Liver injury in paraquat poisoning: A retrospective cohort study.

BACKGROUND AND AIMS: Liver injury is one of the common complications of paraquat (PQ) poisoning, but whether the degree of liver injury is related to patient prognosis is still controversial. This study aimed to investigate whether liver injury was a risk factor for death in PQ-poisoned patients. METHODS: We conducted a retrospective cohort study of PQ-poisoned patients from the past 10 years (2011-2020) from a large tertiary academic medical centre in China. PQ-poisoned patients were divided into a normal liver function group (n = 580) and a liver injury group (n = 60). Propensity score matching (PSM) analysis was then performed. RESULTS: A total of 640 patients with PQ poisoning were included in this study. To reduce the impact of bias, dose of PQ, urinary PQ concentration and time from poisoning to hospital admission were matched between the two groups. A 3:1 PSM analysis was performed, ultimately including 240 patients. Compared with the normal liver function group, patients in the liver injury group were older, had a higher R value ([ALT/ULN]/[ALP/ULN]) (p < .001) and had a higher mortality rate. Cox regression analysis showed that there was no significant association between alanine aminotransferase, alkaline phosphatase, total bilirubin levels and hazard of death, but age, PQ dose, creatine kinase isoenzyme, creatine kinase, white blood cell count, neutrophil percentage and lymphocyte percentage were associated with mortality in patients with PQ poisoning. CONCLUSIONS: The occurrence of liver injury within 48 h after PQ poisoning was a risk factor for mortality, and such liver injury was likely of a hepatocellular nature. Age, PQ dose, creatine kinase isoenzyme and white blood cell count were positively correlated with mortality, while creatine kinase, percentage of neutrophils and lymphocytes were inversely correlated.

Smokers with Elevated Glycated Albumin Could Not Benefit from Dual Antiplatelet Therapy after Minor Stroke or Transient Ischemic Attack.

INTRODUCTION: The aim of this study was to investigate the impact of smoking on dual antiplatelet therapy in patients with minor stroke or transient ischemic attack (TIA) under different glycated albumin (GA) levels. METHODS: We analyzed data from the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial. A subgroup of 3,044 patients with baseline GA levels was included and categorized by smoking status and GA levels. The primary efficacy outcome was a new stroke within 90 days. The safety outcome was any bleeding event at 90 days. The interaction of smoking status with antiplatelet therapy was calculated by Cox proportional hazards regression model. RESULTS: In patients with GA levels ≤15.5%, the proportion of smokers was 37.7% (719/1,908), while in patients with GA levels >15.5%, it was 51.6% (586/1,136). During the 3-month follow-up period, 299 (9.9%) patients had a new stroke occurrence. In patients with elevated GA levels, both smokers and nonsmokers could not benefit from dual antiplatelet therapy (smokers, adjusted hazard ratio [HR] 0.70, 95% confidence interval [CI]: 0.42-1.17; nonsmokers, adjusted HR 0.82, 95% CI: 0.57-1.18). In patients with normal GA levels, dual antiplatelet therapy reduced the risk of stroke recurrence in smokers by 72% (adjusted HR 0.28, 95% CI: 0.14-0.56) and in nonsmokers by 53% (adjusted HR 0.47, 95% CI: 0.26-0.86). However, whether the GA level was elevated or normal, there was no significant interaction between smoking status and antiplatelet therapy. CONCLUSIONS: Smokers with elevated GA levels could not benefit from dual antiplatelet therapy after minor stroke or TIA.

Associations of life's essential 8 with extent of multi-territorial atherosclerotic plaques and stenosis: a cross-sectional study.

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 (< 60), moderate (60-<80), and high (≥ 80) groups. Vascular magnetic resonance imaging was used to evaluate intracranial and extracranial arteries; thoracoabdominal computed tomography angiography to evaluate coronary, subclavian, aorta, renal, ilio-femoral arteries; and ankle-brachial index to evaluate peripheral arteries. The presence of atherosclerotic plaque or stenosis in any territory was defined as plaque or vascular stenosis with 1 territory affected or more in these arteries. The extent of atherosclerotic plaques or stenosis was assessed according to the number of these 8 vascular sites affected, and graded as four grades (none, single territory, 2-3 territories, 4-8 territories). RESULTS: Of 3065 included participants, the average age was 61.2 ± 6.7 years, and 53.5% were women (n = 1639). The moderate and high overall LE8 groups were associated with lower extent of multi-territorial plaques [common odds ratio (cOR) 0.44, 95% confidence interval (CI), 0.35-0.55; cOR 0.16, 95%CI, 0.12-0.21; respectively] and stenosis (cOR 0.51, 95%CI, 0.42-0.62; cOR 0.16, 95%CI, 0.12-0.21; respectively) after adjustment for potential covariates. Similar results were observed for medical LE8 score with the extent of multi-territorial plaques and stenosis (P < 0.05). We also found the association between behavior LE8 score and the extent of multi-territorial stenosis (P < 0.05). CONCLUSIONS: The higher LE8 scores, indicating healthier lifestyle, were associated with lower presence and extent of atherosclerotic plaque and stenosis in southern Chinese adults. Prospective studies are needed to further validate these findings.

