| 1. |
- 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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| 2. |
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| 3. |
- Feroci, M., et al.
(författare)
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The large observatory for x-ray timing
- 2014
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Ingår i: Proceedings of SPIE - The International Society for Optical Engineering. - : SPIE. - 9780819496126
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Konferensbidrag (refereegranskat)abstract
- The Large Observatory For x-ray Timing (LOFT) was studied within ESA M3 Cosmic Vision framework and participated in the final downselection for a launch slot in 2022-2024. Thanks to the unprecedented combination of effective area and spectral resolution of its main instrument, LOFT will study the behaviour of matter under extreme conditions, such as the strong gravitational field in the innermost regions of accretion flows close to black holes and neutron stars, and the supranuclear densities in the interior of neutron stars. The science payload is based on a Large Area Detector (LAD, 10 m2 effective area, 2-30 keV, 240 eV spectral resolution, 1° collimated field of view) and a Wide Field Monitor (WFM, 2-50 keV, 4 steradian field of view, 1 arcmin source location accuracy, 300 eV spectral resolution). The WFM is equipped with an on-board system for bright events (e.g. GRB) localization. The trigger time and position of these events are broadcast to the ground within 30 s from discovery. In this paper we present the status of the mission at the end of its Phase A study.
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| 4. |
- 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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| 5. |
- Feroci, M., et al.
(författare)
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LOFT - The large observatory for x-ray timing
- 2012
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Ingår i: Proceedings of SPIE - The International Society for Optical Engineering. - : SPIE - International Society for Optical Engineering. - 9780819491442 ; , s. 84432D-
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Konferensbidrag (refereegranskat)abstract
- The LOFT mission concept is one of four candidates selected by ESA for the M3 launch opportunity as Medium Size missions of the Cosmic Vision programme. The launch window is currently planned for between 2022 and 2024. LOFT is designed to exploit the diagnostics of rapid X-ray flux and spectral variability that directly probe the motion of matter down to distances very close to black holes and neutron stars, as well as the physical state of ultradense matter. These primary science goals will be addressed by a payload composed of a Large Area Detector (LAD) and a Wide Field Monitor (WFM). The LAD is a collimated (<1 degree field of view) experiment operating in the energy range 2-50 keV, with a 10 m2 peak effective area and an energy resolution of 260 eV at 6 keV. The WFM will operate in the same energy range as the LAD, enabling simultaneous monitoring of a few-steradian wide field of view, with an angular resolution of <5 arcmin. The LAD and WFM experiments will allow us to investigate variability from submillisecond QPO's to yearlong transient outbursts. In this paper we report the current status of the project.
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| 6. |
- Bretzner, M., et al.
(författare)
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MRI Radiomic Signature of White Matter Hyperintensities Is Associated With Clinical Phenotypes
- 2021
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Ingår i: Frontiers in Neuroscience. - : Frontiers Media SA. - 1662-4548 .- 1662-453X. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Neuroimaging measurements of brain structural integrity are thought to be surrogates for brain health, but precise assessments require dedicated advanced image acquisitions. By means of quantitatively describing conventional images, radiomic analyses hold potential for evaluating brain health. We sought to: (1) evaluate radiomics to assess brain structural integrity by predicting white matter hyperintensities burdens (WMH) and (2) uncover associations between predictive radiomic features and clinical phenotypes. Methods: We analyzed a multi-site cohort of 4,163 acute ischemic strokes (AIS) patients with T2-FLAIR MR images with total brain and WMH segmentations. Radiomic features were extracted from normal-appearing brain tissue (brain mask-WMH mask). Radiomics-based prediction of personalized WMH burden was done using ElasticNet linear regression. We built a radiomic signature of WMH with stable selected features predictive of WMH burden and then related this signature to clinical variables using canonical correlation analysis (CCA). Results: Radiomic features were predictive of WMH burden (R-2 = 0.855 +/- 0.011). Seven pairs of canonical variates (CV) significantly correlated the radiomics signature of WMH and clinical traits with respective canonical correlations of 0.81, 0.65, 0.42, 0.24, 0.20, 0.15, and 0.15 (FDR-corrected p-values(CV1-6) < 0.001, p-value(CV7) = 0.012). The clinical CV1 was mainly influenced by age, CV2 by sex, CV3 by history of smoking and diabetes, CV4 by hypertension, CV5 by atrial fibrillation (AF) and diabetes, CV6 by coronary artery disease (CAD), and CV7 by CAD and diabetes. Conclusion: Radiomics extracted from T2-FLAIR images of AIS patients capture microstructural damage of the cerebral parenchyma and correlate with clinical phenotypes, suggesting different radiographical textural abnormalities per cardiovascular risk profile. Further research could evaluate radiomics to predict the progression of WMH and for the follow-up of stroke patients' brain health.
