Clinical and Dynamic Evaluation of the C-Reactive Protein–to–Albumin Ratio in Acute Ischemic Stroke: Interaction with Neurological Severity and Limited Prognostic Utility

Clinical and Dynamic Evaluation of the C-Reactive Protein–to–Albumin Ratio in Acute Ischemic Stroke: Interaction with Neurological Severity and Limited Prognostic Utility | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Clinical and Dynamic Evaluation of the C-Reactive Protein–to–Albumin Ratio in Acute Ischemic Stroke: Interaction with Neurological Severity and Limited Prognostic Utility Hasan Burak Toprak, Mete Erdemir, Elif Bilgiç, Cevdet Furkan Köşker, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9063890/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Background The C-reactive protein–to–albumin ratio has been proposed as a composite inflammatory biomarker associated with adverse outcomes in critically ill patients. However, whether the C-reactive protein–to–albumin ratio provides independent or incremental prognostic information beyond established clinical severity markers in acute ischemic stroke remains uncertain. Methods This retrospective observational cohort study included 146 consecutive adult patients admitted with acute ischemic stroke and managed in an intensive care setting. The C-reactive protein–to–albumin ratio was calculated at emergency department admission and during intensive care follow-up. Multivariable logistic regression models were constructed to evaluate associations between the C-reactive protein–to–albumin ratio, sepsis at admission, and ninety-day mortality, adjusting for age, National Institutes of Health Stroke Scale score, sepsis status, and admission glucose. Incremental prognostic value was assessed using calibration analysis, net reclassification improvement, integrated discrimination improvement, interaction modelling, National Institutes of Health Stroke Scale–stratified analyses, and penalized regression. Results Sepsis was present in 25.3% of patients, and ninety-day mortality occurred in 21.9%. Admission C-reactive protein–to–albumin ratio was not independently associated with sepsis after adjustment (odds ratio 1.023, 95% confidence interval 0.994–1.053; p = 0.117), whereas age and National Institutes of Health Stroke Scale score remained significant predictors. Similarly, the C-reactive protein–to–albumin ratio measured during intensive care was associated with mortality in univariate analysis but lost significance in multivariable models (odds ratio 1.026, 95% confidence interval 0.982–1.070; p = 0.246). Sepsis status and age consistently emerged as the strongest independent predictors of mortality. No significant interaction was observed between the C-reactive protein–to–albumin ratio and National Institutes of Health Stroke Scale score (p = 0.802), and the C-reactive protein–to–albumin ratio was not associated with mortality within National Institutes of Health Stroke Scale–stratified subgroups. Penalized regression did not retain the C-reactive protein–to–albumin ratio as a stable predictor. Addition of the C-reactive protein–to–albumin ratio did not improve model calibration or risk reclassification (net reclassification improvement − 0.057; integrated discrimination improvement 0.011). Conclusions In acute ischemic stroke, the C-reactive protein–to–albumin ratio reflects systemic inflammatory burden but does not provide independent or incremental prognostic value beyond established clinical severity markers. Dynamic assessment of the C-reactive protein–to–albumin ratio does not enhance mortality prediction. The C-reactive protein–to–albumin ratio may therefore be best interpreted as a complementary, rule-in biomarker rather than a primary risk stratification tool. Acute ischemic stroke C-reactive protein–to–albumin ratio Systemic inflammation Neurological severity Intensive care Sepsis Prognostic biomarkers Figures Figure 1 Figure 2 Figure 3 INTRODUCTION Systemic inflammation is a central determinant of short- and long-term outcomes across a wide spectrum of acute and critical illnesses. Among routinely available biomarkers, C-reactive protein reflects the intensity of the acute-phase inflammatory response, whereas serum albumin integrates nutritional status, hepatic synthetic function, and chronic inflammatory burden. The combination of these two biologically distinct parameters into the C-reactive protein–to–albumin ratio has therefore been proposed as a composite marker capturing both inflammatory activity and host vulnerability [ 1 ]. The prognostic relevance of the C-reactive protein–to–albumin ratio was initially established in oncological settings. In patients undergoing surgery for colorectal cancer, Ishizuka et al. demonstrated that elevated preoperative C-reactive protein–to–albumin ratio was independently associated with worse postoperative survival and provided superior prognostic information compared with C-reactive protein or albumin alone [ 1 ]. This conceptual framework positioned the C-reactive protein–to–albumin ratio as a clinically meaningful composite index rather than a purely statistical construct and prompted its evaluation in non-oncological and acute-care populations. Subsequent studies extended C-reactive protein–to–albumin ratio research into critical care. Park et al. reported that the C-reactive protein–to–albumin ratio measured at intensive care unit admission was associated with short-term mortality in heterogeneous intensive care unit cohorts [ 2 ], while Oh et al. demonstrated similar associations with thirty-day mortality in critically ill patients [ 3 ]. Further analyses in postoperative intensive care unit populations suggested that the C-reactive protein–to–albumin ratio may retain prognostic relevance beyond the immediate inflammatory phase [ 4 ]. Collectively, these studies established the C-reactive protein–to–albumin ratio as a marker closely linked to illness severity in critically ill populations. Neurological emergencies represent a distinct clinical context in which systemic inflammation interacts with disease-specific severity and metabolic stress. Acute ischemic stroke is characterized by a rapid inflammatory cascade initiated by cerebral ischemia, blood–brain barrier disruption, and secondary systemic responses. Early stroke-specific studies suggested that the C-reactive protein–to–albumin ratio may be associated with adverse outcomes. Kocatürk and Kocatürk reported an association between elevated C-reactive protein–to–albumin ratio and ninety-day mortality in patients with acute ischemic stroke [ 5 ], while subsequent studies linked the C-reactive protein–to–albumin ratio to stroke severity and clinical prognosis [ 15 , 18 ]. Evidence from neurocritical care populations further supported the association between the C-reactive protein–to–albumin ratio and outcomes. In intensive care unit cohorts, Fındıklı et al. demonstrated that higher C-reactive protein–to–albumin ratio values were associated with in-hospital mortality [ 6 ]. Similar findings were reported in traumatic brain injury and spontaneous intracerebral hemorrhage, where elevated C-reactive protein–to–albumin ratio was associated with unfavourable outcomes and increased mortality risk [ 7 , 8 , 19 ]. These observations suggest that the C-reactive protein–to–albumin ratio reflects systemic inflammatory stress across diverse forms of acute brain injury. Beyond neurological disease, the C-reactive protein–to–albumin ratio has been widely studied in systemic inflammatory conditions. Associations between elevated C-reactive protein–to–albumin ratio and mortality have been reported in peritoneal dialysis [ 9 ], sepsis [ 10 , 20 ], severe burns [ 11 ], acute pancreatitis [ 16 ], coronavirus disease 2019 [ 12 , 13 , 17 ], acute kidney injury [ 21 , 22 ], and large mixed intensive care unit populations [ 24 – 26 ]. Meta-analyses have generally confirmed an overall association between higher C-reactive protein–to–albumin ratio and adverse outcomes, while also highlighting substantial heterogeneity across populations and study designs [ 13 , 20 ]. Despite this extensive literature, several important uncertainties remain. First, many studies evaluated the C-reactive protein–to–albumin ratio in isolation or with limited adjustment for established clinical severity measures, raising concerns about residual confounding. Second, the incremental prognostic value of the C-reactive protein–to–albumin ratio beyond established clinical predictors, particularly neurological severity scores such as the National Institutes of Health Stroke Scale, which remains the dominant prognostic driver in acute ischemic stroke, has rarely been systematically assessed. Third, although dynamic changes in the C-reactive protein–to–albumin ratio over time have been proposed as a potential means of improving prognostic accuracy, empirical evidence supporting this assumption remains limited and inconsistent. Finally, few studies have evaluated whether the C-reactive protein–to–albumin ratio meaningfully improves clinical decision-making using modern decision-analytic approaches. Therefore, this study aimed to rigorously evaluate whether the C-reactive protein–to–albumin ratio provides independent or incremental prognostic value beyond neurological severity and sepsis in critically ill patients with acute ischemic stroke. Specifically, we examined (i) whether the prognostic association of the C-reactive protein–to–albumin ratio is modified by neurological severity as measured by the National Institutes of Health Stroke Scale, (ii) whether the C-reactive protein–to–albumin ratio is associated with mortality within clinically homogeneous National Institutes of Health Stroke Scale–defined subgroups, and (iii) whether the C-reactive protein–to–albumin ratio improves model performance, calibration, or clinical decision-making beyond National Institutes of Health Stroke Scale–based clinical models. METHODS Study Design and Reporting Framework This study was designed as a retrospective observational cohort analysis conducted in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology guidelines. Real-world clinical and laboratory data from adult patients admitted with acute neurological presentations and managed in an intensive care setting were analyzed. All analyses were prespecified prior to model construction to minimize data-driven inference. Study Population and Setting Consecutive adult patients admitted between January 2020 and December 2024 were screened for eligibility. Patients were included if they met the following criteria: (i) age eighteen years or older, (ii) admission through the emergency department with an acute neurological presentation, and (iii) availability of baseline laboratory measurements including C-reactive protein and serum albumin obtained at admission. Patients were excluded if outcome data were missing, if key laboratory variables required for calculation of the C-reactive protein–to–albumin ratio were unavailable, or if clinical records were incomplete. A Strengthening the Reporting of Observational Studies in Epidemiology–compliant flow diagram describing patient selection is presented in Fig. 1 . Clinical Variables and Definitions Demographic variables included age in years and sex. Clinical variables recorded at emergency department admission included the National Institutes of Health Stroke Scale score, sepsis status, and comorbid conditions including hypertension and diabetes mellitus. Sepsis was defined based on a documented clinical diagnosis at admission and coded as a binary variable indicating presence or absence. Demographic characteristics, laboratory findings, and clinical variables at admission were retrieved from the medical records. Baseline stroke severity was assessed at admission using the National Institutes of Health Stroke Scale (NIHSS), a previously published and validated instrument widely used to quantify neurological deficit severity in acute stroke [ 27 ]. Laboratory variables obtained at emergency department admission included C-reactive protein measured in milligrams per liter, serum albumin measured in grams per deciliter, and blood glucose level measured in milligrams per deciliter. The C-reactive protein–to–albumin ratio at admission was calculated by dividing the C-reactive protein value by the serum albumin concentration. Additional laboratory measurements obtained during intensive care follow-up were used to calculate the C-reactive protein–to–albumin ratio during intensive care unit stay. Changes in the C-reactive protein–to–albumin ratio and blood glucose levels between intensive care follow-up and emergency department admission were calculated as the difference between follow-up and baseline values. Outcome Measures The primary outcome was ninety-day all-cause mortality, determined from hospital records and follow-up documentation and coded as a binary variable. A secondary outcome was the presence of sepsis at admission, evaluated to explore its association with inflammatory burden and neurological severity. Descriptive and Baseline Analyses Baseline demographic, clinical, and laboratory characteristics were summarized according to ninety-day mortality status and are presented in Table 1 . Continuous variables were reported as mean plus or minus standard deviation or median with interquartile range, depending on their distribution. Categorical variables were expressed as counts and percentages. Table 1 Baseline characteristics according to 90-day mortality Variable Alive (n = 114) Dead (n = 32) Age (years) 68.1 ± 13.8 76.4 ± 11.0 Male sex, n (%) 55 (48.2) 13 (40.6) NIHSS score at admission (ED) 7.0 [4.0–12.0] 14.0 [8.0–22.0] Sepsis, n (%) 10 (8.8) 27 (84.4) Hypertension, n (%) 87 (77.7) 21 (65.6) Diabetes mellitus, n (%) 32 (28.6) 8 (25.0) CRP at admission (mg/L) 5.1 [2.0–16.0] 6.0 [2.5–38.0] Serum albumin (g/dL) 3.98 ± 0.47 3.55 ± 0.64 Glucose at admission (mg/dL) 124.5 [92.0–187.0] 157.0 [118.0–213.0] C-reactive protein–to–albumin ratio at admission 1.18 [0.64–2.15] 2.00 [0.90–7.40] CAR during ICU stay (CAR_ICU) 1.63 [0.81–4.68] 3.15 [0.90–11.75] ΔCAR (ICU − ED) 0.15 [0.00–0.54] 0.00 [− 0.05–0.51] ΔGlucose (ICU − ED), mg/dL −38.3 [− 75.0–2.8] −35.0 [− 70.0–21.5] This table summarizes baseline demographic characteristics, clinical variables, and laboratory parameters of patients with acute ischemic stroke according to ninety-day all-cause mortality status. Age is presented in years, neurological severity is quantified using the National Institutes of Health Stroke Scale score at emergency department admission, and comorbid conditions include hypertension and diabetes mellitus. Laboratory variables include C-reactive protein, serum albumin, blood glucose level, and the C-reactive protein–to–albumin ratio measured at emergency department admission and during intensive care unit follow-up. Dynamic changes represent the numerical difference between values obtained during intensive care unit follow-up and those measured at emergency department admission. Continuous variables are expressed as mean ± standard deviation or median with interquartile range, depending on data distribution, while categorical variables are expressed as counts and