Aminotransferase Level and the Effects of Dual Antiplatelet in Minor Stroke or Transient Ischemic Attack: A post hoc Analysis of a Randomized Control Trial.

INTRODUCTION: This study was intended to evaluate whether the safety and efficacy of dual antiplatelet treatment in patients with minor ischemic stroke (MIS) or transient ischemic attack (TIA) could be modified by the aminotransferase level. Also, we sought to assess the interaction between aminotransferase level and CYP2C19 loss-of-function status on the efficacy of dual antiplatelet therapy. METHODS: This study is a post hoc analysis of the Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events (CHANCE) study, a double-blinded randomized control trial. We included 5,133 patients with a complete workup of baseline alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. The primary outcome is stroke or TIA recurrence within 90 days. Cox proportional hazard models were used in the evaluation of the efficacy of antiplatelet treatment in patients with different aminotransferase levels and subgroups categorized by the aminotransferase level × CYP2C19 loss-of-function status. RESULTS: The median age of all the included patients was 62 years; 66.3% of the patients were male. More recurrent stroke or TIA occurred in patients with elevated ALT and AST levels within 90 days compared to patients with normal ALT and AST levels (14.5 vs. 11.2%, p = 0.029). Dual antiplatelet treatment with aspirin and clopidogrel reduced recurrence compared with aspirin alone in patients with both normal (adjusted hazard ratio [HR], 95% confidence interval [CI]: 0.72 [0.60-0.86], p < 0.001) and elevated (adjusted HR [95% CI]: 0. 57 [0. 35-0. 92], p = 0. 020) ALT and AST levels (p = 0.64 for interaction). No significant difference in treatment efficacy on 90-day all-cause death or bleeding events was found. CONCLUSIONS: Dual antiplatelet treatment was safe for minor stroke or high-risk TIA patients with mildly elevated aminotransferase. Mild elevation of ALT or AST did not undermine the protective efficacy of the dual antiplatelet regimen in reducing recurrent stroke or TIA within 90 days after MIS or TIA. The interaction between the CYP2C19 loss-of-function allele carrier status and aminotransferase level on the efficacy of dual antiplatelet treatment was not observed.

Prevalence and Prognostic Value of Atrial Cardiopathy in Embolic Stroke of Undetermined Source.

INTRODUCTION: We utilized data from the Third China National Stroke Registry to investigate the prevalence of atrial cardiopathy markers in patients with embolic stroke of undetermined source (ESUS) and to assess their association with death and stroke recurrence. METHODS: In China, patients experiencing transient ischemic attack or ischemic stroke were recruited consecutively by the Third China National Stroke Registry. We compared atrial cardiopathy markers, such as left atrial (LA) enlargement, increased P-wave terminal force in lead V1 (PTFV1), premature atrial contractions, paroxysmal supraventricular tachycardia, advanced interatrial block, prolonged PR interval, prolonged P-wave dispersion, and prolonged P-wave duration between ESUS patients and those with small vessel disease and large artery atherosclerosis strokes. The association between these markers and the recurrence of stroke as well as mortality risk in ESUS patients was evaluated using Cox regression analysis. RESULTS: Of 8528 ischemic stroke patients who underwent a standard diagnostic work-up, 2415 were identified as having ESUS. Multivariable analysis revealed a significant association between elevated PTFV1 and an increased risk of stroke recurrence (HR: 2.50; 95% CI: 1.53-4.09; p < 0.01) as well as mortality (HR: 3.76; 95% CI: 1.58-8.91; p < 0.01) at 1 year in patients with ESUS. Furthermore, we observed that moderate-severe LA enlargement slightly increased the risk of stroke recurrence in patients with ESUS (HR: 1.95; 95% CI: 0.90-4.26; p = 0.09). Both LA diameter (HR: 1.03; 95% CI: 1.00-1.06; p = 0.03) and the top quartile of the LA diameter index (HR: 1.56; 95% CI: 1.03-2.40; p = 0.04) were associated with stroke recurrence in patients with ESUS. CONCLUSIONS: PTFV1 was independently associated with an elevated risk of stroke recurrence and mortality in ESUS patients. Additionally, a trend toward a correlation between LA enlargement and high stroke recurrence risk after ESUS was observed.

