Normobaric Hyperoxia Combined with Endovascular Treatment in Patients with Acute Ischemic Stroke (OPENS-2) Trial: Protocol for a Prospective, Multicenter, Randomized Controlled Study.

Normobaric hyperoxia (NBO) is a potentially promising stroke treatment strategy that could protect the ischemic penumbra and could be administered as an adjunct before vascular recanalization. However, the efficacy and safety of NBO have not been confirmed by randomized controlled trials. The study aims to assess the efficacy and safety of NBO for ischemic stroke due to large artery occlusion (LVO) of acute anterior circulation among patients who had endovascular treatment (EVT) and were randomized within 6 h from symptom onset. Based on the data of the modified Rankin Scale (mRS) score at 90 days from the normobaric hyperoxia combined with EVT for acute ischemic stroke (OPENS: NCT03620370) trial, 284 patients will be included to achieve a 90% power by using Wilcoxon-Mann-Whitney test and the proportional odds model to calculate the sample size. The study is a prospective, multicenter, blinded, randomized controlled trial. The NBO group is administered with mask oxygen therapy of 10 L/min, while the sham NBO group is with that of 1 L/min. The primary outcome is the mRS score at 90 days. Secondary endpoints include cerebral infarct volume at 24-48 h, functional independence (mRS ≤2) at 90 days, and improvement in neurological function at 24 h. Safety outcomes include 90-day mortality, oxygen-related adverse events, and serious adverse events. This study will indicate whether NBO combined with EVT is superior to EVT alone for acute ischemic stroke caused by LVO in subjects randomized within 6 h from symptom onset and will provide some evidence for NBO intervention as an adjunct to thrombectomy for acute stroke.

Neuroprotection on ischemic brain injury by Mg2+/H2 released from endovascular Mg implant.

Most acute ischemic stroke patients with large vessel occlusion require stent implantation for complete recanalization. Yet, due to ischemia-reperfusion injury, over half of these patients still experience poor prognoses. Thus, neuroprotective treatment is imperative to alleviate the ischemic brain injury, and a proof-of-concept study was conducted on "biodegradable neuroprotective stent". This concept is premised on the hypothesis that locally released Mg2+/H2 from Mg metal within the bloodstream could offer synergistic neuroprotection against reperfusion injury in distant cerebral ischemic tissues. Initially, the study evaluated pure Mg's neuroactive potential using oxygen-glucose deprivation/reoxygenation (OGD/R) injured neuron cells. Subsequently, a pure Mg wire was implanted into the common carotid artery of the transient middle cerebral artery occlusion (MCAO) rat model to simulate human brain ischemia/reperfusion injury. In vitro analyses revealed that pure Mg extract aided mouse hippocampal neuronal cell (HT-22) in defending against OGD/R injury. Additionally, the protective effects of the Mg wire on behavioral abnormalities, neural injury, blood-brain barrier disruption, and cerebral blood flow reduction in MCAO rats were verified. Conclusively, Mg-based biodegradable neuroprotective implants could serve as an effective local Mg2+/H2 delivery system for treating distant cerebral ischemic diseases.

Role of Circadian Rhythm Changes on Functional Dependence Despite Successful Repercussion in Patients with Endovascular Treatment.

BACKGROUND: Increasing evidence of circadian biology may influence the physiopathologic mechanism, progression, and recovery of stroke. However, few data have shown about circadian rhythm on futile recanalization (FR) in patients treated with endovascular treatment (EVT). METHODS: From 2017 to 2021, an observational cohort of acute ischemic stroke (AIS) patients with large vessel occlusion (LVO) underwent EVT was conducted. FR was defined as the failure to achieve functional independence in patients at 90 days after EVT, although the occluded vessels reached a recanalization. The effect of circadian rhythm on FR was investigated using the logistic regression model. RESULTS: Of 783 patients, there were 149 patients who had stroke onset between 23:00-6:59, 318 patients between 7:00-14:59, and 316 patients between 15:00-22:59. Patients suffered a stroke during 15:00-22:59 had shorter OTP (p =0.001) time, shorter OTR (p<0.001) time, higher rate of intravenous thrombolysis (p =0.001) than groups of other time intervals. The rate of FR post-EVT in patients who had a stroke between 15:00-22:59 was significantly higher than in those with stroke onset between 23:00-6:59 (p =0.017). After adjusting for confounding factors, the time of stroke occurring during 15:00-22:59 (adjusted OR [aOR], 1.652; 95%CI, 1.024-2.666, p =0.04) was an independent predictor of FR. CONCLUSION: Circadian rhythm can directly or indirectly affect the occurrence, development, and prognosis of AIS. More studies may be needed in the future to validate the results of our study and to explore the potential mechanisms behind the effects of circadian rhythms on FR.

