| 1. |
- Bonkhoff, A. K., et al.
(författare)
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Outcome after acute ischemic stroke is linked to sex-specific lesion patterns
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Acute ischemic stroke affects men and women differently. In particular, women are often reported to experience higher acute stroke severity than men. We derived a low-dimensional representation of anatomical stroke lesions and designed a Bayesian hierarchical modeling framework tailored to estimate possible sex differences in lesion patterns linked to acute stroke severity (National Institute of Health Stroke Scale). This framework was developed in 555 patients (38% female). Findings were validated in an independent cohort (n=503, 41% female). Here, we show brain lesions in regions subserving motor and language functions help explain stroke severity in both men and women, however more widespread lesion patterns are relevant in female patients. Higher stroke severity in women, but not men, is associated with left hemisphere lesions in the vicinity of the posterior circulation. Our results suggest there are sex-specific functional cerebral asymmetries that may be important for future investigations of sex-stratified approaches to management of acute ischemic stroke.
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| 2. |
- 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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| 3. |
- Cole, J. W., et al.
(författare)
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The copy number variation and stroke (CaNVAS) risk and outcome study
- 2021
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 16:4 April
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose The role of copy number variation (CNV) variation in stroke susceptibility and outcome has yet to be explored. The Copy Number Variation and Stroke (CaNVAS) Risk and Outcome study addresses this knowledge gap. Methods Over 24,500 well-phenotyped IS cases, including IS subtypes, and over 43,500 controls have been identified, all with readily available genotyping on GWAS and exome arrays, with case measures of stroke outcome. To evaluate CNV-associated stroke risk and stroke outcome it is planned to: 1) perform Risk Discovery using several analytic approaches to identify CNVs that are associated with the risk of IS and its subtypes, across the age-, sex- and ethnicity-spectrums; 2) perform Risk Replication and Extension to determine whether the identified stroke-associated CNVs replicate in other ethnically diverse datasets and use biomarker data (e.g. methylation, proteomic, RNA, miRNA, etc.) to evaluate how the identified CNVs exert their effects on stroke risk, and lastly; 3) perform outcome-based Replication and Extension analyses of recent findings demonstrating an inverse relationship between CNV burden and stroke outcome at 3 months (mRS), and then determine the key CNV drivers responsible for these associations using existing biomarker data. Results The results of an initial CNV evaluation of 50 samples from each participating dataset are presented demonstrating that the existing GWAS and exome chip data are excellent for the planned CNV analyses. Further, some samples will require additional considerations for analysis, however such samples can readily be identified, as demonstrated by a sample demonstrating clonal mosaicism. Conclusion The CaNVAS study will cost-effectively leverage the numerous advantages of using existing case-control data sets, exploring the relationships between CNV and IS and its subtypes, and outcome at 3 months, in both men and women, in those of African and European-Caucasian descent, this, across the entire adult-age spectrum. Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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| 4. |
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| 5. |
- Kalla, R., et al.
(författare)
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Whole blood profiling of T-cell derived miRNA allows the development of prognostic models in inflammatory bowel disease
- 2020
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Ingår i: Journal of Crohn's & Colitis. - : Elsevier. - 1873-9946 .- 1876-4479. ; 14:12, s. 1724-1733
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: MicroRNAs (miRNAs) are cell-specific small non-coding RNAs that can regulate gene expression and have been implicated in Inflammatory Bowel Disease (IBD) pathogenesis. In our study, we define the cell-specific miRNA profiles and investigate its biomarker potential in IBD.METHODS: In a 2-stage prospective multi-centre case control study, Next Generation sequencing was performed on a discovery cohort of immunomagnetically separated leucocytes from 32 patients (9 CD, 14 UC, 8 healthy controls) and differentially expressed signals were validated in whole blood in 294 patients (97 UC, 98 CD, 98 non-IBD) using quantitative PCR. Correlations were analysed with phenotype, including need for early treatment escalation as a marker of progressive disease using Cox proportional hazards.RESULTS: In stage 1, each leucocyte subset (CD4+ and CD8+ T-cells and CD14+ monocytes) was analysed in IBD and controls. Three specific miRNAs differentiated IBD from controls in CD4+ T-cells, including miR-1307-3p (p=0.01), miR-3615 (p=0.02) and miR-4792 (p=0.01). In the extension cohort, in stage 2, miR-1307-3p was able to predict disease progression in IBD (HR 1.98, IQR:1.20-3.27;logrank p=1.80×10-3), in particular CD (HR 2.81; IQR: 1.11-3.53, p=6.50×10-4). Using blood-based multimarker miRNA models, the estimated chance of escalation in CD was 83% if 2 or more criteria were met and 90% for UC if 3 or more criteria are met.INTERPRETATION: We have identified and validated unique CD4+ T-cell miRNAs that are differentially regulated in IBD. These miRNAs may be able to predict treatment escalation and have the potential for clinical translation; further prospective evaluation is now indicated.