Dipping Pattern and 1-year stroke functional outcome in ischemic stroke or transient ischemic attack.

AIMS: This study aimed to explore whether a relationship exists between dipping patterns and 1-year functional outcome in patients with acute ischemic stroke (IS) or transient ischemic attack (TIA). METHODS: Data from the Blood Pressure and Clinical Outcome in TIA or Ischemic Stroke Study (BOSS), a nationwide, hospital-based, longitudinal cohort study, was used for this study. Patients with acute IS or TIA were recruited within 7 days after onset and ambulatory blood pressure monitoring was performed during hospitalization. Patients were defined as dippers if nocturnal systolic blood pressure fell by ≥10%, non-dippers if 0-10%, and reverse dippers if < 0%. Poor functional outcome was defined as a modified Rankin Scale (mRS) score of 3-5. Logistic regression analysis was used to test the association between dipping patterns and 1-year functional outcome. RESULTS: Among the 1808 IS/TIA patients, 19.19% were dippers, 53.21% were non-dippers, and 27.60% were reverse dippers. Poor functional outcome occurred in 22.44% of reverse dippers, which was significantly higher than that of dippers (16.14%) and non-dippers (16.53%) (P = .014). A univariate analysis revealed that reverse dipping was a risk factor for poor functional outcome (Odds ratio 1.504, 95% confidence interval 1.055-2.145, P = .024). However, this significance disappeared after adjusting for confounders. CONCLUSIONS: Reverse dipping was prevalent in patients with IS/TIA. The higher incidence of 1-year poor functional outcome in reverse dippers warrants further investigation.

2-Methoxyestradiol ameliorates paraquat-induced pulmonary fibrosis by inhibiting the TGF-ß1/Smad2/3 signaling pathway.

Paraquat (PQ) is a highly effective and highly toxic herbicide that is highly toxic to both humans and animals. Pulmonary fibrosis is the primary cause of fatality in patients with PQ poisoning, there is no effective drug treatment yet. 2-Methoxyestradiol (2ME) is a natural metabolite of estradiol with anti-tumor, anti-angiogenesis, and anti-proliferative effects. Whether 2ME has the potential to inhibit pulmonary fibrosis induced by PQ is unclear. This study aims to investigate the potential effects and mechanism of 2ME on PQ-induced pulmonary fibrosis. C57BL/6 mice and A549 cells were exposed to PQ to establish pulmonary fibrosis model. In vivo, Hematoxylin and eosin (H&E) staining was utilized to assess the pathological characteristics. Masson's trichrome staining was employed to evaluate the collagen deposition. Western blot and immunohistochemistry were conducted to determine the expressions of fibrosis markers. In vitro, the expressions of epithelial-mesenchymal transition (EMT) markers were detected using western blot and immunofluorescence to evaluated the potential inhibition of PQ-induced EMT by 2ME. And proteins associated with the TGF-ß1/Smad2/3 signaling pathway were measured by western blot in vivo and in vitro. The result found that 2ME can ameliorated PQ-induced pulmonary fibrosis and inhibit the activation of TGF-ß1/Smad2/3 signaling pathway. These findings suggest that 2ME may serve as a potential therapeutic agent for treating PQ-induced pulmonary fibrosis.

Application of Age, Body Mass Index, Chronic Kidney Disease, Diabetes, and Genotyping Score for Efficacy of Clopidogrel: Secondary Analysis of the CHANCE Trial.

