Mechanism of inflammatory response and therapeutic effects of stem cells in ischemic stroke: current evidence and future perspectives.

Ischemic stroke is a leading cause of death and disability worldwide, with an increasing trend and tendency for onset at a younger age. China, in particular, bears a high burden of stroke cases. In recent years, the inflammatory response after stroke has become a research hotspot: understanding the role of inflammatory response in tissue damage and repair following ischemic stroke is an important direction for its treatment. This review summarizes several major cells involved in the inflammatory response following ischemic stroke, including microglia, neutrophils, monocytes, lymphocytes, and astrocytes. Additionally, we have also highlighted the recent progress in various treatments for ischemic stroke, particularly in the field of stem cell therapy. Overall, understanding the complex interactions between inflammation and ischemic stroke can provide valuable insights for developing treatment strategies and improving patient outcomes. Stem cell therapy may potentially become an important component of ischemic stroke treatment.

Impact of gut microbiota on cardiac aging.

Recent research has suggested imbalances in gut microbiota composition as contributors to cardiac aging. An individual's physical condition, along with lifestyle-associated factors, including diet and medication, are significant determinants of gut microbiota composition. This review discusses evidence of bidirectional associations between aging and gut microbiota, identifying gut microbiota-derived metabolites as potential regulators of cardiac aging. It summarizes the effects of gut microbiota on cardiac aging diseases, including cardiac hypertrophy and fibrosis, heart failure, and atrial fibrillation. Furthermore, this review discusses the potential anti-aging effects of modifying gut microbiota composition through dietary and pharmacological interventions. Lastly, it underscores critical knowledge gaps and outlines future research directions. Given the current limited understanding of the direct relationship between gut microbiota and cardiac aging, there is an urgent need for preclinical and clinical investigations into the mechanistic interactions between gut microbiota and cardiac aging. Such endeavors hold promise for shedding light on the pathophysiology of cardiac aging and uncovering new therapeutic targets for cardiac aging diseases.

Predictive etiological classification of acute ischemic stroke through interpretable machine learning algorithms: a multicenter, prospective cohort study.

BACKGROUND: The prognosis, recurrence rates, and secondary prevention strategies varied significantly among different subtypes of acute ischemic stroke (AIS). Machine learning (ML) techniques can uncover intricate, non-linear relationships within medical data, enabling the identification of factors associated with etiological classification. However, there is currently a lack of research utilizing ML algorithms for predicting AIS etiology. OBJECTIVE: We aimed to use interpretable ML algorithms to develop AIS etiology prediction models, identify critical factors in etiology classification, and enhance existing clinical categorization. METHODS: This study involved patients with the Third China National Stroke Registry (CNSR-III). Nine models, which included Natural Gradient Boosting (NGBoost), Categorical Boosting (CatBoost), Extreme Gradient Boosting (XGBoost), Random Forest (RF), Light Gradient Boosting Machine (LGBM), Gradient Boosting Decision Tree (GBDT), Adaptive Boosting (AdaBoost), Support Vector Machine (SVM), and logistic regression (LR), were employed to predict large artery atherosclerosis (LAA), small vessel occlusion (SVO), and cardioembolism (CE) using an 80:20 randomly split training and test set. We designed an SFS-XGB with 10-fold cross-validation for feature selection. The primary evaluation metrics for the models included the area under the receiver operating characteristic curve (AUC) for discrimination and the Brier score (or calibration plots) for calibration. RESULTS: A total of 5,213 patients were included, comprising 2,471 (47.4%) with LAA, 2,153 (41.3%) with SVO, and 589 (11.3%) with CE. In both LAA and SVO models, the AUC values of the ML models were significantly higher than that of the LR model (P < 0.001). The optimal model for predicting SVO (AUC [RF model] = 0.932) outperformed the optimal LAA model (AUC [NGB model] = 0.917) and the optimal CE model (AUC [LGBM model] = 0.846). Each model displayed relatively satisfactory calibration. Further analysis showed that the optimal CE model could identify potential CE patients in the undetermined etiology (SUE) group, accounting for 1,900 out of 4,156 (45.7%). CONCLUSIONS: The ML algorithm effectively classified patients with LAA, SVO, and CE, demonstrating superior classification performance compared to the LR model. The optimal ML model can identify potential CE patients among SUE patients. These newly identified predictive factors may complement the existing etiological classification system, enabling clinicians to promptly categorize stroke patients' etiology and initiate optimal strategies for secondary prevention.

Relationships between brain structure-function coupling in normal aging and cognition: A cross-ethnicity population-based study.

