Ruyi Zhenbao Tablet and Baimai Ointment Therapy in Acute Ischemic Stroke: A Study Protocol for a Multi-Center, Randomized, Double-blinded, and Parallel-Controlled Trial.

Introduction: Stroke is characterized by high incidence, recurrence rate, and mortality. Patients with acute ischemic stroke (AIS) who are ineligible for acute revascularization therapy require more effective medication treatments. A previous clinical study showed that Ruyi Zhenbao tablets and Baimai ointments might be effective against AIS; however, high-quality clinical evidence supporting their application in AIS is lacking. To explore the efficacy of the two classic Tibetan medicines in the treatment of AIS, a randomized clinical trial will be conducted in patients with AIS who are not eligible for thrombolytic treatment. Methods: A prospective, randomized, multiple-center, double-blinded, placebo-controlled, and parallel-group trial will be conducted. We shall randomize 480 eligible participants to either the intervention or the control group. The distribution ratio of each group will be 1:1:1:1, including 120 patients each in the dual-medication group, the Baimai ointment group, the Ruyi Zhenbao tablet group, and the placebo group. Participants will be treated with medication for 8 weeks, and they will receive three follow-up visits: at 4 weeks (D29), 8 weeks (D56), and 90 days (D90) after commencing treatment. The primary outcome will be D90 change in the simplified Fugl-Meyer score from baseline to posttreatment. The secondary outcomes are as follows: D29 change of simplified Fugl-Meyer score from baseline to posttreatment; proportion of participants whose D29 NIHSS scores decreased by four or more points from baseline D90 proportion of subjects with mRS score of 0-2 (inclusive); D90 proportion of subjects with Barthel index score ≥95; D90 incidence of cardiovascular and cerebrovascular events. Safety endpoint includes mortality within 90 days; proportion of subjects with adverse events/serious adverse events within 90 days. Conclusion: This research protocol lays a solid groundwork for its practical execution. This study is poised to serve as a reference for other Tibetan medicine researchers, contributing to the reduction of stroke-related expenditures globally and, in turn, benefiting a broader population of stroke patients.

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

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

Disruption of cyclin D1 degradation leads to the development of mantle cell lymphoma.

Cyclin D1 has been recognized as an oncogene due to its abnormal upregulation in different types of cancers. Here, we demonstrated that cyclin D1 is SUMOylated, and we identified Itch as a specific E3 ligase recognizing SUMOylated cyclin D1 and mediating SUMO-induced ubiquitination and proteasome degradation of cyclin D1. We generated cyclin D1 mutant mice with mutations in the SUMOylation site, phosphorylation site, or both sites of cyclin D1, and found that double mutant mice developed a Mantle cell lymphoma (MCL)-like phenotype. We showed that arsenic trioxide (ATO) enhances cyclin D1 SUMOylation-mediated degradation through inhibition of cyclin D1 deSUMOylation enzymes, leading to MCL cell apoptosis. Treatment of severe combined immunodeficiency (SCID) mice grafted with MCL cells with ATO resulted in a significant reduction in tumor growth. In this study, we provide novel insights into the mechanisms of MCL tumor development and cyclin D1 regulation and discover a new strategy for MCL treatment.

The causal relationship between sarcopenia-related traits and ischemic stroke: Insights from univariable and multivariable Mendelian randomization analyses.

AIMS: The causal relationship between sarcopenia-related traits and ischemic stroke (IS) remains poorly understood. This study aimed to explore the causal impact of sarcopenia-related traits on IS and to identify key mediators of this association. METHODS: We conducted univariable, multivariable two-sample, and two-step Mendelian randomization (MR) analyses using genome-wide association study (GWAS) data. This included data for appendicular lean mass (ALM), hand grip strength (HGS), and usual walking pace (UWP) from the UK Biobank, and IS data from the MEGASTROKE consortium. Additionally, 21 candidate mediators were analyzed based on their respective GWAS data sets. RESULTS: Each 1-SD increase in genetically proxied ALM was associated with a 7.5% reduction in the risk of IS (95% CI: 0.879-0.974), and this correlation remained after controlling for levels of physical activity and adiposity-related indices. Two-step MR identified that six mediators partially mediated the protective effect of higher ALM on IS, with the most significant being coronary heart disease (CHD, mediating proportion: 39.94%), followed by systolic blood pressure (36.51%), hypertension (23.87%), diastolic blood pressure (15.39%), type-2 diabetes mellitus (T2DM, 12.71%), and low-density lipoprotein cholesterol (7.97%). CONCLUSION: Our study revealed a causal protective effect of higher ALM on IS, independent of physical activity and adiposity-related indices. Moreover, we found that higher ALM could reduce susceptibility to IS partially by lowering the risk of vascular risk factors, including CHD, hypertension, T2DM, and hyperlipidemia. In brief, we elucidated another modifiable factor for IS and implied that maintaining sufficient muscle mass may reduce the risk of such disease.