BACKGROUND AND PURPOSE: The age, body mass index, chronic kidney disease, diabetes, and genotyping (ABCD-GENE) score is a validated risk score integrating CYP2C19 genotypes with clinical risk factors influencing clopidogrel response that would allow the more precise identification of subjects at risk for high platelet reactivity and adverse clinical outcomes. Our objective was to further verify application of the ABCD-GENE score and investigate appropriate cutoff value in patients with minor stroke or transient ischemic attack. METHODS: In this post-analysis of the CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events), the ABCD-GENE score was calculated for all patients enrolled in this study. By using the proposed cutoff of 10, patients were stratified as being at high risk for high platelet reactivity or not. We further categorized the ABCD-GENE score to 0 to 5, 6 to 24, and >24 to investigate the cutoff value of this scale in clinical application. Stroke recurrence at 3 months was considered as the primary outcome. RESULTS: Among a total of 2923 patients with minor stroke/transient ischemic attack, there were 2273 (77.76%) with ABCD-GENE score <10 and 650 (22.24%) patients with ABCD-GENE score ≥10. Compared with the aspirin alone, hazard ratios (95% CIs) of the clopidogrel-aspirin therapy for stroke recurrence were 0.70 (0.54-0.91) and 0.76 (0.46-1.24), among patients of ABCD-GENE scores <10 and ABCD-GENE scores ≥10, respectively. Stratified analyses by ABCD-GENE score 0 to 5, 6 to 24, and >24, hazard ratios of the clopidogrel-aspirin therapy for stroke recurrence were 0.57 (95% CI, 0.38-0.85), 0.78 (0.58-1.06), and 1.20 (0.44-3.28) (P value for trend=0.0052). CONCLUSIONS: Among Chinese minor stroke/transient ischemic attack population, the efficacy of clopidogrel-aspirin therapy was decreased in patients with higher ABCD-GENE score. Our study suggests that CYP2C19 genotypes and clinical risk factors can be integrated by ABCD-GENE score to estimate the efficacy of clopidogrel-aspirin therapy.

Associations of Life's Simple 7 With Cerebral Small Vessel Disease.

BACKGROUND: The purpose of this study is to examine the associations of Life's Simple 7 (LS7) with risks of cerebral small vessel disease (CSVD) and its magnetic resonance imaging markers. METHODS: Community-dwelling residents in Lishui city in China from the cross-sectional survey of the PRECISE study (Polyvascular Evaluation for Cognitive Impairment and Vascular Events) were included in this study from 2017 to 2019. LS7 was analyzed as the total score, medical score (derived from the 3 metrics based on medical history and testing), and behavioral score (based on 4 metrics based on behaviors), and categorized as poor, intermediate, or ideal. A CSVD score or a modified CSVD score was derived from 4 magnetic resonance imaging markers (lacunes, microbleeds, perivascular spaces, and white matter hyperintensity) at baseline. Binary logistic regression or ordinal logistic regression model was used to estimate the relationship of LS7 scores with CSVD and magnetic resonance imaging markers. RESULTS: A total of 3061 participants were included in this study. Compared with poor total LS7 score, ideal LS7 total score was associated with reduced adjusted odds of higher CSVD score (common odds ratio [cOR], 0.73 [95% CI, 0.58-0.90]) and higher modified CSVD score (cOR, 0.78 [95% CI, 0.64-0.95]). Compared with poor LS7 medical score, ideal LS7 medical score was associated with reduced adjusted odds of higher CSVD score (cOR, 0.65 [95% CI, 0.53-0.80]) and higher modified CSVD score (cOR, 0.67 [95% CI, 0.56-0.81]). Higher total LS7 score and LS7 medical score were associated with a lower risk of white matter hyperintensities and lacunes. Higher LS7 behavioral score was associated with lower risk of lacunes. CONCLUSIONS: Ideal LS7 score, indicating excellent cardiovascular health, was associated with lower total CSVD burden. Optimizing the risk factors captured by LS7 may reduce the progression of CSVD.

Small vessel disease burden may not portend unfavorable outcome after thrombectomy for acute large vessel occlusion.

OBJECTIVES: We aimed to investigate the correlation between an overall cerebral small vessel disease (CSVD) burden and outcomes after endovascular treatment (EVT) for patients with acute ischemic stroke (AIS) due to large vessel occlusion (LVO). METHODS: In a multicenter registry study, we enrolled patients with EVT for anterior-circulation LVO-stroke. In 3.0-T MR imaging, we assessed 4 CSVD imaging markers, lacunes, white matter hyperintensities, cerebral microbleeds, and enlarged perivascular spaces, each assigned a score of 0 or 1 and summed up to an overall CSVD burden score of 0-4. We dichotomized the overall CSVD severity as none to mild (score 0-2) and moderate to severe (3-4). Primary outcome was 90-day functional dependence or death (modified Rankin Scale (mRS) 3-6). Secondary outcomes included increase in NIH Stroke Scale ≥ 4 within 24 h (early neurological deterioration (END)) and within 7 days, symptomatic intracranial hemorrhage, 90-day mRS 2-6, and 90-day mortality. RESULTS: Among 311 patients (63.0% male; mean age 65.1 ± 12.7 years), 260 (83.6%) had none-to-mild and 51 (16.4%) had moderate-to-severe overall CSVD burden. Moderate-to-severe CSVD burden was not significantly associated with the primary outcome (47.1% versus 45.4%; p > 0.05 in univariate and multivariate logistic regression), or the secondary outcomes except for a higher risk of END (11.8% versus 3.1%; p < 0.05 in multivariate analyses). Sensitivity analyses with 0-1 versus 2-4 of the CSVD burden score, and the score as an ordinal variable, showed similar results. CONCLUSIONS: An overall moderate-to-severe CSVD burden was not associated with 90-day functional dependence or death, after EVT for anterior-circulation LVO. TRIAL REGISTRATION: ChiCTR1900022154 KEY POINTS: • Moderate-to-severe cerebral small vessel disease burden on MRI should not be an exclusion indicator in determining the eligibility of an acute ischemic stroke patient for endovascular treatment.

