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Abstract Background Prediction of short-term outcomes in young patients with acute ischemic stroke (AIS) may assist in making therapy decisions. Machine learning (ML) is increasingly used in healthcare due to its high accuracy. This study aims to use a ML-based predictive model for poor 3-month functional outcomes in young AIS patients and to compare the predictive performance of ML models with the logistic regression model. Methods We enrolled AIS patients aged between 18 and 50 years from the Third Chinese National Stroke Registry (CNSR-III), collected between 2015 and 2018. A modified Rankin Scale (mRS) ≥ 3 was a poor functional outcome at 3 months. Four ML tree models were developed: The extreme Gradient Boosting (XGBoost), Light Gradient Boosted Machine (lightGBM), Random Forest (RF), and The Gradient Boosting Decision Trees (GBDT), compared with logistic regression. We assess the model performance based on both discrimination and calibration. Results A total of 2268 young patients with a mean age of 44.3 ± 5.5 years were included. Among them, (9%) had poor functional outcomes. The mRS at admission, living alone conditions, and high National Institutes of Health Stroke Scale (NIHSS) at discharge remained independent predictors of poor 3-month outcomes. The best AUC in the test group was XGBoost (AUC = 0.801), followed by GBDT, RF, and lightGBM (AUCs of 0.795, 0, 794, and 0.792, respectively). The XGBoost, RF, and lightGBM models were significantly better than logistic regression (P

Abstract Background An elevated endogenous cortisol level due to the peripartum stress is one of the risk factors of postpartum bovine uterine infections. Selenium is a trace element that elicits anti-inflammation and antioxidation properties. This study aimed to reveal the modulatory effect of selenium on the inflammatory response of primary bovine endometrial stromal cells in the presence of high-level cortisol. The cells were subjected to lipopolysaccharide to establish cellular inflammation. The mRNA expression of toll-like receptor 4 (TLR4), proinflammatory factors, and selenoproteins was measured with qPCR. The activation of NF-κB and MAPK signalling pathways was detected with Western blot and immunofluorescence. Results The pretreatment with sodium selenite (2 and 4 µΜ) resulted in a down-regulation of TLR4 and genes encoding proinflammatory factors, including interleukin (IL)-1β, IL-6, IL-8, tumour necrosis factor α, cyclooxygenase 2, and inducible nitric oxide synthase. Selenium inhibited the activation of NF-κB and the phosphorylation of mitogen-activated protein kinase kinase, extracellular signal-regulated kinase, p38MAPK and c-Jun N-terminal kinase/stress-activated protein kinase. The suppression of those genes and pathways by selenium was more significant in the presence of high cortisol level (30 ng/mL). Meanwhile the gene expression of glutathione peroxidase 1 and 4 was promoted by selenium, and was even higher in the presence of cortisol and selenium. Conclusions The anti-inflammatory action of selenium is probably mediated through NF-κB and MAPK, and is augmented by cortisol in primary bovine endometrial stromal cells.

Abstract Objectives To evaluate the effects and benefits of training radiology residents on contrast-enhanced ultrasound (CEUS) according to the Liver Imaging Reporting and Data System (LI-RADS). Methods In total, 234 patients at high risk of hepatocellular carcinoma (HCC) who underwent CEUS were enrolled, including 27 lesions in the education set and 207 lesions in the test sets (a–d). Forty-five radiology residents and 4 radiology experts involved in CEUS LI-RADS training individually reviewed the test sets before, immediately after, and 3-months after training. The consistency with kappa values of the description of CEUS features, the classification of focal liver lesions (FLLs), and the diagnostic performance were evaluated. Results The level of agreement between the radiology experts and residents improved after training (all p 0.05). The sensitivity, specificity, positive predictive value, and area under the curve (AUC) based on the CEUS LI-RADS classification of the radiology experts in the diagnosis of HCC were 62.9%, 96.4%, 96.3%, and 0.796, respectively. The diagnostic performance of the radiology residents significantly improved after training (all p

Abstract Background Previous research on ABO blood types and stroke has been controversial, predominantly suggesting heightened risk of stroke in non-O blood types. Nonetheless, investigations into the correlation and underlying mechanisms between ABO blood groups and stroke subtypes, especially within Chinese cohorts, remain limited. Methods The ABO blood types of 9,542 ischaemic stroke (IS) patients were inferred using two ABO gene loci (c.261G > del; c.802G > A). The healthy population was derived from the 1000 Genomes Project. Patients were classified by the causative classification system (CCS). Volcano plot and gene ontology (GO) analysis were employed to explore protein differential expression among blood types. Additionally, HT29 and SW480 cell lines with downregulated ABO expression were generated to evaluate its impact on cholesterol uptake and efflux. Results A greater proportion of stroke patients had non-O blood types (70.46%) than did healthy individuals (61.54%). Notable differences in blood type distributions were observed among stroke subtypes, with non-O blood type patients mainly classified as having large artery atherosclerosis (LAA). Clinical baseline characteristics, such as the low-density lipoprotein cholesterol level, activated partial thromboplastin time and thrombin time, varied significantly among blood types. A volcano plot revealed 17 upregulated and 42 downregulated proteins in the O blood type. GO term analysis indicated that downregulated proteins were primarily associated with lipid metabolism pathways. In vitro experiments revealed that reducing ABO gene expression decreased cholesterol uptake and increased cholesterol efflux. Conclusions This study revealed that the non-O blood type increased the risk of LAA stroke through cholesterol metabolism.

Abstract Background Life’s Essential 8 (LE8), the recently updated construct for quantifying cardiovascular health, is related to the risks of cardiovascular events. The present study aimed to evaluate associations of LE8 score with the multi-territorial extent of atherosclerosis in a community-dwelling population. Methods Data were derived from the baseline cross-sectional survey of the PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events (PRECISE) study in Lishui City. The LE8 included overall, medical and behavior LE8 scores, and were categorized as low (

Although essential for cardiovascular therapy, the pleiotropic effects of statins on ischemic stroke lack clinical evidence. This study examined the effects of statins beyond low-density lipoprotein cholesterol (LDL-C) levels on mortality and stroke severity. A total of 825,874 patients with ischemic stroke were included in this study, of whom 125,650 statin users were 1:1 matched with non-users based on their LDL-C levels (±0.05 mmol/L), forming the LDL-C-matched cohort. Associations between preceding statin treatment, in-hospital mortality, and stroke severity (National Institutes of Health Stroke Scale score ≥16) were estimated by multivariate and conditional logistic regression models in overall cohort and LDL-C-matched cohort, respectively. The overall statin effects reduced in-hospital mortality (odds ratio [OR]: 0.72, 95% confidence interval [CI]: 0.65–0.79, p

Background: Higher greenness was associated with a lower risk of adult mortality. However, the effects of greenness on the mortality of infant and child under-5 have not been fully examined. Objectives: The association of greenness on the infant mortality rate (IMR) and child under-5 mortality rate (U5MR) in 147 Chinese cities from 2009 to 2020 was evaluated. Methods: Average and maximum annual population-weighted greenness, IMR (per 1000 live births), and U5MR (per 1000 live births) in 147 cities from 2009 to 2020 were collected, and a longitudinal panel study was conducted. Greenness exposure was evaluated using satellite-derived data at a spatial resolution of 250 m ×250 m in urban regions, and linear mixed-effect models were applied to assess the associations between greenness and IMR or U5MR in China. Results: This national study showed that long-term exposure to greenness was associated with lower IMR and U5MR, respectively. Specifically, a 0.1 increase of Normalized Difference Vegetation Index (NDVI) in greenness was statistically significant with a decrease in IMR (-1.05 ‰, 95 % CI: −1.48, −0.63 ‰) and U5MR (-1.82 ‰, 95 % CI: −2.39, −1.25 ‰) in fully-adjusted model, respectively. In the stratified analyses, greenness effects on U5MR in the western (-2.33 ‰, 95 % CI: −3.43, −1.23 ‰) and central regions (-2.06 ‰, 95 % CI: −3.01, −1.10 ‰) were stronger than that in the eastern region (-0.86 ‰, 95 % CI: −1.66, −0.07 ‰). Conclusions: This nationwide study indicated that exposure to higher greenness was associated with lower mortality rates in infant and child under-5 in China.

