Swelling-dependent self-folding hydrogels show considerable promise for tissue engineering applications. However, current systems face limitations in cell growth within the passive layer. This study introduces a novel approach to developing swelling-dependent bilayer hydrogels using biocompatible and biodegradable composites of methacrylated silk fibroin and methacrylated gelatin (SilMA-GelMA) through a "sonication-photocrosslinking" strategy. The sonication treatment induces beta-sheets (β-sheets) formation in silk fibroin molecules, creating a stable, less swellable passive layer while maintaining material consistency across the bilayer structure. Comprehensive characterization revealed significant differences in swelling ratio, mechanical properties, and degradation profiles between sonicated and nonsonicated layers. The optimized bilayer hydrogel composed of 50% GelMA with 50% SilMA (GS5) as the active layer and sonicated GS5 (GSS5) as the passive layer demonstrated efficient self-folding behavior, forming complete tubular structures after incubation. Furthermore, cell encapsulation experiments with human umbilical vein endothelial cells (HUVECs) revealed high cellular viability and proliferation in both sonicated and nonsonicated hydrogel layers over a 5-day culture period. This biocompatible and biodegradable swelling-dependent self-folding hydrogel provides a promising platform for creating complex, cell-laden tissue engineering constructs with controlled spatial distribution of cells and is particularly suitable for tubular tissue applications such as vascular engineering and the formation of other hollow organ structures where precisely controlled cellular organization is essential for proper function.

Stroke remains a major global public health challenge, with persistent disparities in its burden across countries, and an increasing burden among young adults aged 15-49 has emerged as a growing concern. However, comprehensive evaluations of stroke and its subtypes among young adults in Asia remain limited. This study utilizes data from the 2021 Global Burden of Diseases, Injuries, and Risk Factors Study (GBD), covering the period from 1990 to 2021, to assess the burden of stroke in Asia and provide evidence-based policy and resource allocation. In this study, we extracted GBD 2021 data to estimate the absolute numbers and rates of prevalence, incidence, mortality, disability-adjusted life years (DALYs), years of life lost (YLLs), and years lived with disability (YLDs) due to stroke and its subtypes among young adults (15-49 years) in Asia from 1990 to 2021, with data stratified by year, age group, and sex. In addition, we analyzed major risk factors and projected future trends through 2050. Our analysis showed that in 2021, stroke accounted for 14.70 million (95% UI 13.39–16.01 million) DALYs and 1.14 million (95% UI 0.99–1.32 million) new cases in Asia, with a DALY rate of 620.24 (95% UI 564.66–675.12) per 100,000 and an incidence rate of 48.22 (95% UI 41.81–55.69) per 100,000. From 1990 to 2021, absolute numbers of prevalence, incidence, mortality, DALYs, YLLs, and YLDs increased by 43.56%, 44.82%, 10.68%, 11.02%, 7.64%, and 38.54%, respectively. Although the rates of prevalence and incidence showed slight increases of 0.07% and 0.96%, the rates of mortality, DALYs, YLLs, and YLDs decreased by 22.84%, 22.61%, 24.96%, and 3.42%, respectively. Among stroke subtypes, both ischemic stroke (IS) and intracerebral hemorrhage (ICH) showed increases in the absolute numbers across six metrics, with IS demonstrating more pronounced growth. Subarachnoid hemorrhage (SAH) showed increases in the incidence, prevalence, and YLDs, while its rates of mortality, DALYs, and YLLs declined. The rates of all six metrics decreased for ICH and SAH, whereas the rates of prevalence, incidence, and YLDs for IS increased, alongside reductions in the rates of mortality, DALYs, and YLLs. The absolute numbers and rates of all six metrics increased with age across both sexes, with males consistently showing higher absolute numbers and the highest burden observed in the 45-49 age group. Apart from the prevalence and YLD rates, males demonstrated higher incidence, mortality, DALYs, and YLL rates across all age groups, peaking at 45-49 years. Moreover, the leading contributors to stroke-related DALYs included high systolic blood pressure, smoking, and air pollution. From 2021 to 2050, the prevalence and incidence of stroke will continue to rise, while mortality and DALYs rates are expected to decline. Overall, from 1990 to 2021, the burden of stroke and its subtypes among young adults in Asia has increased significantly, with notable differences across age groups and sex, and with population growth and demographic changes, this burden is expected to further intensify in the future. Therefore, future research and public health policies should focus more on targeted interventions addressing the specific needs of young adults to effectively control and alleviate the burden of stroke.

