The scope, organization, and biological significance of innate immune functions across structural cell types remain poorly defined. To address these fundamental knowledge gaps, we analyze experimental data of transcriptomes generated by our group and others. Our findings demonstrated the following: 1) the 46 identified innate immune structural cell types exhibit a dual functional identity: under physiological conditions, they maintain tissue architecture and organ-specific homeostasis, whereas under immune stress, they transition into environment-supporting innate immune cells that actively participate in pathogen/damage-associated molecular patterns (PAMP/DAMP) sensing and immune effector responses; 2) The majority of environment-supporting innate immune structural cell types are anatomically positioned to be directly exposed to PAMPs and DAMPs; 3) Endothelial cells as prototypic environment-supporting innate immune structural cells redefine the architecture of innate immunity; 4) Environment-supporting innate immune structural cells have been historically underrecognized for their immune functions; and 5) Neuron-associated structural cell types exhibiting innate immune features suggests a potential role for neural cells in tissue-specific inflammatory regulation. This work establishes a new concept that environment-supporting innate immune structural cells are indispensable components of innate immunity that bridge tissue physiology and immune defense. By redefining immunity as a cooperative network of migratory immune cells and resident structural sentinels with endothelial cells and vascular smooth muscle cells serving as prototypic examples, this paradigm provides new mechanistic insight into tissue-specific inflammation, immune responses and immune privilege, and chronic inflammatory disease pathogenesis. Importantly, it opens new therapeutic avenues aimed at selectively targeting structural cell-intrinsic immune programs in cardiovascular disease, infection, inflammation, autoimmunity, transplantation, and cancer.

IntroductionR-loops, RNA-DNA hybrid structures with a displaced single-stranded DNA loop, are key regulators of transcriptional control, chromatin architecture, and genome stability and have emerging roles in inflammatory signaling. However, the relationship between R-loop abundance and strongly modulated inflammatory effector genes in metabolic inflammation and influenza virus infection remains underexplored.MethodsWe performed a locus-centric integrative analysis combining robust differentially expressed genes (DEGs) from multiple inflammatory and infection-related murine and human transcriptomic disease models with experimentally validated multi-cell R-loop annotations from the reference atlas RLoopBase. Our correlation framework evaluated the directional relationship between R-loop abundance and inflammatory gene expression rather than assuming disease-sample-matched R-loop measurements. We further analyzed R-loop regulatory proteins, NRF2-associated R-loop regulators, and overlaps between R-loop regulators and CRISPRi-identified mitochondrial and cellular reactive oxygen species (ROS) regulators.ResultsIn angiotensin II-infused apolipoprotein E-deficient (ApoE−/−) mice, a model of abdominal aortic aneurysm (AAA), genomic regions encoding the top significantly upregulated genes exhibited significantly fewer R-loops than those encoding downregulated genes at days 14 and 28. Similarly, in atherosclerotic ApoE−/− mice fed a high-fat diet for 32 and 78 weeks, upregulated genes were associated with fewer R-loops than downregulated genes. Reduced R-loop abundance was also observed in genomic regions encoding the top significantly upregulated genes in liver tissues from patients with non-alcoholic steatohepatitis (NASH), as well as in monosodium urate (MSU)-stimulated lymphatic endothelial cells (LECs) and influenza virus-infected human umbilical vein endothelial cells (HUVECs). R-loop regulatory proteins upregulated during metabolic inflammation were enriched in immune and inflammatory pathways. NRF2 was identified as a regulator of 27 R-loop regulatory proteins, including 10 positively and 17 negatively regulated proteins. Furthermore, 54 R-loop regulatory proteins overlapped with CRISPRi-identified mitochondrial and cellular ROS regulators, suggesting potential reciprocal regulation between R-loop homeostasis and ROS signaling. Disease-associated changes in pro-ROS and anti-ROS R-loop regulatory proteins further linked R-loop regulation to inflammatory and oxidative stress pathways.DiscussionThese findings identify reduced R-loop abundance at genomic regions encoding strongly upregulated inflammatory genes as a shared feature across multiple models of metabolic inflammation and influenza virus infection. The results further suggest that immune-associated R-loop regulatory proteins and the NRF2–ROS axis may contribute to R-loop remodeling during inflammatory disease. This integrative framework provides new insight into the potential role of R-loops and ROS-sensitive R-loop regulators in inflammatory and metabolic diseases and identifies candidate pathways for future mechanistic investigation and therapeutic targeting.

