Exploring the potential molecular intersection of stroke and major depression disorder.

Stroke and major depression disorder are common neurological diseases, and a large number of clinical studies have shown that there is a close relationship between the two diseases, but whether the two diseases are linked at the genetic level needs to be further explored. The purpose of this study was to explore the comorbidity mechanism of stroke and major depression by using bioinformatics technology and animal experiments. From the GEO database, we gathered transcriptome data of stroke and depression mice (GSE104036, GSE131712, GSE81672, and GSE146845) and identified comorbid gene set through edgR and WGCNA analyses. Further analysis revealed that these genes were enriched in pathways associated with cell death. Programmed cell death gene sets (PCDGs) are generated from genes related to apoptosis, necroptosis, pyroptosis and autophagy. The intersection of PCDGs and comorbid gene set resulted in two hub genes, Mlkl and Nlrp3. Single-cell sequencing analysis indicated that Mlkl and Nlrp3 are mainly influential on endothelial cells and microglia, suggesting that the impairment of these two cell types may be a factor in the relationship between stroke and major depression. This was experimentally confirmed by RT-PCR and immunofluorescence staining. Our research revealed that two specific genes, namely, Mlkl and Nlrp3, play crucial roles in the complex mechanism that links stroke and major depression. Additionally, we have predicted six possible therapeutic agents and the outcomes of docking simulations of target proteins and drug molecules.

The impact of stress hyperglycemia ratio on short-term and long-term outcomes for acute basilar artery occlusion underwent endovascular treatment.

BACKGROUND: Stress hyperglycemia ratio (SHR) reflects a true acute hyperglycemic state during acute basilar artery occlusion (ABAO). We aimed to investigate the association between SHR and short-term and long-term outcomes in patients with ABAO receiving endovascular treatment (EVT). METHODS: We selected patients treated with EVT from the BASILAR study, a nationwide prospective registry. A total 250 patients with documented glucose and glycated hemoglobin (HbA1C) values at admission were included. SHR was calculated as the ratio of glucose/HbA1C. All 250 patients completed 90 days of follow-up and 234 patients (93.6%) completed 1 year of follow-up. The primary outcome was the favorable outcome defined as modified Rankin Scale (mRS) score ≤ 3 at 90 days. Safety outcomes included mortality at 90 days and 1 year, and intracranial hemorrhage. RESULTS: Among the 250 patients included, patients with higher tertiles of SHR were associated with decreased odds of a favorable functional outcome at 90 days (adjusted OR, 0.26; 95% CI, 0.12-0.56; P = 0.001 and adjusted OR, 0.37; 95% CI, 0.18-0.80; P = 0.01; respectively) and 1 year (adjusted OR, 0.34; 95% CI, 0.16-0.73; P = 0.006 and adjusted OR, 0.38; 95% CI, 0.18-0.82; P = 0.01; respectively) after adjusting for confounding covariates. The mortality was comparable across tertiles of SHR groups at 90 days and 1 year. CONCLUSIONS: Our study showed that SHR was associated with a decreased probability of favorable functional outcome both at 90 days and 1 year after EVT in patients with ABAO. The relationship was more pronounced in non-diabetes patients. TRIAL REGISTRATION: Clinical Trial Registry Identifier: ChiCTR1800014759 (November 12, 2013).

Leukoaraiosis in patients with tirofiban before endovascular thrombectomy: A post hoc analysis of a multicentre randomized clinical trial.

BACKGROUND AND PURPOSE: To evaluate the effectiveness and safety of intravenous tirofiban before endovascular thrombectomy in subgroups of acute ischemic stroke patients with different degrees of leukoaraiosis (LA). METHODS: Patients of the RESCUE BT trial whose LA grade could be assessed were included. Eligible patients were dichotomized into two strata according to the van Swieten scale (VSS) score, absent-to-moderate LA (VSS score <3) and severe LA (VSS score ≥3). Furthermore, patients were divided into tirofiban and placebo groups in each stratum. The primary outcome was the 90-day modified Rankin Scale (mRS) score. Safety outcome was radiological intracranial hemorrhage within 48 h. RESULTS: 861 patients were included, 439 patients with absent-to-moderate LA and 422 patients with severe LA. There were no significant differences in 90-day mRS score between the tirofiban and placebo groups in either stratum (absent-to-moderate LA: adjusted OR 0.92 (95%CI, 0.66-1.28), P = 0.62; severe LA: adjusted OR 0.99 (95% CI, 0.69-1.42), P = 0.96). In the severe LA stratum, the occurrence of radiologic intracranial hemorrhage was greater in the tirofiban group compared to the placebo group. (35.7% vs 26.4%; adjusted OR, 1.72 (95% CI, 1.12-2.66); P = 0.014). However, no difference was observed in the absent-to-moderate LA stratum (33.2% vs 29.3%; adjusted OR, 1.15 (95% CI, 0.76-1.75); P = 0.51). CONCLUSION: There was no significant difference in disability severity at 90 days when treating AIS patients using intravenous tirofiban before endovascular therapy, in either absent-to-moderate or severe LA strata. It should be noted that intravenous tirofiban before endovascular therapy increases the incidence of radiologic intracranial hemorrhage in patients with severe LA.