A high-performance nanozyme electrochemical sensor was engineered for the sensitive detection of hydrogen peroxide (H2O2). The sensor is based on a synergistic ternary nanocomposite of ZIF-8, reduced graphene oxide (RGO), and platinum nanoparticles (Pt NPs). In this design, the Pt NPs serve as the catalytic centers with intrinsic peroxidase-like activity, effectively mimicking natural enzymes to catalyze the electrochemical reduction of H2O2. This nanocomposite was immobilized on a glassy carbon electrode (GCE) via a combined drop-casting and electrodeposition strategy. Morphological and structural analyses using scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), and X-ray photoelectron spectroscopy (XPS) confirmed the successful fabrication of a uniform nanocomposite architecture. Systematic optimization revealed that the sensor exhibited excellent detection performance for H2O2, with a sensitivity of 22.3 μA mM-1 cm-2 (n = 4), a detection limit as low as 59 nM (S/N = 3), a limit of quantification of 0.197 μM, and a linear range of 62 nM-13.07 mM, exhibiting good selectivity and reproducibility. Importantly, the sensor was successfully applied for the real-time, in-situ monitoring of H2O2 released from zebrafish embryos under cadmium ion (Cd2+) induced oxidative stress. This work offers a promising tool for the early assessment of heavy metal-induced oxidative damage.

BACKGROUND:Post-stroke cognitive impairment (PSCI) is a frequent and disabling consequence of ischemic stroke. Leukocyte telomere length (LTL), a biomarker of systemic biological aging, has been implicated in cognitive outcomes, but evidence in stroke populations remains limited. We investigated whether baseline LTL and an LTL polygenic risk score (LTL-PRS) are associated with PSCI risk in a large Chinese stroke cohort. METHODS:We analyzed patients with ischemic stroke or transient ischemic attack (TIA) from the Third China National Stroke Registry-impairment of cognition and sleep (CNSR-III-ICONS) sub study. Baseline LTL was estimated from whole-genome sequencing (WGS) using TelSeq. An 18-SNP LTL-PRS (East-Asian weights) was z-standardized. Cognitive status at 12 months was assessed using the Montreal Cognitive Assessment (MoCA); PSCI was defined as an age-, sex-, education-adjusted norm-referenced threshold (z score ≤ -1.5). Fifty-one participants missing education required for the adjusted PSCI definition were excluded, leaving 923 for analysis. Multivariable logistic regression tested associations of LTL and LTL-PRS with PSCI, with exploratory interaction and stratified analyses by age, sex, and stroke subtype. RESULTS:PSCI occurred in 191 of 923 patients (20.7%). Neither continuous LTL nor LTL-PRS was associated with PSCI overall. Exploratory analyses provided nominal evidence of heterogeneity by age (p-interaction = 0.038) and stroke subtype (p-interaction = 0.01), whereas evidence for sex interaction was inconclusive (p-interaction = 0.07). Associations with the MoCA executive function domain were weak and sensitive to covariate adjustment. CONCLUSIONS:Baseline telomere metrics showed, at most, modest and context-dependent associations with PSCI. Neither LTL nor this limited-variant LTL-PRS demonstrated overall prognostic utility, highlighting the need for integrated, longitudinal multi-omic approaches for individualized cognitive risk prediction after stroke.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease partly caused by gain-of-function mutations in superoxide dismutase 1 (SOD1). Here we developed RAG-17, an siRNA-targeting SOD1, using an accessory oligonucleotide conjugate platform for enhanced central nervous system (CNS) delivery. Preclinically, RAG-17 rescued motor neuron degeneration, delayed disease progression, preserved motor function and extended survival in SOD1G93A ALS rodents, even with advanced-stage treatment. In cynomolgus monkeys, intrathecal RAG-17 led to dose-dependent, durable reductions in SOD1 mRNA (CNS) and protein (cerebrospinal fluid (CSF)). In a first-in-human trial in patients with SOD1-ALS (n = 6), participants were assigned to two cohorts-cohort 1 (n = 3) received an initial 60 mg dose (seven doses total) and cohort 2 (n = 3) received an initial 90 mg dose (six doses total). The dose was escalated in 30 mg steps to maintenance doses of 150 mg (n = 5) or 180 mg (n = 1). Thus, the primary safety endpoint was met, showing acceptable safety and tolerability. Treatment-emergent adverse events (TEAEs) occurred in 33% of participants (two of six). All TEAEs were mild to moderate, including muscle tremor (two patients) and elevated alanine aminotransferase (one patient), all of which resolved. No serious adverse events were reported. Furthermore, no other clinically meaningful changes were observed in laboratory parameters, vital signs, the ALS Functional Rating Scale-Revised score, physical or neurological examinations or ECG. The key secondary endpoints showed CSF SOD1 reductions of 69% (cohort 1, day 240) and 56% (cohort 2, day 210), and plasma neurofilament light chain reductions of 62% (cohort 1) and 52% (cohort 2), from baseline; no patient required invasive mechanical ventilation or died by the end of the study. These results demonstrate a favorable safety outcome, supporting the continued clinical evaluation of RAG-17 for SOD1-ALS. ClinicalTrials.gov registration: NCT05903690 .

