Association between combination COVID-19-influenza vaccination and long COVID in middle-aged and older Europeans: A cross-sectional study.

The potential impact of combined COVID-19 and influenza vaccination on long COVID remains uncertain. In the present cross-sectional study, we aimed to investigate the plausible association between them in middle-aged and older Europeans based on the Survey of Health, Ageing, and Retirement in Europe (SHARE). A total of 1910 participants were recruited in the analyses. The study outcome was long COVID. Participants were divided into 4 groups through the self-reported status of COVID-19 and influenza vaccination. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. 1397 participants experienced long COVID. After multivariable adjustment, those vaccinated with neither COVID-19 nor influenza vaccine had higher risk of long COVID (OR, 1.72; 95% CI, 1.26-2.35) compared to those vaccinated with both vaccines. Furthermore, adding the 4 statuses of COVID-19 vaccination/influenza vaccination to conventional risk model improved risk reclassification for long COVID (continuous net reclassification improvement was 16.26% [p = .003], and integrated discrimination improvement was 0.51% [p = .005]). No heterogeneity was found in the subgroup analyses (all p-interaction ≥0.05). Our study might provide a strategy for people aged 50 and over to reduce the occurrence of long COVID, that is, to combine the use of the COVID-19 vaccine and influenza vaccines.

White matter hyperintensity, parent artery steno-occlusion, and neurological deterioration in anterior circulation single subcortical infarction patients.

BACKGROUND: The evidence for the association between white matter hyperintensity (WMH) severity and neurological deterioration (ND) in patients with single subcortical infarction (SSI) remains unclear and whether the association between them is modified by anterior circulation parent artery steno-occlusion (PAS) is unknown. Herein, we aimed to prospectively investigate the internal relevance. METHODS: In this prospective study, the severity of WMH and PAS were assessed in 288 consecutive patients with anterior circulation SSI arriving at our hospital, a tertiary teaching hospital affiliated with Fudan University, 24 h after onset from January 2017 to December 2018. The multivariable logistic regression model was used to estimate the association between WMH severity and the risk of ND within 7 days after stroke onset as well as the interactive effect between WMH severity and PAS on ND among patients with SSI. RESULTS: PAS modified the association between WMH severity and ND among patients with SSI (pinteraction = .029). After multivariate adjustment, the odds ratios of moderate-severe WMH associated with ND were 1.61 (95% CI, 0.50-5.19; ptrend = .428) for patients with PAS, and 0.37 (95% CI, 0.14-0.97; ptrend = .043) for those without PAS. Adding WMH severity to conventional risk factors improved risk prediction for ND in patients without PAS (net reclassification improvement: 48.2%, p = .005; integrated discrimination index: 2.5%, p = .004) but not in those with PAS. CONCLUSION: There was a modified effect of PAS on the association between WMH severity and ND within 7 days after stroke onset among patients with anterior circulation SSI, which deserves more research attention. WMH was negatively associated with ND in anterior circulation SSI patients without PAS.

The association between long-term platelet count and disability-free survival among middle-aged and older Chinese: Evidence from the China Health and Retirement Longitudinal Study.

BACKGROUND AND AIMS: We aimed to assess the associations of baseline and long-term platelet count (PLT) with disability-free survival (DFS) among middle-aged and older Chinese. METHODS AND RESULTS: A total of 7296 participants were recruited in the analysis. Updated mean PLT was defined as the mean of the two PLT measurements (4 years between wave 1-3). The long-term status of PLT was defined as persistent low, attenuated, increased and persistent high PLT according to the optimal cut points from the receiver operating characteristic curves of the two PLT measurements, respectively. The primary outcome was DFS, evaluated by the first occurrence of either disability or mortality. During 6-year visit, 1579 participants experienced disability or all-cause mortality. The rates of primary outcome were significantly higher among participants with elevated baseline PLT and updated mean PLT. Multivariable adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of primary outcome were 1.253 (1.049-1.496) for highest baseline PLT tertile and 1.532 (1.124-2.088) for highest updated mean PLT tertile, comparing to the lowest tertiles. Multivariable-adjusted spline regression models showed a linear association of baseline PLT (plinearity < 0.001) and updated mean PLT (plinearity = 0.005) with primary outcome. Moreover, participants with persistent high PLT and increased PLT had increased risk of primary outcome (ORs [95% CIs]: 1.825 [1.282-2.597] and 1.767 [1.046-2.985], respectively), compared with the reference of those with persistent low PLT. CONCLUSION: This study proved elevated baseline PLT, especially long-term persist high or increased PLT was associated with less likelihood of DFS among middle-aged and older Chinese.