Methylprednisolone as Adjunct to Endovascular Thrombectomy for Large-Vessel Occlusion Stroke: The MARVEL Randomized Clinical Trial.

Importance: It is uncertain whether intravenous methylprednisolone improves outcomes for patients with acute ischemic stroke due to large-vessel occlusion (LVO) undergoing endovascular thrombectomy. Objective: To assess the efficacy and adverse events of adjunctive intravenous low-dose methylprednisolone to endovascular thrombectomy for acute ischemic stroke secondary to LVO. Design, Setting, and Participants: This investigator-initiated, randomized, double-blind, placebo-controlled trial was implemented at 82 hospitals in China, enrolling 1680 patients with stroke and proximal intracranial LVO presenting within 24 hours of time last known to be well. Recruitment took place between February 9, 2022, and June 30, 2023, with a final follow-up on September 30, 2023. Interventions: Eligible patients were randomly assigned to intravenous methylprednisolone (n = 839) at 2 mg/kg/d or placebo (n = 841) for 3 days adjunctive to endovascular thrombectomy. Main Outcomes and Measures: The primary efficacy outcome was disability level at 90 days as measured by the overall distribution of the modified Rankin Scale scores (range, 0 [no symptoms] to 6 [death]). The primary safety outcomes included mortality at 90 days and the incidence of symptomatic intracranial hemorrhage within 48 hours. Results: Among 1680 patients randomized (median age, 69 years; 727 female [43.3%]), 1673 (99.6%) completed the trial. The median 90-day modified Rankin Scale score was 3 (IQR, 1-5) in the methylprednisolone group vs 3 (IQR, 1-6) in the placebo group (adjusted generalized odds ratio for a lower level of disability, 1.10 [95% CI, 0.96-1.25]; P = .17). In the methylprednisolone group, there was a lower mortality rate (23.2% vs 28.5%; adjusted risk ratio, 0.84 [95% CI, 0.71-0.98]; P = .03) and a lower rate of symptomatic intracranial hemorrhage (8.6% vs 11.7%; adjusted risk ratio, 0.74 [95% CI, 0.55-0.99]; P = .04) compared with placebo. Conclusions and Relevance: Among patients with acute ischemic stroke due to LVO undergoing endovascular thrombectomy, adjunctive methylprednisolone added to endovascular thrombectomy did not significantly improve the degree of overall disability. Trial Registration: ChiCTR.org.cn Identifier: ChiCTR2100051729.

Efficacy and safety of tirofiban combined with endovascular therapy for basilar artery occlusion stroke due to large artery atherosclerosis.

BACKGROUND: This study aimed to evaluate the efficacy and safety of adjuvant tirofiban in patients with acute basilar artery occlusion due to large-artery atherosclerotic (LAA) receiving endovascular therapy (EVT). METHODS: This was a non-randomized, multicenter study using data from the Endovascular Treatment for Acute BASILAR Artery Occlusion (BASILAR) registry. Patients with acute basilar artery occlusion due to LAA within 24h of symptom onset who underwent EVT were included. Patients were divided into tirofiban and non-tirofiban groups according to whether tirofiban was used. The primary outcome was the ordinal modified Rankin scale score at 90 days. Safety outcomes were mortality within 90 days and symptomatic intracranial hemorrhage (sICH) within 48 h. RESULTS: A total of 417 patients were included, of whom 275 patients were in the tirofiban group and 142 patients in the non-tirofiban group. Compared with patients in the non-tirofiban group, patients in the tirofiban group were associated with a favorable shift in functional outcome at 90 days (6[4-6] vs 5 [2-6]; adjusted common OR, 2.51; 95 % CI, 1.64-3.83). The mortality was lower in the tirofiban group than the non-tirofiban group (40.7 % vs 58.5 %; adjusted OR, 0.35; 95 % CI, 0.21-0.56). The rate of sICH was 12.2 % in the non-tirofiban group and 5.2 % in the tirofiban group (adjusted OR, 0.37; 95 % CI, 0.17-0.80; P = 0.012). CONCLUSION: Tirofiban plus EVT might improve functional outcomes with a good safety for patients with acute basilar artery occlusion due to LAA. The results need to be confirmed in a randomized trial.

