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Background: Ischemic stroke is the leading cause of death and long-term disability worldwide. After stroke, microglia exhibit not only pro-inflammatory phenotype to aggravate the neuroinflammation, but also anti-inflammatory phenotype to play a neuroprotective role. Studies on the spatial and temporal changes in microglia and the underlying mechanisms help to elucidate the inflammatory cascade after stroke. The regulation of microglia polarization provides new insights for the intervention of post-stroke inflammation., Objective: We aimed to investigate the phenotypic change of microglia in the acute phase of ischemic stroke and the effects of Dl-3-n-butylphthalide (NBP) on microglia. TSPO-PET was used to image microglia and evaluate the efficacy of NBP., Methods: We constructed an MCAO model in rats and administered NBP daily. The infarct volumes in the NBP-treated and control groups were measured. TSPO-PET/CT was used to demonstrate the activation of microglia and the effects of NBP. Additionally, we investigated the effects of NBP on TSPO expression. In vitro, microglia were exposed to glucose oxygen deprivation, and the effects of NBP on microglia and TSPO expression were verified., Results: NBP improved neurological severity scores and reduced infarct volume in the acute phase of ischemic stroke. NBP facilitated microglia to adopt the anti-inflammatory phenotype and reduce the pro-inflammatory phenotype. NBP decreased the expressions of inflammatory cytokines. TSPO-PET/CT observed increase in uptake in the infarct lesion, and this uptake was reduced in response to NBP. NBP reduced TSPO expression in microglia after stroke. In vitro experiments further verified that NBP facilitated the transition of microglia towards the anti-inflammatory phenotype, and inhibited inflammatory cytokine secretion and TSPO expression., Conclusion: We illustrated that NBP fosters the shift of microglia towards the anti-inflammatory phenotype while diminishing their inclination towards the pro-inflammatory phenotype, thereby exerting neuroprotective effects. NBP reduces TSPO expression in microglia, which can be observed by TSPO-PET/CT imaging., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In this study, we aimed to develop brain-targeted co-delivery liposomes for the concurrent delivery of Panax notoginseng saponins (PNS) and acetylsalicylic acid (ASA) for the treatment of ischemic stroke. Within this system, PNS served as a cholesterol substitute, integrating into the phospholipid bilayer of the liposomes, while ASA was encapsulated internally. A poly-2-methacryloyloxyethyl phosphorylcholine (PMPC) polymer was synthesized and incorporated into the liposome surface. This formulation demonstrated an enhanced PNS-loading capacity and facilitated the synchronized delivery of key saponin components. Following PMPC modification, the liposomes exhibited prolonged circulation and improved transport across the blood-brain barrier (BBB) through acetylcholine receptor-mediated pathways. Furthermore, the co-delivery system exhibited enhanced therapeutic efficacy in a rat model of cerebral ischemia-reperfusion injury via the phosphoinositide 3-kinase/protein kinase C pathway. Additional analyses revealed significant effects on the metabolism of neurotransmitters, amino acids, folate, and various other pathways, indicating a multi-faceted therapeutic effect. Overall, this study presents an innovative research strategy for the comprehensive delivery of diverse components in traditional Chinese medicine formulations, highlighting the potential for synergistic treatments that combine traditional Chinese medicine with chemical agents., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: Thrombolytic therapy is the primary treatment for acute ischemic stroke. Extending the therapeutic time window can effectively reduce the harmful side effects associated with thrombolytic therapy. Although electroacupuncture (EA) has been shown to extend this time window, the specific mechanisms remain unclear., Methods: We developed an embolic stroke model in rats and administered EA during thrombolytic therapy with recombinant tissue plasminogen activator (rt-PA) either 4.5 or 6 h after stroke onset. Neurological deficits were evaluated at 2 and 24 h post-stroke. Brain tissue was collected for analysis using 2,3,5-triphenyl tetrazolium chloride (TTC) staining, water content measurement, blood-brain barrier (BBB) permeability assessment, electron microscopy, and TUNEL assay. Immunofluorescence staining, western blotting, and enzyme-linked immunosorbent assays were employed to quantify the expression of proteins related to BBB integrity and pyroptosis., Results: Neuronal damage and BBB disruption along with increased expression of pyroptosis-related proteins were observed following thrombolytic therapy at the 6-hour mark. EA treatment improved neurological outcomes, reduced infarct volume, and alleviated BBB disruption. EA also inhibited the expression of matrix metalloproteinase 9 (MMP9) and enhanced the expression of tissue inhibitor of metalloproteinases 1 (TIMP1), helping to maintain BBB integrity. Furthermore, EA reduced the expression of pyroptosis-related proteins, including gasdermin D (GSDMD), interleukin-1β (IL-1β), and interleukin-18 (IL-18). EA also reduced the co-expression of GSDMD and MMP9 in brain tissues., Conclusions: EA may be a promising therapeutic approach for extending the thrombolytic therapy window by protecting the BBB and inhibiting GSDMD-mediated pyroptosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: The intricate roles of NMDA receptors, specifically those containing the NR2A or NR2B subunit, in ischemic stroke pathology necessitate targeted therapeutic investigations. Building on our prior discovery showcasing the neuroprotective potential of 2-(benzofuran-2-yl)-2-imidazoline (2-BFI), an imidazoline I2 receptor ligand, in inhibiting NMDA receptor currents during ischemic stroke, this study aims to elucidate the specific impact of 2-BFI on NR2A- and NR2B-containing NMDARs., Experimental Approach: Through whole-cell patch-clamp techniques, we observed an inhibition by 2-BFI on NR2A-containing NMDAR currents (IC50 = 238.6 μM) and NR2B-containing NMDAR currents (IC50 = 18.47 μM). Experiments with HEK293 cells expressing exogenous receptor subunits revealed a significantly higher affinity of 2-BFI towards NR2B-containing NMDARs. In vivo studies involved the co-administration of 2-BFI and the NR2A subunit antagonist NVP-AAM077 in rats subjected to transient middle cerebral artery occlusion (tMCAO). Key results 2-BFI exhibited a pronounced preference for inhibiting NR2B-containing NMDAR currents, leading to a notable mitigation of cerebral ischemic injury when administered in conjunction with NVP-AAM077 in the tMCAO rat model. Furthermore, alterations in the expression of downstream proteins specific to NR2B-containing NMDA receptors were observed, suggesting targeted molecular effects. Conclusion and implications This study unveils the neuroprotective potential of 2-BFI in ischemic stroke by selectively inhibiting NR2B-containing NMDA receptors. These findings lay the foundation for precise therapeutic strategies, showcasing the differential roles of NR2A and NR2B subunits and paving the way for advancements in targeted interventions for ischemic stroke treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ischemic stroke (IS) is characterized by intricate pathophysiological mechanisms, where single-target treatments have often proven insufficient. Thus, multi-target therapeutic approaches are essential for effective IS management. In this study, we employed a molecular hybridization strategy, merging the structures of the iNOS inhibitor 1400W and the multi-target neuroprotective agent NBP, to develop a series of novel iNOS inhibitors BN-1 ∼ BN-4 with neuroprotective properties. Among these, BN-4 exhibited the most potent cell protective activity in OGD/R-induced SH-SY5Y and BV-2 cells. BN-4 not only reduced ROS levels induced by OGD/R in SH-SY5Y cells but also mitigated necrosis and apoptosis. By binding to iNOS in a manner similar to 1400W, BN-4 significantly inhibited iNOS activity. Furthermore, BN-4 demonstrated high stability, excellent blood-brain barrier permeability, and more than 100-fold increase in aqueous solubility compared to NBP. Additionally, BN-4 notably decreased infarct size and showed neuroprotective effects in tMCAO rats. These findings indicate that BN-4 holds promise as a novel candidate for treatment IS, offering enhanced therapeutic efficacy due to its superior pharmacokinetic and pharmacodynamic properties., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yihua Zhang, Zhangjian Huang, Jianbing Wu, Duorui Ji has patent pending to China Pharmaceutical University. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Irisin is a glycosylated protein formed from the hydrolysis of fibronectin type III domain-containing protein 5 (FNDC5). Irisin is widely involved in the regulation of glucose and lipid metabolism. In addition, recent studies have demonstrated that Irisin can inhibit inflammation, restrain oxidative stress and have neuroprotective effects, which suggests that Irisin may have a good therapeutic effect on central nervous system diseases. Therefore, this review summarizes the role of Irisin in central nervous system diseases, including its signal pathways and possible mechanisms, etc. Irisin may be a potential candidate drug for the treatment of central nervous system diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background and Objectives: Although dexmedetomidine (DEX) is widely administered during endovascular treatment (EVT) to enhance procedural adherence of patients with acute ischemic stroke (AIS) with large vessel occlusion, there is limited research on the association of DEX and outcomes among these patients. Hence, this study aimed to explore the safety and outcomes of DEX during conscious sedation (CS) in a real-world setting among patients undergoing EVT., Methods: This study was an individual patient-level pooled analysis of 2 multicenter randomized clinical trials RESCUE-BT and DEVT. This study included patients who underwent EVT because of occlusion of the internal carotid artery or middle cerebral artery. The DEX group included those receiving intraprocedural DEX for CS, whereas the patients without intraprocedural DEX sedation were categorized into the non-DEX group. The primary outcome was functional independence (modified Rankin Scale score of 0-2 at 90 days). Adjusted odds ratio (aOR) and 95% CI were obtained by logistic regression models., Results: A total of 728 patients were included in this study, of whom 308 (42.3%) were female. The median (interquartile range) age was 69 (59-76) years; the median baseline NIH Stroke Scale score was 16 (12-19). Compared with the non-DEX group, the DEX group had a significantly lower rate of functional independence (40.3% vs 51.3%; aOR 0.66; 95% CI 0.46-0.93; p = 0.019). There was a significantly higher rate of unstable procedural hemodynamics in the DEX group (9.7% vs 2.3%; aOR 4.60, 95% CI 2.12-9.99, p < 0.001). In subgroup analysis, similar results were found in intraprocedural DEX-treated patients when compared with local anesthesia or intraprocedural midazolam-treated patients, respectively., Discussion: There was a negative association between procedural DEX administration during CS and functional outcomes in patients with AIS receiving EVT in a real-world setting. A larger cohort is warranted to validate our findings., Classification of Evidence: This study provides Class II evidence that the use of DEX during EVT of AIS is associated with a worse outcome compared with other agents.

Background and Objectives: Hemorrhagic transformation may be a potentially devastating complication of IV thrombolysis (IVT) in acute ischemic stroke, but what degree of hemorrhage indicates the greatest negative effect is not known. We aimed to define the associations between hemorrhagic transformation patterns, classified according to clinical and imaging categories, and clinical outcomes after IVT., Methods: We conducted a post hoc analysis from the international Enhanced Control of Hypertension and Thrombolysis Stroke Study. Symptomatic intracerebral hemorrhage (sICH) was defined based on established criteria, such as the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) criteria. Asymptomatic intracerebral hemorrhage (aICH) was defined as any intracerebral hemorrhage that did not meet the criteria for sICH. Imaging subtypes of hemorrhagic transformation were assessed using the Heidelberg Bleeding Classification system. The primary outcome was death or major disability, defined by modified Rankin scale (mRS) scores 3-6 at 90 days. Secondary outcomes included death, death or disability (mRS 2-6), and poor health-related quality of life (HRQoL), defined as an overall heath utility score ≤0.7 (mean)., Results: Of the 4,370 participants, 779 (17.8%) developed any intracranial hemorrhage (ICH), with a median time from randomization to hemorrhage of 23.5 hours (interquartile range 18.92-26.07). According to the SITS-MOST criteria, 62 patients (1.4% of 4,370) were classified as sICH, and 717 patients (16.4% of 4,370) were classified as aICH. sICH per SITS-MOST criteria was associated with death or major disability (odds ratio [OR] 23.05, 95% CI 8.97-59.23), death (OR 20.14, 95% CI 11.32-35.84), death or disability (OR 61.36, 95% CI 8.40-448.01), and poor HRQoL (OR 17.87, 95% CI 7.47-42.71). Similarly, aICH per SITS-MOST criteria was also associated with death or major disability (OR 2.23, 95% CI 1.84-2.70), death (OR 1.82, 95% CI 1.39-2.38), death or disability (OR 2.29, 95% CI 1.87-2.80), and poor HRQoL (OR 1.81, 95% CI 1.50-2.18). Comparable associations were observed for sICH and aICH defined by other criteria, as well as for imaging subtypes based on Heidelberg Bleeding Classification system., Discussion: All forms of post-IVT hemorrhagic transformation in acute ischemic stroke are associated with increased odds of poor clinical outcomes. Of note, aICH after IVT should not be considered clinically innocuous., Trial Registration Information: ClinicalTrials.gov (NCT01422616).