Combined effects of high sensitivity C-reactive protein and triglyceride-glucose index on risk of cardiovascular disease among middle-aged and older Chinese: Evidence from the China Health and Retirement Longitudinal Study.

BACKGROUND AND AIMS: High sensitivity C-reactive protein (hsCRP) and triglyceride glucose (TyG) index were proved to be independent risk factors of cardiovascular disease (CVD). However, individual hsCRP or TyG index might not provide sufficient predictive value on CVD risk. The current study aimed to evaluate the cumulative effect of hsCRP and TyG index on CVD risk prospectively. METHODS AND RESULTS: A total of 9626 participants were enrolled in the analysis. The TyG index was calculated as ln(triglyceride [mg/dL] × fasting glucose [mg/dL]/2). The primary outcome was new-onset CVD events (cardiac events or stroke), and the secondary outcomes were new-onset cardiac events and stroke, separately. Participants were divided into 4 groups through the median of hsCRP and TyG index. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using multivariable Cox proportion hazard models. From 2013 to 2018, 1730 participants experienced CVD (570 stroke and 1306 cardiac events). Linear associations were found between hsCRP, TyG index, hsCRP/TyG ratio and CVD (all p < 0.05). Compared to participants with low hsCRP/low TyG index, multivariable adjusted HRs (95% CIs) for those with high hsCRP/high TyG index were 1.17 (1.03-1.37) for CVD. No interaction of hsCRP and TyG index was found on CVD (p-interaction ≥0.05). Furthermore, adding hsCRP and TyG index simultaneously to conventional risk model improved risk reclassification for CVD, stroke and cardiac events (all p < 0.05). CONCLUSION: The present study suggested combination of hsCRP and TyG index might better improved the ability for risk stratification of CVD among middle-aged and older Chinese.

Grip strength affects the association between platelet count and disability-free survival: Evidence from the China Health and Retirement Longitudinal Study.

BACKGROUND AND AIMS: Previous studies found elevated platelet count (PLT), especially long-term persist high or increased PLT was associated with less likelihood disability-free survival (DFS). However, whether grip strength affects the relationship between them is still not elucidated. METHODS: A total of 6252 participants were recruited in the analysis based on the China Health and Retirement Longitudinal Study. The primary outcome was DFS, evaluated by a composite endpoint based on the first occurrence of either disability (having difficulty in at least one of the 6 activities of daily living: namely, dressing, bathing, continence, eating, getting into or out of bed, and toileting) or all-cause mortality. RESULTS: The association of PLT with primary outcome was significantly modified by grip strength (pinteraction = 0.022). The rates of primary outcome were significantly lower among participants with lower baseline PLT in participants with normal grip strength (multivariable odds ratio [OR], 0.67; 95% confidence interval [CI], 0.54-0.84; ptrend < 0.001), but not in those with low grip strength (multivariable OR, 1.70; 95% CI, 0.88-3.15; ptrend = 0.135), for the lowest quartile vs the highest quartile. Adding baseline PLT (quartiles or continuous) to a model containing conventional risk factors significantly improved risk reclassification for primary outcome among those with normal grip strength (most of p < 0.05). CONCLUSION: An inverse dose-response association of PLT with DFS was found among participants with normal grip strength, but not among those with low grip strength. Low grip strength might weaken the benefit of low PLT on DFS among middle-aged and older Chinese.

Diet, Lifestyle Behaviours and Other Risk Factors Associated With Type 2 Diabetes Beyond Body Mass Index: A Mendelian Randomization Study.