Short-Term Effect of Ambient Temperature in Acute Ischemic Stroke with Endovascular Treatment Due to Large Vessel Occlusion.

Purpose: Acute ischemic stroke (AIS) stands as the primary cause of mortality and extended disability globally. While prior studies have examined the connection between stroke and local weather, they have produced conflicting results. Our goal was to examine the correlation between temperature and functional prognosis in patients with large vessel occlusion (LVO) undergoing endovascular therapy (EVT). Patients and methods: This study included a total of 1809 patients. Temperatures from stroke onset to groin puncture were categorized into Cold (10th percentile of temperature), Cool (10th-50th percentile of temperature), Warm (50th-90th percentile of temperature), and Hot (90th percentile of temperature) groups. The primary efficacy result was the modified Rankin Scale (mRS) score at 90 days. Safety outcomes included mortality, symptomatic intracranial hemorrhage (sICH) and complications after cerebral infarction. Results: The primary efficacy results demonstrated a statistical enhancement in functional outcomes at 90 days for patients in the Warm group compared to the Cold group (adjusted common odds ratio [OR]: 1.386; 95% confidence interval [CI]: 1.024-1.878, P=0.035). Secondary efficacy results showed that temperature was associated with a higher rate of 90-day functional independence (adjusted OR: 1.016; 95% CI: 1.004-1.029; P=0.009), which was higher in the Warm group compared with patients in the Cold group (adjusted OR: 1.646; 95% CI: 1.107-2.448, P=0.014). There were no significant differences between groups in terms of sICH, 90-day mortality, and post-infarction complications. Conclusion: Compared with Cold temperature, Warm temperature is associated with better functional outcomes and reduced mortality risk without increasing the risk of sICH.

The effectiveness and safety of human urinary kallidinogenase in acute ischemic stroke patients undergoing endovascular therapy.

The effectiveness and safety of human urinary kallidinogenase (HUK) in acute ischemic stroke (AIS) patients undergoing endovascular therapy (EVT) due to large vessel occlusion (LVO) was unclear. A pooled analysis was performed using individual data from the DEVT and RESCUE BT trials. Patients were divided into two groups based on HUK treatment. The primary outcome was the 90-day modified Rankin Scale (mRS) score. Safety outcomes included 90-day mortality and symptomatic intracranial hemorrhage (sICH) within 48 hours. A total of 1174 patients were included in the study. Of these, 150 (12.8%) patients received HUK. The adjusted common odds ratio (OR) of the mRS score was 1.458 (95% confidence interval [CI] = 1.072-1.983; p = 0.016) favoring HUK. The incidence of sICH (2.0% vs. 8.6%; adjusted OR: 0.198; 95% CI: 0.061-0.638; p = 0.007) and mortality (11.3% vs.18.5%; adjusted OR: 0.496; 95% CI: 0.286-0.862; p = 0.013) was lower in HUK group than non-HUK group. This association was consistent with propensity score-matching and the inverse probability of treatment weighting analysis. In conclusion, HUK was safe and associated with a preferable prognosis in AIS patients due to LVO in the anterior circulation.

Investigation of the Binding Interaction of Mfsd2a with NEDD4-2 via Molecular Dynamics Simulations.

Major facilitator superfamily domain-containing 2a (Mfsd2a) is a sodium-dependent lysophosphatidylcholine cotransporter that plays an important role in maintaining the integrity of the blood-brain barrier and neurological function. Abnormal degradation of Mfsd2a often leads to dysfunction of the blood-brain barrier, while upregulation of Mfsd2a can retrieve neurological damage. It has been reported that Mfsd2a can be specifically recognized and ubiquitinated by neural precursor cell-expressed developmentally downregulated gene 4 type 2 (NEDD4-2) ubiquitin ligase and finally degraded through the proteasome pathway. However, the structural basis for the specific binding of Mfsd2a to NEDD4-2 is unclear. In this work, we combined deep learning and molecular dynamics simulations to obtain a Mfsd2a structure with high quality and a stable Mfsd2a/NEDD4-2-WW3 interaction model. Moreover, molecular mechanics generalized Born surface area (MM-GBSA) methods coupled with per-residue energy decomposition studies were carried out to analyze the key residues that dominate the binding interaction. Based on these results, we designed three peptides containing the key residues by truncating the Mfsd2a sequences. One of them was found to significantly inhibit Mfsd2a ubiquitination, which was further validated in an oxygen-glucose deprivation (OGD) model in a human microvascular endothelial cell line. This work provides some new insights into the understanding of Mfsd2a and NEDD4-2 interaction and might promote further development of drugs targeting Mfsd2a ubiquitination.