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| 7. |
- Feroci, M., et al.
(författare)
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The Large Observatory for X-ray Timing (LOFT)
- 2012
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Ingår i: Experimental Astronomy. - : Springer Science and Business Media LLC. - 0922-6435 .- 1572-9508. ; 34:2, s. 415-444
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Tidskriftsartikel (refereegranskat)abstract
- High-time-resolution X-ray observations of compact objects provide direct access to strong-field gravity, to the equation of state of ultradense matter and to black hole masses and spins. A 10 m(2)-class instrument in combination with good spectral resolution is required to exploit the relevant diagnostics and answer two of the fundamental questions of the European Space Agency (ESA) Cosmic Vision Theme "Matter under extreme conditions", namely: does matter orbiting close to the event horizon follow the predictions of general relativity? What is the equation of state of matter in neutron stars? The Large Observatory For X-ray Timing (LOFT), selected by ESA as one of the four Cosmic Vision M3 candidate missions to undergo an assessment phase, will revolutionise the study of collapsed objects in our galaxy and of the brightest supermassive black holes in active galactic nuclei. Thanks to an innovative design and the development of large-area monolithic silicon drift detectors, the Large Area Detector (LAD) on board LOFT will achieve an effective area of similar to 12 m(2) (more than an order of magnitude larger than any spaceborne predecessor) in the 2-30 keV range (up to 50 keV in expanded mode), yet still fits a conventional platform and small/medium-class launcher. With this large area and a spectral resolution of < 260 eV, LOFT will yield unprecedented information on strongly curved spacetimes and matter under extreme conditions of pressure and magnetic field strength.
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| 8. |
- 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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| 9. |
- 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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| 10. |
- Hong, S. M., et al.
(författare)
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Excessive White Matter Hyperintensity Increases Susceptibility to Poor Functional Outcomes After Acute Ischemic Stroke
- 2021
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Ingår i: Frontiers in Neurology. - : Frontiers Media SA. - 1664-2295. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To personalize the prognostication of post-stroke outcome using MRI-detected cerebrovascular pathology, we sought to investigate the association between the excessive white matter hyperintensity (WMH) burden unaccounted for by the traditional stroke risk profile of individual patients and their long-term functional outcomes after a stroke. Methods: We included 890 patients who survived after an acute ischemic stroke from the MRI-Genetics Interface Exploration (MRI-GENIE) study, for whom data on vascular risk factors (VRFs), including age, sex, atrial fibrillation, diabetes mellitus, hypertension, coronary artery disease, smoking, prior stroke history, as well as acute stroke severity, 3- to-6-month modified Rankin Scale score (mRS), WMH, and brain volumes, were available. We defined the unaccounted WMH (uWMH) burden via modeling of expected WMH burden based on the VRF profile of each individual patient. The association of uWMH and mRS score was analyzed by linear regression analysis. The odds ratios of patients who achieved full functional independence (mRS < 2) in between trichotomized uWMH burden groups were calculated by pair-wise comparisons. Results: The expected WMH volume was estimated with respect to known VRFs. The uWMH burden was associated with a long-term functional outcome (beta = 0.104, p < 0.01). Excessive uWMH burden significantly reduced the odds of achieving full functional independence after a stroke compared to the low and average uWMH burden [OR = 0.4, 95% CI: (0.25, 0.63), p < 0.01 and OR = 0.61, 95% CI: (0.42, 0.87), p < 0.01, respectively]. Conclusion: The excessive amount of uWMH burden unaccounted for by the traditional VRF profile was associated with worse post-stroke functional outcomes. Further studies are needed to evaluate a lifetime brain injury reflected in WMH unrelated to the VRF profile of a patient as an important factor for stroke recovery and a plausible indicator of brain health.
