Introduction: Acute ischemic stroke (AIS) is a leading cause of mortality and disability worldwide. Social Isolation (SI) has been identified as a modifiable risk factor for stroke and a contributing factor to poorer functional outcomes. SI has been increasingly recognized as a significant stressor that can impact metabolic health through various biological mechanisms. The relationship between SI and metabolic dysfunction is complex and involves interactions among the neuroendocrine, immune, and metabolic systems. However, studies investigating the role of SI in the development of host metabolic dysfunction in the context of stroke are limited. Hypothesis: Isolation alters metabolic pathways after stroke. Methods: We analyzed untargeted serum metabolic profiles of AIS patients (N=100) 24 hours after last known well, along with questionnaires regarding SI and loneliness, to assess metabolic differences between socially isolated and socially interactive individuals. Samples were collected from patients ranging from 29 to 89 years old, with 66 males and 34 females. SI was measured via the Lubben Social Network Scale collected from patients during their hospitalization. Results: We found that there is a significant correlation between Lubben Social Network score and alterations in genes related to insulin resistance and glycolysis (FDR adjusted p <0.05). Interestingly, acetyl-CoA carboxylase and glycogen phosphorylase were significantly downregulated in patients with lower Lubben Social Network scores, suggesting isolated individuals have lower rates of metabolic turnover. Our results also demonstrated that suppressor of cytokine signaling (SOCS) was shown to be upregulated with an increased Lubben Social Network scores, suggesting that SI patients have systemic cytokine signaling and inflammation compared to non-SI stroke patients. Conclusion: In summary, systemic alterations in metabolic activity are pronounced after stroke, correlate with SI status pre-injury and functional outcome post-injury, and have the potential to directly affect cellular function. We demonstrated that socially isolated individuals are more likely to have metabolic dysfunction, which is a significant risk factor for post stroke disability and recurrent stroke. These metabolic factors should be analyzed additionally through the lens of sex, race, and other social determinants of health that affect stroke severity and functional outcomes.

Abstract Background Accumulating evidence shows that sodium-glucose co-transporter-2 (SGLT-2) inhibitors reduce cardiovascular outcomes. However, this favorable effect is unclear for newly atrial fibrillation (AF) development compared to other anti-diabetic drugs. Purpose We investigated the association of SGLT-2 inhibitor for newly AF development compared to dipeptidyl peptidase-4 (DPP-4) inhibitors in patients with type 2 diabetes. Methods Using the Korean National Health Insurance Service database, among 2,160,911 type 2 diabetes patients (age ≥20 years) between 1 May 2016 and 31 December 2018, we studied 42,806 patients with SGLT-2 inhibitors and 448,715 patients with DPP-4 inhibitors who had not prior AF diagnosis. Propensity score-matching (1:1 ratio) was used to correct for differences between the groups. Results During a median follow-up of 1.3 years, after propensity score matching, compared with patients with DPP-4 inhibitors (n=42,786), patients with SGLT-2 inhibitors (n=42,786) have shown lower incidence and risk of AF (2.7 and 3.3 per 1000 person-years; hazard ratio 0.73, 95% confidence interval 0.55-0.97; p=0.028) aand an absolute rate difference of −0.7 [95% confidence interval (CI) −1.3 to −0.1, p=0.034] per 1000 person-years by on-treatment analysis. In intention-to-treat analysis, these results were consistent (2.6 and 3.2 per 1000 person-years; hazard ratio 0.83, 95% confidence interval 0.66-1.03; p=0.092) with an absolute rate difference of −0.5 [95% confidence interval (CI) −1.2 to −0.1, p=0.093] per 1000 person-years . In subgroup analysis, SGLT-2 inhibitors were associated with lower risks of AF in heart failure compared to their counterparts in intention-to-treat analysis (p for interaction=0.036). Conclusion Based on this nationwide cohort of type 2 diabetes patients treated with SGLT-2 inhibitors or DPP-4 inhibitors, SGLT-2 inhibitors were associated with protection against newly AF development after adjusting for clinical confounders.Incidence rates and adjusted HR