Polyacrylamide (PAM) hydrogels are promising candidates for flexible wearable sensors but suffer from limitations including toxic cross-linkers(N,N '-methylenebis(acrylamide), BIS), prolonged gelation times, high-temperature requirements, and inadequate mechanical properties. Herein, a quadruple-functional MXene was employed to fabricate high-performance PAM hydrogels within 5 min at ambient temperature. MXenes served simultaneously as an initiating accelerator (replacing toxic BIS), physical cross-linker, conductive agent, and reinforcing nanofiller. Reductive MXene nanosheets catalyzed ultrafast polymerization of acrylamide monomers via redox reactions with ammonium persulfate(APS), facilitating a green, low-energy fabrication process and preventing MXene nanosheets reaggregation within the hydrogel network. By adjusting the MXene content, the optimized hydrogel (6 mg/mL MXene) demonstrated exceptional mechanical performance, with 1558% elongation at break and 119 kPa tensile strength, exceeding traditional BIS/PAM hydrogels (1081% elongation, 74 kPa strength). This enhancement is attributed to the uniform honeycomb-like porous structure and dual-network architecture comprising covalent PAM backbone and physical hydrogen-bonded MXene cross-links. Additionally, the MXene incorporation confers electrical conductivity (0.3 S/m) and photothermal performance, with temperature increase up to 21.8 degrees C under near-infrared (NIR) irradiation and good photothermal stability. As a strain sensor, the hydrogel exhibits two-stage sensing response with gauge factor (GF) of 1.1 (0-235%) and 2.4 (235-400%), rapid response time (35 ms), recovery time (98 ms), and excellent cyclic stability. In L929 cytotoxicity assays, MXene/PAM hydrogels demonstrate improved biocompatibility compared to BIS/PAM hydrogels. The sensor accurately monitors both large human movements (finger, wrist, bending, handwriting) and subtle physiological activities (pulse and throat vibrations). This study introduces a rapid, eco-friendly method for fabricating multifunctional PAM hydrogels with enhanced mechanical, conductive, photothermal, and biocompatible properties for flexible electronic skin and biomedical devices.

BACKGROUND:Minocycline has been reported as a multi-target anti-neuroinflammatory drug with potential benefits for ischaemic stroke in preclinical models and small-scale clinical studies. The EMPHASIS trial was designed to provide robust evidence regarding its efficacy and safety in patients with acute ischaemic stroke. METHODS:A multicentre, double-blind, randomised, placebo-controlled trial was conducted at 58 hospitals across China. Patients who had an ischaemic stroke in the previous 72 h with a National Institutes of Health Stroke Scale (NIHSS) score ranging from 4 to 25 and a level of consciousness score (subscale 1a of the NIHSS) of 1 or less were randomly assigned in a 1:1 ratio to receive minocycline or placebo in addition to routine treatment. Minocycline (loading dose of 200 mg, followed by 100 mg every 12 h for the subsequent 4 days) or matching placebo was administered orally. Block randomisation with a fixed block size of four stratified by study site was done with a computer-generated randomisation sequence. All patients, treating clinicians, and investigators involved in the trial were fully masked to treatment allocation. The primary outcome was an excellent functional outcome at 90 days (with a modified Rankin Scale [mRS] score of 0-1) and was analysed in all patients who were randomised and received at least one dose of the study drug, without imputation for missing data. Safety outcomes were assessed in participants who received at least one dose of the study drug and had at least one safety evaluation and included symptomatic intracranial haemorrhage at 24 h and 6 days. This trial was registered with ClinicalTrials.gov (NCT05836740) and is now completed. FINDINGS:Between May 19, 2023, and May 20, 2024, 1724 patients were randomly assigned to minocycline (n=862) or placebo (n=862) groups. Median age was 65 years (IQR 57-71). 1151 (66·8%) patients were male and 573 (33·2%) were female. Median NIHSS score at baseline was 5 (IQR 4-7). Four patients withdrew consent (three in the minocycline group and one in the placebo group) and 19 patients were lost to follow-up (nine in the minocycline group and ten in the placebo group). At 90 days, 447 (52·6%) of 850 patients with minocycline and 403 (47·4%) of 851 with placebo had an mRS score of 0-1 (adjusted risk ratio 1·11, 95% CI 1·03-1·20; p=0·0061). Ordinal analysis across the full range of mRS scores also favoured minocycline, with an adjusted common odds ratio of 1·19 (95% CI 1·03-1·38; p=0·018). The incidence of symptomatic intracranial haemorrhage was similar between the minocycline and placebo groups at 24 h (1/860 [0·1%] vs 0/861 [0%]) and 6 days (3/859 [0·3%] vs 0/861 [0%]). No significant differences were observed in other safety outcomes, including serious adverse events (40/862 [4·6%] in the minocycline group vs 51/862 [5·9%] in the placebo group; p=0·24). INTERPRETATION:Minocycline therapy initiated within 72 h of acute ischaemic stroke provided a significant functional outcome benefit compared with placebo at 90 days, without safety concerns. Future studies are needed to confirm these findings and to establish whether the benefits extend to patients with more severe or minor strokes. FUNDING:National Natural Science Foundation of China, Beijing Healthunion Cardio-cerebrovascular Disease Prevention and Treatment Foundation, Noncommunicable Chronic Diseases-National Science and Technology Major Project, Beijing Municipal Science & Technology Commission, Chinese Institutes for Medical Research, Capital's Funds for Health Improvement and Research, and National Key R&D Program of China.