percentages. Multivariable Modelling Strategy Sepsis Model A multivariable logistic regression model was constructed to identify factors independently associated with the presence of sepsis at emergency department admission, as presented in Table 2 . The model included the C-reactive protein–to–albumin ratio at admission, age, National Institutes of Health Stroke Scale score at admission, and blood glucose level at admission. All variables were selected a priori based on established clinical relevance and prior literature. Table 2 Multivariable logistic regression model for sepsis Variable OR 95% CI p-value C-reactive protein–to–albumin ratio at admission 1.023 0.994–1.053 0.117 Age (per year) 1.057 1.014–1.101 0.009 NIHSS score at admission (per point) 1.100 1.037–1.166 0.002 Glucose at admission (per mg/dL) 1.007 1.000–1.015 0.055 Multivariable logistic regression analysis evaluating demographic, neurological, and laboratory factors independently associated with the presence of sepsis at emergency department admission. The model includes age, neurological severity assessed by the National Institutes of Health Stroke Scale score, admission blood glucose level, and the C-reactive protein–to–albumin ratio measured at admission. Effect estimates are reported as odds ratios with corresponding ninety-five percent confidence intervals, allowing assessment of the relative contribution of systemic inflammatory burden and neurological severity to early infectious complications. Mortality Models A clinical multivariable logistic regression model excluding the C-reactive protein–to–albumin ratio was first developed to identify established predictors of ninety-day all-cause mortality, as presented in Table 3 . This reference model included sepsis status at admission, age, National Institutes of Health Stroke Scale score at admission, and blood glucose level at admission. Table 3 Clinical Multivariable Logistic Regression Model for Ninety-Day Mortality Without the C-Reactive Protein–to–Albumin Ratio Variable OR 95% CI p-value NIHSS score at admission (ED) (per point) 1.087 0.987–1.197 0.089 Age (years) (per year) 1.071 1.007–1.140 0.030 Sepsis (yes vs no) 52.01 12.71–212.78 < 0.001 Glucose at admission (mg/dL) (per mg/dL) 1.010 1.001–1.019 0.037 This table presents the reference multivariable clinical model for predicting ninety-day all-cause mortality in patients with acute ischemic stroke. The model includes established clinical predictors, namely sepsis status at admission, age, neurological severity measured by the National Institutes of Health Stroke Scale score at emergency department admission, and admission blood glucose level. Odds ratios with ninety-five percent confidence intervals are reported to quantify the independent association of each variable with mortality. This model serves as the baseline framework against which the incremental prognostic value of inflammatory biomarkers is evaluated. To evaluate the incremental prognostic value of inflammatory burden, a second multivariable model was constructed by adding the C-reactive protein–to–albumin ratio measured during intensive care follow-up to the clinical reference model, as presented in Table 4 . Effect estimates were reported as odds ratios with corresponding ninety-five percent confidence intervals. Table 4 Multivariable Logistic Regression Model for Ninety-Day Mortality Including the C-Reactive Protein–to–Albumin Ratio Variable OR 95% CI p-value C-reactive protein–to–albumin ratio during intensive care unit follow-up 1.026 0.982–1.070 0.246 NIHSS score at admission (ED) (per point) 1.081 0.991–1.181 0.080 Age (years) (per year) 1.069 1.007–1.140 0.032 Sepsis (yes vs no) 52.01 12.71–212.78 < 0.001 Glucose at admission (mg/dL) (per mg/dL) 1.008 0.999–1.017 0.069 Multivariable logistic regression model assessing whether the C-reactive protein–to–albumin ratio measured during intensive care unit follow-up provides additional prognostic information beyond established clinical predictors. The model adjusts for age, sepsis status, neurological severity assessed by the National Institutes of Health Stroke Scale score, and admission blood glucose level. Effect estimates are expressed as odds ratios with ninety-five percent confidence intervals. Comparison with the clinical reference model allows evaluation of the incremental contribution of systemic inflammatory burden to mortality prediction. Univariate Analyses Univariate logistic regression analyses were performed to evaluate crude associations between individual clinical and laboratory variables and ninety-day mortality, as presented in Table 5 . Variables examined included the C-reactive protein–to–albumin ratio during intensive care stay, sepsis status, National Institutes of Health Stroke Scale score at admission, age, and blood glucose level at admission. Table 5 Univariate Associations Between Clinical and Laboratory Variables and Ninety-Day All-Cause Mortality Variable OR 95% CI p-value C-reactive protein–to–albumin ratio during intensive care unit follow-up 1.027 1.001–1.052 0.038 Sepsis (yes vs no) 65.0 19.0–224.0 < 0.001 NIHSS score at admission (ED) (per point) 1.095 1.039–1.153 0.001 Age (years) (per year) 1.056 1.019–1.091 0.003 Glucose at admission (mg/dL) (per mg/dL) 1.005 0.999–1.011 0.091 Univariate logistic regression analyses examining crude associations between individual demographic, clinical, and laboratory variables and ninety-day all-cause mortality. Variables evaluated include age, sepsis status, neurological severity measured by the National Institutes of Health Stroke Scale score, admission blood glucose level, and the C-reactive protein–to–albumin ratio measured during intensive care unit follow-up. Odds ratios with ninety-five percent confidence intervals are presented to illustrate unadjusted effect sizes prior to multivariable modelling. Interaction and Effect Modification Effect modification between systemic inflammatory burden and neurological severity was evaluated by including an interaction term between the C-reactive protein–to–albumin ratio at admission and the National Institutes of Health Stroke Scale score at admission in the multivariable mortality model. Statistical significance of interaction was assessed using the Wald test. Results are presented in Table 6 , with adjusted marginal effects illustrated in Fig. 2 . Table 6 Interaction Between the C-Reactive Protein–to–Albumin Ratio and Neurological Severity in Relation to Ninety-Day Mortality Variable OR 95% CI p-value C-reactive protein–to–albumin ratio at admission 1.040 0.982–1.101 0.178 NIHSS score at admission (ED) 1.087 0.987–1.197 0.091 CAR × NIHSS interaction at ED admission 0.999 0.993–1.005 0.802 Age (years) 1.071 1.007–1.140 0.030 Sepsis (yes vs no) 52.01 12.71–212.78 < 0.001 Glucose at admission (mg/dL) 1.010 1.001–1.019 0.039 Multivariable logistic regression model including an interaction term between the C-reactive protein–to–albumin ratio measured at admission and neurological severity assessed by the National Institutes of Health Stroke Scale score. This analysis evaluates whether the prognostic association of systemic inflammatory burden varies across different levels of neurological severity. Effect estimates are reported as odds ratios with ninety-five percent confidence intervals. A non-significant interaction term indicates absence of meaningful effect modification. Stratified Analyses by Neurological Severity To further explore potential heterogeneity of effects, patients were stratified a priori into clinically relevant neurological severity categories based on admission National Institutes of Health Stroke Scale scores of zero to four, five to fourteen, and fifteen or higher. Within each stratum, the association between the C-reactive protein–to–albumin ratio and ninety-day mortality was evaluated using logistic regression models. Results are presented in Table 7 . Table 7 National Institutes of Health Stroke Scale–Stratified Associations Between the C-Reactive Protein–to–Albumin Ratio and Ninety-Day Mortality Neurological severity category based on admission NIHSS score) group OR (CAR) 95% CI Lower 95% CI Upper p-value 0–4 (Mild) 1.011 0.822 1.243 0.999 5–14 (Moderate) 1.076 0.973 1.190 0.151 ≥ 15 (Severe) 1.114 0.836 1.483 0.467 Stratified logistic regression analyses assessing the association between the C-reactive protein–to–albumin ratio and ninety-day all-cause mortality within clinically predefined neurological severity categories based on admission National Institutes of Health Stroke Scale scores. Separate models are presented for mild, moderate, and severe neurological impairment, allowing evaluation of heterogeneity of effects across severity strata. Penalized Regression Analysis To assess predictor stability and reduce the risk of overfitting, penalized logistic regression using the least absolute shrinkage and selection operator was performed. The penalty parameter was selected through cross-validation. Variables with non-zero coefficients were retained, allowing evaluation of the robustness of the C-reactive protein–to–albumin ratio relative to established clinical predictors, as presented in Table S1. Calibration and Risk Reclassification Model calibration was assessed using bootstrap-corrected calibration plots comparing predicted and observed mortality risk for the clinical reference model and the model incorporating the C-reactive protein–to–albumin ratio, as shown in Fig. 3 . Incremental prognostic value was further evaluated using net reclassification improvement and integrated discrimination improvement metrics, as presented in Table 8 . Table 8 Risk Reclassification and Discrimination Analyses After Addition of the C-Reactive Protein–to–Albumin Ratio Metric Estimate 95% CI p-value NRI −0.057 −0.205 to 0.086 0.918 IDI 0.011 −0.016 to 0.035 0.942 Net reclassification improvement and integrated discrimination improvement analyses evaluating whether inclusion of the C-reactive protein–to–albumin ratio improves patient risk classification and discrimination for ninety-day all-cause mortality beyond the clinical reference model. Estimates are presented with ninety-five percent confidence intervals. Non-significant values indicate lack of incremental prognostic utility. Statistical Analysis All statistical analyses were performed using Python-based statistical libraries. Logistic regression models were fitted using maximum likelihood estimation. Effect estimates were reported as odds ratios with corresponding ninety-five percent confidence intervals. Two-sided p-values less than 0.05 were considered statistically significant. Missing data were evaluated prior to analysis. Variables with substantial missingness were excluded to preserve internal validity and avoid data-driven imputation bias. This analytical framework was specifically designed to move beyond significance testing by integrating interaction modelling, stratified analyses, penalized regression, and calibration- and reclassification-based performance metrics to rigorously assess incremental prognostic and clinical utility. RESULTS Study Population and Baseline Characteristics A total of 180 patients were initially assessed for eligibility. After exclusion of 34 patients due to missing key laboratory data or duplicate records, 146 patients were included in the final analysis, as illustrated in Fig. 1 . Baseline demographic, clinical, and laboratory characteristics of the study population are summarized in Table 1 . The mean age of the cohort was 69.9 plus or minus 13.7 years, and 68 patients (46.6 percent) were male. At emergency department admission, the median National Institutes of Health Stroke Scale score was 9.0, with an interquartile range of 4.0 to 15.0, reflecting a wide spectrum of neurological severity. Sepsis was present in 37 patients (25.3 percent). Hypertension and diabetes mellitus were observed in 108 patients (74.0 percent) and 40 patients (27.4 percent), respectively, while atrial fibrillation was documented in 34 patients (23.3 percent). Regarding laboratory parameters, the median C-reactive protein level at admission was 5.3 milligrams per liter, with an interquartile range of 2.0 to 16.9 milligrams per liter, and the mean serum albumin concentration was 3.89 plus or minus 0.52 grams per deciliter. The median admission glucose level was 134.0 milligrams per deciliter, with an interquartile range of 98.0 to 195.0 milligrams per deciliter. The median C-reactive protein–to–albumin ratio at admission was 1.40, with an interquartile range of 0.64 to 2.80, which increased to 1.90, with an interquartile range of 0.85 to 6.10, during intensive care follow-up. The median change in the C-reactive protein–to–albumin ratio between intensive care follow-up and emergency department admission was 0.10, with an interquartile range of 0.00 to 0.52. The median change in blood glucose level between intensive care follow-up and emergency department admission was minus 37.0 milligrams per deciliter, with an interquartile range of minus 73.0 to 6.0 milligrams per deciliter. Ninety-day mortality occurred in 32 patients (21.9 percent), as shown in Table 1 . Factors Associated with Sepsis at Admission Factors associated with sepsis at admission were evaluated using a multivariable logistic regression model incorporating demographic, clinical, and laboratory variables, as presented in Table 2 . In this model, age, expressed per year, with an odds ratio of 1.057 and a ninety-five percent confidence interval of 1.014 to 1.101, and the National Institutes of Health Stroke Scale score at admission, expressed per point, with an odds ratio of 1.100 and a ninety-five percent confidence interval of 1.037 to 1.166, were independently associated with the presence of sepsis. Admission C-reactive protein–to–albumin ratio showed a positive but non-significant association with sepsis, with an odds ratio of 1.023 and a ninety-five percent confidence interval of 0.994 to 1.053. Blood glucose level demonstrated a borderline association, whereas hypertension and diabetes mellitus were not independently associated with sepsis. Clinical Model for Ninety-Day Mortality Without the C-Reactive Protein–to–Albumin Ratio In the multivariable clinical model excluding the C-reactive protein–to–albumin ratio, sepsis emerged as the strongest independent predictor of ninety-day mortality, with an odds ratio of 52.01 and a ninety-five percent confidence interval of 12.71 to 212.78. Age was also independently associated with mortality, with an odds ratio per year of 1.071 and a ninety-five percent confidence interval of 1.007 to 1.140, as was admission glucose level, with an odds ratio per milligram per deciliter of 1.010 and a ninety-five percent confidence interval of 1.001 to 1.019. Admission National Institutes of Health Stroke Scale score demonstrated a borderline association with mortality. This clinical model served as the reference framework for subsequent analyses evaluating the incremental prognostic value of the C-reactive protein–to–albumin ratio, as presented in Table 3 . Incremental Prognostic Value of the C-Reactive Protein–to–Albumin Ratio for Mortality When the C-reactive protein–to–albumin ratio measured during intensive