Association of functional outcomes between intravenous tirofiban and endovascular thrombectomy in imaging-screened patients with large vessel occlusion stroke: a secondary analysis of randomized clinical trial.

BACKGROUND: In the RESCUE BT (Endovascular Treatment With versus Without Tirofiban for Stroke Patients with Large Vessel Occlusion) trial, enrollment in extended time window was based on non-contrast computed tomography. To assess whether perioperative intravenous tirofiban would further enhance the clinical benefit of endovascular therapy in the RESCUE BT trial according to advanced imaging criteria based on current American Heart Association/American Stroke Association (AHA/ASA) guidelines. METHODS: This is a secondary analysis of the RESCUE BT trial. Patients who were eligible for endovascular thrombectomy in the 6-hour window and met the criteria of the DAWN or DEFUSE 3 trials in the extended window according to the AHA/ASA guidelines were analyzed. The primary outcome was the distribution of the 90-day modified Rankin Scale (mRS) scores. Safety outcomes included the incidence of symptomatic intracranial hemorrhage (sICH) within 48 hours and 90-day mortality. RESULTS: A total of 652 patients (319 in tirofiban group and 333 in placebo group) who meeting the AHA/ASA guidelines were included in this analysis, with median (IQR) age of 68 (58-75) years, 278 (42.6%) were women. The median 90-day mRS score was 3 (IQR, 1-4) in the tirofiban group, and 3 (IQR, 1-4) in the placebo group. The adjusted common odds ratio (OR) for a lower level of disability with tirofiban than with placebo was 1.08 (95% confidence interval [CI], 0.83-1.42). The incidence of sICH (10.1% versus 6.3%; adjusted OR 1.70; [95% CI, 0.95-3.04]) was not significantly different between groups. However, intravenous tirofiban might be associated with lower disability level (adjusted common OR, 1.74 [95% CI, 1.14-2.65]; P=0.01) in patients with large artery atherosclerosis. CONCLUSIONS: There was no significant difference in the severity of disability at 90 days with intravenous tirofiban compared to placebo in patients who underwent endovascular therapy according to AHA/ASA guidelines. We observed potential benefits of tirofiban in patients with large artery atherosclerosis, but there was an increased risk of sICH in patients with cardioembolism stroke.

Choline consumption reduces CVD risk via body composition modification.

Despite extensive research on the relationship between choline and cardiovascular disease (CVD), conflicting findings have been reported. We aim to investigate the relationship between choline and CVD. Our analysis screened a retrospective cohort study of 14,663 participants from the National Health and Nutrition Examination Survey conducted between 2013 and 2018. Propensity score matching and restricted cubic splines was used to access the association between choline intake and the risk of CVD. A two-sample Mendelian randomization (MR) analysis was conducted to examine the potential causality. Additionally, sets of single cell RNA-sequencing data were extracted and analyzed, in order to explore the role of choline metabolism pathway in the progression and severity of the CVD and the underlying potential mechanisms involved. The adjusted odds ratios and 95% confidence intervals for stroke were 0.72 (0.53-0.98; p = 0.035) for quartile 3 and 0.54 (0.39-0.75; p < 0.001) for quartile 4. A stratified analysis revealed that the relationship between choline intake and stroke varied among different body mass index and waist circumference groups. The results of MR analysis showed that choline and phosphatidylcholine had a predominantly negative causal effect on fat percentage, fat mass, and fat-free mass, while glycine had opposite effects. Results from bioinformatics analysis revealed that alterations in the choline metabolism pathway following stroke may be associated with the prognosis. Our study indicated that the consumption of an appropriate quantity of choline in the diet may help to protect against CVD and the effect may be choline-mediated, resulting in a healthier body composition. Furthermore, the regulation of the choline metabolism pathway following stroke may be a promising therapeutic target.

Dock5 Deficiency Promotes Proteinuric Kidney Diseases via Modulating Podocyte Lipid Metabolism.

