Improve Stroke Outcomes Research Articles

Notoginsenoside R1 alleviates cerebral ischemia/reperfusion injury by inhibiting the TLR4/MyD88/NF-κB signaling pathway through microbiota-gut-brain axis

BackgroundIschemic stroke (IS) ranks as the second common cause of death worldwide. However, a narrow thrombolysis timeframe and ischemia-reperfusion (I/R) injury limits patient recovery. Moreover, anticoagulation and antithrombotic drugs do not meet the clinical requirements. Studies have demonstrated close communication between the brain and gut microbiota in IS. Notoginsenoside R1 (NG-R1), a significant component of the total saponins from Panax notoginseng, has been demonstrated to be effective against cerebral I/R injury. Total saponins have been used to treat IS in Chinese pharmacopoeia. Furthermore, previous research has indicated that the absorption of NG-R1 was controlled by gut microbiota. Study designThis study aimed to access the impact of NG-R1 treatment on neuroinflammation and investigate the microbiota-related mechanisms. ResultsNG-R1 significantly reduced neuronal death and neuroinflammation in middle cerebral artery occlusion/reperfusion (MCAO/R) models. 16S rRNA sequencing revealed that NG-R1 treatment displayed the reversal of microbiota related with MCAO/R models. Additionally, NG-R1 administration attenuated intestinal inflammation, gut barrier destruction, and systemic inflammation. Furthermore, microbiota transplantation from NG-R1 exhibited a similar effect in the MCAO/R models. ConclusionIn summary, NG-R1 treatment resulted in the restoration of the structure of the blood-brain barrier (BBB) and reduction in neuroinflammation via suppressing the stimulation of astrocytes and microglia in the cerebral ischemic area. Mechanistic research demonstrated that NG-R1 treatment suppressed the toll-like receptor 4/myeloid differentiation primary response 88/nuclear factor kappa B (TLR4/MyD88/NF-κB) signaling pathway in both the ischemic brain and colon. NG-R1 treatment enhanced microbiota dysbiosis by inhibiting the TLR4 signaling pathway to protect MCAO/R models. These findings elucidate the mechanisms by which NG-R1 improve stroke outcomes and provide some basis for Panax notoginseng saponins in clinical treatment.

Stroke rehabilitation in low resource countries: time to provide an organised service

Introduction: Stroke is one of the leading causes of death and disability in lowand middle-income countries (LMICs). The proven efficacy for rehabilitation interventions in improving stroke outcomes in LMICs supports the need to strengthen the rehabilitation workforce. Low-cost physical rehabilitation interventions requiring minimal resources, self-rehabilitation, tele-rehabilitation and involvement of family and other carers can be a solution and improve functional outcomes.
 Method: A literature search using the terms Stroke and Rehabilitation were carried out by the Chief Librarian at St. Richard’s Hospital, the University Hospital Sussex. Four databases, namely Ovid Medline, EMBASE, CINAHL and Ebsco CINAHL, were searched using appropriate subject headings and free text terms such as stroke and rehabilitation . We used free text terms to look for concepts synonymous with rehabilitation in LMICs. We did not search for individual countries or continents/sub-continents.
 Results: Relevant results from 2015 to current were included. Twenty articles were finally chosen which included the most relevant and useful information for the purpose of this article.
 Conclusion: Populations in LMICs are exposed to health systems which do not include rehabilitation services. In addition, there are personal barriers to accessing quality stroke rehabilitation that could improve stroke survival and functional outcomes. Although there have been some improvements in the development of stroke rehabilitation in some LMICs, further investment is required to ensure that LMICs continue to receive the best quality rehabilitation services. There are measures that can be put in place to reduce these deficiencies. Collaboration between LMICs and developed countries has been growing but this needs to be extended, especially in training doctors in Rehabilitation Medicine and upskilling therapists. The World Health Organisation Rehabilitation 2030 is an action plan to scale up rehabilitation so that countries, especially LMICs, can be better prepared to address the evolving rehabilitation needs of populations by 2030.