A stroke, also known as cerebrovascular accident, is a medical emergency that occurs when the blood supply to the brain is interrupted. This disruption can happen in two main ways: through a hemorrhagic stroke, where a blood vessel in the brain bursts, or through an ischemic stroke, where a blood clot blocks an artery. Both types of stroke cause damage to brain cells, leading to a range of health complications. Globally, stroke ranks as the second leading cause of death and disability.This review provides an overview of stroke, focusing on its early detection, current treatment options, and emerging therapies. We discuss the complex mechanisms that contribute to stroke development, including the roles of cells, biomolecules, and blood vessels. Additionally, the review explores recent advances in the use of nanoparticles to enhance the efficacy of the pharmacotherapy of stroke, particularly ischemic stroke. Ongoing clinical trials in stroke management are also highlighted. Timely diagnosis and prompt intervention are critical for improving patient outcomes.We aim to increase awareness and understanding of stroke among researchers and healthcare professionals, ultimately improving patient care., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

Xingnaojing injection (XNJ), is the first-line Chinese medicine injection approved for treating ischemic stroke (IS). XNJ can attenuate the inflammatory responses and oxidative stress, thus reversing neuronal damage of IS. This study aims to prepare the biomimetic nanoparticles (Bo-GEVs/XNJM) of nasal administration for IS treatment. The grapefruit extracellular vesicles (GEVs) loaded with microemulsions sourced from Xingnaojing injection (XNJM) are modified with borneol (Bo) to bypass the blood-brain barrier (BBB). Bo-GEVs/XNJM has the property of brain-targeting, and in vivo and in vitro experiments have validated that it has positive effects in reducing apoptosis, inhibiting oxidative stress, anti-inflammation, protecting mitochondrial function, and protecting the BBB. In summary, Bo-GEVs/XNJM has good neuroprotective effects, and provides an interventional method for the treatment of ischemic stroke., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Ischemic stroke is an acute central nervous system disease that poses a threat to human health. It induces a series of severe pathological mechanisms, ultimately leading to neuronal cell death in the brain due to local ischemia and hypoxia. Buyang Huanwu decoction (BYHWD), as a representative formula for treating ischemic stroke, has shown good therapeutic effects in stroke patients., Aim of the Study: This study aimed to explore the mechanism of BYHWD in promoting neural remodeling after ischemic stroke from the perspective of neuronal synaptic plasticity, based on the cAMP/PKA/CREB signaling pathway., Materials and Methods: A modified suture technique was employed to establish a rat model of MCAO. The rats were divided into sham, model, and BYHWD (20 g/kg) groups. After the corresponding intervention, rat brains from each group were collected. TMT quantitative proteomics technology was employed for the research. Following proteomics studies, we investigated the mechanism of BYHWD in the intervention of ischemic stroke through animal experiments and cell experiments. The experimental animals were divided into sham, model, and BYHWD (5 g/kg, 10 g/kg, and 20 g/kg) groups. Infarct volume and severity of brain injury were measured by TTC staining. HE staining was utilized to evaluate alterations in tissue morphology. The Golgi staining was used to observe changes in cell body, dendrites, and dendritic spines. Transmission electron microscopy was used to observe the ultrastructure of synapses in the cortex and hippocampus. TUNEL staining was conducted to identify apoptotic neurons. Meanwhile, a stable and reliable (OGD/R) SH-SY5Y cell model was established. The effect of BYHWD-containing serum on SH-SY5Y cell viability was measured by CCK-8 kit. The apoptosis situation of SH-SY5Y cells was determined by Annexin V-FITC/PI. Immunofluorescence was employed to measure the fluorescence intensity of synaptic-related factors Syt1, Psd95, and Syn1. Synaptic plasticity pathways were assessed by using RT-qPCR and Western blot to determine the expression levels of cAMP, Psd95, Prkacb, Creb1/p-Creb1, BDNF, Shank2, Syn1, Syt1, Bcl-2, Bcl-2/Bax mRNA and proteins., Results: After treatment with BYHWD, notable alterations were detected in the signaling pathways linked to synaptic plasticity and the cAMP signaling pathway-related targets among the intervention targets. This trend of change was also reflected in other bioinformatics analyses, indicating the important role of synaptic plasticity changes before and after modeling and drug intervention. The results of vivo and vitro experiments showed that BYHWD improved local pathological changes, and reduced cerebral infarct volume, and neurological function scores in MCAO rats. It increased dendritic spine density, improved synaptic structural plasticity, and had a certain neuroprotective effect. BYHWD increased the postsynaptic membrane thickness, synaptic interface curvature, and synaptic quantity. 10% BYHWD-containing serum was determined as the optimal concentration for treatment. 10% BYHWD-containing serum significantly reduced the overall apoptotic rate of (OGD/R) SH-SY5Y cells. Immunofluorescence experiments demonstrated that 10% BYHWD-containing serum could improve synaptic plasticity and increase the relative expression levels of synaptic-related proteins Syt1, Psd95, and Syn1. BYHWD and decoction-containing serum upregulated the mRNA and protein expression levels in (OGD/R) SH-SY5Y cells and MCAO rats, suggesting its ability to improve damaged neuronal synaptic plasticity and enhance transmission efficiency, which might be achieved through the regulation of the cAMP/PKA/CREB pathway., Conclusions: This study may provide a basis for clinical medication by elucidating the underlying experimental evidence for the promotion of neural plasticity after ischemic stroke by BYHWD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: No treatment is available to prevent brain oedema, which can occur after a large hemispheric infarction. Glibenclamide has previously been shown to improve functional outcome and reduce neurological or oedema-related death in patients younger than 70 years who were at risk of brain oedema after an acute ischaemic stroke. We aimed to assess whether intravenous glibenclamide could improve functional outcome at 90 days in patients with large hemispheric infarction., Methods: CHARM was a phase 3, double-blind, placebo-controlled, randomised trial conducted across 143 acute stroke centres in 21 countries. We included patients aged 18-85 years with a large stroke, defined either by an Alberta Stroke Program Early CT Score (ASPECTS) of 1-5 or by an ischaemic core lesion volume of 80-300 mL on CT perfusion or MRI diffusion-weighted imaging. Patients were randomly assigned in a 1:1 ratio to either intravenous glibenclamide (8·6 mg over 72 h) or placebo. The study drug was started within 10 h of stroke onset. The primary efficacy outcome was the shift in the distribution of scores on the modified Rankin Scale at day 90, as a measure of functional outcome. The primary efficacy outcome was analysed in a modified intention-to-treat population, which included all randomly assigned patients aged 18-70 years. The safety population comprised all randomly assigned patients who received a dose. This trial is registered with ClinicalTrials.gov (NCT02864953). The trial was stopped early by the sponsor for strategic and operational reasons (slow enrolment because of COVID-19), before any unblinding or knowledge of the trial results., Findings: Between Aug 29, 2018, and May 23, 2023, 535 patients were enrolled and randomly assigned, of whom 518 received a dose (safety population) and 431 were aged 18-70 years and comprised the modified intention-to-treat population (217 were assigned glibenclamide and 214 placebo). The mean age of patients was 58·7 (SD 9·0) years in the placebo group and 58·0 (9·5) years in the glibenclamide group; the median US National Institutes of Health Stroke Scale (NIHSS) score was 19 (IQR 16-23) in the placebo group and 19 (IQR 16-22) in the glibenclamide group; and the mean time from stroke onset to study drug start was 8·9 h (SD 2·1) in the placebo group and 9·2 h (2·1) in the glibenclamide group. Intravenous glibenclamide was not associated with a favourable shift in the modified Rankin scale at 90 days (common odds ratio [OR] 1·17 [95% CI 0·80-1·71], p=0·42). 90-day mortality was 29% (61 of 214) in the placebo group and 32% (70 of 217) in the glibenclamide group (hazard ratio 1·20 [0·85-1·70]; p=0·30). Serious adverse events in the prespecified safety population were consistent with the known safety profile of glibenclamide and included hypoglycaemia in 15 (6%) of 259 patients in the glibenclamide group and in four (2%) of 259 patients in the placebo group, leading to dose interruption or reduction in seven (3%) patients in the glibenclamide group and in one (<1%) in the placebo group., Interpretation: Intravenous glibenclamide did not improve functional outcome in patients aged 18-70 years after large hemispheric infarction, although the trial was underpowered to make definitive conclusions because it was stopped early. Future prospective evaluation could be warranted to identify a possible benefit of intravenous glibenclamide in specific subgroups., Funding: Biogen., Competing Interests: Declaration of interests KNS has received research support from Biogen administered as a grant to Yale University; other research support from the US National Institutes of Health (NIH), American Heart Association, and Hyperfine, received consulting fees from CSL Behring, Rhaeos, Cerevasc, Astrocyte, Bexorg, and Brain Q; owns equity in Alva Health as a co-founder; and has served on data safety and monitoring board for Zoll, Sense, and Phillips. GWA has received consulting fees from Biogen related to the conduct of the CHARM trial; consulting fees from Genentech and RapidAI; and has equity in RapidAI. JLS has received consulting fees for advising on rigorous and safe clinical trial design and conduct from Biogen, Medtronic, Phenox, and Rapid Medical. BJM has received research support from Biogen administered as a grant to their previous institution (University of Pittsburgh Medical Center); has received grant funding from the NIH; and has equity interest in Celdara Medical. HEH has received consulting fees from Biogen related to the conduct of the CHARM trial; consulting fees from RapidAI; and grant funding from the NIH. CC has received research funding from Biogen related to the conduct of the CHARM trial in France; grant funding from French Ministry of Health and Agence Nationale de la Recherche; and consulting fees from Bayer. KT has received lecture fees from Daiichi-Sankyo, Otsuka, Janssen, Bayer, and Bristol Myers Squibb. RL is an employee of Biogen. MWa, RL, JC, NL, and KD are employees and stockholders of Biogen. RGN reports consulting fees for advisory roles with Anaconda, Biogen, Cerenovus, Genentech, Philips, Hybernia, Hyperfine, Imperative Care, Medtronic, Phenox, Philips, Prolong Pharmaceuticals, Stryker Neurovascular, Shanghai Wallaby, and Synchron; and stock options for advisory roles with Astrocyte, Brainomix, Cerebrotech, Ceretrieve, Corindus Vascular Robotics, CrestecBio, Euphrates Vascular, Vesalio, Viz-AI, RapidPulse, and Perfuze. RGN is one of the Principal Investigators of the “Endovascular Therapy for Low NIHSS Ischemic Strokes (ENDOLOW)” trial; is the Principal Investigator of the “Combined Thrombectomy for Distal MediUm Vessel Occlusion StroKe (DUSK)” trial; and is an investor in Viz-AI, Perfuze, Cerebrotech, Reist/Q’Apel Medical, Truvic, Tulavi Therapeutics, Vastrax, Piraeus Medical, Brain4Care, Quantanosis AI, and Viseon. JMS has received grant funding from the NIH and US Department of Veterans Affairs; consulting fees from Biogen; and owns stocks or options from Remedy Pharmaceuticals, Martin Pharmaceuticals, and Woolsey Pharmaceuticals. WTK has received research funding from Biogen related to the conduct of the CHARM trial; grant funding from the NIH, the American Heart Association, and the Alzheimer's Association; research funding from NControl Therapeutics; research funding from Hyperfine; consulting fees from Biogen, Acasti Pharma, and Astrocyte Pharmaceuticals; and owns stocks or options from Woolsey Pharmaceuticals and Acasti Pharma. BC and MWi declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Autophagy has been recently emerged as a prominent factor in the pathogenesis of ischemic stroke (IS) and is increasingly being considered as a potential therapeutic target for IS. Gnetum parvifolium has been identified as a potential therapeutic agent for inflammatory diseases such as rheumatism and traumatic injuries. However, the pharmacological effects of Gnetupindin A (GA), a stilbene compound isolated from Gnetum parvifolium, have not been fully elucidated until now., Objective: Here we identified the therapeutic potential of GA for IS, deeply exploring the possible mechanisms related to its regulation of autophagy., Methods: The mouse model of middle cerebral artery occlusion-reperfusion (MCAO/R) and the oxygen-glucose deprivation reperfusion (OGD/R)-exposed cells served as models to study the protection of GA against IS. The adeno-associated virus (AAV) encoding shAtg5, in conjunction with autophagy inhibitor 3-Methyladenine (3-MA) were utilized to explore the role of GA in regulating autophagy following IS. Molecular docking, CETSA, and DARTS were used to identify the specific therapeutic target of GA. PI3K inhibitor LY294002 was employed to test the participation of PI3K in GA-mediated autophagy and neuroprotective effects following IS., Results: Our findings revealed that treatment with GA significantly alleviated the brain infract volume, edema, improved neurological deficits and attenuated apoptosis. Mechanistically, we found that GA promoted autophagic flow both in vivo and in vitro after IS. Notably, neural-targeted knockdown of Atg5 abolished the neuroprotective effects mediated by GA. Inhibition of autophagy using 3-MA blocked the attenuation on apoptosis induced by GA. Moreover, molecular docking, CETSA, and DARTS analysis demonstrated that GA specifically targeted PI3K and further inhibited the activation of PI3K/AKT/mTOR signaling pathway. LY294002, which inhibits PI3K, reversed GA-induced autophagy and neuroprotective effects on OGD/R-treated cells., Conclusion: We demonstrated, for the first time, that GA protects against IS through promoting the PI3K/AKT/mTOR-dependent autophagy pathway. Our findings provide a novel mechanistic insight into the anti-IS effect of GA in regulating autophagy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier GmbH.)

