BACKGROUND:Whether diffusion‑weighted imaging infarction patterns influence the efficacy and safety of early oral ticagrelor‑aspirin with intravenous thrombolysis in moderate acute ischemic stroke is uncertain. We assessed treatment effects by infarction pattern in this thrombolysis setting. METHODS:This was a subgroup analysis of the TAPIS trial (Ticagrelor With Aspirin Dual Antiplatelet Therapy Combined With Intravenous Thrombolysis in Patients With Ischemic Stroke), a 60-center, randomized, double‑blind trial in China. Patients aged 18 to 80 years with noncardioembolic stroke (National Institutes of Health Stroke Scale score 4-10) who received intravenous thrombolysis within 4.5 hours of onset were randomized within 6 hours to ticagrelor‑aspirin or placebo. Diffusion‑weighted imaging patterns were centrally adjudicated as multiple acute infarcts (MAIs; ≥2 lesions) or non‑MAIs (single infarction or diffusion‑weighted imaging-negative). The primary efficacy outcome was modified Rankin Scale score of 0 to 1 at 90 days; safety outcome was symptomatic intracranial hemorrhage. Treatment‑by‑pattern interaction was assessed. RESULTS:Among 1307 patients (94.6% of full analysis set; median age, 65.5 years; 71.2% male; median National Institutes of Health Stroke Scale score, 6.0), 409 (31.3%) had MAIs and 898 (68.7%) non‑MAIs (20.8% diffusion‑weighted imaging-negative, 79.2% single infarction). MAIs were associated with poorer prognosis than non‑MAIs (excellent outcome: 58.9% versus 69.2%; adjusted risk ratio, 0.92 [95% CI, 0.84-1.00]). Ticagrelor‑aspirin was associated with a higher likelihood of excellent outcome versus placebo in MAIs (64.4% versus 53.4%; risk ratio, 1.21 [95% CI, 1.02-1.42]), whereas no significant benefit was observed in non‑MAIs (71.2% versus 67.1%; risk ratio, 1.06 [95% CI, 0.97-1.16]; Pinteraction=0.18). Early neurological improvement showed significant heterogeneity by infarction pattern (Pinteraction=0.02); the treatment‑by‑pattern interaction for the primary outcome was nominally significant after adjusting for rescue tirofiban use (P=0.04). Symptomatic intracranial hemorrhage occurred in MAIs: 1 of 205 (0.5%) versus 2 of 204 (1.0%); non‑MAIs: 1 of 448 (0.2%) versus 1 of 450 (0.2%). CONCLUSIONS:In thrombolyzed patients with moderate noncardioembolic stroke, MAIs were associated with poorer functional outcomes. Early ticagrelor‑aspirin showed directionally consistent benefits without excess bleeding in patients with MAIs, though the primary interaction was not significant. These hypothesis‑generating findings may inform future trials of diffusion‑weighted imaging infarction pattern as an imaging biomarker to guide antiplatelet therapy in early reperfusion. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT06316570.

BackgroundInflammation has an important impact on the pathological progression associated with ischemic stroke. Serum uric acid (UA) to lymphocyte ratio (ULR) is a biomarker that responds to the level of inflammation but is not definitively associated with the clinical outcomes in patients with acute ischemic stroke (AIS).MethodsThe data were obtained from the Third China National Stroke Registry (CNSR-III). Enrolled AIS patients were grouped by ULR quartiles at admission. The outcomes were poor functional outcomes (modified Rankin Scale [mRS] score of 3–6 or 2–6) and all-cause mortality at 3 months and 1 year. The associations of ULR with the risk of poor functional outcome and all-cause mortality were analyzed by multivariable logistic regression and Cox proportional hazards regression.ResultsA total of 8,241 patients were included from the CNSR-III study. After adjusting for confounders, it was found that patients in the highest ULR quartile had higher mRS scores of 2–6 (odds ratio [OR], 1.33; 95% confidence interval [CI], 1.15–1.53) and 3–6 (OR, 1.35; 95% CI, 1.16–1.57) at the 3-month follow-up. Additionally, the highest ULR quartile was associated with an increased risk of all-cause mortality at the 3-month follow-up (hazard ratio [HR], 1.97; 95%CI, 1.22–3.18). Similar results were observed at the 1-year follow-up.ConclusionElevated ULR increased the risks of poorer functional outcomes and all-cause mortality in the AIS patients. However, this observational study was limited by potential unmeasured confounders, selection bias, residual confounding, and restricted generalizability to other populations.