Background The aim of this study was to investigate the efficacy and safety of tenecteplase versus alteplase in patients with acute ischemic stroke, considering their diabetes history and admission hyperglycemia status. Methods and Results This was a post hoc analysis of the TRACE‐2 (Tenecteplase Reperfusion Therapy in Acute Ischemic Cerebrovascular Events‐2) randomized clinical trial that enrolled patients in China between June 2021 and May 2022. Eligible patients with acute ischemic stroke for standard intravenous thrombolysis, but ineligible for endovascular thrombectomy, were randomly assigned (1:1) to tenecteplase or alteplase within 4.5 hours of symptom onset. Admission hyperglycemia was defined as plasma glucose >7.8 mmol/L. The primary efficacy and safety outcome were excellent functional outcome at 90 days (modified Rankin Scale score of 0–1) and symptomatic intracranial hemorrhage within 36 hours, respectively. The Cochran–Mantel–Haenszel χ2 test was used for the outcomes. Of the 1382 patients included, 369 (26.7%) had a history of diabetes, and 482 (34.9%) experienced admission hyperglycemia. The primary efficacy outcome, comparing tenecteplase to alteplase, was achieved in 93 (56.7%) versus 97 (48.3%) among patients with a history of diabetes (P=0.11) and 335 (64.6%) versus 300 (62.2%) among those without diabetes (P=0.45), respectively. The primary efficacy outcome for tenecteplase versus alteplase was comparable among patients with and without admission hyperglycemia (57.5% versus 53.9%, P = 0.44; 65.4% versus 60.4%, P=0.12, respectively). No significant difference in the risk of symptomatic intracranial hemorrhage within 36 hours was observed between tenecteplase and alteplase, regardless of diabetes history or admission hyperglycemia. Conclusions This study demonstrated that intravenous tenecteplase exhibits similar clinical outcomes compared with alteplase, irrespective of the patient's glucose metabolism status. Registration URL: https://clinicaltrials.gov; Unique identifier: NCT04797013.

Summary: Background: To assess the long-term impact of residential air pollution and green space exposure on cause-specific mortality in individuals with type 2 diabetes mellitus (T2DM). Methods: This study includes 174,063 participants newly diagnosed with T2DM from a prospective cohort in Shanghai, China, enrolled between 2011 and 2013. Residential annual levels of air pollutants, including fine (PM2.5) and coarse (PM2.5-10) particulate matter, nitrogen dioxide (NO2), along with the normalized difference vegetation index (NDVI), were derived from satellite-based exposure models. Findings: During a median follow-up of 7.9 years (equivalent to 1,333,343 person-years), this study recorded 22,205 deaths. Higher exposure to PM2.5 was significantly associated with increased risks for all mortality outcomes, whilst PM2.5-10 showed no significant impacts. The strongest associations of PM2.5 were observed for diabetes with peripheral vascular diseases [hazard ratio (HR): 2.70; per 10 μg/m3 increase] and gastrointestinal cancer (2.44). Effects of NO2 became significant at concentrations exceeding approximately 45 μg/m³, with the highest associations for lung cancer (1.20) and gastrointestinal cancer (1.19). Conversely, each interquartile range increase in NDVI (0.10) was linked to reduced mortality risks across different causes, with HRs ranging from 0.76 to 1.00. The association between greenness and mortality was partly and significantly mediated by reduced PM2.5 (23.80%) and NO2 (26.60%). There was a significant and negative interaction between NO2 and greenness, but no interaction was found between PM2.5 and greenness. Interpretation: Our findings highlight the vulnerability of individuals with T2DM to the adverse health effects of air pollution and emphasise the potential protective effects of greenness infrastructure. Funding: The 6th Three-year Action Program of Shanghai Municipality for Strengthening the Construction of Public Health System (GWVI-11.1-22), the National Key Research and Development Program (2022YFC3702701), and the National Natural Science Foundation of China (82030103, 82373532).

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

Background: Ambient air pollution might serve as a prognostic factor for ovarian cancer (OC) survival, yet the relationships between plant-based diet indices (PDIs) and OC survival remain unclear. We aimed to investigate the associations of comprehensive air pollution and PDIs with OC survival and explored the effects of air pollution-diet interactions. Methods: The present study encompassed 658 patients diagnosed with OC. The overall plant-based diet index (PDI), the healthful PDI (hPDI), and the unhealthful PDI (uPDI) were evaluated by a self-reported validated food frequency questionnaire. In addition, an air pollution score (APS) was formulated by summing the concentrations of particulate matter with a diameter of 2.5 microns or less, ozone, and nitrogen dioxide. Cox proportional hazard models were applied to calculate hazard ratios (HRs) and 95 % confidence intervals (CIs). The potential interactions of APS with PDIs in relation to overall survival (OS) were assessed on both multiplicative and additive scales. Results: Throughout a median follow-up of 37.60 (interquartile: 24.77–50.70) months, 123 deaths were confirmed. Comparing to the lowest tertiles, highest uPDI was associated with lower OS of OC (HR = 2.06, 95 % CI = 1.30, 3.28; P-trend

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

Summary: Background: Short-term exposure to particulate matter air pollution has been associated with the exacerbations of COPD, but its association with COPD mortality was not fully elucidated. We aimed to assess the association between short-term particulate matter exposure and the risk of COPD mortality in China using individual-level data. Methods: We derived 2.26 million COPD deaths from a national death registry database in Chinese mainland between 2013 and 2019. Exposures to fine particulate matter (PM2.5) and coarse particulate matter (PM2.5-10) were assessed by satellite-based models of a 1 × 1 km resolution and assigned to each individual based on residential address. The associations of PM2.5 and PM2.5-10 with COPD mortality were examined using a time-stratified case-crossover design and conditional logistic regressions with distributed lag models. We further conducted stratified analyses by age, sex, education level, and season. Findings: Short-term exposures to both PM2.5 and PM2.5-10 were associated with increased risks of COPD mortality. These associations appeared and peaked on the concurrent day, attenuated and became nonsignificant after 5 or 7 days, respectively. The exposure-response curves were approximately linear without discernible thresholds. An interquartile range increase in PM2.5 and PM2.5-10 concentrations was associated with 4.23% (95% CI: 3.75%, 4.72%) and 2.67% (95% CI: 2.18%, 3.16%) higher risks of COPD mortality over lag 0–7 d, respectively. The associations of PM2.5 and PM2.5-10 attenuated slightly but were still significant in the mutual-adjustment models. A larger association of PM2.5-10 was observed in the warm season. Interpretation: This individual-level, nationwide, case-crossover study suggests that short-term exposure to PM2.5 and PM2.5-10 might act as one of the environmental risk factors for COPD mortality. Funding: This study is supported by the National Key Research and Development Program of China (2023YFC3708304 and 2022YFC3702701), the National Natural Science Foundation of China (82304090 and 82030103), the 3-year Action Plan for Strengthening the Construction of the Public Health System in Shanghai (GWVI-11.2-YQ31), and the Science and Technology Commission of Shanghai Municipality (21TQ015).

Background and Purpose Non-high-density lipoprotein cholesterol (non-HDL-C), which represents the total cholesterol content of all pro-atherogenic lipoproteins, has recently been included as a new target for lipid-lowering therapy in high-risk atherosclerotic patients in multiple guidelines. Herein, we aimed to explore the relationship between non-HDL-C level and the efficacy and safety of ticagrelor-aspirin versus clopidogrel-aspirin in preventing stroke recurrence. Methods This study comprised a post hoc analysis of the CHANCE-2 (Ticagrelor or Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events II) trial, from which 5,901 patients with complete data on non-HDL-C were included and categorized by median non-HDL-C levels, using a cutoff of 3.5 mmol/L. The primary efficacy and safety outcomes were recurrent stroke and severe or moderate bleeding within 90 days. Results Ticagrelor-aspirin significantly reduced the risk of recurrent stroke in patients with low non-HDL-C (71 [4.8%] vs. 119 [7.7%]; adjusted hazard ratio [HR] 0.54; 95% confidence interval [CI], 0.40–0.74), but not in those with high non-HDL-C (107 [7.3%] vs. 108 [7.6%]; adjusted HR, 0.88; 95% CI, 0.67–1.16), compared with clopidogrel-aspirin (P for interaction=0.010). When analyzed as a continuous variable, the benefit of ticagrelor-aspirin for recurrent stroke decreased as non-HDL-C levels increased. No significant differences in the treatment assignments across the non-HDL-C groups were observed in terms of the rate of severe or moderate bleeding (5 [0.3%] vs. 8 [0.5%] in the low non-HDL-C group; 4 [0.3%] vs. 2 [0.1%] in the high non-HDL-C group; P for interaction=0.425). Conclusion CHANCE-2 participants with low non-HDL-C levels received more clinical benefit from ticagrelor-aspirin versus clopidogrel-aspirin compared to those with high non-HDL-C, following minor ischemic stroke or transient ischemic attack.