We appreciate Dr. Lai's interest and comments on our article.[1] In our current study, we demonstrated an association between aspirin use and the risk of hepatocellular carcinoma (HCC) using a Korean nationwide population‐based cohort of patients with chronic hepatitis B. Immortal time bias, which can often mislead to an overestimation of the effect size, can be involved in most observational studies evaluating drug effects.[2] Immortal time refers to a follow‐up period during which outcomes could not have occurred.[3,4] It typically occurs when there is a gap between cohort entry and an initial exposure to the drug, in which the span of time is inevitably event‐free and thus “immortal.” In our study, because the index date of the aspirin‐treated group was set to the 180th day after the date of the first aspirin prescription, immortal time could not have intervened. If the index date of a patient who was prescribed aspirin for 90 days had been set to the first prescription date, those 90 days would correspond to an immortal time, during which the patient necessarily had to be event‐free. In Case A, we believe the period after the patient has been exposed to aspirin for 90 days, which Dr. Lai suggests to be an “immortal time,” should be regarded only as an “unexposed period” because an event can occur at any time point during that period. In addition, in Case B, Dr. Lai considered the period between stopping and resuming aspirin an immortal time. Because an effective treatment duration of aspirin for HCC chemoprevention remains unclear, we adopted a selection criterion of 90 consecutive days of aspirin use to define aspirin users.[5] Discontinuation or resumption of aspirin after a sufficient exposure to aspirin (≥90 consecutive days) was not considered in the analysis. Thus, the period that Dr. Lai designated as immortal time in Case B cannot be called immoral time in the same context as aforementioned. CONFLICT OF INTEREST Yun Bin Lee received grants from Samjin Pharmaceuticals and Yuhan Pharmaceuticals.

Introduction: Acute ischemic stroke (AIS) is a leading cause of mortality and disability worldwide. Social Isolation (SI) has been identified as a modifiable risk factor for stroke and a contributing factor to poorer functional outcomes. SI has been increasingly recognized as a significant stressor that can impact metabolic health through various biological mechanisms. The relationship between SI and metabolic dysfunction is complex and involves interactions among the neuroendocrine, immune, and metabolic systems. However, studies investigating the role of SI in the development of host metabolic dysfunction in the context of stroke are limited. Hypothesis: Isolation alters metabolic pathways after stroke. Methods: We analyzed untargeted serum metabolic profiles of AIS patients (N=100) 24 hours after last known well, along with questionnaires regarding SI and loneliness, to assess metabolic differences between socially isolated and socially interactive individuals. Samples were collected from patients ranging from 29 to 89 years old, with 66 males and 34 females. SI was measured via the Lubben Social Network Scale collected from patients during their hospitalization. Results: We found that there is a significant correlation between Lubben Social Network score and alterations in genes related to insulin resistance and glycolysis (FDR adjusted p <0.05). Interestingly, acetyl-CoA carboxylase and glycogen phosphorylase were significantly downregulated in patients with lower Lubben Social Network scores, suggesting isolated individuals have lower rates of metabolic turnover. Our results also demonstrated that suppressor of cytokine signaling (SOCS) was shown to be upregulated with an increased Lubben Social Network scores, suggesting that SI patients have systemic cytokine signaling and inflammation compared to non-SI stroke patients. Conclusion: In summary, systemic alterations in metabolic activity are pronounced after stroke, correlate with SI status pre-injury and functional outcome post-injury, and have the potential to directly affect cellular function. We demonstrated that socially isolated individuals are more likely to have metabolic dysfunction, which is a significant risk factor for post stroke disability and recurrent stroke. These metabolic factors should be analyzed additionally through the lens of sex, race, and other social determinants of health that affect stroke severity and functional outcomes.

Abstract Background Accumulating evidence shows that sodium-glucose co-transporter-2 (SGLT-2) inhibitors reduce cardiovascular outcomes. However, this favorable effect is unclear for newly atrial fibrillation (AF) development compared to other anti-diabetic drugs. Purpose We investigated the association of SGLT-2 inhibitor for newly AF development compared to dipeptidyl peptidase-4 (DPP-4) inhibitors in patients with type 2 diabetes. Methods Using the Korean National Health Insurance Service database, among 2,160,911 type 2 diabetes patients (age ≥20 years) between 1 May 2016 and 31 December 2018, we studied 42,806 patients with SGLT-2 inhibitors and 448,715 patients with DPP-4 inhibitors who had not prior AF diagnosis. Propensity score-matching (1:1 ratio) was used to correct for differences between the groups. Results During a median follow-up of 1.3 years, after propensity score matching, compared with patients with DPP-4 inhibitors (n=42,786), patients with SGLT-2 inhibitors (n=42,786) have shown lower incidence and risk of AF (2.7 and 3.3 per 1000 person-years; hazard ratio 0.73, 95% confidence interval 0.55-0.97; p=0.028) aand an absolute rate difference of −0.7 [95% confidence interval (CI) −1.3 to −0.1, p=0.034] per 1000 person-years by on-treatment analysis. In intention-to-treat analysis, these results were consistent (2.6 and 3.2 per 1000 person-years; hazard ratio 0.83, 95% confidence interval 0.66-1.03; p=0.092) with an absolute rate difference of −0.5 [95% confidence interval (CI) −1.2 to −0.1, p=0.093] per 1000 person-years . In subgroup analysis, SGLT-2 inhibitors were associated with lower risks of AF in heart failure compared to their counterparts in intention-to-treat analysis (p for interaction=0.036). Conclusion Based on this nationwide cohort of type 2 diabetes patients treated with SGLT-2 inhibitors or DPP-4 inhibitors, SGLT-2 inhibitors were associated with protection against newly AF development after adjusting for clinical confounders.Incidence rates and adjusted HR