Predictive values of baseline matrix metalloproteinase 9 levels in peripheral blood on 3-month outcomes of high-risk patients with minor stroke or transient ischemic attack.

BACKGROUND AND PURPOSE: To explore the relationship between baseline levels of matrix metalloproteinase 9 (MMP9) in peripheral blood and the outcomes in patients with acute minor stroke and transient ischemic attack (TIA). METHODS: We assessed data from patients with acute minor ischemic stroke or TIA who were included in the CHANCE (Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events) trial. Baseline level of MMP9 in peripheral blood is classified into five quintiles. We assessed the relationship between the baseline MMP9 and outcomes of stroke recurrence, composite vascular events, and poor functional outcomes within 90 days after stroke onset. RESULTS: Of the 3014 patients included, 295 (9.79%) had recurrent stroke, 289 (9.59%) had recurrent ischemic stroke, 297 (9.85%) had combined vascular events, and 199 (6.64%) had poor functional outcomes within 90 days. We used MMP9 concentrations near hazard ratio (HR) = 1 (Q3) in restricted cubic splines as the reference. The result showed that, compared to patients in the Q3 group, patients in the highest quintile (Q5 group) had an increased risk of poor functional outcomes at 90 days after adjusting the risk factors and confounders (p = 0.030), which may be associated with an increased risk of combined vascular events (p = 0.052). Using Cox regression models or logistic regression models with restricted cubic spline, we also observed that higher MMP9 ratios were associated with an increased risk of stroke recurrence, combined events, and poor functional outcomes at a range of concentrations. CONCLUSIONS: For patients with acute minor stroke or TIA, higher baseline MMP9 level was associated with an increased risk of poor functional outcomes, which might be related to stroke recurrence and combined vascular events.

Nontraditional Risk Factors for Residual Recurrence Risk in Patients with Ischemic Stroke of Different Etiologies.

BACKGROUND AND OBJECTIVE: With the popularization of guideline-based secondary prevention based on traditional risk factors, rates of stroke recurrence reduced greatly after ischemic stroke (IS) or transient ischemic attack (TIA), but the residual risk still exists. We aim to evaluate which IS subtype benefits the most from the current secondary prevention and to evaluate nontraditional risk factors for residual recurrence risk of different IS etiologies. METHODS: The study included IS/TIA patients who participated in both biomarker substudy and imaging substudy of the Third China National Stroke Registry. We used 5 guideline-recommended interventions (antiplatelet, statins, anticoagulant, antihypertensive, and antidiabetic therapies) to document the performance of secondary prevention care. Residual risk was defined as the risk of stroke recurrence despite adherence to these 5 guideline-based secondary prevention strategies. Risk factors associated with stroke recurrence were analyzed by using Cox regression models. RESULTS: In total, 9,733 patients were included in this study. At 3 months, 4,186 (43.0%) patients adhered to 5 secondary prevention strategies, and the residual risk of recurrence was 5.1%. According to Trial of Org 10172 in Acute Stroke Treatment subtypes, cardioembolism benefited the most from current secondary prevention (relative risk reduction: 65.2%), followed by large-artery atherosclerosis (LAA) (29.0%) and small-artery occlusion (SAO) (20.0%). Despite adhering to secondary prevention strategies, high sensitivity C-reactive protein, interleukin-6 (IL-6) levels, and impaired renal function were independent risk factors for the residual recurrence risk of LAA subtype, while IL-6 and trimethylamine N-oxide significantly contributed to the residual risk of SAO subtype. CONCLUSIONS: LAA and SAO subtypes own the specific nontraditional risk factors while inflammation is a common risk factor for residual recurrence risk of both.

The Association between Baseline and 3-Month Albuminuria and 1-Year Prognosis of Ischemic Stroke.