OBJECTIVES: Our aim in this study was to identify promising targets for the prevention of type 2 diabetes in addition to weight loss. We conducted a Mendelian randomization (MR) study to investigate the body mass index (BMI)-independent associations of 16 risk factors, including diet, lifestyle behaviours and others, with type 2 diabetes. METHODS: We selected genetic variants as instrumental variables for diet, sleep traits, smoking, physical activity, education and blood pressure (BP) from European-descent genome-wide association studies (GWASs). Summary statistics for type 2 diabetes were derived from a recent GWAS with 74,124 European cases and 824,006 European controls. The inverse-variance weighted MR method was used to assess the associations of the risk factors with type 2 diabetes, followed by validation of robustness using different MR methods in sensitivity analyses. RESULTS: Genetically predicted insomnia (odds ratio [OR], 1.10; 95% confidence interval [CI], 1.06 to 1.15), smoking initiation (OR, 1.14; 95% CI, 1.06 to 1.21), educational level (OR, 0.69; 95% CI, 0.65 to 0.74), hypertension (OR, 6.50; 95% CI, 3.13 to 13.50), systolic BP (OR, 1.02; 95% CI, 1.02 to 1.03) and diastolic BP (OR, 1.03; 95% CI, 1.02 to 1.03) had BMI-independent effects on type 2 diabetes risk. In addition, alcohol dependence (OR, 1.10; 95% CI, 1.05 to 1.16; BMI-adjusted OR, 1.04; 95% CI, 0.98 to 1.09) and vegetarian diet (OR, 0.50; 95% CI, 0.33 to 0.74; BMI-adjusted OR, 0.78; 95% CI, 0.57 to 1.06) appeared to be correlated with type 2 diabetes via a BMI-mediated pathway. Sensitivity analyses further confirmed the relationship between these factors and type 2 diabetes. CONCLUSIONS: In this systematic MR study, insomnia, smoking, education and BP had BMI-independent causal effects on the risk of type 2 diabetes, whereas alcohol dependence and vegetarian diet were associated with type 2 diabetes through BMI.

Self-reported daytime napping, daytime sleepiness, and other sleep phenotypes in the development of cardiometabolic diseases: a Mendelian randomization study.

AIMS: Sleep disorders are associated with an increased risk of cardiometabolic diseases in observational studies, but the causality remains unclear. In this study, we leveraged two-sample Mendelian randomization (MR) analyses to assess the causal associations of self-reported daytime napping, daytime sleepiness, and other sleep phenotypes with cardiometabolic diseases including ischaemic stroke (IS), coronary artery disease (CAD), heart failure (HF), and Type 2 diabetes mellitus (T2DM). METHODS AND RESULTS: We selected genetic variants as instrumental variables for self-reported daytime napping, daytime sleepiness, morning person, insomnia, short sleep duration, and long sleep duration from European-descent genome-wide association studies (GWASs). Summary statistics for cardiometabolic diseases originated from four different GWASs with a total of 2 500 086 participants. We used the inverse-variance weighted method to explore the role of self-reported sleep phenotypes on the aetiology of cardiometabolic diseases in the main analyses, followed by several sensitivity analyses for robustness validation. Genetically predicted self-reported daytime napping [T2DM: OR, 1.56 (95% confidence interval, 1.21-2.02)], insomnia [IS: OR, 1.07 (1.04-1.11)]; CAD: OR, 1.13 (1.08-1.17); HF: OR, 1.10 (1.07-1.14); T2DM: OR, 1.16 (1.11-1.22); and short sleep duration [CAD: OR, 1.37 (1.21-1.55)] were causally associated with an elevated risk of cardiometabolic diseases. Moreover, genetically determined self-reported daytime sleepiness [CAD: OR, 2.05 (1.18-3.57); HF: OR, 1.82 (1.15-2.87)] and morning person [HF: 1.06 OR, (1.01-1.11)] had potential detrimental effect on cardiometabolic risks. CONCLUSION: Self-reported daytime napping, insomnia, and short sleep duration had causal roles in the development of cardiometabolic diseases, while self-reported daytime sleepiness and morning person was the potential risk factor for cardiometabolic diseases.

Contribution of metabolic risk factors and lifestyle behaviors to cardiovascular disease: A mendelian randomization study.