We appreciate Dr. Lai's interest and comments on our article.[1] In our current study, we demonstrated an association between aspirin use and the risk of hepatocellular carcinoma (HCC) using a Korean nationwide population‐based cohort of patients with chronic hepatitis B. Immortal time bias, which can often mislead to an overestimation of the effect size, can be involved in most observational studies evaluating drug effects.[2] Immortal time refers to a follow‐up period during which outcomes could not have occurred.[3,4] It typically occurs when there is a gap between cohort entry and an initial exposure to the drug, in which the span of time is inevitably event‐free and thus “immortal.” In our study, because the index date of the aspirin‐treated group was set to the 180th day after the date of the first aspirin prescription, immortal time could not have intervened. If the index date of a patient who was prescribed aspirin for 90 days had been set to the first prescription date, those 90 days would correspond to an immortal time, during which the patient necessarily had to be event‐free. In Case A, we believe the period after the patient has been exposed to aspirin for 90 days, which Dr. Lai suggests to be an “immortal time,” should be regarded only as an “unexposed period” because an event can occur at any time point during that period. In addition, in Case B, Dr. Lai considered the period between stopping and resuming aspirin an immortal time. Because an effective treatment duration of aspirin for HCC chemoprevention remains unclear, we adopted a selection criterion of 90 consecutive days of aspirin use to define aspirin users.[5] Discontinuation or resumption of aspirin after a sufficient exposure to aspirin (≥90 consecutive days) was not considered in the analysis. Thus, the period that Dr. Lai designated as immortal time in Case B cannot be called immoral time in the same context as aforementioned. CONFLICT OF INTEREST Yun Bin Lee received grants from Samjin Pharmaceuticals and Yuhan Pharmaceuticals.

Abstract Background and Aims Studies on differential effect of aspirin therapy on HCC risk across the spectrum of liver diseases are lacking. We investigated the association between aspirin use and risks of HCC, liver‐associated death, and major bleeding in chronic hepatitis B (CHB) patients with or without cirrhosis. Approach and Results We identified 329,635 eligible adults with CHB from 2007 through 2017, using the Korean National Health Insurance Service database, including patients who received aspirin for ≥90 consecutive days ( n = 20,200) and patients who never received antiplatelet therapy ( n = 309,435). Risks of HCC, liver‐associated mortality, and major bleeding were estimated in a propensity‐score–matched cohort (19,003 pairs), accounting for competing risks. With a median follow‐up of 6.7 years, 10‐year cumulative incidence of HCC was 9.5% in the aspirin‐treated group and 11.3% in the untreated group (adjusted subdistribution hazard ratio [aSHR], 0.85; 95% CI, 0.78–0.92). However, among patients with cirrhosis (2479 pairs), an association of aspirin use with HCC risk was not evident (aSHR, 1.00; 95% CI, 0.85–1.18). Cirrhosis status had a significant effect on the association between aspirin use and HCC risk ( pinteraction , n = 0.04). Aspirin use was also associated with lower liver‐associated mortality (aSHR, 0.80; 95% CI, 0.71–0.90). Moreover, aspirin use was not associated with major bleeding risk (aSHR, 1.09; 95% CI, 0.99–1.21). Conclusions Aspirin use was associated with reduced risks of HCC and liver‐associated mortality in adults with CHB. Cirrhosis status had a substantial effect on the association between aspirin use and HCC risk.

INTRODUCTION: This multicenter, double-blind, placebo-controlled trial, commissioned by South Korea's Ministry of Food and Drug Safety, evaluated the effect of oxiracetam for preventing post-stroke cognitive impairment (PSCI) and explored potential interaction with physical activity using neuroimaging. PATIENTS AND METHODS: Patients at high risk of PSCI, reporting subjective cognitive decline ⩾3 months after stroke, were randomized 1:1 to receive oxiracetam or placebo for 36 weeks. Physical activity was tracked via wrist-worn actigraphy. Coprimary endpoints were changes in Mini-Mental State Examination (MMSE) and Clinical Dementia Rating-Sum of Boxes (CDR-SB). Secondary outcomes included neuropsychological assessments and resting-state functional magnetic resonance imaging network metrics. RESULTS: Of 500 enrolled participants (mean age 68.9 years; median 32 months post-stroke), 457 completed the study. There were no statistically significant differences between groups in changes in MMSE (oxiracetam: +0.13 ± 2.27 vs placebo: +0.27 ± 2.09; p = 0.49) or CDR-SB scores (-0.14 ± 0.70 vs -0.08 ± 0.80; p = 0.38). No evidence of interaction was observed between oxiracetam and physical activity. Exploratory analyses suggested favorable trends in functional segregation and CDR-SB scores among highly active oxiracetam participants. DISCUSSION AND CONCLUSION: Oxiracetam did not demonstrate benefit in preventing PSCI in high-risk patients. These findings support the recent regulatory decision to suspend its use in South Korea.