A method, improved d-SPE extration couple with ultra performance liquid chromatography tandem-mass spectrometry (UPLC-MS/MS), was developed for the determination of pentachlorophenol and its sodium salt residue in eggs. The sodium pentachlorophenol in the eggs was converted firstly into pentachlorophenol under acidic conditions, extracted by 1.5% (v/v) acetic acid/acetonitril, and the extraction solution was purified finally by disperse solid phase extraction. The composition of dispersive sorbents was optimized based on the recoveries and matrix effects. The recoveries at fortification levels of 0.5, 5 and 50.0 μg/kg in eggs ranged from 72.2% to 89.8% with the relative standard deviations of 0.2%~0.8%. The limits of quantification (LOQ) was 0.5 μg/kg. Market samples were quantified, and PCP residues were found, but all the detection levels were below the method LOQ. We demonstrated that UPLC – MS/MS in combination with modified d-SPE can be used to routinely monitor PCP residues in egg samples.

ABSTRACTStaphylococcus pseudintermedius (S. pseudintermedius) is a common pathogen that causes canine corneal ulcers. However, the pathogenesis remained unclear. In this study, it has been demonstrated that S. pseudintermedius invaded canine corneal epithelial cells (CCECs) intracellularly, mediating oxidative damage and pyroptosis by promoting the accumulation of intracellular reactive oxygen species (ROS) and activating the NLRP3 inflammasome. The canine corneal stroma was infected with S. pseudintermedius to establish the canine corneal ulcer model in vivo. The intracellular infectious model in CCECs was established in vitro to explore the mechanism of the ROS – NLRP3 signalling pathway during the S. pseudintermedius infection by adding NAC or MCC950. Results showed that the expression of NLRP3 and gasdermin D (GSDMD) proteins increased significantly in the infected corneas (p < 0.01). The intracellular infection of S. pseudintermedius was confirmed by transmission electron microscopy and immunofluorescent 3D imaging. Flow cytometry analysis revealed that ROS and pyroptosis rates increased in the experimental group in contrast to the control group (p

Background Recent Mendelian randomization and meta‐analysis highlight the relevance of MCP‐1 (monocyte chemoattractant protein‐1) in stroke. We aimed to investigate the associations between MCP‐1 and clinical outcomes in patients with ischemic stroke or transient ischemic attack and test whether inflammation mediates or jointly contributes to the relationships. Methods and Results A total of 10 700 patients from the Third China National Stroke Registry study were included. Multivariable Cox regression was used for recurrent stroke and all‐cause death, and logistic regression was used for poor functional outcome. Mediation analyses were performed to clarify whether inflammation mediates the associations. After adjusting for potential confounders, low MCP‐1 level (

Abstract Somatic mutations related to clonal hematopoiesis of indeterminate potential (CHIP) are risk factors for stroke. The impact of DNMT3A, the most mutated gene in CHIP, on clinical functional outcomes of acute ischemic stroke (AIS) remains unclear. In a well‐characterized cohort of 8524 ischemic stroke patients, we demonstrated that DNMT3A‐driven CHIP was significantly associated with neurological disability in these patients. With a stroke mouse model of transient middle cerebral artery occlusion (tMCAO), we demonstrated that DNMT3A protein levels in the brain penumbra increased. The DNMT3A inhibitor RG108 administration amplified neutrophil proliferation in the blood, promoted neutrophil infiltration into the brain penumbra, and exaggerated proinflammatory activation in tMCAO male mice. DNMT3A inhibition also significantly increased infarct volume and worsened neurobehavioral function in tMCAO male mice. In conclusion, DNMT3A somatic mutations are associated with worsened neurological disability in some patients with AIS, potentially through increased neutrophil proliferation and infiltration in the ischemic brain region. These findings suggest a possible mechanism for proinflammatory activation and tissue damage in the affected brain tissue, highlighting the need for further research in this area.

Background Tenecteplase, a bioengineered variant of alteplase, is a new alternative thrombolytic agent. The ORIGINAL study aims to evaluate the efficacy and safety of tenecteplase versus standard care in Chinese patients with acute ischemic stroke within 4.5 hours of symptom onset. Methods This is a multicenter phase III study that employs a randomized (1:1), active‐controlled, parallel‐group, prospective, open‐label, blinded–end point design. Adult participants (aged ≥18 years) with acute ischemic stroke who are eligible for intravenous thrombolysis within 4.5 hours of symptom onset according to current guideline recommendations are recruited from ≈55 neurology clinics/stroke centers throughout China. Results The primary objective of the ORIGINAL study is to demonstrate the noninferiority of tenecteplase (0.25 mg/kg) to alteplase (0.9 mg/kg) on the basis of the proportion of patients who achieve a modified Rankin Scale score of 0 or 1 on day 90, that is, a favorable functional outcome. The prespecified noninferiority risk ratio margin is 0.937. Secondary end points include other functional outcomes and the following safety end points: adjudicated symptomatic intracerebral hemorrhage (up to 36 hours after the end of study drug administration) based on the European Cooperative Acute Stroke Study III definition; all‐cause death within 90 days; and the proportion of patients with a modified Rankin Scale score of 5 or 6 on day 90. Conclusions It is anticipated that the results of this study will contribute to the growing body of evidence for the noninferiority of tenecteplase to alteplase given within 4.5 hours of acute ischemic stroke symptom onset and support a new indication for tenecteplase in China. Clinical Trial Registration Information NCT04915729 (https://clinicaltrials.gov/study/NCT04915729)

Background and objectives: Many studies suggested that short-term exposure to fine particulate matter (PM2.5) and coarse particulate matter (PM2.5–10) was linked to elevated risk of cerebrovascular disease. However, little is known about the potentially differential effects of PM2.5 and PM2.5–10 on various types of cerebrovascular disease. Methods: We collected individual cerebrovascular death records for all residents in Shanghai, China from 2005 to 2021. Residential daily air pollution data were predicted from a satellite model. The associations between particulate matters (PM) and cerebrovascular mortality were investigated by an individual-level, time-stratified, case-crossover design. The data was analyzed by the conditional logistic regression combined with the distributed lag model with a maximum lag of 7 days. Furthermore, we explored the effect modifications by sex, age and season. Results: A total of 388,823 cerebrovascular deaths were included. Monotonous increases were observed for mortality of all cerebrovascular diseases except for hemorrhagic stroke. A 10 μg/m3 rise in PM2.5 was related to rises of 1.35% [95% confidence interval (CI): 1.04%, 1.66%] in mortality of all cerebrovascular diseases, 1.84% (95% CI: 1.25%, 2.44%) in ischemic stroke, 1.53% (95% CI: 1.07%, 1.99%) in cerebrovascular sequelae and 1.56% (95% CI: 1.08%, 2.05%) in ischemic stroke sequelae. The excess risk estimates per each 10 μg/m3 rise in PM2.5–10 were 1.47% (95% CI: 1.10%, 1.84%), 1.53% (95% CI: 0.83%, 2.24%), 1.93% (95% CI: 1.38%, 2.49%) and 2.22% (95% CI: 1.64%, 2.81%), respectively. The associations of both pollutants with all cerebrovascular outcomes were robust after controlling for co-pollutants. The associations were greater in females, individuals > 80 years, and during the warm season. Conclusions: Short-term exposures to both PM2.5 and PM2.5–10 may independently increase the mortality risk of cerebrovascular diseases, particularly of ischemic stroke and stroke sequelae.

Background We aim to identify the distinct lesion patterns and regions associated with functional outcome and inflammation in patients with acute ischemic stroke, and investigate whether the association between lesion patterns and functional outcome was mediated by inflammation. Methods and Results We performed nonnegative matrix factorization to derived low‐dimensional lesion patterns (atoms), and Bayesian linear regression models were applied to explore the associations of lesion patterns with inflammatory factors including high‐sensitivity C‐reactive protein and interleukin‐6, as well as functional outcome (defined as modified Rankin Scale score at 3 months). The difference distribution mean and 95% highest probability density interval (HPDI) were calculated. Mediation analysis was used to examine the mediating effects of inflammation on the relationships between lesion patterns and functional outcome. Seven lesion patterns were derived from 5914 patients with acute ischemic stroke. Lesion patterns distributed in the cortical regions were associated with inflammatory response, including atom 1 (interleukin‐6: mean, 0.113 [95% HPDI, 0.073–0.162]; high‐sensitivity C‐reactive protein: mean, 0.082 [95% HPDI, 0.038–0.123]) and atom 4 (interleukin‐6: mean, 0.113 [95% HPDI, 0.071–0.167]; high‐sensitivity C‐reactive protein: mean, 0.108 [95% HPDI, 0.058–0.165]). These lesion patterns were also significantly associated with functional outcome (atom 1: mean, 1.958 [95% HPDI, 1.538–2.383]; atom 4: mean, 2.245 [95% HPDI, 1.773–2.741]). Mediation analysis suggested that interleukin‐6 explained 15.34% and 7.47% in the association of atom 1 and atom 4 with functional outcome, respectively. Conclusions Certain lesion patterns that are associated with both inflammation and functional outcome of acute ischemic stroke, especially cortical infarction, may play a role in functional outcome through modulating inflammatory reactions.

