Language：English   Publisher：Scientific Reports  

This study evaluated the factors predisposing women to a more substantial functional decline than men in the chronic phase of stroke. Sex differences in functional worsening and improvement, defined as an increase and decrease in one or more modified Rankin Scale scores between the 3-month and each assessment point throughout 5 years after ischemic stroke were examined using data from a multicenter prospective stroke registry in Japan. Logistic regression analysis was performed to estimate the risk of unfavorable outcomes in women after adjusting for potential confounders. The interactions between sex and confounders were also assessed. Among 6848 patients who survived for 5 years poststroke, 39.3% were female. Female survivors were more likely to experience unfavorable functional outcomes throughout 5 years post-stroke than male survivors. The higher risk of functional worsening in women than men was more apparent among patients aged > 75 years and those without limb weakness (P for interaction for age 0.04 and for limb weakness 0.03). Older female patients, frequently experiencing frailty and multimorbidity, should be targeted in poststroke interventions to reduce the burden of long-term disability after stroke. Female patients without apparent motor impairment might also benefit from physical activity programs to maintain muscle strength.

DOI： 10.1038/s41598-025-97668-y

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Language：English   Publisher：Nature Publishing Group  

Language：English   Publisher：Hypertension Research  

The aim of this study was to determine whether pulse pressure (PP), an indicator of arterial stiffness, was independently associated with the risk of acute kidney injury (AKI) following intracerebral hemorrhage (ICH). We enrolled patients with acute ICH from a multicenter stroke registry in Fukuoka, Japan, from June 2007 to September 2019. The mean PP, measured three times on the third day after admission, was categorized into three groups based on tertiles: G1 < 54 mmHg, G2 54–64 mmHg, and G3 ≥ 65 mmHg. AKI was defined as an increase of ≥0.3 mg/dL or ≥150% in serum creatinine levels above baseline during hospitalization. The associations between PP and AKI were evaluated using logistic regression analyses. Overall, 1512 patients with acute ICH (mean age: 69.8 ± 13.5 years; 56.4% men) were included in the analysis. The incidence rates of AKI were 5.6%, 11.0%, and 13.2% in groups G1, G2, and G3, respectively. The odds ratio (95% confidence interval) of AKI was significantly elevated in G2 (1.77 [1.07–2.91]) and G3 (1.82 [1.10–3.03]) compared to G1, even after adjusting for initial systolic blood pressure (SBP) values on admission and subsequent SBP reductions. This significant association was observed in patients with an initial SBP < 200 mmHg (P for heterogeneity, 0.045) and those receiving intravenous antihypertensive therapy in the acute stage (P for heterogeneity, 0.03). High PP should be recognized as a novel potential risk factor for AKI following ICH.

DOI： 10.1038/s41440-024-02046-2

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Language：English   Publisher：Cerebrovascular Diseases  

Introduction: There has been limited research on predicting the functional prognosis of patients with nonsurgical intracerebral hemorrhage (ICH) from the acute stage. The aim of this study was to develop a risk prediction model for the natural course in patients with nonsurgical ICH and to evaluate its performance using a multicenter hospital-based prospective study of stroke patients in Japan. Methods: We consecutively registered a total of 1,017 patients with acute ICH (mean age, 68 years) who underwent conservative treatment and followed them up for 3 months. The study outcome was a poor functional outcome (modified Rankin Scale score, 4-6) at 3 months after ICH onset. To develop the risk prediction model for natural course in patients with nonsurgical ICH, we included the following clinical common factors assessed on admission in daily clinical practice for ICH: age, sex, medical history (hypertension, diabetes mellitus, dyslipidemia, pre-stroke dementia, previous stroke, coronary artery disease, smoking status, alcohol drinking status, oral anticoagulation, and antiplatelet medication), admission status (time from onset to admission, systolic blood pressure, diastolic blood pressure, pulse pressure, plasma glucose levels, severity of the stroke), and neuroradiologic data (ICH location, intraventricular hemorrhage, and hematoma volume). The risk prediction model for poor functional outcome was developed using logistic regression analysis. In addition, the risk prediction model was translated into a point-based simple risk score (FSR ICH score) using the approach in the Framingham Heart Study. Results: At 3 months after the ICH onset, 323 (31.8%) patients developed a poor functional outcome. Age, diabetes mellitus, prestroke dementia, NIHSS score on admission, intraventricular hemorrhage, and hematoma volume were included in the risk prediction model. This model demonstrated excellent discrimination (C statistic = 0.884 [95% confidence interval, 0.863-0.905]; optimism-corrected C statistic based on 200 bootstrap samples = 0.877) and calibration (Hosmer-Lemeshow goodness-of-fit test: p = 0.72). The FSR ICH score, a point-based simple risk score, also showed excellent discrimination, with a C statistic of 0.882 (95% CI: 0.861-0.903). Conclusions: We developed a new risk prediction model for 3-month poor functional outcome in patients with nonsurgical ICH using a multicenter hospital-based prospective study in Japan. The current risk prediction model has the potential to be a useful tool for estimating the natural course in patients with nonsurgical ICH, aiding in making treatment decisions, including surgical options, early formulation of rehabilitation plans, and efficient utilization of medical resources.