Remote ischemic preconditioning prevents high-altitude cerebral edema by enhancing glucose metabolic reprogramming.

AIMS: Incidence of acute mountain sickness (AMS) ranges from 40%-90%, with high-altitude cerebral edema (HACE) representing a life-threatening end stage of severe AMS. However, practical and convenient preventive strategies for HACE are lacking. Remote ischemic preconditioning (RIPC) has demonstrated preventive effects on ischemia- or hypoxia-induced cardiovascular and cerebrovascular diseases. This study aimed to investigate the potential molecular mechanism of HACE and the application of RIPC in preventing HACE onset. METHODS: A hypobaric hypoxia chamber was used to simulate a high-altitude environment of 7000 meters. Metabolomics and metabolic flux analysis were employed to assay metabolite levels. Transcriptomics and quantitative real-time PCR (q-PCR) were used to investigate gene expression levels. Immunofluorescence staining was performed on neurons to label cellular proteins. The fluorescent probes Mito-Dendra2, iATPSnFR1.0, and CMTMRos were used to observe mitochondria, ATP, and membrane potential in cultured neurons, respectively. TUNEL staining was performed to detect and quantify apoptotic cell death. Hematoxylin and eosin (H&E) staining was utilized to analyze pathological changes, such as tissue swelling in cerebral cortex samples. The Rotarod test was performed to assess motor coordination and balance in rats. Oxygen-glucose deprivation (OGD) of cultured cells was employed as an in vitro model to simulate the hypoxia and hypoglycemia induced by RIPC in animal experiments. RESULTS: We revealed a causative perturbation of glucose metabolism in the brain preceding cerebral edema. Ischemic preconditioning treatment significantly reprograms glucose metabolism, ameliorating cell apoptosis and hypoxia-induced energy deprivation. Notably, ischemic preconditioning improves mitochondrial membrane potential and ATP production through enhanced glucose-coupled mitochondrial metabolism. In vivo studies confirm that RIPC alleviates cerebral edema, reduces cell apoptosis induced by high-altitude hypoxia, and improves motor dysfunction resulting from cerebral edema. CONCLUSIONS: Our study elucidates the metabolic basis of HACE pathogenesis. This study provides a new strategy for preventing HACE that RIPC reduces brain edema through reprogramming metabolism, highlighting the potential of targeting metabolic reprogramming for neuroprotective interventions in neurological diseases caused by ischemia or hypoxia.

Effects of batroxobin on the antithrombotic system in patients with cerebral venous thrombosis: Clues to mechanisms.

BACKGROUND AND PURPOSE: More evidence supports the benefits of batroxobin combined with anticoagulation in correcting acute cerebral venous thrombosis (CVT). The dynamic fluctuations of peripheral blood platelets, fibrinolysis, and coagulation biomarkers during this therapy were analyzed. METHODS: We investigated batroxobin's effects on the antithrombotic system under two regimens. The pretreatment group included patients on anticoagulants for at least 1 week before starting batroxobin. The simultaneous treatment group began both treatments upon admission. The control group received only anticoagulation. Batroxobin was given on alternate days at doses of 10BU, 5BU, and 5BU, totaling three doses. Anticoagulation was continuous. Baseline data were T0; the next day after each batroxobin dose was T1, T2, and T3. Data from these four time points was analyzed. RESULTS: The time-point paired sample T-test results of the pretreatment group [n = 60; mean age (SD), 43.3(16.5); 38 (63.35%) women] showed that batroxobin significantly inhibited ADP-induced platelet aggregation rate (T1-T0: p = 0.015; T2-T0: p = 0.025; T3-T0: p = 0.013), decreased fibrinogen level (T1-T0: p < 0.001; T2-T0: p < 0.001; T3-T0: p < 0.001), and increased D-dimer (T1-T0:p < 0.001; T2-T0: p < 0.001; T3-T0: p < 0.001), TT (T1-T0:p = 0.046; T2-T0: p = 0.003; T3-T0: p < 0.001), and APTT (T1-T0:p = 0.021; T2-T0: p = 0.012; T3-T0: p = 0.026). Compared to the control group, the simultaneous treatment group showed significantly higher TT (T2: p = 0.002; T3: p = 0.004) and D-dimer (T1: p < 0.001; T2: p < 0.001; T3: p < 0.001) values, while fibrinogen (T2: p < 0.001; T3: p < 0.001) levels were significantly lower. Using batroxobin can alleviate the amplitude of changes in coagulation indicators other than TT caused by anticoagulants. The above conclusions are consistent with the results of repeated measurement data analysis. CONCLUSIONS: Batroxobin can significantly inhibit ADP-induced platelet aggregation rate, increase D-dimer, decrease fibrinogen, and prolong TT and APTT in the presence of anticoagulant agents. Using batroxobin can reduce the amplitude of changes in coagulation indicators caused by anticoagulants. These results reveal the potential mechanism of batroxobin combined with anticoagulation in the safe and effective treatment of CVT.