Introduction:Chronic obstructive pulmonary disease (COPD) is a heterogeneous inflammatory disorder characterized by persistent immune dysregulation and progressive structural deterioration of the lung. However, how COPD reshapes lung architecture, immune signaling, and cellular identity at a systems level remains incompletely understood. Methods:We performed integrative, multi-dimensional transcriptomic analysis of human COPD lung datasets to evaluate alterations in immune signaling, regulated cell death pathways, fibrosis-associated programs, cell type-specific transcriptional identity, and immune checkpoint regulation. Genetic and cytokine-based perturbations targeting trained immunity pathways were analyzed to assess functional relevance. Results:COPD induced broad transcriptional activation of cytokines, secretory and plasma membrane proteins, CD markers, innate immune genes, and trained immunity genes. Deficiency of SET7, a promoter of trained immunity, or overexpression of IL-37, an inhibitor of trained immunity, attenuated expression of COPD-upregulated immune genes. COPD also promoted tissue injury through coordinated upregulation of genes regulating multiple forms of regulated cell death, including autosis, autophagy, parthanatos, immunogenic cell death, mitochondrial permeability transition-associated death, lysosomal cell death, apoptosis, necroptosis, ferroptosis, mitotic cell death, and proliferation-associated cell death. In parallel, COPD enhanced epithelial-to-mesenchymal transition and fibrosis-related transcriptional programs. Transcriptomic identity was disrupted in 10 of 14 major human lung cell types, with evidence of pathological trans-differentiation marked by aberrant expression of over 50 cell type-specific marker genes. Alveolar macrophages exhibited extensive dysregulation of immune checkpoint ligand; notably, PVR (CD155) expression was reduced in severe emphysema, while experimental PVR overexpression suppressed pro-inflammatory gene expression in both alveolar and interstitial macrophages. Additionally, COPD impaired the suppressive capacity of CD4+Foxp3+ regulatory T cells through downregulation of key immunosuppressive genes, including those associated with FoxP3+, TIGIT+, and LPS-responsive Tregs. Shared immunosuppressive gene signatures were identified between PVR-overexpression-inducing CD4+ T cells and IL-10-mediated regulatory pathways in T cells and monocytes. Discussion:Collectively, these findings demonstrate that COPD reprograms the lung toward an immune-like organ by promoting immune cell-like trans-differentiation of structural cells, activating diverse regulated cell death pathways, and altering immune checkpoint signaling. These mechanisms highlight potential therapeutic targets for immunomodulatory intervention in COPD.

RationaleInflammatory monocyte (MC) subset polarization is a hallmark of systemic and tissue inflammatory feature in diabetes. The underlying molecular mechanism remains unclear.Methods and resultsBlood pro-inflammatory Ly6Chigh and anti-inflammatory Ly6Clow MC subsets were isolated from control (C57/BL6), type 1 diabetes mellitus (T1DM), and type 2 diabetes mellitus (T2DM) mice by flow cytometry sorting and subjected to bulk high-throughput RNA-sequencing. Intensive and integrative functional bioinformatic studies were performed by analyzing the transcriptome through seven pairs of comparison between Ly6Chigh and Ly6Clow MC subsets and between different mouse groups. We examined molecular features of three key immune activation signals in innate and adaptive immune responses, including signal 1 antigen (Ag)-presenting, signal 2 immune checkpoint, and signal 3 cytokine, and their upstream transcription factors (TF). A total of 10 differentially expressed genes (DEG) of MHC-II molecules (signal 1) presented a low expression profile in Ly6Chigh MCs from all mice and mostly further reduced in T2DM Ly6Chigh MC. Ly6Chigh MCs show high intercellular inflammatory propagation based on immune checkpoint/cytokine-ligand expression but low intracellular inflammatory capacity based on immune checkpoint/cytokine-receptor expression, both further enhanced in T1/T2DM. In contrast, Ly6Clow MCs exhibit low intercellular propagation but high intracellular inflammatory capacity; both also increased in T1/T2DM. Furthermore, 921 upstream DEG transcription factors and 17 transcriptional axes were recognized in diabetic Ly6Chigh MCs by IPA upstream regulator analysis. Finally, three critical transcriptional axes that drove the altered immunological phenotype in Ly6Chigh MCs were recognized: ↓PAX5-↓CIITA-↓Cd74/H2-Eb2 for reduced Ag-presenting power, ↓MYC-↑Sema4a for elevated intercellular inflammatory propagation capacity, and ↑CEBPA/E-↑Csf2ra/3r for enhanced intracellular inflammatory propagation capacity in MC.ConclusionsWe have three major discoveries: 1) Ly6Chigh MCs exhibit lower Ag-presenting power, which was further suppressed in T2DM, mostly via ↓PAX5-↓CIITA-↓CD74 regulation. 2) Ly6Chigh MCs display high intercellular inflammatory propagation but low intracellular inflammatory capacity, both further enhanced in T1/T2DM, mostly via ↓MYC-↑Sema4a and ↑CEBPA/E-↑Csf2ra/3r regulation. 3) Ly6Clow MCs acquired additional intercellular and intracellular inflammatory capacity in T1/T2DM.