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| 6. |
- Andersen, M. S., et al.
(författare)
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To facilitate a fair bioeconomy transition, stronger regional-level linkages are needed
- 2022
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Ingår i: Biofuels Bioproducts & Biorefining-Biofpr. - : Wiley. - 1932-104X .- 1932-1031. ; 16:4, s. 929-941
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Tidskriftsartikel (refereegranskat)abstract
- The great hopes in Brussels that a circular bioeconomy will help bridge the growing divide between urban and rural areas and allow the hinterlands to prosper from 'green growth' are addressed in this article, which reflects on insights from three Nordic case studies of brown, green and blue biomass use at different levels of technology readiness. A closer examination of the forward, backward, fiscal and final demand linkages at regional level from increased biomass utilization, from eastern Finland and northern Sweden to Jutland and North Atlantic islands, suggests that linkages are and will remain relatively weak, predominantly dashing the expectations. As suppliers and exporters of natural resources, disadvantaged regions may all too easily get locked into a 'staples trap', where the value creation evaporates owing in part to the steep start-up costs and the associated boom-and-bust cycles, which place them in a weak position vis-a-vis the resource manufacturers and consumers. To make the prospects of development, employment and prosperity in the hinterlands materialize, measures are needed to strengthen the regional-level economic linkages. Regional-level revolving funds based on benefit-sharing instruments related to natural resources can be used to bolster economic development, as reflected in such schemes present in both China and Canada. We call for further research into whether and how such approaches can be replicated successfully by channeling revenues from biomass cultivation to regional-scale revolving funds, with mandates to strengthen long-term economic linkages and prosperity within the hinterlands. (c) 2022 The Authors. Biofuels, Bioproducts and Biorefining published by Society of Industrial Chemistry and John Wiley & Sons Ltd
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| 7. |
- Bergemalm, Daniel, 1977-, et al.
(författare)
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Systemic Inflammation in Preclinical Ulcerative Colitis
- 2021
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Ingår i: Gastroenterology. - : AGA Institute. - 0016-5085 .- 1528-0012. ; 161:5, s. 1526-1539.e9
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Preclinical ulcerative colitis is poorly defined. We aimed to characterize the preclinical systemic inflammation in ulcerative colitis, using a comprehensive set of proteins.Methods: We obtained plasma samples biobanked from individuals who developed ulcerative colitis later in life (n = 72) and matched healthy controls (n = 140) within a population-based screening cohort. We measured 92 proteins related to inflammation using a proximity extension assay. The biologic relevance of these findings was validated in an inception cohort of patients with ulcerative colitis (n = 101) and healthy controls (n = 50). To examine the influence of genetic and environmental factors on these markers, a cohort of healthy twin siblings of patients with ulcerative colitis (n = 41) and matched healthy controls (n = 37) were explored.Results: Six proteins (MMP10, CXCL9, CCL11, SLAMF1, CXCL11 and MCP-1) were up-regulated (P < .05) in preclinical ulcerative colitis compared with controls based on both univariate and multivariable models. Ingenuity Pathway Analyses identified several potential key regulators, including interleukin-1β, tumor necrosis factor, interferon-gamma, oncostatin M, nuclear factor-κB, interleukin-6, and interleukin-4. For validation, we built a multivariable model to predict disease in the inception cohort. The model discriminated treatment-naïve patients with ulcerative colitis from controls with leave-one-out cross-validation (area under the curve = 0.92). Consistently, MMP10, CXCL9, CXCL11, and MCP-1, but not CCL11 and SLAMF1, were significantly up-regulated among the healthy twin siblings, even though their relative abundances seemed higher in incident ulcerative colitis.Conclusions: A set of inflammatory proteins are up-regulated several years before a diagnosis of ulcerative colitis. These proteins were highly predictive of an ulcerative colitis diagnosis, and some seemed to be up-regulated already at exposure to genetic and environmental risk factors.
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| 8. |
- Bonkhoff, A.K., et al.