Effectiveness of metformin pretreatment for stroke severity: A propensity score matching study.

BACKGROUND AND OBJECTIVE: Metformin pretreatment might have neuroprotective effects. We aimed to determine the therapeutic effects of the antidiabetic medication metformin on ischemic stroke severity and discharge outcomes. METHODS: We analyzed data on 1303 ischemic stroke patients who were on antidiabetic medications from the Massachusetts General Hospital (MGH) Advanced Comprehensive Stroke Center dataset (n = 8943, 2012-2022). We applied propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) analyses to investigate the effect of current usage of metformin (versus alternate antidiabetic treatment) on acute stroke clinical severity and discharge outcomes. RESULTS: Of the 1303 patients who were on antidiabetic medications at the time of stroke admission, 730 (56%) were taking metformin. Metformin users were younger and more frequently had hypertension, whereas less frequently had prior CAD, AFib, and chronic kidney disease. The clinical features and laboratory values of the two groups were evenly distributed after PSM. Metformin-treated patients had statistically significant lower stroke severity on admission [National Institutes of Health Stroke Scale (NIHSS) (median, interquartile range) 3.0 (1.0-8.0) vs. 4.0 (2.0-11.3), p = 0.011], better functional independence at discharge (modified Rankin scale score 0-2, 36.3% vs. 25.4%, p < 0.001) and less in-hospital mortality (4.5% vs. 11.3%, p = 0.018). IPTW analysis results were consistent with PSM results. CONCLUSIONS: Among diabetic patients with acute ischemic stroke, metformin appears to confer neuroprotection. Our results extend previous findings to the general stroke population. Stroke patients with diabetes mellitus who were treated with metformin prior to stroke, even when combined with additional antidiabetic medications, experienced less severe strokes upon admission and had better functional outcomes during hospitalization.

Basilar artery occlusion management: An international survey of gender influence on management.

BACKGROUND: The superiority of endovascular thrombectomy (EVT) over medical management was not established in two early basilar artery occlusion (BAO) randomized controlled trials. Despite this, many clinicians recommended EVT for acute BAO under certain circumstances. This paper aims to compare physicians' diagnostic and management strategies of BAO according to gender. METHODS: From January to March 2022 an international survey was conducted regarding management strategies in acute BAO. We compared responses between clinicians by identifying gender. Questions were designed to examine clinical and imaging parameters influencing management of patients with BAO. RESULTS: Among the 1245 respondents from 73 countries, 311 (25.0%) identified as female. This figure was 13.6% amongst interventionists. Geographically, female respondents were lowest in Asia (14.5%) and North America (23.9%). The proportion of respondents identifying as female was consistent regardless of their years of experience. Female respondents were more likely to choose time of onset as time of first estimated stroke like symptom (48.0% vs. 38.5%, p < .01), were less likely to favor thrombectomy in the V4 segment of vertebrobasilar artery occlusions (31.5% vs. 43.3%, p < .01), and were less likely to find it acceptable to enroll all patients who met trial criteria in the standard medical treatment arm of a clinical trial (41.2% vs. 47.0%, p = .01). Male respondents were more likely to agree that thrombolysis would not alter their decision on proceeding with EVT (93.7% vs. 88.3%, p < .01). CONCLUSIONS: Female clinicians appear to be significantly underrepresented in stroke medicine. This is most pronounced amongst interventionists and in Asia. Although male and female opinions were closely aligned on many aspects of BAO management, differences in opinion were observed in a number of significant areas which influence decision making.