Increased efforts in neuroscience seek to understand how macro-anatomical and physiological connectomes cooperatively work to generate cognitive behaviors. However, the structure-function coupling characteristics in normal aging individuals remain unclear. Here, we developed an index, the Coupling in Brain Structural connectome and Functional connectome (C-BSF) index, to quantify regional structure-function coupling in a large community-based cohort. C-BSF used diffusion tensor imaging (DTI) and resting-state functional magnetic resonance imaging (fMRI) data from the Polyvascular Evaluation for Cognitive Impairment and Vascular Events study (PRECISE) cohort (2007 individuals, age: 61.15 ± 6.49 years) and the Sydney Memory and Ageing Study (MAS) cohort (254 individuals, age: 83.45 ± 4.33 years). We observed that structure-function coupling was the strongest in the visual network and the weakest in the ventral attention network. We also observed that the weaker structure-function coupling was associated with increased age and worse cognitive level of the participant. Meanwhile, the structure-function coupling in the visual network was associated with the visuospatial performance and partially mediated the connections between age and the visuospatial function. This work contributes to our understanding of the underlying brain mechanisms by which aging affects cognition and also help establish early diagnosis and treatment approaches for neurological diseases in the elderly.

Polypropylene sulfide methotrexate nanoparticles target the synovial lymphatic system to restore immune tolerance in rheumatoid arthritis.

Around 40 % of patients fail to achieve primary clinical outcomes for rheumatoid arthritis (RA). The growth of lymphatic system in the synovial membrane, is a primary response during RA inflammation. It is suggested that a delivery strategy targeting immunosuppressive agents to the synovial lymph nodes and then to the immune cells is beneficial for resolving arthritis. This study introduced a synthetic polypropylene sulfide methotrexate nano-delivery system (PPS-MTX), which was prepared by covalently bonding methotrexate to polypropylene sulfide, with a diameter size range of 36 nm. It enhanced joint accumulation and retention, which can be selectively uptake by antigen-presenting cells in the synovial lymphatic system. The results indicated that PPS-MTX nanoparticles effectively improved arthritis disease progression and restored the immune tolerance microenvironment in the synovial lymphatic system, promoting peripheral tolerance in collagen-induced arthritis mice. Additionally, no systemic toxicity was observed. This study presents a promising targeted strategy for inducing immune tolerance in the treatment of rheumatoid arthritis.

Prebiotic inulin controls Th17 cells mediated central nervous system autoimmunity through modulating the gut microbiota and short chain fatty acids.

Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory demyelination occurring in the central nervous system (CNS). Inulin is a common prebiotic that can improve metabolic disorders by modulating the gut microbiota. However, its capacity to affect CNS autoimmunity is poorly recognized. Experimental autoimmune encephalomyelitis (EAE) is a classical mouse model of MS. Herein, we found that oral administration of inulin ameliorated the severity EAE in mice, accompanied by reductions in inflammatory cell infiltration and demyelination in the CNS. These reductions were associated with decreased proportion and numbers of Th17 cells in brain and spleen. Consistent with the findings, the serum concentrations of IL-17, IL-6, and TNF-α were reduced in inulin treated EAE mice. Moreover, the proliferation of auto-reactive lymphocytes, against MOG35-55 antigen, was attenuated ex vivo. Mechanistically, inulin treatment altered the composition of gut microbiota. It increased Lactobacillus and Dubosiella whereas decreased g_Prevotellaceae_NK3B31_group at the genus level, alongside with elevated concentration of butyric acid in fecal content and serum. In vitro, butyrate, but not inulin, could inhibit the activation of MOG35-55 stimulated lymphocytes. Furthermore, fecal microbiota transplantation assay confirmed that fecal contents of inulin-treated normal mice had an ameliorative effect on EAE mice. In contrast, antibiotic cocktail (ABX) treatment diminished the therapeutic effect of inulin in EAE mice as well as the reduction of Th17 cells, while supplementation with Lactobacillus reuteri restored the amelioration effect. These results confirmed that the attenuation of inulin on Th17 cells and inflammatory demyelination in EAE mice was dependent on its modulation on gut microbiota and metabolites. Our findings provide a potential therapeutic regimen for prebiotic inulin supplementation in patients with multiple sclerosis.

Glycated albumin levels are associated with adverse stroke outcomes in patients with acute ischemic stroke in China.