A Comprehensive Prediction Model for Futile Recanalization in AIS Patients Post-Endovascular Therapy: Integrating Clinical, Imaging, and No-Reflow Biomarkers.

Our study aimed to construct a predictive model for identifying instances of futile recanalization in patients with anterior circulation occlusion acute ischemic stroke (AIS) who achieved complete reperfusion following endovascular therapy. We included 173 AIS patients who attained complete reperfusion, as indicated by a Modified Thrombolysis in Cerebral Infarction (mTICI) scale score of 3. Our approach involved a thorough analysis of clinical factors, imaging biomarkers, and potential no-reflow biomarkers through both univariate and multivariate analyses to identify predictors of futile recanalization. The comprehensive model includes clinical factors such as age, presence of diabetes, admission NIHSS score, and the number of stent retriever passes; imaging biomarkers like poor collaterals; and potential no-reflow biomarkers, notably disrupted blood-brain barrier (OR 4.321, 95% CI 1.794-10.405; p = 0.001), neutrophil-to-lymphocyte ratio (NLR; OR 1.095, 95% CI 1.009-1.188; p = 0.030), and D-dimer (OR 1.134, 95% CI 1.017-1.266; p = 0.024). The model demonstrated high predictive accuracy, with a C-index of 0.901 (95% CI 0.855-0.947) and 0.911 (95% CI 0.863-0.954) in the original and bootstrapping validation samples, respectively. Notably, the comprehensive model showed significantly improved predictive performance over models that did not include no-reflow biomarkers, evidenced by an integrated discrimination improvement of 8.86% (95% CI 4.34%-13.39%; p < 0.001) and a categorized reclassification improvement of 18.38% (95% CI 3.53%-33.23%; p = 0.015). This model, which leverages the potential of no-reflow biomarkers, could be especially beneficial in healthcare settings with limited resources. It provides a valuable tool for predicting futile recanalization, thereby informing clinical decision-making. Future research could explore further refinements to this model and its application in diverse clinical settings.

Effects of Tirofiban on Neurological Deterioration in Patients With Acute Ischemic Stroke: A Randomized Clinical Trial.

Importance: Evidence supports using antiplatelet therapy in patients with acute ischemic stroke. However, neurological deterioration remains common under the currently recommended antiplatelet regimen, leading to poor clinical outcomes. Objective: To determine whether intravenous tirofiban administered within 24 hours of stroke onset prevents early neurological deterioration in patients with acute noncardioembolic stroke compared with oral aspirin. Design, Setting, and Participants: This investigator-initiated, multicenter, open-label, randomized clinical trial with blinded end-point assessment was conducted at 10 comprehensive stroke centers in China between September 2020 and March 2023. Eligible patients were aged 18 to 80 years with acute noncardioembolic stroke within 24 hours of onset and had a National Institutes of Health Stroke Scale (NIHSS) score of 4 to 20. Intervention: Patients were assigned randomly (1:1) to receive intravenous tirofiban or oral aspirin for 72 hours using a central, web-based, computer-generated randomization schedule; all patients then received oral aspirin. Main Outcome: The primary efficacy outcome was early neurological deterioration (increase in NIHSS score ≥4 points) within 72 hours after randomization. The primary safety outcome was symptomatic intracerebral hemorrhage within 72 hours after randomization. Results: A total of 425 patients were included in the intravenous tirofiban (n = 213) or oral aspirin (n = 212) groups. Median (IQR) age was 64.0 years (56.0-71.0); 124 patients (29.2%) were female, and 301 (70.8%) were male. Early neurological deterioration occurred in 9 patients (4.2%) in the tirofiban group and 28 patients (13.2%) in the aspirin group (adjusted relative risk, 0.32; 95% CI, 0.16-0.65; P = .002). No patients in the tirofiban group experienced intracerebral hemorrhage. At 90-day follow-up, 3 patients (1.3%) in the tirofiban group and 3 (1.5%) in the aspirin group died (adjusted RR, 1.15; 95% CI, 0.27-8.54; P = .63), and the median (IQR) modified Rankin scale scores were 1.0 (0-1.25) and 1.0 (0-2), respectively (adjusted odds ratio, 1.28; 95% CI, 0.90-1.83; P = .17). Conclusions and Relevance: In patients with noncardioembolic stroke who were seen within 24 hours of symptom onset, tirofiban decreased the risk of early neurological deterioration but did not increase the risk of symptomatic intracerebral hemorrhage or systematic bleeding. Trial Registration: ClinicalTrials.gov Identifier: NCT04491695.