Background: Ischemic stroke is a common cerebrovascular disease characterized by high incidence, disability, mortality, and recurrence. The limitations of current pharmacological treatments, which have primarily single neuroprotective action and a narrow therapeutic time window, lead to unsatisfactory therapeutic efficacy. Activation of autophagy can facilitate neural regeneration., Objective: To clarify whether salidroside can promote axonal sprouting through autophagy resulting in protecting neurons., Methods: In vivo, a Middle Cerebral Artery Occlusion/reperfusion (MCAO/IR) model was used, and in vitro, an Oxygen-Glucose Deprivation/Reoxygenation (OGD/R)-induced primary neuronal cell model was employed to evaluate the neuroprotective effects of salidroside. BDA neurotracer, immunofluorescence, and Western blot (WB) were utilized to determine its impact on axonal sprouting and the levels of related proteins (MAP2, GAP43, and PSD-95). Proteomics, transmission electron microscopy (TEM), and WB were applied to identify the effects on autophagy-related proteins (beclin1, LC3, p62, and LAMP2), autophagosomes and lysosomes. The mechanism of salidroside in promoting axonal sprouting through inducing autophagy was further confirmed by blocking with the autophagy inhibitor 3-MA., Results: Salidroside reduced neurologic deficits and infarct volume induced by MCAO/IR in vivo and protected OGD/R induced primary neuronal cells in vitro. Both in vivo and in vitro, it increased the number and length of axons and upregulated the expression of key axonal proteins (MAP2, GAP43, and PSD-95) and mediated autophagy-related proteins. Mechanistic studies showed that the promoting effects of salidroside on autophagy and axonal sprouting disappeared after the blockade by 3-MA., Conclusion: This study reports for the first time that the neuroprotective effect of salidroside in ischemic stroke can be executed through mediating autophagy-related protein (beclin1, LC3, p62, and LAMP2), resulting in induced axonal sprouting or mature protein (MAP2, GAP43, and PSD-95)., Competing Interests: Declaration of competing interest Authors have no conflicts of interest., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Purpose: This study aims to document the transition from alteplase to tenecteplase within a rural stroke network in the Midwest. It emphasizes the planning and execution of the transition, and evaluates safety and outcomes of tenecteplase compared to alteplase one year after the adoption of the new thrombolytic., Methods: This is a retrospective observational study of patients who were treated with thrombolytic therapy for suspected acute ischemic stroke at Southern Illinois Healthcare rural stroke network between July 2017 and July 2024. For each patient, demographics, past medical history, clinical presentation, National Institutes of Health Stroke Scale (NIHSS), and laboratory values were reviewed. Type of thrombolytic was noted. Door-to-needle time (DTN) and complications of thrombolytic therapy including symptomatic ICH (sICH) were reviewed. The primary outcome was the rate of sICH after administration of thrombolytic therapy. Secondary outcomes included target DTN ≤ 60 minutes and modified Rankin Scale (mRS) 0-2 at 30 days., Results: Out of 279 patients treated with thrombolytics, 215 (77 %) received alteplase, and 64 (23 %) received tenecteplase. The two groups were severity matched, and did not differ in terms of demographics or baseline comorbidities. Median DTN (IQR) was comparable between alteplase and tenecteplase, in minutes ((50 (40-69) vs. 53 (37-65)). In three distinct regression models for each of the predetermined outcomes, accounting for markers of stroke severity, the type of thrombolytic was not associated with development of sICH (OR 1.59, SE 1.445, p = 0.61), target DTN ≤ 60 min (OR 0.996, SE 0.304, p = 0.988), nor mRS 0-2 at 30 days (OR 1.086, SE 0.446, p = 0.842)., Conclusions: In our population, safety and outcome of thrombolytic therapy for acute ischemic stroke did not differ based on the type of thrombolytic used. Our study highlights the planning and execution of the transition from alteplase to tenecteplase, with challenges faced and lessons learned, and supports the use of tenecteplase in real-world rural practice., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Tirofiban is a fast-acting glycoprotein IIb-IIIa inhibitor that inhibits the final common pathway to platelet aggregation and has been studied as adjuvant therapy for acute ischemic stroke (AIS). Since the prior meta-analysis new randomized controlled trials (RCTs) have been published. This meta-analysis aimed to update the current knowledge on the efficacy of tirofiban for patients with AIS not submitted to reperfusion therapies., Methods: We systematically searched PubMed, Embase, and Cochrane Central Register of Controlled Trials for RCTs reporting the use of tirofiban in AIS. The efficacy outcomes were favorable functional outcome, functional disability, modified Rankin Scale change at 90 days, and changes in the National Institutes of Health Stroke Scale score after 24 hours and 7 days of the symptom onset. The safety outcomes include symptomatic intracranial hemorrhage (sICH), any intracranial hemorrhage (ICH), and all-cause mortality., Results: A higher rate of favorable functional outcome was associated with tirofiban administration (RR= 1.09; 95 % CI 1.04-1.14; p<0.001). The mRS after 90 days was significantly lower in the tirofiban group (MD= -0.55; 95 % CI -0.90 - [-0.20]; p<0.01). Tirofiban administration was not significantly associated with higher rates of sICH in AIS patients (RR= 0.85; 95 % CI 0.26-2.81; p = 0.79) or any ICH compared to the control group (RR= 1.01; 95 % CI 0.42-2.39; p = 0.98). All-cause mortality was similar between groups (RR= 0.64; 95 % CI 0.34-1.23; p = 0.18)., Conclusion: Tirofiban increases the number of patients achieving a favorable functional outcome in patients. There was no improvement in NIHSS after 24 hours and 7 days. Tirofiban did not increase the risk of sICH or any ICH, and mortality was similar between groups., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Contemporary thrombolytics in acute ischemic stroke are limited to administration within 4.5 hours of last known normal. JX10 (formerly TMS-007), a Stachybotrys microspora triprenyl phenol family member, may extend this therapeutic window., Methods: In this multicenter, randomized, double-blind, placebo-controlled, dose-escalation phase 2a study, JX10 or placebo was administered as a single intravenous infusion to Japanese patients with acute ischemic stroke who were unable to receive tissue-type plasminogen activator or thrombectomy within 12 hours of last known normal. Primary end point was incidence of symptomatic intracranial hemorrhage with a worsening National Institutes of Health Stroke Scale score of ≥4 points within 24 hours of drug administration (symptomatic intracranial hemorrhage incidence)., Results: Ninety patients received either placebo (n=38; female 26.3%) or JX10 at 1, 3, or 6 mg/kg (n=6, 18, 28; female 0%, 33.3%, and 42.9%, respectively). Median age (range) and baseline median (range) National Institutes of Health Stroke Scale scores were respectively 76.5 (42-87) and 8 (6-21) for the combined JX10 cohort (JX10 Cohorts) and 75.0 (34-85) and 8 (6-22) for placebo. Median (range) dosing time since last known normal was 9.5 (5.0-12.1) and 10.0 (3.7-12.0) hours for JX10 Cohorts and placebo, respectively. Symptomatic intracranial hemorrhage incidence was 0% (0/52 [95% CI, 0.0-5.6]) for JX10 Cohorts versus 2.6% (1/38 [95% CI, 0.1-13.8]) for placebo ( P =0.42). Vessel patency at 24 hours (secondary end point) in patients with baseline arterial occlusive lesion score <3 (39/90) improved in 58.3% (14/24) of patients in JX10 Cohorts versus 26.7% (4/15) for placebo (odds ratio, 4.23 [95% CI, 0.99-18.07]). In JX10 Cohorts, a significantly higher proportion of patients had modified Rankin Scale scores of 0 to 1 on day 90 (secondary end point) versus placebo (JX10: 21/52, 40.4% versus placebo: 7/38, 18.4%; P =0.03)., Conclusions: JX10 was well tolerated and may expand the acute ischemic stroke therapeutic window as a novel thrombolytic agent., Registration: URL: https://rctportal.niph.go.jp/en; Unique identifier: jRCT2080223786., Competing Interests: Dr Niizuma reports study funding and article processing charges from TMS Co, Ltd. Dr Nishimura was a TMS Co, Ltd, employee during the conduct of the study, owns TMS Co, Ltd, stocks and stock options, and reports consulting fees from TMS Co, Ltd, as well as recipient of license fees for JX10-related patents. K. Hasegawa is an employee and shareholder of TMS Co, Ltd, and reports license fees for JX10-related patents. Dr Hasumi is a Director of the Board and shareholder of TMS Co, Ltd, an employee of Tokyo University of Agriculture and Technology, and reports grants from TMS Co, Ltd, and EPS Corporation, as well as license fees for JX10-related patents. Dr Wald is an employee and shareholder of Biogen. Dr Bell is a former employee of Biogen Inc. Drs Kuribayashi and Toda are employees of Biogen Japan Ltd and shareholders of Biogen Inc. Dr Tominaga declares consulting fees and license fees for a JX10-related patent from TMS Co, Ltd. The other authors report no conflicts.