BACKGROUND AND AIM: Glycated albumin (GA) is a biomarker monitoring glycemia 2-4 weeks before stroke onset. This study was designed to explore the association between GA levels with poststroke outcomes in patients with acute ischemic stroke or transient ischemic attack (TIA). METHOD: Participants with ischemic stroke or TIA who had a baseline GA measurement were included in the Third China National Stroke Registry study. The effect of GA on stroke recurrence, poor functional outcomes, and combined vascular events was examined during the 1-year follow-up period. Multivariate Cox and logistic regression models were performed to evaluate the association. Discrimination tests were used to examine the incremental predictive value of GA when incorporating it into the conventional model. RESULTS: A total of 3861 participants were enrolled. At the 3-month follow-up, the elevated GA level was associated with an increased risk of poor functional outcomes (adjusted odds ratio [OR], 1.45; 95% confidence interval [CI], 1.01-2.09). A similar increase was observed for stroke recurrence (adjusted hazard ratio [HR], 1.56; 95% CI, 1.09-2.24), poor functional outcomes (adjusted OR, 1.62; 95% CI, 1.07-2.45), and combined vascular events (adjusted HR, 1.55; 95% CI, 1.09-2.20) at the 1-year follow-up. In nondiabetic patients, the association between GA and poor functional outcomes was more pronounced (adjusted OR, 1.62; 95% CI, 1.05-2.50). Adding GA into the conventional model resulted in slight improvements in predicting poor functional outcomes (net reclassification improvement [NRI]: 12.30% at 1 year). CONCLUSION: This study demonstrated that elevated GA levels in serum were associated with stroke adverse outcomes, including stroke recurrence, poor functional outcomes, and combined vascular events, in patients with ischemic stroke or TIA.

Tenecteplase vs Alteplase for Patients With Acute Ischemic Stroke: The ORIGINAL Randomized Clinical Trial.

Importance: Tenecteplase is a bioengineered variant of alteplase with greater fibrin specificity and a longer half-life, allowing single-bolus administration. Evidence on the treatment effect of tenecteplase 0.25 mg/kg in Chinese patients with acute ischemic stroke (AIS) is limited. Objective: To establish the noninferiority of tenecteplase to alteplase in patients with AIS within 4.5 hours of symptom onset. Design, Setting, and Participants: The ORIGINAL study was a multicenter, active-controlled, parallel-group, randomized, open-label, blinded end point, noninferiority trial conducted between July 14, 2021, and July 14, 2023. Participants were recruited from 55 neurology clinics and stroke centers in China and were eligible if they had AIS with a National Institutes of Health Stroke Scale score of 1 to 25 with measurable neurologic deficit and were symptomatic for at least 30 minutes without significant improvement. Interventions: Patients were randomized (1:1) within 4.5 hours of symptom onset to receive intravenous tenecteplase (0.25 mg/kg) or intravenous alteplase (0.9 mg/kg). Main Outcomes and Measures: The primary outcome was the proportion of patients with a modified Rankin Scale (mRS) score of 0 or 1 (no symptoms or no significant disability) at day 90, tested for noninferiority (risk ratio [RR] margin, 0.937). Safety end points included symptomatic intracerebral hemorrhage (per European Cooperative Acute Stroke Study III definition) and 90-day all-cause mortality. Results: Among the 1489 patients randomized, 1465 patients were included in the full analysis set (732 in the tenecteplase group; 733 in the alteplase group) and 446 (30.4%) were female. The primary outcome occurred in 72.7% (532/732) of patients receiving tenecteplase and 70.3% (515/733) receiving alteplase (RR, 1.03 [95% CI, 0.97-1.09]; noninferiority threshold met). Symptomatic intracerebral hemorrhage occurred in 9 patients (1.2%) in each group (RR, 1.01 [95% CI, 0.37-2.70]). The 90-day mortality rate was 4.6% (34/732) in the tenecteplase group and 5.8% (43/736) in the alteplase group (RR, 0.80 [95% CI, 0.51-1.23]). Conclusions and Relevance: In patients with AIS eligible for intravenous thrombolysis within 4.5 hours after stroke onset, tenecteplase was noninferior to alteplase with respect to excellent functional outcome (mRS score of 0 or 1) at 90 days and had a similar safety profile. Findings from this study support tenecteplase as a suitable alternative to alteplase in this setting. Trial Registration: ClinicalTrials.gov Identifier: NCT04915729.

Tibial transverse transport promotes wound healing in diabetic foot ulcers by stimulating endothelial progenitor cell mobilization and homing mediated neovascularization.