INTRODUCTION: The association between the changes in albuminuria levels and the clinical prognosis of stroke is unknown. The present study aimed to explore the relationships between changes in albuminuria and the risk of adverse stroke outcomes. METHODS: The patients with ischemic stroke or transient ischemic attack from the Third China National Stroke Registry (CNSR-III) who had the urinary albumin-to-creatinine ratio (ACR) detected at baseline and 3-month were recruited. They were classified into 4 groups according to baseline and 3-month ACR and followed up for 1 year. RESULTS: A total of 5,311 patients were finally included in the study. There were 3,738 (70.4%), 483 (9.1%), 451 (8.5%), and 639 (12.0%) patients with no albuminuria, baseline albuminuria, 3-month albuminuria, and persistent albuminuria, respectively. After adjustment for confounding variables, persistent albuminuria was independently associated with all-cause death (hazard ratio [HR], 2.23; 95% CI, 1.17-4.25; p = 0.02), stroke recurrence (HR, 1.55; 95% CI, 1.02-2.36; p = 0.04), and poor functional outcome (OR, 2.22; 95% CI, 1.66-2.96; p < 0.001). Baseline albuminuria was independently associated with poor functional outcome (OR, 1.65; 95% CI, 1.19-2.28; p = 0.003), while 3-month albuminuria was independently associated with stroke recurrence (HR, 1.68; 95% CI, 1.06-2.65; p = 0.03). CONCLUSIONS: Changes in albuminuria can predict adverse 1-year outcomes in Chinese ischemic stroke patients. In particular, persistent albuminuria was independently associated with 1-year all-cause death, stroke recurrence, and poor functional outcome.

Association of Urine Albumin-Creatinine Ratio and Cystatin C-Based Estimated GFR with Outcomes in Patients with Ischemic Stroke.

BACKGROUND/AIMS: Data about the independent and combined effects of cystatin C-based estimated glomerular filtration rate (eGFRcys) and albuminuria on the risk of poor outcome in stroke patients are limited. The aim was to elucidate how these two renal markers affect the clinical outcomes after ischemic stroke separately and jointly. METHODS: The study subjects consisted of 10,197 patients with ischemic stroke from the third China National Stroke Registry. The study outcomes were all-cause mortality, poststroke disability, recurrence of stroke, and cardiocerebral vascular disease (CVD) composite events. Cox proportional hazard models and multivariable logistic regression model were applied to evaluate the effects of eGFRcys and urine albumin-creatinine ratio (ACR) on these outcomes. RESULTS: Both reduced eGFRcys and increased ACR were independently associated with higher incidences of all-cause death and poststroke disability (p < 0.01). Mildly decreased eGFRcys (60-89 mL/min/1.73 m2) is associated with increased risk of all-cause death and poststroke disability in the presence of high-normal ACR (10-29 mg/g). Patients with both eGFRcys <45 mL/min/1.73 m2 and ACR ≥30 mg/g at baseline had a 6.8-fold risk for all-cause mortality and 3.6-fold risk for poststroke disability, compared with patients with eGFRcys of 90-119 mL/min/1.73 m2 and ACR <10 mg/g. In addition, increased ACR was associated with recurrent stroke and CVD composite event, while reduced eGFRcys showed no relationship with these outcomes. CONCLUSIONS: Both decreased eGFRcys and albuminuria are independent risk factors for all-cause death and poststroke disability. Combining the two markers is useful for improving risk stratification even in those without chronic kidney disease.

Genetically predicted childhood obesity and adult atrial fibrillation: A mendelian randomization study.

BACKGROUND AND AIMS: It is unclear whether the association of childhood obesity with adult atrial fibrillation observed in observational studies reflects causal effects. The aim of this study was to evaluate the association of childhood obesity with adult atrial fibrillation using genetic instruments. METHODS AND RESULTS: We used a two-sample Mendelian randomization (MR) design to evaluate the association between childhood obesity and adult atrial fibrillation. Two sets of genetic variants (15 single nucleotide polymorphisms [SNPs] for childhood body mass index [BMI] and 12 SNPs for dichotomous childhood obesity) were selected as instruments. Summary data on SNP-childhood obesity and SNP-atrial fibrillation associations were obtained from recently published genome-wide association studies. Effect estimates were evaluated using inverse-variance weighted (IVW) methods. Other MR analyses, including MR-Egger, simple and weighted median, weighted MBE and MR-PRESSO methods were performed in sensitivity analyses. The IVW models showed that both a genetically predicted one-standard deviation increase in childhood BMI (kg/m2) and higher log-odds of childhood obesity were associated with a substantial increase in the risk of atrial fibrillation (OR = 1.22, 95% CI: 1.11-1.34, P < 0.001; OR = 1.09, 95% CI: 1.04-1.14, P < 0.001). MR-Egger regression showed no evidence of genetic pleiotropy for childhood BMI (intercept = 0.000, 95% CI: -0.024 to 0.023), but for childhood obesity (intercept = -0.036, 95% CI: -0.057 to -0.015). Similar results were observed using leave-one-out and other MR methods in sensitivity analyses. CONCLUSIONS: This MR analysis found a consistent association between genetically predicted childhood obesity and an increased risk of adult atrial fibrillation. Further research is warranted to validate our findings.