care follow-up was added to the clinical model, sepsis and age remained independently associated with ninety-day mortality, whereas the C-reactive protein–to–albumin ratio did not demonstrate an independent association. Admission National Institutes of Health Stroke Scale score and glucose level retained only borderline associations after adjustment. Importantly, inclusion of the C-reactive protein–to–albumin ratio did not materially alter the effect estimates of established clinical predictors, indicating limited incremental prognostic value beyond the clinical model, as shown in Table 4 . Univariate Predictors of Ninety-Day Mortality In univariate logistic regression analyses, the C-reactive protein–to–albumin ratio measured during intensive care follow-up was associated with ninety-day mortality. Sepsis, National Institutes of Health Stroke Scale score, and age also demonstrated strong unadjusted associations with mortality, whereas admission glucose level did not reach statistical significance. These findings highlight that the apparent prognostic signal of the C-reactive protein–to–albumin ratio is attenuated after adjustment for clinical severity and age, as presented in Table 5 . Interaction Between the C-Reactive Protein–to–Albumin Ratio and Neurological Severity Effect modification was formally evaluated by including an interaction term between the C-reactive protein–to–albumin ratio at admission and the National Institutes of Health Stroke Scale score at admission in the multivariable mortality model. The interaction term was not statistically significant, indicating that the prognostic effect of the C-reactive protein–to–albumin ratio did not meaningfully vary across levels of neurological severity. Marginal effect analysis further demonstrated that the adjusted odds ratio of the C-reactive protein–to–albumin ratio for ninety-day mortality remained close to unity across the entire National Institutes of Health Stroke Scale spectrum, with confidence intervals consistently crossing the null value, as illustrated in Fig. 2 and Table 6 . National Institutes of Health Stroke Scale–Stratified Associations In analyses stratified by neurological severity, the association between the C-reactive protein–to–albumin ratio and ninety-day mortality was evaluated separately within clinically predefined National Institutes of Health Stroke Scale categories. The C-reactive protein–to–albumin ratio was not significantly associated with mortality in any National Institutes of Health Stroke Scale category. Odds ratios for the C-reactive protein–to–albumin ratio remained close to unity across mild, moderate, and severe neurological impairment, with wide confidence intervals consistently crossing the null value, as presented in Table 7 . These findings further support the absence of clinically meaningful effect modification by baseline neurological severity. Penalized Regression Analysis In penalized logistic regression using the least absolute shrinkage and selection operator, National Institutes of Health Stroke Scale score, age, sepsis status, and admission glucose were retained as stable predictors of ninety-day mortality, whereas the C-reactive protein–to–albumin ratio was not selected. Serum albumin, hypertension, and diabetes mellitus were eliminated during penalization, indicating limited robustness of these variables when model complexity was constrained, as shown in Table S1. Calibration, Risk Reclassification, and Clinical Utility Calibration plots demonstrated good agreement between predicted and observed mortality risk for both the clinical model and the clinical model augmented with the C-reactive protein–to–albumin ratio, with no meaningful improvement after inclusion of the C-reactive protein–to–albumin ratio. Risk reclassification analysis further showed no significant improvement in patient risk stratification following the addition of the C-reactive protein–to–albumin ratio. Neither the net reclassification improvement nor the integrated discrimination improvement reached statistical significance, indicating that the C-reactive protein–to–albumin ratio did not enhance discrimination or clinical risk assignment beyond established predictors, as presented in Fig. 3 and Table 8 . DISCUSSION In this single-centre cohort of critically ill patients with acute ischemic stroke, we found that the C-reactive protein–to–albumin ratio does not provide independent or incremental prognostic value beyond neurological severity and sepsis, despite its apparent univariate associations with adverse outcomes. Three principal findings emerge. First, although the C-reactive protein–to–albumin ratio was associated with adverse outcomes in univariate analyses, it did not retain independent prognostic significance after adjustment for clinical severity and age. Second, dynamic assessment of the C-reactive protein–to–albumin ratio during intensive care follow-up did not confer incremental prognostic value. Third, established clinical markers, particularly sepsis status and neurological severity as measured by the National Institutes of Health Stroke Scale, consistently dominated outcome prediction across all analytical frameworks. These findings align with emerging evidence suggesting that the apparent prognostic signal of the C-reactive protein–to–albumin ratio may largely reflect underlying disease severity rather than independent biological risk. Recent pooled analyses have shown that while elevated C-reactive protein–to–albumin ratio is associated with adverse outcomes at the population level, substantial heterogeneity exists across stroke subtypes, severity strata, and analytical models, particularly after adjustment for neurological severity and systemic complications [ 28 ]. The biological rationale for the C-reactive protein–to–albumin ratio is well established. C-reactive protein reflects acute-phase inflammatory activation, whereas serum albumin integrates nutritional reserve, hepatic function, and chronic inflammatory burden. Prior stroke-specific studies have reported associations between elevated C-reactive protein–to–albumin ratio and mortality, stroke severity, hemorrhagic transformation, and functional outcomes [ 5 , 15 , 18 , 29 – 31 ]. For example, Xu et al. demonstrated that higher admission C-reactive protein–to–albumin ratio was associated with hemorrhagic transformation and poor functional outcome following thrombolysis [ 29 ], while cohort studies from different geographic regions reported similar associations with adverse outcomes [ 30 , 31 ]. However, many of these studies relied on limited adjustment strategies or focused on early or univariate associations. Meta-analytic data indicate that the strength of the association between C-reactive protein–to–albumin ratio and stroke outcomes diminishes substantially when models incorporate robust clinical severity measures, particularly the National Institutes of Health Stroke Scale score [ 28 ]. Our findings extend this literature by demonstrating that, even in a critically ill stroke population, the C-reactive protein–to–albumin ratio does not provide independent prognostic information once neurological severity and sepsis are adequately accounted for. A plausible explanation for these discrepancies is residual confounding and under adjustment for neurological severity and systemic complications in prior studies, which may have led to overestimation of the independent prognostic contribution of inflammatory biomarkers. Neurological severity emerged as a central determinant of both sepsis and mortality in our cohort. The National Institutes of Health Stroke Scale score was independently associated with sepsis at admission and demonstrated consistent associations with mortality across all models. This observation reinforces the concept that neurological injury burden is a primary driver of downstream systemic inflammation and adverse outcomes after stroke. Prior studies reporting strong correlations between the C-reactive protein–to–albumin ratio and stroke severity further support the interpretation that this biomarker may function predominantly as a surrogate marker of neurological damage rather than an independent prognostic factor [ 15 , 18 , 30 ]. Sepsis status was the strongest predictor of mortality in all multivariable models, with effect sizes far exceeding those of laboratory biomarkers. This finding is consistent with large intensive care unit cohorts demonstrating that infection-driven systemic inflammation is a dominant contributor to short-term mortality risk [ 2 , 6 , 24 – 26 ]. Notably, the inclusion of the C-reactive protein–to–albumin ratio did not materially alter the effect estimates of sepsis or age, underscoring its limited incremental contribution once major clinical determinants are considered. A key objective of the present study was to assess whether the prognostic relevance of the C-reactive protein–to–albumin ratio varies across levels of neurological severity. Contrary to some earlier hypotheses, we observed no significant interaction between the C-reactive protein–to–albumin ratio and the National Institutes of Health Stroke Scale score. Stratified analyses across mild, moderate, and severe neurological impairment further demonstrated that the C-reactive protein–to–albumin ratio was not associated with mortality within any severity category. These findings contrast with reports suggesting differential prognostic effects of inflammatory markers across stroke severity strata [ 29 , 32 ], but are consistent with more recent large-scale observational analyses showing that neurological severity exerts a uniform and dominant influence across inflammatory states [ 28 , 33 ]. Collectively, these results indicate that effect modification by baseline neurological severity is limited for the C-reactive protein–to–albumin ratio. Beyond statistical association, clinical adoption of biomarkers requires demonstration of incremental prognostic utility. In the present study, the addition of the C-reactive protein–to–albumin ratio did not improve model calibration, discrimination, or risk reclassification, as reflected by non-significant net reclassification improvement and integrated discrimination improvement estimates. Penalized regression further confirmed the lack of robustness of the C-reactive protein–to–albumin ratio, as it was consistently excluded when model complexity was constrained. These findings are concordant with recent studies employing modern modelling techniques, including penalized regression and nomogram-based approaches, which have shown that although the C-reactive protein–to–albumin ratio may enter multivariable models, its contribution is often unstable and overshadowed by established clinical predictors [ 22 , 33 ]. This may explain why, despite extensive observational evidence, the C-reactive protein–to–albumin ratio has not been incorporated into major stroke or critical care guidelines. Importantly, the absence of independent prognostic value does not negate the clinical relevance of the C-reactive protein–to–albumin ratio. Several studies have demonstrated that extremely elevated C-reactive protein–to–albumin ratio values are associated with high specificity for adverse outcomes, particularly in selected subgroups such as very elderly stroke patients or those with profound systemic inflammation [ 34 , 35 , 36 ]. In this context, the C-reactive protein–to–albumin ratio may function as a rule-in biomarker identifying a subset of patients with heightened inflammatory vulnerability, while offering limited utility for broad risk stratification. From a practical standpoint, the C-reactive protein–to–albumin ratio should be interpreted alongside, rather than in place of, established clinical severity measures. Its greatest value may lie in augmenting clinical judgment in selected high-risk scenarios rather than serving as a standalone prognostic tool. The strengths of this study include comprehensive adjustment for clinical severity, formal evaluation of interaction and stratified effects, the use of penalized regression to assess predictor robustness, and explicit analysis of incremental prognostic value using multiple complementary performance metrics. With 146 patients and 32 outcome events, the study was sufficiently powered to evaluate incremental prognostic effects while minimizing overfitting through penalized regression and internal validation strategies. Several limitations should be acknowledged. The retrospective single-centre design may limit external generalizability, residual confounding cannot be entirely excluded, and analyses relied on routinely collected laboratory data. Therefore, external validation in independent and ideally multicentre stroke cohorts is warranted. In conclusion, the C-reactive protein–to–albumin ratio reflects systemic inflammatory burden in acute ischemic stroke but does not provide independent or incremental prognostic information beyond established clinical severity markers. Dynamic changes in the C-reactive protein–to–albumin ratio do not enhance mortality prediction, and its prognostic effect is not modified by neurological severity. These findings reconcile heterogeneous results in the literature and support a complementary, context-specific role for the C-reactive protein–to–albumin ratio rather than its use as a primary risk stratification tool. Declarations Funding This research did not receive any specific grant from funding agencies in the public, commercial, or non-profit sectors. Conflicts of Interest The authors declare that they have no competing interests. Ethics Approval and Consent to Participate The study was conducted in accordance with the principles of the Declaration of Helsinki. Ethical approval was obtained from the Ethics Committee of Gulhane Training and Research Hospital in 2026. Due to the retrospective observational design of the study, the requirement for written informed consent was waived by the ethics committee. Consent for Publication Not applicable. Ethics Approval and Consent to Participate The study was conducted in accordance with the Declaration of Helsinki. Ethical approval was obtained from the institutional ethics committee. Due to the retrospective observational design of the study, the requirement for informed consent was waived by the ethics committee. Availability of Data and Materials The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request. Authors’ Contributions All authors contributed to the study conception and design. Data collection and analysis were performed by the authors. All authors contributed to data interpretation, manuscript drafting, and critical revision. All authors read and approved of the final manuscript. Acknowledgements The authors thank the clinical and intensive care staff involved in the management of the patients included in this study. References Ishizuka M, Nagata H, Takagi K, Iwasaki Y, Shibuya N, Kubota K. Clinical significance of the C-reactive protein to albumin ratio for survival after surgery for colorectal cancer. 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Which Parameter is the Most Effective Predictor of Poor Outcomes in Sepsis: C-reactive Protein, Albumin, or C-reactive Protein/Albumin Ratio? J Clin Pract Res. 2022;44(3):334. 