Our study aimed to determine the prevalence and clinical phenotypes of JAK2 pathogenic mutation carriers in the CNSR-III ischemic stroke (IS) cohort, and to develop a pre-test genetic screening model for identifying high-risk individuals. We performed retrospective characterization of JAK2 pathogenic variants using targeted sequencing data in the CNSR-III cohort. Clinical and laboratory characteristics of JAK2 V617F mutation carriers and non-carriers were tested in a logistic regression model to identify key features. V617F screening score was developed to predict positive JAK2 V617F test results. 46 cases (0.4

BACKGROUND:Arterial stiffness (AS), a key cardiovascular disease (CVD) risk factor, arises from structural stiffening due to arterial remodeling and load-dependent stiffening from elevated blood pressure (BP). However, their contributions to CVD risk and the mediating role of hypertension remain uncertain. We aimed to quantify the associations of AS components with incident CVD and assess hypertension's mediating effects. METHODS:Among 12,684 Kailuan cohort participants, AS (measured via brachial-ankle pulse wave velocity [baPWV]) and hypertension were assessed at baseline (2010-2014). The exposures were four AS components: measured, total, structural, and load-dependent stiffness. Total stiffness was derived from measured baPWV and concurrent BP. Structural stiffness was calculated by adjusting total stiffness to a reference BP (120/80 mmHg) using participant-specific models, with load-dependent stiffness defined as the residual. Cox models evaluated associations between AS components and incident CVD. Mediation analysis decomposed each component's total effect into direct and hypertension- mediated indirect effects. RESULTS:Over a median follow-up of 11.35 years, 803 CVD events occurred. Each 1-SD increase in AS components was associated with higher CVD risk, with adjusted hazard ratios (95% CIs) of 1.21 (1.14, 1.29) for measured, 1.20 (1.13, 1.28) for total, 1.17 (1.10, 1.25) for structural, and 1.20 (1.11, 1.30) for load-dependent stiffness. Hypertension mediated 48.7%, 50.6%, 24.0%, 75.9% of these associations for measured, total, structural, and load-dependent stiffness, respectively. CONCLUSIONS:Load-dependent stiffness appears to act mainly via hypertension, whereas structural stiffness may reflect BP-independent vascular damage. Thus, combining BP control with vascular protection strategies may help prevent CVD.

Background The Naples Prognostic Score (NPS), a novel inflammatory and nutritional score, has attracted widespread attention in the prognosis of various diseases but remains unclear in acute ischemic stroke or transient ischemic attack. We aimed to investigate the association between NPS and poor functional outcomes and test whether PhenoAge acceleration (PAA) mediates or jointly contributes to the relationships. Methods This prospective cohort study included patients with acute ischemic stroke or transient ischemic attack from the CNSR‐III (Third China National Stroke Registry). The NPS (range, 0–4) was calculated based on serum albumin, total cholesterol, neutrophil/lymphocyte ratio, and lymphocyte/monocyte ratio, and categorized as low (0), medium (1 or 2), or high (3 or 4). Logistic regression was used to assess the association between NPS and poor functional outcomes (modified Rankin Scale [mRS] score, 2–6/3–6). Mediation analyses were performed to explore the role of PAA. Results A total of 7932 patients from the CNSR‐III were included in the analysis. High NPS was significantly associated with poor functional outcomes at 3 months (adjusted odds ratio [OR], 1.69 [95% CI, 1.13–2.52], P=0.010 for mRS 3–6; adjusted OR, 1.31 [95% CI, 1.00–1.71], P=0.048 for mRS 2–6). PAA partially mediated the observed association, with mediation proportions of 13.90% and 12.82% for mRS 3 to 6 and 2 to 6 at 3 months, respectively. Patients with both high NPS and PAA ≥0 had the highest risks of poor outcomes (adjusted OR, 2.16 [95% CI, 1.73–2.70] for mRS 3–6; adjusted OR, 1.51 [95% CI, 1.25–1.84] for mRS 2–6). Similar results were observed at 1 year. Incorporating combined NPS and PAA into the basic model improved predictive performance for short‐ and long‐term poor functional outcomes. Conclusions High NPS was associated with increased risk of poor functional outcomes at 3‐month and 1‐year follow‐ups in patients with acute ischemic stroke or transient ischemic attack. This association was partially mediated and jointly influenced by PAA.