Background Hyperhomocysteinemia (HHcy) has been linked to development of Alzheimer’s disease (AD) neuropathologically characterized by the accumulation of amyloid β (Aβ). Microglia (MG) play a crucial role in uptake of Aβ fibrils, and its dysfunction worsens AD. However, the effect of HHcy on MG Aβ phagocytosis remains unstudied. Methods We isolated MG from the cerebrum of HHcy mice with genetic cystathionine-β-synthase deficiency ( Cbs −/− ) and performed bulk RNA-seq. We performed meta-analysis over transcriptomes of Cbs −/− mouse MG, human and mouse AD MG, MG Aβ phagocytosis model, human AD methylome, and GWAS AD genes. Results HHcy and hypomethylation conditions were identified in Cbs −/− mice. Through Cbs −/− MG transcriptome analysis, 353 MG DEGs were identified. Phagosome formation and integrin signaling pathways were found suppressed in Cbs −/− MG. By analyzing MG transcriptomes from 4 AD patient and 7 mouse AD datasets, 409 human and 777 mouse AD MG DEGs were identified, of which 37 were found common in both species. Through further combinatory analysis with transcriptome from MG Aβ phagocytosis model, we identified 130 functional-validated Aβ phagocytic AD MG DEGs (20 in human AD, 110 in mouse AD), which reflected a compensatory activation of Aβ phagocytosis. Interestingly, we identified 14 human Aβ phagocytic AD MG DEGs which represented impaired MG Aβ phagocytosis in human AD. Finally, through a cascade of meta-analysis of transcriptome of AD MG, functional phagocytosis, HHcy MG, and human AD brain methylome dataset, we identified 5 HHcy-suppressed phagocytic AD MG DEGs (Flt1, Calponin 3, Igf1, Cacna2d4, and Celsr) which were reported to regulate MG/MΦ migration and Aβ phagocytosis. Conclusions We established molecular signatures for a compensatory response of Aβ phagocytosis activation in human and mouse AD MG and impaired Aβ phagocytosis in human AD MG. Our discoveries suggested that hypomethylation may modulate HHcy-suppressed MG Aβ phagocytosis in AD.

目的 探索血清丙氨酸转氨酶(alanine aminotransferase,ALT)水平与急性缺血性脑血管病不良临床结局的关系.方法 以中国国家卒中登记研究Ⅱ中丙氨酸转氨酶(alanine aminotransferase,ALT)水平<120?U/L的急性缺血性卒中或TIA患者为研究对象.随访研究对象的1年全因死亡、复发性卒中(包括缺血性卒中、脑出血及蛛网膜下腔出血)、复合终点事件和不良功能结局,其中复合终点事件包括复发性卒中和全因死亡,不良功能结局定义为mRS?3～6分.根据入组患者的血清ALT水平由低到高进行ALT五分位数分层(Q1～Q5),采用多因素logistic回归分析评估血清ALT水平与1年全因死亡、卒中复发、复合终点事件和不良功能结局的相关性.结果 研究共纳入17178例患者,平均年龄(64.8±11.9)岁,女性6368例(37.1％).多因素logistic回归分析结果显示,相对于A LT最低五分位数患者,最高五分位数患者1年内全因死亡风险降低45％(OR?0.55,95％CI?0.43～0.70,P<0.01)、卒中复发风险降低39％(OR?0.61,95％CI?0.45～0.83,P<0.01)、复合终点事件风险降低38％(OR?0.62,95％CI?0.49～0.77,P<0.01),不良功能结局风险降低33％(OR?0.67,95％CI?0.56～0.80,P<0.01).年龄、性别、糖尿病、血脂异常和饮酒对ALT与各结局指标之间的相关性无交互作用.结论 血清ALT水平与AIS或TIA患者1年全因死亡率、卒中复发、复合终点事件和功能不良结局的风险呈负相关.