DOI： 10.1159/000543362

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Language：English   Publisher：National Center for Global Health and Medicine  

<p>This study aimed to determine whether procedure volume is associated with 30-day mortality following endovascular thrombectomy (EVT) or intravenous recombinant tissue plasminogen activator (IV rt-PA) for stroke during the introduction period of EVT in Japan. Using nationwide claims records, we investigated data from 8,227 patients undergoing EVT and 13,406 and 6,035 patients undergoing rt-PA monotherapy in hospitals with and without EVT capability, respectively, between April 2014 and February 2016 in Japan. Procedure volume was categorized into three groups according to tertiles of the annual number of EVTs or IV rt-PA injections performed in the hospitals. Hierarchical logistic regression demonstrated that the odds ratio (95% confidence interval) of 30-day mortality following EVT was significantly lower in middle- (0.77 [0.62–0.96]) and high- (0.69 [0.53–0.89]) volume hospitals than that in low-volume hospitals even after adjusting for potential confounding factors. The generalized additive mixed models revealed no obvious threshold volume of EVT to reduce the mortality risk. By contrast, mortality risk following IV rt-PA monotherapy did not decrease in hospitals without EVT capability but did with increasing IV rt-PA volume in hospitals with EVT capability (P for heterogeneity 0.003). The risk of 30-day mortality after EVT for acute ischemic stroke decreased linearly according to EVT procedure volume in each hospital. However, the association between IV rt-PA volume and mortality risk was modified by the hospital's EVT capability. Further research is warranted to determine whether the volume-outcome relationship we observed is a temporary phenomenon following EVT or a consistent trend over time.</p>

DOI： 10.35772/ghm.2025.01053

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Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publisher：PLoS ONE  

Background It is unclear whether abdominal adiposity has an additional effect on post-stroke outcomes. This study aimed to determine whether waist circumference (WC) is independently associated with clinical outcomes after acute ischemic stroke. Methods We enrolled patients with acute ischemic stroke from a multicenter hospital-based stroke registry in Fukuoka, Japan. We measured WC on admission and categorized patients into four groups (Q1–Q4) according to the quartiles in females and males. The clinical outcomes were poor functional outcome (modified Rankin scale score 2–6) and death from any cause. Logistic regression analysis was performed to estimate the odds ratio and 95% confidence interval of the outcomes of interest after adjusting for potential confounding factors, including body mass index (BMI). Results A total of 11,989 patients (70.3±12.2 years, females: 36.1%) were included in the analysis. The risk of poor functional outcome significantly decreased for Q2–Q4 (vs. Q1) at discharge and Q2–Q3 (vs. Q1) at 3 months, even after adjusting for potential confounders, including BMI. In contrast, adjustment of BMI eliminated the significant association between WC and all-cause death at discharge and 3 months. The association between high WC and favorable functional outcome was not affected by fasting insulin levels or homeostatic model assessment for insulin resistance and was only found in patients without diabetes (P = 0.02 for heterogeneity). Conclusions These findings suggest that abdominal adiposity has an additional impact on post-stroke functional outcome, independent of body weight and insulin action.

DOI： 10.1371/journal.pone.0296833

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Language：English   Publisher：PLoS ONE  