10.14744/etd.2021.20737 . Ülker M, Domac SF, Demir M, Karacı R. The Relationship of CRP/Albumin Ratio with Etiology and Prognosis in Acute Ischemic Stroke. Bosphorus Med Journal/Boğaziçi Tıp Dergisi. 2022;9(4):209–15. 10.14744/bmj.2022.60352 . Mariadi IK, Somayana G, Shalim CP, Sindhughosa DA, Daniella D, Purwanta MLA. (2023). Prognostic value of C-reactive protein-to-albumin ratio in acute pancreatitis: a systematic review and meta-analysis. F1000Research , 12 , 748. 10.12688/f1000research.134938.2 Deniz, Ç. D., Baran, N., Ugur A. R., … Koç, M. (2022). Evaluation of the relationship between C-reactive protein/albumin ratio and hospitalization in novel coronavirus disease-19 (COVID-19). International Journal of Medical Biochemistry, 5(1), 8–14. doi:10.14744/ijmb.2021.57070. Afsin DE, Kerget B. Evaluation of the Relationship between CRP/Albumin Ratio and Pulmonary Function Parameters in Patients with Post-Acute COVID-19. Clin Lab. 2022;68(8). 10.7754/Clin.Lab.2021.211102 . Akpınar, C. K., Kocaturk, O., Aykac, O., Acar, B. A., Dogan, H., Onalan, A., … Ozdemir,A. O. (2023). Can C-reactive protein/albumin ratio be a prognostic factor in acute stroke patients undergoing mechanical thrombectomy? Clinical Neurology and Neurosurgery, 231, 107856. doi:10.1016/j.clineuro.2023.107856. Wang Y, Gong Y, Chen D, Xu F, Yang P. C-reactive protein/albumin ratio is associated with mortality in patients with moderate to severe traumatic brain injury. World Neurosurg. 2023;173:e234–40. 10.1016/j.wneu.2023.02.037 . Liu Y, Gao Y, Liang B, Liang Z. The prognostic value of C-reactive protein to albumin ratio in patients with sepsis: a systematic review and meta-analysis. Aging Male. 2023;26(1):2261540. 10.1080/13685538.2023.2261540 . Liu B, Lv D. Prognostic value of C-reactive protein to albumin ratio for mortality in acute kidney injury. BMC Nephrol. 2023;24(1):44, 1–7. 10.1186/s12882-023-03090-9 . Zhou X, Fu S, Wu Y, Guo Z, Dian W, Sun H, Liao Y. C-reactive protein-to-albumin ratio as a biomarker in patients with sepsis: a novel LASSO-COX based prognostic nomogram. Sci Rep. 2023;13(1):15309. 10.1038/s41598-023-42601-4 . Jeon, Y. H., Lee, S. W., Jeon, Y., Cho, J. H., Jung, J., Lee, J., … Lim, J. H. (2024).The impact of C-reactive protein-to-albumin ratio on mortality in patients with acute kidney injury requiring continuous renal replacement therapy: a multicenter retrospective study. Nephron, 148(6), 379–389. doi: 10.1159/000534970. Karabağ, Y., Çağdaş, M., Rencuzogullari, I., Karakoyun, S., Artaç, İ., İliş, D., …Halil Tanboğa, I. (2018). Relationship between C-reactive protein/albumin ratio and coronary artery disease severity in patients with stable angina pectoris. Journal of clinical laboratory analysis, 32(7), e22457. doi:10.1002/jcla.22457. Çakmak G, Tünay A. The Relationship Between CRP/Albumin Ratio and In-Hospital Mortality in Intensive Care Patients: A Retrospective Observational Study. Istanbul Med J. 2025;26(4):348–55. 10.4274/imj.galenos.2025.99217 . Goldstein LB, Samsa GP. Reliability of the National Institutes of Health Stroke Scale: extension to non-neurologists in the context of a clinical trial. Stroke. 1997;28(2):307–10. Chang J, Zhang X, Wang W, Liu L. C-reactive protein-to-albumin ratio as a predictor of 28-day mortality in critically ill pediatric patients: a retrospective cohort study. BMC Pediatr. 2025;25(1):864. 10.1186/s12887-025-06261-9 . Yang, J., Chen, Y., Wan, J., Li, F., Yang, X., Shen, B., … Zhang, Y. (2025). Prognostic value of the C-reactive protein to albumin ratio in patients with stroke: a meta-analysis.Scientific Reports, 15(1), 21150. doi:10.1038/s41598-025-07327-5. Xu, T., Xia, L., Wu, Y., Xu, Y., Xu, X., Zhang, W., … Han, Z. (2023). High ratio of C-reactive protein to albumin is associated with hemorrhagic transformation and poor functional outcomes in acute ischemic stroke patients after thrombolysis. Frontiers in Aging Neuroscience, 15, 1109144. doi:10.3389/fnagi.2023.1109144. Du, Y., Zhang, J., Li, N., Guo, J., Liu, X., Bian, L., … Liu, Y. (2022). Association between the C-reactive protein to albumin ratio and adverse clinical prognosis in patients with young stroke. Frontiers in Neurology, 13, 989769. doi:10.3389/fneur.2022.989769. Yu D, Guo G, Wan F, Hu B. The association between C-reactive protein to albumin ratio and adverse outcomes in acute ischemic stroke patients: a study in the Korean population. Heliyon. 2024;10(20). 10.1016/j.heliyon.2024.e39212 . Yuan, J., Cheng, Y., Han, X., Zhu, N., Ma, W., Li, J., … Liu, F. (2024). Association between C-reactive protein/albumin ratio and all-cause mortality in patients with stroke: Evidence from NHANES cohort study. Nutrition, Metabolism and Cardiovascular Diseases, 34(10), 2305–2314. doi:10.1016/j.numecd.2024.05.024. Dogan, H., Simsek, S., Bayram, A. H., Topal, A., Pamuk, M. B., Ozmuk, O., … Akpinar,C. K. (2025). Predictive Value of C-Reactive Protein/Albumin Ratio (CAR) for Malnutrition and Sarcopenia in Acute Ischemic Stroke Patients. Journal of Clinical Medicine, 14(19), 6804. doi:10.3390/jcm14196804. Soylu VG, Karahan E, YILMAZ A, TAŞKIN Ö, Demir U. Assessment of the relationship between C-Reactive Protein/Albumin ratio and 28-day mortality in critically very elderly patients (≥ 85 years) with acute ischemic stroke. Neurol Asia. 2022;27(3):575–81. 10.54029/2022kwi . Yang F, Sang W, Liu Y, Wang J. The C-reactive protein-to-albumin ratio as a diagnostic biomarker for rheumatoid arthritis: a cross-sectional NHANES analysis. Front Med. 2025;12:1624527. 10.3389/fmed.2025.1624527 . Additional Declarations No competing interests reported. Supplementary Files Supplementarytables.docx GraphicalAbstracthighresolution.png Cite Share Download PDF Status: Under Review Version 1 posted Reviewers invited by journal 07 Apr, 2026 Editor assigned by journal 06 Apr, 2026 Editor invited by journal 16 Mar, 2026 Submission checks completed at journal 14 Mar, 2026 First submitted to journal 14 Mar, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9063890","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":620840044,"identity":"3db297b5-ef09-4dca-9b72-6efd787f79af","order_by":0,"name":"Hasan Burak Toprak","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxElEQVRIiWNgGAWjYBACAwkozQ8iEwqI0sIMoSUbQFoMSNFicABMEaHFXLr/4OPCPXbGxudXJ354YMAgzy92AL8WyzmHmY1nPEs2M7vxdrME0GGGM2cnEHDYjWQ2aZ4DzDZmN85uAGlJMLhNnJZ6G+MZZzf/IEXLYTMD/t5tRNpy57Cx8YwDx40lbvBus0gwkCDCL7cbHz4uOFBt2N9/dvPNHxU28vzSBLSAACRmJMAqJQgrR2jhP0Cc6lEwCkbBKBh5AACua0OUO/SomAAAAABJRU5ErkJggg==","orcid":"","institution":"Gulhane Training and Research Hospital","correspondingAuthor":true,"prefix":"","firstName":"Hasan","middleName":"Burak","lastName":"Toprak","suffix":""},{"id":620840047,"identity":"66b62f75-22b7-4f76-90a0-21148ba8cea5","order_by":1,"name":"Mete Erdemir","email":"","orcid":"","institution":"Gulhane Training and Research Hospital","correspondingAuthor":false,"prefix":"","firstName":"Mete","middleName":"","lastName":"Erdemir","suffix":""},{"id":620840048,"identity":"8f33eb56-fd2b-42c4-b477-a2588bf0ad24","order_by":2,"name":"Elif Bilgiç","email":"","orcid":"","institution":"Gulhane Training and Research Hospital","correspondingAuthor":false,"prefix":"","firstName":"Elif","middleName":"","lastName":"Bilgiç","suffix":""},{"id":620840049,"identity":"b17633d2-4063-46da-849f-18658c05e120","order_by":3,"name":"Cevdet Furkan Köşker","email":"","orcid":"","institution":"Gulhane Training and Research Hospital","correspondingAuthor":false,"prefix":"","firstName":"Cevdet","middleName":"Furkan","lastName":"Köşker","suffix":""},{"id":620840050,"identity":"155d5796-8375-4aa2-94db-101582b712aa","order_by":4,"name":"Şerife Bozdaş","email":"","orcid":"","institution":"Gulhane Training and Research Hospital","correspondingAuthor":false,"prefix":"","firstName":"Şerife","middleName":"","lastName":"Bozdaş","suffix":""},{"id":620840052,"identity":"1d664970-955d-47a8-8cc5-bd889966ded9","order_by":5,"name":"Meltem Bilge","email":"","orcid":"","institution":"Gulhane Training and Research Hospital","correspondingAuthor":false,"prefix":"","firstName":"Meltem","middleName":"","lastName":"Bilge","suffix":""},{"id":620840054,"identity":"bfdb8fe7-e046-4c19-8e4b-2a08865fbc6c","order_by":6,"name":"Gürhan Taşkın","email":"","orcid":"","institution":"Gulhane Training and Research Hospital","correspondingAuthor":false,"prefix":"","firstName":"Gürhan","middleName":"","lastName":"Taşkın","suffix":""},{"id":620840055,"identity":"7bebd713-446c-4250-9c76-1fa1659718f3","order_by":7,"name":"Levent Yamanel","email":"","orcid":"","institution":"Gulhane Training and Research Hospital","correspondingAuthor":false,"prefix":"","firstName":"Levent","middleName":"","lastName":"Yamanel","suffix":""}],"badges":[],"createdAt":"2026-03-08 11:38:30","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9063890/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9063890/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":106948410,"identity":"b9faf2f5-d0b8-4970-9189-34b55b516413","added_by":"auto","created_at":"2026-04-15 07:01:00","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":114298,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePatient Selection and Study Flow Diagram\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFlow diagram illustrating patient screening, exclusion criteria, and final cohort selection for the retrospective observational study of acute ischemic stroke patients managed in an intensive care setting. The diagram is constructed in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology guidelines.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-9063890/v1/14ac02c7b5cf5f17ff32b3b9.png"},{"id":106948411,"identity":"eb1226e9-5612-420f-80e7-821ed99d0092","added_by":"auto","created_at":"2026-04-15 07:01:00","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":53843,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMarginal Effects of the C-Reactive Protein–to–Albumin Ratio on Ninety-Day Mortality Across Neurological Severity\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGraphical representation of adjusted marginal effects derived from the interaction model between the C-reactive protein–to–albumin ratio and neurological severity measured by the National Institutes of Health Stroke Scale score. The plot demonstrates the stability of the estimated odds ratio for mortality across the full spectrum of neurological severity, with shaded areas indicating ninety-five percent confidence intervals.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-9063890/v1/fc379c7c7fb43170cbd19af1.png"},{"id":106961647,"identity":"077bb1cc-0e47-4806-a1b6-fcb0204e397a","added_by":"auto","created_at":"2026-04-15 09:26:26","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":35320,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCalibration of Clinical Prediction Models with and Without the C-Reactive Protein–to–Albumin Ratio\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBootstrap-corrected calibration plots comparing observed and predicted probabilities of ninety-day all-cause mortality for the clinical reference model and the model incorporating the C-reactive protein–to–albumin ratio. The plots illustrate agreement between predicted and observed risks and allow visual assessment of any improvement in model calibration after inclusion of the inflammatory biomarker.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-9063890/v1/fa9f8a698a202d610979be20.png"},{"id":106963524,"identity":"41ddd8fa-bfc7-49f7-b964-2cf08dea70e1","added_by":"auto","created_at":"2026-04-15 09:44:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1802756,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9063890/v1/0d4ef062-f080-4a5d-a92b-ebaeb1da2c79.pdf"},{"id":106961921,"identity":"664bf57b-8e86-4fd3-a677-5dccc6a892f6","added_by":"auto","created_at":"2026-04-15 09:27:48","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":14672,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarytables.docx","url":"https://assets-eu.researchsquare.com/files/rs-9063890/v1/cd6c075c100f0bcb4f130688.docx"},{"id":106961418,"identity":"fd8b3d9a-49ef-4867-aa82-d652598b17ce","added_by":"auto","created_at":"2026-04-15 09:25:29","extension":"png","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":3266509,"visible":true,"origin":"","legend":"","description":"","filename":"GraphicalAbstracthighresolution.png","url":"https://assets-eu.researchsquare.com/files/rs-9063890/v1/08a0dc9b71c836120a97e492.png"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical and Dynamic Evaluation of the C-Reactive Protein–to–Albumin Ratio in Acute Ischemic Stroke: Interaction with Neurological Severity and Limited Prognostic Utility","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eSystemic inflammation is a central determinant of short- and long-term outcomes across a wide spectrum of acute and critical illnesses. Among routinely available biomarkers, C-reactive protein reflects the intensity of the acute-phase inflammatory response, whereas serum albumin integrates nutritional status, hepatic synthetic function, and chronic inflammatory burden. The combination of these two biologically distinct parameters into the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio has therefore been proposed as a composite marker capturing both inflammatory activity and host vulnerability [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe prognostic relevance of the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio was initially established in oncological settings. In patients undergoing surgery for colorectal cancer, Ishizuka et al. demonstrated that elevated preoperative C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio was independently associated with worse postoperative survival and provided superior prognostic information compared with C-reactive protein or albumin alone [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. This conceptual framework positioned the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio as a clinically meaningful composite index rather than a purely statistical construct and prompted its evaluation in non-oncological and acute-care populations.\u003c/p\u003e \u003cp\u003eSubsequent studies extended C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio research into critical care. Park et al. reported that the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio measured at intensive care unit admission was associated with short-term mortality in heterogeneous intensive care unit cohorts [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], while Oh et al. demonstrated similar associations with thirty-day mortality in critically ill patients [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Further analyses in postoperative intensive care unit populations suggested that the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio may retain prognostic relevance beyond the immediate inflammatory phase [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Collectively, these studies established the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio as a marker closely linked to illness severity in critically ill populations.