Abstract Background Acute kidney disease (AKD) evolves a spectrum of acute and subacute kidney disease requiring a global strategy to address. The present study aimed to explore the impact of AKD on the prognosis of ischemic stroke. Methods The Third China National Stroke Registry (CNSR-III) was a nationwide registry of ischemic stroke or transient ischemic attack between August 2015 and March 2018. As a subgroup of CNSR-III, the patients who had serum creatinine (sCr) and serum cystatin C (sCysC) centrally tested on admission and at 3-month, and with 1-year follow-up data were enrolled. Modified AKD criteria were applied to identify patients with AKD during the first 3 months post stroke according to the guidelines developed by the Kidney Disease: Improving Global Outcomes in 2012. The primary clinical outcome was 1-year all-cause death, and secondary outcomes were stroke recurrence and post stroke disability. Results Five thousand sixty-five patients were recruited in the study. AKD was identified in 3.9%, 6.7%, 9.9% and 6.2% of the patients by using sCr, sCr-based estimated glomerular filtration rate (eGFRsCr), sCysC-based eGFR (eGFRsCysC), and combined sCr and sCysC-based eGFR (eGFRsCr+sCysC) criteria, respectively. AKD defined as sCr or eGFRsCr criteria significantly increased the risk of all-cause mortality (adjusted HR 2.67, 95% CI: 1.27–5.61; adjusted HR 2.19, 95% CI: 1.17–4.10) and post stroke disability (adjusted OR 1.60, 95% CI: 1.04–2.44; adjusted OR 1.51, 95% CI: 1.08–2.11). AKD diagnosed by eGFRsCysC or eGFRsCr+sCysC criteria had no significant impact on the risk of all-cause death and post stroke disability. AKD, defined by whichever criteria, was not associated with the risk of stroke recurrence in the adjusted model. Conclusions AKD, diagnosed by sCr or eGFRsCr criteria, were independently associated with 1-year all-cause death and post stroke disability in Chinese ischemic stroke patients.

Abstract Little is known about the relationship between baseline systolic blood pressure (SBP) and subsequent clinical events in patients with different lesion patterns on diffusion weighted imaging (DWI). We analyzed the Acute Non‐disabling Cerebrovascular Events (CHANCE) trial dataset. Patients were categorized into negative DW imaging (no detectable lesions), lacunar infarction (single lesion ≤15 mm) and non‐lacunar infarction (single lesion >15 mm or multiple lesions) based on lesion patterns on DWI. The primary outcome was recurrent stroke within 90 days. Cox proportional hazards models were used to assess the association between SBP levels and stroke outcomes in patients with different lesion patterns. A total of 1089 patients were analyzed. We found 258 cases (23.7%) with negative DW imaging, 392 (36.0%) with lacunar infarction and 439 (40.3%) with non‐lacunar infarction. Patients with non‐lacunar infarction had the highest incidence of stroke at 90‐day (P < .001). In non‐lacunar infarction group, compared with SBP < 160 mmHg, patients with SBP ≥ 160 mmHg had significantly higher risk of 90‐day recurrent stroke (20.3% vs. 10.7%; adjusted hazard ratio 1.81, 95% confidence interval 1.09–3.00). No significant association was found between SBP and clinical outcomes in patients with negative DWI and lacunar stroke groups. The result at 1 year was similar as at 90‐day. Therefore, non‐lacunar infarction, the most common lesion pattern in CHANCE study, had the highest risk of recurrent stroke and combined vascular events both in 90 days and 1 year. High baseline SBP was significantly associated with increased risk of short‐ and long‐term recurrent strokes in patients with non‐lacunar infarction.

Background and Purpose: Existing studies on the association between hemoglobin values and stroke outcomes mostly focus on the lower side and mortality, often the only and primary endpoint. The current study was conducted to assess the association between hemoglobin concentration and a variety of poor stroke outcomes in patients with acute ischemic stroke. Methods: We studied 8,321 patients enrolled in the China National Stroke Registry (CNSR) between 2007 and 2008. Patients were divided into 7 groups, and a logistic regression model was used to evaluate the association. Endpoints of interest included 1-year all-cause mortality, stroke recurrence, combined endpoint, and stroke disability. Stroke disability was defined as a modified Rankin Scale of 2-6. Results: Patients with low and high hemoglobin values (<= 11.6 g/dL and >16.1 g/dL) had higher proportion of poststroke adverse events than those in other groups. As compared with the fourth group of hemoglobin values of 13.5-14.2 g/dL, the adjusted odds ratios (ORs) with 95% confidence interval (CI) of low hemoglobin values (<= 11.6 g/dL) were 2.25 (1.72-2.93) for all-cause mortality, 1.30 (1.04-1.61) for stroke recurrence, 1.63 (1.33-2.01) for combined end-point, and 1.37 (1.12-1.67) for stroke disability, respectively. And, the ORs of high hemoglobin values (>16.1 g/dL) for adverse stroke outcomes were 1.72 (1.25-2.37), 1.43 (1.13-1.82), 1.43 (1.13-1.81), and 1.31 (1.06-1.63), respectively. Stratified analysis showed significant interactions between sex and categories of hemoglobin values for all-cause mortality (p = 0.05), stroke recurrence (p = 0.03), and combined endpoint (p = 0.01) but not for stroke disability (p = 0.24). Conclusions: Our study found both low and high hemoglobin values were associated with adverse stroke outcomes including all-cause mortality, stroke recurrence, combined endpoint, and stroke disability, which showed a U-shaped association. And, significant interactions between sex and hemoglobin concentration on all-cause mortality and stroke recurrence were also identified. (c) 2021 S. Karger AG, Basel