Nerinetide Reduces Early Infarct Growth Among Stroke Patients Undergoing EVT Without Intravenous Alteplase

Background Nerinetide treatment was associated with better clinical outcomes among patients with stroke undergoing endovascular treatment who were not treated with concurrent alteplase in the randomized ESCAPE‐NA1 (Efficacy and Safety of Nerinetide for the Treatment of Acute Ischemic Stroke) trial. In patients receiving alteplase, no such effect was seen due to an inactivation of nerinetide by plasmin – the product of tissue plasminogen activation. We hypothesized that improved outcomes in the no‐alteplase patients were associated with reduced infarct growth, a radiological correlate of improved stroke outcomes. Methods Data are from the no‐alteplase stratum of the ESCAPE‐NA1 trial. Patients who underwent computer tomography perfusion (CTP) as part of routine clinical care were included. Admission CTP source data were processed using RAPID software. Infarct core at baseline was defined as areas of relative cerebral blood flow <30% on CTP. Final infarct volume was determined via manual segmentation on 24‐hour CT or magnetic resonance diffusion‐weighted imaging. We compared infarct growth (defined as 24‐hour infarct volume minus CTP‐estimated baseline infarct core) among no‐alteplase patients treated with versus without nerinetide. Results CTP maps were available in 413/1105 (37%) ESCAPE‐NA1 participants. Of these, 179 (43%) were treated without alteplase, 79 (44%) received nerinetide, and 100 (56%) received placebo. Prior administration of alteplase modified the treatment effect of nerinetide on infarct growth in a multivariable model that was adjusted for age, sex, baseline infarct core volume, expanded Thrombolysis in Cerebral Infarction score, and time from baseline imaging to reperfusion ( P = 0.005). In no‐alteplase patients, infarct growth was larger over 24 hours in the control (34.9 mL interquartile range[IQR] [6.8–127]) versus nerinetide (19.6 mL IQR [1.7–49.1]; P = 0.008) groups. In patients who received prior alteplase (n = 234), there was no difference in infarct growth between those who received placebo versus nerinetide (10.5 mL IQR [−1.3 to 67.4] versus 12.8 mL IQR [0.35–55.5]; P = 0.62). Conclusion Nerinetide was associated with decreased infarct growth in acute ischemic stroke patients undergoing thrombectomy without concurrent alteplase in the ESCAPE‐NA1 trial.

Abstract TP291: Near-Infrared II Photobiomodulation Protects Against Stroke via Endothelial Nitric Oxide Phosphorylation

Since endothelial dysfunction is implicated in stroke pathogenesis and is featured with suppressed endothelial nitric oxide (NO) synthase (eNOS) and NO deficiency, restoring endothelial NO represents a promising approach to treating stroke injury. We have shown that near-infrared II (NIR-II) laser treatment enhances the phosphorylation of eNOS at serine 1176 (S1176) and augments NO production. Here, we further determine the beneficial effect of NIR-II laser on stroke injury. Wild-type (WT) C57BL/6J and unphosphorylatable eNOS mutant mice with S1176A mutation (S1176A) were treated by NIR-II laser (1064 nm) at an irradiance of 50 mW/cm2 (5 min daily for 4 days) prior to the middle cerebral artery occlusion (MCAO, 30 min) by a filament. The ischemic and reperfusion (30 min) values of cerebral blood flow (CBF) were confirmed by laser Doppler flowmetry. Neurological deficit and infarct volume was evaluated 48 h after reperfusion. One- and two-way ANOVAs and the Kruskal-Wallis followed by Dunn's tests were used for statistical evaluation. The NIR-II laser-pretreated WT mice demonstrated significantly increased CBF reperfusion and decreased infarct volume compared with untreated mice. The neurologic scoring showed less severe deficits in the laser-treated mice than in the non-treated mice (1.1 vs. 1.8). To determine the involvement of S1176-dependent eNOS phosphorylation in NIR-II effects, we further treated S1176A mice. MCAO followed by reperfusion resulted in decreased CBF and an increased infarct volume in S1176A mice compared to WT mice. The infarct volume was significantly larger in laser-treated S1176A compared to laser-treated WT mice. Neurological deficit in S1176A mice showed no improvement with the laser pretreatment (2.3 vs. 2.6) and was significantly more severe in the laser-treated S1176A compared to the laser-treated WT mice. In conclusion, pretreatment with a 1064 nm laser at 50 mW/cm2 improved stroke outcomes via S1176 eNOS phosphorylation. NIR-II photobiomodulation offers a non-invasive and low-risk treatment for stroke. This new modality using a physical parameter could lead to the development of innovative therapies to prevent and treat a wide array of cerebrovascular diseases.