BACKGROUND: Diabetic foot ulcers (DFUs) are a common and serious complication of diabetes, often leading to amputation and decreased quality of life. Current treatment methods have limited success rates, highlighting the need for new approaches. This study investigates the potential of tibial transverse transport (TTT) to promote wound healing in DFUs. METHODS: To test this hypothesis, the study used New Zealand White rabbits to establish a diabetic model and simulate foot ulcers, followed by the treatment of unilateral TTT or bilateral TTT. The study employed histological analysis, flow cytometry, ELISA, and qPCR to assess the impact of TTT on tissue repair and endothelial progenitor cell (EPC) mobilization and homing, aiming to understand the underlying biological processes in wound healing. RESULTS: TTT significantly enhanced wound healing in diabetic rabbit foot ulcers. Specifically, bilateral TTT led to complete wound healing by day 19, faster than the unilateral TTT group, which healed by day 26, and the sham operation group, which nearly healed by day 37. Histological analysis showed improved tissue architecture, collagen deposition, and neovascularization in TTT-treated groups. Furthermore, TTT treatment resulted in a significant increase in VEGFR2 expression and VEGFR2/Tie-2 positive cells, particularly in the bilateral group. These findings were corroborated by qPCR results, which showed increased expression of VEGFA and CXCL12 by TTT. Conclusions: TTT may be a promising treatment for DFUs, significantly enhancing wound healing by stimulating EPC mobilization and homing mediated angiogenesis. This novel approach could substantially improve treatment outcomes for diabetic patients with chronic foot ulcers.

TTT accelerates wound healing in diabetic rabbit instep ulcers, with both unilateral and bilateral surgeries effective, and bilateral TTT showing enhanced efficacy.TTT boosts angiogenesis and collagen fiber formation, leading to increased granulation tissue and re-epithelialization of wounds.TTT induces the mobilization and homing of endothelial progenitor cells to promote angiogenesis and wound healing.

Combined therapeutic strategy based on blocking the deleterious effects of AGEs for accelerating diabetic wound healing.

Diabetic foot ulcer is a serious complication of diabetes. Excessive accumulation of advanced glycation end products (AGEs) is one of the critical pathogenic factors in postponing diabetic wound healing. The main pathogenic mechanisms of AGEs include inducing cellular dysfunction, prolonging inflammatory response, increasing oxidative stress and reducing endogenous nitric oxide (NO) production. Combination therapy of blocking the deleterious effects of AGEs and supplementing exogenous NO is hypothesized to promote diabetic wound healing. Here, we presented nanoparticles/hydrogel composite dressings to co-delivery rosiglitazone and S-nitroso glutathione into the wound bed. The designed co-delivery system augmented the survival of fibroblasts, reduced oxidative stress levels, reversed the change of mitochondrial membrane potential and decreased the proinflammatory cytokine expression. Local sustained release of therapeutic agents significantly improved the wound healing of diabetic rats including increasing the wound closure rate, alleviating inflammation, promoting collagen fiber production and angiogenesis. Our finding indicated this local deliver strategy aimed at inhibiting the toxic effects of AGEs has great clinical potential for diabetic wound treatment.

Galloyl-boosted gold nanorods: Unleashing personalized cancer immunotherapy potential.

Cancer immunotherapy has emerged as a potent treatment strategy by harnessing the host immune system to target cancer cells. However, challenges including low tumor vaccine immunogenicity and tumor heterogeneity hinder its clinical efficacy. To address these issues, we propose a novel nanoplatform integrating photothermal material gold nanorods (GNRs) with polyphenols for enhanced immunotherapy efficacy via photothermal therapy. Polyphenols, natural compounds with phenolic hydroxyl groups, are known for their ability to bind tightly to various molecules, making them ideal for antigen capture. We synthesized GNRs modified with polyphenols (GNR-PA and GNR-GA) and demonstrated their ability to induce immunogenic cell death upon laser irradiation, releasing tumor-associated antigens (TAAs). The surface polyphenols on GNRs effectively captured released TAAs to shield them from clearance. In vivo studies confirmed increased accumulation of GNR-GA in lymph nodes and enhanced dendritic cell maturation, leading to promoted effector T cell infiltration into tumors. Furthermore, treatment combined with PD-1/PD-L1 pathway blockade demonstrated potent tumor regression and systemic immunotherapy efficacy. Our findings highlight the potential of this photothermal nanoplatform as a promising strategy to overcome the limitations of current cancer immunotherapy approaches and improve therapeutic outcomes.

Association between window ventilation frequency and depressive symptoms among older Chinese adults.