Hydrogel-based wound dressings, which facilitate rapid wound closure and healing, are essential for effective wound management. However, the development of an ideal hydrogel that possesses excellent mechanical properties, effective self-healing capabilities, tissue adherence and antimicrobial characteristics for wound dressing presents a significant challenge in clinical settings. Inspired by lotus-fiber and mussel, we synthesized a novel multifunctional hydrogel composed of bacterial cellulose-reinforced dopamine-grafted oxidized hyaluronic acid/polyacrylamide (OHA-DA/PAM/BC). This was achieved through a one-pot reaction that employed free radical polymerization of acrylamide, dynamic Schiff bonding and intermolecular hydrogen bonding. Compared with the pure PAM hydrogels, which exhibited an elongation at break of 4022% and a maximum tensile strength of 26.42 kPa, the OHA-DA/PAM hydrogel demonstrated significantly enhanced stretchability at 9949% and an increased tensile strength of 34.73 kPa when 0.3% OHA-DA was incorporated during hydrogel formulation. Notably, the addition of 0.8% BC significantly enhanced the tensile strength to 57.04 kPa and super-stretchability to 10679%. The OHA-DA/PAM/BC hydrogel also exhibited remarkable self-healing capabilities, achieving a mechanical recovery of 84.74% within 12 h. Additionally, its adhesive and injectable properties are advantageous for dynamic wound repair. Furthermore, the OHA-DA/PAM/BC hydrogel exhibited minimal hemolytic activity and potent intrinsic antibacterial properties against both Escherichia coli and Staphylococcus aureus. In a mouse model of wound healing, this hydrogel reduced the healing duration to 14 days while enhancing the regeneration of both skin structure and function. Histological analyses further revealed that the hydrogel significantly promoted the development of well-organized granulation tissue, angiogenic tissue and collagen accumulation in the wound region. This study successfully developed an OHA-DA/PAM/BC multifunctional hydrogel characterized by exceptional stretchability, self-healing, adhesiveness, injectability and antibacterial activity, demonstrating a significant impact on wound healing in vivo. These findings indicated that the OHA-DA/PAM/BC hydrogel holds substantial potential as wound dressings for future clinical applications.

BACKGROUND:Acute ischaemic stroke, due to its high mortality and disability rates, imposes a significant economic and social burden worldwide. Typically, endovascular treatment within the therapeutic window is provided to salvage the ischaemic penumbra; however, even when recanalisation is successful during endovascular treatment, the clinical outcomes may still be disappointing. This highlights the necessity of further research, so as to discover better solutions to futile recanalisation and improve patient outcomes. OBJECTIVE:To investigate the efficacy and safety of Y-6 sublingual tablets (cilostazol and dexborneol) compared with a placebo in the treatment of patients with acute ischaemic stroke caused by large vessel occlusion. METHOD:The efficacy and safety of Y-6 sublingual tablets in patients with acute ischaemic stroke are evaluated in a phase II, randomised, double-blind, double-dummy, placebo-controlled, parallel clinical trial. Eligible patients having provided informed consent are randomised into five groups for a 28-day treatment period. The primary outcome is the percentage of patients achieving the modified Rankin Scale score of 0-1 at 90 days. DISCUSSION:The EFfects of Y-6 SUblingual Tablets for PaTients with AcUte Ischemic StRokE trial assesses whether Y-6 sublingual tablets are effective and safe in improving the clinical outcomes of patients with acute ischaemic stroke caused by large vessel occlusion. TRIAL REGISTRATION NUMBER:NCT06138834.