Abstract WP327: Altered Bone Marrow Microenvironment Impacts Endothelial Precursor Cell Development and Egress in Mice With Type 2 Diabetes

Endothelial precursor cells (EPCs) are vital contributors to angiogenesis, a crucial process in tissue repair and functional recovery after ischemic stroke. However, in the context of Type 2 Diabetes Mellitus (T2DM), angiogenesis is compromised, particularly after ischemic stroke. The mechanisms underlying the impacts of T2DM on EPC dynamics in the bone marrow (BM), as well as its repercussions on functional recovery post-stroke, remain incompletely understood. We found that the EPC populations were significantly diminished in the BM of diabetic mice compared to control mice prior to stroke by immunofluorescence staining (IF). Interestingly, the number of EPC was not significantly changed in the BM of diabetic mice after stroke, in contrast to the reduction seen in the control mice, suggesting an inherent impairment of EPC production and migration in the diabetic BM milieu. Consistent with this finding, VEGF, a critical factor for EPC proliferation and migration, was found to be increased in the BM in the control mice but reduced in the diabetic mice after ischemic stroke. There was also an overall reduction of CD115 and Ly6G expression in the BM of diabetic mice, indicative of an altered microenvironment for hematopoiesis that could further affect EPC dynamics. Single-cell RNA sequencing of cells revealed the presence of hematopoietic precursor cells (HPC), monocytes, granulocytes, and macrophages among the clustered cell populations. Enrichment analysis unveiled pathways associated with mitotic DNA replication, myeloid cell differentiation, and leukocyte migration among the differentially expressed genes in HPC between diabetic and control BM. Strikingly, genes linked to the angiogenesis and endothelial cell migration were also down regulated in T2DM BM, potentially contributing to the impaired angiogenic response observed in T2DM after stroke. These findings underscore the intricate interplay among T2DM, EPC function, angiogenesis, and post-stroke recovery. The identification of disrupted pathways in the BM environment provides valuable insights into the compromised angiogenic response observed in diabetes and novel targets for therapeutic interventions in improving stroke outcomes in patients with T2DM.

Abstract WMP111: Intra-Arterial Administration of Cerebral Endothelial Cell Derived Small Extracellular Vesicles Reduces Neurovascular Damage and Improves Neurological Outcome After Acute Ischemia in the Aged Rat

Stroke is a leading cause of death and disability worldwide, mainly affecting the elderly. Endovascular thrombectomy (EVT) is a standard of care therapy for stroke patients with large-vessel occlusion, however, the majority of these patients do not achieve full functional improvement. The present study tested the hypothesis that intra-arterial (IA) administration of cerebral endothelial cell derived small extracellular vesicles (CEC-sEVs) following transient middle cerebral artery occlusion (tMCAO) improves stroke outcome in the aged rat. CEC-sEVs (1x10 11 particles/injection) isolated from healthy adult rats were employed. Male aged rats (18 months, n=10/group) subjected to 3h tMCAO were randomly divided into the experimental groups. To examine whether IA injection of CEC-sEVs improves stroke outcome, CEC-sEVs were administered via the internal carotid artery (ICA) immediately following reperfusion by withdrawal of the occlusion filament. To examine whether intravenous administration (IV) of CEC-sEVs during tMCAO and then followed by IA CEC-sEVs upon reperfusion further enhances stroke outcome, CEC-sEVs were given at 30 min of tMCAO via a tail vein and upon reperfusion via the ICA. The ischemic rats treated with IA saline were used as a control. Neurological outcome and infarct volume were assessed in a blinded manner. IA CEC-sEVs upon reperfusion significantly reduced infarct volume (24±5% vs 31±6% in saline, p<0.05) which was associated with robust improvement of neurological function from weeks 2 to 4 after tMCAO compared to saline treated rats. Moreover, rats treated with CEC-sEVs IV at 30min followed by IA treatment upon reperfusion further reduced infarct volume (16±6%) compared to rats treated with IA saline or CEC-sEVs. These rats also exhibited robust and early improvement of neurological function starting at 1d after tMCAO. In conclusion, IA administration of CEC-sEVs upon reperfusion significantly reduces ischemic damage, while an additional early (30min post stroke) dose of IV CEC-sEVs further enhances and accelerates the therapeutic effect of IA CEC-sEVs in the aged rats after tMCAO. Our data suggest that CEC-sEVs could potentially may be a therapy to amplify the efficacy of EVT even for elderly patients with acute ischemic stroke.

