| 1. |
- Ibanez, L., et al.
(författare)
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Multi-ancestry GWAS reveals excitotoxicity associated with outcome after ischaemic stroke
- 2022
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 145:7, s. 2394-2406
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Tidskriftsartikel (refereegranskat)abstract
- During the first hours after stroke onset, neurological deficits can be highly unstable: some patients rapidly improve, while others deteriorate. This early neurological instability has a major impact on long-term outcome. Here, we aimed to determine the genetic architecture of early neurological instability measured by the difference between the National Institutes of Health Stroke Scale (NIHSS) within 6 h of stroke onset and NIHSS at 24 h. A total of 5876 individuals from seven countries (Spain, Finland, Poland, USA, Costa Rica, Mexico and Korea) were studied using a multi-ancestry meta-analyses. We found that 8.7% of NIHSS at 24 h of variance was explained by common genetic variations, and also that early neurological instability has a different genetic architecture from that of stroke risk. Eight loci (1p21.1, 1q42.2, 2p25.1, 2q31.2, 2q33.3, 5q33.2, 7p21.2 and 13q31.1) were genome-wide significant and explained 1.8% of the variability suggesting that additional variants influence early change in neurological deficits. We used functional genomics and bioinformatic annotation to identify the genes driving the association from each locus. Expression quantitative trait loci mapping and summary data-based Mendelian randomization indicate that ADAM23 (log Bayes factor = 5.41) was driving the association for 2q33.3. Gene-based analyses suggested that GRIA1 (log Bayes factor = 5.19), which is predominantly expressed in the brain, is the gene driving the association for the 5q33.2 locus. These analyses also nominated GNPAT (log Bayes factor = 7.64) ABCB5 (log Bayes factor = 5.97) for the 1p21.1 and 7p21.1 loci. Human brain single-nuclei RNA-sequencing indicates that the gene expression of ADAM23 and GRIA1 is enriched in neurons. ADAM23, a presynaptic protein and GRIA1, a protein subunit of the AMPA receptor, are part of a synaptic protein complex that modulates neuronal excitability. These data provide the first genetic evidence in humans that excitotoxicity may contribute to early neurological instability after acute ischaemic stroke. Ibanez et al. perform a multi-ancestry meta-analysis to investigate the genetic architecture of early stroke outcomes. Two of the eight genome-wide significant loci identified-ADAM23 and GRIA1-are involved in synaptic excitability, suggesting that excitotoxicity contributes to neurological instability after ischaemic stroke.
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| 2. |
- Poli, Sven, et al.
(författare)
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Penumbral Rescue by normobaric O?=?O administration in patients with ischemic stroke and target mismatch proFile (PROOF): Study protocol of a phase IIb trial
- 2024
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Ingår i: INTERNATIONAL JOURNAL OF STROKE. - 1747-4930 .- 1747-4949. ; 19:1, s. 120-126
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Tidskriftsartikel (refereegranskat)abstract
- Rationale: Oxygen is essential for cellular energy metabolism. Neurons are particularly vulnerable to hypoxia. Increasing oxygen supply shortly after stroke onset could preserve the ischemic penumbra until revascularization occurs.Aims: PROOF investigates the use of normobaric oxygen (NBO) therapy within 6 h of symptom onset/notice for brain-protective bridging until endovascular revascularization of acute intracranial anterior-circulation occlusion.Methods and design: Randomized (1:1), standard treatment-controlled, open-label, blinded endpoint, multicenter adaptive phase IIb trial.Study outcomes: Primary outcome is ischemic core growth (mL) from baseline to 24 h (intention-to-treat analysis). Secondary efficacy outcomes include change in NIHSS from baseline to 24 h, mRS at 90 days, cognitive and emotional function, and quality of life. Safety outcomes include mortality, intracranial hemorrhage, and respiratory failure. Exploratory analyses of imaging and blood biomarkers will be conducted.Sample size: Using an adaptive design with interim analysis at 80 patients per arm, up to 456 participants (228 per arm) would be needed for 80% power (one-sided alpha 0.05) to detect a mean reduction of ischemic core growth by 6.68 mL, assuming 21.4 mL standard deviation.Discussion: By enrolling endovascular thrombectomy candidates in an early time window, the trial replicates insights from preclinical studies in which NBO showed beneficial effects, namely early initiation of near 100% inspired oxygen during short temporary ischemia. Primary outcome assessment at 24 h on follow-up imaging reduces variability due to withdrawal of care and early clinical confounders such as delayed extubation and aspiration pneumonia.
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| 3. |
- Psychogios, Marios, et al.
(författare)
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European Stroke Organisation guidelines on treatment of patients with intracranial atherosclerotic disease
- 2022
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Ingår i: European Stroke Journal. - : SAGE Publications. - 2396-9881 .- 2396-9873.
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the present European Stroke Organisation guideline is to provide clinically useful evidence-basedrecommendations on the management of patients with intracranial atherosclerotic disease (ICAD). The guidelines wereprepared following the Standard Operational Procedure of the European Stroke Organisation guidelines and accordingto GRADE methodology. ICAD represents a major cause of ischemic stroke worldwide, and patients affected by thiscondition are exposed to a high risk for future strokes and other major cardiovascular events, despite best medicaltherapy available. We identified 11 relevant clinical problems affecting ICAD patients and formulated the correspondingPopulation Intervention Comparator Outcomes (PICO) questions. The first two questions refer to the asymptomaticstage of the disease, which is being increasingly detected thanks to the routine use of noninvasive vascular imaging. Wewere not able to provide evidence-based recommendations regarding the optimal detection strategy and management ofasymptomatic ICAD, and further research in the field is encouraged as subclinical ICAD may represent a big opportunityto improve primary stroke prevention. The second block of PICOs (3–5) is dedicated to the management of acutelarge vessel occlusion (LVO) ischemic stroke caused by ICAD, a clinical presentation of this disease that is becomingincreasingly relevant and problematic, since it is associated with more refractory endovascular reperfusion procedures.An operational definition of probable ICAD-related LVO is proposed in the guideline. Despite the challenging context,no dedicated randomized clinical trials (RCTs) were identified, and therefore the guideline can only provide withsuggestions derived from observational studies and our expert consensus, such as the escalated use of glycoproteinIIb-IIIa inhibitors and angioplasty/stenting in cases of refractory thrombectomies due to underlying ICAD. The last blockof PICOs is devoted to the secondary prevention of patients with symptomatic ICAD. Moderate-level evidence wasfound to recommend against the use of oral anticoagulation as preferred antithrombotic drug, in favor of antiplatelets.Low-level evidence based our recommendation in favor of double antiplatelet as the antithrombotic treatment of choicein symptomatic ICAD patients, which we suggest to maintain during 90days as per our expert consensus. Endovasculartherapy with intracranial angioplasty and or stenting is not recommended as a treatment of first choice in high-gradesymptomatic ICAD (moderate-level evidence). Regarding neurosurgical interventions, the available evidence does notsupport their use as front line therapies in patients with high-grade ICAD. There is not enough evidence as to provideany specific recommendation regarding the use of remote ischemic conditioning in ICAD patients, and further RCTsare needed to shed light on the utility of this promising therapy. Finally, we dedicate the last PICO to the importanceof aggressive vascular risk factor management in ICAD, although the evidence derived from RCTs specifically addressingthis question is still scarce
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