Background and Objectives: Antiplatelet therapy is recommended as the standard treatment for patients with acute ischemic stroke (AIS) who, for several reasons, did not receive thrombolysis or thrombectomy. However, whether tirofiban or aspirin provides greater benefits for these patients remains unclear. Therefore, we aimed to perform a meta-analysis comparing the functional outcomes and hemorrhagic risks associated with tirofiban and aspirin in the management of AIS., Methods: We searched PubMed, EMBASE, Web of Science, and Cochrane Library for studies comparing tirofiban to aspirin in patients with AIS who did not receive thrombolysis or thrombectomy until September 2024. Outcomes were modified Rankin Scale (mRS) and mortality at 90 days, symptomatic intracranial hemorrhage, and any bleeding events. Statistical analysis was performed using the R Studio (version 2024.04.1+748)., Results: We included 3 randomized controlled trials with a total of 1959 patients, of whom 996 (50.8 %) were in the tirofiban group. Excellent (mRS 0-1) functional outcome (RR 1.25, 95 % CI: 1.05-1.49; I 2 = 70 %) and favorable (mRS 0-2) functional outcome at 90 days (RR 1.09, 95 % CI: 1.01-1.16; I 2 = 35 %) were significantly higher in tirofiban compared to aspirin. Furthermore, tirofiban showed no difference in mortality (RR 0.77, 95 % CI: 0.24-2.53; I 2 = 56 %), or symptomatic intracranial hemorrhage (RR 3.42, 95 % CI: 0.27-43.30; I 2 = 38 %). However, any bleeding event (RR 1.75, 95 % CI: 1.25-2.45; I 2 = 0 %) was more common in the tirofiban group. Lastly, the meta-regression analysis showed that the outcomes were not influenced by the initial NIHSS of the included studies (p > 0.05)., Conclusion: Tirofiban is associated with better functional outcomes at 90 days, with no difference in mortality. Additionally, despite being associated with higher bleeding events, there is no difference in symptomatic intracranial hemorrhage. Therefore, our results suggest that tirofiban is a promising alternative to aspirin., Competing Interests: Conflict of Interest The authors declare no conflicts of interest related to the research, authorship, or publication of this scientific paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Metabolic dysregulation in the ischemic region has been increasingly recognized as a contributing factor to ischemic stroke pathogenesis. Taohong Siwu decoction (THSWD), a traditional Chinese medicine preparation used to enhance blood circulation, is frequently employed in treating ischemic stroke. However, the metabolic regulatory mechanism underlying the therapeutic effects of THSWD in ischemic stroke remains largely unexplored. In this study, we employed desorption electrospray ionization mass spectrometry imaging (DESI-MSI) to investigate the metabolic changes in the brain tissue of ischemic stroke rat model. Our investigation revealed that 30 metabolites exhibited significant dysregulation in the ischemic brain regions, specifically the cortex and striatum, following ischemic injury. Following the treatment of THSWD, almost all the dysregulated metabolites got different degrees of callback. Further pathway analysis indicated that THSWD might exert its therapeutic effects by restoring energy metabolism, improving neurotransmitter metabolism, recovering polyamine metabolism, and so on. DESI-MSI offers a favorable methodology for investigating the alterations in the spatial distribution and level within the ischemic brain region following treatment with THSWD in ischemic stroke. These findings provide a novel perspective on the underlying mechanisms of the efficacy of THSWD in ischemic stroke treatment., Competing Interests: Declarations. Ethics approval: The use of laboratory animals and all study protocols were approved by the Animal Protection Committee and Use Committee of Anhui University of Chinese Medicine. Source of biological material: Male Sprague–Dawley rats (250 − 290 g) were provided by Liaoning Changsheng Biotechnology Co., Ltd. Statement on animal welfare: The management and use of animals during the experiment comply with the relevant regulations of “Guide for the Care and Use of Laboratory Animals issued by the National Research Council of the United States (2010),” “Regulations for the administration of affairs concerning laboratory animals (2017)” issued by the Science and Technology Commission of China, and the relevant regulations provided by the Animal Protection Committee and Use Committee of Anhui University of Chinese Medicine. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Object: The treatment results of combination of arterial injection of tirofiban with endovascular therapy (EVT) for acute large vessel occlusion (LVO) stroke due to intracranial atherosclerotic disease (ICAD) were inconsistent. This meta-analysis aims to assess the safety and efficacy of ICAD-LVO treatment by intra-arterial injection of tirofiban combined with EVT., Methods: Relevant studies were identified through a systematic literature search in Pubmed, EMBASE, Web of Science and Cochrane Library databases, covering articles published from January 2010 to July 2024. The efficacy outcomes assessed in the meta-analysis included favorable functional outcome and recanalization rates. Safety outcomes included mortality and symptomatic intracranial haemorrhage (sICH)., Results: The meta-analysis consisted of data from 11 studies, which included 1 randomised controlled trial (RCT), 5 prospective cohort studies, and 5 retrospective cohort studies, encompassing a total of 2869 patients. The findings showed that tirofiban+EVT for ICAD-LVO was associated with significant improvements in favorable functional outcomes (RR, 1.12; 95 %CI, 1.04-1.21; P=0.005) and reductions in mortality rates (RR, 0.72; 95 %CI, 0.62-0.83; P<0.0001), despite no significant differences in the incidence of sICH (RR, 0.75; 95 % CI, 0.55-1.02; P=0.07) and recanalization rates (RR, 1.02; 95 % CI, 0.99-1.05; P=0.15). Subgroup analysis showed that the application of tirofiban significantly increased favorable functional outcomes in patients with anterior circulation stroke (RR, 1.23; 95 % CI, 1.06-1.42; P=0.005), but there was no significant difference in posterior circulation stroke (RR, 1.08; 95 % CI, 0.83-1.41; P=0.55). In addition, the use of tirofiban in patients with posterior circulation stroke might reduce the incidence of sICH (RR, 0.50; 95 % CI, 0.26-0.96; P=0.04)., Conclusion: Tirofiban combined with EVT may be an effective treatment strategy for the treatment of ICAD-LVO, but only for patients with anterior circulation and remains unclear for patients with posterior circulation., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Oral anticoagulation (OAC) is a risk factor for intracerebral hemorrhage (ICH) which is an important source of disability and mortality. OAC-associated ICH (OAC-ICH) patients have worse outcomes as compared to ICH patients not on OAC, likely because of the associated larger stroke volumes, higher propensity to intraventricular hemorrhage, and a higher risk of rebleeding. Although current guidelines recommend that OAC should be reversed quickly, many health care systems have not developed a process for optimizing that aspect of care., Methods: Through the IMPROVE Stroke Care Consortium, a group of nine Hub hospitals and their 57 regional community hospitals, a systems of care improvement project was implemented. Performance reviews identified best practices which were disseminated throughout all centers. We compared the median door-to-reversal (DTR) time before and after an institutional campaign to speed the process with a target time of 60 min., Results: Over two years of the study, there were 6,699 ischemic strokes, 152 subarachnoid hemorrhages, and 889 intracerebral hemorrhages. During that time, 73 ICH patients received reversal agents emergently. The overall baseline median DTR time was 123 min (IQR 99, 361 minutes). By the end of the program, the median DTR time had trended down to 84 min (IQR 58.5, 151 min) which is a 31.7 % reduction of DTR from baseline, though times remained somewhat variable (p=0.08)., Conclusions: An integrated stroke systems of care approach was associated with a reduction in DTR times for patients presenting with acute ICH and concurrent use of anticoagulants despite lack of definitive guidelines around targets for OAC reversal times or operational guidance on protocols and agents., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Brad Kolls, MD, PhD reports financial support was provided by Medtronic Inc. Brad Kolls, MD, PhD reports financial support was provided by Daiichi Sankyo Inc. Brad Kolls, MD, PhD reports financial support was provided by Chiesi Pharmaceuticals Inc. Brad Kolls, MD, PhD reports financial support was provided by Pulsara. Brad Kolls, MD, PhD reports financial support was provided by Corazon. Brad Kolls, MD, PhD reports financial support was provided by Amwell. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: Patients with suspected ischemic stroke and use of Direct Oral Anticoagulants (DOACs) within 48 h are excluded from thrombolysis. We aimed to determine practice patterns across institutions in the NIH StrokeNet, a network of hospitals to conduct NIH-funded stroke clinical trials, in the United States., Methods: A survey was sent electronically to all NIH StrokeNet regional coordinating centers. The survey questions were geared towards understanding practice patterns with intravenous thrombolysis use in patients on DOACs. We reported proportions and percentages answers to the questions. We compared the likelihood of thrombolysis use in patients with recent DOAC ingestion (never vs. all other responses) across characteristics of survey responder using Chi Square., Results: A total of 83 site principal investigators completed the survey; 78.3 % would never give thrombolysis to an otherwise eligible patients within 12-24 h from last DOAC ingestion and 54.2 % would never give thrombolysis to an otherwise eligible patient within 24-48 h from last DOAC ingestion. A higher proportion of vascular neurologists would never give thrombolysis in patients with DOAC ingestion within 12-48 h compared to other subspecialties (60.7 % vs. 36.4 %, p = 0.05). Nearly, 80 % would change their practice if a well-designed prospective study demonstrated that the symptomatic intracranial hemorrhage rate is not >5 %., Conclusions: A well-designed prospective study with a set safety threshold is likely to change practice patterns in giving thrombolysis in patients with recent DOAC ingestion, particularly among vascular neurologists who are more likely to never give thrombolysis in this setting., Competing Interests: Declaration of competing interest The authors have relevant disclosures or conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Cerebral edema, a significant complication arising from acute ischemic stroke (IS), has a critical influence on morbidity and mortality. p38MAPK has been shown to promote neuronal apoptosis and brain damage. However, the role of the p38MAPK inhibitor SKF-86002 in protecting against ischemic injury and cerebral edema remains unclear., Methods: Infarct area was examined by TTC staining in middle cerebral artery occlusion (MCAO) mice. Neurological score and brain water content were evaluated. TUNEL and NeuN staining were used to assess neuronal apoptosis and the survival of neurons. Blood-brain barrier (BBB) permeability was determined by Evans blue. Double immunofluorescence staining detected the colocalization of AQP4 and CX43 in astrocytes. IHC staining revealed CX43 and AQP4 expression. EDU staining detected the proliferation of Oxygen and glucose deprivation/reoxygenation (OGD/R)-treated astrocytes. Levels of oxidative stress markers were determined using commercial kits. ELISA was used to assess the secretion of pro-inflammatory factors. RT-qPCR measured the expression of CX43, AQP4 and pro-inflammatory factors. Western blot analyzed the levels of p-p38/p38, AQP4 and CX43. Co-immunoprecipitation (Co-IP) determined the interaction between CX43 and AQP4., Results: SKF-86002 attenuated brain damage, edema, and neuronal apoptosis in MCAO mice. Astrocyte proliferation was suppressed, and oxidative stress and inflammation were alleviated by SKF-86002 treatment. SKF-86002 negatively regulated p38 signaling and the expression of AQP4 and CX43. Additionally, the expression of CX43/AQP4 within astrocytes was modulated by SKF-86002., Conclusion: In summary, SKF-86002 alleviated IS injury and cerebral edema by inhibiting astrocyte proliferation, oxidative stress and inflammation. This effect was associated with the suppression of CX43/AQP4, suggesting that SKF-86002 shows promise as a novel therapeutic approach for preventing IS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Intravenous thrombolysis remains the primary treatment for acute ischemic stroke (AIS); however, administration is time sensitive. Teleneurology services have increased in popularity in recent years due to their ability to aid in triaging patients with neurological conditions. Teleneurology services were implemented at this comprehensive stroke center, in August 2023 to aid in streamlining the administration of tenecteplase in AIS patients. Currently, there are no studies assessing whether the implementation of teleneurology services at a comprehensive stroke center influences tenecteplase door-to-needle time. The purpose of this study is to evaluate the difference in door-to-needle times when tenecteplase is administered with versus without a teleneurology consult., Methods: This was an institutional review board approved, retrospective cohort study conducted at a single comprehensive stroke center. Adult patients who presented to the emergency department between January 1st, 2022 and April 1st, 2023 were included if they received tenecteplase for the treatment of AIS. The primary outcome was door-to-needle time, defined as the moment the patient first enters the door of the emergency department to the moment the IV bolus of fibrinolytic is administered. Secondary outcomes included the proportion of patients with door-to-needle time within 45 min, neurological improvement at 24 h and discharge, and rate of hemorrhagic conversion., Results: A total of 93 patients were included with 43 patients in the pre-teleneurology group and 50 patients in the post-teleneurology group. Baseline characteristics were comparable between both treatment groups. The median door-to-needle time was significantly reduced in the post-teleneurology group (49 minutes [IQR, 40.0-70.0] preintervention vs. 34.5 minutes [IQR, 23.8-43.0] postintervention, p < 0.01). For secondary outcomes, the post-teleneurology group had more patients with a door-to-needle time within 45 minutes (44.2% vs. 80.0%, p < 0.01). There was no significant difference in early neurological improvement (58.1% vs. 54.0%), neurological improvement at discharge (60.5% vs. 62.0%), or hemorrhagic conversion (7.0% vs. 12.0%)., Conclusion: Among patients who received tenecteplase for the treatment of AIS, there was a significant reduction in door-to-needle time with the use of teleneurology services. There was no difference in neurological improvement or rate of hemorrhagic conversion., Competing Interests: Declaration of competing interest None. Katelyn Butler, PharmD, Staff Pharmacist, Department of Pharmacy. Morton Plant Hospital. Clearwater, Florida. (727)-461–8184, Katelyn.Butler@BayCare.org. No disclosures to report. Christine Price, PharmD, PGY1 Pharmacy Residency Director, Clinical Coordinator, Department of Pharmacy. Morton Plant Hospital. Clearwater, Florida. (727)-462–7454, Christine.Price@BayCare.org. No disclosures to report. Kaitlin Rzasa, PharmD, BCPS, Staff Pharmacist, Department of Pharmacy. AdventHealth Tampa. Tampa, Florida. 813–396-6145, kaitlin.rzasa@adventhealth.com. No disclosures to report. Jazmyn LeMay, PharmD, BS, Pharmacy Intern, Department of Pharmacy. Morton Plant Hospital. Clearwater, Florida. (727)-462–7000, Jazmynsingh@usf.edu. No disclosures to report., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Diet-derived circulating antioxidants have been associated with functional outcome after ischemic stroke (IS), but the causality remains unclear. The aim of our study is to explore the potential causal effect of diet-derived circulating antioxidants on long-term functional outcome (at 3 months) following IS through the utilization of the Mendelian randomization (MR) approach., Materials and Methods: For this two-sample MR analysis, genetic variants associated with the diet-derived circulating antioxidants, including selenium, zinc, vitamin A (retinol), vitamin C, and vitamin E (α-tocopherol and γ-tocopherol), were identified in a large-scale Genome-Wide Association Studies (GWAS) database and utilized as instrumental variables (IVs). Summary data for long-term functional outcome after IS were obtained from the Genetics of Ischemic Stroke Functional Outcome (GISCOME) network of 6021 patients. Our study used the Inverse-variance weighting method as our primary MR method and also performed a series of sensitivity analyses for pleiotropy and heterogeneity., Results: We observed that selenium (odds ratio (OR)=0.81; 95 % confidence interval (CI): 0.68-0.97; p=0.02) was significantly associated with poor functional outcome (modified Rankin Scale score≥3) after IS. Genetic liabilities to other diet-derived circulating antioxidants were not strongly associated with functional outcome after IS (all p>0.05). Sensitivity analyses confirmed the reliability of these results., Conclusion: This MR study suggested the positive effect of selenium on the long-term functional outcome after IS. Giving a longer period of selenium exposure can be used as a potential treatment to improve recovery after IS., Competing Interests: Declaration of competing interest The authors declare no conflict of interest exits in the submission of this manuscript, and the manuscript has been approved for publication by all authors., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Intravenous thrombolysis (IVT) with alteplase (TPA) in hyperglycemic stroke patients is associated with an increased risk of symptomatic intracranial hemorrhage (sICH) and poor functional outcomes. We aimed to explore the association between admission hyperglycemia and sICH in large vessel occlusion stroke (LVOS) patients treated with TNK versus TPA before endovascular thrombectomy (EVT)., Methods: We reviewed consecutive LVOS patients treated with TPA or TNK before EVT from 01/2020 to 06/2023. EVT was performed across five comprehensive stroke centers (CSCs) in Pennsylvania. Of 569 patients, 462 met inclusion criteria: LVOS, pre-stroke modified Rankin Scale (mRS) 0-2, and last-known-well to IVT (LKW-to-IVT) ≤ 4.5 h. The rates of sICH and parenchymal hematomas (PHs) between TPA and TNK cohorts were assessed., Results: Of 462 patients, 254 (55%) received TNK, and 208 (45%) received TPA. Admission hyperglycemia (≥ 140 mg/dl) was present in 153 (33.1%) patients. Hyperglycemic patients were more frequently diabetic (p < 0.001). Admission hyperglycemia was associated with a significantly increased rate of sICH (5.9% versus 1.6%, p = 0.019) and PH (20.3% versus 11.3%, p = 0.010). Hyperglycemic patients had a significantly higher degree of overall disability as compared to normoglycemic patients (90d-mRS shift aOR 0.611, p = 0.007). Comparable rates of sICH and PH were observed in the hyperglycemic and normoglycemic cohorts among both TNK and TPA groups., Conclusion: In LVOS patients receiving IVT before EVT, admission hyperglycemia significantly increased the risk of sICH and PH and was associated with worse outcomes at 90 days. No differences in sICH or PH were observed between TNK and TPA groups., Competing Interests: Declarations. Conflict of interest: CMS has research grants from Medtronic, Stryker, Penumbra, Cerenovus, Route 92, MIVI, Balt, Microvention, NICO, NIH/NINDS, and consulting agreements with Medtronic, Stryker, Viz.ai, Balt, Microvention, Werfen and ownership of NTI, Reist. ARA is consultant for Cerenovus and Stryker Neurovascular. RGN reports consulting fees for advisory roles with Anaconda, Biogen, Cerenovus, Genentech, Philips, Hybernia, Hyperfine, Imperative Care, Medtronic, Phenox, Philips, Prolong Pharmaceuticals, Stryker Neurovascular, Shanghai Wallaby, Synchron, and stock options for advisory roles with Astrocyte, Brainomix, Cerebrotech, Ceretrieve, Corindus Vascular Robotics, CrestecBio Inc., Euphrates Vascular, Inc., Vesalio, Viz-AI, RapidPulse and Perfuze. RGN is one of the Principal Investigators of the “Endovascular Therapy for Low NIHSS Ischemic Strokes (ENDOLOW)” trial. Funding for this project is provided by Cerenovus. RGN is the Principal Investigator of the “Combined Thrombectomy for Distal MediUm Vessel Occlusion StroKe (DUSK)” trial. Funding for this project is provided by Stryker Neurovascular. RGN is an investor in Viz-AI, Perfuze, Cerebrotech, Reist/Q’Apel Medical, Truvic, Tulavi Therapeutics, Vastrax, Piraeus Medical, Brain4Care, Quantanosis AI, and Viseon. BAG is a consultant for Medtronic, Microvention, and Stryker. Ethics approval: The Geisinger IRB approved the study (2022–0571), additional individual site IRBs were in place as well as data use agreements for de-identified data. Consent was waived due to the retrospective nature of the study., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: A recently published individual participant-level meta-analysis found that EVT alone was not non-inferior to combined intravenous thrombolysis (IVT) and EVT. Our aim was to determine factors that influence physicians' treatment choice of IVT-alone versus EVT-alone versus a combined approach., Methods: We performed an international, structured, invite-only survey among physicians treating patients presenting with AIS. Respondents were asked 16 multiple choice questions. Fourteen questions involved the respondent being provided with a clinical scenario. In each scenario, a patient was presenting with an AIS with LVO, varying a single clinical or imaging feature., Results: A total of 282 stroke physicians (mean age 46 years, 75 % males) participated in the survey. In LVO stroke, eligible for both IVT and EVT, without other qualifiers, 220 (85.9 %) respondents chose to pursue a combined approach. For age over 80 years, 191 (74 %) participants opted for combined approach, which decreased to 121 (48.2 %) with dementia and 148 (57.4 %) if the patient was on dual anti-platelet therapy (DAPT). Of respondents choosing combination therapy in a patient above the age of 80, only 105 (56.8 %) would pursue the same in a patient with dementia. For imaging factors, 177 (72.8 %) opted for a combined approach for intracranial carotid occlusion, which decreased to 160 (65.3 %) in tandem occlusions. Overall, 88 (38 %) respondents agreed to the statement "I am uncomfortable with uncertainty in patient care"., Conclusions: In a typical patient with AIS due to LVO, most respondents still choose a combined revascularization approach but discrepancy in decision-making increases in complex scenarios., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Inc.)