Coexistent cerebral small vessel disease and multiple infarctions predict recurrent stroke.

BACKGROUND AND PURPOSE: To investigate the association of different status of cerebral small vessel disease (CSVD) and infarction number with recurrence after acute minor stroke and transient ischaemic attack (TIA). METHODS: This study was a post hoc analysis of the Clopidogrel in High-risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial, and includes 886 patients with acute minor stroke and TIA. The status of CSVD and infarction number was recorded for each individual. Infarction number were classified as multiple acute infarctions (MAIs≥2), single acute infarction (SAI =1), and non-acute infarction (NAI =0). The CSVD burden were grouped into non-CSVD (0 score) and CSVD (1-4 score). The primary outcome was a recurrent stroke at the 1-year follow-up. The secondary outcomes were recurrent ischaemic stroke, composite vascular event (CVE), and TIA. We analyzed the relationships between different status of CSVD burden and infarction pattern with the risk of outcomes using multivariable Cox regression models. RESULTS: Among all 886 patients included in present analysis, recurrent stroke was occurred in 93 (10.5%) patients during 1-year follow-up. After adjusted for all potential covariates, compared with patients with non-CSVD and NAI, patients with CSVD and MAIs were associated with approximately 9.5-fold increased risk of recurrent stroke at 1 year (HR 9.560, 95% CI 1.273-71.787, p=0.028). Similar results observed in ischaemic stroke and CVE. CONCLUSION: The status of CSVD and infarction number predicted recurrent stroke in patients with acute minor stroke and TIA, especially for those with coexistent CSVD and MAIs.

Persisting cognitive impairment predicts functional dependence at 1 year after stroke and transient ischemic attack: a longitudinal, cohort study.

OBJECTIVE: Minor stroke or transient ischemic attack (TIA) usually have mild and nondisabling symptoms, and these functional deficits may recover fully e.g., TIA, however, part of them still suffer from cognitive impairment and poor outcomes. We conducted a study to determine the relationship between cognition evaluated by Montreal Cognitive Assessment (MoCA) and poor functional outcomes assessed by the Modified Rankin Scale (mRS) (mRS ≥ 2) and Stroke Impact Scale (SIS)-16(SIS-16<25%). METHODS: The data of this study come from the impairment of cognition and Sleep (ICONS) after acute ischemic stroke or transient ischemic attack in Chinese patients study. A total of 1675 minor stroke patients and TIA patients were finally recruited. Patients' cognition were evaluated by Montreal Cognitive Assessment (MoCA) scale at 2-week (2w), 3 months (3 m) and 1 year(1y). Cognitive impairment (CI) was defined as MoCA score ≤ 22. According to MoCA score, patients were divided into 4 groups: no PSCI group: with MoCA-2w>22 and MoCA-3 m>22; improved PSCI group: with MoCA-2w ≤ 2 and MoCA-3 m>22;delayed PSCI group: MoCA-2w>22 and MoCA-3 m ≤ 22; persisting PSCI group: with MoCA-2w ≤ 22 and MoCA-3 m ≤ 22. RESULTS: A total of 1675 stroke patients were recruited in this study. There were 818 patients (48.84%) who had PSCI at baseline. Of these, 123 patients (15%) had mRS ≥2 at 3 months. The persisting PSCI group was a significant predictor of functional dependence at 3 months and 1 year after stroke and when adjusted for covariates such as gender, age, history of stroke, depression and intracranial atherosclerotic stenosis, stroke subtype and acute infarction type. CONCLUSION: Persisting PSCI increased the risk of poor functional outcome after 3 months and 1 year follow-up. These high-risk individuals should be identified for targeted rehabilitation and counseling to improve longer-term post-stroke outcome.

Intraluminal Thrombus and Outcomes of Patients With Acute Large Vessel Occlusive Stroke Undergoing Endovascular Treatment.