Abstract Background Insulin resistance is linked to atherosclerotic cardiovascular diseases and stroke, whereas less is known about adipose tissue specific insulin resistance and outcomes after ischemic stroke. This study aimed to estimate the association between adipose tissue specific insulin resistance and prognosis of nondiabetic patients with ischemic stroke. Methods Patients with ischemic stroke without a history of diabetes mellitus in the Third China National Stroke Registry were included. Adipose tissue specific insulin resistance index (Adipo-IR) was calculated by fasting serum insulin and free fatty acids and categorized into 5 groups according to the quintiles. Outcomes included stroke recurrence (ischemic or hemorrhagic), combined vascular events, all-cause death, and poor outcome (modified Rankin Scale, 3–6) at 12 months after stroke onset. We assessed the association between Adipo-IR and risk of prognosis by multivariable Cox/logistic regression models adjusted for potential covariates. Results Among 2,222 patients, 69.0% were men with a mean age of 62.5 years. At 12 months, 185 (8.3%) patients had recurrent stroke, 193 (8.7%) had combined vascular events, 58 (2.6%) died, and 250 (11.5%) had a poor outcome. Compared with patients with the lowest quintile, patients with the second, third, fourth, fifth quintiles of the Adipo-IR were associated with an increased risk of stroke recurrence (hazard ratio [HR], 1.77; 95% CI, 1.04–3.03; P = 0.04; HR, 2.19; 95% CI, 1.30–3.68; P = 0.003; HR, 1.84; 95% CI, 1.06–3.21; P = 0.03; HR, 2.11; 95% CI, 1.20–3.71; P = 0.01, respectively) and marginally associated with an increased risk of combined vascular events ( HR, 1.60; 95%CI, 0.97–2.64; P = 0.07; HR, 1.91; 95% CI, 1.17–3.13; P = 0.01; HR, 1.62; 95% CI, 0.96–2.75; P = 0.07; HR, 1.80; 95% CI, 1.05–3.09; P = 0.03, respectively) at 12 months after adjustment for potential covariates. Adipo-IR was not associated with mortality and poor outcome at 12 months. Conclusions These findings suggest that adipose tissue specific insulin resistance is independently associated with recurrent stroke and combined vascular events after acute ischemic stroke in nondiabetic patients.

The spatial disparity of air pollutants is one of the key influential factors for environmental inequality. We quantitatively evaluated the evolution of PM2.5 spatial disparity in China during 2013–2020, and investigated the associations between PM2.5 spatial disparity and economic indicators. Differences in PM2.5 between more- and less-polluted cities declined over time, suggesting decreased absolute disparity. However, the more polluted cities in 2013 remained so in 2017 and 2020, and vice versa, indicating persistent relative disparity. PM2.5 pollution levels increased with higher GDP per capita in less-developed areas of China, but such negative effects weakened over time, while economic development tended to promote cleaner air in developed areas of China. Therefore, policies to improve air quality and promote economic development simultaneously are needed in China to reduce the disparity of air pollution and promote all people to enjoy environmental equality.

Abstract Background Data are limited on the association of metabolic dysfunction-associated fatty liver disease (MAFLD) with systemic atherosclerosis. This study aimed to examine the relationship between MAFLD and the extent of atherosclerotic plaques and stenosis, and presence of polyvascular disease (PolyVD). Methods In this cross-sectional study, MAFLD was diagnosed based on the presence of metabolic dysfunction (MD) and fatty liver disease (FLD). MAFLD was divided into three subtypes: MAFLD with diabetes mellitus (DM), MAFLD with overweight or obesity (OW), as well as MAFLD with lean/normal weight and at least two metabolic abnormalities. Atherosclerosis was evaluated, with vascular magnetic resonance imaging for intracranial and extracranial arteries, thoracoabdominal computed tomography angiography for coronary, subclavian, aorta, renal, iliofemoral arteries, and ankle-brachial index for peripheral arteries. The extent of plaques and stenosis was defined according to the number of these eight vascular sites affected. PolyVD was defined as the presence of stenosis in at least two vascular sites. Results This study included 3047 participants, with the mean age of 61.2 ± 6.7 years and 46.6% of male (n = 1420). After adjusting for potential confounders, MAFLD was associated with higher extent of plaques (cOR, 2.14, 95% CI 1.85–2.48) and stenosis (cOR, 1.47, 95% CI 1.26–1.71), and higher odds of presence of PolyVD (OR, 1.55, 95% CI 1.24–1.94) as compared with Non-MAFLD. In addition, DM-MAFLD and OW-MAFLD were associated with the extent of atherosclerotic plaques and stenosis, and presence of PolyVD (All P

ABSTRACTChinese onion is a common vegetable in daily diet, especially in Southwest China. We collected 184 samples from farm and market in Chongqing Municipality during 2020–2021 and established a multi-residue method for analysis of 79 pesticide residues on Chinese onion. Sixty-three of 184 samples were found pesticide resdues, accounting for 34.2%. A total of 31 pesticides were detected, and 6 pesticides in 11 samples have exceeded the Chinese MRLs, 5.98% of all samples. The chronic and acute dietary exposure assessment showed the %ADI and the %ARfD value were 0.005%–5.46% and 0.03%–297.95%, respectively. The %ARfD of most pesticides were acceptable except for cyhalothrin (297.95%, children; 140.17%, adults) and carbofuran (107.94%, children). The study indicated that pesticide residues on Chinese onion had different concentration levels which were low commonly. The establishment of MRLs for several pesticides (cyfluthrin, carbendazim, propamocarb) in Chinese onion is required for better estimation of dietary risk.

Endometritis represents a prevalent condition in perinatal dairy cows. Bovine endometrial epithelial cells (BEECs), as the primary interface between cavity and the external environment, are particularly vulnerable to infection by pathogenic bacteria following parturition. A20 is essential for regulating inflammation and modulating immune responses. Nevertheless, the exact role of A20 in the BEECs in response to inflammatory response is not fully understood. An endometritis model infected by Escherichia coli (E. coli) in vivo and a BEECs inflammation model induced with lipopolysaccharide (LPS) in vitro were built to investigate the function and governing mechanisms of A20 in endometritis. The results showed that infection with E. coli resulted in endometrial damage, inflammatory cell infiltration, and upregulation of inflammatory factors in dairy cows. Furthermore, A20 expression was upregulated in the endometrium of cows with endometritis and in BEECs following LPS stimulation. A20 overexpression attenuated the level of proinflammatory cytokines in LPS-stimulated BEECs; conversely, A20 knockdown lead to an exacerbated response to LPS stimulation. The overexpression of A20 was shown to activate autophagy and suppress the NF-κB signaling pathway in LPS-stimulated BEECs. However, blocking autophagy with chloroquine notably attenuated the anti-inflammatory effect of A20, leading to the activation of the NF-κB signaling pathway. In summary, the study demonstrated that A20’s suppression of inflammation in LPS-stimulated BEECs is associated with the activation of autophagy. Therefore, the A20 protein showed potential as a novel treatment focus for managing endometritis in dairy cows.