Abstract WP126: Improved Stroke Outcomes Following Implementation of RapidAI Platform at Ascension-Illinois

Introduction: The rapid advancement of artificial intelligence (AI) technologies holds promise for improving healthcare outcomes. RapidAI is a software solution that utilizes AI to rapidly analyze imaging data to identify vascular occlusions and salvageable tissue. Physicians receive notifications and can review source images on the Rapid mobile app (RMA). Methods: Data for this study were obtained from the Get with the Guidelines Stroke database. The study focused on adult patients (18 years or older) admitted to Alexian Brothers Medical Center in Illinois between 2019-2022 who were diagnosed with acute ischemic stroke. Primary outcomes were the number of AIS patients treated with thrombolysis (IV tPA or IV TNK) and/or mechanical thrombectomy (MT) and time to treatment. Door to MT puncture times for transfer patients were analyzed separately from direct presentation patients. Discharge Modified Rankin score (mRS) was assessed as a secondary clinical outcome. Results: This analysis included 1,732 patients, 1,193 prior to installation of the RapidAI platform and 539 after installation of Rapid CTP, CTA, ASPECTS, LVO and RMA. Median door to femoral puncture time for MT cases decreased from 2 hr 28 min to 1 hr 58 min (p=0.012) post-Rapid for non-transfer patients. Door to femoral puncture times for transfer patients were unchanged. MT procedure volume increased from 9.6% to 14.5% (p=0.007). IV tPA/TNK volume and door-to-needle (DTN) times were unchanged; 15% treated with tPA/TNK pre-Rapid and 14% post-Rapid, DTN 48 vs 47 min. There was an improvement in the distribution of discharge mRS scores in post-Rapid patients (p<0.0001). Discussion: Following implementation of the AI software platform there was a significant increase in patients treated with MT, faster door to MT times for non-transfer patients, and improved discharge mRS scores. These data support future studies expanding the use of AI technology to improve stroke outcomes.

Abstract TP247: Focused Approach to Tailor Native American Stroke Awareness Messaging in Montana

Overall, African Americans, Hispanics, and Native Americans have higher stroke risks, stroke occurrence at an earlier age, and for some people of color possibly more severe strokes than non-Hispanic whites. Native Americans make up approximately 6.5% of the population of Montana—equating to around 78,000 people. A focused objective of the Mission: Lifeline Stroke Montana initiative was to specifically engage with Native Americans through public awareness campaigns to improve stroke outcomes in Montana. Method: In 2021 a survey was deployed to Native Americans in Montana to evaluate knowledge, awareness, and understanding of stroke risk factors, signs and symptoms, and what to do in the event of a stroke. Surveys were collected from eight tribal nations. The results of this survey guided message development to create a tailored public awareness campaign. Results: Analysis of the 398 surveys collected showed a representative sampling of respondents by age, gender, education, and geographic area. The key findings were:· Less than 38% of respondents reported having ever talked with a healthcare provider about their risk of stroke, with men being less likely than women to have discussed their stroke risk.· Nearly 94% of respondents said they knew high blood pressure was a risk factor for stroke but have not discussed their personal risk with a healthcare provider.· When asked what action they would take in the event of a possible stroke, over 75% of respondents said they would call 911. Less than half of the respondents indicated the best mode of transportation, in the event of a possible stroke, was an ambulance. Conclusion: Based on survey findings, specific engagement strategies were centered around two main messages:-Know the risk factors for stroke and talk with a healthcare provider about your risk. -Stroke is a medical emergency that requires immediate attention. Call 9-1-1 at the first sign of stroke to access treatment through Montana’s Stroke System of Care. A post-campaign survey will be deployed in the fall of 2023. This survey will aim to assess the effectiveness of these tailored campaign initiatives.

Abstract TMP37: Improved Outcomes for Acute Ischemic Stroke Patients After Implementation of the RapidAI Platform in a Comprehensive Stroke Center in Santiago, Chile

Introduction: In Latin America (LATAM), the prevalence of stroke is alarmingly high. The advancement of artificial intelligence (AI) technologies has potential to dramatically improve healthcare outcomes. RapidAI is a software solution that utilizes AI to quickly analyze imaging data to identify vascular occlusions and salvageable tissue. Physicians receive notifications and can review source images on the Rapid mobile app (RMA). Methods: This was a retrospective analysis of 1,672 consecutive acute stroke patients (AIS) treated at Clinica Alemana de Santiago between 2014-2023. Primary outcomes were the number of AIS patients treated with thrombolysis (IV tPA), mechanical thrombectomy (MT), or decompressive craniectomies as well as time to treatment. Secondary outcomes included discharge Modified Rankin score (mRS) and hospital length of stay (LOS). Results: This analysis included 824 patients pre-RapidAI installation and 848 after installation of Rapid CTP with hypodensity, CTA, ASPECTS, LVO and RMA communication. The baseline NIHSS and last know well to hospital arrival was balanced between the 2 study cohorts. Median time to IV tPA improved by 42 minutes (80 to 38 minutes, p < 0.0001). IV tPA utilization increased from 23% to 30% post-Rapid (p = 0.0033). MT procedure utilization increased from 5% pre-Rapid to 10% (p < 0.0001). Decompressive craniectomies were reduced from 13 to 4, LOS was unchanged. There was a favorable shift in the distribution of mRS scores at discharge in post-Rapid patients (p = 0.031) and a significant increase in mRS 0-1 outcomes (61% vs 45%). Discussion: Following implementation of the AI software platform in a comprehensive stroke center like Clinica Alemana, there was a significant increase in patients treated with IV tPA, faster door to tPA and/or MT times, a decrease in the number of DCTs, and improved discharge mRS scores. This work supports future studies expanding the use of AI technology for improving stroke outcomes in LATAM.