Genetically predicted high serum sex hormone-binding globulin levels are associated with lower ischemic stroke risk: A sex-stratified Mendelian randomization study.

OBJECTIVE: Cross-sectional and cohort studies have found insufficient evidence of a causal relationship between sex hormone-binding globulin and ischemic stroke, only associations. Here, we performed a sex-stratified, bidirectional, two-sample Mendelian randomization analysis to evaluate whether a causal relationship exists between sex hormone-binding globulin and ischemic stroke. METHODS: Single-nucleotide polymorphisms associated with sex hormone-binding globulin and ischemic stroke were screened from genome-wide association studies summary data as instrumental variables to enable a bidirectional, two-sample Mendelian randomization study design. Inverse-variance weighted analysis was used as the main method to evaluate potential causality, and additional methods, including the weighted median and MR-Egger tests, were used to validate the Mendelian randomization results. Cochran's Q statistic, MR-Egger intercept test, and Mendelian Randomization-Pleiotropy Residual Sum and Outlier global test were used as sensitivity analysis techniques to assure the reliability of the results. Multivariable analysis was used to show the robustness of the results with key theorized confounders. RESULTS: Inverse-variance weighted analysis showed that genetically predicted higher serum sex hormone-binding globulin levels were associated with significantly decreased risk of ischemic stroke in males (odds radio = 0.934, 95 % confidence interval = 0.885-0.985, P = 0.012) and females (odds radio = 0.924, 95 % confidence interval = 0.868-0.983, P = 0.013). In an analysis of ischemic stroke subtypes, genetically predicted higher serum sex hormone-binding globulin levels were also associated with significantly decreased risk of small-vessel occlusion in both males (odds radio = 0.849, 95 % confidence interval = 0.759-0.949, P = 0.004) and females (odds radio = 0.829, 95 % confidence interval = 0.724-0.949, P = 0.006). The association remained in sensitivity analyses and multivariable analyses. The reverse analysis suggested an association between genetically predicted risk of cardioembolism and increased serum sex hormone-binding globulin in females (Beta = 0.029 nmol/L, Standard Error = 0.010, P = 0.003). CONCLUSION: Our findings provide new insight into the etiology of ischemic stroke and suggest that modulating serum sex hormone-binding globulin may be a therapeutic strategy to protect against ischemic stroke.

A tear-free and edible dehydrated vegetables packaging film with enhanced mechanical and barrier properties from soluble soybean polysaccharide blending carboxylated nanocellulose.

The aim of the study was to develop soybean polysaccharide (SSPS) -carboxylated nanocellulose (CNC) blending films with enhanced mechanical and barrier properties to be used as a tear-free and edible packaging materials. The films were formed by casting method, with CNC as the strengthening unit and glycerol as the plasticizer. The effect of CNC on structural and physical performances of the SSPS-CNC films were studied. SEM indicated that the film will stratify with excess CNC (10 %), but the film remains intact and compact. Incorporation of CNC into SSPS films did not change peak position in the XRD pattern significantly. Hydrogen bonds among SSPS, glycerol and CNC were indicated by the FTIR spectra. The compounding of CNC greatly lessened the light transmittance and hydrophilicity (CA increased from 55.42° to 70.67°), but perfected the barrier (WVP decreased from 3.595 × 10-10 to 2.593 × 10-10 g m-1 s-1 Pa-1) and mechanical properties (TS improved from 0.806 to 1.317 MPa). The results of packaging dehydrated vegetable indicated that the SSPS-8CNC film can effectively inhibit the packaged cabbage absorption water vapor. As a consequence, SSPS film perfected by CNC is hopeful to pack dehydrated vegetables in instant foods.

Dabigatran etexilate versus warfarin in cerebral venous thrombosis in Chinese patients (CHOICE-CVT): An open-label, randomized controlled trial.

