60 degrees. Rotating this state by an additional 60 degrees will yield a state which is mutually orthogonal to the first two states. Generalizing this procedure, one can generate N + 1 mutually orthogonal N-photon states that cyclicly evolve from one to another upon a geometric rotation by 180/(N + 1) degrees.
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- Bankel, Johan, 1959, et al.
(författare)
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Benchmarking engineering curricula with the CDIO syllabus
- 2005
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Ingår i: International Journal of Engineering Education. - 0949-149X. ; 21:1, s. 121-133
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Tidskriftsartikel (refereegranskat)abstract
- Four internationally-renowned universities-Chalmers University of Technology, Linkoping University, Royal Institute of Technology (Sweden), and the Massachusetts Institute of Technology (USA)-developed a benchmark survey that may be used by any engineering school to benchmark curricula for teaching of personal, interpersonal and system building skills. These skills are enumerated in the CDIO Syllabus. Teaching activities were categorized as Introduce, Teach or Utilize, based on intent, time spent, and linkage to learning objectives, assignments and assessment criteria. Interviews were used to collect the data from instructors of the schools' engineering programs. The data was then reduced and analyzed to illuminate patterns of teaching. The results indicate that much effort is expended in covering these topics, but often in an inefficient, uncoordinated and unplanned manner. For example, there are often frequent repetitions of introducing a topic, without ever teaching it. In other instances, students are expected to utilize knowledge without having been taught it. The results of the benchmark survey indicate that a consistent and deliberately designed curriculum in this area could demand no additional resources, yet provide a much more effective education. The survey gives useful indications of how to begin such a curriculum redesign process.
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- Bjordal, K, et al.
(författare)
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A 12 country field study of the EORTC QLQ-C30 (version 3.0) and the head and neck cancer specific module (EORTC QLQ-H&N35) in head and neck patients
- 2000
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Ingår i: European Journal of Cancer. - 1879-0852. ; 36:14, s. 1796-1807
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Tidskriftsartikel (refereegranskat)abstract
- This study tests the reliability and validity of the European Organization for Research and Treatment of Cancer (EORTC) head and neck cancer module (QLQ-H&N35) and version 3.0 of the EORTC Core Questionnaire (QLQ-C30) in 622 head and neck cancer patients from 12 countries. The patients completed the QLQ-C30, the QLQ-H&N35 and a debriefing questionnaire before antineoplastic treatment or at a follow-up. 232 patients receiving treatment completed a second questionnaire after treatment. Compliance was high and the questionnaire was well accepted by the patients. Multitrait scaling analysis confirmed the proposed scale structure of the QLQ-H&N35. The QLQ-H&N35 was responsive to differences between disease status, site and patients with different Karnofsky performance status, and to changes over time. The new physical functioning scale (with a four-point response format) of version 3.0 of the QLQ-C30 was shown to be more reliable than previous versions. Thus, the QLQ-H&N35, in conjunction with the QLQ-C30, appears to be reliable, valid and applicable to broad multicultural samples of head and neck cancer patients.
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