Background This study aimed to examine whether post-stroke early body temperature is associated with neurological damage in the acute phase and functional outcomes at three months. Methods We included 7,177 patients with acute ischemic stroke within 24 h of onset. Axillary temperature was measured daily in the morning for seven days. Mean body temperature was grouped into five quintiles (Q1: 35.1–36.5◦C, Q2: 36.5–36.7◦C, Q3: 36.7–36.8◦C, Q4: 36.8–37.1◦C, and Q5: 37.1–39.1◦C). Clinical outcomes included neurological improvement during hospitalization and poor functional outcome (modified Rankin scale score, 3–6) at three months. A logistic regression analysis was performed to evaluate the association between body temperature and clinical outcomes. Results The patient’s mean (SD) age was 70.6 (12.3) years, and 35.7% of patients were women. Mean body temperature was significantly associated with less neurological improvement from Q2 (odds ratios [95% confidence interval], 0.77 [0.65–0.99] vs. Q1) to Q5 (0.33 [0.28–0.40], P for trend <0.001) even after adjusting for potential confounders, including baseline neurological severity, C-reactive protein levels, and post-stroke acute infections. The multivariable-adjusted risk of poor functional outcome linearly increased from Q2 (1.36 [1.03–1.79]) to Q5 (6.44 [5.19–8.96], P for trend <0.001). These associations were maintained even in the analyses excluding patients with acute infectious diseases. Multivariable-adjusted risk of poor functional outcome was higher in patients with early body temperature elevation on days 1–3 and with longer duration with body temperature >37.0◦C. Conclusions Post-stroke early high body temperature is independently associated with unfavorable outcomes following acute ischemic stroke.

DOI： 10.1371/journal.pone.0296639

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Language：English   Publisher：PLoS ONE  

Background The association between clinical outcomes in ischemic stroke patients and decreases in serum uric acid levels, which often occur during the acute phase, remains unknown. Herein, we aimed to investigate the association using a large-scale, multicenter stroke registry. Methods We analyzed 4,621 acute ischemic stroke patients enrolled in the Fukuoka Stroke Registry between June 2007 and September 2019 whose uric acid levels were measured at least twice during hospitalization (including on admission). The study outcomes were poor functional outcome (modified Rankin Scale score ≥3) and functional dependence (modified Rankin Scale score 3–5) at 3 months after stroke onset. Changes in uric acid levels after admission were evaluated using a decrease rate that was classified into 4 sex-specific grades ranging from G1 (no change/increase after admission) to G4 (most decreased). Multivariable logistic regression analyses were used to assess the associations between decreases in uric acid levels and the outcomes. Results The frequencies of the poor functional outcome and functional dependence were lowest in G1 and highest in G4. The odds ratios (95% confidence intervals) of G4 were significantly higher for poor functional outcome (2.66 [2.05–3.44]) and functional dependence (2.61 [2.00–3.42]) when compared with G1 after adjusting for confounding factors. We observed no heterogeneity in results for subgroups categorized according to age, sex, stroke subtype, neurological severity, chronic kidney disease, or uric acid level on admission. Conclusions Decreases in serum uric acid levels were independently associated with unfavorable outcomes after acute ischemic stroke.

DOI： 10.1371/journal.pone.0287721

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Language：English   Publisher：Scientific Reports  

This study aimed to determine whether body weight is associated with functional outcome after acute ischemic stroke. We measured the body mass index (BMI) and assessed clinical outcomes in patients with acute ischemic stroke. The BMI was categorized into underweight (< 18.5 kg/m2), normal weight (18.5–22.9 kg/m2), overweight (23.0–24.9 kg/m2), and obesity (≥ 25.0 kg/m2). The association between BMI and a poor functional outcome (modified Rankin Scale [mRS] score: 3–6) was evaluated. We included 11,749 patients with acute ischemic stroke (70.3 ± 12.2 years, 36.1% women). The risk of a 3-month poor functional outcome was higher for underweight, lower for overweight, and did not change for obesity in reference to a normal weight even after adjusting for covariates by logistic regression analysis. Restricted cubic splines and SHapley Additive exPlanation values in eXtreme Gradient Boosting model also showed non-linear relationships. Associations between BMI and a poor functional outcome were maintained even after excluding death (mRS score: 3–5) or including mild disability (mRS score: 2–6) as the outcome. The associations were strong in older patients, non-diabetic patients, and patients with mild stroke. Body weight has a non-linear relationship with the risk of a poor functional outcome after acute ischemic stroke.

DOI： 10.1038/s41598-023-35894-y

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Language：English   Publisher：Stroke  