\u003c/p\u003e \u003cp\u003eNeurological emergencies represent a distinct clinical context in which systemic inflammation interacts with disease-specific severity and metabolic stress. Acute ischemic stroke is characterized by a rapid inflammatory cascade initiated by cerebral ischemia, blood\u0026ndash;brain barrier disruption, and secondary systemic responses. Early stroke-specific studies suggested that the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio may be associated with adverse outcomes. Kocat\u0026uuml;rk and Kocat\u0026uuml;rk reported an association between elevated C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio and ninety-day mortality in patients with acute ischemic stroke [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], while subsequent studies linked the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio to stroke severity and clinical prognosis [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eEvidence from neurocritical care populations further supported the association between the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio and outcomes. In intensive care unit cohorts, Fındıklı et al. demonstrated that higher C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio values were associated with in-hospital mortality [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Similar findings were reported in traumatic brain injury and spontaneous intracerebral hemorrhage, where elevated C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio was associated with unfavourable outcomes and increased mortality risk [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. These observations suggest that the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio reflects systemic inflammatory stress across diverse forms of acute brain injury.\u003c/p\u003e \u003cp\u003eBeyond neurological disease, the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio has been widely studied in systemic inflammatory conditions. Associations between elevated C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio and mortality have been reported in peritoneal dialysis [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], sepsis [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], severe burns [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], acute pancreatitis [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], coronavirus disease 2019 [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], acute kidney injury [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], and large mixed intensive care unit populations [\u003cspan additionalcitationids=\"CR25\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Meta-analyses have generally confirmed an overall association between higher C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio and adverse outcomes, while also highlighting substantial heterogeneity across populations and study designs [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDespite this extensive literature, several important uncertainties remain. First, many studies evaluated the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio in isolation or with limited adjustment for established clinical severity measures, raising concerns about residual confounding. Second, the incremental prognostic value of the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio beyond established clinical predictors, particularly neurological severity scores such as the National Institutes of Health Stroke Scale, which remains the dominant prognostic driver in acute ischemic stroke, has rarely been systematically assessed. Third, although dynamic changes in the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio over time have been proposed as a potential means of improving prognostic accuracy, empirical evidence supporting this assumption remains limited and inconsistent. Finally, few studies have evaluated whether the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio meaningfully improves clinical decision-making using modern decision-analytic approaches.\u003c/p\u003e \u003cp\u003eTherefore, this study aimed to rigorously evaluate whether the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio provides independent or incremental prognostic value beyond neurological severity and sepsis in critically ill patients with acute ischemic stroke. Specifically, we examined (i) whether the prognostic association of the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio is modified by neurological severity as measured by the National Institutes of Health Stroke Scale, (ii) whether the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio is associated with mortality within clinically homogeneous National Institutes of Health Stroke Scale\u0026ndash;defined subgroups, and (iii) whether the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio improves model performance, calibration, or clinical decision-making beyond National Institutes of Health Stroke Scale\u0026ndash;based clinical models.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Reporting Framework\u003c/h2\u003e \u003cp\u003e This study was designed as a retrospective observational cohort analysis conducted in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology guidelines. Real-world clinical and laboratory data from adult patients admitted with acute neurological presentations and managed in an intensive care setting were analyzed. All analyses were prespecified prior to model construction to minimize data-driven inference.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy Population and Setting\u003c/h3\u003e\n\u003cp\u003eConsecutive adult patients admitted between January 2020 and December 2024 were screened for eligibility. Patients were included if they met the following criteria: (i) age eighteen years or older, (ii) admission through the emergency department with an acute neurological presentation, and (iii) availability of baseline laboratory measurements including C-reactive protein and serum albumin obtained at admission.\u003c/p\u003e \u003cp\u003ePatients were excluded if outcome data were missing, if key laboratory variables required for calculation of the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio were unavailable, or if clinical records were incomplete.\u003c/p\u003e \u003cp\u003eA Strengthening the Reporting of Observational Studies in Epidemiology\u0026ndash;compliant flow diagram describing patient selection is presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eClinical Variables and Definitions\u003c/h3\u003e\n\u003cp\u003eDemographic variables included age in years and sex. Clinical variables recorded at emergency department admission included the National Institutes of Health Stroke Scale score, sepsis status, and comorbid conditions including hypertension and diabetes mellitus. Sepsis was defined based on a documented clinical diagnosis at admission and coded as a binary variable indicating presence or absence.\u003c/p\u003e \u003cp\u003eDemographic characteristics, laboratory findings, and clinical variables at admission were retrieved from the medical records. Baseline stroke severity was assessed at admission using the National Institutes of Health Stroke Scale (NIHSS), a previously published and validated instrument widely used to quantify neurological deficit severity in acute stroke [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eLaboratory variables obtained at emergency department admission included C-reactive protein measured in milligrams per liter, serum albumin measured in grams per deciliter, and blood glucose level measured in milligrams per deciliter. The C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio at admission was calculated by dividing the C-reactive protein value by the serum albumin concentration.\u003c/p\u003e \u003cp\u003eAdditional laboratory measurements obtained during intensive care follow-up were used to calculate the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio during intensive care unit stay. Changes in the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio and blood glucose levels between intensive care follow-up and emergency department admission were calculated as the difference between follow-up and baseline values.\u003c/p\u003e\n\u003ch3\u003eOutcome Measures\u003c/h3\u003e\n\u003cp\u003eThe primary outcome was ninety-day all-cause mortality, determined from hospital records and follow-up documentation and coded as a binary variable. A secondary outcome was the presence of sepsis at admission, evaluated to explore its association with inflammatory burden and neurological severity.\u003c/p\u003e\n\u003ch3\u003eDescriptive and Baseline Analyses\u003c/h3\u003e\n\u003cp\u003eBaseline demographic, clinical, and laboratory characteristics were summarized according to ninety-day mortality status and are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Continuous variables were reported as mean plus or minus standard deviation or median with interquartile range, depending on their distribution. Categorical variables were expressed as counts and percentages.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics according to 90-day mortality\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAlive (n\u0026thinsp;=\u0026thinsp;114)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDead (n\u0026thinsp;=\u0026thinsp;32)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e68.1\u0026thinsp;\u0026plusmn;\u0026thinsp;13.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e76.4\u0026thinsp;\u0026plusmn;\u0026thinsp;11.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale sex, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55 (48.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (40.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNIHSS score at admission (ED)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.0 [4.0\u0026ndash;12.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14.0 [8.0\u0026ndash;22.0]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSepsis, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (8.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27 (84.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e87 (77.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (65.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes mellitus, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (28.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (25.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRP at admission (mg/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.1 [2.0\u0026ndash;16.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.0 [2.5\u0026ndash;38.0]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum albumin (g/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.98\u0026thinsp;\u0026plusmn;\u0026thinsp;0.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.55\u0026thinsp;\u0026plusmn;\u0026thinsp;0.64\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlucose at admission (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e124.5 [92.0\u0026ndash;187.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e157.0 [118.0\u0026ndash;213.0]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC-reactive protein\u0026ndash;to\u0026ndash;albumin ratio at admission\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.18 [0.64\u0026ndash;2.15]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.00 [0.90\u0026ndash;7.40]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCAR during ICU stay (CAR_ICU)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.63 [0.81\u0026ndash;4.68]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.15 [0.90\u0026ndash;11.75]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eΔCAR (ICU\u0026thinsp;\u0026minus;\u0026thinsp;ED)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.15 [0.00\u0026ndash;0.54]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.00 [\u0026minus;\u0026thinsp;0.05\u0026ndash;0.51]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eΔGlucose (ICU\u0026thinsp;\u0026minus;\u0026thinsp;ED), mg/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026minus;38.3 [\u0026minus;\u0026thinsp;75.0\u0026ndash;2.8]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026minus;35.0 [\u0026minus;\u0026thinsp;70.0\u0026ndash;21.5]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eThis table summarizes baseline demographic characteristics, clinical variables, and laboratory parameters of patients with acute ischemic stroke according to ninety-day all-cause mortality status. Age is presented in years, neurological severity is quantified using the National Institutes of Health Stroke Scale score at emergency department admission, and comorbid conditions include hypertension and diabetes mellitus. Laboratory variables include C-reactive protein, serum albumin, blood glucose level, and the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio measured at emergency department admission and during intensive care unit follow-up. Dynamic changes represent the numerical difference between values obtained during intensive care unit follow-up and those measured at emergency department admission. Continuous variables are expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation or median with interquartile range, depending on data distribution, while categorical variables are expressed as counts and percentages.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eMultivariable Modelling Strategy\u003c/h2\u003e \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e \u003ch2\u003eSepsis Model\u003c/h2\u003e \u003cp\u003eA multivariable logistic regression model was constructed to identify factors independently associated with the presence of sepsis at emergency department admission, as presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The model included the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio at admission, age, National Institutes of Health Stroke Scale score at admission, and blood glucose level at admission. All variables were selected a priori based on established clinical relevance and prior literature.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMultivariable logistic regression model for sepsis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC-reactive protein\u0026ndash;to\u0026ndash;albumin ratio at admission\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.994\u0026ndash;1.053\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.117\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (per year)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.057\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.014\u0026ndash;1.101\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNIHSS score at admission (per point)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.037\u0026ndash;1.166\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlucose at admission (per mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.007\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.000\u0026ndash;1.015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.055\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eMultivariable logistic regression analysis evaluating demographic, neurological, and laboratory factors independently associated with the presence of sepsis at emergency department admission. The model includes age, neurological severity assessed by the National Institutes of Health Stroke Scale score, admission blood glucose level, and the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio measured at admission. Effect estimates are reported as odds ratios with corresponding ninety-five percent confidence intervals, allowing assessment of the relative contribution of systemic inflammatory burden and neurological severity to early infectious complications.