Developing effective nanoplatforms for chemo-immunotherapy to achieve enhanced tumor suppression and systemic antitumor immunity has recently received extensive attention. Herein, we formulated a multifunctional DNA sandwich nanodevice, DSWAC/siPD-L1, based on triangular DNA origami, to implement enhanced cancer chemo-immunotherapy. Taking advantage of the tumor-targeting ability of the AS1411 aptamer, DSWAC/siPD-L1 efficiently delivered doxorubicin (DOX), CpG, and siPD-L1 into tumor cells. Moreover, the sandwich cavity spatially protects siPD-L1 from degradation, and the featured design of the DNA/RNA duplex linkers ensures effective intracellular release of siPD-L1. The pH-responsive release of cytotoxic DOX induces apoptosis and initial mild immunogenic cell death of tumor cells, presenting antigens to enhance the maturation of dendritic cells (DCs) with the assistance of the immune adjuvant CpG, thereby activating cytotoxic T lymphocytes to amplify antitumor immunity. Simultaneously, siPD-L1 downregulated the endogenous expression of PD-L1 to inhibit adaptive tumor immune escape. DSWAC/siPD-L1 initiated the iterative revolution of the cancer-immunity cycle, leading to the inhibition of primary and metastatic tumors, as demonstrated by DC maturation and T-cell infiltration in established subcutaneous primary tumor model and metastatic lung tumor model. Furthermore, the superior antitumor effect of DSWAC/siPD-L1 resulted in approximately 91 % inhibition of primary tumor growth and 93 % prevention of lung metastasis. Collectively, this study describes a siPD-L1-based sandwich DNA nanodevice functionalized with AS1411/CpG for enhanced cancer chemo-immunotherapy, inspiring the creation of more innovative drug nanocarriers and the exploitation of novel cancer therapies.

Oil-water separation remains a critical environmental challenge for treating industrial effluents and marine oil spills. This study presents a novel SiO2/CMC-Fe3+ (SCF) composite mesh fabricated through an environmentally friendly two-step approach: hydrophilic silicon dioxide (SiO2) nanoparticle deposition on copper mesh, followed by CMC-Fe3+ hydrogel surface modification. The synergistic interactions among SiO2 nanoparticles, CMC-Fe3+ hydrogel, and copper substrate through hydrogen bonding and metal chelation create a hierarchical structure, exhibiting superhydrophilicity and underwater superoleophobicity. Under gravity-driven conditions, the SCF mesh achieves high performance with >99% separation efficiency and up to 4.019 × 104 L·m-2·h-1 water flux across diverse oil types. The mesh demonstrates excellent durability, maintaining >99.5% efficiency after 60 cycles and exhibiting stability under harsh conditions, including extreme pH, high salinity, and temperature variations, with separation efficiencies above 98% after extended testing. The combination of high performance, enhanced stability, cost-effectiveness, and environmental compatibility positions the SCF mesh as a promising solution for offshore oil spill management, underwater oil treatment, and industrial oily wastewater purification.

The role of intra-arterial tenecteplase for acute large vessel occlusion (LVO) stroke after successful endovascular therapy is uncertain. To assess the efficacy and safety of intra-arterial tenecteplase in patients with successful endovascular therapy (defined as a score on the expanded Thrombolysis in Cerebral Infarction [eTICI] scale of 2b to 3) after endovascular therapy. This was a prospective, open-label, blinded end point, randomized trial. Recruitment took place between February 16, 2023, and March 23, 2024, with final follow-up on July 4, 2024. The study was conducted across 19 centers in China. Patients with acute anterior circulation LVO treated between 4.5 and 24 hours from the time that the patient was last known to be well were included. After successful endovascular recanalization, defined as eTICI 2b or greater, patients were randomized to receive intra-arterial tenecteplase at 0.125 mg/kg (n = 126) or standard medical treatment (n = 129). The primary end point was excellent outcome at 90 days, defined as modified Rankin Scale (mRS) score of 0 to 1 (range, 0 [no symptoms] to 6 [death]). There were a total of 7 secondary efficacy end points (mRS score of 0-1 at 90 days, mRS score at 90 days, mRS score of 0-2 at 90 days, mRS score of 0-3 at 90 days, National Institutes of Health Stroke Scale score of 0-1 or improved ≥10 points at 36 hours, European Quality of Life Visual Analogue Scale score at 90 days, time to maximum volume > 6 s at 24 hours, and infarct core volume change from baseline) and 3 safety end points, including symptomatic intracranial hemorrhage (sICH) within 48 hours, any intracranial hemorrhage within 48 hours, and all-cause mortality within 90 days. Among 256 patients who were randomized (median [IQR] age, 71.6 [61.3-79.2] years; 113 [44.1%] females), 255 (99.6%) completed the trial. The rate of patients with an mRS score of 0 to 1 at 90 days was 40.5% in the intra-arterial tenecteplase group (n = 51) and 26.4% in the standard medical treatment group (n = 34) (relative risk, 1.44 [95% CI, 1.06-1.95]; P = .02). Of 7 prespecified secondary efficacy end points, none showed a significant difference. Intra-arterial tenecteplase after endovascular therapy did not increase the incidence of sICH within 48 hours after treatment compared with standard medical treatment (5.6% vs 6.2%; relative risk, 0.95 [95% CI, 0.36-2.53]; P = .92). Mortality at 90 days was 21.4% with intra-arterial tenecteplase and 21.7% with standard medical treatment (relative risk, 0.76 [95% CI, 0.40-1.43]; P = .78). In patients with acute LVO presenting between 4.5 and 24 hours of symptom onset, intra-arterial tenecteplase after successful thrombectomy had a greater likelihood of excellent neurological outcome at 90 days without increasing the risk of sICH or mortality. However, because none of the secondary efficacy analyses supported the primary finding, further trials are needed to confirm the results. ClinicalTrials.gov Identifier: NCT05624190