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| 11. |
- Bonkhoff, A. K., et al.
(författare)
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Deep profiling of multiple ischemic lesions in a large, multi-center cohort: Frequency, spatial distribution, and associations to clinical characteristics
- 2022
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Ingår i: Frontiers in Neuroscience. - : Frontiers Media SA. - 1662-453X .- 1662-4548. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- Background purposeA substantial number of patients with acute ischemic stroke (AIS) experience multiple acute lesions (MAL). We here aimed to scrutinize MAL in a large radiologically deep-phenotyped cohort. Materials and methodsAnalyses relied upon imaging and clinical data from the international MRI-GENIE study. Imaging data comprised both Fluid-attenuated inversion recovery (FLAIR) for white matter hyperintensity (WMH) burden estimation and diffusion-weighted imaging (DWI) sequences for the assessment of acute stroke lesions. The initial step featured the systematic evaluation of occurrences of MAL within one and several vascular supply territories. Associations between MAL and important imaging and clinical characteristics were subsequently determined. The interaction effect between single and multiple lesion status and lesion volume was estimated by means of Bayesian hierarchical regression modeling for both stroke severity and functional outcome. ResultsWe analyzed 2,466 patients (age = 63.4 +/- 14.8, 39% women), 49.7% of which presented with a single lesion. Another 37.4% experienced MAL in a single vascular territory, while 12.9% featured lesions in multiple vascular territories. Within most territories, MAL occurred as frequently as single lesions (ratio similar to 1:1). Only the brainstem region comprised fewer patients with MAL (ratio 1:4). Patients with MAL presented with a significantly higher lesion volume and acute NIHSS (7.7 vs. 1.7 ml and 4 vs. 3, p(FDR) < 0.001). In contrast, patients with a single lesion were characterized by a significantly higher WMH burden (6.1 vs. 5.3 ml, p(FDR) = 0.048). Functional outcome did not differ significantly between patients with single versus multiple lesions. Bayesian analyses suggested that the association between lesion volume and stroke severity between single and multiple lesions was the same in case of anterior circulation stroke. In case of posterior circulation stroke, lesion volume was linked to a higher NIHSS only among those with MAL. ConclusionMultiple lesions, especially those within one vascular territory, occurred more frequently than previously reported. Overall, multiple lesions were distinctly linked to a higher acute stroke severity, a higher total DWI lesion volume and a lower WMH lesion volume. In posterior circulation stroke, lesion volume was linked to a higher stroke severity in multiple lesions only.
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| 12. |
- 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. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 99:13
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objectives To examine whether high white matter hyperintensity (WMH) burden is associated with greater stroke severity and worse functional outcomes in lesion pattern-specific ways. Methods MR 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 lowWMHburden 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. Results A 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. Discussion Higher 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.
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| 13. |
- Bretzner, Martin, et al.
(författare)
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Radiomics-Derived Brain Age Predicts Functional Outcome After Acute Ischemic Stroke.
- 2023
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Ingår i: Neurology. - 1526-632X .- 0028-3878. ; 100:8
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Tidskriftsartikel (refereegranskat)abstract
- While chronological age is one of the most influential determinants of poststroke outcomes, little is known of the impact of neuroimaging-derived biological "brain age." We hypothesized that radiomics analyses of T2-FLAIR images texture would provide brain age estimates and that advanced brain age of patients with stroke will be associated with cardiovascular risk factors and worse functional outcomes.We extracted radiomics from T2-FLAIR images acquired during acute stroke clinical evaluation. Brain age was determined from brain parenchyma radiomics using an ElasticNet linear regression model. Subsequently, relative brain age (RBA), which expresses brain age in comparison with chronological age-matched peers, was estimated. Finally, we built a linear regression model of RBA using clinical cardiovascular characteristics as inputs and a logistic regression model of favorable functional outcomes taking RBA as input.We reviewed 4,163 patients from a large multisite ischemic stroke cohort (mean age = 62.8 years, 42.0% female patients). T2-FLAIR radiomics predicted chronological ages (mean absolute error = 6.9 years, r = 0.81). After adjustment for covariates, RBA was higher and therefore described older-appearing brains in patients with hypertension, diabetes mellitus, a history of smoking, and a history of a prior stroke. In multivariate analyses, age, RBA, NIHSS, and a history of prior stroke were all significantly associated with functional outcome (respective adjusted odds ratios: 0.58, 0.76, 0.48, 0.55; all p-values < 0.001). Moreover, the negative effect of RBA on outcome was especially pronounced in minor strokes.T2-FLAIR radiomics can be used to predict brain age and derive RBA. Older-appearing brains, characterized by a higher RBA, reflect cardiovascular risk factor accumulation and are linked to worse outcomes after stroke.