Blood pressure management after endovascular thrombectomy: Insights of recent randomized controlled trials.

BACKGROUND: The ideal blood pressure (BP) target in patients who undergo endovascular thrombectomy (EVT) with successful reperfusion is uncertain. Observational studies show that elevated BP during this period is associated with a higher risk of intracranial hemorrhage (ICH) and worse clinical outcomes. Several randomized controlled trials (RCTs) have explored whether intensive BP lowering improves clinical outcomes in these patients. AIMS: This review aims to summarize the recent RCTs that compare intensive and conventional BP management strategies following EVT and discuss the innovative directions to improve. RESULT: The recently published RCTs failed to demonstrate the benefit of intensive BP control on the functional outcome and decreasing the risk of ICH. The complex mechanism in cerebral blood flow regulation and the inappropriate BP range chosen in RCTs may be the reasons behind the inconsistent results between observational studies and RCTs. Individualized BP management, reducing BP variability, and multi-stage BP management should be paid more attention in future exploration. CONCLUSION: Intensive BP target did not improve clinical outcomes after successful EVT as compared with a conventional BP target. Further research is required to identify the optimal BP management strategy after reperfusion.

Model-predicted brain temperature computational imaging by multimodal noninvasive functional neuromonitoring of cerebral oxygen metabolism and hemodynamics: MRI-derived and clinical validation.

Brain temperature, a crucial yet under-researched neurophysiological parameter, is governed by the equilibrium between cerebral oxygen metabolism and hemodynamics. Therapeutic hypothermia has been demonstrated as an effective intervention for acute brain injuries, enhancing survival rates and prognosis. The success of this treatment hinges on the precise regulation of brain temperature. However, the absence of comprehensive brain temperature monitoring methods during therapy, combined with a limited understanding of human brain heat transmission mechanisms, significantly hampers the advancement of hypothermia-based neuroprotective therapies. Leveraging the principles of bioheat transfer and MRI technology, this study conducted quantitative analyses of brain heat transfer during mild hypothermia therapy. Utilizing MRI, we reconstructed brain structures, estimated cerebral blood flow and oxygen consumption parameters, and developed a brain temperature calculation model founded on bioheat transfer theory. Employing computational cerebral hemodynamic simulation analysis, we established an intracranial arterial fluid dynamics model to predict brain temperature variations across different therapeutic hypothermia modalities. We introduce a noninvasive, spatially resolved, and optimized mathematical bio-heat model that synergizes model-predicted and MRI-derived data for brain temperature prediction and imaging. Our findings reveal that the brain temperature images generated by our model reflect distinct spatial variations across individual participants, aligning with experimentally observed temperatures.

Progress and recognition of idiopathic intracranial hypertension: A narrative review.

BACKGROUND: Idiopathic intracranial hypertension (IIH) mainly affects obese young women, causing elevated intracranial pressure, headaches, and papilledema, risking vision loss and severe headaches. Despite weight loss as the primary treatment, the underlying mechanisms remain unclear. Recent research explores novel therapeutic targets. AIMS: This review aimed to provide a comprehensive understanding of IIH's pathophysiology and clinical features to inform pathogenesis and improve treatment strategies. METHODS: Recent publications on IIH were searched and summarized using PubMed, Web of Science, and MEDLINE. RESULTS: The review highlights potential pathomechanisms and therapeutic advances in IIH. CONCLUSION: IIH incidence is rising, with growing evidence linking it to metabolic and hormonal disturbances. Early diagnosis and treatment remain challenging.

Mild hypothermia therapy attenuates early BBB leakage in acute ischaemic stroke.

Reperfusion therapy inevitably leads to brain-blood barrier (BBB) disruption and promotes damage despite its benefits for acute ischaemic stroke (AIS). An effective brain cytoprotective treatment is still needed as an adjunct to reperfusion therapy. Here, we explore the potential benefits of therapeutic hypothermia (HT) in attenuating early BBB leakage and improving neurological outcomes. Mild HT was induced during the early and peri-recanalization stages in a mouse model of transient middle cerebral artery occlusion and reperfusion (tMCAO/R). The results showed that mild HT attenuated early BBB leakage in AIS, decreased the infarction volume, and improved functional outcomes. RNA sequencing data of the microvessels indicated that HT decreased the transcription of the actin polymerization-related pathway. We further discovered that HT attenuated the ROCK1/MLC pathway, leading to a decrease in the polymerization of G-actin to F-actin. Arachidonic acid (AA), a known structural ROCK agonist, partially counteracted the protective effects of HT in the tMCAO/R model. Our study highlights the importance of early vascular protection during reperfusion and provides a new strategy for attenuating early BBB leakage by HT treatment for ischaemic stroke.