Background Elevated white blood cell count, fibrinogen levels, and lower levels of albumin signify higher systemic inflammatory response, hypercoagulable state, and poorer nutritional status, respectively. However, a consistent conclusion could not be drawn on whether the association between inflammatory markers and cardiovascular disease was affected by the presence of chronic kidney disease (CKD). We aimed to explore the association between inflammation and adverse outcomes in patients with acute ischemic stroke (AIS), as well as whether this association differs due to the presence of CKD. Methods and Results This research was based on the Third China National Stroke Registry. The main adverse outcomes were poor functional outcome, stroke recurrence, and combined vascular event after 1 year. Inflammation was defined as the worst quartile of at least 2 of the aforementioned 3 markers. Finally, 8493 patients with AIS were enrolled in this study. The adjusted odds ratios/hazard ratios and 95% CIs of inflammation were 1.58 (1.34–1.86) for poor functional outcomes, 1.25 (1.06–1.47) for stroke recurrence, and 1.25 (1.06–1.46) for combined vascular event. The association between inflammation and adverse outcomes existed only in patients with AIS without CKD, although the interaction between CKD and inflammation was not statistically significant. (P for interaction >0.05). Conclusions Inflammation, which was defined as a combination of fibrinogen, white blood cell count, and albumin, was associated with all 1‐year adverse outcomes among patients with AIS. Routine assessment of these biomarkers could become a potential part of the clinical evaluation for patients with AIS, especially those without CKD, aiding clinicians in risk stratification and treatment decision‐making.

BackgroundThere is evidence of an association between the gut microbiota and progression of stroke. However, the relationship between gut microbial metabolites, specifically bile acids (BAs), and post-ischemic stroke disability and poor functional outcomes remains unexplored.MethodsPatients with acute ischemic stroke (AIS) or transient ischemic attack (TIA) in the Third China National Stroke Registry were grouped according to total bile acid (TBA) quartile on admission. Association of TBA with disability and poor functional outcomes were evaluated using logistic regression models and restricted cubic splines.ResultsData for 9,536 patients were included. After adjusting for confounders, the risks of disability and poor functional outcomes were significantly lower in the highest TBA quartile than in the lowest TBA quartile at the 3-month follow-up, with respective odds ratios (ORs) of 0.65 (95% confidence interval [CI] 0.55–0.78; p

The aim of the research was to obtain a high healthcare honeysuckle beverage with strong antioxidant activity. Honeysuckle (Lonicera japonica Thunb) was used as the raw material in this experiment. The effects of fermentation temperature, fermentation time, lactic acid bacteria inoculation amount, and sugar addition amount on the sensory quality of honeysuckle beverage were investigated by single factor test and orthogonal test, and the best process was obtained. The physicochemical indexes and antioxidant activity of honeysuckle beverages fermented with lactic acid bacteria were studied. The results showed that the fermentation temperature of the beverage was 37 °C, the fermentation time was 24 h, the inoculation amount of Lactiplantibacillus plantarum and Lactobacillus acidophilus mixed starter (1:1) was 3%, and 8% white granulated sugar was added. The highest sensory score was 87.30 ± 0.17, which was the optimal process. The honeysuckle liquid mixed inoculation with Lactiplantibacillus plantarum and Lactobacillus acidophilus was fermented for 24 h. The number of viable bacteria reached 9.84 ± 0.02 lg cfu/mL, the pH value was 3.10 ± 0.01, and the total polyphenol content was 7.53 ± 0.03 mg GAE/g. The number of lactic acid bacteria, pH, total polyphenol content, and free radical scavenging rate were significantly increased (p

Background Insulin resistance as a significant vascular risk factor has been studied in relation to cerebral small vessel disease (SVD). Evidence suggests that insulin resistance might trigger high blood pressure (BP). Therefore, we aimed to investigate whether insulin resistance impacts SVD with a mediating effect of BP in nondiabetic subjects. Methods and Results PRECISE (Polyvascular Evaluation for Cognitive Impairment and Vascular Events) study participants underwent brain and vascular imaging techniques and metabolomic risk factors measurements. Insulin resistance was evaluated by the insulin sensitivity index and the Homeostatic Model Assessment for Insulin Resistance based on the standard oral glucose tolerance test. On average, 2752 nondiabetic subjects (47.1% men) aged 60.9 years were included. The multivariable logistic regression model and linear regression model tested the association of insulin resistance with BP components (including systolic BP [SBP], diastolic BP (DBP), and pulse pressure [PP]) and SVD, and of BP components with SVD. In the mediation analysis, SBP, DBP, and PP were found to partially mediate the detrimental effect of insulin resistance (assessed by the insulin sensitivity index) on lacunes (mediation percentage: SBP, 31.15%; DBP, 34.21%; PP, 10.43%), white matter hyperintensity (mediation percentage: SBP, 37.34%; DBP, 44.15%; PP, 9.80%), and SVD total burden (mediation percentage: SBP, 42.07%; DBP, 49.29%; PP, 11.71%) (all P

Background Acute ischemic stroke is a major cause of mortality and disability worldwide, with approximately 7.4% to 7.7% recurrence within the first 3 months. This study aimed to identify potential biomarkers for predicting stroke recurrence. Methods and Results We conducted a nested case–control study using a hospital‐based cohort from the Third China National Stroke Registry selecting 214 age‐ and sex‐matched patients with ischemic stroke with hypertension and no history of diabetes or heart disease. Using data‐independent acquisition for discovery and multiple reaction monitoring for quantitative validation, we identified 26 differentially expressed proteins in large‐artery atherosclerosis (Causative Classification of Ischemic Stroke [CCS]1), 16 in small‐artery occlusion (CCS3), and 25 in undetermined causes (CCS5) among patients with recurrent stroke. In the CCS1 and CCS3 subgroups, differentially expressed proteins were associated with platelet aggregation, neuronal death/cerebroprotection, and immune response, whereas differentially expressed proteins in the CCS5 subgroup were linked to altered metabolic functions. Validated recurrence predictors included proteins associated with neutrophil activity and vascular inflammation (TAGLN2 [transgelin 2], ITGAM [integrin subunit α M]/TAGLN2 ratio, ITGAM/MYL9 [myosin light chain 9] ratio, TAGLN2/RSU1 [Ras suppressor protein 1] ratio) in the CCS3 subgroup and proteins associated with endothelial plasticity and blood–brain barrier integrity (ITGAM/MYL9 ratio and COL1A2 [collagen type I α 2 chain]/MYL9 ratio) in the CCS3 and CCS5 subgroups, respectively. Conclusions These findings provide a foundation for developing a blood‐based biomarker panel, using causative classifications, which may be used in routine clinical practice to predict stroke recurrence.

The therapeutic mechanism of oleanolic acid (OA) in breast cancer has been widely reported, but little has been known about the combined effects of transcriptome and gut microbiome. In this study, the phenotypic effect of oleanolic acid on mice was tested at the end of the administration cycle, and RNA sequencing on murine tumor tissue and 16S-rRNA sequencing on intestinal contents were conducted to analyze gene expression profiles and microbial diversity between the control group and OA treated group using 4T1-induced mice breast cancer model. As a result, it has been confirmed that oleanolic acid would play a significant inhibitory effect on the development of breast tumors in mice. Based on the integrative analysis of the transcriptomic and metagenomic data, it was found that the abundance of Lactobacillus in the intestinal flora of mice significantly increased in the OA group. Moreover, the up-regulation of Il10 had a significant effect on inhibiting the tumor progression, which played a role through cytokine-cytokine receptor interaction pathway.

Abstract Background The high under-five mortality rate (U5MR) in Africa is a significant public health concern. Previous studies have found that satellite retrieved light at night (LAN) data with long-term and global coverage can be used as a proxy for socio-economic development and urbanization. Currently, few studies on the effects of LAN on child mortality have been conducted in Africa, a region with varying levels of urbanization between countries. Objective To quantify the correlation between risk of child mortality and LAN as an indicator of urbanization and economic development in Africa. Methods Using data from the Demographic and Health Survey (DHS) database conducted in 15 African countries out of 46 countries from 2005 to 2013, this study estimated LAN levels for children based on their year of birth and residential addresses. This study used Cox proportional hazards models to assess the association between LAN and the risk of child mortality in Africa. Results The mean U5MR was 95 per 1,000 livebirths among the 15 African countries during 2005–2013. After adjusting for covariates, each 10-unit increment in LAN was associated with a 5.3% reduction in the risk of U5MR. The effect estimates were more pronounced in areas with lower LAN. Conclusion In Africa, the risk of U5MR decreased with increasing LAN, especially in areas with lower LAN. The results suggest that the development of urbanization and socio-economic conditions may be beneficial to child health, especially in regions with low LAN. The use of LAN as a proxy may offer an intriguing approach for identifying areas requiring targeted development in urbanization and socio-economic conditions.