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| 14. |
- Bonkhoff, Anna K, et al.
(författare)
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The relevance of rich club regions for functional outcome post-stroke is enhanced in women.
- 2023
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Ingår i: Human brain mapping. - : Wiley. - 1097-0193 .- 1065-9471. ; 44:4, s. 1579-1592
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Tidskriftsartikel (refereegranskat)abstract
- This study aimed to investigate the influence of stroke lesions in predefined highly interconnected (rich-club) brain regions on functional outcome post-stroke, determine their spatial specificity and explore the effects of biological sex on their relevance. We analyzed MRI data recorded at index stroke and ~3-months modified Rankin Scale (mRS) data from patients with acute ischemic stroke enrolled in the multisite MRI-GENIE study. Spatially normalized structural stroke lesions were parcellated into 108 atlas-defined bilateral (sub)cortical brain regions. Unfavorable outcome (mRS>2) was modeled in a Bayesian logistic regression framework. Effects of individual brain regions were captured as two compound effects for (i) six bilateral rich club and (ii) all further non-rich club regions. In spatial specificity analyses, we randomized the split into "rich club" and "non-rich club" regions and compared the effect of the actual rich club regions to the distribution of effects from 1000 combinations of six random regions. In sex-specific analyses, we introduced an additional hierarchical level in our model structure to compare male and female-specific rich club effects. A total of 822 patients (age: 64.7[15.0], 39% women) were analyzed. Rich club regions had substantial relevance in explaining unfavorable functional outcome (mean of posterior distribution: 0.08, area under the curve: 0.8). In particular, the rich club-combination had a higher relevance than 98.4% of random constellations. Rich club regions were substantially more important in explaining long-term outcome in women than in men. All in all, lesions in rich club regions were associated with increased odds of unfavorable outcome. These effects were spatially specific and more pronounced in women.
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| 15. |
- Feigin, Valery L., et al.
(författare)
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Global, regional, and national burden of stroke and its risk factors, 1990-2019 : a systematic analysis for the Global Burden of Disease Study 2019
- 2021
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Ingår i: Lancet Neurology. - : Elsevier. - 1474-4422 .- 1474-4465. ; 20:10, s. 795-820
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Tidskriftsartikel (refereegranskat)abstract
- Background Regularly updated data on stroke and its pathological types, including data on their incidence, prevalence, mortality, disability, risk factors, and epidemiological trends, are important for evidence-based stroke care planning and resource allocation. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) aims to provide a standardised and comprehensive measurement of these metrics at global, regional, and national levels. Methods We applied GBD 2019 analytical tools to calculate stroke incidence, prevalence, mortality, disability-adjusted life-years (DALYs), and the population attributable fraction (PAF) of DALYs (with corresponding 95% uncertainty intervals [UIs]) associated with 19 risk factors, for 204 countries and territories from 1990 to 2019. These estimates were provided for ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage, and all strokes combined, and stratified by sex, age group, and World Bank country income level. Findings In 2019, there were 12.2 million (95% UI 11.0-13.6) incident cases of stroke, 101 million (93.2-111) prevalent cases of stroke, 143 million (133-153) DALYs due to stroke, and 6.55 million (6.00-7.02) deaths from stroke. Globally, stroke remained the second-leading cause of death (11.6% [10.8-12.2] of total deaths) and the third-leading cause of death and disability combined (5.7% [5.1-6.2] of total DALYs) in 2019. From 1990 to 2019, the absolute number of incident strokes increased by 70.0% (67.0-73.0), prevalent strokes increased by 85.0% (83.0-88.0), deaths from stroke increased by 43.0% (31.0-55.0), and DALYs due to stroke increased by 32.0% (22.0-42.0). During the