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e\n\u003ch3\u003eMortality Models\u003c/h3\u003e\n\u003cp\u003eA clinical multivariable logistic regression model excluding the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio was first developed to identify established predictors of ninety-day all-cause mortality, as presented in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. This reference model included sepsis status at admission, age, National Institutes of Health Stroke Scale score at admission, and blood glucose level at admission.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical Multivariable Logistic Regression Model for Ninety-Day Mortality Without the C-Reactive Protein\u0026ndash;to\u0026ndash;Albumin Ratio\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNIHSS score at admission (ED) (per point)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.087\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.987\u0026ndash;1.197\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.089\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years) (per year)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.071\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.007\u0026ndash;1.140\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.030\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSepsis (yes vs no)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e52.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12.71\u0026ndash;212.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlucose at admission (mg/dL) (per mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.001\u0026ndash;1.019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.037\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eThis table presents the reference multivariable clinical model for predicting ninety-day all-cause mortality in patients with acute ischemic stroke. The model includes established clinical predictors, namely sepsis status at admission, age, neurological severity measured by the National Institutes of Health Stroke Scale score at emergency department admission, and admission blood glucose level. Odds ratios with ninety-five percent confidence intervals are reported to quantify the independent association of each variable with mortality. This model serves as the baseline framework against which the incremental prognostic value of inflammatory biomarkers is evaluated.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTo evaluate the incremental prognostic value of inflammatory burden, a second multivariable model was constructed by adding the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio measured during intensive care follow-up to the clinical reference model, as presented in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. Effect estimates were reported as odds ratios with corresponding ninety-five percent confidence intervals.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMultivariable Logistic Regression Model for Ninety-Day Mortality Including the C-Reactive Protein\u0026ndash;to\u0026ndash;Albumin Ratio\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eC-reactive protein\u0026ndash;to\u0026ndash;albumin ratio during intensive care unit follow-up\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.026\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.982\u0026ndash;1.070\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.246\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNIHSS score at admission (ED)\u003c/b\u003e (per point)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.081\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.991\u0026ndash;1.181\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.080\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge (years)\u003c/b\u003e (per year)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.069\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.007\u0026ndash;1.140\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.032\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSepsis (yes vs no)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e52.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12.71\u0026ndash;212.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGlucose at admission (mg/dL)\u003c/b\u003e (per mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.999\u0026ndash;1.017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.069\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eMultivariable logistic regression model assessing whether the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio measured during intensive care unit follow-up provides additional prognostic information beyond established clinical predictors. The model adjusts for age, sepsis status, neurological severity assessed by the National Institutes of Health Stroke Scale score, and admission blood glucose level. Effect estimates are expressed as odds ratios with ninety-five percent confidence intervals. Comparison with the clinical reference model allows evaluation of the incremental contribution of systemic inflammatory burden to mortality prediction.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eUnivariate Analyses\u003c/h2\u003e \u003cp\u003eUnivariate logistic regression analyses were performed to evaluate crude associations between individual clinical and laboratory variables and ninety-day mortality, as presented in Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e. Variables examined included the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio during intensive care stay, sepsis status, National Institutes of Health Stroke Scale score at admission, age, and blood glucose level at admission.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate Associations Between Clinical and Laboratory Variables and Ninety-Day All-Cause Mortality\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eC-reactive protein\u0026ndash;to\u0026ndash;albumin ratio during intensive care unit follow-up\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.027\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.001\u0026ndash;1.052\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.038\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSepsis (yes vs no)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e65.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e19.0\u0026ndash;224.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNIHSS score at admission (ED)\u003c/b\u003e (per point)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.095\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.039\u0026ndash;1.153\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge (years)\u003c/b\u003e (per year)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.056\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.019\u0026ndash;1.091\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGlucose at admission (mg/dL)\u003c/b\u003e (per mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.999\u0026ndash;1.011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.091\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eUnivariate logistic regression analyses examining crude associations between individual demographic, clinical, and laboratory variables and ninety-day all-cause mortality. Variables evaluated include age, sepsis status, neurological severity measured by the National Institutes of Health Stroke Scale score, admission blood glucose level, and the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio measured during intensive care unit follow-up. Odds ratios with ninety-five percent confidence intervals are presented to illustrate unadjusted effect sizes prior to multivariable modelling.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eInteraction and Effect Modification\u003c/h2\u003e \u003cp\u003eEffect modification between systemic inflammatory burden and neurological severity was evaluated by including an interaction term between the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio at admission and the National Institutes of Health Stroke Scale score at admission in the multivariable mortality model. Statistical significance of interaction was assessed using the Wald test. Results are presented in Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e, with adjusted marginal effects illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003eInteraction Between the C-Reactive Protein\u0026ndash;to\u0026ndash;Albumin Ratio and Neurological Severity in Relation to Ninety-Day Mortality\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eC-reactive protein\u0026ndash;to\u0026ndash;albumin ratio at admission\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.040\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.982\u0026ndash;1.101\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.178\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNIHSS score at admission (ED)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.087\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.987\u0026ndash;1.197\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.091\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCAR \u0026times; NIHSS interaction at ED admission\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.993\u0026ndash;1.005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.802\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge (years)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.071\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.007\u0026ndash;1.140\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.030\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSepsis (yes vs no)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e52.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12.71\u0026ndash;212.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGlucose at admission (mg/dL)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.001\u0026ndash;1.019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.039\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eMultivariable logistic regression model including an interaction term between the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio measured at admission and neurological severity assessed by the National Institutes of Health Stroke Scale score. This analysis evaluates whether the prognostic association of systemic inflammatory burden varies across different levels of neurological severity. Effect estimates are reported as odds ratios with ninety-five percent confidence intervals. A non-significant interaction term indicates absence of meaningful effect modification.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eStratified Analyses by Neurological Severity\u003c/h2\u003e \u003cp\u003eTo further explore potential heterogeneity of effects, patients were stratified a priori into clinically relevant neurological severity categories based on admission National Institutes of Health Stroke Scale scores of zero to four, five to fourteen, and fifteen or higher. Within each stratum, the association between the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio and ninety-day mortality was evaluated using logistic regression models. Results are presented in Table\u0026nbsp;\u003cspan refid=\"Tab7\" class=\"InternalRef\"\u003e7\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab7\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 7\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eNational Institutes of Health Stroke Scale\u0026ndash;Stratified Associations Between the C-Reactive Protein\u0026ndash;to\u0026ndash;Albumin Ratio and Ninety-Day Mortality\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeurological severity category based on admission NIHSS score) group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOR (CAR)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% CI Lower\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e95% CI Upper\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e0\u0026ndash;4 (Mild)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.822\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.243\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.999\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e5\u0026ndash;14 (Moderate)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.076\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.973\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.190\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.151\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e\u0026ge;\u0026thinsp;15 (Severe)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.114\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.836\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.483\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.467\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eStratified logistic regression analyses assessing the association between the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio and ninety-day all-cause mortality within clinically predefined neurological severity categories based on admission National Institutes of Health Stroke Scale scores. Separate models are presented for mild, moderate, and severe neurological impairment, allowing evaluation of heterogeneity of effects across severity strata.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003ePenalized Regression Analysis\u003c/h2\u003e \u003cp\u003eTo assess predictor stability and reduce the risk of overfitting, penalized logistic regression using the least absolute shrinkage and selection operator was performed. The penalty parameter was selected through cross-validation. Variables with non-zero coefficients were retained, allowing evaluation of the robustness of the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio relative to established clinical predictors, as presented in Table S1.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eCalibration and Risk Reclassification\u003c/h2\u003e \u003cp\u003eModel calibration was assessed using bootstrap-corrected calibration plots comparing predicted and observed mortality risk for the clinical reference model and the model incorporating the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Incremental prognostic value was further evaluated using net reclassification improvement and integrated discrimination improvement metrics, as presented in Table\u0026nbsp;\u003cspan refid=\"Tab8\" class=\"InternalRef\"\u003e8\u003c/span\u003e.