To capture temporal pattern of physical function frailty before and after cardiovascular disease (CVD), including heart disease and stroke incidence event, among older adults. A total of 23,307 participants aged over 50 years from three cohorts: English Longitudinal Study of Ageing (ELSA), and Health and Retirement Study (HRS) and China Health and Retirement Longitudinal Study (CHARLS) were studied. Physical function frailty was assessed by mobility and daily function scores. Higher scores indicated more severe physical function frailty. CVD was ascertained by self-reported physician-diagnosed heart disease or stroke. Four subtypes of heart disease including angina, heart attack, coronary heart disease and heart failure were also assessed. In participants who experienced a CVD event, physical function frailty (measured by the mobility and daily function scores) were already present prior to the event and worsened thereafter. Short-term increase of mobility scores following the CVD diagnosis were observed (ELSA: β = 4.40, 95

BACKGROUND:Deep brain stimulation for Parkinson's disease is often performed under conscious sedation or general anesthesia. However, anesthetic agents may influence intraoperative microelectrode recording, and the optimal anesthesia method for microelectrode recording remains unclear. This study compared general anesthesia and conscious sedation in preserving microelectrode recording signal intensity during deep brain stimulation. METHODS:In this prospective, noninferiority randomized controlled trial, patients with Parkinson's disease (United Kingdom Brain Bank criteria) undergoing elective bilateral surgery were randomized 1:1 to the conscious sedation or the general anesthesia group. During surgery, a desflurane anesthetic titrated against the quality of the electrophysiologic signal was applied in the general anesthesia group, whereas patients in the conscious sedation group received dexmedetomidine anesthesia. The primary outcome was the proportion of patients with high-quality microelectrode recording (normalized root mean square greater than 2.0), assessed postoperatively off-line. Secondary outcomes included operation and recording duration, 6-month clinical efficacy, and complication rates. RESULTS:Of 188 randomized patients (94 general anesthesia, 93 conscious sedation), desflurane anesthesia was noninferior for high normalized root mean square proportion (89.4% vs . 90.3%; difference, -0.96%; 95% CI, -9.62 to 7.70). The general anesthesia group had shorter operative time (difference, -9.07 min; 95% CI, -13.99 to -4.14; P < 0.001). At 6 months, changes in Unified Parkinson's Disease Rating Scale score (difference, -2.50; 95% CI, -7.20 to 2.20; P = 0.297), levodopa equivalent daily dose (difference, -58.4 mg; 95% CI, -133.56 to 16.75; P = 0.128), and complication rates (general anesthesia: 10.9% vs . conscious sedation: 8.9%; P = 0.655) were comparable between the groups. CONCLUSIONS:General anesthesia is noninferior to conscious sedation for microelectrode-guided subthalamic nucleus deep brain stimulation, providing equivalent signal intensity and clinical outcomes while improving procedural efficiency, supporting its use as a valid clinical option.

OBJECTIVE:To evaluate cardiovascular benefits associated with sustained intensive and moderate interventions targeting body mass index (BMI), systolic blood pressure (SBP), fasting blood glucose (FBG) level, and total cholesterol (TC) concentration. METHODS:Using longitudinal data (from June 2006-October 2007 to December 2017) of 94,661 cardiovascular disease (CVD)-free participants aged 30 years and older from the Kailuan cohort, we emulated a target trial to assess the long-term effectiveness of intensive (BMI <25 kg/m2, SBP <120 mm Hg, FBG <5.6 mmol/L, TC <5.2 mmol/L) and moderate (BMI <30 kg/m2, SBP <140 mm Hg, FBG <7.0 mmol/L, TC <6.2 mmol/L) interventions on 10-year risk of incident CVD. The target trial emulation framework with the parametric g-formula was used to simulate counterfactual outcomes under dynamic interventions, accounting for time-varying confounders and competitive events. RESULTS:Compared with the natural course CVD risk of 6.48%, intensive interventions yielded a 49% decrease in relative risk (risk ratio, 0.51; 95% CI, 0.49 to 0.54), translating to approximately 3 fewer CVD cases per 100 individuals during 10 years (absolute risk reduction, -3.15%; 95% CI, -3.36% to -2.98%), which extended the restricted mean CVD-free time from 9.32 to 9.51 years. Of all the individual risk factors, SBP control yielded the largest benefits. Notably, even moderate interventions produced a 25% relative reduction in CVD risk, with the average proportion intervened on decreasing from 74.8% to 37.6%. Greater absolute risk reductions were observed in male participants and adults aged 60 years and older. CONCLUSION:Long-term interventions addressing cardiometabolic risk factors have considerable public health implications for primary prevention of CVD in China and other Western Pacific countries, where suboptimal cardiometabolic risk profiles remain prevalent.