OBJECTIVES: Indoor air pollution exposure is harmful to people's physical and mental health, especially in the elderly population. Depressive symptoms are the most common mental health issue among elderly individuals. However, evidence linking the frequency of indoor natural ventilation to depressive symptoms in the elderly population is limited. METHODS: This study included 7887 individuals 65 years and older from 2017 to 2018 the China Longitudinal Healthy Longevity Survey (CLHLS). The frequency of indoor window ventilation was measured as the self-reported times of ventilation of indoor window per week in each season, and the four seasons' scores were added up to calculate the annual ventilation frequency. Depressive symptoms were measured by the 10-item Center for Epidemiologic Studies Short Depression Scale (CESD). Using three models adjusted for demographic, socio-economic, health status, and environmental factors successively, the correlation between indoor window ventilation frequency and depressive symptoms was verified through logistic regression. RESULTS: Among the 7887 elderly people included in this study, 1952 (24.7 %) had depressive symptoms. In the fully adjusted model, compared with the lower indoor annual ventilation frequency group, high indoor annual ventilation frequency group was significantly associated with a 33 % (OR: 0.67, 95%CI: 0.51-0.88) lower probability of depressive symptoms. Subgroup analysis and sensitivity analysis yielded similar results. CONCLUSIONS: High frequency of window ventilation is significantly associated with the lower risk of depressive symptoms in Chinese individuals aged 65 and older. This result provides strong evidence for health intervention and policy formulation.

Clinical characteristics, in-hospital management, and outcomes among patients hospitalized for acute ischemic stroke in rural vs. urban hospitals in China: a nationwide hospital-based study.

BACKGROUND: Efforts to improve rural stroke care have intensified in China. However, high-quality comprehensive data on the differences in care and outcomes between urban and rural hospitals are limited. METHODS: We analyzed data on patients with acute ischemic stroke hospitalized in the China Stroke Center Alliance hospitals from 2015 to 2022. The in-hospital management measures assessed included nine acute and five discharge management measures. Outcomes evaluated included death or discharge against medical advice (DAMA), major adverse cardiovascular events (MACE), disability at discharge, and in-hospital complications. RESULTS: We enrolled 1,583,271 patients with acute ischemic stroke from 1,930 hospitals, comprising 1 086 (56.3%) rural sites with 735 452 patients and 844 (43.7%) urban sites with 847 891 patients. Patients in rural hospitals demonstrate suboptimal management measures compared to those in urban hospitals, including lower rates of intravenous recombinant tissue plasminogen activator within 4.5 h (26.0% vs. 28.3%; difference, -2.3% [-2.5% to -2.0%]), endovascular treatment (0.6% vs. 1.9%; difference, -1.3% [-1.3% to -1.2%]), vessel assessment (88.5% vs. 92.0%; difference, -3.5% [95% CI, -3.6% to -3.4%]), and anticoagulants for atrial fibrillation at discharge (42.9% vs. 47.7%; difference, -4.8% [95% CI, -5.4% to -4.2%]). Overall, the rural-urban disparity in in-hospital outcomes was small. Rural patients had a slightly higher rate of in-hospital death/DAMA (9.0% vs. 8.0%; aOR, 1.22 [95% CI, 1.20-1.23]; aRD, 1.3% [95% CI, 1.2%-1.4%]) and a slightly lower rate of complications (10.9% vs. 13.0%; aOR, 0.83 [95% CI, 0.82-0.84]; aRD, -1.3% [95% CI, -1.3%-1.3%]). No notable rural-urban differences were observed in MACE and disability at discharge. CONCLUSIONS: Patients in rural hospitals demonstrated suboptimal management measures and had higher rates of in-hospital death/DAMA compared to those in urban hospitals. Prioritizing the allocation of health resources to rural hospitals is essential to improve healthcare quality and outcomes. DATA ACCESS STATEMENT: The data supporting the findings of this study are available from the corresponding author upon reasonable request.

Duration of Benefit and Risk of Dual Antiplatelet Therapy up to 72 Hours After Mild Ischemic Stroke and Transient Ischemic Attack.