Remote ischemic conditioning prevents ischemic cerebrovascular events in children with moyamoya disease: a randomized controlled trial.

BACKGROUND: Moyamoya disease (MMD) is a significant cause of childhood stroke and transient ischemic attacks (TIAs). This study aimed to assess the safety and efficacy of remote ischemic conditioning (RIC) in children with MMD. METHODS: In a single-center pilot study, 46 MMD patients aged 4 to 14 years, with no history of reconstructive surgery, were randomly assigned to receive either RIC or sham RIC treatment twice daily for a year. The primary outcome measured was the cumulative incidence of major adverse cerebrovascular events (MACEs). Secondary outcomes included ischemic stroke, recurrent TIA, hemorrhagic stroke, revascularization rates, and clinical improvement assessed using the patient global impression of change (PGIC) scale during follow-up. RIC-related adverse events were also recorded, and cerebral hemodynamics were evaluated using transcranial Doppler. RESULTS: All 46 patients completed the final follow-up (23 each in the RIC and sham RIC groups). No severe adverse events associated with RIC were observed. Kaplan-Meier analysis indicated a significant reduction in MACEs frequency after RIC treatment [log-rank test (Mantel-Cox), P = 0.021]. At 3-year follow-up, two (4.35%) patients had an ischemic stroke, four (8.70%) experienced TIAs, and two (4.35%) underwent revascularization as the qualifying MACEs. The clinical improvement rate in the RIC group was higher than the sham RIC group on the PGIC scale (65.2% vs. 26.1%, P < 0.01). No statistical difference in cerebral hemodynamics post-treatment was observed. CONCLUSIONS: RIC is a safe and effective adjunct therapy for asymptomatic children with MMD. This was largely due to the reduced incidence of ischemic cerebrovascular events.

Ticking Brain: Circadian Rhythm as a New Target for Cerebroprotection.

Circadian rhythm is a master process observed in nearly every type of cell throughout the body, and it macroscopically regulates daily physiology. Recent clinical trials have revealed the effects of circadian variation on the incidence, pathophysiological processes, and prognosis of acute ischemic stroke. Furthermore, core clock genes, the cell-autonomous pacemakers of the circadian rhythm, affect the neurovascular unit-composing cells in a nonparallel manner after the same pathophysiological processes of ischemia/reperfusion. In this review, we discuss the influence of circadian rhythms and clock genes on each type of neurovascular unit cell in the pathophysiological processes of acute ischemic stroke.

The impact of high-altitude and cold environment on brain and heart damage in rats with hemorrhagic shock.

BACKGROUND: Hemorrhagic shock (HS) causes severe organ damage, worsened by high-altitude conditions with lower oxygen and temperatures. Existing research lacks specific insights on brain and heart damage under these conditions. This study hypothesizes that high-altitude and cold (HAC) environments exacerbate HS-induced damage in the brain and heart, aiming to improve treatment strategies. MATERIALS AND METHODS: Twenty-four male Sprague-Dawley (SD) rats (200-250 g of weight) were randomly assigned into sham, HS + normal, HS + HAC (4,000 m), and HS + HAC (6,000 m). The HS model was established in SD rats (35% loss of total blood volume), and histopathological injuries of the brain and heart were detected using hematoxylin and eosin staining, Sirius red staining, and immunohistochemistry. Apoptosis of the brain and heart tissues was detected by terminal transferase-mediated dUTP nick end labeling (TUNEL) immunofluorescence staining. To determine the levels of tumor necrosis factor-α (TNF-α), interferon-gamma (IFN-γ), monocyte chemoattractant protein-1 (Mcp-1), BCL2-associated X (BAX), and myeloid cell leukemia-1 (Mcl-1) protein, western blotting assay was used. RESULTS: The HAC environment induced pathological damage to the brain and heart and aggravated the degree of cardiac fibrosis in HS rats. However, it did not cause apoptosis of the brain and heart. In addition, it upregulated TNF-α, IFN-γ, Mcp-1, and BAX protein levels, but downregulated Mcl-1 protein levels (P < 0.05). CONCLUSIONS: The HAC environment aggravated the degree of brain and heart damage in HS rats, which may be related to neuron nucleus pyknosis, myocardial fibrosis, and inflammatory and apoptosis activation.