BACKGROUND AND AIMS: Etiologic associations between some modifiable factors (metabolic risk factors and lifestyle behaviors) and cardiovascular disease (CVD) remain unclear. To identify targets for CVD prevention, we evaluated the causal associations of these factors with coronary artery disease (CAD) and ischemic stroke using a two-sample Mendelian randomization (MR) method. METHODS AND RESULTS: Previously published genome-wide association studies (GWASs) for blood pressure (BP), glucose, lipids, overweight, smoking, alcohol intake, sedentariness, and education were used to identify instruments for 15 modifiable factors. We extracted effects of the genetic variants used as instruments for the exposures on coronary artery disease (CAD) and ischemic stroke from large GWASs (N = 60 801 cases/123 504 controls for CAD and N = 40 585 cases/406 111 controls for ischemic stroke). Genetically predicted hypertension (CAD: OR, 5.19 [95% CI, 4.21-6.41]; ischemic stroke: OR, 4.92 [4.12-5.86]), systolic BP (CAD: OR, 1.03 [1.03-1.04]; ischemic stroke: OR, 1.03 [1.03-1.03]), diastolic BP (CAD: OR, 1.05 [1.05-1.06]; ischemic stroke: OR, 1.05 [1.04-1.05]), type 2 diabetes (CAD: OR, 1.11 [1.08-1.15]; ischemic stroke: OR, 1.07 [1.04-1.10]), smoking initiation (CAD: OR, 1.26 [1.18-1.35]; ischemic stroke: OR, 1.24 [1.16-1.33]), educational attainment (CAD: OR, 0.62 [0.58-0.66]; ischemic stroke: OR, 0.68 [0.63-0.72]), low-density lipoprotein cholesterol (CAD: OR, 1.55 [1.41-1.71]), high-density lipoprotein cholesterol (CAD: OR, 0.82 [0.74-0.91]), triglycerides (CAD: OR, 1.29 [1.14-1.45]), body mass index (CAD: OR, 1.25 [1.19-1.32]), and alcohol dependence (OR, 1.04 [1.03-1.06]) were causally related to CVD. CONCLUSION: This systematic MR study identified 11 modifiable factors as causal risk factors for CVD, indicating that these factors are important targets for preventing CVD.

Association of serum growth differentiation factor-15 levels with the risks of death and vascular events in patients with ischemic stroke: The role of diabetes.

BACKGROUND AND AIMS: Researchers have not determined whether the association between growth differentiation factor-15 (GDF-15) levels and stroke outcomes is modified by the diabetes status. We aimed to evaluate the prognostic value of GDF-15 among patients with ischemic stroke stratified by diabetes. METHODS AND RESULTS: A total of 3001 patients with ischemic stroke were selected from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) and included in this study. The primary outcome was a composite outcome of death and vascular events at 3 months after acute ischemic stroke. An elevated GDF-15 level was significantly associated with the primary outcome in patients with diabetes but not in those without diabetes (pinteraction = 0.038). The multivariate-adjusted hazard ratio (95% confidence intervals) for the primary outcome was 3.33 (1.07-10.35) when 2 extreme tertiles were compared, and a linear association between GDF-15 levels and the primary outcome was observed in patients with diabetes (p for linearity = 0.046). The addition of serum GDF-15 to conventional risk factors improved the risk prediction for the primary outcome in patients with diabetes (net reclassification improvement: 31.98%, p = 0.043; integrated discrimination index: 0.85%, p = 0.034) but not in those without diabetes. CONCLUSIONS: A modifying effect of the diabetes status on the association between serum GDF-15 levels and ischemic stroke prognosis was observed. Elevated serum GDF-15 levels were associated with the primary outcome within 3 months after ischemic stroke in patients with diabetes, suggesting that GDF-15 may be an important prognostic factor for ischemic stroke in patients with diabetes.

Association between annual household income and adverse outcomes in patients who had ischaemic stroke.

BACKGROUND AND PURPOSE: The association between annual household income and prognosis of ischaemic stroke remains debatable. We aimed to prospectively investigate the relationship between annual household income and prognosis at 3 months after ischaemic stroke. METHODS: We included 3975 participants from the China Antihypertensive Trial in Acute Ischemic Stroke. All participants were categorised into three groups according to annual household income per capita: <¥10 000 (Chinese Yuan Renminbi (RMB)), ¥10 000-19 999 and ≥¥20 000. The primary outcome was a composite outcome of death and major disability (modified Rankin Scale score ≥3) at 3 months after stroke onset, and secondary outcomes included major disability, death, and vascular events. A meta-analysis was conducted to incorporate the results of the current study and previous studies on the association of income level with outcomes after stroke. RESULTS: Within 3 months after ischaemic stroke, 1002 participants (25.20%) experienced primary outcome (880 major disabilities and 122 deaths). After multivariate adjustment, low annual household income level was associated with increased risk of the primary outcome (OR 1.60; 95% CI: 1.12 to 2.31; Ptrend=0.034) when two extreme groups were compared. The meta-analysis confirmed the significant association between income level and death or major disability after stroke (pooled relative risk for lowest vs highest income level, 1.31 (95% CI: 1.18 to 1.45)). CONCLUSIONS: Low annual household income per capita was significantly associated with increased risks of adverse clinical outcomes at 3 months after ischaemic stroke, independently of established risk factors. Further studies from other samples are needed to replicate our findings due to a reason for excluding some patients who had a severe stroke in this study. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (http://wwwclinicaltrialsgov) Registry (NCT01840072).