(författare)
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Association of Stroke Lesion Pattern and White Matter Hyperintensity Burden With Stroke Severity and Outcome
- 2022
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Ingår i: Neurology. - 0028-3878. ; 99:13, s. 1364-1379
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Tidskriftsartikel (refereegranskat)abstract
- Background and ObjectivesTo examine whether high white matter hyperintensity (WMH) burden is associated with greater stroke severity and worse functional outcomes in lesion pattern-specific ways.MethodsMR neuroimaging and NIH Stroke Scale data at index stroke and the modified Rankin Scale (mRS) score at 3-6 months after stroke were obtained from the MRI-Genetics Interface Exploration study of patients with acute ischemic stroke (AIS). Individual WMH volume was automatically derived from fluid-attenuated inversion recovery images. Stroke lesions were automatically segmented from diffusion-weighted imaging (DWI) images, parcellated into atlas-defined brain regions and further condensed to 10 lesion patterns via machine learning-based dimensionality reduction. Stroke lesion effects on AIS severity and unfavorable outcomes (mRS score >2) were modeled within purpose-built Bayesian linear and logistic regression frameworks. Interaction effects between stroke lesions and a high vs low WMH burden were integrated via hierarchical model structures. Models were adjusted for age, age2, sex, total DWI lesion and WMH volumes, and comorbidities. Data were split into derivation and validation cohorts.ResultsA total of 928 patients with AIS contributed to acute stroke severity analyses (age: 64.8 [14.5] years, 40% women) and 698 patients to long-term functional outcome analyses (age: 65.9 [14.7] years, 41% women). Stroke severity was mainly explained by lesions focused on bilateral subcortical and left hemispherically pronounced cortical regions across patients with both a high and low WMH burden. Lesions centered on left-hemispheric insular, opercular, and inferior frontal regions and lesions affecting right-hemispheric temporoparietal regions had more pronounced effects on stroke severity in case of high compared with low WMH burden. Unfavorable outcomes were predominantly explained by lesions in bilateral subcortical regions. In difference to the lesion location-specific WMH effects on stroke severity, higher WMH burden increased the odds of unfavorable outcomes independent of lesion location.DiscussionHigher WMH burden may be associated with an increased stroke severity in case of stroke lesions involving left-hemispheric insular, opercular, and inferior frontal regions (potentially linked to language functions) and right-hemispheric temporoparietal regions (potentially linked to attention). Our findings suggest that patients with specific constellations of WMH burden and lesion locations may have greater benefits from acute recanalization treatments. Future clinical studies are warranted to systematically assess this assumption and guide more tailored treatment decisions. © American Academy of Neurology.
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| 9. |
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| 10. |
- Johansson, Malin, et al.
(författare)
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Genetic Predisposition to Mosaic Chromosomal Loss Is Associated with Functional Outcome after Ischemic Stroke
- 2021
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Ingår i: Neurology: Genetics. - 2376-7839. ; 7:6
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Tidskriftsartikel (refereegranskat)abstract
- Background and ObjectivesTo test the hypothesis that a predisposition to acquired genetic alterations is associated with ischemic stroke outcome by investigating the association between a polygenic risk score (PRS) for mosaic loss of chromosome Y (mLOY) and outcome in a large international data set.MethodsWe used data from the genome-wide association study performed within the Genetics of Ischemic Stroke Functional Outcome network, which included 6,165 patients (3,497 men and 2,668 women) with acute ischemic stroke of mainly European ancestry. We assessed a weighted PRS for mLOY and examined possible associations with the modified Rankin Scale (mRS) score 3 months poststroke in logistic regression models. We investigated the whole study sample as well as men and women separately.ResultsIncreasing PRS for mLOY was associated with poor functional outcome (mRS score >2) with an odds ratio (OR) of 1.11 (95% confidence interval [CI] 1.03-1.19) per 1 SD increase in the PRS after adjustment for age, sex, ancestry, stroke severity (NIH Stroke Scale), smoking, and diabetes mellitus. In sex-stratified analyses, we found a statistically significant association in women (adjusted OR 1.20, 95% CI 1.08-1.33). In men, the association was in the same direction (adjusted OR 1.04, 95% CI 0.95-1.14), and we observed no significant genotype-sex interaction.DiscussionIn this exploratory study, we found associations between genetic variants predisposing to mLOY and stroke outcome. The significant association in women suggests underlying mechanisms related to genomic instability that operate in both sexes. These findings need replication and mechanistic exploration.
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