Improving stroke outcomes in hyperglycemic mice by modulating tPA/NMDAR signaling to reduce inflammation and hemorrhages

AbstractThe pharmacological intervention for ischemic stroke hinges on intravenous administration of the recombinant tissue-type plasminogen activator (rtPA, Alteplase/Actilyse) either as a standalone treatment or in conjunction with thrombectomy. However, despite its clinical significance, broader use of rtPA is constrained because of the risk of hemorrhagic transformations (HTs). Furthermore, the presence of diabetes or chronic hyperglycemia is associated with an elevated risk of HT subsequent to thrombolysis. This detrimental impact of tPA on the neurovascular unit in patients with hyperglycemia has been ascribed to its capacity to induce endothelial N-methyl-D-aspartate receptor (NMDAR) signaling, contributing to compromised blood-brain barrier integrity and neuroinflammatory processes. In a mouse model of thromboembolic stroke with chronic hyperglycemia, we assessed the effectiveness of rtPA and N-acetylcysteine (NAC) as thrombolytic agents. We also tested the effect of blocking tPA/NMDAR signaling using a monoclonal antibody, Glunomab. Magnetic resonance imaging, speckle contrast imaging, flow cytometry, and behavioral tasks were used to evaluate stroke outcomes. In hyperglycemic animals, treatment with rtPA resulted in lower recanalization rates and increased HTs. Conversely, NAC treatment reduced lesion sizes while mitigating HTs. After a single administration, either in standalone or combined with rtPA-induced thrombolysis, Glunomab reduced brain lesion volumes, HTs, and neuroinflammation after stroke, translating into improved neurological outcomes. Additionally, we demonstrated the therapeutic efficacy of Glunomab in combination with NAC or as a standalone strategy in chronic hyperglycemic animals. Counteracting tPA-dependent endothelial NMDAR signaling limits ischemic damages induced by both endogenous and exogenous tPA, including HTs and inflammatory processes after ischemic stroke in hyperglycemic animals.

Neuroprotection during Thrombectomy for Acute Ischemic Stroke: A Review of Future Therapies.

Stroke is a major cause of death and disability worldwide. Endovascular thrombectomy has been impactful in decreasing mortality. However, many clinical results continue to show suboptimal functional outcomes despite high recanalization rates. This gap in recanalization and symptomatic improvement suggests a need for adjunctive therapies in post-thrombectomy care. With greater insight into ischemia-reperfusion injury, recent preclinical testing of neuroprotective agents has shifted towards preventing oxidative stress through upregulation of antioxidants and downstream effectors, with positive results. Advances in multiple neuroprotective therapies, including uric acid, activated protein C, nerinetide, otaplimastat, imatinib, verapamil, butylphthalide, edaravone, nelonemdaz, ApTOLL, regional hypothermia, remote ischemic conditioning, normobaric oxygen, and especially nuclear factor erythroid 2-related factor 2, have promising evidence for improving stroke care. Sedation and blood pressure management in endovascular thrombectomy also play crucial roles in improved stroke outcomes. A hand-in-hand approach with both endovascular therapy and neuroprotection may be the key to targeting disability due to stroke.

A retrospective analysis of the social determinants of health affecting stroke outcomes in a small hospital situated in a health professional shortage area (HPSA).

Where someone lives is a major determinant of population health. In the United States, people who live in Health Professional Shortage Areas are considered medically underserved and have a higher propensity for conditions such as stroke, hypertension, and diabetes. Our goal was to better understand the diverse needs of patients presenting to the Crouse Hospital emergency department with stroke symptoms. Crouse Hospital is a small community hospital located in a shortage area serving both urban and rural populations in and around Syracuse, New York. Despite its small size, Crouse Hospital quickly became a major comprehensive stroke center in Central New York. With this study we assessed the social factors affecting the stroke patient population in the community and compared these characteristics between those living in served and underserved areas. Informed by the social determinants of health framework, we analyzed 1731 incidents of stroke that occurred between January 2019 and January 2021, and observed that the circumstances associated with stroke varied by service category and race, with White patients and those from served areas having better stroke outcomes compared to those residing in underserved areas and those that were not White. Our analyses help us to understand the underlying factors influencing the observed disparities and allow us to move forward by implementing informed community-based interventions to decrease stroke incidence and improve post-stroke care. Using our example other small hospitals can enact similar strategies to address the social determinants affecting their patients to improve stroke outcomes in their region.