same period, age-standardised rates of stroke incidence decreased by 17.0% (15.0-18.0), mortality decreased by 36.0% (31.0-42.0), prevalence decreased by 6.0% (5.0-7.0), and DALYs decreased by 36.0% (31.0-42.0). However, among people younger than 70 years, prevalence rates increased by 22.0% (21.0-24.0) and incidence rates increased by 15.0% (12.0-18.0). In 2019, the age-standardised stroke-related mortality rate was 3.6 (3.5-3.8) times higher in the World Bank low-income group than in the World Bank high-income group, and the age-standardised stroke-related DALY rate was 3.7 (3.5-3.9) times higher in the low-income group than the high-income group. Ischaemic stroke constituted 62.4% of all incident strokes in 2019 (7.63 million [6.57-8.96]), while intracerebral haemorrhage constituted 27.9% (3.41 million [2.97-3.91]) and subarachnoid haemorrhage constituted 9.7% (1.18 million [1.01-1.39]). In 2019, the five leading risk factors for stroke were high systolic blood pressure (contributing to 79.6 million [67.7-90.8] DALYs or 55.5% [48.2-62.0] of total stroke DALYs), high body-mass index (34.9 million [22.3-48.6] DALYs or 24.3% [15.7-33.2]), high fasting plasma glucose (28.9 million [19.8-41.5] DALYs or 20.2% [13.8-29.1]), ambient particulate matter pollution (28.7 million [23.4-33.4] DALYs or 20.1% [16.6-23.0]), and smoking (25.3 million [22.6-28.2] DALYs or 17.6% [16.4-19.0]). Interpretation The annual number of strokes and deaths due to stroke increased substantially from 1990 to 2019, despite substantial reductions in age-standardised rates, particularly among people older than 70 years. The highest age-standardised stroke-related mortality and DALY rates were in the World Bank low-income group. The fastest-growing risk factor for stroke between 1990 and 2019 was high body-mass index. Without urgent implementation of effective primary prevention strategies, the stroke burden will probably continue to grow across the world, particularly in low-income countries.
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| 16. |
- Gilani, Sarwat I, et al.
(författare)
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Urinary Extracellular Vesicles of Podocyte Origin and Renal Injury in Preeclampsia
- 2017
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Ingår i: Journal of the American Society of Nephrology: JASN. - 1533-3450. ; 28:11, s. 3363-3372
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Tidskriftsartikel (refereegranskat)abstract
- Renal histologic expression of the podocyte-specific protein, nephrin, but not podocin, is reduced in preeclamptic compared with normotensive pregnancies. We hypothesized that renal expression of podocyte-specific proteins would be reflected in urinary extracellular vesicles (EVs) of podocyte origin and accompanied by increased urinary soluble nephrin levels (nephrinuria) in preeclampsia. We further postulated that podocyte injury and attendant formation of EVs are related mechanistically to cellfree fetal hemoglobin (HbF) in maternal plasma. Our study population included preeclamptic (n=49) and normotensive (n=42) pregnant women recruited at delivery. Plasma measurements included HbF concentrations and concentrations of the endogenous chelators haptoglobin, hemopexin, and α1- microglobulin. We assessed concentrations of urinary EVs containing immunologically detectable podocyte-specific proteins by digital flow cytometry and measured nephrinuria by ELISA. The mechanistic role of HbF in podocyte injury was studied in pregnant rabbits. Compared with urine from women with normotensive pregnancies, urine from women with preeclamptic pregnancies contained a high ratio of podocin-positive to nephrin-positive urinary EVs (podocin(+) EVs-to-nephrin(+) EVs ratio) and increased nephrinuria, both of which correlated with proteinuria. Plasma levels of hemopexin, which were decreased in women with preeclampsia, negatively correlated with proteinuria, urinary podocin(+) EVs-to-nephrin(+) EVs ratio, and nephrinuria. Administration of HbF to pregnant rabbits increased the number of urinary EVs of podocyte origin. These findings provide evidence that urinary EVs are reflective of preeclampsia-related altered podocyte protein expression. Furthermore, renal injury in preeclampsia associated with an elevated urinary podocin(+) EVs-to-nephrin(+) EVs ratio and may be mediated by prolonged exposure to cellfree HbF.
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