ABSTRACT Background and Purpose Ambient air pollution is an established risk factor for incident stroke, but whether post-discharge pollutant exposure influences stroke recurrence remains unknown. We investigated the association between post-discharge exposure to six ambient air pollutants and stroke recurrence in patients with acute ischemic stroke. Methods We analyzed data from 27,346 patients in the CRCS-K-NIH nationwide multicenter registry of acute ischemic stroke patients (2014–2021) with confirmed ischemic stroke, residential address data, and matched air quality records. The primary exposure was the 3-month post-discharge average concentration of PM 10 , PM 2.5 , NO₂, SO₂, CO, and O₃, assessed at the district level using inverse-distance weighted interpolation. The primary outcome was stroke recurrence from 3 to 15 months post-discharge. Cause-specific Cox proportional hazards models accounting for the multilevel data structure were used, with all-cause mortality as a competing risk. Restricted cubic splines assessed nonlinear dose-response relationships. Results During follow-up (median 364.8 days), 765 patients experienced stroke recurrence and 471 died. Among the six pollutants, only SO₂ showed a statistically significant association with recurrence (P for overall association in the restricted cubic spline analysis = 0.024). A potential threshold was identified at approximately 8.2 ppb, above which recurrence risk increased progressively (P for non-linearity = 0.095). The association was numerically stronger among older adults (≥75 years; P for interaction = 0.051) and women (P for interaction = 0.062). The highest SO₂ concentrations were observed in harbor cities (Incheon, Ulsan, Busan), consistent with maritime shipping emissions. No significant associations were observed for the other five pollutants. Conclusions Elevated post-discharge SO₂ exposure is associated with increased stroke recurrence risk, particularly in harbor regions and among older adults and women. These findings support incorporating ambient air quality monitoring into secondary stroke prevention strategies.

BACKGROUND: Whether comprehensive prestroke risk factor (RF) management-defined by the extent to which existing major RFs meet prespecified treatment and biomarker criteria-is associated with 3-month functional outcomes after ischemic stroke remains unclear. METHODS: We analyzed patients with ischemic stroke from the CRCS-K-NIH (Clinical Research Collaborations for Stroke in Korea-National Institutes for Health) registry (2011-2022), a multicenter stroke registry in Korea. Hypertension, diabetes, dyslipidemia, and atrial fibrillation were considered as major RFs for ischemic stroke. Comprehensive prestroke RF management was categorized as well controlled (all present RFs meeting study-defined control criteria), partially controlled (some RFs meeting this criteria), or poorly controlled (no RFs meeting this criteria). The primary outcome was 3-month modified Rankin Scale score of 0 to 2, indicating functional independence (good outcome). RESULTS: Among 63 570 patients with ≥1 major RFs, 28.6% were poorly controlled, 35.6% partially controlled, and 35.8% well controlled. The rate of 3-month good outcome was 66.0% among those with 1 RF, 60.8% in 2, and 55.0% in ≥3. After multivariable adjustment, both well-controlled and partially controlled groups had significantly higher odds of achieving good 3-month outcomes compared with poorly controlled patients, consistently across RF burden strata(well controlled: adjusted odds ratio, 1.16 [95% CI, 1.08-1.25] for 1 RF, 1.34 [95% CI, 1.21-1.48] for 2, and 1.23 [95% CI, 1.03-1.48] for ≥3; partially controlled: 1.16 [95% CI, 1.06-1.26] for 2; 1.22 [95% CI, 1.05-1.42] for ≥3) and in the overall cohort (well controlled: 1.22 [95% CI, 1.15-1.29], partially controlled: 1.14 [95% CI, 1.07-1.22]). CONCLUSIONS: Comprehensive prestroke RF management, defined by study-specific treatment- and biomarker-based criteria, was independently associated with a higher likelihood of favorable 3-month outcomes across levels of RF burden. These findings suggest that effective prestroke management of existing RFs may improve poststroke functional outcomes, regardless of the number of RFs present.

Background: Anemia has been shown to be independently associated with poor outcomes in critically ill patients.Despite this, the impact of hemoglobin (Hb) levels on prognosis among patients with severe acute ischemic stroke (AIS) requiring neurocritical care has not been well