Background The relationship between aminotransferases and cardiovascular outcomes has been inconsistent in previous studies. We aimed to investigate the association of aminotransferases with clinical outcomes after acute ischemic stroke (AIS) or transient ischemic attack (TIA). Methods 17,178 AIS or TIA patients with serum alanine aminotransferase (ALT) levels < 120 U/L were included from the China National Stroke Registry (CNSR) for current analysis. Composite endpoint is comprised of recurrent stroke and all-cause mortality. Poor functional outcome is defined as modified Rankin scale of 3-6. Multivariable logistic regression was used to evaluate the risks of one-year all-cause mortality, recurrent stroke, composite endpoint and poor functional outcome according to increasing sex-specific quintiles of ALT/ aspartate aminotransferase (AST) respectively. Results One-year incidences of all-cause mortality, recurrent stroke, composite endpoint and poor functional outcome were 11.9%, 6.0%, 13.7% and 28.2% respectively in patients with the lowest quintile of ALT, and 7.4%, 3.6%, 9.0% and 17.9% respectively in the highest quintile. Compared with the lowest ALT quintile, the adjusted odds ratios with 95% confidence interval of the highest quintile were 0.55 (0.43-0.70) for all-cause mortality, 0.61 (0.45-0.83) for stroke recurrence, 0.62 (0.49-0.77) for composite endpoint, and 0.67 (0.56-0.80) for poor functional outcome. There was no significant interaction of ALT with age, sex, diabetes, dyslipidemia and alcohol consumption for all outcomes (p for interaction ≥ 0.10). Conclusions Low serum ALT may serve as an independent predictor for all-cause mortality, stroke recurrence, composite endpoint and poor functional outcome after stroke.

Background The impact of estimated glomerular filtration rate (eGFR) on clinical short‐term outcomes after stroke thrombolysis with tissue plasminogen activator remains controversial. Methods and Results We analyzed 18 320 ischemic stroke patients who received intravenous tissue plasminogen activator at participating hospitals in the Chinese Stroke Center Alliance between June 2015 and November 2017. Multivariate logistic regression models were used to evaluate associations between eGFR (<45, 45–59, 60–89, and ≥90 mL/min per 1.73 m2) and in‐hospital mortality and symptomatic intracerebral hemorrhage, adjusting for patient and hospital characteristics and the hospital clustering effect. Of the 18 320 patients receiving tissue plasminogen activator, 601 (3.3%) had an eGFR <45, 625 (3.4%) had an eGFR 45 to 59, 3679 (20.1%) had an eGFR 60 to 89, and 13 415 (73.2%) had an eGFR ≥90. As compared with eGFR ≥90, eGFR values <45 (6.7% versus 0.9%, adjusted odds ratio, 3.59; 95% CI, 2.18–5.91), 45 to 59 (4.0% versus 0.9%, adjusted odds ratio, 2.00; 95% CI, 1.18–3.38), and 60 to 89 (2.5% versus 0.9%, adjusted odds ratio, 1.67; 95% CI, 1.20–2.34) were independently associated with increased odds of in‐hospital mortality. However, there was no statistically significant association between eGFR and symptomatic intracerebral hemorrhage. Conclusions eGFR was associated with an increased risk of in‐hospital mortality in acute ischemic stroke patients after treatment with tissue plasminogen activator. eGFR is an important predictor of poststroke short‐term death but not of symptomatic intracerebral hemorrhage.