\u003c/p\u003e \u003ctable float=\"Yes\" id=\"Tab9\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 8\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eRisk Reclassification and Discrimination Analyses After Addition of the C-Reactive Protein\u0026ndash;to\u0026ndash;Albumin Ratio\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eMetric\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003eEstimate\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eNRI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e\u0026minus;0.057\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e\u0026minus;0.205 to 0.086\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\n \u003cp\u003e0.918\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eIDI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e0.011\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e\u0026minus;0.016 to 0.035\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\n \u003cp\u003e0.942\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003eNet reclassification improvement and integrated discrimination improvement analyses evaluating whether inclusion of the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio improves patient risk classification and discrimination for ninety-day all-cause mortality beyond the clinical reference model. Estimates are presented with ninety-five percent confidence intervals. Non-significant values indicate lack of incremental prognostic utility.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n\u003c/table\u003e\n\n\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\n\u003cp\u003eAll statistical analyses were performed using Python-based statistical libraries. Logistic regression models were fitted using maximum likelihood estimation. Effect estimates were reported as odds ratios with corresponding ninety-five percent confidence intervals. Two-sided p-values less than 0.05 were considered statistically significant.\u003c/p\u003e\n\u003cp\u003eMissing data were evaluated prior to analysis. Variables with substantial missingness were excluded to preserve internal validity and avoid data-driven imputation bias.\u003c/p\u003e\n\u003cp\u003eThis analytical framework was specifically designed to move beyond significance testing by integrating interaction modelling, stratified analyses, penalized regression, and calibration- and reclassification-based performance metrics to rigorously assess incremental prognostic and clinical utility.\u003c/p\u003e\n\u003cp\u003e\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eStudy Population and Baseline Characteristics\u003c/h2\u003e \u003cp\u003eA total of 180 patients were initially assessed for eligibility. After exclusion of 34 patients due to missing key laboratory data or duplicate records, 146 patients were included in the final analysis, as illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Baseline demographic, clinical, and laboratory characteristics of the study population are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eThe mean age of the cohort was 69.9 plus or minus 13.7 years, and 68 patients (46.6 percent) were male. At emergency department admission, the median National Institutes of Health Stroke Scale score was 9.0, with an interquartile range of 4.0 to 15.0, reflecting a wide spectrum of neurological severity.\u003c/p\u003e \u003cp\u003eSepsis was present in 37 patients (25.3 percent). Hypertension and diabetes mellitus were observed in 108 patients (74.0 percent) and 40 patients (27.4 percent), respectively, while atrial fibrillation was documented in 34 patients (23.3 percent).\u003c/p\u003e \u003cp\u003eRegarding laboratory parameters, the median C-reactive protein level at admission was 5.3 milligrams per liter, with an interquartile range of 2.0 to 16.9 milligrams per liter, and the mean serum albumin concentration was 3.89 plus or minus 0.52 grams per deciliter. The median admission glucose level was 134.0 milligrams per deciliter, with an interquartile range of 98.0 to 195.0 milligrams per deciliter.\u003c/p\u003e \u003cp\u003eThe median C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio at admission was 1.40, with an interquartile range of 0.64 to 2.80, which increased to 1.90, with an interquartile range of 0.85 to 6.10, during intensive care follow-up. The median change in the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio between intensive care follow-up and emergency department admission was 0.10, with an interquartile range of 0.00 to 0.52. The median change in blood glucose level between intensive care follow-up and emergency department admission was minus 37.0 milligrams per deciliter, with an interquartile range of minus 73.0 to 6.0 milligrams per deciliter.\u003c/p\u003e \u003cp\u003eNinety-day mortality occurred in 32 patients (21.9 percent), as shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eFactors Associated with Sepsis at Admission\u003c/h2\u003e \u003cp\u003eFactors associated with sepsis at admission were evaluated using a multivariable logistic regression model incorporating demographic, clinical, and laboratory variables, as presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. In this model, age, expressed per year, with an odds ratio of 1.057 and a ninety-five percent confidence interval of 1.014 to 1.101, and the National Institutes of Health Stroke Scale score at admission, expressed per point, with an odds ratio of 1.100 and a ninety-five percent confidence interval of 1.037 to 1.166, were independently associated with the presence of sepsis.\u003c/p\u003e \u003cp\u003eAdmission C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio showed a positive but non-significant association with sepsis, with an odds ratio of 1.023 and a ninety-five percent confidence interval of 0.994 to 1.053. Blood glucose level demonstrated a borderline association, whereas hypertension and diabetes mellitus were not independently associated with sepsis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eClinical Model for Ninety-Day Mortality Without the C-Reactive Protein\u0026ndash;to\u0026ndash;Albumin Ratio\u003c/h2\u003e \u003cp\u003eIn the multivariable clinical model excluding the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio, sepsis emerged as the strongest independent predictor of ninety-day mortality, with an odds ratio of 52.01 and a ninety-five percent confidence interval of 12.71 to 212.78. Age was also independently associated with mortality, with an odds ratio per year of 1.071 and a ninety-five percent confidence interval of 1.007 to 1.140, as was admission glucose level, with an odds ratio per milligram per deciliter of 1.010 and a ninety-five percent confidence interval of 1.001 to 1.019. Admission National Institutes of Health Stroke Scale score demonstrated a borderline association with mortality.\u003c/p\u003e \u003cp\u003eThis clinical model served as the reference framework for subsequent analyses evaluating the incremental prognostic value of the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio, as presented in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eIncremental Prognostic Value of the C-Reactive Protein\u0026ndash;to\u0026ndash;Albumin Ratio for Mortality\u003c/h2\u003e \u003cp\u003eWhen the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio measured during intensive care follow-up was added to the clinical model, sepsis and age remained independently associated with ninety-day mortality, whereas the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio did not demonstrate an independent association. Admission National Institutes of Health Stroke Scale score and glucose level retained only borderline associations after adjustment. Importantly, inclusion of the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio did not materially alter the effect estimates of established clinical predictors, indicating limited incremental prognostic value beyond the clinical model, as shown in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003eUnivariate Predictors of Ninety-Day Mortality\u003c/h2\u003e \u003cp\u003eIn univariate logistic regression analyses, the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio measured during intensive care follow-up was associated with ninety-day mortality. Sepsis, National Institutes of Health Stroke Scale score, and age also demonstrated strong unadjusted associations with mortality, whereas admission glucose level did not reach statistical significance. These findings highlight that the apparent prognostic signal of the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio is attenuated after adjustment for clinical severity and age, as presented in Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e.\u003c/p\u003e \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e \u003ch2\u003eInteraction Between the C-Reactive Protein\u0026ndash;to\u0026ndash;Albumin Ratio and Neurological Severity\u003c/h2\u003e \u003cp\u003eEffect modification was formally evaluated by including an interaction term between the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio at admission and the National Institutes of Health Stroke Scale score at admission in the multivariable mortality model. The interaction term was not statistically significant, indicating that the prognostic effect of the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio did not meaningfully vary across levels of neurological severity.\u003c/p\u003e \u003cp\u003eMarginal effect analysis further demonstrated that the adjusted odds ratio of the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio for ninety-day mortality remained close to unity across the entire National Institutes of Health Stroke Scale spectrum, with confidence intervals consistently crossing the null value, as illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec24\" class=\"Section2\"\u003e \u003ch2\u003eNational Institutes of Health Stroke Scale\u0026ndash;Stratified Associations\u003c/h2\u003e \u003cp\u003eIn analyses stratified by neurological severity, the association between the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio and ninety-day mortality was evaluated separately within clinically predefined National Institutes of Health Stroke Scale categories. The C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio was not significantly associated with mortality in any National Institutes of Health Stroke Scale category. Odds ratios for the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio remained close to unity across mild, moderate, and severe neurological impairment, with wide confidence intervals consistently crossing the null value, as presented in Table\u0026nbsp;\u003cspan refid=\"Tab7\" class=\"InternalRef\"\u003e7\u003c/span\u003e. These findings further support the absence of clinically meaningful effect modification by baseline neurological severity.\u003c/p\u003e \u003cdiv id=\"Sec25\" class=\"Section3\"\u003e \u003ch2\u003ePenalized Regression Analysis\u003c/h2\u003e \u003cp\u003eIn penalized logistic regression using the least absolute shrinkage and selection operator, National Institutes of Health Stroke Scale score, age, sepsis status, and admission glucose were retained as stable predictors of ninety-day mortality, whereas the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio was not selected. Serum albumin, hypertension, and diabetes mellitus were eliminated during penalization, indicating limited robustness of these variables when model complexity was constrained, as shown in Table S1.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec26\" class=\"Section3\"\u003e \u003ch2\u003eCalibration, Risk Reclassification, and Clinical Utility\u003c/h2\u003e \u003cp\u003eCalibration plots demonstrated good agreement between predicted and observed mortality risk for both the clinical model and the clinical model augmented with the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio, with no meaningful improvement after inclusion of the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio. Risk reclassification analysis further showed no significant improvement in patient risk stratification following the addition of the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio. Neither the net reclassification improvement nor the integrated discrimination improvement reached statistical significance, indicating that the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio did not enhance discrimination or clinical risk assignment beyond established predictors, as presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Table\u0026nbsp;\u003cspan refid=\"Tab8\" class=\"InternalRef\"\u003e8\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this single-centre cohort of critically ill patients with acute ischemic stroke, we found that the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio does not provide independent or incremental prognostic value beyond neurological severity and sepsis, despite its apparent univariate associations with adverse outcomes. Three principal findings emerge. First, although the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio was associated with adverse outcomes in univariate analyses, it did not retain independent prognostic significance after adjustment for clinical severity and age. Second, dynamic assessment of the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio during intensive care follow-up did not confer incremental prognostic value. Third, established clinical markers, particularly sepsis status and neurological severity as measured by the National Institutes of Health Stroke Scale, consistently dominated outcome prediction across all analytical frameworks.\u003c/p\u003e \u003cp\u003eThese findings align with emerging evidence suggesting that the apparent prognostic signal of the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio may largely reflect underlying disease severity rather than independent biological risk. Recent pooled analyses have shown that while elevated C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio is associated with adverse outcomes at the population level, substantial heterogeneity exists across stroke subtypes, severity strata, and analytical models, particularly after adjustment for neurological severity and systemic complications [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe biological rationale for the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio is well established. C-reactive protein reflects acute-phase inflammatory activation, whereas serum albumin integrates nutritional reserve, hepatic function, and chronic inflammatory burden. Prior stroke-specific studies have reported associations between elevated C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio and mortality, stroke severity, hemorrhagic transformation, and functional outcomes [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan additionalcitationids=\"CR30\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. For example, Xu et al. demonstrated that higher admission C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio was associated with hemorrhagic transformation and poor functional outcome following thrombolysis [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], while cohort studies from different geographic regions reported similar associations with adverse outcomes [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHowever, many of these studies relied on limited adjustment strategies or focused on early or univariate associations. Meta-analytic data indicate that the strength of the association between C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio and stroke outcomes diminishes substantially when models incorporate robust clinical severity measures, particularly the National Institutes of Health Stroke Scale score [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Our findings extend this literature by demonstrating that, even in a critically ill stroke population, the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio does not provide independent prognostic information once neurological severity and sepsis are adequately accounted for. A plausible explanation for these discrepancies is residual confounding and under adjustment for neurological severity and systemic complications in prior studies, which may have led to overestimation of the independent prognostic contribution of inflammatory biomarkers.