Ischemic stroke is followed by an increased susceptibility to bacterial infections, which exacerbate histological stroke outcome, neurological deficits and memory impairment due to increased neuroinflammation and neurotransmitter dysfunction. Pharmacological activation of nicotinic acetylcholine receptors was suggested to mitigate brain inflammatory responses in ischemic stroke. The functional responses associated with nicotinic acetylcholine receptor activation were unknown. In this study, male NMRI mice subjected to transient intraluminal middle cerebral artery occlusion (MCAO) were intraperitoneally exposed to vehicle treatment or Escherichia coli lipopolysaccharide (LPS; 4 mg/kg)-induced sepsis-like state 24 h post-MCAO, followed by intraperitoneal administration of vehicle or nicotine (0.5 mg/kg) 30 min later. Over 96 h, rectal temperature, neurological deficits, spontaneous locomotor activity, working memory, ischemic injury, synaptic plasticity, and brain inflammatory responses were evaluated by temperature measurement, behavioral analysis, infarct volumetry, electrophysiological recordings, and polymerase-chain reaction analysis. LPS-induced sepsis induced hypothermia, increased general and focal neurological deficits, reduced spontaneous exploration behavior, reduced working memory, and increased infarct volume post-MCAO. Additional treatment with nicotine attenuated LPS-induced hypothermia, reduced neurological deficits, restored exploration behavior, restored working memory, and reduced infarct volume. Local field potential recordings revealed that LPS-induced sepsis decreased long-term potentiation (LTP) in the dentate gyrus post-MCAO, whereas concomitant nicotine exposure restored LTP in the contralateral dentate gyrus. LPS-induced sepsis increased microglial/ macrophage Iba-1 mRNA and astrocytic GFAP mRNA levels post-MCAO, whereas add-on nicotine treatment reduced astrocytic GFAP mRNA. Taken together, these findings indicate that acute nicotine exposure enhances functional stroke recovery. Future studies will have to evaluate the effects of (1) chronic nicotine exposure, a clinically relevant vascular risk factor, and (2) the cessation of nicotine exposure, which is widely recommended post-stroke, but might have detrimental effects in the early stroke recovery phase., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Vasospasm is a common iatrogenic event during mechanical thrombectomy (MT). In such circumstances, intra-arterial nimodipine administration is occasionally considered. However, its use in the treatment of iatrogenic vasospasm during MT has been poorly studied. We investigated the impact of iatrogenic vasospasm treated with intra-arterial nimodipine on outcomes after MT for large vessel occlusion stroke., Methods: We conducted a retrospective analysis of the multicenter observational registry Endovascular Treatment in Ischemic Stroke (ETIS). Consecutive patients treated with MT between January 2015 and December 2022 were included. Patients treated with medical treatment alone, without MT, were excluded. We also excluded patients who received another in situ vasodilator molecule during the procedure. Outcomes were compared according to the occurrence of cervical and/or intracranial arterial vasospasm requiring intraoperative use of in situ nimodipine based on operator's decision, using a propensity score approach. The primary outcome was a modified Rankin Scale (mRS) score of 0-2 at 90 days. Secondary outcomes included excellent outcome (mRS score 0-1), final recanalization, mortality, intracranial hemorrhage and procedural complications. Secondary analyses were performed according to the vasospasm location (intracranial or cervical)., Results: Among 13,678 patients in the registry during the study period, 434 received intra-arterial nimodipine for the treatment of MT-related vasospasm. In the main analysis, comparable odds of favorable outcome were observed, whereas excellent outcome was significantly less frequent in the group with vasospasm requiring nimodipine (adjusted odds ratio [aOR] 0.78, 95% confidence interval [CI] 0.63-0.97). Perfect recanalization, defined as a final modified Thrombolysis In Cerebral Infarction score of 3 (aOR 0.63, 95% CI 0.42-0.93), was also rarer in the vasospasm group. Intracranial vasospasm treated with nimodipine was significantly associated with worse clinical outcome (aOR 0.64, 95% CI 0.45-0.92), in contrast to the cervical location (aOR 1.37, 95% CI 0.54-3.08)., Conclusion: Arterial vasospasm occurring during the MT procedure and requiring intra-arterial nimodipine administration was associated with worse outcomes, especially in case of intracranial vasospasm. Although this study cannot formally differentiate whether the negative consequences were due to the vasospasm itself, or nimodipine administration or both, there might be an important signal toward a substantial clinical impact of iatrogenic vasospasm during MT., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Purpose of Review: Ischemic stroke is the second deadly disease worldwide, but current treatment is very limited. The brain, rich in lipids and high in oxygen consumption, is susceptible to damage from oxidative stress after ischemic stroke. Thus, antioxidants are promising neuroprotective agents for treatment and prevention of ischemic stroke. Coenzyme Q10 is the only lipophilic antioxidant that can be synthesized de novo by cells and plays a key role as an electron carrier in the oxidative phosphorylation of the mitochondrial electron transport chain. However, the reduced form of coenzyme Q10 (Ubiquinol) levels are significantly deficient in the brain. The aim of this article is to review the therapeutic effects and mechanisms of coenzyme Q10 in ischemic stroke., Recent Findings: Current studies have found that coenzyme Q10 protects and treats ischemic stroke through multiple mechanisms based on the evidence from in vitro experiments, in vivo experiments, and clinical observations. For the first time, we reviewed the neuroprotective effects of coenzyme Q10 in ischemic stroke. Coenzyme Q10 exerts neuroprotective effects after ischemic stroke through anti-oxidative stress, anti-nitrosative stress, anti-inflammation, and anti-cell death. Here, we provided the evidence on the therapeutic and preventive effects of coenzyme Q10 in ischemic stroke and suggested the potential value of coenzyme Q10 as a medication candidate., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: In intracranial medium-vessel occlusions (MeVOs), intravenous thrombolysis (IVT) shows inconsistent effectiveness and endovascular interventions remains unproven. We evaluated a new therapeutic strategy based on a second IVT using tenecteplase for MeVOs without early recanalization post-alteplase., Patients and Methods: This retrospective, comparative study included consecutively low bleeding risk MeVO patients treated with alteplase 0.9 mg/kg at two stroke centers. One center used a conventional single-IVT approach; the other applied a dual-IVT strategy, incorporating a 1-h post-alteplase MRI and additional tenecteplase, 0.25 mg/kg, if occlusion persisted. Primary outcomes were 24-h successful recanalization for efficacy and symptomatic intracranial hemorrhage (sICH) for safety. Secondary outcomes included 3-month excellent outcomes (modified Rankin Scale score of 0-1). Comparisons were conducted in the overall cohort and a propensity score-matched subgroup., Results: Among 146 patients in the dual-IVT group, 103 failed to achieve recanalization at 1 h and of these 96 met all eligible criteria and received additional tenecteplase. Successful recanalization at 24 h was higher in the 146 dual-IVT cohort patients than in the 148 single-IVT cohort patients (84% vs 61%, p  < 0.0001), with similar sICH rate (3 vs 2, p  = 0.68). Dual-IVT strategy was an independent predictor of 24-h successful recanalization (OR, 2.7 [95% CI, 1.52-4.88]; p  < 0.001). Dual-IVT cohort patients achieved higher rates of excellent outcome (69% vs 44%, p  < 0.0001). Propensity score matching analyses supported all these associations., Conclusion: In this retrospective study, a dual-IVT strategy in selected MeVO patients was associated with higher odds of 24-h recanalization, with no safety concerns. However, potential center-level confounding and biases seriously limit these findings' interpretation., Trial Registration: ClinicalTrials.gov Identifier: NCT05809921 ., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: I.S reports consultant fees for Bayer, BMS/Pfizer, Boehringer Ingelheim outside the submitted work, Medtronic, Novartis, Novo Nordisk, Bioprojet, Astra-Zeneca, Alexion and speaker activities for AstraZeneca, Bayer, BMS/Pfizer, Boehringer Ingelheim, Medtronic, Novartis, Novo Nordisk; DS reports consultant fees for BMS/Pfizer, Boehringer-Ingelheim outside the submitted work, Novartis and speaker activities for BMS/Pfizer, Boehringer-Ingelheim, Novo Nordisk, Servier, Sanofi; Other authors do not report any conflicting interests.