Therapeutic Potentials of Near-Infrared II Photobiomodulation to Treat Cerebrovascular Diseases via Nitric Oxide Signalling.

Endothelial dysfunction featuring insufficient endothelial nitric oxide synthase (eNOS) and accompanying nitric oxide (NO) deficiency is implicated in the pathogenesis of cardiovascular diseases. Restoring endothelial NO represents a promising approach to treating cerebrovascular diseases, including stroke. Low-power near-infrared (NIR) light shows diverse beneficial effects, broadly defined as photobiomodulation (PBM). The literature reports that PBM increases bioavailable NO. These lines of evidence indicate that PBM could be used to treat cerebrovascular diseases. Recent investigations revealed that PBM improved stroke outcomes in animal models via augmenting NO signalling and other pathways. However, clinical trials of PBM using NIR light in the NIR-I window (630-900nm) have yet to demonstrate the beneficial effect of PBM on ischaemic stroke. Since NIR light in the NIR-II window (1000-1700nm) with the largest penetration depth into tissues compared to NIR I has also been reported to augment NO bioavailability and cerebral blood flow ameliorating stroke injury, PBM using NIR-II light may be suitable for therapeutic use. This new non-pharmacological modality using a physical parameter of NIR-II laser could provide a new avenue for therapeutic strategies for cerebrovascular diseases. Since impaired NO production has been associated with neurological abnormalities, this novel therapeutic approach could be broadly explored to treat various disease conditions such as traumatic brain injury, stroke, and Alzheimer's disease. This review summarises recent findings on PBM in treating stroke and discusses its potential to treat other neurological diseases.

Gut microbiota-derived acetate promotes long-term recovery through angiogenesis guided by lymphatic ingrowth in older adults with stroke.

Ischemic stroke is a leading cause of morbidity and mortality in older adults. Therefore, in this study, we sought to understand the interplay between the microbiota, gut, and brain in the context of stroke in older adults. To determine whether gut microbiota from younger individuals promotes recovery through angiogenesis in both elderly stroke patients and aged stroke mice, we explored the changes in gut microbiota and the correlation between short-chain fatty acids (SCFAs) and angiogenesis in the aged stroke population. Then, we altered the gut microbiome in aged mice by transplanting microbiota from younger donors before inducing experimental stroke to explore the mechanism by which gut microbiota-derived SCFAs promote angiogenesis. Part I: We conducted a single-center, double-blind trial to compare gut microbiota diversity and SCFA levels in fecal samples from older stroke patients with those from younger stroke patients. Additionally, we measured levels of vascular endothelial growth factor (VEGF) and VEGFC levels in plasma to assess their correlation with SCFA levels. Part II: We performed fecal microbiota transplantation (FMT) 3 days before inducing ischemic stroke in aged male mice (16-18) via distal middle cerebral artery occlusion (dMCAO). The FMT was conducted using gut microbiomes from either young donors (2-3 months) or aged donors (16-18 months). In older stroke patients, gut microbiota diversity was significantly reduced compared to that in younger stroke patients. Furthermore, levels of acetate, a bacterially derived SCFA, were lower and positively correlated with angiogenesis markers (VEGF and VEGF-C). In aged stroke mice, transplantation of young microbiota improved stroke outcomes by promoting angiogenesis, which was facilitated by lymphatic ingrowth into the cortex. This protective effect was linked to gut microbiota-derived acetate, which enhanced lymphangiogenesis by replenishing acetyl coenzyme A. (a) Gut microbiota-derived acetate promotes angiogenesis post-stroke and (b) lymphatic ingrowth into the cerebral cortex was observed in post-dMCAO mice. These findings suggest that selectively promoting SCFA-producing bacteria, particularly acetate-producers, could be a promising therapeutic strategy to reduce functional impairments in older stroke subjects.

Berberine Mediates the Production of Butyrate to Ameliorate Cerebral Ischemia via the Gut Microbiota in Mice.