Podocytes are particularly sensitive to lipid accumulation, which has recently emerged as a crucial pathological process in the progression of proteinuric kidney diseases like diabetic kidney disease and focal segmental glomerulosclerosis. However, the underlying mechanism remains unclear. Here, podocytes predominantly expressed protein dedicator of cytokinesis 5 (Dock5) is screened to be critically related to podocyte lipid lipotoxicity. Its expression is reduced in both proteinuric kidney disease patients and mouse models. Podocyte-specific deficiency of Dock5 exacerbated podocyte injury and glomeruli pathology in proteinuric kidney disease, which is mainly through modulating fatty acid uptake by the liver X receptor α  (LXRα)/scavenger receptor class B (CD36) signaling pathway. Specifically, Dock5 deficiency enhanced CD36-mediated fatty acid uptake of podocytes via upregulating LXRα in an m6 A-dependent way. Moreover, the rescue of Dock5 expression ameliorated podocyte injury and proteinuric kidney disease. Thus, the findings suggest that Dock5 deficiency is a critical contributor to podocyte lipotoxicity and may serve as a promising therapeutic target in proteinuric kidney diseases.

Adjunct Intraarterial or Intravenous Tirofiban Versus No Tirofiban After Successful Recanalization of Basilar Artery Occlusion Stroke: The BASILAR Registry.

BACKGROUND: Approximately half of patients who achieve successful reperfusion do not achieve functional independence. The present study sought to investigate the clinical outcomes and safety of intraarterial or intravenous tirofiban as adjunct therapy in patients with acute basilar artery occlusion who had achieved successful recanalization with endovascular treatment. METHODS AND RESULTS: In the national, prospective BASILAR (Endovascular Treatment for Acute Basilar Artery Occlusion Study) registry, 458 patients who met inclusion criteria were divided into 3 groups based on tirofiban administration (no tirofiban, n=262; intravenous tirofiban, n=101; intraarterial+intravenous tirofiban, n=95). Their clinical outcomes were compared with 90-day modified Rankin Scale scores. Adjusted odds ratios (aORs) and 95% CIs were obtained by logistic regression models and propensity score matching. Safety outcomes included any intracranial hemorrhage (ICH), symptomatic ICH, and mortality. Among 458 included patients, 184 (40.2%) achieved a favorable outcome (modified Rankin Scale score 0-3). There were no differences between the intravenous tirofiban group and the no tirofiban group in terms of safety and clinical outcomes (all P>0.05). Compared with the no tirofiban group, the intraarterial+intravenous tirofiban group had higher odds of 90-day modified Rankin Scale score 0 to 3 (aOR, 2.44 [95% CI, 1.30-4.64], P=0.006) and lower 3-month mortality (aOR, 0.38 [95% CI, 0.19-0.71], P=0.002) without an increase in any ICH (aOR, 0.34 [95% CI, 0.09-1.01], P=0.07) or symptomatic ICH (aOR, 0.23 [95% CI, 0.03-0.90], P=0.05). Similar results of intraarterial+intravenous tirofiban on improving clinical outcomes were detected in novel cohorts constructed by propensity score matching. CONCLUSIONS: Intraarterial+intravenous rather than intravenous tirofiban improved clinical outcomes without increasing the frequency of symptomatic ICH among patients with basilar artery occlusion after successful endovascular treatment. Further studies are needed to delineate the roles of intraarterial+intravenous tirofiban in patients with basilar artery occlusion receiving endovascular treatment.

Mitochondrial glycerol 3-phosphate dehydrogenase deficiency exacerbates lipotoxic cardiomyopathy.

Metabolic diseases such as obesity and diabetes induce lipotoxic cardiomyopathy, which is characterized by myocardial lipid accumulation, dysfunction, hypertrophy, fibrosis and mitochondrial dysfunction. Here, we identify that mitochondrial glycerol 3-phosphate dehydrogenase (mGPDH) is a pivotal regulator of cardiac fatty acid metabolism and function in the setting of lipotoxic cardiomyopathy. Cardiomyocyte-specific deletion of mGPDH promotes high-fat diet induced cardiac dysfunction, pathological hypertrophy, myocardial fibrosis, and lipid accumulation. Mechanically, mGPDH deficiency inhibits the expression of desuccinylase SIRT5, and in turn, the hypersuccinylates majority of enzymes in the fatty acid oxidation (FAO) cycle and promotes the degradation of these enzymes. Moreover, manipulating SIRT5 abolishes the effects of mGPDH ablation or overexpression on cardiac function. Finally, restoration of mGPDH improves lipid accumulation and cardiomyopathy in both diet-induced and genetic obese mouse models. Thus, our study indicates that targeting mGPDH could be a promising strategy for lipotoxic cardiomyopathy in the context of obesity and diabetes.