Abstract Background and purpose Nonvalvular atrial fibrillation (NVAF) is a risk factor for stroke. This study was undertaken to determine the influence of NVAF on the mortality and recurrent stroke after a minor stroke event. Methods Data were derived from the Third China National Stroke Registry (CNSR-III) which enrolled 15,166 subjects during August 2015 through March 2018 in China. Patients with minor stroke (NIHSS ≤ 5) within 24 h after onset were included. Clinical outcomes including all-cause mortality, cardiovascular death, recurrent ischemic stroke, and recurrent hemorrhagic stroke were collected. The Cox proportional hazards models were used to determine the association between NVAF and clinical outcomes. Results A total of 4,753 patients were included in our study. Of them, 222 patients had NVAF (4.7%) (mean age, 71.1 years) and 4,531 patients were without AF (95.3%) (mean age, 61.4 years). NVAF was associated with 12-month cardiovascular mortality in both univariate (hazards ratio [HR], 4.13; 95% confidence interval [CI], 1.84 to 9.31; P

Abstract Background Estimated glucose disposal rate (eGDR), a simple and noninvasive measure of insulin resistance, has been proven to be an independent risk factor for first-time stroke and all-cause mortality. In this study, we aimed to investigate the associations between eGDR and the stroke outcome in patients with first-time acute ischemic stroke (AIS). Methods We included first-time AIS patients with available data on eGDR in the China National Stroke Registry III (CNSR-III), and divided the subjects into lower eGDR group (eGDR ≤ 6 mg/kg/min) and higher eGDR group (eGDR > 6 mg/kg/min). The primary outcome was excellent functional outcome (modified Rankin Scale score 0–1) at 3 months. Secondary outcomes included stroke recurrence and favorable functional outcome (modified Rankin Scale score 0–2) at 3 months, and functional outcome and combined vascular event at one year. Univariate and multivariate analyses were performed to evaluate the association between eGDR and outcomes. Results A total of 6,271 patients with AIS were included in this study. The median values of eGDR in lower and higher eGDR group were 5.0 mg/kg/min (interquartile range, 4.2–5.6) and 7.6 mg/kg/min (interquartile range, 6.8–9.6), respectively. Patients with higher eGDR were significantly associated with higher incidence of excellent functional outcome (adjusted odds ratio, 1.24; 95% confidence interval, 1.06–1.45; P

Abstract Ischemic stroke is a leading cause of global mortality and long-term disability. However, there is a paucity of whole-genome sequencing studies on ischemic stroke, resulting in limited knowledge of the interplay between genomic and phenotypic variations among affected patients. Here, we outline the STROMICS design and present the first whole-genome analysis on ischemic stroke by deeply sequencing and analyzing 10,241 stroke patients from China. We identified 135.59 million variants, > 42% of which were novel. Notable disparities in allele frequency were observed between Chinese and other populations for 89 variants associated with stroke risk and 10 variants linked to response to stroke medications. We investigated the population structure of the participants, generating a map of genetic selection consisting of 31 adaptive signals. The adaption of the MTHFR rs1801133-G allele, which links to genetically evaluated VB9 (folate acid) in southern Chinese patients, suggests a gene-specific folate supplement strategy. Through genome-wide association analysis of 18 stroke-related traits, we discovered 10 novel genetic-phenotypic associations and extensive cross-trait pleiotropy at 6 lipid-trait loci of therapeutic relevance. Additionally, we found that the set of loss-of-function and cysteine-altering variants present in the causal gene NOTCH3 for the autosomal dominant stroke disorder CADASIL displayed a broad neuro-imaging spectrum. These findings deepen our understanding of the relationship between the population and individual genetic layout and clinical phenotype among stroke patients, and provide a foundation for future efforts to utilize human genetic knowledge to investigate mechanisms underlying ischemic stroke outcomes, discover novel therapeutic targets, and advance precision medicine.

Abstract Background Serum uric acid (SUA), an end-product of purine catabolism diffused in the blood, is positively associated with the risk of type 2 diabetes mellitus (T2DM). However, in the T2DM population, the association of SUA fluctuation ( $$\Delta$$ Δ SUA) with the functional outcome of ischemic stroke (IS) is still unclear. Accordingly, this study aimed to assess the correlation between $$\Delta$$ Δ SUA and short-term IS functional outcomes in T2DM patients. Methods All T2DM patients diagnosed with IS in the China National Stroke Registry III were included. $$\Delta$$ Δ SUA, which was defined as the difference between the SUA levels at baseline and 3 months after symptom onset, was classified into two groups, i.e., elevated $$\Delta$$ Δ SUA ( $$\Delta$$ Δ SUA > 0) and reduced $$\Delta$$ Δ SUA ( $$\Delta$$ Δ SUA $$\le$$ ≤ 0). The outcomes measured using the Modified Rankin Scale (mRS) were scored from 0 to 6, and poor functional outcome was defined as an mRS score of 3–6 at 3 months after IS. Results Among the 1255 participants (mean age: 61.6 ± 9.8 years), 64.9% were men. Patients with elevated $$\Delta$$ Δ SUA had a lower incidence of poor functional outcomes at 3 months. Compared with reduced $$\Delta$$ Δ SUA, elevated $$\Delta$$ Δ SUA at 0–50 μmol/L (odds ratio [OR] = 0.46, 95% confidence interval [CI] = 0.28–0.78, p = 0.004) and 50–100 μmol/L (OR = 0.40, 95% CI = 0.21–0.77, p = 0.006) was significantly correlated with a reduced risk of poor functional outcomes at 3 months. Conclusion This study showed that a moderate increase in $$\Delta$$ Δ SUA in the range of 0–100 μmol/L at 3 months after IS might be beneficial in T2DM adults and more studies are warranted to confirm this.

Abstract Background In large-scale high-throughput sequencing projects and biobank construction, sample tagging is essential to prevent sample mix-ups. Despite the availability of fingerprint panels for DNA data, little research has been conducted on sample tagging of whole genome bisulfite sequencing (WGBS) data. This study aims to construct a pipeline and identify applicable fingerprint panels to address this problem. Results Using autosome-wide A/T polymorphic single nucleotide variants (SNVs) obtained from whole genome sequencing (WGS) and WGBS of individuals from the Third China National Stroke Registry, we designed a fingerprint panel and constructed an optimized pipeline for tagging WGBS data. This pipeline used Bis-SNP to call genotypes from the WGBS data, and optimized genotype comparison by eliminating wildtype homozygous and missing genotypes, and retaining variants with identical genomic coordinates and reference/alternative alleles. WGS-based and WGBS-based genotypes called from identical or different samples were extensively compared using hap.py. In the first batch of 94 samples, the genotype consistency rates were between 71.01%-84.23% and 51.43%-60.50% for the matched and mismatched WGS and WGBS data using the autosome-wide A/T polymorphic SNV panel. This capability to tag WGBS data was validated among the second batch of 240 samples, with genotype consistency rates ranging from 70.61%-84.65% to 49.58%-61.42% for the matched and mismatched data, respectively. We also determined that the number of genetic variants required to correctly tag WGBS data was on the order of thousands through testing six fingerprint panels with different orders for the number of variants. Additionally, we affirmed this result with two self-designed panels of 1351 and 1278 SNVs, respectively. Furthermore, this study confirmed that using the number of genetic variants with identical coordinates and ref/alt alleles, or identical genotypes could not correctly tag WGBS data. Conclusion This study proposed an optimized pipeline, applicable fingerprint panels, and a lower boundary for the number of fingerprint genetic variants needed for correct sample tagging of WGBS data, which are valuable for tagging WGBS data and integrating multi-omics data for biobanks.