The mechanisms underlying the continuum from asymptomatic intracranial atherosclerotic stenosis (aICAS) to symptomatic intracranial large-artery atherosclerotic ischemic stroke (iLAA-IS) remain unclear. We investigated the gut microbiota-metabolite axis in this transition to identify predictive biomarkers and clarify key functional pathways. In a case-control study (63 iLAA-IS cases; 56 aICAS controls), fecal shotgun metagenomics and untargeted plasma metabolomics were profiled. Using machine learning with 10-fold nested cross-validation, we identified five robust biomarkers associated with the transition: Alistipes putredinis (risk-associated) and four protective features (Segatella copri, Gln-Gly, Methionine Sulfoxide, and N6-Acetyl-L-Lysine). Integrated models incorporating these markers significantly improved predictive performance relative to conventional risk factors (e.g., mean AUC of Gln-Gly: 0.9104 vs. 0.7188). Mechanistic analyses revealed a Segatella copri-centered metabolic dysregulation: its depletion coincided with a broad loss of anabolic pathways (BCAA biosynthesis, folate-SAM-methionine metabolism, and tRNA charging), which were positively linked to amino acid-related metabolites. In contrast, the pathways of Alistipes putredinis showed no such coupling. These findings suggest that the aICAS-to-iLAA-IS transition is characterized by chronic metabolic dysregulation, involving a Segatella copri-centered microbiota-metabolite axis. This multi-omic signature offers novel insights into stroke pathogenesis and potential targets for prevention.

Introduction:Ginkgo biloba leaf extracts belong to the most popular herbal medicines for the treatment of neurological disorders, including Alzheimer's disease (AD) or stroke. EGb 761, a proprietary ginkgo leaf extract, has been shown to improve brain cell energy supply, to enhance neurogenesis and neuroplasticity, to decrease blood viscosity and improve brain perfusion. Thereby it improves cognitive performance, neuropsychiatric symptoms and activities of daily living in patients with dementia or mild cognitive impairment. It has further been shown to be beneficial for patients after ischaemic stroke. Therefore, the aim of this meta-analysis was to evaluate the treatment effects of EGb 761 in patients who had developed dementia following a cerebral infarction. Methods:We performed a meta-analysis of pooled data from clinical trials with EGb 761 in mild to moderate dementia in the subgroup of patients who had a cerebral infarction. Four randomised, placebo-controlled trials with homogeneous patient selection and design were included. Previous stroke was diagnosed by neuroimaging. The analysis focused on the comparison of treatment effects in the domains of cognition, activities of daily living and global assessment. Results:The meta-analysis included data from 488 patients. Significant treatment effects of 240 mg EGb 761 daily versus placebo were found for cognition (p = 0.0467), activities of daily living (p = 0.0230), and global clinical impression (p = 0.0371). The rates of adverse events and adverse drug reactions in the EGb 761 group were like those in the placebo group. Conclusion:The results of our meta-analysis of patients with mild to moderate dementia who had previously had a cerebral infarction verified by neuroimaging showed statistically significant and clinically relevant benefits of EGb 761. The drug was shown to be safe and well tolerated and is a promising treatment option for patients developing dementia after cerebral infarction. Further dedicated clinical trials are needed to confirm these results.