Background: It remains unclear how chronic kidney disease and its underlying pathological conditions, kidney dysfunction, and kidney damage, are associated with cardiovascular outcomes. This study aimed to determine whether kidney dysfunction (ie, decreased estimated glomerular filtration rate), kidney damage (ie, proteinuria), or both are associated with the long-term outcomes after ischemic stroke. Methods: A total of 12 576 patients (mean age, 73.0±12.6 years; 41.3% women) with ischemic stroke who were registered in a hospital-based multicenter registry, Fukuoka Stroke Registry, between June 2007 and September 2019, were prospectively followed up after stroke onset. Kidney function was assessed by estimated glomerular filtration rate and categorized into G1: ≥60 mL/(min·1.73 m2), G2: 45-59 mL/(min·1.73 m2), and G3: <45 mL/(min·1.73 m2). Kidney damage was evaluated by proteinuria using a urine dipstick test and classified into P1: -, P2: ±/1+, and P3: ≥2+. Hazard ratios and 95% CI for events of interest were estimated by a Cox proportional hazards model. Long-term outcomes included recurrence of stroke and all-cause death. Results: During the median follow-up of 4.3 years (interquartile range, 2.1-7.3 years), 2481 patients had recurrent stroke (48.0/1000 patient-years) and 4032 patients died (67.3/1000 patient-years). Chronic kidney disease was independently associated with increased risks of stroke recurrence and all-cause death even after adjustment for multiple confounding factors, including traditional cardiovascular risk factors. Both estimated glomerular filtration rate and proteinuria were independently associated with increased risks of stroke recurrence (multivariable-adjusted hazard ratio [95% CI], G3: 1.22 [1.09-1.37] versus G1, P3: 1.25 [1.07-1.46] versus P1) and death (G3: 1.45 [1.33-1.57] versus G1, P3: 1.62 [1.45-1.81] versus P1). In subgroup analyses, effect modifications were found in the association of proteinuria with death by age and stroke subtype. Conclusions: Kidney dysfunction and kidney damage were independently, but differently, associated with increased risks of recurrent stroke and all-cause death.

DOI： 10.1161/STROKEAHA.122.040958

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Language：English   Publisher：Journal of the Neurological Sciences  

Background and purpose: This study examined the association between age and clinical outcomes after ischemic stroke, and whether the effect of age on post-stroke outcomes can be modified by various factors. Methods: We included 12,171 patients with acute ischemic stroke, who were functionally independent before stroke onset, in a multicenter hospital-based study conducted in Fukuoka, Japan. Patients were categorized into six groups according to age: ≤ 45, 46–55, 56–65, 66–75, 76–85, and > 85 years. Logistic regression analysis was performed to estimate an odds ratio for poor functional outcome (modified Rankin scale score of 3–6 at 3 months) for each age group. Interaction effects of age and various factors were analyzed using a multivariable model. Results: The mean age of the patients was 70.3 ± 12.2 years, and 63.9% were men. Neurological deficits at onset were more severe in the older age groups. The odds ratio of poor functional outcome linearly increased (P for trend <0.001), even after adjusting for potential confounders. Sex, body mass index, hypertension, and diabetes mellitus significantly modified the effect of age on the outcome (P < 0.05). The unfavorable effect of older age was greater in female patients and those with low body weight, whereas the protective effect of younger age was smaller in patients with hypertension or diabetes mellitus. Conclusions: Functional outcome worsened with age in patients with acute ischemic stroke, especially in females and those with low body weight, hypertension, or hyperglycemia.

DOI： 10.1016/j.jns.2023.120589

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Cerebrovascular Diseases  

Introduction: Data on sex differences in poststroke functional status for a period longer than 1 year based on large cohorts are sparse. This study aimed to determine whether there are sex differences in long-term functional decline after ischemic stroke. Methods: We tracked functional status for 5 years among 3-month survivors of acute ischemic stroke and compared outcomes between women and men using a large-scale hospital-based stroke registry in Fukuoka, Japan. Functional status was assessed using the modified Rankin Scale (mRS). Functional dependency was defined as an mRS score of 3, 4, or 5. Logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals of outcomes after adjusting for possible confounders. Results: A total of 8,446 patients (71.9 ± 12.5 years, 3,377 (40.0%) female patients) were enrolled in this study. Female sex was associated with a higher risk of functional dependency at 5 years poststroke even when adjusting for age, 3-month mRS score, and other confounding factors (multivariable-adjusted OR vs. men, 1.56 [95% confidence interval, 1.26-1.93]). This significant association of female sex with higher dependency at 5 years was also found among patients who were independent at 3 months poststroke. Subgroup analysis showed that increased risk of functional dependency in female patients was more marked in patients aged ≥75 years than in those aged <75 years (p for heterogeneity = 0.02). Conversely, female sex was associated with a lower risk of death. No sex difference was observed in stroke recurrence during 5 years poststroke. Discussion/Conclusion: This longitudinal observational study suggests that female sex was independently associated with an increased risk of functional decline in the chronic phase of stroke, especially in older patients. There was no sex difference in 5-year stroke recurrence, and thus, other factors might be involved in more significant deterioration of functional status in female survivors of ischemic stroke. Further studies are needed to elucidate underlying causes of sex differences in long-term functional decline after stroke.