Safety and efficacy of tirofiban in preventing neurological deterioration in acute ischemic stroke (TREND): Protocol for an investigator-initiated, multicenter, prospective, randomized, open-label, masked endpoint trial.

INTRODUCTION: Antithrombotic therapy prevents adverse ischemic events following acute ischemic stroke (AIS). Intravenous tirofiban provides desirable antiplatelet effects, especially in patients who are vulnerable to neurological deterioration (ND). AIM: The aim of the study was to test the hypothesis that intravenous administration of tirofiban, initiated within 24 h of ictus and continued for consecutive 72 h, would be more effective than aspirin in reducing the risk of ND within 72 h of enrollment among patients with potentially atherothrombotic ischemic stroke. METHODS: The Safety and Efficacy of Tirofiban in Preventing Neurological Deterioration in Acute Ischemic Stroke (TREND) trial is an investigator-initiated, multicenter, prospective, randomized, open-label, masked endpoint study. Its eligibility criteria included AIS secondary to potential atherosclerosis, a National Institutes of Health Stroke Scale (NIHSS) score ranging from 4 to 20 points, ineligibility for recanalization therapy, and administration within 24 h postsymptom onset. Randomization was performed at a 1:1 ratio to allocate 420 patients into two groups to receive an intravenous tirofiban bridge to oral antiplatelet drugs or direct oral antiplatelet drugs. OUTCOMES: The primary outcome is the proportion of patients with a ≥4-point increase in NIHSS score within 72 h of intervention compared to the score at enrollment. The key secondary outcomes include changes in NIHSS score, modified Rankin scale (mRS) score at 90 days, and dichotomized mRS scores (0-2 vs. 3-6 and 0-1 vs. 2-6) at 90 days. The safety variables are symptomatic intracerebral hemorrhage, any intracerebral hemorrhage, and systemic hemorrhage within 72 h after randomization and 90-day mortality. CONCLUSIONS: The TREND trial may identify the suitability of intravenous tirofiban as a routine clinical strategy to prevent ND in patients with AIS within 24 h of the onset of symptoms. TRIAL REGISTRATION: http://www.clinicaltrials.gov (identifier: NCT04491695).

A systematic review of exosomes in remote ischemic conditioning.

BACKGROUND: Remote ischemic conditioning (RIC) is considered a promising non-pharmacological therapeutic strategy to mitigate ischemic injury. Although the precise mechanisms of RIC's protective effects remain elusive, existing data suggest that exosomes contribute significantly to these processes through cell-to-cell communication OBJECTIVE: This review aims to elucidate the role of exosomes in RIC-mediated multi-organ protection. METHODS: We systematically searched multiple databases through October 2023 for preclinical studies evaluating the effect of exosomes in ischemic models using RIC procedures. Key outcomes, such as improved organ function and reduced infarct size, were recorded. Articles were selected and data were extracted by independent pairs of reviewers. FINDINGS: A total of 16 relevant studies were identified in this review, showing that circulating exosomes derived from the plasma of RIC-treated animals exhibited protective effects akin to those of the RIC procedure itself. Exosome concentrations were measured in eight studies, six of which reported significant increases in the RIC group. Additional findings indicated that RIC might primarily modulate the expression of miRNAs and bioactive molecules delivered by exosomes, rather than directly altering circulating exosome levels. Notably, the expression of 11 distinct exosomal miRNAs was altered after RIC intervention, potentially involving multiple pathways. CONCLUSION: Exosomes appear to play a pivotal role in the protective effects induced by RIC. Clarifying their function in RIC under different pathological situations represents a grand challenge for future research.

Advancing stroke therapy: innovative approaches with stem cell-derived extracellular vesicles.