BACKGROUND: The efficacy and safety of dabigatran etexilate for Chinese patients with cerebral venous thrombosis (CVT) has not been well established. METHODS: CHOICE-CVT was an exploratory, single-center, randomized, open-label study in the National Center for Neurological Disorders involving Chinese patients with CVT aged 18 to 80 years who were randomly assigned (1:1) to either dabigatran etexilate or warfarin. Oral anticoagulants were initiated after 10-15 days of LMWH. The primary efficacy and safety endpoints included the number of patients with recurrent CVT and/or deep venous thrombosis (DVT) and major clinical bleeding within 180 days. Secondary efficacy endpoints included venous recanalization and change in papilledema at day 180. Secondary safety outcomes comprised death, clinical nonmajor bleeding, and any bleeding. The study was registered with ClinicalTrials.gov under NCT03930940. RESULTS: Between October 2017 and February 2023, a total of 89 patients were enrolled and randomly assigned to receive either dabigatran etexilate (n = 44) or warfarin (n = 45). At day 180, the dabigatran etexilate group showed a statistically nonsignificant but likely clinically significant number of patients with recurrent CVT and/or DVT (8 (18.2%; 95% CI, 6.3-30.0) vs 3 (6.7%; 95% CI, 0.0-14.2), p = 0.099, with a power (1-ß) of 38.401%) compared with the warfarin group. The dabigatran etexilate group showed a comparable number of patients with clinical major bleeding (0 (0) vs 0 (0) p = 1.000), and clinical nonmajor bleeding (1 (2.3%; 95% CI, 0.0-6.9) vs 1 (2.2%; 95% CI, 0.0-6.7)) but demonstrated a lower risk of any bleeding (1 (2.3%; 95% CI, 0.0-6.9) vs 9 (20.0%; 95% CI, 7.8-32.2)) compared with the warfarin group. Most patients in both groups achieved venous recanalization according to the Modified Qureshi scale (27 (75%; 95% CI, 60.1-89.9) in the dabigatran etexilate group vs 34 (82.9%; 95% CI, 70.9-95.0) in the warfarin group) and exhibited improvement in papilledema as per the Frisén classification (35 (97.2%; 95% CI, 91.6-100.0) in the dabigatran etexilate group vs 37 (88.1%, 95% CI, 77.9-98.3) in the warfarin group). CONCLUSIONS: These findings regarding efficacy and safety support the consideration of dabigatran etexilate therapy as a viable treatment option for Chinese patients with CVT.

Night shift work was associated with functional outcomes in acute ischemic stroke patients treated with endovascular thrombectomy.

Objective: This study aimed to explore the impact of late night shift work on the functional outcomes of patients with acute ischemic stroke (AIS) treated with endovascular thrombectomy (EVT). Methods: Consecutive AIS patients who underwent EVT between June 2019 and June 2021 were enrolled and divided into non-night shift work and night shift work groups based on their occupational histories. The primary outcome was the modified Rankin Scale score defined 3-month functional outcome. The secondary outcomes were 3-month mortality, symptomatic intracerebral hemorrhage (sICH), ICH and early recanalization. Results: A total of 285 patients were enrolled, 35 patients (12.3%) were night shift workers, who were younger (P < 0.001) and had a significantly higher prevalence of smoking (P < 0.001), hyperlipidemia (P = 0.002), coronary heart disease (P = 0.031), and atrial fibrillation (P < 0.001). The 3-month favorable outcomes were achieved in 44.8% and 25.7% of patients in the non-night shift work and night shift work groups, respectively (adjusted odds ratio [OR]: 0.24, 95% CI: 0.10-0.57; adjusted P = 0.001). No difference was found in 3-month mortality (adjusted OR: 0.43; 95% CI: 0.14-1.25, adjusted P = 0.121), rates of ICH (adjusted OR: 0.73; 95% CI: 0.33-1.60; adjusted P = 0.430), sICH (adjusted OR: 0.75; 95% CI: 0.34-1.67; adjusted P = 0.487), or early successful recanalization (adjusted OR: 0.42; 95% CI: 0.12-1.56; adjusted P = 0.197). These results were consistent after PSM analysis. Conclusion: Our findings suggest that late night shift work is significantly associated with unfavorable outcomes in patients with AIS after EVT.

Thrombolysis with Recombinant Human Prourokinase 4.5-6 h After Acute Ischemic Stroke: A Phase IIa, Randomized, and Open-Label Multicenter Clinical Trial.