BACKGROUND:Evidence on the association between the stress hyperglycemia ratio (SHR) and adverse outcomes in patients with mild ischemic stroke (IS) or high-risk transient ischemic attack remains limited. METHODS:This was a secondary analysis of the INSPIRES (Intensive Statin and Antiplatelet Therapy for Acute High-Risk Intracranial or Extracranial Atherosclerosis) randomized clinical trial. SHR was calculated as admission blood glucose (mmol/L) divided by (1.59* HbA1c [%]-2.59). Multivariable Cox regression models were used to assess the association between SHR and adverse clinical outcomes, adjusting for age, sex, and other potential factors. The primary efficacy outcome was any stroke (ischemic or hemorrhagic) within 90 days. Secondary efficacy outcomes comprised composite vascular events, recurrent IS, poor functional outcome, and early neurological deterioration. The primary safety outcome was moderate-to-severe bleeding within 90 days. RESULTS:The INSPIRES trial, ultimately enrolled 6100 patients with mild IS or high-risk transient ischemic attack caused by intracranial or extracranial atherosclerosis, of whom 4515 were included in this secondary analysis. The median age was 65 years (interquartile range, 57-71), and 2894 (64.10%) were male. During the 90-day follow-up, recurrent stroke occurred in 356 patients (7.88%), composite vascular events in 363 (8.04%), recurrent IS in 340 (7.53%), poor functional outcome in 474 (10.51%), and early neurological deterioration in 196 (4.34%). After adjustment for conventional confounders, compared with patients in the lower SHR group (Q1), those with higher SHR levels (Q4) had significantly increased risks of recurrent stroke (hazard ratio [HR], 1.84 [95% CI, 1.30-2.61]), composite vascular events (HR, 1.72 [95% CI, 1.22-2.41]), recurrent IS (HR, 1.79 [95% CI, 1.25-2.55]), poor functional outcome (HR, 1.56 [95% CI, 1.13-2.15]), and early neurological deterioration (HR, 1.62 [95% CI, 1.00-2.61]). In contrast, SHR was not significantly associated with any safety outcomes. CONCLUSIONS:Among patients with acute mild IS or high-risk transient ischemic attack of presumed atherosclerotic cause, elevated SHR levels were independently associated with increased risks of recurrent stroke, composite vascular events, recurrent IS, poor functional outcome, and early neurological deterioration.