BackgroundData on the association between serum alkaline phosphatase (ALP) levels and clinical outcomes in patients with ischemic stroke (IS) are inconsistent and limited. Therefore, this study aimed to investigate the correlation between ALP and prognosis in patients with IS.MethodsPatients with acute ischemic stroke (AIS) or transient ischemic attack (TIA) from the Third China National Stroke Registry were divided into four groups according to the quartiles of serum ALP levels on admission. Cox proportional hazards and logistic regression models were used to evaluate the correlation between ALP and the risk of all-cause mortality, disability (modified Rankin Scale (mRS) score 3–5), and poor functional outcomes (mRS score 3–6).ResultsA total of 11,405 patients were included in the study. Higher levels of ALP were associated with all-cause mortality at 3 months (adjusted hazard ratio [HR] per standard deviation [SD]: 1.16; 95% confidence interval (CI): 1.07–1.27; p = 0.001) and 1 year (adjusted HR: 1.11; 95% CI: 1.03–1.20; p = 0.010). At the 3-month follow-up, each SD increase of ALP was associated with a 12 and 14% higher risk of disability (adjusted odds ratio (OR): 1.12; 95% CI: 1.06–1.18; p

Summary: Background: The atherogenicity of remnant cholesterol (RC), a contributor to residual risk of cardiovascular events, has been underlined by recent guidelines. We aimed to evaluate the relationship between RC levels and the efficacy and safety of genotype-guided dual antiplatelet therapy in the CHANCE-2 trial. Methods: This post-hoc study used data from the CHANCE-2 trial, which was a randomised, double-blind, placebo-controlled trial of 6412 patients (aged >40 years) enrolled from 202 hospitals in China, between Sept 23, 2019, and March 22, 2021, who carried CYP2C19 loss-of-function alleles and had either an acute minor stroke or high-risk transient ischaemic attack (TIA), and could start treatment within 24 h of symptom onset. Participants received either (1:1) ticagrelor plus aspirin (control) or clopidogrel plus aspirin (intervention) and the effect of reducing the 3-month risk of any new stroke was assessed (ischemic or haemorrhagic, primary outcome). From the CHANCE-2 study population, we enrolled 5890 patients with complete data on RC. The cutoff point of RC for distinguishing patients with greater benefit from ticagrelor-aspirin versus clopidogrel-aspirin was determined with subpopulation treatment effect pattern plot. The primary efficacy and safety outcome was recurrent stroke and severe or moderate bleeding within 90 days, respectively. CHANCE-2 is registered with ClinicalTrials.gov, NCT04078737. Findings: The cutoff to define elevated RC was 0.91 mmol/L. Ticagrelor-aspirin versus clopidogrel-aspirin was associated with a reduced risk of recurrent stroke in patients with non-elevated RC levels (122 [5.3%] versus 179 [7.8%]; hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.54–0.85), but this benefit was absent in those with elevated RC levels (58 [8.4%] versus 48 [7.3%]; HR, 1.10; 95% CI, 0.73–1.65; P-interaction = 0.03). When analyzed as a continuous variable, the benefit of ticagrelor-aspirin on recurrent stroke decreased as RC levels increased. The rates of severe or moderate bleeding between treatment groups were similar across RC categories (0.3% versus 0.3%, P-interaction = 0.95). Interpretation: Our post-hoc findings suggest that RC could be a potential biomarker to discriminate patients who received more benefits from ticagrelor-aspirin versus clopidogrel-aspirin therapy in CYP2C19 loss-of-function carriers with minor stroke or TIA. These findings need to be validated in an independent study. Funding: The National Key Research and Development Program of China, Beijing Natural Science Foundation Haidian original innovation joint fund, Fund for Young Talents of Beijing Medical Management Center, the high-level public health talents, Training Fund for Open Projects at Clinical Institutes and Departments of Capital Medical University; and Salubris.

Abstract Acute ischemic stroke (AIS) is a major cause of disability and mortality worldwide. Non-cardioembolic ischemic stroke (NCIS), which constitutes the majority of AIS cases, is highly heterogeneous, thus requiring precision medicine treatments. This study aimed to investigate the molecular mechanisms underlying NCIS heterogeneity. We integrated data from the Third China National Stroke Registry, including clinical phenotypes, biomarkers, and whole-genome sequencing data for 7695 patients with NCIS. We identified 30 molecular clusters based on 63 biomarkers and explored the comprehensive landscape of biological heterogeneity and subpopulations in NCIS. Dimensionality reduction revealed fine-scale subpopulation structures associated with specific biomarkers. The subpopulations with biomarkers for inflammation, abnormal liver and kidney function, homocysteine metabolism, lipid metabolism, and gut microbiota metabolism were associated with a high risk of unfavorable clinical outcomes, including stroke recurrence, disability, and mortality. Several genes encoding potential drug targets were identified as putative causal genes that drive the clusters, such as CDK10, ERCC3, and CHEK2. We comprehensively characterized the genetic architecture of these subpopulations, identified their molecular signatures, and revealed the potential of the polybiomarkers and polygenic prediction for assessing clinical outcomes. Our study demonstrates the power of large-scale molecular biomarkers and genomics to understand the underlying biological mechanisms of and advance precision medicine for NCIS.

Abstract Background and purpose Conflicting reports of obesity paradox have led to confusion about weight management strategies for post-stroke patients. The main purpose of this study is to determine whether the obesity paradox measured by body mass index (BMI) or by waist-to-height ratio (WHtR) is real. Methods We evaluated the association of general obesity measured by BMI, and abdominal obesity measured by WHtR with 1-year all-cause mortality, recurrence of stroke and combined vascular events of acute ischemic stroke (AIS) patients in a cohort —— the Third China National Stroke Registry (CNSR-III). Cox proportional hazards models and restricted cubic splines were performed to investigate the association between obesity and clinical outcomes. Results A total of 14,146 patients with ischemic stroke were included. When BMI was used as a measure of obesity, compared to the normal weight patients, mortality decreased in overweight patients (hazard ratio [HR] 0.74 [95% confidence interval (CI) 0.61–0.91], P = 0.0035) and obese patients (HR 0.54 [0.40–0.73], P

Objective: We aimed to explore the multifaceted etiology of recurrent implantation failure (RIF) and evaluate the efficacy of various management strategies, with a focus on refining examination protocols and treatment pathways to improve implantation success rates in patients undergoing in vitro fertilization-embryo transfer. Mechanism: The development of RIF can be attributed to a complex causal network of factors. Chromosomal anomalies, such as aneuploidies, directly impact the genetic viability of embryos. Immune system dysregulation, marked by the presence of autoantibodies, disrupts the normal immunological tolerance required for successful implantation. Endocrine disruptions interfere with the hormonal balance essential for preparing the endometrium for implantation. Anatomical irregularities in the female reproductive tract can physically impede the embryo’s ability to implant. Lifestyle factors, including diet, stress, and environmental exposures, influence both male and female reproductive health, affecting gamete quality and implantation potential. These diverse factors interact in a multifaceted manner, making a personalized diagnostic and therapeutic approach essential for addressing the specific causes in each case of RIF. Findings in brief: The review synthesizes current understanding of RIF’s etiology, highlighting the need for innovative interventions and adjustments in clinical practice. It emphasizes the significance of a highly personalized approach in managing RIF, incorporating refined examination protocols and tailor-made treatment pathways to address the unique combination of factors present in each case. Conclusions: Effective management of RIF requires innovative interventions and a shift in clinical practice towards personalized care. Identifying gaps in the current understanding of RIF points towards a clear direction for future research, aimed at refining treatment protocols and improving outcomes for patients. This contributes significantly to the broader field of reproductive medicine, aiming to alleviate the clinical and psychological burdens of RIF.

Background This study aimed to investigate the efficacy and safety of ticagrelor–aspirin versus clopidogrel–aspirin in Chinese patients by the presence and clinical presentation of intracranial artery stenosis (ICAS) using randomized trial data from the CHANCE‐2 (Clopidogrel in High‐Risk Patients With Acute Nondisabling Cerebrovascular Events‐II) trial. Methods and Results A total of 6412 patients with minor stroke or transient ischemic attack who carried CYP2C19 loss‐of‐function alleles were randomized to either the ticagrelor–aspirin or clopidogrel–aspirin group. Patients without imaging of the intracranial artery were excluded from the nonprespecified subgroup analysis of CHANCE‐2. All patients included were classified into the following groups: without ICAS, symptomatic ICAS, or asymptomatic ICAS. The primary efficacy outcome was new strokes within 90 days. There were 5893 patients (median age, 64.8 years; 33.9% women) included, and 172 (4.9%), 171 (10.5%), and 57 (7.7%) cases of new strokes occurred within 90 days in the without ICAS, with symptomatic ICAS, and with asymptomatic ICAS groups, respectively. Ticagrelor–aspirin was associated with reduced risk of new stroke in patients without ICAS (62 [3.5%] versus 110 [6.3%]; hazard ratio [HR], 0.57 [95% CI, 0.41–0.78]) but not in those with symptomatic ICAS (HR, 0.77 [95% CI, 0.56–1.05]) or in those with asymptomatic ICAS (HR, 0.77 [95% CI, 0.43–1.38]) compared with clopidogrel–aspirin (P for interaction=0.14). There were no significant differences in the proportion of severe or moderate bleeding events among different ICAS groups. Conclusions Patients without ICAS received a significantly greater benefit from ticagrelor–aspirin than clopidogrel–aspirin after minor ischemic stroke or transient ischemic attack, and there was no statistically significant difference between treatments in patients with symptomatic ICAS or asymptomatic ICAS. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04078737.