Ischemic stroke (IS) is a vascular disease group concomitant with high morbidity and mortality. Berberine is a bioactive substance and it has been known to improve stroke, but its mechanism is yet to be proven. Mice were fed with BBR for 14 days. Then, the mice were made into MCAO/R models. Neurological score, infarct volume, neuronal damage and markers associated with inflammation were detected. We tested the changes in intestinal flora in model mice after BBR administration using 16SrRNA sequencing. Chromatography-mass spectrometry was used to detect butyrate chemically. Tissue immunofluorescence was used to detect the changes in the microglia and astroglia in the mice brains. Our findings suggest that berberine improves stroke outcomes by modulating the gut microbiota. Specifically, after MCAO/R mice were given berberine, the beneficial bacteria producing butyric acid increased significantly, and the mice also had significantly higher levels of butyric acid. The administration of butyric acid and an inhibitor of butyric acid synthesis, heptanoyl-CoA, showed that butyric acid improved the stroke outcomes in the model mice. In addition, butyric acid could inhibit the activation of the microglia and astrocytes in the brains of model mice, thereby inhibiting the generation of pro-inflammatory factors IL-6, IL-1β and TNF-α as well as improving stroke outcomes. Our results suggest that berberine may improve stroke outcomes by modulating the gut flora to increase the abundance of butyric acid. These findings elucidate the mechanisms by which berberine improves stroke outcomes and provide some basis for clinical treatment.

Clinical presentation, risk factors, and outcomes of stroke in Shabwah Governorate, Yemen

Background: There is a lack of reliable information on stroke risk factors, clinical presentation, and mortality. The aim of this study was to describe stroke risk factors, clinical presentations, and in-hospital mortality and to identify the independent predictors of mortality among stroke patients admitted to three hospitals in Shabwa Governorate, Yemen. Methods: This retrospective and cross-sectional study was conducted from July 1, 2022, to June 30, 2023, in three hospitals in Shabwah Governorate, namely, Shabwah General Hospital Authority, Al Shifa Specialized Hospital, and Afya Specialized Hospital. Results: We involved 124 stroke cases, of whom 92 (74.2%) were males and 32 (25.8%) were females. Their mean age was 64.98±16.22 years, and hypertension was the most common risk factor, accounting for 71.0% (n=88) of cases. Ischemic stroke was detected in 95 (76.6%) cases, intracerebral hemorrhage (ICH) was detected in 25 (20.2%) patients, and subarachnoid hemorrhage (SAH) was detected in 4 (3.2%) cases. The in-hospital mortality was 27(21.8%), and according to bivariate analysis, the in-hospital mortality was significantly associated with hypertension (p=0.015), diabetes mellitus (DM) (p<0.0001), ischemic heart disease (p=0.002), rheumatic heart disease (p<0, 0001), and cardiomyopathy (p=0.004). In addition, in-hospital mortality was significantly associated with coma (p<0.0001), ischemic stroke (p<0.0001), ICH (p=0.013), and SAH (p=0.032). However, in multivariate logistic regression analysis, only coma (adjusted odds ratio [OR]=11.21, 95% confidence interval [CI]=3.42–36.75, p<0.0001) and DM (adjusted OR=5.8, 95% CI=1.79–18.85, p=0.003) were found to be independent risk factors for in-hospital mortality. Conclusion: In Shabwah Governorate, Yemen, ischemic strokes were more common than hemorrhagic strokes, with men more likely to have a stroke than women and the majority of cases being elderly. DM and coma were found to be independent risk factors for in-hospital mortality. Therefore, appropriate treatment of DM and other vascular risk factors is recommended to improve stroke outcomes.

Effect of pre-stroke antiplatelet use on stroke outcomes in acute small vessel occlusion stroke with moderate to severe white matter burden

BackgroundCerebral small vessel disease is characterized by white matter hyperintensities (WMH) and acute small vessel occlusion (SVO) stroke. We investigated the effect of prior antiplatelet use (APU) on stroke outcome in 1151 patients with acute SVO stroke patients and moderate to severe WMH. MethodsUsing a multicenter database, this retrospective study used quantitative WMH volume measurements and propensity score matching (PSM) for comparisons between patients with prior APU and without APU. Primary outcomes were stroke progression and poor functional outcome (modified Rankin Scale>2) at 3 months. Logistic regression analyses assessed associations between prior APU, WMH burden, and stroke outcomes. ResultsStroke progression was lower in the prior APU group in both the total cohort (14.8% vs. 6.9%, p < 0.001) and the PSM cohort (16.3% vs. 6.9%, p < 0.001). The proportion of poor functional outcomes at 3 months was not significantly different in the total cohort, but the PSM cohort showed a lower proportion in the prior APU group (30.8% vs. 20.2%, p = 0.002). Logistic regression analysis confirmed that prior APU was associated with a reduced risk of stroke progression (OR, 0.39; 95% CI, 0.22–0.70; p = 0.001) and poor functional outcome at 3 months (OR, 0.37; 95% CI, 0.23–0.59; p < 0.001). ConclusionPrior APU is associated with reduced stroke progression and improved functional outcome at 3 months in acute SVO stroke patients with moderate to severe WMH. Early treatment of WMH and acute SVO stroke may have potential benefits in improving stroke outcomes.

