Atsushi Takayama

Early vs Late (E–L) treatment initiation comparisons, which are prone to immortal time bias, are widely considered amenable to causal inference through target trial emulation (TTE) using clone–censor–weighting (CCW). However, whether standard CCW yields a well-defined causal estimand for the E–L comparison under ideal implementation conditions has not been formally examined. We conducted a structural simulation study to evaluate CCW–based TTE for E–L comparisons. The design varied along 3 dimensions: treatment-initiation mechanisms (random vs baseline–confounded timing), benefit–harm structures governing delayed-treatment harm and posttreatment benefit, and 5 distinct E–L initiation-window configurations. We implemented CCW as conventionally recommended and summarized the estimated 12-month marginal risk ratios across settings. Depending on the placement and structure of the initiation windows, estimated risk ratios exhibited systematic window-dependent variation, including direction reversals across window specifications, even in settings where the true marginal causal contrast was 1 by design. These patterns were not consistently explained by weight instability or lack of support overlap. Our findings indicate that, in E–L comparisons, the window-defined strategy contrast estimated using CCW–based TTE can be strongly shaped by risk accumulated before treatment initiation under the specified windows, underscoring the need for caution when interpreting E–L analyses.

Background: Boredom proneness is a common yet underexplored psychological trait among older adults, linked to depression, loneliness, and reduced quality of life. Despite its clinical relevance, validated instruments for assessing boredom in this population are scarce. This study aimed to validate the Japanese version of the Boredom Proneness Scale (JBPS) and to develop a short form specifically designed for older adults (s-BPSO). Methods: We conducted two cross-sectional surveys in Japan. The first, a paper-based survey ( n = 5,382; mean age = 82), targeted community-dwelling older adults aged ≥ 75 years in Sukagawa City. The second, an internet-based national survey ( n = 4,124; mean age = 66), recruited participants aged ≥ 50 years. Structural validity of the JBPS was assessed via exploratory and confirmatory factor analysis. Reliability was evaluated using internal consistency and test–retest analysis. The s-BPSO was derived using item response theory and validated independently using data from the second survey. Convergent validity was examined through correlations with validated measures of mental and physical health. Results: The JBPS demonstrated good internal consistency (Cronbach’s α = 0.87) and test–retest reliability (ICC = 0.84). Exploratory factor analysis supported a three-factor structure, though model fit in confirmatory analysis was modest. The JBPS showed strong correlations with depressive symptoms, loneliness, and HRQOL measures. Existing short versions of the BPS performed poorly in this older sample. A newly developed 6-item short version (s-BPSO) based on a two-factor structure exhibited acceptable model fit (CFI = 0.987, RMSEA = 0.056), high internal consistency (α = 0.80), and strong correlation with the full JBPS ( r = 0.86). Higher boredom scores were associated with older age, lower income and education, reduced IADL, and lower HRQOL. Conclusions: The JBPS and s-BPSO are valid and reliable instruments for assessing boredom proneness among older Japanese adults. The s-BPSO provides a concise alternative for use in epidemiological surveys and clinical practice. These tools may inform interventions aimed at promoting active and mentally healthy aging, and support future cross-cultural research on aging-related psychological traits.

Traditional epidemiologic designs typically assume that the exposed and unexposed groups are mutually exclusive, forming the foundation for causal inference. Target trial emulation (TTE), an increasingly adopted framework for estimating causal effects from observational data, may not always require this assumption. Although often applied in settings with nonmutually exclusive treatment assignment, the implications of such structures for causal estimation are underexplored. In real-world contexts, patients may receive combination or single-agent treatments, or neither, leading to ambiguous group distinctions that challenge effect validity. We conducted a simulation study evaluating multiple TTE implementation strategies under nonmutually exclusive treatment assignment. Treatment overlap and covariate alignment were systematically varied to assess how emulation strategies perform under violations of mutual exclusivity. Our results show that nonmutually exclusive assignment can introduce substantial bias unless treatment overlap and positivity are explicitly addressed during propensity score estimation and outcome modeling. Notably, when covariate overlap is sufficient, nonmutually exclusive assignment can recover marginal effects with performance comparable to or exceeding mutually exclusive assignment. However, when overlap is poor, even advanced strategies fail to recover the true marginal effect. These findings underscore the importance of aligning study design, estimand, and treatment-assignment structure when applying TTE in real-world settings.