Background:Stroke is a leading cause of mortality and disability globally, with high rates of adverse outcomes. We aimed to develop and test a clinically accessible and explainable predictive model for post-stroke composite outcomes that could identify patients at high-risk for targeted interventions. Methods:This modelling study used artificial intelligence to develop and validate a prognostic predictive model for post-stroke outcomes at 3 months and over 5 years, using comprehensive data from the third China National Stroke Registry (CNSR-III; 2015-2018). The development cohort comprised 11,313 patients from CNSR-III. Validation cohort 1 (n = 2627 from CNSR-III; internal validation) were selected at random on the basis of hospital assignment. Validation cohort 2 (external validation) included 5158 patients with a history of ischaemic stroke, excluding those diagnosed with TIA, from the CHANCE-2 trial (2019-2021) done at 202 centres in China. Validation cohort 3 (external validation: disability and mortality) involved 3855 patients with a history of acute ischaemic stroke or TIA from a single centre in the Clinical Research Center for Stroke-Fifth Division (CRCS-5) cohort (2011-2024) in South Korea. We evaluated 309 hospitalisation variables, including baseline characteristics, medical history, hospitalisation data, biomarkers, geographical factors, National Institutes of Health Stroke Scale (NIHSS) scores, modified Rankin Scale (mRS), and stroke polygenic risk scores, using an extreme gradient boosting tree model. Feature importance was assessed via Shapley values. Primary outcomes were 3-month stroke recurrence, disability (mRS >2), and mortality. Secondary outcomes were assessed at six additional time points over 5 years. A nested cross-validation scheme was employed for feature selection and internal validation in 80% of patients (n = 11,313) from CNSR-III cohort. Testing was performed in the remaining 20% of patients (n = 2627) from CNSR-III (validation cohort 1). External validation was performed in validation cohorts 2 and 3. Findings:Global and domain-specific delta-NIHSS(admission-discharge) emerged as the strongest predictor of stroke recurrence, disability, and mortality. The Delta-NIHSS-based Predictor for Post-Stroke Composite Outcomes (DISCO) model, integrating 16 delta-NIHSS(admission-to-discharge) measures, age, gender, TOAST subtypes, history of TIA, stroke, diabetes and mRS at discharge, achieved the area under the receiver operating curve (AUCs) of 0.805 and 0.815 for recurrence and mortality and of 0.852 for disability at 3 months in validation cohort 2. The 1% patients with highest-risk exhibited a 19.27-fold relative risk (RR) for recurrence, 36.59-fold RR for disability, and 225.5-fold RR for mortality at 3 months. The DISCO model is available at https://www.discosysu.cn. Interpretation:The DISCO model, incorporating 23 clinical variables, demonstrates high accuracy, robustness, clinical accessibility, and explainability in predicting post-stroke outcomes. The predictive strength of delta-NIHSS(admission-discharge) provides mechanistic insights into stroke outcomes and could potentially inform future acute stroke treatment and rehabilitation strategies. Future studies, with external validation across diverse ancestries and mechanistic studies elucidating the predictive power of delta-NIHSS in stroke recovery, are warranted. Funding:National Key Research and Development Program of China, National Natural Science Foundation of China, Young Elite Scientists Sponsorship Program by the China Association for Science and Technology, and Young Talents Supporting Program of Capital Medical University.

BACKGROUND:Inflammation is an important mechanism in ischemic stroke and high-risk transient ischemic attack, but clinical inflammatory markers on antiplatelet therapy remain to be studied. This study was designed compare the neutrophil count (NC) on the efficacy and safety of clopidogrel-aspirin with that of aspirin in patients with ischemic stroke or high-risk transient ischemic attack caused by intracranial or extracranial atherosclerosis. METHODS:The INSPIRES (Intensive Statin and Antiplatelet Therapy for High-Risk Intracranial or Extracranial Atherosclerosis) study was a post hoc analysis of the multicenter, randomized, double-blind, placebo-controlled, 2-by-2 factorial trial. The primary efficacy and safety outcomes were 90-day stroke and moderate-to-severe bleeding. The differences in the efficacy outcome were calculated with cox proportional hazards model and the generalized linear model as well as logistic regression. RESULTS:The study included 5929 patients of median age 65 years (interquartile range, 57-71 years), 3800 (64.09%) of whom were men; 1983 (33.45%) had a low NC (≤3.65×109/L), 1973 (33.28%) had an intermediate NC (3.654.97×109/L). Patients with ischemic stroke or transient ischemic attack with a higher NC benefited more from clopidogrel-aspirin than from aspirin alone. There was no significant difference in the primary safety outcome of moderate-to-severe bleeding according to antiplatelet therapy or NC. CONCLUSIONS:The post hoc analysis suggested patients with a higher NC obtained greater benefit from clopidogrel-aspirin than from aspirin without an increase in bleeding risk. The findings may serve as a reference indicator for future anti-inflammatory therapy. However, further research is needed to explore the mechanism.

Background:Based on recent reviews, vascular cognitive impairment (VCI) encompasses a spectrum of cognitive deficits caused by cerebrovascular disease and its risk factors, ranging from mild cognitive impairment to dementia, and often coexists with neurodegenerative conditions like Alzheimer's disease. VCI is categorized into four clinical-imaging subtypes, including post-stroke cognitive impairment (PSCI)-a common stroke complication and major VCI subtype. Current guidelines recommend cholinesterase inhibitors and NMDA receptor antagonists as first-line treatments for VCI, with expert consensus supporting donepezil and rivastigmine for PSCI. However, existing evidence primarily derives from placebo-controlled or head-to-head drug comparisons, lacking comprehensive evaluations of multiple cognitive enhancers. This study aims to systematically assess the efficacy and safety of cognitive-enhancing drugs in VCI, with a focused analysis on PSCI, to better inform clinical decision-making and improve patient outcomes. Methods:We systematically searched four databases using predefined search strategies. Eligible studies were selected based on predetermined criteria. The included studies were analyzed with StataSE 16.0, RevMan 5.3, and Grade software to compare the efficacy and safety of cognitive-enhancing drugs to identify the optimal treatment for VCI and PSCI. Results:Sixteen studies (5,599 participants) were included. In terms of cognitive outcomes, sailuotong was superior to placebo on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) (MD = -3.00, 95% CI: -4.50, -1.50) and ranked best (SUCRA 88.5%). Memantine was most effective on the Mini-Mental State Examination (MMSE) (MD = 1.23, 95% CI: 0.23-2.23; SUCRA 80.8%). For the secondary outcome, the MoCA assessment showed that Ginkgo biloba extract significantly improved Montreal Cognitive Assessment (MoCA) scores compared to placebo (MD = 1.29, 95% CI: 1.24, 1.35). Regarding safety, donepezil significantly increased the risk of overall adverse events compared to placebo (OR: 1.57; 95% CI: 1.19-2.06). Conclusion:Our network meta-analysis suggests that memantine might have the best effect for PSCI, with sailuotong potentially serving as a secondary option. However, these estimates are based on a small randomized controlled trial and a sparse network. Therefore, the current evidence is limited, highlighting the need for more high-quality studies to robustly validate the therapeutic potential of these interventions for VCI and PSCI. Systematic review registration:https://www.crd.york.ac.uk/PROSPERO/, identifier in PROSPERO (CRD420250627957).