Background and Purpose: To investigate the association of renal function with in-hospital death and recurrent stroke in patients with acute stroke. Methods: Data were from the Chinese Stroke Center Alliance (CSCA) with a sample of 511 036 patients. Baseline eGFR was calculated with the Chinese modification of CKD-EPI equation and categorized into 4 groups. Logistic regression models with generalized estimating equations were used to evaluate the risks for in-hospital death and recurrent stroke among eGFR categories with and without stratification for hypertension, diabetes mellitus (DM) and atrial fibrillation (AF). A cubic spline smoothing technique was used to interpolate the overall trend of risks through the range of eGFR. Results: Of 501 497 patients, 70.1% had an eGFR ≥90, 21.7% an eGFR 60 to 89, 4.1% an eGFR 45 to 59, 4.1% an eGFR<45 mL/min/1.73 m 2 . In-hospital death occurred in 3.0% of patients with an eGFR of <45, 1.5% an eGFR of 45 to 59, 0.9% an eGFR of 60 to 89, and 0.5% an eGFR ≥90. Recurrent stroke occurred in 7.6%, 7.2%, 6.5% and 5.9% respectively. Compared with eGFR ≥ 90, the adjusted odds ratios with 95% CI of eGFR <45, 45-59 and 60-90 were 3.97 (3.42-4.61), 1.95 (1.70-2.45) and 1.37 (1.22-1.53) for in-hospital death and 1.02 (0.94-1.11), 0.98 (0.91-1.06) and 0.98 (0.93-1.03) for recurrent stroke. A significantly statistical interaction between DM and categories of eGFR for stroke recurrent was identified (interaction P =0.001). The other results were almost consistent in stratified analyses by hypertension, DM or AF. There was a J-shaped relationship between eGFR and in-hospital death. A linear relationship was observed between eGFR and recurrent stroke. Conclusions: Low eGFR was associated with increased risk of all-cause mortality but not with recurrent stroke in patient with acute stroke.

Using data from the Blood Pressure and Clinical Outcome in TIA or Ischemic Stroke (BOSS) study, we aim to test the applicability and feasibility of stroke secondary prevention recommendations from the 2017 American College of Cardiology/American Heart Association guideline. Patients were categorized based on their blood pressure (BP) status at 3 months. The nonhypertension group was defined as those without a diagnosis of hypertension. The other patients were further divided into three subgroups according to office BP measured at 3-month visit (BP <130/80, 130-139/80-89, and >= 140/90 mm Hg). The primary outcome was any stroke within one year. The associations between BP status and 1-year prognosis (recurrent stroke, recurrent stroke/TIA, and poor functional outcome [modified Rankin scale score 3-6]) were estimated. Among 2341 IS/TIA patients, additional 1056 patients were classified as uncontrolled hypertension at the 90-day visit according to the new guidelines. Adjusted hazard/odds ratios (95% confidence intervals [CI]) for recurrent stroke in BP <130/80, 130-139/80-89, and >= 140/90 compared with nonhypertension group were 2.42 (95% CI: 0.87-6.76), and 4.30 (95% CI: 1.73-10.70), respectively. The prevalence of hypertension and uncontrolled BP among BOSS study population was substantially higher based on the new guidelines. BP of 130-139/80-89 did not show the worsened clinical outcomes compared with people without hypertension. Our study adds to the growing uncertainty about secondary prevention BP goal for IS/TIA patients.

Background and purposeThe efficacy of dual antiplatelet treatment may be modified by many factors. The aim was to assess whether the effect of clopidogrel plus aspirin versus aspirin alone on recurrent stroke would be affected by admission activated partial thromboplastin time (aPTT).MethodsData were derived from the Clopidogrel in High‐Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial. A total of 5074 patients were categorized into three groups based on the aPTT distribution according to the 15th and 85th percentile. The primary outcome was any stroke within 90 days. The interaction of aPTT with antiplatelet therapy on stroke risk was assessed with a Cox proportional hazards model with adjustment for covariates.ResultsIn the high aPTT group (defined as ≥35.9 s), stroke occurred in 6.7% of patients in the clopidogrel–aspirin arm and 11.9% in the aspirin arm [adjusted hazard ratio (HR) 0.50; 95% confidence interval (CI) 0.29–0.85]. In the medium aPTT group (24.6–35.8 s), stroke occurred in 7.7% of patients in the clopidogrel–aspirin arm and 11.8% in the aspirin arm (adjusted HR 0.62; 95% CI 0.50–0.75). Furthermore, in the low aPTT group (≤24.5 s), stroke occurred in 11.2% of patients in the clopidogrel–aspirin arm and 9.9% in the aspirin arm (adjusted HR 1.07; 95% CI 0.65–1.62). The interaction P value of antiplatelet therapy with aPTT level at the cut‐point of approximately 25 s or below was significant (P < 0.05).ConclusionsDual antiplatelet therapy was superior to single antiplatelet therapy in the high or medium aPTT group but not in the low aPTT group.