Serum Growth Differentiation Factor 15 Levels Are Associated With Depression After Ischemic Stroke.

Background The effect of serum growth differentiation factor 15 (GDF-15) on poststroke depression (PSD) remains unknown. This study aimed to investigate the association between serum GDF-15 and PSD among patients with ischemic stroke. Methods and Results This study was based on a random sample from CATIS (China Antihypertensive Trial in Acute Ischemic Stroke). A total of 572 patients from 7 participating hospitals with GDF-15 levels were included in this analysis. The study outcome was depression (Hamilton Depression Rating Scale score ≥8) at 3 months after ischemic stroke. A total of 231 (40.4%) patients with stroke experienced PSD within 3 months. The multivariate-adjusted odds ratio of PSD associated with the highest tertile of serum GDF-15 was 2.92 (95% CI, 1.36-6.27) compared with the lowest tertile. Each SD increase in log-transformed GDF-15 was associated with a 42% (95% CI, 2%-97%) increased risk of PSD, and a linear association between serum GDF-15 and the risk of PSD was observed (P for linearity=0.006). Conclusions Elevated serum GDF-15 levels in the acute phase of ischemic stroke were independently associated with PSD, suggesting that GDF-15 may be a valuable prognostic biomarker for PSD.

Plasma osteopontin levels and adverse clinical outcomes after ischemic stroke.

BACKGROUND AND AIMS: Osteopontin is implicated in atherosclerosis, and its expression is upregulated in response to brain injury. The aim of this study was to prospectively investigate the associations between plasma osteopontin levels and adverse clinical outcomes in ischemic stroke patients. METHODS: We measured baseline plasma osteopontin levels in 3545 ischemic stroke patients from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). The primary outcome was the composite outcome of death and major disability (modified Rankin scale score ≥3) at 1 year after ischemic stroke, and secondary outcomes included major disability, death, and the composite outcome of death and vascular events. RESULTS: During 1 year of follow-up, patients in the fourth quartile of plasma osteopontin had the highest risks of primary outcome, major disability, death, and the composite outcome of death and vascular events. After multivariate adjustment, the odds ratios or hazard ratios (95 % confidence intervals) associated with each standard deviation increase in log-transformed osteopontin were 1.20 (1.09-1.33) for primary outcome, 1.11 (1.00-1.23) for major disability, 1.29 (1.10-1.52) for death, and 1.15 (1.01-1.30) for the composite outcome of death and vascular events. The addition of plasma osteopontin to conventional risk factors significantly improved the risk reclassification for the primary outcome (net reclassification improvement: 16.91%, p < 0.001; integrated discrimination improvement: 0.43%, p = 0.002). CONCLUSIONS: Elevated plasma osteopontin levels at baseline were associated with increased risks of adverse clinical outcomes at 1 year after ischemic stroke, suggesting that osteopontin is a promising prognostic biomarker for ischemic stroke.

Causal associations of serum matrix metalloproteinase-8 level with ischaemic stroke and ischaemic stroke subtypes: a Mendelian randomization study.