BACKGROUND:The effect of the difference between cystatin C- and creatinine-based estimated glomerular filtration rates (eGFRdiff) on stroke outcomes is unclear. This study investigated the association between eGFRdiff and stroke prognosis. METHODS:Participants with ischaemic stroke or transient ischaemic attack were recruited from the Third China National Stroke Registry, a multicenter, prospective cohort. eGFRdiff was calculated using the absolute difference (eGFRabdiff defined as cystatin C-based (eGFRcys) minus creatinine-based (eGFRcr)) and the ratio (eGFRrediff) between eGFRcys and eGFRcr estimates. eGFRabdiff (< -15, -15-15, ≥ 15 mL/min/1.73 m2) and eGFRrediff (< 0.6, ≥ 0.6) were analyzed. Time-updated eGFRdiff (ΔeGFRdiff) was defined as the change from baseline to 1-year blood re-examination and tertiled. Outcomes included 5-year all-cause mortality, stroke disability, and stroke recurrence. RESULTS:Among 10,293 participants, 35.2% had an eGFRabdiff < -15 mL/min/1.73 m2, and 3.5% had an eGFRrediff < 0.6. Compared with midrange eGFRabdiff, participants with eGFRabdiff < -15 mL/min/1.73 m2 had an odds ratio (OR) of 1.19 (95% confidence interval (CI), 1.05-1.35) for disability and a hazard ratio (HR) of 1.28 (95% CI, 1.12-1.46) for mortality. eGFRrediff < 0.6 was associated with a higher risk for disability (OR, 1.66; 95% CI, 1.25-2.19) and mortality (HR, 1.49; 95% CI, 1.17-1.90). Participants with the largest ΔeGFRdiff declines had higher mortality (OR, 1.44; 95% CI, 1.14-1.82) and borderline disability risk significance (HR, 1.25; 95% CI, 0.96-1.61). CONCLUSIONS:Significant and widening eGFRdiff were independently associated with increased risks of post-stroke disability and mortality, highlighting the importance of monitoring eGFRcys and eGFRcr in stroke management.

Haematoma expansion (HE) is a significant factor in poor outcomes following intracerebral haemorrhage (ICH). Studies have suggested that acute intensive antihypertensive treatment could reduce HE. However, the impact of early intensive blood pressure reduction on patients with ICH at high risk of HE remains unclear. Therefore, screening ICH patients for high risk of HE upon admission and initiating early intensive blood pressure reduction could improve their prognosis. In this study we utilise a five-point scoring system integrating a deep learning system based on non-contrast CT imaging and clinical predictors to identify ICH patients at high risk of HE. This study aims to compare the efficacy, safety, and feasibility of early intensive antihypertensive treatment versus standard antihypertensive treatment for patients identified as being at high risk of HE. The early intensive antihypertensive treatment in high-risk population of intracerebral haemorrhage expansion predicted by artificial intelligence (ARCHES), is a multicentre, prospective, randomised, open-label, blinded-endpoints clinical trial that will include an estimated 680 participants. ICH patients within 6 h of symptom onset, and at high risk of haematoma expansion with ≥ 3 points on the artificial intelligence-based haematoma expansion 5-point prediction score, will be randomly assigned to receive either intensive antihypertensive treatment (targeting systolic blood pressure control between 130 and 140 mmHg within the first hour of treatment, and maintaining this level for 7 days) or standard antihypertensive treatment (targeting systolic blood pressure control between 140 and 180 mmHg, and maintaining for 7 days). The primary outcome is death or severe disability at 90 days. The ARCHES study aims to verify the hypothesis that early intensive blood pressure lowering leads to reduced HE and improved functional outcomes with good safety in ICH patients at high risk of HE. This study was registered at the Clinical Trials under registry number NCT06242938. Registered on Feb 2, 2024. https://clinicaltrials.gov/study/NCT06242938.

Objective Evidence on the association of levels of serum uric acid (SUA) with muscle mass has been inconsistent and limited to that from studies with a cross-sectional design. This study investigated the longitudinal association of baseline and changes in SUA levels with low muscle mass and distinct trajectories of muscle mass. Methods Data were taken from the Kailuan study (an ongoing Chinese population-based cohort study), in which 87,284 and 66,129 participants respectively had records of baseline SUA levels and changes in SUA levels from baseline to the second follow-up visit. The primary outcome was incident low muscle mass, and the secondary outcome was muscle mass trajectory, which was identified by group-based trajectory modeling. Cox regressions and multinominal logistic regressions were performed to assess the aforementioned associations. Results During a median follow-up of 13.05 years, a total of 5916 (6.78%) cases of incident low muscle mass occurred, and three trajectories of muscle mass were identified. The risk of incident low muscle mass decreased by 28% (hazard ratio [HR] 0.72; 95% confidence interval [CI] 0.66–0.78) in the Q4 group of baseline SUA, 23% (HR 0.77; 95% CI 0.71–0.85) in the stable high SUA, and 22% (HR 0.78; 95% CI 0.70–0.87) in the Q4 group of changes in SUA, compared with their counterparts. Additionally, these participants were associated with 53%, 50%, and 57% higher risks of following a low-stable pattern of muscle mass, with relative risks (95% CI) of 0.47 (0.39–0.56), 0.50 (0.41–0.60), and 0.43 (0.37–0.50), respectively. Conclusions Higher SUA levels were longitudinally associated with a lower incidence of low muscle mass; however, causality cannot be inferred.