Sleep disorders as both risk factors for, and a consequence of, stroke: A narrative review.

Sleep disorders are increasingly implicated as risk factors for stroke, as well as a determinant of stroke outcome. They can also occur secondary to the stroke itself. In this review, we describe the variety of different sleep disorders associated with stroke and analyze their effect on stroke risk and outcome. A search term-based literature review ("sleep," "insomnia," "narcolepsy," "restless legs syndrome," "periodic limb movements during sleep," "excessive daytime sleepiness" AND "stroke" OR "cerebrovascular" in PubMed; "stroke" and "sleep" in ClinicalTrials.gov) was performed. English articles from 1990 to March 2023 were considered. Increasing evidence suggests that sleep disorders are risk factors for stroke. In addition, sleep disturbance has been reported in half of all stroke sufferers; specifically, an increase is not only sleep-related breathing disorders but also periodic limb movements during sleep, narcolepsy, rapid eye movement (REM) sleep behavior disorder, insomnia, sleep duration, and circadian rhythm sleep-wake disorders. Poststroke sleep disturbance has been associated with worse outcome. Sleep disorders are risk factors for stroke and associated with worse stroke outcome. They are also a common consequence of stroke. Recent guidelines suggest screening for sleep disorders after stroke. It is possible that treatment of sleep disorders could both reduce stroke risk and improve stroke outcome, although further data from clinical trials are required.

Obesity-induced Ly6CHigh and Ly6CLow monocyte subset changes abolish post-ischemic limb conditioning benefits in stroke recovery

Remote limb conditioning (RLC), performed by intermittent interruption of blood flow to a limb, triggers endogenous tolerance mechanisms and improves stroke outcomes. The underlying mechanism for the protective effect involves a shift of circulating monocytes to a Ly6CHigh proinflammatory subset in normal metabolic conditions. The current study investigates the effect of RLC on stroke outcomes in subjects with obesity, a vascular comorbidity. Compared to lean mice, obese stroke mice displayed significantly higher circulating monocytes (monocytosis), increased CD45High monocytes/macrophages infiltration to the injured brain, worse acute outcomes, and delayed recovery. Unlike lean mice, obese mice with RLC at 2 hours post-stroke failed to shift circulating monocytes to pro-inflammatory status and nullified RLC-induced functional benefit. The absence of the monocyte shift was also observed in splenocytes incubated with RLC serum from obese mice, while the shift was observed in the cultures with RLC serum from lean mice. These results showed that the alteration of monocytosis and subsets underlies negating RLC benefits in obese mice and suggest careful considerations of comorbidities at the time of RLC application for stroke therapy.

Localization of early infarction on non-contrast CT images in acute ischemic stroke with deep learning approach

Localization of early infarction on first-line Non-contrast computed tomogram (NCCT) guides prompt treatment to improve stroke outcome. Our previous study has shown a good performance in the identification of ischemic injury on NCCT. In the present study, we developed a deep learning (DL) localization model to help localize the early infarction sign on NCCT. This retrospective study included consecutive 517 ischemic stroke (IS) patients who received NCCT within 12 h after stroke onset. A total of 21,436 infarction patches and 20,391 non-infarction patches were extracted from the slice pool of 1,634 NCCT according to brain symmetricity property. The generated patches were fed into different pretrained convolutional neural network (CNN) models such as Visual Geometry Group 16 (VGG16), GoogleNet, Residual Networks 50 (ResNet50), Inception-ResNet-v2 (IR-v2), Inception-v3 and Inception-v4. The selected VGG16 model could detect the early infarction in both supratentorial and infratentorial regions to achieve an average area under curve (AUC) 0.73 after extensive customization. The properly tuned-VGG16 model could identify the early infarction in the cortical, subcortical and cortical plus subcortical areas of supratentorial region with the mean AUC > 0.70. Further, the model could attain 95.6% of accuracy on recognizing infarction lesion in 494 out of 517 IS patients.