Background Inflammation and blood-brain barrier disruption may contribute to the pathogenesis of ischaemic stroke. Minocycline was shown to exert anti-inflammatory effects by attenuating microglial activation and protecting blood-brain barrier in preclinical studies. Previous small-scale clinical studies have suggested that minocycline may have a potential beneficial effect on prognosis in acute ischaemic stroke. However, the efficacy and safety of minocycline in patients with acute ischaemic stroke need to be further confirmed.Study aims We designed the study, Efficacy and Safety of Minocycline in Patients with Moderate to Severe Acute Ischaemic Stroke (EMPHASIS), to evaluate the effect of minocycline in improving the functional outcome and the drug safety in patients with acute ischaemic stroke.Methods The EMPHASIS study is a multicentre, randomised, double-blind, placebo-controlled trial aiming to recruit patients with acute ischaemic stroke. Patients who had ischaemic stroke within 72 hours of onset, a National Institutes of Health Stroke Scale score between 4 and 25 and Ia≤1 (moderate-to-severe) will be randomly allocated to either minocycline or placebo groups in a 1:1 ratio. Patients will receive minocycline (or placebo) with a loading dose of 200 mg, and subsequent 100 mg every 12 hours for 4 days. All patients will receive routine guideline-based treatment. The primary efficacy outcome is an excellent functional outcome assessed by the proportion of modified Rankin Scale score of 0–1 at 90±7 days. The main safety outcomes include the number of symptomatic intracranial haemorrhage at 24±2 hours and 6±1 days.Discussion The EMPHASIS trial is the first phase III trial to investigate whether minocycline is effective and safe in improving functional outcome at 90 days in patients with moderate-to-severe acute ischaemic stroke. The data generated may provide valuable evidence of a potential anti-inflammation treatment for ischaemic stroke.

Rapamycin (RAPA) is widely used in biomedical applications due to its antitumor, autoimmune disease and neuroprotective effects. However, direct administration of RAPA may lead to side effects such as excessive suppression of the immune system, severe infections and increased risk of tumors. Zeolitic imidazolate framework-8 (ZIF-8) is one of the most promising MOFs that shows great potential in the field of drug delivery. In this study, we successfully prepared nano-ZIF-8 particles of uniform size and monodispersity by optimizing the reaction time, stirring time, and reactant concentration. ZIF-8 was used as a carrier loaded with RAPA (ZIF-8@RAPA), which was characterized by XRD, FTIR, UV-vis, TGA, and zeta potential, and the results revealed that ZIF-8@RAPA with a dodecahedral morphology, a particle size of 82 nm +/- 4.7 nm, and a drug-loading rate of up to 11.53 % was successfully synthesized and that the loaded RAPA could achieve long-lasting slow release. Furthermore, we monitored the structural evolution of ZIF-8@RAPA in PBS. We found that the structural stability of ZIF-8@RAPA could be maintained for up to 6 weeks, followed by the gradual cleavage and disintegration of the crystal structure, and the reformation of micro-crystals (dia(Zn)) at 8 weeks, which is presumed to be affected by the [HPO4]2-in the PBS solution. In addition, the biocompatibility of the ZIF-8@RAPA delivery system was comprehensively evaluated using macrophage RAW 264.7 and the zebrafish embryo model. The results revealed that the biotoxicity of ZIF-8@RAPA was concentration dependent and that it had good biocompatibility when it was applied at concentrations lower than 100 mu g/mL. In summary, our study preliminarily elucidated the in vitro disintegration and reconstruction mechanisms of nano-ZIF-8@RAPA crystals and demonstrated their feasibility for application in biomedical fields.