\u003c/p\u003e \u003cp\u003eNeurological severity emerged as a central determinant of both sepsis and mortality in our cohort. The National Institutes of Health Stroke Scale score was independently associated with sepsis at admission and demonstrated consistent associations with mortality across all models. This observation reinforces the concept that neurological injury burden is a primary driver of downstream systemic inflammation and adverse outcomes after stroke. Prior studies reporting strong correlations between the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio and stroke severity further support the interpretation that this biomarker may function predominantly as a surrogate marker of neurological damage rather than an independent prognostic factor [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSepsis status was the strongest predictor of mortality in all multivariable models, with effect sizes far exceeding those of laboratory biomarkers. This finding is consistent with large intensive care unit cohorts demonstrating that infection-driven systemic inflammation is a dominant contributor to short-term mortality risk [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan additionalcitationids=\"CR25\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Notably, the inclusion of the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio did not materially alter the effect estimates of sepsis or age, underscoring its limited incremental contribution once major clinical determinants are considered.\u003c/p\u003e \u003cp\u003eA key objective of the present study was to assess whether the prognostic relevance of the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio varies across levels of neurological severity. Contrary to some earlier hypotheses, we observed no significant interaction between the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio and the National Institutes of Health Stroke Scale score. Stratified analyses across mild, moderate, and severe neurological impairment further demonstrated that the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio was not associated with mortality within any severity category.\u003c/p\u003e \u003cp\u003eThese findings contrast with reports suggesting differential prognostic effects of inflammatory markers across stroke severity strata [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e], but are consistent with more recent large-scale observational analyses showing that neurological severity exerts a uniform and dominant influence across inflammatory states [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Collectively, these results indicate that effect modification by baseline neurological severity is limited for the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio.\u003c/p\u003e \u003cp\u003eBeyond statistical association, clinical adoption of biomarkers requires demonstration of incremental prognostic utility. In the present study, the addition of the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio did not improve model calibration, discrimination, or risk reclassification, as reflected by non-significant net reclassification improvement and integrated discrimination improvement estimates. Penalized regression further confirmed the lack of robustness of the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio, as it was consistently excluded when model complexity was constrained.\u003c/p\u003e \u003cp\u003eThese findings are concordant with recent studies employing modern modelling techniques, including penalized regression and nomogram-based approaches, which have shown that although the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio may enter multivariable models, its contribution is often unstable and overshadowed by established clinical predictors [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. This may explain why, despite extensive observational evidence, the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio has not been incorporated into major stroke or critical care guidelines.\u003c/p\u003e \u003cp\u003eImportantly, the absence of independent prognostic value does not negate the clinical relevance of the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio. Several studies have demonstrated that extremely elevated C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio values are associated with high specificity for adverse outcomes, particularly in selected subgroups such as very elderly stroke patients or those with profound systemic inflammation [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. In this context, the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio may function as a rule-in biomarker identifying a subset of patients with heightened inflammatory vulnerability, while offering limited utility for broad risk stratification.\u003c/p\u003e \u003cp\u003eFrom a practical standpoint, the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio should be interpreted alongside, rather than in place of, established clinical severity measures. Its greatest value may lie in augmenting clinical judgment in selected high-risk scenarios rather than serving as a standalone prognostic tool.\u003c/p\u003e \u003cp\u003eThe strengths of this study include comprehensive adjustment for clinical severity, formal evaluation of interaction and stratified effects, the use of penalized regression to assess predictor robustness, and explicit analysis of incremental prognostic value using multiple complementary performance metrics. With 146 patients and 32 outcome events, the study was sufficiently powered to evaluate incremental prognostic effects while minimizing overfitting through penalized regression and internal validation strategies.\u003c/p\u003e \u003cp\u003eSeveral limitations should be acknowledged. The retrospective single-centre design may limit external generalizability, residual confounding cannot be entirely excluded, and analyses relied on routinely collected laboratory data. Therefore, external validation in independent and ideally multicentre stroke cohorts is warranted.\u003c/p\u003e \u003cp\u003eIn conclusion, the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio reflects systemic inflammatory burden in acute ischemic stroke but does not provide independent or incremental prognostic information beyond established clinical severity markers. Dynamic changes in the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio do not enhance mortality prediction, and its prognostic effect is not modified by neurological severity. These findings reconcile heterogeneous results in the literature and support a complementary, context-specific role for the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio rather than its use as a primary risk stratification tool.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or non-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval and Consent to Participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was conducted in accordance with the principles of the Declaration of Helsinki. Ethical approval was obtained from the Ethics Committee of Gulhane Training and Research Hospital in 2026. Due to the retrospective observational design of the study, the requirement for written informed consent was waived by the ethics committee.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for Publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval and Consent to Participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was conducted in accordance with the Declaration of Helsinki. Ethical approval was obtained from the institutional ethics committee. Due to the retrospective observational design of the study, the requirement for informed consent was waived by the ethics committee.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of Data and Materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study conception and design. Data collection and analysis were performed by the authors. All authors contributed to data interpretation, manuscript drafting, and critical revision. All authors read and approved of the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank the clinical and intensive care staff involved in the management of the patients included in this study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eIshizuka M, Nagata H, Takagi K, Iwasaki Y, Shibuya N, Kubota K. Clinical significance of the C-reactive protein to albumin ratio for survival after surgery for colorectal cancer. Ann Surg Oncol. 2016;23(3):900\u0026ndash;7. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1245/s10434-015-4948-7\u003c/span\u003e\u003cspan address=\"10.1245/s10434-015-4948-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePark JE, Chung KS, Song JH, Kim SY, Kim EY, Jung JY, Leem AY. 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Front Med. 2025;12:1624527. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fmed.2025.1624527\u003c/span\u003e\u003cspan address=\"10.3389/fmed.2025.1624527\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Acute ischemic stroke, C-reactive protein–to–albumin ratio, Systemic inflammation, Neurological severity, Intensive care, Sepsis, Prognostic biomarkers","lastPublishedDoi":"10.21203/rs.3.rs-9063890/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9063890/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio has been proposed as a composite inflammatory biomarker associated with adverse outcomes in critically ill patients. However, whether the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio provides independent or incremental prognostic information beyond established clinical severity markers in acute ischemic stroke remains uncertain.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis retrospective observational cohort study included 146 consecutive adult patients admitted with acute ischemic stroke and managed in an intensive care setting. The C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio was calculated at emergency department admission and during intensive care follow-up. Multivariable logistic regression models were constructed to evaluate associations between the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio, sepsis at admission, and ninety-day mortality, adjusting for age, National Institutes of Health Stroke Scale score, sepsis status, and admission glucose. Incremental prognostic value was assessed using calibration analysis, net reclassification improvement, integrated discrimination improvement, interaction modelling, National Institutes of Health Stroke Scale\u0026ndash;stratified analyses, and penalized regression.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eSepsis was present in 25.3% of patients, and ninety-day mortality occurred in 21.9%. Admission C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio was not independently associated with sepsis after adjustment (odds ratio 1.023, 95% confidence interval 0.994\u0026ndash;1.053; p\u0026thinsp;=\u0026thinsp;0.117), whereas age and National Institutes of Health Stroke Scale score remained significant predictors. Similarly, the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio measured during intensive care was associated with mortality in univariate analysis but lost significance in multivariable models (odds ratio 1.026, 95% confidence interval 0.982\u0026ndash;1.070; p\u0026thinsp;=\u0026thinsp;0.246). Sepsis status and age consistently emerged as the strongest independent predictors of mortality. No significant interaction was observed between the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio and National Institutes of Health Stroke Scale score (p\u0026thinsp;=\u0026thinsp;0.802), and the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio was not associated with mortality within National Institutes of Health Stroke Scale\u0026ndash;stratified subgroups. Penalized regression did not retain the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio as a stable predictor. Addition of the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio did not improve model calibration or risk reclassification (net reclassification improvement\u0026thinsp;\u0026minus;\u0026thinsp;0.057; integrated discrimination improvement 0.011).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eIn acute ischemic stroke, the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio reflects systemic inflammatory burden but does not provide independent or incremental prognostic value beyond established clinical severity markers. Dynamic assessment of the C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio does not enhance mortality prediction. The C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio may therefore be best interpreted as a complementary, rule-in biomarker rather than a primary risk stratification tool.\u003c/p\u003e","manuscriptTitle":"Clinical and Dynamic Evaluation of the C-Reactive Protein–to–Albumin Ratio in Acute Ischemic Stroke: Interaction with Neurological Severity and Limited Prognostic Utility","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-15 07:00:38","doi":"10.21203/rs.3.rs-9063890/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2026-04-07T19:39:34+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-06T10:38:43+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-03-16T11:19:23+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-14T06:58:05+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Neurology","date":"2026-03-14T06:53:47+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8d671137-3a95-400c-897c-83ef7e35dc34","owner":[],"postedDate":"April 15th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-15T07:00:38+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-15 07:00:38","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9063890","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9063890","identity":"rs-9063890","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}