Astrocyte-derived lactate aggravates brain injury of ischemic stroke in mice by promoting the formation of protein lactylation.

Aim: Although lactate supplementation at the reperfusion stage of ischemic stroke has been shown to offer neuroprotection, whether the role of accumulated lactate at the ischemia phase is neuroprotection or not remains largely unknown. Thus, in this study, we aimed to investigate the roles and mechanisms of accumulated brain lactate at the ischemia stage in regulating brain injury of ischemic stroke. Methods and Results: Pharmacological inhibition of lactate production by either inhibiting LDHA or glycolysis markedly attenuated the mouse brain injury of ischemic stroke. In contrast, additional lactate supplement further aggravates brain injury, which may be closely related to the induction of neuronal death and A1 astrocytes. The contributing roles of increased lactate at the ischemic stage may be related to the promotive formation of protein lysine lactylation (Kla), while the post-treatment of lactate at the reperfusion stage did not influence the brain protein Kla levels with neuroprotection. Increased protein Kla levels were found mainly in neurons by the HPLC-MS/MS analysis and immunofluorescent staining. Then, pharmacological inhibition of lactate production or blocking the lactate shuttle to neurons showed markedly decreased protein Kla levels in the ischemic brains. Additionally, Ldha specific knockout in astrocytes (Aldh1l1 CreERT2; Ldha fl/fl mice, cKO) mice with MCAO were constructed and the results showed that the protein Kla level was decreased accompanied by a decrease in the volume of cerebral infarction in cKO mice compared to the control groups. Furthermore, blocking the protein Kla formation by inhibiting the writer p300 with its antagonist A-485 significantly alleviates neuronal death and glial activation of cerebral ischemia with a reduction in the protein Kla level, resulting in extending reperfusion window and improving functional recovery for ischemic stroke. Conclusion: Collectively, increased brain lactate derived from astrocytes aggravates ischemic brain injury by promoting the protein Kla formation, suggesting that inhibiting lactate production or the formation of protein Kla at the ischemia stage presents new therapeutic targets for the treatment of ischemic stroke.

True first-pass effect in patients undergoing thrombectomy for acute large core strokes.

OBJECTIVE: The impact of true first-pass effect (T-FPE, achieving substantial recanalization with extended thrombolysis in cerebral infarction; eTICI 3 after 1 thrombectomy) and outcomes on acute ischemic stroke (AIS) with large ischemic core remains uncertain. We aimed to study the association between T-FPE and outcomes in AIS patients with large core infarct through a real-world multicenter study. METHODS: From a prospective multicentric registry, we collected the data of all consecutive acute stroke patients with a large ischemic core who underwent thrombectomy and compared the outcomes of patients who achieved T-FPE and those who did not. In addition, we compared the outcomes of patients with different numbers of thrombectomy pass to identify the effectiveness of T-FPE. Multivariate analysis was performed to determine the predictors of T-FPE. The primary outcome was good functional outcome (modified Rankin Scale score; mRS 0-3) at 90 days. Safety outcomes included a 90-day mortality and symptomatic intracerebral hemorrhage within 48 hours after thrombectomy. RESULTS: Between November 2021 and February 2023, 447 eligible patients at 38 stroke centers were enrolled. Out of 447 thrombectomy patients, T-FPE was achieved in 102 individuals (22.8%). T-FPE was significantly associated with a higher proportion of good functional outcome (mRS 0-3 at 3 months, OR 2.221, 95% CI 1.418-3.479, p < 0.001) and lower mortality than non-T-FPE patients (31.4% vs. 45.5%, p = 0.012). The occlusion sites and lower DBP were strong predictors of T-FPE. INTERPRETATION: T-FPE was associated with favorable outcomes at 90 days in AIS patients with a large ischemic core who underwent EVT.

Remote Ischemic Conditioning With Medical Management or Reperfusion Therapy for Acute Ischemic Stroke: A Systematic Review and Meta-Analysis.