We investigate the application of Shouwu Yizhi prescription (SYP) in decubation of patients with ischemic stroke (IS). The clinical data of 106 patients recovering from IS who came to our hospital from December 2019 to December 2020 were selected for retrospective analysis, and they were separated into experimental group ( n  = 53, basic treatment + SYP) and control group ( n  = 53, basic treatment) based on the principle of random grouping. The clinical indexes such as lipid indexes and neurological disability score (NDS) after treatment were compared between both groups to comprehensively evaluate the clinical effects of different treatment regimens. Except for high-density lipoprotein cholesterol value, the lipid indexes in the experimental group after treatment were remarkably lower than those in the control group ( P  < 0.001). After treatment, the levels of hypersensitive C-reactive protein, homocysteine and lipoprotein-associated phospholipase A2 were remarkably lower in the experimental group than control group ( P  < 0.05). After treatment, the experimental group had remarkably higher mean scores of Montreal Cognitive Assessment, Fugl-Meyer Assessment in upper and lower limbs and lower NDS than control group ( P  < 0.001). SYP is an efficient treatment plan in decubation of IS, which can effectively improve the blood lipid indexes and neurological function of patients, and further studies will help establish a better solution for such patients.

Introduction: There is a longstanding clinical uncertainty regarding the optimal timing of initiating oral anticoagulants (OAC) for non-valvular atrial fibrillation following acute ischemic stroke. Current international recommendations are based on expert opinions, while significant diversity among clinicians is noted in everyday practice., Methods: We conducted an updated systematic review and meta-analysis including all available randomized-controlled clinical trials (RCTs) and observational cohort studies that investigated early versus later OAC-initiation for atrial fibrillation after acute ischemic stroke. The primary outcome was defined as the composite of ischemic and hemorrhagic events and mortality at follow-up. Secondary outcomes included the components of the composite outcome (ischemic stroke recurrence, intracranial hemorrhage, major bleeding, and all-cause mortality). Pooled estimates were calculated with random-effects model., Results: Nine studies (two RCTs and seven observational) were included comprising a total of 4946 patients with early OAC-initiation versus 4573 patients with later OAC-initiation following acute ischemic stroke. Early OAC-initiation was associated with reduced risk of the composite outcome (RR = 0.74; 95% CI:0.56-0.98; I 2  = 46%) and ischemic stroke recurrence (RR = 0.64; 95% CI:0.43-0.95; I 2  = 60%) compared to late OAC-initiation. Regarding safety outcomes, similar rates of intracranial hemorrhage (RR = 0.98; 95% CI:0.57-1.69; I 2  = 21%), major bleeding (RR = 0.78; 95% CI:0.40-1.51; I 2  = 0%), and mortality (RR = 0.94; 95% CI:0.61-1.45; I 2  = 0%) were observed. There were no subgroup differences, when RCTs and observational studies were separately evaluated., Conclusions: Early OAC-initiation in acute ischemic stroke patients with non-valvular atrial fibrillation appears to have better efficacy and a similar safety profile compared to later OAC-initiation., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: This study aimed to report the safety and efficacy of off-label intravenous thrombolysis (IVT) with alteplase after sequentially liberalizing our institutional guidelines allowing IVT for patients under direct oral anticoagulants (DOACs) regardless of plasma levels, time of last intake, and without prior anticoagulation reversal therapy., Patients and Methods: We utilized the target-trial methodology to emulate hypothetical criteria of a randomized controlled trial in our prospective stroke registry. Consecutive DOAC patients (06/2021-11/2023) otherwise qualifying for IVT were included. Safety and efficacy outcomes (symptomatic intracranial hemorrhage [ICH], any radiological ICH, major bleeding, 90-day mortality, 90-day good functional outcome [mRS 0-2 or return to baseline]) were assessed using inverse-probability-weighted regression-adjustment comparing patients with versus without IVT., Results: Ninety eight patients fulfilled the target-trial criteria. IVT was given in 49/98 (50%) patients at a median of 178 (interquartile range 134-285) min after symptom onset with median DOAC plasma level of 77 ng/ml (15 patients had plasma levels > 100 ng/ml; 25/49 [51%] were treated within 12 h after last DOAC ingestion). Endovascular therapy was more frequent in patients without IVT (73% vs 33%). Symptomatic ICH occurred in 0/49 patients receiving IVT and 2/49 patients without IVT (adjusted difference -2.5%; 95% CI -5.9 to 0.8). The rates of any radiological ICH were comparable. Patients receiving IVT were more likely to have good functional outcomes., Discussion and Conclusion: After liberalizing our approach for IVT regardless of recent DOAC intake, we did not experience any safety concerns. The association of IVT with better functional outcomes warrants prospective randomized controlled trials., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MBG reports grants from the Bangerter-Rhyner-Foundation, Swiss Stroke Society, European Stroke Organisation, European Academy of Neurology and Insel Gruppe AG (all outside the submitted work). MA reports speaker honoraria from Astra Zeneca, Bayer, Covidien, Medtronic, Sanofi and honoraria for scientific advisory boards from Amgen, Bayer, BMS, Daiichi Sankyo, Medtronic, Pfizer, and research funding from the Swiss National Science Foundation (SNSF), and the Swiss Heart Foundation (SHF). UF reports financial support for the SWIFT DIRECT trial (Medtronic), research grants from Medtronic BEYOND SWIFT registry, SNSF, SHF, consulting fees from Medtronic, Stryker and CSL Behring (fees paid to institution); membership of a Data Safety Monitoring Board for the IN EXTREMIS trial and TITAN trial and Portola (Alexion) Advisory board (fees paid to institution). DS is on the advisory board of Bayer Switzerland AG and Portola/Alexion. He reports research funding from SNSF, SHF, Bangerter-Rhyner Foundation, Bayer Foundation, and Portola/Alexion. TRM reports grants from the Bangerter-Rhyner Foundation, the Baasch-Medicus Foundation, the University of Bern, the Swiss National Science Foundation and the Swiss Heart Foundation. All other authors report no competing interests.

Background: Despite its increasing use, there are limited data on the risk of intracranial hemorrhage (ICH) after intravenous thrombolysis with tenecteplase in the setting of acute ischemic stroke. Our aim was to investigate the incidence and predictors of ICH after tenecteplase administration., Methods: We reviewed data from the prospective ongoing multicenter TETRIS (Tenecteplase Treatment in Ischemic Stroke) registry. Patients with available day-1 imaging were included in this study. Clinical, imaging and biological variables were collected. Follow-up imaging performed 24 h after IVT was locally reviewed by senior neuroradiologists and neurologists. The incidence of parenchymal hematoma (PH) and any ICH were investigated. Potential predictors of PH and any ICH were assessed in multivariable logistic regressions. Subgroup analyses focusing on patients intended for endovascular treatment were performed., Results: PH and any ICH occurred in 126/1321 (incidence rate: 9.5%, 95% CI 8.1-11.2) and 521/1321 (39.4%, 95% CI 36.8-42.1) patients, respectively. Symptomatic ICH was observed in 77/1321 (5.8%; 95% CI 4.7-7.2). PH occurrence was significantly associated with poorer functional outcomes ( p  < 0.0001) and death ( p  < 0.0001) after 3 months. Older age (aOR = 1.03; 95% CI 1.01-1.05), male gender (aOR = 2.07; 95% CI 1.28-3.36), a history of hypertension (aOR = 2.08; 95% CI 1.19-3.62), a higher baseline NIHSS (aOR = 1.07; 95% CI 1.03-1.10) and higher admission blood glucose level (aOR = 1.12; 95% CI 1.05-1.19) were independently associated with PH occurrence. Similar associations were observed in the subgroup of patients intended for endovascular treatment., Conclusion: We quantified the incidence of ICH after IVT with tenecteplase in a real-life prospective registry and determined independent predictors of ICH. These findings allow to identify patients at high risk of ICH., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