Background:Diabetes is a risk factor of poor stroke outcomes. A randomized clinical trial has demonstrated that Panax notoginseng saponins (Xuesaitong soft capsules) can improve the functional outcome in ischemic stroke patients. However, it remains uncertain whether comorbid diabetes exerts an influence on the therapeutic outcomes of Xuesaitong. Methods:The PANDA (efficacy and safety of Panax notoginseng saponins in the treatment of adults with ischemic stroke in China) trial was a multicenter, randomized, double-blind, placebo-controlled trial comprising 3542 patients. The present prespecified analyses investigated the effect of concomitant use of antidiabetic drugs, a history of diabetes, and baseline fasting blood glucose levels on outcomes in participants randomized to receive Xuesaitong soft capsules versus placebo. The primary outcome was the proportion of patients achieving functional independence. Results:In the modified intention-to-treat dataset, there were 722 patients with diabetes or treated hyperglycemia during hospitalization (369 in the Xuesaitong group and 353 in the placebo group) and 2244 patients without (1118 in the Xuesaitong group and 1126 in the placebo group). Among patients with diabetes or treated hyperglycemia during hospitalization, the proportion of patients with functional independence at 3 months was 83.20 % (n = 307) in the Xuesaitong group and 79.60 % (n = 281) in the placebo group (odds ratio, 1.27; 95 % confidence intervals [CI], 0.87-1.85; P = 0.215). Regarding patients without diabetes or treated hyperglycemia during hospitalization, the proportion was 91.32 % (n = 1021) in the Xuesaitong group and 83.21 % (n = 937) in the control group (OR, 2.12; 95 % CI, 1.64-2.76; P < 0.001; P for interaction = 0.027). The sensitivity analyses indicated similar significant results. Conclusion:In the PANDA trial, patients without, rather than with, diabetes or treated hyperglycemia during hospitalization received greater benefit from Xuesaitong soft capsules regarding functional independence at 3 months.

BACKGROUND:Evidence supporting the early addition of antiplatelet therapy to intravenous thrombolysis in patients with acute ischaemic stroke remains inconclusive. We aimed to investigate the efficacy and safety of early oral dual antiplatelet therapy (DAPT), started within 6 h of onset, as an adjunct to intravenous thrombolysis. METHODS:TAPIS was a randomised, double-blind, placebo-controlled trial done in 60 hospitals across China. We enrolled patients treated with intravenous thrombolysis for ischaemic stroke, with a National Institutes of Health Stroke Scale score of 4-10. We randomly assigned (1:1) patients to receive oral aspirin plus ticagrelor (DAPT group) or corresponding placebo within 6 h of stroke onset, either before, during, or after receiving thrombolysis. Ticagrelor or placebo was continued for days 2-7 in each group, with open-label aspirin administered for days 2-90. Patients, clinicians, and investigators were masked to the group assignment. The primary efficacy outcome was an excellent functional outcome (modified Rankin Scale score 0-1) at 90 days. The primary safety outcome was symptomatic intracranial haemorrhage within 36 h. This trial was registered with ClinicalTrials.gov (NCT06316570) and is completed. FINDINGS:Between April 3, 2024, and Sept 30, 2025, we randomly assigned 1382 patients to the early DAPT (n=690 [49·9%]) or placebo (n=692 [50·1%]) groups. The median age was 65·6 years (IQR 58·3-72·0), 991 (71·7%) were men, and 391 (28·3%) were women. At 90 days, 474 (68·7%) patients in the early DAPT group and 429 (62·0%) in the placebo group achieved excellent functional outcomes (risk ratio 1·11 [95% CI 1·03-1·20; p=0·0089). Symptomatic intracranial haemorrhage within 36 h occurred in six (0·9%) patients in the early DAPT group versus five (0·7%) in the control group (risk ratio 1·20 [95% CI 0·37-3·93; p=0.76). INTERPRETATION:Among patients treated with intravenous thrombolysis for moderate ischaemic stroke, initiation of oral DAPT within 6 h of onset improved the likelihood of excellent functional outcomes at 90 days. Although no significant between-group difference in symptomatic intracranial haemorrhage was detected, wide CIs precluded exclusion of a small increased risk. FUNDING:National Natural Science Foundation of China, Capital's Funds for Health Improvement and Research, Noncommunicable Chronic Diseases-National Science and Technology Major Project, Beijing Municipal Science & Technology Commission, and the New Cornerstone Science Foundation.