BACKGROUND AND OBJECTIVES: Clopidogrel-aspirin initiated within 72 hours of symptom onset is effective in patients with mild ischemic stroke or transient ischemic attack (TIA) in the Intensive Statin and Antiplatelet Therapy for Acute High-risk Intracranial or Extracranial Atherosclerosis (INSPIRES) trial. Uncertainties remain about the duration of the treatment effect. This study aimed to assess duration of benefit and risk of clopidogrel-aspirin in these patients. METHODS: The INSPIRES trial was a 2*2 factorial placebo-controlled randomized trial conducted in 222 hospitals in China. The 2 treatments did not interact and were evaluated separately. In this study, we performed secondary analyses based on antiplatelet treatment. All patients with mild stroke or TIA of presumed atherosclerotic cause within 72 hours of symptom onset enrolled in the trial were included. Patients were randomly assigned to receive clopidogrel-aspirin on days 1-21 followed by clopidogrel on days 22-90 or aspirin alone for 90 days. The primary efficacy outcome was major ischemic event which included the composite of ischemic stroke and nonhemorrhagic death. The primary safety outcome was moderate-to-severe bleeding. We estimated the risk difference between the 2 treatments for each stratified week. RESULTS: All 6,100 patients in the trial were included (3,050 in each group). The mean age was 65 years, and 3,915 patients (64.2%) were men. Compared with aspirin alone, the reduction of major ischemic events by clopidogrel-aspirin mainly occurred in the first week (absolute risk reduction [ARR] 1.42%, 95% CI 0.53%-2.32%) and remained in the second week (ARR 0.49%, 95% CI 0.09%-0.90%) and the third week (ARR 0.29%, 95% CI -0.05% to 0.62%). Numerical higher risk of moderate-to-severe bleedings in the clopidogrel-aspirin group was observed in the first 3 weeks (absolute risk increase 0.05% [95% CI -0.10% to 0.20%], 0.10% [95% CI -0.09% to 0.29%], and 0.18% [95% CI -0.03% to 0.40%] in the first, second, and third weeks, respectively). CONCLUSIONS: Among patients with mild ischemic stroke or high-risk TIA of presumed atherosclerotic cause, the net benefit of clopidogrel-aspirin initiated within 72 hours of symptom onset was pronounced in the first week and continued to a lesser degree in the following 2 weeks, outweighing the low, but ongoing hemorrhagic risk. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT03635749. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that among patients with mild ischemic stroke or high-risk TIA of presumed atherosclerotic cause, the net benefit of clopidogrel-aspirin initiated within 72 hours of symptom onset was pronounced in the first week and continued to a lesser degree in the following 2 weeks, outweighing the low but ongoing hemorrhagic risk.

Lipoprotein-associated phospholipase A2 Activity Levels is Associated with Artery to Artery Embolism in Symptomatic Intracranial Atherosclerotic Disease.

BACKGROUND: Lipoprotein-associated phospholipase A2 activity (Lp-PLA2-A) is a pivotal enzyme involved in the inflammatory process and atherosclerotic plaque vulnerability. This study aimed to investigate the potential of Lp-PLA2-A as a biomarker for reflecting artery-to-artery embolism (AAE), a critical mechanism with high risk of stroke recurrence in symptomatic intracranial atherosclerotic disease (sICAD). METHODS: The current analysis included a cohort of 1,908 patients with sICAD and baseline levels of Lp-PLA2-A from the Third China National Stroke Registry (CNSR-III). The baseline Lp-PLA2-A levels were quantified centrally using an automatic enzyme assay system. Diagnosis of sICAD was made by experienced stroke neurologists based on the presence of a cerebral infarction within the territory of a stenotic (>50%) or occluded artery, or when clinical symptoms were consistent with the diagnosis. Infarct lesions affecting the cortex serve as imaging biomarkers for stroke mechanism involving AAE.The relationship between baseline Lp-PLA2-A quartile levels and the presence of cortical infarction was analyzed using multivariate logistic regression. RESULTS: Compared to patients in the first Lp-PLA2-A quartile, those in the second, third and fourth quartiles demonstrated a significantly higher proportion of AAE. The proportion of patients with cortical infarction increased with rising Lp-PLA2-A quartiles, observed at 39.3%, 47.1%, 47.4%, and 50.7% for the first, second, third and fourth quartiles respectively (P for trend=0.004). Compared with the first quartile, the odds ratios (ORs) were 1.38 (95% CI = 1.06-1.79) for the second, 1.33 (95% CI = 1.02-1.72) for the third quartile and 1.48 (95% CI = 1.14-1.92) for the fourth quartile. The association between higher Lp-PLA2-A and increased proportion of cortical infarction was also present in the subgroups defined by age <65 years, male, and high-sensitivity C-reactive protein ≥2 mg/L. In sensitivity analyses, the positive correlation between Lp-PLA2-A levels and proportion of cortical infarction remained consistent. CONCLUSIONS: This research highlights the significance of Lp-PLA2-A as a biomarker for reflecting stroke mechanism in sICAD. Additional studies are warranted to explore the potential of targeting Lp-PLA2-associated inflammatory pathways as a pivotal approach in arresting the advancement of intracranial atherosclerotic stenosis and reducing the incidence of embolic strokes.