BACKGROUND AND OBJECTIVES: Remote ischemic conditioning (RIC) is a low-cost, accessible, and noninvasive neuroprotective treatment strategy, but its efficacy and safety in acute ischemic stroke are controversial. With the publication of several randomized controlled trials (RCTs) and the recent results of the RESIST trial, it may be possible to identify the patient population that may (or may not) benefit from RIC. This systematic review and meta-analysis aims to evaluate the effectiveness and safety of RIC in patients with ischemic stroke receiving different treatments by pooling data of all randomized controlled studies to date. METHODS: We searched the PubMed, Embase, Cochrane, Elsevier, and Web of Science databases to obtain articles in all languages from inception until May 25, 2023. The primary outcome was the modified Rankin Scale (mRS) score at the specified endpoint time in the trial. The secondary outcomes were change in NIH Stroke Scale (NIHSS) and recurrence of stroke events. The safety outcomes were cardiovascular events, cerebral hemorrhage, and mortality. The quality of articles was evaluated through the Cochrane risk assessment tool. This study was registered in PROSPERO (CRD42023430073). RESULTS: There were 7,657 patients from 22 RCTs included. Compared with the control group, patients who received RIC did not have improved mRS functional outcomes, regardless of whether they received medical management, reperfusion therapy with intravenous thrombolysis (IVT), or mechanical thrombectomy (MT). In the medical management group, patients who received RIC had decreased incidence of stroke recurrence (risk ratio 0.63, 95% CI 0.43-0.92, p = 0.02) and lower follow-up NIHSS score by 1.72 points compared with the control group (p < 0.00001). There was no increased risk of adverse events including death or cerebral hemorrhage in the IVT or medical management group. DISCUSSION: In patients with ischemic stroke who are not eligible for reperfusion therapy, RIC did not affect mRS functional outcomes but significantly improved the NIHSS score at the follow-up endpoint and reduced stroke recurrence, without increasing the risk of cerebral hemorrhage or death. In patients who received IVT or MT, the benefit of RIC was not observed.

Endovascular Therapy and Outcomes Among Patients With Very Large Ischemic Core Stroke.

Importance: The association of endovascular therapy (EVT) with outcomes is unclear for patients with very low Alberta Stroke Program Early Computed Tomography Score (ASPECTS) within 24 hours of stroke onset. Objective: To explore the association of EVT with functional and safety outcomes among patients with ASPECTS of 0 to 2 scored with noncontrast computed tomography. Design, Setting, and Participants: This cohort study used data from an ongoing, prospective, observational, nationwide registry including all patients treated at 38 stroke centers in China with an occlusion in the internal carotid artery or M1 or M2 segment of the middle cerebral artery within 24 hours of witnessed symptom onset. Patients with ASPECTS of 0 to 2 between November 1, 2021, and February 8, 2023, were included in analysis. Data were analyzed October to November 2023. Exposures: EVT vs standard medical treatment (SMT). Main Outcomes and Measures: The primary outcome was favorable functional outcome, defined as modified Rankin Scale score (mRS) of 0 to 3, at 90 days. Safety outcomes included symptomatic intracerebral hemorrhage (sICH) within 48 hours and mortality at 90 days. Results: A total of 245 patients (median [IQR] age, 71 [63-78] years; 118 [48%] women) with ASPECTS of 0 to 2 were included, of whom 111 patients (45.1%) received SMT and 135 patients (54.9%) received EVT. The EVT group had significantly greater odds of favorable functional outcome at 90 days than the SMT group (30 patients [22.2%] vs 11 patients [9.9%]; P = .01; adjusted odds ratio [aOR], 3.07 [95% CI, 1.29-7.31]; P = .01). Patients in the EVT group, compared with the SMT group, had significantly greater odds of any ICH (56 patients [41.5%] vs 16 patients [11.4%]; P < .001; aOR, 4.27 [95% CI, 2.19-8.35]; P < .001) and sICH (24 patients [17.8%] vs 1 patient [0.9%]; P < .001; aOR, 23.07 [95% CI, 2.99-177.79]; P = .003) within 48 hours. There were no differences between groups for 90-day mortality (80 patients [59.3%] vs 59 patients [53.2%]; P = .34; aOR, 1.38 [95% CI, 0.77-2.47]; P = .28). The results remained robust in the propensity score-matched analysis. Conclusions and Relevance: In this cohort study of patients with very low ASPECTS based on NCCT within 24 hours of stroke onset, those treated with EVT had higher odds of a favorable functional outcome compared with those who received SMT. Randomized clinical trials are needed to assess these findings.

Endovascular treatment versus standard medical treatment in patients with established large infarct: a cohort study.