Nimodipine might be effective in subcortical vascular dementia (VaD). Its benefit in preventing further cognitive decline in patients with acute ischemic stroke (AIS) and vascular mild cognitive impairment (VaMCI) remains to be established. In this multicenter, double-blind trial, we randomly assigned 654 eligible patients to nimodipine 30 mg three times a day or placebo. The primary outcome was any cognitive decline defined by the changes on the Mini-Mental State Examination (Delta MMSE <=-3) or vascular AD assessment scale cognitive subscale (Delta ADAS-cog >= 4) at 6 months. Secondary outcomes included any distribution shift of Delta ADAS-cog, Delta MMSE or cognitive improvement defined by Delta ADAS-cog <=-2, or Delta MMSE >= 0. The primary outcome in the nimodipine group and placebo group were similar for Delta MMSE <=-3 (4.18% and 7.22%, respectively, P = 0.15) and Delta ADAS-cog >= 4 (8.36% and 8.93% respectively, P = 0.88). The distribution shift of Delta ADAS-cog and Delta MMSE differed significantly between the two groups (P = 0.03 and P = 0.05 respectively). Cognitive improvement occurred in 55.4% in the nimodipine group and 43.6% in the placebo group measured by Delta ADAS-cog <=-2 (Odds Ratio, 1.54; 95% confidence interval [CI] 1.10-2.14, P < 0.01) or 84.0% and 74.6% respectively by Delta MMSE >= 0 (Odds Ratio, 1.79; 95% CI 1.18-2.70, P < 0.01). Nimodipine was associated with better cognitive function in the memory domain. The adverse events rate was similar in two groups. This study is registered with ClinicalTrials.gov, NCT01220622. Nimodipine did not show benefit to prevent cognitive decline in AIS patients with VaMCI, but improved cognition moderately, especially measured in the memory domain. (C) 2018 Science China Press. Published by Elsevier B.V. and Science China Press. All rights reserved.

Background: There are considerable gaps in adherence to evidence-based stroke care in China. Our primary aim was to determine whether a multifaceted quality improvement (QI) intervention could improve adherence to the 9 evidence-based performance measures among Chinese patients with acute ischemic stroke (AIS). Methods: The Multifaceted Intervention to Improve AIS Care (GOLDEN BRIDGE-AIS) trial was a two-arm, multicenter, cluster-randomized, controlled trial. Patient hospitalized with AIS were included. Hospitals were randomized (1:1) to the intervention or a usual care control arm. The multifaceted QI intervention involved a clinical pathway, written care protocols, oversight by a quality coordinator, and a monitoring and feedback system of performance measures. The primary outcome was adherence to AIS evidence-based performance measures. Results: 4800 patients were enrolled from 40 hospitals, n=2400 intervention and n=2400 control with 12-month follow-up. Interventional hospital patients were more likely to receive acute and discharge treatments than those in the control hospitals (composite measure 88.2% vs 84.8%, adjusted OR, 1.38 [95% CI, 1.11-1.71], p value=0.003) (Table). Kaplan-Meier estimates showed a reduction in the secondary outcomes of 12-month new clinical vascular events in the intervention versus control group (HR 0.73, 95% CI, 0.61-0.87; p value<0.001) (Figure). Conclusion: Among patients with AIS treated in China, a multifaceted QI intervention improved the composite adherence to the evidence-based treatments as well as significantly reduced new vascular events. Trial Registration: clinicaltrials.gov Identifier: NCT02212912.

Aim: The impact of international normalized ratio (INR) on prognosis after acute ischemic stroke without anticoagulation therapy is unclear. Herein, the association between baseline INR and stroke outcomes in patients without anticoagulation therapy was investigated. Methods: A total of 14,782 ischemic stroke patients from the China National Stroke Registry. were included in this analysis. The period of follow-up was 1 year after stroke onset. Multivariate logistic regression models were used to estimate the relationship between INR and stroke outcomes including all-cause death, recurrent stroke, composite end point, and poor functional outcome. Results: Of 14,782 patients with stroke, all-cause death occurred in 1080 (7.3%), recurrence stroke in 538 (3.9%), combined end point in 1319 (8.9%), and poor functional outcome in 3001 (20.3%). Compared with the medium INR group (0.9-1.1), the odds ratios with confidence intervals of 95% for the high INR group (> 1.1) were 1.58 (1.32-1.98) for all-cause death, 1.40 (1.10-1.79) for stroke recurrence, 1.52 (1.29-1.79) for combined end point, and 1.21 (1.06-1.39) for poor functional outcome. No association between low INR (< 0.9) and any stroke outcomes was found compared with the medium group. Conclusions: Increased admission INR was associated with adverse stroke outcomes among acute ischemic stroke patients without atrial fibrillation or anticoagulation therapy.