CT perfusion parameter estimation in stroke using neural network with transformer and physical model priors.

OBJECTIVES: CT perfusion (CTP) imaging is vital in treating acute ischemic stroke by identifying salvageable tissue and the infarcted core. CTP images allow quantitative estimation of CT perfusion parameters, which can provide information on the degree of tissue hypoperfusion and its salvage potential. Traditional methods for estimating perfusion parameters, such as singular value decomposition (SVD) and its variations, are known to be sensitive to noise and inaccuracies in the arterial input function. To our knowledge, there has been no implementation of deep learning methods for CT perfusion parameter estimation. MATERIALS & METHODS: In this work, we propose a deep learning method based on the Transformer model, named CTPerformer-Net, for CT perfusion parameter estimation. In addition, our method incorporates some physical priors. We integrate physical consistency prior, smoothness prior and the physical model prior through the design of the loss function. We also generate a simulation dataset based on physical model prior for training the network model. RESULTS: In the simulation dataset, CTPerformer-Net exhibits a 23.4 % increase in correlation coefficients, a 95.2 % decrease in system error, and a 90.7 % reduction in random error when contrasted with block-circulant SVD. CTPerformer-Net successfully identifies hypoperfused and infarcted lesions in 103 real CTP images from the ISLES 2018 challenge dataset. It achieves a mean dice score of 0.36 for the infarct core segmentation, which is slightly higher than the commercially available software (dice coefficient: 0.34) used as a reference level by the challenge. CONCLUSION: Experimental results on the simulation dataset demonstrate that CTPerformer-Net achieves better performance compared to block-circulant SVD. The real-world patient dataset confirms the validity of CTPerformer-Net.

Clopidogrel and Aspirin Initiated Between 24 to 72 Hours for Mild Ischemic Stroke: A Subgroup Analysis of the INSPIRES Randomized Clinical Trial.

Importance: Prior trials showed that dual antiplatelet therapy could reduce the risk of early new stroke in patients with acute mild ischemic stroke or transient ischemic attack (TIA) within 24 hours of symptom onset. However, it is currently uncertain whether dual antiplatelet therapy can reduce the risk of early new stroke in patients with a more delayed initiation time window. Objective: To evaluate the efficacy and safety of clopidogrel and aspirin among patients with mild ischemic stroke or TIA when initiated within 24 hours, from more than 24 hours to 48 hours, and from more than 48 hours to 72 hours. Design, Setting, and Participants: The Intensive Statin and Antiplatelet Therapy for Acute High-Risk Intracranial or Extracranial Atherosclerosis randomized clinical trial was a double-blind, placebo-controlled, multicenter, 2-by-2 factorial randomized clinical trial conducted at 222 hospitals in China from September 17, 2018, to October 15, 2022. All patients with acute mild ischemic stroke and TIA were included in this subgroup analysis and categorized into 3 groups according to time from symptom onset to randomization (group 1: ≤24 hours; group 2: >24 to ≤48 hours; and group 3: >48 to 72 hours). Patients were followed up for 90 days. Interventions: All patients received clopidogrel combined with aspirin (clopidogrel 300 mg loading dose on day 1, followed by 75 mg daily on days 2 to 90, and aspirin 100 to 300 mg on the first day and then 100 mg daily for days 2 to 90) or aspirin alone (100 to 300 mg on day 1 and then 100 mg daily for days 2 to 90) within 72 hours after symptom onset. Main Outcomes and Measures: The primary outcome was new stroke (ischemic or hemorrhagic) within 90 days. The primary safety outcome was moderate-to-severe bleeding, according to Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries criteria. Results: This analysis included a total of 6100 patients (3050 in the clopidogrel-aspirin group and 3050 in the aspirin group). The median age was 65 years (IQR, 57-71 years), and 3915 patients (64.2%) were male. In the population with time to randomization of 24 hours or less, stroke occurred in the next 90 days in 97 of 783 patients (12.4%); among those randomized from more than 24 hours to 48 hours, in 211 of 2552 patients (8.3%) among those randomized from more than 24 hours to 48 hours, and in 193 of 2765 patients (7.0%). The clopidogrel-aspirin group had a lower risk of new stroke within 90 days compared with the aspirin alone group both in patients with time to randomization of from 48 to 72 hours (5.8% vs 8.2%; hazard ratio [HR], 0.70 [95% CI, 0.53-0.94]), of more than 24 to 48 hours (7.6% vs 8.9%; HR, 0.85 [95% CI, 0.65-1.12]), and of 24 hours or less (11.5% vs 13.4%; HR, 0.83 [95% CI, 0.55-1.25]) (P = .38 for interaction). Among those with time to randomization of more than 48 to 72 hours, moderate-to-severe bleeding occurred in 12 patients (0.9%) in the clopidogrel-aspirin group and in 6 patients (0.4%) in the aspirin-alone group (HR, 2.00 [95% CI, 0.73-5.43]), while moderate-to-severe bleeding in those with time to randomization of more than 24 hours to 48 hours occurred in 9 patients (0.7%) in the clopidogrel-aspirin group and in 4 patients (0.3%) in the aspirin-alone group (HR, 2.25 [95% CI, 0.68-7.39]) and in those with time to randomization of within 24 hours, occurred in 6 patients (1.5%) in the clopidogrel-aspirin group and in 3 patients (0.8%) in the aspirin-alone group (HR, 1.57 [95% CI, 0.36-6.83]) (P = .92 for interaction). Conclusions and Relevance: In this randomized clinical trial of antiplatelet therapy in China, patients with mild ischemic stroke or TIA had consistent benefit from dual antiplatelet therapy with clopidogrel and aspirin vs aspirin alone when initiated within 72 hours after symptom onset, with a similar increase in the risk of moderate-to-severe bleeding. Patients should receive dual antiplatelet therapy with clopidogrel and aspirin within 72 hours after symptom onset. Trial Registration: ClinicalTrials.gov Identifier: NCT03635749.