As the brain's resident immune patrol, microglia mediate endogenous immune responses to central nervous system injury in ischemic stroke, thereby eliciting either neuroprotective or neurotoxic effects. The association of microglia-mediated neuroinflammation with the progression of ischemic stroke is evident through diverse signaling pathways, notably involving inflammasomes. Within microglia, inflammasomes play a pivotal role in promoting the maturation of interleukin-1β (IL-1β) and interleukin-18 (IL-18), facilitating pyroptosis, and triggering immune infiltration, ultimately leading to neuronal cell dysfunction. Addressing the persistent and widespread inflammation holds promise as a breakthrough in enhancing the treatment of ischemic stroke., Competing Interests: Declarations. Ethics Approval: Not applicable. Consent to Participate: Not applicable. Consent for Publication: Not applicable. Competing Interests: The authors have no relevant financial or non-financial interests to disclose., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Recombinant prourokinase (rhPro-UK) is a specific plasmin activator, which has been approved to treat acute myocardial infarction in China., Aim: This phase 3 trial aimed to further demonstrate the efficacy and safety of rhPro-UK in patients with acute ischemic stroke (AIS) within 4.5 h of symptom onset., Methods and Design: RhPro-UK in AIS within 4.5 h of stroke onset trial-2 (PROST-2) is a multicenter, prospective randomized, open-label, blinded end-point, non-inferiority, recombinant tissue plasmin activator (rt-PA)-controlled, phase 3 trial. A total of 1552 patients who are eligible for intravenous thrombolytic therapy from 72 clinical sites will be randomly assigned to receive either rhPro-UK 35 mg (15 mg bolus + 20 mg infusion/30 min) or rt-PA 0.9 mg/kg (10% bolus + 90% infusion/1 h)., Study Outcomes: The primary outcome is the proportion of patients with a modified Rankin Scale (mRS) score of 0-1 at 90 days. Secondary efficacy outcomes include the proportion of patients with mRS score of 0-2, the distribution of mRS, self-care ability in daily life on the Barthel Index at 90 days, the proportion of subjects with ⩾ 4 points decrease in National Institutes of Health Stroke Scale (NIHSS) score or NIHSS score ⩽ 1 from baseline at 24 h and 7 days after treatment. Safety outcomes are symptomatic intracranial hemorrhage (sICH) and major systematic bleeding within 7 days as well as death from all causes within 90 days., Discussion: The results from the PROST-2 trial will comprehensively elucidate the efficacy and safety profile of rhPro-UK as a potential alternative agent for stroke thrombolysis., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT05700591., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Hydrogen sulfide (H 2 S) is a gasotransmitter that has been studied for its potential therapeutic effects, including its role in the pathophysiology and treatment of stroke. This systematic review and meta-analysis aimed to determine the sufficiency of overall preclinical evidence to guide the initiation of clinical stroke trials with H 2 S and provide tailored recommendations for their design. PubMed, Web of Science, Scopus, EMBASE, and MEDLINE were searched for studies evaluating the effect of any H 2 S donor on in vivo animal models of regional ischemic stroke, and 34 publications were identified. Pooling of the effect sizes using the random-effect model revealed that H 2 S decreased the infarct area by 34.5% (95% confidence interval (CI) 28.2-40.8%, p < 0.0001), with substantial variability among the studies (I 2 = 89.8%). H 2 S also caused a 37.9% reduction in the neurological deficit score (95% CI 29.0-46.8%, p < 0.0001, I 2 = 63.8%) and in the brain water content (3.2%, 95% CI 1.4-4.9%, p = 0.0014, I 2 = 94.6%). Overall, the studies had a high risk of bias and low quality of evidence (median quality score 5/15, interquartile range 4-9). The majority of the included studies had a "high" or "unclear" risk of bias, and none of the studies overall had a "low" risk. In conclusion, H 2 S significantly improves structural and functional outcomes in in vivo animal models of ischemic stroke. However, the level of evidence from preclinical studies is not sufficient to proceed to clinical trials due to the low external validity, high risk of bias, and variable design of existing animal studies., Competing Interests: Declarations. Ethics approval: The study was not subject to ethics committee approval because it did not involve any experimental or clinical intervention. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background and Purpose: Randomized controlled trials (RCTs) proved the efficacy of short-term dual antiplatelet therapy (DAPT) in secondary prevention of minor ischemic stroke or high-risk transient ischemic attack (TIA). We aimed at evaluating effectiveness and safety of short-term DAPT in real-world, where treatment use is broader than in RCTs., Methods: READAPT (REAl-life study on short-term Dual Antiplatelet treatment in Patients with ischemic stroke or Transient ischemic attack) (NCT05476081) was an observational multicenter real-world study with a 90-day follow-up. We included patients aged 18+ receiving short-term DAPT soon after ischemic stroke or TIA. No stringent NIHSS and ABCD 2 score cut-offs were applied but adherence to guidelines was recommended. Primary effectiveness outcome was stroke (ischemic or hemorrhagic) or death due to vascular causes, primary safety outcome was moderate-to-severe bleeding. Secondary outcomes were the type of ischemic and hemorrhagic events, disability, cause of death, and compliance to treatment., Results: We included 1920 patients; 69.9% started DAPT after an ischemic stroke; only 8.9% strictly followed entry criteria or procedures of RCTs. Primary effectiveness outcome occurred in 3.9% and primary safety outcome in 0.6% of cases. In total, 3.3% cerebrovascular ischemic recurrences occurred, 0.2% intracerebral hemorrhages, and 2.7% bleedings; 0.2% of patients died due to vascular causes. Patients with NIHSS score ⩽5 and those without acute lesions at neuroimaging had significantly higher primary effectiveness outcomes than their counterparts. Additionally, DAPT start >24 h after symptom onset was associated with a lower likelihood of bleeding., Conclusions: In real-world, most of the patients who receive DAPT after an ischemic stroke or a TIA do not follow RCTs entry criteria and procedures. Nevertheless, short-term DAPT remains effective and safe in this population. No safety concerns are raised in patients with low-risk TIA, more severe stroke, and delayed treatment start., Competing Interests: Declaration of conflicting interestThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AZ reports compensation from Angels Initiative, Boehringer-Ingelheim, Daiichi Sankyo, CSL Behring, Bayer, and Astra Zeneca; and he is member of ESO guidelines, ISA-AII guidelines, and IRETAS steering committee. RO reports compensations from Novartis and Allergan, Teva Pharmaceutical Industries, Eli Lilly and Company, SS reports compensations from Novartis, NovoNordisk, Allergan, AstraZeneca, Pfizer Canada, Inc, Eli Lilly and Company, Teva Pharmaceutical Industries, H. Lundbeck A/S, and Abbott Canada; employment by Università degli Studi dell’Aquila. MPa reports compensation from Daiichi Sankyo Company, Bristol Myers Squibb, Bayer, and Pfizer Canada, Inc. DT reports compensation from Alexion, AstraZeneca, Medtronic, and Pfizer. The other authors report no conflicts.

Introduction/background: Early identification of suspected stroke patients who might be eligible for a reperfusion strategy is a daily challenge in the management of patient referrals. The aim of this study was to evaluate the performance of a remote medical assessment in identifying patients eligible for endovascular therapy (EVT) while not eligible for intravenous thrombolysis (IVT), compared with a decision based on bedside clinico-radiological data., Methods: Patients admitted to the emergency department for acute neurological symptoms lasting for less than 24h were prospectively included. Assessment of the clinical severity and medical history was performed simultaneously by two vascular neurologists (VNs), one remotely using a mobile telemedicine solution (NOMADEEC), the other at the bedside. RACE score was calculated from the NIHSS score. At the end of the evaluation, both VNs quoted their treatment convictions (IVT/EVT). Final therapeutic decision following brain and vascular imaging was recorded and compared to remote and bedside predictions. The performances of three different conditions were evaluated: complete medical evaluation (NIHSS+medical history), NIHSS score alone, and RACE score alone. Remote and bedside performances were also compared. Diagnostic accuracy parameters (sensitivity, specificity, positive and negative predictive values) of each condition were estimated, along with their two-sided 95% binomial confidence intervals., Results: Out of 215 enrolled patients, 186 had a complete evaluation, 91 (54.3%) were diagnosed with an ischemic stroke or transient ischemic attack and 46 (24.7%) had an intracranial occlusion. Considering the three conditions evaluated remotely, RACE score-based decision provided the best sensitivity 54.6% [95% CI 23.4; 83.2]/specificity 80.6% [73.9; 86.2] combination. However, the complete medical evaluation had the best specificity (88.6% [82.9; 92.9] compared to RACE scores alone (P=0.038). Remote and bedside performances did not differ (κ=0.68 [0.59; 0.77])., Discussion/conclusion: This real-life study performed in the setting of emergency demonstrates that remote medical evaluations including recording of extensive medical information and NIHSS examination to address patient's eligibility to revascularization treatment is swiftly feasible and is as effective as bedside prediction to EVT and/or IVT. Remote standardized medical evaluation might improve the decision of patients' primary orientation and avoid overcrowding of comprehensive stroke centres., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Cerebral ischemia-reperfusion injury produces excessive reactive oxygen and nitrogen species, including superoxide, nitric oxide, and peroxynitrite (ONOO - ). We recently developed a new ONOO - -triggered metal-free carbon monoxide donor (PCOD585), exhibiting a notable neuroprotective outcome on the rat middle cerebral artery occlusion model and rendering an exciting intervention opportunity toward ischemia-induced brain injuries. However, its therapeutic mechanism still needs to be addressed. In the pharmacological study, we found PCOD585 inhibited neuronal Bcl2/Bax/caspase-3 apoptosis pathway in the peri-infarcted area of stroke by scavenging ONOO - . ONOO - scavenging further led to decreased Acyl-CoA synthetase long-chain family member 4 and increased glutathione peroxidase 4, to minimize lipoperoxidation. Additionally, the carbon monoxide release upon the ONOO - reaction with PCOD585 further inhibited the neuronal Iron-dependent ferroptosis associated with ischemia-reperfusion. Such a synergistic neuroprotective mechanism of PCOD585 yields as potent a neuroprotective effect as Edaravone. Additionally, PCOD585 penetrates the blood-brain barrier and reduces the degradation of zonula occludens-1 by inhibiting matrix metalloproteinase-9, thereby protecting the integrity of the blood-brain barrier. Our study provides a new perspective for developing multi-functional compounds to treat ischemic stroke., Competing Interests: Declarations. Ethics Approval: The animal experiment was conducted by the national and institutional guidelines on ethics and biosafety, and the protocol was approved by the Institutional Animal Care and Use Committee of Xuzhou Medical University (License ID: 201907W079). Consent to Participate: Not applicable. Consent for Publication: Not applicable. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Whether minor ischemic stroke (MIS) patients can benefit from intravenous thrombolysis (IVT) remains controversial. The association between the efficacy of IVT and baseline National Institute of Health Stroke Scale (NIHSS) score is unclear in MIS, while the association in moderate and severe stroke is known. This study aimed to explore the effect of IVT in patients with MIS and analyze its efficacy in patients with different baseline NIHSS scores., Methods: Patients with a NIHSS score ≤5 within 4.5 h of stroke onset were screened in 32 centers. Patients with and without IVT were matched to a ratio of 1:1 with propensity scores. An excellent outcome was defined as a modified Rankin Scale (mRS) score ≤1 at three months after stroke onset. Safety outcomes included mortality and symptomatic intracranial hemorrhage (sICH). Multivariate analysis was used to compute the adjusted odds ratio (OR) for excellent outcomes. The effect of IVT was further analyzed in subgroups according to the baseline NIHSS score., Results: Of the 23,853 screened, 3336 patients with MIS who arrived at the hospital within 4.5 h of onset were included. The 1163 patients treated with IVT were matched with 1163 patients without IVT. IVT in minor strokes generated an adjusted OR of 1.38 (95% CI: 1.09-1.75, p  = 0.009) for excellent outcomes. There were no significant differences in mortality (0.17% vs. 0.09%, p =  1.000) and sICH (0.69% vs. 0.86%, p =  0.813) between patients with and without IVT. Subgroup analysis showed that there was no significant effect of IVT in the baseline NIHSS 0-1 or 2-3 subgroups, with adjusted OR of 0.816 (95% CI 0.437-1.53, p  = 0.525) and1.22 (95% CI 0.845-1.77, p  = 0.287), respectively. In patients with NIHSS score of 4-5, IVT was significantly effective, with an adjusted OR of 1.53 (95% CI 1.02-2.30, p  = 0.038)., Conclusion: IVT can improve MIS outcomes. The risks of sICH and mortality did not increase, especially in patients with NIHSS scores 4 to 5, who could benefit from IVT significantly.