Intracranial atherosclerosis burden is an arising key index for the risk and prognosis for Intracranial Atherosclerosis Stenosis (ICAS). The present study estimated one-year prognosis for patients of symptomatic ICAS with different degrees of intracranial atherosclerosis burden (ICASB) and identified whether the category of multiple and single acute infarction was associated with atherosclerosis burden. A total of 2864 consecutive patients, from 22 hospitals across China, who experienced an acute cerebral ischemia <7 days after onset of symptoms were evaluated. All patients underwent magnetic resonance angiography, and the degree of intracranial stenosis with the ICASB was calculated. The patients were categorized into three groups according to ICASB grading: <4, 4-5 and >5scores. Multivariate Cox proportional hazards regression models were used to estimate the impact of the hazard ratios(HR) of the putative determinants of recurrent stroke in one year. In the groups with ICASB 4-5 and ICASB >5scores recurrent stroke were significantly higher than the other (P<0.0001). On multivariate logistic analysis, ICASB (4-5) indicated more stroke recurrence at 12 months (adjusted hazard ratio, 1.96; 95% confidence interval, 1.08-3.56; P=0.027), compared to the ICASB<4scores and >5 groups (P<0.001). Moreover, proportion of single and multiple infarction lesions differs with different ICASB. Multiple lesions were related with higher of ICASB(P<0.001). Intracranial atherosclerosis burden was associated with recurrent stroke at 12 months. Multiple infarction lesions were associated with higher ICASB score which indicate higher risk of recurrent.

Background and Purpose— Alkaline phosphatase (ALP) is associated with risk of adverse cardiovascular events in patients with kidney failure. However, there is little data about effects of ALP on stroke outcomes in patients with preserved kidney function. The study aimed to explore the association between serum ALP level and clinical outcomes after stroke in patients with preserved kidney function. Methods— We included 16 367 stroke patients with preserved kidney function from the China National Stroke Registry for current analysis. Serum ALP levels were tested by automated enzymatic method using unfrozen samples in each center. Participants were divided into 5 groups according to ALP quintiles. Composite end point comprised of recurrent stroke, myocardial infarction, other ischemic vascular events, and all-cause mortality. Poor functional outcome is defined as modified Rankin Scale score of 3 to 6. Multivariable logistic regression was used to evaluate the independent association of serum ALP with 1-year all-cause mortality, recurrent stroke, composite end point, and poor functional outcome. Results— The mean age of the included 16 367 patients was 63.9 years, and 63.3% of them were men. Among the top ALP quintile (>98.0 U/L), 1-year incidences of all-cause mortality, recurrent stroke, composite end point, and poor functional outcome were 12.6%, 5.7%, 14.4%, and 27.0%, respectively. Compared with the lowest ALP quintile (≤59.0 U/L), the adjusted odds ratios of the top quintile were 1.36 (1.10–1.68) for all-cause mortality, 1.45 (1.11–1.90) for stroke recurrence, 1.35 (1.12–1.63) for composite end point, and 1.36 (1.17–1.60) for poor functional outcome. There was no significant interaction between age, sex, or alcohol consumption and ALP ( P for interaction ≥0.10) for all outcomes. Conclusions— In patients with preserved kidney function, ALP may be an independent predictor of all-cause mortality, stroke recurrence, composite end point, and poor functional outcome after stroke.

Background and Purpose— Alkaline phosphatase (ALP) is associated with risk of adverse cardiovascular events in patients with kidney failure. However, there is little data about effects of ALP on stroke outcomes in patients with preserved kidney function. The study aimed to explore the association between serum ALP level and clinical outcomes after stroke in patients with preserved kidney function. Methods— We included 16 367 stroke patients with preserved kidney function from the China National Stroke Registry for current analysis. Serum ALP levels were tested by automated enzymatic method using unfrozen samples in each center. Participants were divided into 5 groups according to ALP quintiles. Composite end point comprised of recurrent stroke, myocardial infarction, other ischemic vascular events, and all-cause mortality. Poor functional outcome is defined as modified Rankin Scale score of 3 to 6. Multivariable logistic regression was used to evaluate the independent association of serum ALP with 1-year all-cause mortality, recurrent stroke, composite end point, and poor functional outcome. Results— The mean age of the included 16 367 patients was 63.9 years, and 63.3% of them were men. Among the top ALP quintile (>98.0 U/L), 1-year incidences of all-cause mortality, recurrent stroke, composite end point, and poor functional outcome were 12.6%, 5.7%, 14.4%, and 27.0%, respectively. Compared with the lowest ALP quintile (⩽59.0 U/L), the adjusted odds ratios of the top quintile were 1.36 (1.10–1.68) for all-cause mortality, 1.45 (1.11–1.90) for stroke recurrence, 1.35 (1.12–1.63) for composite end point, and 1.36 (1.17–1.60) for poor functional outcome. There was no significant interaction between age, sex, or alcohol consumption and ALP (P for interaction ≥0.10) for all outcomes. Conclusions— In patients with preserved kidney function, ALP may be an independent predictor of all-cause mortality, stroke recurrence, composite end point, and poor functional outcome after stroke.