Stroke is a leading cause of mortality and long-term disability globally, with acute ischemic stroke (AIS) being the most common subtype. Despite significant advances in reperfusion therapies, their limited time window and associated risks underscore the necessity for novel treatment strategies. Stem cell-derived extracellular vesicles (EVs) have emerged as a promising therapeutic approach due to their ability to modulate the post-stroke microenvironment and facilitate neuroprotection and neurorestoration. This review synthesizes current research on the therapeutic potential of stem cell-derived EVs in AIS, focusing on their origin, biogenesis, mechanisms of action, and strategies for enhancing their targeting capacity and therapeutic efficacy. Additionally, we explore innovative combination therapies and discuss both the challenges and prospects of EV-based treatments. Our findings reveal that stem cell-derived EVs exhibit diverse therapeutic effects in AIS, such as promoting neuronal survival, diminishing neuroinflammation, protecting the blood-brain barrier, and enhancing angiogenesis and neurogenesis. Various strategies, including targeting modifications and cargo modifications, have been developed to improve the efficacy of EVs. Combining EVs with other treatments, such as reperfusion therapy, stem cell transplantation, nanomedicine, and gut microbiome modulation, holds great promise for improving stroke outcomes. However, challenges such as the heterogeneity of EVs and the need for standardized protocols for EV production and quality control remain to be addressed. Stem cell-derived EVs represent a novel therapeutic avenue for AIS, offering the potential to address the limitations of current treatments. Further research is needed to optimize EV-based therapies and translate their benefits to clinical practice, with an emphasis on ensuring safety, overcoming regulatory hurdles, and enhancing the specificity and efficacy of EV delivery to target tissues.

Statins for neuroprotection in spontaneous intracerebral haemorrhage (STATIC): protocol for a multicentre, prospective and randomised controlled trial.

INTRODUCTION: Intracerebral haemorrhage (ICH) is a neurological emergency with high morbidity and mortality, and current treatment is limited. Emerging evidence has reported that statins can exert neuroprotective effects in cerebrovascular diseases. However, most of the published clinical studies are retrospective. Therefore, it is important to conduct a prospective randomised controlled trial to further validate the efficacy and safety of statins in patients with ICH. METHODS AND ANALYSIS: The present study is performed at Xuan Wu Hospital Capital Medical University, Beijing Fengtai You'anmen Hospital and Shunping County Hospital, Hebei Province. The target number of patients is 98. Eligible patients are randomly assigned in a 1:1 ratio to the statins group or the control group. The primary outcome is the perihaemorrhagic oedema to haematoma ratio at 7 days. Secondary outcomes include mortality at 30 days, haematoma resolution rate at 7 days, National Institute of Health stroke scale (NIHSS) score at 7 days or discharge, ordinal distribution of modified Rankin scale (mRS) score at 90 days, the proportion of patients with an mRS score of 0-2 on day 90, the proportion of patients with an mRS score of 0-3 on day 90, absolute haematoma volume changes between initial and 7-day follow-up CT scan, absolute perihaematomal oedema changes between initial and 7-day follow-up CT scan. ETHICS AND DISSEMINATION: The trial has been approved by the ethics committees of Xuan Wu Hospital Capital Medical University, Beijing Fengtai You'anmen Hospital and Shunping County Hospital, Hebei Province. The results will be disseminated in a peer-reviewed journal and in conference reports. TRIAL REGISTRATION NUMBER: NCT04857632.

Stroke-heart syndrome: current progress and future outlook.

Stroke can lead to cardiac complications such as arrhythmia, myocardial injury, and cardiac dysfunction, collectively termed stroke-heart syndrome (SHS). These cardiac alterations typically peak within 72 h of stroke onset and can have long-term effects on cardiac function. Post-stroke cardiac complications seriously affect prognosis and are the second most frequent cause of death in patients with stroke. Although traditional vascular risk factors contribute to SHS, other potential mechanisms indirectly induced by stroke have also been recognized. Accumulating clinical and experimental evidence has emphasized the role of central autonomic network disorders and inflammation as key pathophysiological mechanisms of SHS. Therefore, an assessment of post-stroke cardiac dysautonomia is necessary. Currently, the development of treatment strategies for SHS is a vital but challenging task. Identifying potential key mediators and signaling pathways of SHS is essential for developing therapeutic targets. Therapies targeting pathophysiological mechanisms may be promising. Remote ischemic conditioning exerts protective effects through humoral, nerve, and immune-inflammatory regulatory mechanisms, potentially preventing the development of SHS. In the future, well-designed trials are required to verify its clinical efficacy. This comprehensive review provides valuable insights for future research.