BACKGROUND: Ischemic stroke is a major cause of disability and death worldwide. A narrow therapeutic window profoundly constrained the utilization of alteplase. OBJECTIVES: To investigate therapeutic effects and safety of intravenous recombinant human prourokinase (rhPro-UK) in patients with acute ischemic stroke (AIS) in the 4.5-6 h therapeutic time windows. METHODS: We conducted a phase IIa, randomized, and open-label multicenter clinical trial. Between 4.5 and 6 h after the onset of AIS, patients were randomly administrated to receive intravenous rhPro-UK at a 50 mg or 35 mg dose. The primary endpoint was excellent functional outcome defined as modified Rankin scale (mRS) score of 1 or less at 90 days. The secondary outcome was the treatment response, which was based on an at least 4-point improvement from baseline National Institutes of Health stroke scale (NIHSS) score at 24 h after drug administration. Safety endpoints included death, symptomatic intracerebral hemorrhage (sICH), and other serious adverse events. RESULTS: We enrolled 80 patients in the 4.5-6 h therapeutic time windows at 17 medical centers in China from December 2016 to November 2017. A total of 39 patients were treated with 50 mg rhPro-UK, and 39 were treated with 35 mg rhPro-UK. Compared with the baseline, the NIHSS score at 24 h and days 7, 14, 30, and 90 was decreased significantly among patients treated with either rhPro-UK 50 mg or 35 mg. The mean reduction in the NIHSS from baseline to 90 days after the onset was 3.56 and 5.79 in the rhPro-UK 50 mg group and the rhPro-UK 35 mg group, respectively. The rates of functional independence at 90 days of rhPro-UK 50 mg and 35 mg were 61.54% and 69.23%, respectively (P = 0.475), and the proportion of patients with functional response to treatment at 24 h were 28.21% and 33.33% (P = 0.624). No sICH occurred in the two groups, and death occurred in only one patient in the rhPro-UK 50 mg group. There was no significant difference in mortality at 90 days and the rate of other serious adverse events between two groups. CONCLUSION: In the 4.5-6 h time window, more than 60% of patients at either dose of rhPro-UK (50 mg or 35 mg) achieved functional independence at 90 days without increased mortality and sICH risk. Thus, intravenous rhPro-UK was effective and safe for patients with AIS within 4.5-6 h after stroke onset. While no significant differences were identified between different dosages of rhPro-UK regarding clinical outcomes, it is a logical step to further test the safety and efficacy of the low dose of rhPro-UK in a well-powered phase III study. TRIAL REGISTRATION: http://www.chictr.org.cn . Identifier: ChiCTR1800016519. Date of registration: 6 June 2018.

Predicting Futile Recanalization in Acute Ischemic Stroke Patients Undergoing Endovascular Thrombectomy: The Role of White Blood Cell Count to Mean Platelet Volume Ratio.

BACKGROUND: Approximately half of AIS patients have an unfavorable outcome even after complete reperfusion. White blood cell (WBC) count to mean platelet volume (MPV) ratio (WMR) may be a promising predictive factor for futile recanalization. This study aimed to determine the predictive value of WMR in identifying individuals at higher risk of futile recanalization. METHODS: In this retrospective cohort study, 296 patients who achieved complete reperfusion after endovascular treatment (EVT) were included in the analysis. WBC count and MPV were collected at admission. Multivariable logistic regression was used to examine the independent association of the WMR with functional outcomes at three months. Net reclassification improvement (NRI) and integrated discrimination improvement (IDI) analyses were used to compare the accuracy of WMR for predicting futile recanalization. RESULTS: The adjusted odds ratios for the fourth quartile of WMR were 3.142 (95% CI 1.405- 7.027, P = 0.005) for unfavorable outcomes at 3 months in comparison with the first quartile. The inclusion of WMR in the traditional model enabled a more accurate prediction of unfavorable outcomes (NRI 0.250, P = 0.031; IDI 0.022, P = 0.017). CONCLUSION: Elevated WMR at admission was independently associated with futile recanalization among AIS patients who received EVT and might be useful in identifying futile recanalization.

Elevating nucleic acid delivery via a stable anionic peptide-dextran ternary system.

Nucleic acid-based therapies hold promise for treating previously intractable diseases but require effective delivery vectors to protect the therapeutic agents and ensure efficient transfection. Cationic polymeric vectors are particularly notable for their adaptability, high transfection efficiency, and low cost, but their positive charge often attracts blood proteins, causing aggregation and reduced transfection efficiency. Addressing this, we designed an anionic peptide-grafted dextran (Dex-LipE5H) to serve as a cross-linkable coating to bolster the stability of cationic polymer/nucleic acid complexes. The Dex-LipE5H was synthesized through a Michael addition reaction, combining an anionic peptide (LipE5H) with dextran modified by divinyl sulfone. We demonstrated Dex-lipE5H utility in a novel ternary nucleic acid delivery system, CDex-LipE5H/PEI/nucleic acid. CDex-LipE5H/PEI/nucleic acid demonstrated lower cytotoxicity and superior anti-protein absorption ability compared to PEI/pDNA and Dex-LipE5H/PEI/pDNA. Most notably, the crosslinked CDex-LipE5H/PEI/pDNA demonstrated remarkable transfection performance in HepG2 cells, which poses significant transfection challenges, even in a medium with 20% serum. This system's effective siRNA interference performance was further validated through a PCSK9 gene knockdown assay. This investigation provides novel insights and contributes to the design of cost-effective, next-generation nucleic acid delivery systems with enhanced blood stability and transfection efficiency.