Perioperative depressive symptoms (PDSs) are common among patients who undergo major surgery and can lead to worse clinical outcomes. Esketamine has been reported to alleviate PDSs in patients undergoing certain types of surgery. However, there is a lack of evidence from large-scale, multisurgery studies to support its therapeutic effects in individuals with preexisting moderate-to-severe PDSs. Thus, we designed this multicenter, randomized, placebo-controlled and double-blinded trial to investigate whether esketamine is associated with greater improvements than the placebo among patients undergoing major surgery. Patients with moderate-to-severe PDSs who underwent major surgery were assessed for eligibility and randomly assigned to receive esketamine or placebo intraoperatively. The primary outcome was the remission rate 3 days after surgery, which was defined as a Montgomery-Åsberg Depression Rating Scale score less than or equal to 10. The secondary outcomes included pain, esketamine-related psychotic symptoms and safety outcomes after surgery. A total of 435 patients were randomized to receive either esketamine (n = 218) or placebo (n = 217). The remission rate was greater in the esketamine group than in the placebo group at 3 days post-surgery (28.3% vs. 11.3%; OR 3.12 [95% CI, 1.79-5.55]; P < 0.001). The rates of acute pain were similar between the two groups. Intraoperative treatment with esketamine resulted in a greater proportion of participants whose depressive symptoms improved, but careful monitoring was necessary because of the possibility of developing dissociative symptoms. The clinical application of esketamine for depressive symptoms should consider its benefits and risks in the future. TRIAL REGISTRATION: Clinicaltrial.gov NCT04425473. LIST OF CHEMICAL COMPOUNDS: Esketamine (PubChem CID: 182137) and Ketamine (PubChem CID: 3821).

Hypertriglyceridemia (HTG) is a crucial risk factor for cardiovascular disease, metabolic syndrome, and type 2 diabetes. However, its early detection remains challenging due to the dynamic fluctuations in plasma triglyceride levels and their limited utility in predicting long-term dyslipidemia. This study aimed to elucidate the role of asymmetric dimethylguanidino valeric acid (ADGV) in HTG through integrated cohort analyses and mechanistic cellular experiments. Circulating ADGV levels were quantified in a cross-sectional cohort from southern China (n = 588) and assessed its prospective association with incident HTG in an independent prospective cohort from northern China (n = 348, median follow-up: 1.8 years). Hepatocyte experiments were performed to examine biological plausibility and explore potential mechanisms linking ADGV to hepatic triglyceride metabolism. Elevated ADGV levels were significantly associated with increased risk of HTG and remained independently associated after adjustment for age, gender, BMI, eGFR, lifestyle factors, and liver function. Complementary in vitro studies in hepatocytes revealed that ADGV promoted triglyceride accumulation by stimulating de novo fatty acid synthesis, mediated through regulating the expression of key metabolic genes (ACC, CPT1α, and PGC1α). Higher circulating ADGV was independently associated with prevalent and incident hypertriglyceridemia across a cross-sectional cohort and an independent prospective cohort, and hepatocyte experiments support a contributory role of ADGV in hepatic lipogenesis.