BACKGROUND AND PURPOSE: Elevated serum matrix metalloproteinase-8 (MMP-8) concentrations are associated with high risk of vascular disease, but the causality remains unclear. A two-sample Mendelian randomization (MR) study was performed to examine the causal effect of serum MMP-8 concentrations on the risk of ischaemic stroke, ischaemic stroke subtypes and coronary artery disease. METHODS: Ten independent single-nucleotide polymorphisms related to serum MMP-8 concentrations were identified as instrumental variables from a genome-wide association study of 6049 European subjects. Genetic association estimates for ischaemic stroke were obtained from the Multiancestry Genome-wide Association Study of Stroke consortium with 446,696 European individuals. The inverse-variance weighted method was applied to assess the causal associations of serum MMP-8 with ischaemic stroke and its subtypes in the main analysis. RESULTS: No significant causal association was observed for MMP-8 levels with total ischaemic stroke, large artery stroke or cardioembolic stroke. Genetically determined 1 - unit higher log-transformed serum MMP-8 concentration was associated with an increased risk of small vessel stroke (odds ratio 1.25; 95% confidence interval 1.12-1.39; p < 0.001). In secondary analysis, a similar adverse impact was reported for MMP-8 on coronary artery disease (odds ratio 1.05; 95% confidence interval 1.01-1.10; p = 0.017). Sensitivity analyses further confirmed the relationship between serum MMP-8 level and small vessel stroke and coronary artery disease. Mendelian randomization Egger regression showed no evidence of pleiotropic bias. CONCLUSIONS: High serum MMP-8 concentrations were causally associated with increased risks of small vessel stroke and coronary artery disease. The mechanism underlying the effect of serum MMP-8 on the vascular system requires further investigation.

Association between serum netrin-1 and prognosis of ischemic stroke: The role of lipid component levels.

BACKGROUND AND AIMS: High serum netrin-1 levels decrease the risk of ischemic stroke and are negatively associated with outcomes after ischemic stroke. However, it remains unclear whether the association between netrin-1 and ischemic stroke prognosis is modified by lipid component levels. METHODS AND RESULTS: We measured baseline serum netrin-1 levels in 3065 ischemic stroke patients from China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). The primary outcome was a combination of death and major disability (modified Rankin Scale score≥3) at 3 months after ischemic stroke. Total cholesterol (TC) levels could modify the association between netrin-1 and prognosis of ischemic stroke (Pinteraction = 0.040). After multivariate adjustment, the odds ratios of the primary outcome associated with the highest quartile of netrin-1 were 0.39 (95%CI, 0.17-0.90; Ptrend = 0.004) for the patients with high TC levels and 0.82 (95%CI, 0.61-1.11; Ptrend = 0.149) for those with normal TC levels. Adding netrin-1 to conventional risk factors improved risk prediction for the primary outcome in the patients with high TC levels (net reclassification improvement: 26.8%, P = 0.015; integrated discrimination index: 1.6%, P = 0.028) but not in those with normal TC levels. CONCLUSIONS: Elevated netrin-1 is associated with improved prognosis at 3 months after ischemic stroke in the patients with high TC levels but not in those with normal TC levels. Further prospective studies from other populations and randomized clinical trials are needed to verify our findings and clarify the potential mechanisms.

Increased Serum Complement C3 Levels Are Associated With Adverse Clinical Outcomes After Ischemic Stroke.

BACKGROUND AND PURPOSE: Complement C3 has been implicated in inflammation and ischemia/reperfusion injury, but its impact on the prognosis of ischemic stroke remains unclear. Aim of this study was to prospectively investigate the association between serum complement C3 and adverse clinical outcomes after ischemic stroke. METHODS: We measured serum complement C3 levels for 3474 patients with ischemic stroke in 26 participating hospitals and collected data of clinical outcomes at 3 months after ischemic stroke. The primary outcome was composite outcome of death and major disability (modified Rankin Scale score ≥3) at 3 months after stroke onset and secondary outcomes included major disability, death, and vascular events. RESULTS: During 3 months of follow-up, 866 participants (25.4%) developed primary outcome. After multivariate adjustment, elevated serum complement C3 levels were associated with increased risk of primary outcome (odds ratio, 1.30 [95% CI, 1.02-1.65]; Ptrend=0.038) when 2 extreme tertiles were compared. Each SD increase of log-transformed complement C3 was associated with 13% (95% CI, 2%-25%) increased risk of primary outcome. Multivariable-adjusted spline regression model showed a linear relationship between serum complement C3 and the risk of primary outcome (Plinearity=0.022). Addition of serum complement C3 to conventional risk factors significantly improved the risk prediction of primary outcome (net reclassification index: 8.87%, P=0.028; integrated discrimination index: 0.19%, P=0.029). CONCLUSIONS: High serum complement C3 levels at baseline were associated with increased risks of adverse clinical outcomes at 3 months after ischemic stroke, suggesting that serum complement C3 may be a valuable prognostic biomarker for ischemic stroke.