Characteristics and Mechanism of Acute Ischemic Stroke in NAVF Patients With Prior Oral Anticoagulant Therapy.

OBJECTIVES: We aimed to analyze the characteristics and mechanisms of acute ischemic stroke (AIS) in patients with nonvalvular atrial fibrillation (NVAF) who received prior anticoagulant therapy. METHODS: We retrospectively analyzed the data of patients with NVAF and AIS between January 2016 and December 2021. Patients were divided into non-anticoagulant, adequate anticoagulant, and insufficient anticoagulant groups according to their prior anticoagulant status. Patients with prior anticoagulant therapy were further divided into warfarin and direct oral anticoagulant groups. RESULTS: A total of 749 patients (661 without anticoagulants, 33 with adequate anticoagulants, and 55 with insufficient anticoagulants) were included. Patients with adequate anticoagulant had a milder National Institute of Health Stroke Scale at presentation ( P =0.001) and discharge ( P =0.003), a higher proportion of Modified Rankin Scale (mRS) ≤2 at discharge ( P =0.011), and lower rates of massive infarction ( P =0.008) than patients without anticoagulant. Compared with the non-anticoagulant group, the proportion of intravenous thrombolysis was significantly lower in the adequate anticoagulant ( P <0.001) and insufficient anticoagulant ( P =0.009) groups. Patients in the adequate anticoagulant group had higher rates of responsible cerebral atherosclerotic stenosis ( P =0.001 and 0.006, respectively) and competing large artery atherosclerotic mechanisms ( P =0.006 and 0.009, respectively) than those in the other 2 groups. Compared with warfarin, direct oral anticoagulant was associated with higher rates of Modified Rankin Scale ≤2 at discharge ( P =0.003). CONCLUSIONS: Adequate anticoagulant therapy may be associated with milder stroke severity and better outcomes at discharge in patients with NVAF. Competing large artery atherosclerotic mechanisms may be associated with anticoagulant failure in patients with NAVF with prior adequate anticoagulant therapy.

Predicting ischemic stroke risk from atrial fibrillation based on multi-spectral fundus images using deep learning.

Background: Ischemic stroke (IS) is one of the most common serious secondary diseases of atrial fibrillation (AF) within 1 year after its occurrence, both of which have manifestations of ischemia and hypoxia of the small vessels in the early phase of the condition. The fundus is a collection of capillaries, while the retina responds differently to light of different wavelengths. Predicting the risk of IS occurring secondary to AF, based on subtle differences in fundus images of different wavelengths, is yet to be explored. This study was conducted to predict the risk of IS occurring secondary to AF based on multi-spectrum fundus images using deep learning. Methods: A total of 150 AF participants without suffering from IS within 1 year after discharge and 100 IS participants with persistent arrhythmia symptoms or a history of AF diagnosis in the last year (defined as patients who would develop IS within 1 year after AF, based on fundus pathological manifestations generally prior to symptoms of the brain) were recruited. Fundus images at 548, 605, and 810 nm wavelengths were collected. Three classical deep neural network (DNN) models (Inception V3, ResNet50, SE50) were trained. Sociodemographic and selected routine clinical data were obtained. Results: The accuracy of all DNNs with the single-spectral or multi-spectral combination images at the three wavelengths as input reached above 78%. The IS detection performance of DNNs with 605 nm spectral images as input was relatively more stable than with the other wavelengths. The multi-spectral combination models acquired a higher area under the curve (AUC) scores than the single-spectral models. Conclusions: The probability of IS secondary to AF could be predicted based on multi-spectrum fundus images using deep learning, and combinations of multi-spectrum images improved the performance of DNNs. Acquiring different spectral fundus images is advantageous for the early prevention of cardiovascular and cerebrovascular diseases. The method in this study is a beneficial preliminary and initiative exploration for diseases that are difficult to predict the onset time such as IS.

Malignant Middle Cerebral Artery Infarction during Early versus Late Endovascular Treatment in Acute Ischemic Stroke.