Background: Intravenous thrombolysis (IVT) is an approved treatment for patients with acute ischemic stroke irrespective of sex. However, the current literature on sex differences in functional outcomes following IVT is inconsistent. So far, a number of studies-including a previous analysis based on data from the Austrian Stroke Unit Registry (ASUR)-detected significant sex-related differences in functional outcome, while others did not report any differences between women and men. In addition, currently there is a lack of data on how sex-related differences evolve over time., Aims: To assess time trends of sex-related differences in functional outcome of ischemic stroke in a large nationwide cohort and to investigate associations of patient characteristics with functional outcome post thrombolysis in women and men. These data will offer crucial insights into whether sex differences in functional outcome persist despite the large advances in acute stroke treatment., Methods: We analyzed retrospective data of consecutive patients with acute ischemic stroke treated with IVT in 39 stroke centers contributing to the ASUR between 2006 and 2021. We included patients over 18 years of age diagnosed with an acute ischemic stroke who received IVT and with available data on functional outcome at 3 months after treatment. The primary outcome parameter was favorable functional outcome (modified Rankin Scale (mRS) of 0-2) at 3 months. Multivariable logistic regression analysis was performed in the overall population and stratified by sex to assess associations of baseline characteristics with functional outcome., Results: Among 11,840 patients receiving IVT, 2489 of 5503 (45.4%) women achieved favorable functional outcome compared to 3787 of 6337 (59.8%) men. Overall, female sex was a statistically significant predictor of functional outcome after thrombolysis, but additional predictors of outcome differed between women and men. Female sex was independently associated with decreased chances of achieving functional independency (adjusted odds ratio (adjOR) = 0.87, 95% confidence interval (CI) = 0.79-0.96, p = 0.005) and we detected a statistically significant improvement in functional outcome over time only in men (year of treatment, adjOR (per year) = 1.04, 95% CI = 1.02-1.06, p < 0.001) but not in women (adjOR (per year) = 1.01, 95% CI = 0.99-1.03, p = 0.280). Hypertension, smoking, and longer or unknown onset-to-door times were statistically significant predictors of outcome only in male patients, whereas atrial fibrillation, prior myocardial infarction, and longer door-to-needle times were significantly associated with outcome only in women., Conclusions: Sex differences in functional outcome after IVT for acute ischemic stroke are persisting over the past years. Results of our analysis can increase awareness and a resulting focus on sex differences in predictors of outcome could be helpful in mitigating these differences in the future by supporting a more individualized patient care in clinical routine. Follow-up analyses are needed to assess this potential impact and its effect in the future., Data Access Statement: Data from the Austrian Stroke Unit Registry can only be accessed by the employed statistician (D.M.), access inquiries have to be addressed to the registry's academic review board., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: M.M. reports honoraria from Boehringer-Ingelheim. M.K. reports honoraria from Daiichi Sankyo, Boehringer-Ingelheim, Sanofi-Aventis; travel grants from Pfizer, the Austrian Stroke Society and the European Stroke Organization; and grants from the Austrian National Bank Anniversary Fund, the Austrian Research Promotaion Agency, and VASCage. S.K. reports grants from VASCage. The remaining authors report no disclosures.

Objectives: Tenecteplase, a modified variant of alteplase with greater fibrin specificity and longer plasma half-life, may have better efficacy and safety than alteplase in patients with acute ischemic stroke (AIS). We aimed to compare the benefits and risks of tenecteplase versus alteplase in the treatment of AIS., Methods: Electronic databases were searched up to 10 February 2023 for randomized controlled trials evaluating the effect of tenecteplase versus alteplase in the treatment of AIS. The primary outcome was functional outcome at 90 days, and secondary outcomes including the symptomatic intracranial haemorrhage (SICH), and major neurological improvement. Subgroup analysis was performed based on the different dosage of tenecteplase., Results: Ten studies with a total of 5123 patients were analysed in this meta-analysis. Overall, no significant difference between tenecteplase and alteplase was observed for functional outcome at 90 days (excellent: OR 1.08, 95%CI 0.93-1.26, I 2  = 26%; good: OR 1.04, 95%CI 0.83-1.30, I 2  = 56%; poor: OR 0.95, 95%CI 0.75-1.21, I 2  = 31%), SICH (OR 1.12, 95%CI 0.79-1.59, I 2  = 0%), and early major neurological improvement (OR 1.26, 95%CI 0.80-1.96, I 2  = 65%). The subgroup analysis suggested that the 0.25 mg/kg dose of tenecteplase had potentially greater efficacy and lower symptomatic intracerebral haemorrhage risk compared with 0.25 mg/kg dose tenecteplase., Conclusions: Among AIS patients, there was no significant difference on clinical outcomes between tenecteplase and alteplase. Subgroup analysis demonstrated that 0.25 mg/kg doses of tenecteplase were more beneficial than 0.4 mg/kg doses of tenecteplase. Further studies are required to identify the optimal dosage of tenecteplase.

Objective: To explore the safety of intravenous thrombolysis with alteplase (rt-PA) in the treatment of acute ischemic stroke (AIS) in the elderly (≥ 80 years old) and with analyze the influencing factors of its clinical outcome., Methods: A total of 144 elderly patients (≥ 80 years old) with AIS who were admitted to our hospital from April 2018 to October 2019 were divided into the elderly thrombolytic group (n = 55) and the elderly non-thrombolytic group (n = 89) according to their different treatment methods, and 166 non-elderly AIS thrombolytic patients in the same period were selected as the non-elderly thrombolytic group. Routine antiplatelet therapy or anticoagulant therapy was given to the elderly non-thrombolytic group, while intravenous thrombolysis with rt-PA was given to the elderly thrombolytic group and the non-elderly thrombolytic group. The changes in National Institutes of Health Stroke Scale (NIHSS), Modified Rankin Scale (mRS), and intracranial hemorrhage transformation within 7 days, mortality within 3 months were used to evaluate the prognosis and safety of patients in each group. Binary Logistic regression was used to analyze the independent factors affecting the long-term prognosis of thrombolytic therapy for AIS in the elderly., Results: After the treatment, the short-term prognosis and the long-term prognosis improvement rates in the non-elderly thrombolytic group and the elderly thrombolytic group were higher than that in the elderly non-thrombolytic group (P < 0.05). There was no statistical difference in mortality between the elderly thrombolytic group and the elderly non-thrombolytic group or in intracranial hemorrhage transformation among the different groups (P > 0.05). Binary logistic regression analysis showed that NIHSS score before treatment was an independent risk factor affecting the long-term prognosis of elderly AIS patients after thrombolysis (P < 0.05)., Conclusion: Elderly AIS patients after rt-PA thrombolysis therapy can improve the short-term, long-term prognosis. The risk of intracranial hemorrhage transformation and death is not higher than that of elderly non thrombolytic patients, indicating that rt-PA treatment is safe for elderly AIS patients. The NIHSS score before treatment was an independent risk factor affecting the long-term prognosis of elderly AIS patients after thrombolytic therapy., Competing Interests: Declarations. Ethics approval and consent to participate: All patients signed an informed consent form, and this study was approved by the Medical Ethics Committee of Ruian People’s Hospital (LZM2018001). We confirm that all experiments were conducted in accordance with the relevant guidelines and regulations of the Helsinki Declaration. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The physiological and pharmacological benefits of hydrogen sulfide (H 2 S) are well established, and various H 2 S and persulfide donors have been developed. However, few studies have examined the in vivo pharmacokinetics of sulfur donors, as most activity and metabolism tests are conducted in vitro , limiting insights into their clinical applications. This study utilized butylphthalide (NBP), an approved drug for ischemic stroke, by integrating H 2 S and persulfide moieties directly into NBP's carbonyl groups. We systematically compared drug metabolism in vitro and in vivo and evaluated donor efficacy in ischemia-reperfusion models. Results revealed notable in vitro / in vivo metabolic differences, with thioacid-containing donors showing promising therapeutic effects in cerebral ischemia, reducing infarct size, oxidative stress, and neuronal apoptosis.

Background and Objectives: In recent years, researchers have sought to address the challenges of obtaining informed consent for participation in acute stroke trials. We studied outcomes related to the use of deferral of consent in the phase 3 Alteplase Compared to Tenecteplase (AcT) trial., Methods: As part of our protocol, we captured methods of consent, participant withdrawals, door-to-randomization times, and door-to-needle times. Participants at 3 sites were invited to complete a survey of attitudes regarding consent for AcT and for acute stroke trials generally., Results: The AcT trial enrolled 1,600 participants from 22 centers across Canada of whom 1,537 were enrolled through deferral of consent (96.0%) and 63 (4.0%) were enrolled by prospective verbal consent followed by written informed consent. Of those enrolled by deferral of consent, 95% (1,454/1,537) consented to ongoing participation. Door-to-randomization times were similar regardless of method of consent, with an overall median of 30 minutes (interquartile range [IQR] 22-42): 29 minutes (IQR 22-42) in the deferral of consent group vs 32 minutes (IQR 25-44) in the prospective consent group ( p = 0.1602). Survey respondents overwhelming agreed or strongly agreed with the use of deferral of consent in AcT (86%) and in any acute stroke trial (76%)., Discussion: Deferral of consent was broadly acceptable to participants in the AcT trial as demonstrated by low rates of withdrawal and by survey results. Door-to-randomization times using deferral of consent in AcT were short, although a system of prospective verbal consent used at 1 center took only slightly longer. These results support the importance of innovation around consent for acute stroke trials.

Currently, the adjuvant therapy to optimize the restorative process after stroke is required due to the unsatisfied therapeutic efficacy. A combined extract of black sticky rice and dill showed potential in the preclinical state, so we hypothesized that it could provide clinical benefits. A three-arm, randomized, placebo-controlled study was set up to elucidate this issue. Both males and females (18-80 years old) who had experienced transient ischemic attacks or ischemic strokes within the last 5-10 days with an NIHSS score ≤ 7 and received standard treatment were randomly assigned to receive either a placebo or capsule containing a combined extract of black sticky rice and dill at a dose of 600 or 1200 mg per day. The safety parameters, movement control, and degree of disability were assessed 1, 2, and 6 weeks after the intervention, and serum stroke biomarkers were assessed at the mentioned time points, except at 2 weeks. After week 1, the high-dose (1200 mg/day) treatment group had improved NIHSSS, VCAM1, and MMP-9. Both S100β and VCAM1 also improved at week 6, while the low-dose treatment group (600 mg/day) only exhibited improved VCAM1. Therefore, a high dose of the developed adjuvant supplement improves stroke recovery by improving motor impairment by reducing endothelial dysfunction and inflammation.

Collaterals improve recanalization in acute ischemic stroke patients treated with intravenous thrombolysis, but the mechanisms are poorly understood. To investigate it, an in vitro flow model of the middle cerebral artery was developed with or without collaterals. An occlusion was achieved using human blood clots. Recanalization time, thrombolysis (clot length decrease and red blood cell (RBC) release), pressure gradient across the clot and clot compaction were measured. Results showed that with or without collateral alteplase-treated RBC dominant clots showed recanalization time 98±23 min vs 130±35 min (difference 32 min, 95% CI -6-58 min), relative clot reduction 31.8±14.9% vs 30.3±13.2% (difference 1.5%, 95% CI 10.4-13.4%) and RBC release 0.30±0.07 vs 0.27±0.09 (difference 0.03, 95% CI 0.04-0.10). Similar results were observed with fibrin-dominant clots. In RBC dominant clots, the presence vs absence of collateral caused different pressure gradients across the clot 0.41±0.09 vs 0.70±0.09 mmHg (difference 0.29 mmHg, 95% CI -0.17-0.41 mmHg), and caused the reduction of initial clot compaction by 5%. These findings align with observations in patients, where collaterals shortened recanalization time. However, collaterals did not increase thrombolysis. Instead, they decreased the pressure gradient across the clot, resulting in less clot compaction and easier distal displacement of the clot., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Thalerová et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The association of lipid-lowering drug targets and their gene variants with cardiovascular diseases has been previously clarified. However, the relationship between gene variants of lipid-lowering drug targets and the adverse prognosis of ischemic stroke patients remains unclear., Methods and Results: Multiple single-nucleotide polymorphisms associated with 6 lipid-lowering drug targets were genotyped for patients with ischemic stroke. The primary outcome was death or major disability within 2 years after ischemic stroke. Genetic risk score was constructed from significant single-nucleotide polymorphisms identified via additive models, which was calculated by multiplying the number of risk alleles at each locus by the corresponding beta coefficient and then summing the products. The rs2006760-C of the HMGCR , rs11206510-T of PCSK9 , and rs1864163-G and rs9929488-G of CETP were associated with increased odds of adverse outcomes within 2 years after ischemic stroke. Each additional risk allele was associated with higher odds of adverse outcomes. Genetic risk score was positively associated with the odds of primary outcome (odds ratio [OR], 1.48 [95% CI, 1.15-1.90]; P trend  = 0.001), major disability (OR, 1.56 [95% CI, 1.16-2.08]; P trend  = 0.002), death (hazard ratio [HR], 1.58 [95% CI, 1.12-2.25]; P trend  = 0.011), and the composite outcome of death or cardiovascular events (HR, 1.41 [95% CI, 1.08-1.85]; P trend  = 0.010) when 2 extreme quartiles were compared., Conclusions: rs2006760-C of HMGCR , rs11206510-T of PCSK9 , and rs1864163-G and rs9929488-G of CETP were associated with increased odds of adverse outcomes within 2 years after ischemic stroke. Furthermore, higher GRS was positively related to the odds of poor outcomes in patients with ischemic stroke. Registration: URL: https://www.clinicaltrials.gov; Identifier: NCT01840072.