BACKGROUND:The Pooled Cohort Equations (PCE) and Prediction for Atherosclerotic Cardiovascular Disease (ASCVD) Risk in China (China-PAR) models tend to overestimate risk, whereas the Predicting Risk of Cardiovascular Disease Events (PREVENT) equations may underestimate risk in many contemporary cohorts. OBJECTIVES:This study aimed to validate and determine if recalibration of these risk scores using contemporary population-level data improves risk stratification for primary prevention in China. METHODS:These risk scores were first validated and then recalibrated in the Kailuan study. Participants aged 40 to 79 years without ASCVD at baseline were included. Original and recalibrated models were assessed for discrimination and calibration. RESULTS:Of 79,497 participants, 4,425 ASCVD events occurred over a median follow-up of 10 years (Q1-Q3: 10-10 years). All 3 original models showed good discrimination in women (Harrell's C-index: PCE 0.735 [95% CI: 0.712-0.757], China-PAR 0.738 [95% CI: 0.715-0.760], PREVENT 0.737 [95% CI: 0.713-0.759]) and moderate discrimination in men (PCE 0.675 [95% CI: 0.667-0.683], China-PAR 0.685 [95% CI: 0.677-0.693], and PREVENT 0.685 [95% CI: 0.677-0.693]). Original models showed differential mean calibration in 10-year ASCVD risk estimation: PCE overestimated by 34.9% (men [95% CI: 32.8%-36.9%]) and 15.1% (women [95% CI: 6.8%-22.7%]); China-PAR by 17.7% (men [95% CI: 15.1%-20.2%]) and 48.2% (women [95% CI: 43.1%-52.8%]); PREVENT underestimated by 29.4% (men [95% CI: 25.4%-33.5%]) and 2.7% (women [95% CI: -6.5% to 12.8%]). After recalibrating to the local population, observed vs predicted risks exhibited improved alignment for the recalibrated models. CONCLUSIONS:In this Chinese cohort, the original PCE and China-PAR overestimated 10-year ASCVD risk, whereas PREVENT underestimated it. Recalibration mitigated such misestimation in the local population, potentially enhancing risk stratification in primary cardiovascular prevention in China.

OBJECTIVE:To assess the efficacy and safety of edaravone dexborneol, a multitarget brain cytoprotectant composed of antioxidant and anti-inflammatory ingredients, in improving functional outcomes among patients with acute ischaemic stroke undergoing endovascular thrombectomy. DESIGN:Multicentre, double blind, randomised, placebo controlled trial. SETTING:106 hospitals in China between March 2022 and May 2023. PARTICIPANTS:1362 patients with clinically diagnosed acute ischaemic stroke within 24 hours of symptom onset, aged 18-80 years, with a National Institutes of Health Stroke Scale (NIHSS) score of 6-25 and an Alberta Stroke Program Early Computed Tomography Score (ASPECTS) of 6-10, confirmed large vessel occlusion in the anterior circulation, and planned endovascular thrombectomy. INTERVENTIONS:Patients were randomly allocated in a 1:1 ratio to receive edaravone dexborneol 37.5 mg (edaravone, 30 mg; (+)-dexborneol, 7.5 mg; 690 patients) or placebo (672 patients) before endovascular thrombectomy and continued the regimen twice daily for a consecutive period of 10-14 days. MAIN OUTCOME MEASURES:Functional independence at 90 days, defined as a modified Rankin Scale score (range 0 (no symptoms) to 6 (death)) of 0-2, and serious adverse events. RESULTS:One patient from each group was lost to follow-up at 90 days. Of the 1360 patients included in the intention-to-treat analysis, 379 (55.0%) of 689 patients in the edaravone dexborneol group and 333 (49.6%) of 671 patients in the placebo group achieved functional independence on day 90 (risk ratio 1.11, 95% confidence interval (CI) 1.00 to 1.23; P=0.05; risk difference 5.4%, 95% CI 0.1% to 10.7%). Patients with mismatch at admission (defined as NIHSS score ≥10 and ASPECTS ≥9 or NIHSS score ≥20 and ≥7) were more likely to achieve functional independence in the subgroup analysis (55.5% (178/321) versus 42.9% (134/312); risk ratio 1.29, 1.10 to 1.52; risk difference 13.0%, 5.6% to 20.3%; P for interaction=0.003). The rates of serious adverse events were similar in the two groups (27.2% (188/690) versus 25.7% (173/672); risk ratio 1.06, 0.89 to 1.26; risk difference 1.5%, -3.2% to 6.2%: P=0.53). CONCLUSIONS:Among patients with acute ischaemic stroke within 24 hours of symptom onset who underwent endovascular thrombectomy, those treated with edaravone dexborneol, compared with placebo, were more likely to achieve functional independence at 90 days without increased safety concerns. This effect seemed to be primarily driven by the subgroup with mismatch present at admission, suggesting that dedicated trials in this population may be warranted. TRIAL REGISTRATION:ClinicalTrials.gov NCT05249920.