INTRODUCTION: Endovascular treatment (EVT) performed in the early time window has been shown to decrease the incidence of malignant middle cerebral artery infarction (MMI). However, the incidence of MMI in patients undergoing EVT during the late time window is unclear. This study aimed to investigate the prevalence of MMI in patients undergoing late EVT and compare it with that in patients undergoing early EVT. METHODS: We retrospectively analyzed consecutive patients with anterior large vessel occlusion stroke who underwent EVT at Xuanwu Hospital between January 2013 and June 2021. Eligible patients were divided into early EVT (within 6 h) and late EVT (6-24 h) groups according to the time from their stroke onset to puncture and compared. The occurrence of MMI post-EVT was the primary outcome. RESULTS: A total of 605 patients were recruited, of whom 300 (50.4%) underwent EVT within 6 h and 305 (49.6%) underwent EVT within 6-24 h. A total of 119 patients (19.7%) developed MMI. 68 patients (22.7%) in the early EVT group and 51 patients (16.7 %) in the late EVT group developed MMI (p = 0.066). After adjusting for covariate variables, late EVT was independently associated with a lower incidence of MMI (odds ratio, 0.404; 95% confidence interval, 0.242-0.675; p = 0.001). CONCLUSION: MMI is not an uncommon phenomenon in the modern thrombectomy era. Compared with the early time window, patients selected by stricter radiological criteria to undergo EVT in the late time window are independently associated with a lower incidence of MMI.

Efficacy and Safety of Recombinant Human Prourokinase in the Treatment of Acute Ischemic Stroke Within 4.5 Hours of Stroke Onset: A Phase 3 Randomized Clinical Trial.

Importance: Recombinant human prourokinase (rhPro-UK) is a thrombolytic agent that has shown promising findings in a phase 2 clinical trial in patients with acute ischemic stroke (AIS). Objective: To evaluate the efficacy and safety of rhPro-UK thrombolysis within 4.5 hours of symptom onset in patients with AIS. Design, Setting, and Participants: This randomized, alteplase-controlled, open-label, phase 3 clinical trial was conducted from May 2018 to May 2020 at 35 medical centers in China. A total of 684 patients were screened and 674 patients were enrolled. Included patients were aged 18 to 80 years with a diagnosis of AIS and received treatment within 4.5 hours of stroke onset. Data were analyzed from June to October 2020. Interventions: Eligible patients were randomly assigned (1:1) to receive intravenous rhPro-UK or alteplase. Main Outcomes and Measures: The primary objective was to assess whether rhPro-UK was noninferior to alteplase. The noninferiority margin was a between-group difference of less than 10%. The primary outcome was a modified Rankin Scale score of 0 to 1 at 90 days. Results: Among 663 patients in the modified intention-to-treat population (mean [SD] age, 61.00 [10.20] years; 161 females [24.3%]), there were 330 patients in the rhPro-UK group and 333 patients in the alteplase group. The median (IQR) baseline National Institutes of Health Stroke Scale score was 6.00 (5.00-9.00). There were 23 deaths, and 619 patients (93.4%) completed the 3-month follow-up. The primary outcome occurred in 215 patients (65.2%) in the rhPro-UK group and 214 patients (64.3%) in the alteplase group (risk difference, 0.89; 95.4% CI, -6.52 to 8.29). Symptomatic intracerebral hemorrhage occurred in 5 patients (1.5%) in the rhPro-UK group and 6 patients (1.8%) in the alteplase group (P > .99). Systemic bleeding within 90 days occurred more frequently in the alteplase group (141 patients [42.2%]) than the rhPro-UK group (85 patients [25.8%]) (P < .001). By 90 days, 5 thrombolysis-related deaths each had occurred in the rhPro-UK group (1.5%) and alteplase group (1.5%) (P > .99). Conclusions and Relevance: This study found that intravenous rhPro-UK within 4.5 hours of AIS onset was noninferior to alteplase. The rhPro-UK group showed a similar rate of symptomatic ICH but fewer cases of systemic bleeding than the alteplase group. Trial Registration: ClinicalTrials.gov Identifier: NCT03541668.

Safety and Tolerability of Direct Ischemic Postconditioning Following Thrombectomy for Acute Ischemic Stroke.