BACKGROUND: Previous trials confirmed the benefit of endovascular treatment (EVT) in acute large core stroke, but the effect of EVT on outcomes in these patients based on noncontrast computed tomography (NCCT) in real-world clinical practice was unclear. The aim of this study was to explore the effect of EVT versus standard medical treatment (SMT) in patients with large ischemic core stroke defined as Alberta Stroke Program Early CT Score (ASPECTS) ≤5 based on NCCT alone. MATERIALS AND METHODS: Patients with acute large core stroke at 38 Chinese centers between November 2021 and February 2023 were reviewed from a prospectively maintained database. The primary outcome was favorable functional outcome [modified Rankin Scale score (mRS), 0-3] at 90 days. Safety outcomes included 48 h symptomatic intracerebral hemorrhage (sICH) and 90-day mortality. RESULTS: Of 745 eligible patients recruited at 38 stroke centers between November 2021 and February 2023, 490 were treated with EVT+SMT and 255 with SMT alone. One hundred and eighty-one (36.9%) in the EVT group achieved favorable functional independence versus 48 (18.8%) treated with SMT only [adjusted risk ratio (RR), 1.86; 95% CI: 1.43-2.42, P <0.001; adjusted risk difference (RD), 13.77; 95% CI: 7.40-20.15, P <0.001]. The proportion of sICH was significantly higher in patients undergoing EVT (13.3 vs. 2.4%; adjusted RR, 5.17; 95% CI: 2.17-12.32, P <0.001; adjusted RD, 10.10; 95% CI: 6.12-14.09, P <0.001). No significant difference of mortality between the groups was observed (41.8 vs. 49.0%; adjusted RR, 0.91; 95% CI: 0.77-1.07, P =0.24; adjusted RD, -5.91; 95% CI: -12.91-1.09, P =0.1). CONCLUSION: Among patients with acute large core stroke based on NCCT in real-world, EVT is associated with better functional outcomes at 90 days despite of higher risk of sICH. Rates of procedure-related complications were relatively higher in the EVT+SMT group.

Growth hormone promotes myelin repair after chronic hypoxia via triggering pericyte-dependent angiogenesis.

White matter injury (WMI) causes oligodendrocyte precursor cell (OPC) differentiation arrest and functional deficits, with no effective therapies to date. Here, we report increased expression of growth hormone (GH) in the hypoxic neonatal mouse brain, a model of WMI. GH treatment during or post hypoxic exposure rescues hypoxia-induced hypomyelination and promotes functional recovery in adolescent mice. Single-cell sequencing reveals that Ghr mRNA expression is highly enriched in vascular cells. Cell-lineage labeling and tracing identify the GHR-expressing vascular cells as a subpopulation of pericytes. These cells display tip-cell-like morphology with kinetic polarized filopodia revealed by two-photon live imaging and seemingly direct blood vessel branching and bridging. Gain-of-function and loss-of-function experiments indicate that GHR signaling in pericytes is sufficient to modulate angiogenesis in neonatal brains, which enhances OPC differentiation and myelination indirectly. These findings demonstrate that targeting GHR and/or downstream effectors may represent a promising therapeutic strategy for WMI.

Perfusion vs non-perfusion computed tomography imaging in the late window of emergent large vessel ischemic stroke: A systematic review and meta-analysis.

BACKGROUND: Guidelines recommend the treatment of emergent large vessel ischemic stroke (ELVIS) patients presenting beyond 6 hours of last known well time with endovascular thrombectomy (EVT) based on perfusion computed tomography (CT) neuroimaging. We compared the outcomes (long-term good clinical outcomes, symptomatic intracranial hemorrhage (sICH), and mortality) of ELVIS patients according to the type of CT neuroimaging they underwent. METHODS: We searched the following databases: Medline, Embase, CENTRAL, and Scopus from January 1, 2015, to June 14, 2023. We included studies of late-presenting ELVIS patients undergoing EVT that had with data for non-perfusion and perfusion CT neuroimaging. We followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Data were pooled using a random effects model. RESULTS: We found 7 observational cohorts. Non-perfusion versus perfusion CT was not statistically significantly different for both long-term clinical (n = 3,224; RR: 0.96; 95% CI 0.86 to 1.06; I2 = 18%) and sICH (n = 3,724; RR: 1.08 95% CI 0.60 to 1.94; I2 = 76%). Perfusion CT had less mortality (n = 3874; RR: 1.22; 95% CI 1.07 to 1.40; I2 = 0%). The certainty of these findings is very low because of limitations in the risk of bias, indirectness, and imprecision domains of the Grading of Recommendations, Assessment, Development and Evaluations. CONCLUSION: The use of either non-perfusion or perfusion CT neuroimaging may have little to no effect on long-term clinical outcomes and sICH for late-presenting EVT patients. Perfusion CT neuroimaging may be associated with a reduced the risk of mortality. Evidence uncertainty warrants randomized trial data.