Health-related quality of life (HRQOL) is a key determinant of loss of independence (LOI) among older adults. However, the relationship between late-life HRQOL trajectory patterns and the risk of LOI remains unclear. This study utilized 5-year longitudinal data from the Sukagawa Study, and group-based trajectory modeling. HRQOL trajectories were analyzed using the mental component scale (MCS) and physical component scale (PCS) from the SF-8. Hazard ratios (HRs) and 95% confidence intervals (CIs) for LOI or death were calculated using Cox proportional hazards regression. Among 4043 participants (median age 78.8 years, interquartile range [IQR] 75.8–82.5; 56% women), HRQOL change score trajectories were categorized as decline, stable, and increase for MCS (11.7%, 81.0%, 7.2%) and PCS (10.9%, 81.4%, 7.6%). Over a mean follow-up of 66.4 months (IQR 48.0–73.0), LOI or death incidence was 42.5 per 1000 person-years (95% CI 39.8–45.2). Compared to the stable group, MCS decline was associated with higher LOI or death risk (HR 1.51, 95% CI 1.04–2.18), and an increase was associated with lower risk (HR 0.26, 95% CI 0.11–0.57). PCS decline was linked to higher LOI risk (HR 1.66, 95% CI 1.17–2.37), while an increase showed no significant association (HR 1.07, 95% CI 0.61–1.89). Longitudinal HRQOL trajectory is closely related to LOI risk among community-dwelling older adults. A declining trajectory in physical and mental components is strongly associated with higher LOI risk, while an increasing trajectory in the mental component is possibly associated with lower risk. Graphical Abstract

Aims: We aimed to investigate the temporal risk patterns of severe hypovolemia induced by sodium‐glucose cotransporter‐2 inhibitors (SGLT2i) in patients with type 2 diabetes mellitus. Materials and Methods: We conducted a self‐controlled case series using claims data from Japan. Patients who were prescribed SGLT2i for treating type 2 diabetes mellitus and experienced severe hypovolemia were enrolled. The primary analysis evaluated the adjusted incidence rate ratios (IRRs) of exposure risk periods (Days 1 to 30, Days 31 to 90, Days 91 to 180 and Days ≥181) with their corresponding 95% confidence intervals (CIs), calculated using a multivariable conditional Poisson regression model, relative to that of the unexposed control period. Results: A total of 1200 new users of SGLT2i with 1334 severe hypovolemia events were included. The median follow‐up and treatment periods were 3.66 and 2.53 years, respectively. The cohort was predominantly male (78.4%) with a median age of 54.1 years. A higher risk of severe hypovolemia associated with SGLT2i was observed particularly in the first 30 days (adjusted IRR 7.39, 95% CI 6.09–8.96) of treatment initiation. Secondary analyses highlighted the first 22 to 28 days (adjusted IRR 15.24, 95% CI 11.92–19.48) of treatment as the highest risk period for severe hypovolemia. Conclusions: SGLT2i use in patients with type 2 diabetes mellitus was associated with a higher risk of severe hypovolemia, particularly within the first 30 days of treatment initiation, with the highest risk observed during 22 to 28 days.

Background: Self-care is increasingly recognized as the foundation of person-centered healthcare and a key driver for simultaneously improving population health outcomes and reducing healthcare expenditures. While the Self-Care Inventory (SCI) has been validated in several languages, Japan lacks a standardized instrument for assessing self-care in the general adult population. Moreover, it remains unclear whether the SCI reflects culturally specific self-care behaviors and retains its psychological measurement properties in non-Western contexts. Addressing both aspects, this study aimed to evaluate the Japanese version of the SCI (JSCI) in terms of its psychometric properties and its association with concrete health behaviors.Methods: We adapted the JSCI following COSMIN guidelines using forward/backward translation, expert review, and cognitive debriefing. Psychometric evaluation was based on two samples: a nationwide web-based survey (n = 504) and a community-based paper survey (n = 75). Structural validity was examined via CFA; internal consistency via Cronbach’s alpha and McDonald’s omega; and test–retest reliability via ICCs. Convergent and criterion validity were assessed through correlations with relevant psychological constructs. Measurement invariance and DIF across modes were tested, and associations with five external self-care behaviors were evaluated using AUC.Results: The hypothesized three-factor structure of the JSCI was supported across both administration modes (CFI = 0.926–0.942; SRMR < 0.06), although some subscales had elevated RMSEA. Internal consistency was acceptable to high (α = 0.75–0.85; ω = 0.81–0.92). ICCs indicated moderate to good temporal stability. JSCI scores correlated with self-care efficacy and other related constructs, supporting convergent and criterion validity. Configural invariance was confirmed, and no significant DIF was detected across modes. JSCI scores modestly discriminated individuals engaging in concrete self-care behaviors such as physical activity, strength training, Helicobacter pylori testing, and having a regular primary or dental care provider (AUCs = 0.62–0.80).Conclusions: The JSCI demonstrated satisfactory psychometric properties and structural validity across diverse research settings. Its observed associations with a range of meaningful self-care behaviors support the scale’s ecological and practical relevance in the Japanese context. The JSCI may serve as a reliable tool for evaluating and promoting self-care in both research and population health initiatives.