DOI： 10.1159/000526940

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Language：English   Publisher：Regulatory Toxicology and Pharmacology  

The benchmark dose (BMD) approach is updated to create an international harmonizing process following rapid theoretical sophistication. We calculated the lower limit of BMD confidence interval (BMDL) for carcinogenicity based on 193 tumorigenicity bioassay data published in 50 pesticide risk assessment reports by the Food Safety Commission of Japan (FSCJ) to validate the appropriateness and necessity for the refinement of the FSCJ-established BMD guidance. Three well-known BMD software, PROAST, BMDS, and BBMD were used to compare their BMDLs with no-observed-adverse-effect levels (NOAELs) for carcinogenicity. Recently implemented methodologies such as model averaging or Bayesian inference were also used. Our results indicate that the BMD approach provides a point of departure similar to the NOAEL approach if the data used exhibit a clear dose-response relationship. In some cases, particularly in software with a frequentist approach, the calculation failed to provide BMDL or provided considerably lower BMDLs than NOAELs. However, most of the datasets that resulted in failed calculations or extremely low BMDLs exhibited unclear dose-response relationships, i.e., non-monotonous and sporadic responses. The expert review on the shape of the dose-response plot would help better apply the BMD approach. Furthermore, we observed that Bayesian approaches provided fewer failed or extreme BMD calculations than the frequentist approaches.

DOI： 10.1016/j.yrtph.2022.105201

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Language：English   Publisher：PLoS ONE  

Background Very few comparative studies have focused on the differences in the causes of ischemic stroke between young adults and non-young adults. This study was performed to determine what causes of ischemic stroke are more important in young adults than in non-young adults using a large-scale multicenter hospital-based stroke registry in Fukuoka, Japan. Methods and results We investigated data on 15,860 consecutive patients aged ≥18 years with acute ischemic stroke (mean age: 73.5 ± 12.4 years, 58.2% men) who were hospitalized between 2007 and 2019. In total, 779 patients were categorized as young adults (≤50 years of age). Although vascular risk factors, including hypertension, diabetes mellitus, and dyslipidemia, were less frequent in young adults than in non-young adults, the prevalence of diabetes mellitus and dyslipidemia in young adults aged >40 years were comparable to those of non-young adults. Lifestyle-related risk factors such as smoking, drinking, and obesity were more frequent in young adults than in non-young adults. As young adults became older, the proportions of cardioembolism and stroke of other determined etiologies decreased, but those of large-artery atherosclerosis and small-vessel occlusion increased. Some embolic sources (high-risk sources: arterial myxoma, dilated cardiomyopathy, and intracardiac thrombus; medium-risk sources: atrial septal defect, nonbacterial thrombotic endocarditis, patent foramen ovale, and left ventricular hypokinesis) and uncommon causes (vascular diseases: reversible cerebral vasoconstriction syndrome, moyamoya disease, other vascular causes, arterial dissection, and cerebral venous thrombosis; hematologic diseases: antiphospholipid syndrome and protein S deficiency) were more prevalent in young adults than in non-young adults, and these trends decreased with age. Conclusions Certain embolic sources and uncommon causes may be etiologically important causes of ischemic stroke in young adults. However, the contribution of conventional vascular risk factors and lifestyle-related risk factors is not negligible with advancing age, even in young adults.

DOI： 10.1371/journal.pone.0268481

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Language：Japanese   Publisher：Japanese Pharmacological Society  

<p>Benchmark Dose (BMD) approach is the way to calculate the risk at the lower dosage of chemical exposure, applying a mathematical model to the dose-response relationship. Although a number of the guidelines and software have been developed worldwide, the harmonization of BMD application is still undergoing. Before applying in actual risk assessment, it is essential to evaluate whether the BMD and NOAEL approaches give the same range of POD values and how different BMD values the major BMD software would give.</p><p>Here, we calculated the lower limit of BMD confidence interval (BMDL) from 201 tumorigenicity data publicized in the pesticide risk assessment reports by the Food Safety Commission of Japan (FSCJ). We applied three well-known BMD software, PROAST, BMDS, and BBMD, to compare their BMDLs to NOAELs and LOAELs and between the recently implemented methodologies such as model averaging (MA) or Bayesian inference.</p><p>Our result indicates that the BMD approach gives Point of Departure (POD) similar to the NOAEL approach if the data applied show a clear dose-response relationship. However, most of the datasets that resulted in failed calculation or extremely low BMDLs showed unclear dose-response relationships, such as non-monotonous and sporadic responses. We also noted that the Bayesian inference software gave failed calculation or extreme BMDLs less than the frequentist approaches.</p>

DOI： 10.1254/jpssuppl.95.0_1-p-075

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)