BACKGROUND: Experimental studies have demonstrated the neuroprotection of ischemic postconditioning (IPostC) in acute ischemic stroke by attenuating ischemia-reperfusion injury. This study aimed to investigate the safety and tolerability of direct IPostC in both a dog model and patients with acute ischemic stroke treated with thrombectomy. METHODS: The study involved 2 parts. First, IPostC was induced by repeated balloon inflation and deflation in dogs, where a low-pressure balloon was navigated to the anterior spinal artery, and 4 cycles of 5-minute ischemia followed by 5-minute reperfusion were performed. Vascular injuries were assessed using angiography and vascular tissue specimens. Then, a 3+3 dose-escalation trial was conducted in patients with acute ischemic stroke following successful thrombectomy recanalization. Patients received direct IPostC with ischemia and reperfusion durations in progressive increments of 0, 1, 2, 3, 4, and 5 minutes ×4 cycles. Major adverse responses were defined as vessel perforation, rupture, dissection, reocclusion, severe vasospasm, thrombotic events, and rupture of the balloon. RESULTS: IPostC was investigated in 4 dogs. No vessel perforation or rupture, dissection, or vasospasm was observed under the angiography. Only 1 vessel experienced mild injury between the intima and the internal elastic membrane detected on a histopathologic slide. Then, 18 patients were recruited. The duration of IPostC was progressively escalated with no major response happened. No patient experienced agitation, discomfort, or other tolerability issues. Five patients (27.8%) experienced any intracranial hemorrhage after thrombectomy, and 1 (5.6%) was symptomatic. At 3-month follow-up, no patient died, and 9 patients (50%) achieved functional independence. CONCLUSIONS: Direct IPostC inducing by 4 cycles of 5-minute ischemia followed by 5-minute reperfusion is safe, feasible, and tolerable in patients with acute ischemic stroke treated with thrombectomy. Further investigations are needed to determine the safety and preliminary efficacy of direct IPostC. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT05153655.

Efficacy and Safety of Panax notoginseng Saponins in the Treatment of Adults With Ischemic Stroke in China: A Randomized Clinical Trial.

Importance: Preclinical and clinical studies have suggested the neuroprotective effect of Panax notoginseng saponins (Xuesaitong soft capsules). However, robust evidence in patients with ischemic stroke is lacking. Objective: To assess the efficacy and safety of Xuesaitong soft capsules in patients with ischemic stroke. Design, Setting, and Participants: This multicenter, double-blind, placebo-controlled randomized clinical trial was conducted at 67 tertiary health centers in China from July 1, 2018, to June 30, 2020. Included patients were aged 18 to 75 years with a diagnosis of ischemic stroke and a National Institutes of Health Stroke Scale score between 4 and 15. Interventions: Eligible patients were randomly assigned within 14 days after symptom onset to receive either treatment with Xuesaitong soft capsules (120 mg orally twice daily) or placebo (120 mg orally twice daily) for 3 months. Main Outcomes and Measures: The primary outcome was functional independence at 3 months, defined as a modified Rankin Scale score of 0 to 2. Results: Among 3072 eligible patients with ischemic stroke who were randomized, 2966 (96.5%) were included in the modified intention-to-treat cohort (median [IQR] age, 62 [55-68] years; 1982 male [66.8%]). The number of patients who achieved functional independence at 3 months was 1328 (89.3%) in the Xuesaitong group and 1218 (82.4%) in the control group (odds ratio, 1.95; 95% CI, 1.56-2.44; P < .001). In the safety cohort, serious adverse events occurred in 15 of 1488 patients (1.0%) in the Xuesaitong group and 16 of 1482 (1.1%) in the control group (P = .85). Conclusions and Relevance: In this randomized clinical trial, Xuesaitong soft capsules significantly increased the likelihood of functional independence at 3 months in patients with ischemic stroke, indicating that this may be a safe and effective alternative therapy to improve prognosis in this population. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR1800016363.

Design and Test of Spatial Cognitive Training and Evaluation System Based on Virtual Reality Head-Mounted Display With EEG Recording.

The field of spatial cognitive training and evaluation has rapidly evolved. However, the low learning motivation and engagement of the subjects hinder the widespread use of spatial cognitive training. This study designed a home-based spatial cognitive training and evaluation system (SCTES), which aimed to train subjects on spatial cognitive tasks for 20 days, and compared the brain activities before and after the training. This study also evaluated the feasibility of using a portable all-in-one prototype for cognitive training that combined a virtual reality (VR) head-mounted display with high-quality electroencephalogram (EEG) recording. During the course of training, the length of the navigation path and the distance between the starting position and the platform position revealed significant behavioral differences. In the testing sessions, the subjects showed significant behavioral differences in the time it took to complete the test task before and after training. After only four days of training, the subjects demonstrated significant differences in the Granger causality analysis (GCA) characteristics of brain regions in the δ , θ , α1 , ß2 , and γ frequency bands of the EEG, as well as significant differences in the GCA of the EEG in the ß1 , ß2 , and γ frequency bands between the two test sessions. The proposed SCTES used a compact and all-in-one form factor to train and evaluate spatial cognition and collect EEG signals and behavioral data simultaneously. The recorded EEG data can be used to quantitatively assess the efficacy of spatial training in patients with spatial cognitive impairments.