BACKGROUND AND PURPOSE: Intraluminal thrombus (ILT) is an emerging imaging marker in acute ischemic stroke. We aimed to investigate the association of ILT with outcomes of acute large vessel occlusion (LVO) patients receiving endovascular treatment. METHODS: Acute LVO stroke patients who underwent endovascular treatment within 24 hours, in a prospective, nationwide registry were enrolled. Pretreatment digital subtraction angiography was reviewed for the presence of ILT. The primary outcome was 90-day functional dependence (modified Rankin Scale scores, 3-6). Secondary outcomes included 24-hour LVO, 90-day death, and symptomatic intracranial hemorrhage. RESULTS: Among 711 patients enrolled, 75 (10.5%) with ILT were less likely to have 90-day functional dependence compared with those without ILT (adjusted odds ratio, 0.53 [95% CI, 0.31-0.90]; P=0.021). The same trend was found among those with successful reperfusion (modified Thrombolysis in Cerebral Infarction 2b-3; P=0.008) but not in those without successful reperfusion (P=0.107). Presence of ILT was also independently associated with a lower rate of 24-hour LVO (adjusted odds ratio 0.34 [95% CI, 0.13-0.89]; P=0.028). However, those with or without ILT had similar risks of symptomatic intracranial hemorrhage and 90-day death. CONCLUSIONS: Among acute LVO patients receiving endovascular treatment, pretreatment ILT-positive patients may have a better 90-day functional outcome (versus ILT-negative) but similar risk of death and symptomatic intracranial hemorrhage. The possibly favorable effect of ILT patients remained in those with successful reperfusion. Registration: URL: http://www.chictr.org.cn; Unique identifier: ChiCTR1900022154.

Discovery of novel ketoxime ether derivatives with potent FXR agonistic activity, oral effectiveness and high liver/blood ratio.

The farnesoid X receptor (FXR) is a promising therapeutic target for nonalcoholic steatohepatitis (NASH) and other bile acid related diseases because it plays a critical role in fibrosis, inflammation and bile acid homeostasis. Obeticholic acid (OCA), a FXR agonist which was synthesized from chenodeoxycholic acid, showed desirable curative effects in clinical trials. However, the pruritus which was the main side effect of OCA limited its further applications in NASH. Although pruritus was also observed in the clinical trials of non-steroidal FXR agonists, the proportion of patients with pruritus was much smaller than that of OCA. Thus, we decided to develop non-steroidal FXR agonists and discovered a series of novel FXR agonists which were synthesized from GW4064 by replacing the stilbene group with ketoxime ether. Encouragingly, in the following biological tests, our target compounds 13j and 13z not only showed potent FXR agonistic activities in vitro, but also effectively promoted the expression of target genes in vivo. More importantly, in the pharmacokinetic experiments, compounds 13j and 13z displayed high liver/blood ratio characteristics which were helpful to reduce the potential side effects which were caused by prolonged systemic activation of FXR. In summary, our compounds were good choices for the development of non-steroidal FXR agonists and were deserved further investigation.

Paraquat promotes acute lung injury in rats by regulating alveolar macrophage polarization through glycolysis.

The present study investigates whether paraquat (PQ) regulates polarization of alveolar macrophages through glycolysis and promotes the occurrence of acute lung injury in rats. In vivo, the PQ intraperitoneal injection was used to construct a model of acute lung injury in rats. In vitro, the study measured the effect of different concentrations of PQ on the viability of the alveolar macrophages, and explored the polarization and glycolysis metabolism of alveolar macrophages at different time points after PQ intervention. Compared with the normal control (NC) group, the lung pathological damage in rats increased gradually after PQ poisoning, reaching a significant degree at 48 h after poisoning. The PQ-poisoned rat serum showed increased expressions of interleukin-6 (IL-6), tumor necrosis factor- α (TNF-α), and M1 macrophage marker, iNOS, while the expression of interleukin-10 (IL-10) and M2 macrophage marker, Arg1, decreased. The toxic effect of PQ on alveolar macrophages was dose- and time-dependent. Compared with the NC group, IL-6 and TNF-α in the cell supernatant gradually increased after PQ intervention, while the IL-10 content gradually decreased. The PQ intervention in alveolar macrophages increased the expression of intracellular glycolysis rate-limiting enzyme pyruvate kinase isozymes M1/M2 (PKM1/M2), lactate, lactate/pyruvate ratio, and the polarization of alveolar macrophage towards M1. Inhibition of cellular glycolysis significantly reduced the PQ-induced alveolar macrophage polarization to M1 type. Thus, PQ induced increased polarization of lung macrophages toward M1 and decreased polarization toward M2, promoting acute lung injury. Therefore, it can be concluded that PQ regulates the polarization of alveolar macrophages through glycolysis.