Because regional physician maldistribution is considered a potential contributor to disparities in healthcare outcomes, several countries regulate the number of physicians and specialists per region to ameliorate health disparities. However, the association between regional physician maldistribution and specific outcomes, such as out-of-hospital cardiac arrest (OHCA) at the regional level, remains unclear. This study aims to evaluate the association between regional physician and specialist maldistribution and OHCA outcomes. This ecological study used 12 years of longitudinal public open datasets in Japan. We examined the disparity trends of indices of physician and specialist (emergency physicians, cardiologists, and cardiac surgeons) distribution using the Gini index. We also examined the physician uneven distribution index, a newly introduced policy index incorporating local demand and supply of medical services. Next, we analyzed the association between these distributions and OHCA-related outcomes (30-day survival rate and 30-day favorable neurological outcome). The overall number of physicians and each specialist steadily increased throughout all regions and the observation period, but the trends in the regional distribution of specialists for each region were not always synchronized with the distribution of overall physicians. Although the disparity within each index has gradually decreased, the disparity of specialists remained high compared with overall physicians. Moreover, regional physician distributions, which showed the lowest level of disparity across regions, were consistently associated with OHCA-related outcomes, whereas the regional disparity of specialists, which consistently exhibited a higher level of disparity, was not associated with the outcomes. Paradoxically, the unevenly distributed specialist distribution indices did not reflect their relevant outcomes, despite their direct involvement in the specific outcomes. Therefore, our findings call into question the validity of policies aimed at correcting the total number of physicians without considering the impact of specialists on healthcare outcomes.

Objectives: Early initiation of xanthine oxidase inhibitors may benefit patients with preserved kidney function. However, a direct comparison between the impact of allopurinol and that of febuxostat on long-term kidney function among this population is lacking. Methods: We conducted a retrospective cohort study with a new-user, active-comparator design among patients with estimated glomerular filtration rate (eGFR) within the reference range and no proteinuria. The primary outcome was a composite incidence of significant eGFR decline (≥40% decline from baseline) and all-cause death at 5 years. Adjusted hazard ratios were estimated using Cox’s proportional hazard models with inverse probability of treatment and censoring weighting. Results: We analysed 1142 patients (287 with allopurinol and 855 with febuxostat). The adjusted hazard ratios (95% confidence intervals) for allopurinol initiators compared to febuxostat initiators for the composite outcome at 5 years were 0.84 (0.74–0.95). The cause-specific adjusted hazard ratios for allopurinol initiators relative to febuxostat initiators were 0.82 (0.70–0.94) for significant eGFR decline >5 years and 1.08 (0.91–1.24) for all-cause death >5 years. Conclusions: Allopurinol initiators preserved kidney function better than febuxostat >5 years. Clinicians should exercise caution not only when prescribing but also when selecting xanthine oxidase inhibitors, even for patients with preserved kidney function.

Background: Tadalafil, commonly prescribed for benign prostatic hyperplasia (BPH), may benefit patients with Type 2 diabetes mellitus (T2DM) for glycemic markers and complications. However, the association between the long‐term use of tadalafil and the incidence of T2DM has not been investigated.Methods: We emulated a target trial of tadalafil use (5 mg/day) and the risk of T2DM using a population‐based claims database in Japan. Patients who initiated tadalafil or alpha‐blockers for BPH and had no history of diabetes diagnosis, no dispensing of glucose‐lowering drugs, and no history of hemoglobin A1c levels of ≥6.5% (47–48 mmol/mol) were included. The primary outcome was the incidence of T2DM. Pooled logistic regression was used to estimate adjusted risk ratios (RRs) and 5‐year cumulative incidence differences (CIDs).Results: A total of 5180 participants initiated tadalafil treatment and were compared with 20,049 patients who initiated alpha‐blockers. The median follow‐up time for each arm was 27.2 months (interquartile range [IQR], 12.0–47.9) in tadalafil users and 31.3 months (IQR, 13.7–57.2) in alpha‐blocker users. The incidence rates of T2DM in tadalafil and alpha‐blocker users were 5.4 (95% confidence interval [CI], 4.0–7.2) and 8.8 (95% CI, 7.8–9.8) per 1000‐person years, respectively. Initiation of tadalafil was associated with a reduced risk of T2DM (RR, 0.47; 95% CI, 0.39–0.62; 5‐year CID, −0.031; 95% CI, −0.040 to −0.019).Conclusion: The incidence of T2DM was lower in men with BPH treated with tadalafil than in those treated with alpha‐blockers. Thus, tadalafil may be more beneficial than alpha‐blockers in preventing T2DM.