Summary: In counteracting highly infectious and disruptive respiratory diseases such as COVID-19, vaccination remains the primary and safest way to prevent disease, reduce the severity of illness, and save lives. Unfortunately, vaccination is often not the first intervention deployed for a new pandemic, as it takes time to develop and test vaccines, and confirmation of safety requires a period of observation after vaccination to detect potential late-onset vaccine-associated adverse events. In the meantime, nonpharmacologic public health interventions such as mask-wearing and social distancing can provide some degree of protection. As climate change, with its environmental impacts on pathogen evolution and international mobility continue to rise, highly infectious respiratory diseases will likely emerge more frequently and their impact is expected to be substantial. How quickly a safe and efficacious vaccine can be deployed against rising infectious respiratory diseases may be the most important challenge that humanity will face in the near future. While some organizations are engaged in addressing the World Health Organization's ''blueprint for priority diseases'', the lack of worldwide preparedness, and the uncertainty around universal vaccine availability, remain major concerns. We therefore propose the establishment of an international candidate vaccine pool repository for potential respiratory diseases, supported by multiple stakeholders and countries that contribute facilities, technologies, and other medical and financial resources. The types and categories of candidate vaccines can be determined based on information from previous pandemics and epidemics. Each participant country or region can focus on developing one or a few vaccine types or categories, together covering most if not all possible potential infectious diseases. The safety of these vaccines can be tested using animal models. Information for effective candidates that can be potentially applied to humans will then be shared across all participants. When a new pandemic arises, these pre-selected and tested vaccines can be quickly tested in RCTs for human populations.

Aims: Few population-based studies have investigated the association between insulin resistance and atherosclerotic burden in intra- and extra-cranial arteries. The purpose of this study is to explore the relationship between insulin resistance and intra- and extra-cranial atherosclerotic burden in community-based nondiabetic participants. Methods: This is a cross-sectional analysis from a population-based prospective cohort-PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events (PRECISE) study in China. The homeostasis model assessment of insulin resistance (HOMA-IR) and insulin sensitivity indices (ISI0–120) were stratified by the quartiles, respectively. The atherosclerotic presence of plaques and burden was evaluated by high-resolution MRI. Binary or ordinal logistic regression was performed to assess the association between HOMA-IR or ISI0–120 and the presence and burden of atherosclerosis. Results: Among the 2754 participants, the mean age was 60.9 ± 6.6 years, and 1296 (47.1%) were males. Compared with the lowest quartile of HOMR-IR, the highest quartile of HOMA-IR (indicating a higher level of insulin resistance) was associated with an increased presence of plaques (OR:1.54, 95% CI:1.14–2.08), and atherosclerotic burden (OR:1.53, 95%CI:1.14–2.07) in intracranial arteries. Meanwhile, we observed a similar relationship between HOMA-IR and the presence or burden in extracranial atherosclerosis. The first (indicating a higher level of insulin resistance) quartiles of ISI0–120 were associated with the intracranial plaques (Q1, OR:1.56, 95%CI:1.16–2.11) and atherosclerotic burden (Q1, OR:1.57, 95%CI:1.17–2.12), but not extracranial plaques or atherosclerotic burden, compared with the fourth quartile of ISI0–120. Conclusions: Insulin resistance was associated with an increased intra-and extra-cranial atherosclerotic burden in the nondiabetic elderly Chinese population.

A simple protocol for the sulfur-promoted conversion of aromatic aldehydes to aromatic nitriles has been developed. This strategy enables the one-pot conversion of inexpensive and readily available aromatic aldehydes into highly valuable aromatic nitriles using a cheap inorganic ammonium salt as the nitrogen source in the absence of metals. Significantly, a broad scope of substrates was explored using this strategy, and various groups, including alkyl, alkoxyl, alkylthiol, hydroxyl, amino, aryl, alkenyl, cyano, carboxyl, and borate ester groups were tolerated, and good to excellent yields were achieved in most cases. Additionally, polycyclic aromatic aldehydes and heteroaromatic aldehydes also could be converted to the corre-sponding nitriles with satisfactory yields. This method can be utilized as a powerful tool for the cyanation of complex molecules.

Abstract Background Considerable attention has been paid to reproductive toxicity of fine particulate matter (PM2.5). However, the relationship between prenatal PM2.5 exposure and anogenital distance (AGD) has not been well studied. We aim to investigate the potential effects of prenatal exposure to PM2.5 on newborn AGD. Methods Prenatal PM2.5 exposure of 2332 participates in Shanghai (2013–2016) was estimated using high-performance machine learning models. Anoscrotal distance (AGDas) in male infants and anofourchette distance (AGDaf) in female infants were measured by well-trained examiners within 3 days after birth. We applied multiple linear regression models and multiple informant models to estimate the association between prenatal PM2.5 exposure and AGD. Results Multiple linear regression models showed that a 10 μg/m3 increase in PM2.5 exposure during full pregnancy, the second and third trimesters was inversely associated with AGDas (adjusted beta = − 1.76, 95% CI: − 2.21, − 1.31; − 0.73, 95% CI: − 1.06, − 0.40; and − 0.52; 95% CI: − 0.87, − 0.18, respectively) in males. A 10 μg/m3 increase in PM2.5 exposure during the full pregnancy, the first, second, and third trimesters was inversely associated with AGDaf (adjusted beta = − 4.55; 95% CI: − 5.18, − 3.92; − 0.78; 95% CI: − 1.10, − 0.46; − 1.11; 95% CI: − 1.46, − 0.77; − 1.45; 95% CI: − 1.78, − 1.12, respectively) in females after adjusting for potential confounders. Multiple informant models showed consistent but slightly attenuated associations. Conclusion Our study observed a significant association between gestational PM2.5 exposure during pregnancy and shortened AGD in newborns, and provided new evidence on potential reproductive toxicity of prenatal PM2.5 exposure.

Abstract Background and purpose Mild acute ischemic stroke (AIS) patients with large vessel occlusion (LVO) may benefit from thrombolysis or thrombectomy therapy. However, the predictors for LVO in mild AIS patients have not been extensively explored. We aimed to investigate the predictors for LVO in mild AIS patients. Methods We collected the data of consecutive AIS patients with a National Institutes of Health Stroke Scale (NIHSS) score ≤ 5 from The Third China National Stroke Registry - a prospective nationwide registry of AIS or transient ischemic attack (TIA) patients in China from August 2015 to March 2018. Patients were divided into LVO and non-LVO group based on the vascular imaging during the hospitalization. Multivariable regression analyses involving clinical characteristics and NIHSS subitems was performed to detect the predictors for LVO. Result A total of 7653 mild AIS patients from The Third China National Stroke Registry were included in this study. Among them, 620 patients (8.1%) had LVO. The level of consciousness (adjusted odds ratio, 1.87; 95% confidence interval, 1.08 to 3.23), visual field (adjusted odds ratio, 2.10; 95% confidence interval, 1.43 to 3.06) and sensory (adjusted odds ratio, 0.75; 95% confidence interval, 0.60 to 0.94) were predictors for mild AIS patients with LVO. Conclusions Impaired LOC, visual field and sensory were independently predictors for LVO in mild stroke patients. Further studies are warranted to test these predictors in prehospital setting and in other population.

Few national studies have systemically examined the effects of criteria air pollutants on cardiovascular morbidity. This study aimed to investigate the associations between all criteria air pollutants and hospitalization of cause-specific cardiovascular diseases (CVD) in China. We obtained data on CVD hospitalization events of four major categories and 12 specific diseases from 153 hospitals distributed in 20 provincial-level regions from 2013 to 2020. We adopted a time-stratified case-crossover study design using individual cases to capture the effect of short-term exposure to six criteria air pollutants on CVD hospitalizations, using conditional logistic regression models. More than 1.1 million CVD hospitalization events were included. The lag pattern exploration demonstrated the largest effect for six air pollutants on lag 0–1 day. PM2.5, PM10, NO2, and CO were significantly associated with increased hospitalization from ischemic heart diseases, cerebrovascular diseases, other heart diseases, and five specific causes of CVD. The effect estimates of NO2 were the most robust when adjusting for co-pollutants. The concentration-response curves were positive and linear for most pollutant–endpoint pairs (except for O3), and these positive associations remained even below the 24-h levels recommended by WHO Air Quality Guidelines and China Air Quality Standards. This nationwide case-crossover study in China demonstrated that short-term exposure to multiple ambient air pollutants may significantly increase the risk of cause-specific CVD hospitalizations even under the most stringent air quality regulations, striking an alert for potential CVD patients against these environmental risk factors.