Balloon Angioplasty vs Medical Management for Intracranial Artery Stenosis: The BASIS Randomized Clinical Trial.

Importance: Previous randomized clinical trials did not demonstrate the superiority of endovascular stenting over aggressive medical management for patients with symptomatic intracranial atherosclerotic stenosis (sICAS). However, balloon angioplasty has not been investigated in a randomized clinical trial. Objective: To determine whether balloon angioplasty plus aggressive medical management is superior to aggressive medical management alone for patients with sICAS. Design, Setting, and Participants: A randomized, open-label, blinded end point clinical trial at 31 centers across China. Eligible patients aged 35 to 80 years with sICAS defined as recent transient ischemic attack (<90 days) or ischemic stroke (14-90 days) before enrollment attributed to a 70% to 99% atherosclerotic stenosis of a major intracranial artery receiving treatment with at least 1 antithrombotic drug and/or standard risk factor management were recruited between November 8, 2018, and April 2, 2022 (final follow-up: April 3, 2023). Interventions: Submaximal balloon angioplasty plus aggressive medical management (n = 249) or aggressive medical management alone (n = 252). Aggressive medical management included dual antiplatelet therapy for the first 90 days and risk factor control. Main Outcomes and Measures: The primary outcome was a composite of any stroke or death within 30 days after enrollment or after balloon angioplasty of the qualifying lesion or any ischemic stroke in the qualifying artery territory or revascularization of the qualifying artery after 30 days through 12 months after enrollment. Results: Among 512 randomized patients, 501 were confirmed eligible (mean age, 58.0 years; 158 [31.5%] women) and completed the trial. The incidence of the primary outcome was lower in the balloon angioplasty group than the medical management group (4.4% vs 13.5%; hazard ratio, 0.32 [95% CI, 0.16-0.63]; P < .001). The respective rates of any stroke or all-cause death within 30 days were 3.2% and 1.6%. Beyond 30 days through 1 year after enrollment, the rates of any ischemic stroke in the qualifying artery territory were 0.4% and 7.5%, respectively, and revascularization of the qualifying artery occurred in 1.2% and 8.3%, respectively. The rate of symptomatic intracranial hemorrhage in the balloon angioplasty and medical management groups was 1.2% and 0.4%, respectively. In the balloon angioplasty group, procedural complications occurred in 17.4% of patients and arterial dissection occurred in 14.5% of patients. Conclusions and Relevance: In patients with sICAS, balloon angioplasty plus aggressive medical management, compared with aggressive medical management alone, statistically significantly lowered the risk of a composite outcome of any stroke or death within 30 days or an ischemic stroke or revascularization of the qualifying artery after 30 days through 12 months. The findings suggest that balloon angioplasty plus aggressive medical management may be an effective treatment for sICAS, although the risk of stroke or death within 30 days of balloon angioplasty should be considered in clinical practice. Trial Registration: ClinicalTrials.gov Identifier: NCT03703635.