Published papers

Context: Previous metabolomics studies suggest potential associations between menopausal changes in lipids and an increased risk of metabolic syndrome (MetS). However, longitudinal data on other key metabolites, such as branched-chain amino acids (BCAAs) and homocysteine, remain limited, and most studies lack long-term follow-up across the menopause transition. Objective: This study aimed to investigate longitudinal changes in circulating metabolites during menopause over a mean follow-up of 5 years and assess their associations with subsequent MetS development. Methods: Premenopausal women from the Tsuruoka Metabolomics Cohort Study who participated in at least one follow-up survey were included. Menopausal status, data on MetS, and plasma metabolites profiled using capillary electrophoresis mass spectrometry were assessed at each visit. Thirty-one metabolites were examined for associations with menopausal status using mixed-effects models. The association of these menopause-related metabolites with MetS development was examined via logistic regression analysis adjusted for follow-up duration. Results: Among 953 women (aged 43.8 ± 5.4 years), 316 (33.2%) reached menopause during follow-up (5.0 ± 1.1 years). Eighteen metabolites changed significantly with menopause, particularly those related to BCAA metabolism, urea cycle, and homocysteine metabolism. Of 695 women without MetS at baseline, 65 (9.4%) developed MetS. Glutamate (odds ratio [95% CI]: 1.95 [1.49-2.57]) was associated with higher MetS risk. Higher levels of glutamate, valine, leucine, and cystine were significantly associated with the development of hyperglycemia. Conclusion: Longitudinal changes in charged metabolites occur across the menopausal transition, with specific metabolites such as glutamate possibly contributing to the metabolic alterations underlying increased MetS risk.

Background: In Japan, experiences post-prison release unfold within a stigmatizing social climate and punitive drug policy environment. This study examined wave-specific associations between subjective quality of life (QOL) and post-release difficulties and gender-related differences. Methods: Data from the Voice Bridges Project were used for cross-sectional analyses at early post-release (n = 827), 1 year (n = 381), and 2 years (n = 218). Multivariate linear regressions assessed associations between QOL and five self-reported difficulties (financial, health, substance-related, family, interpersonal). Sex-stratified analyses were also performed. Results: Across all waves, financial difficulties were most consistently associated with lower QOL. Health problems were independently associated with lower QOL at baseline. At 1 year, substance-related issues and family problems were associated with lower QOL, with the former showing the strongest association. At 2 years, financial difficulties remained strongly associated with lower QOL. Other domains were not associated in adjusted models. Patterns among men largely mirrored the overall sample. Among women, QOL was strongly associated with substance-related issues at baseline but not with financial difficulties at any wave. Small samples made later-wave estimates imprecise. Conclusion: Although these exploratory analyses do not support causal inference or within-person change effects, they organize QOL-linked difficulty domains as candidate priority areas for needs assessments in Japan.

Background: Premenstrual syndrome (PMS) is a common menstruation-related condition among adolescent girls. Vulnerability to environmental and social factors such as living under war, exposure to political violence (EPV), and human insecurity significantly influence the health and well-being of adolescents more generally. However, research on the association between PMS and social determinants in conflict settings remains limited. This study aimed to identify the severity of PMS and its association with EPV, human insecurity, and well-being among adolescent girls in Palestine refugee camps in the West Bank. Methods: This cross-sectional study included 1,399 girls aged 15–18 years residing in 19 Palestinian refugee camps in the West Bank, occupied Palestinian territory. PMS severity was measured using a scale developed based on the literature, expert input, and the girls’ experiences, comprising two categories: “none to mild” and “moderate to severe.” EPV was assessed based on past experiences at individual, familial, collective, and cumulative levels. Multivariate analyses were conducted using five regression models with a primary focus on the relationship between PMS severity and EPV. Results: The prevalence of PMS with at least one symptom was 92.1%. PMS severity was positively associated with collective EPV (adjusted odds ratio [AOR], 1.5; 95% confidence interval [CI], 1.1–2.1), whereas individual and familial EPV were only significant when included separately in the model. Girls who experienced two or three types of cumulative EPV (AOR, 2.5; 95% CI, 1.6–3.7) were more likely to experience severe PMS. High levels of human insecurity (AOR, 1.3; 95% CI, 1.0–1.6) and depression-like symptoms (AOR, 1.9; 95% CI, 1.3–2.7) were significantly associated with PMS severity. Conclusions: The results demonstrate a significant association between PMS severity and EPV, human insecurity, and low levels of well-being. These findings suggest that prolonged occupation and unresolved conflict may adversely impact adolescent health and exacerbate PMS symptoms, highlighting the need to recognize PMS as a public health concern. In protracted conflict settings, integrating psychosocial support and menstrual health education into schools and community-based programs such as primary healthcare facilities may help adolescent girls manage PMS, menstruation-related symptoms, and associated stressors more effectively.

Background: Heated tobacco product (HTP) use in Japan has rapidly increased. Despite this rapid spread, little is known about the health effects of HTP use. We conducted a longitudinal cohort study to investigate the change in smoking habits following the spread of HTP use and its effect on forced expiratory volume in 1 second (FEV1) decline. Methods: Participants consisted of a resident population (n = 2,612; mean age, 67.7 years) with FEV1 measurement in 2012–2014 and 2018–2019, and a worksite population (n = 722; mean age 49.3 years) without FEV1 data. Participants were categorized as combustible cigarette-only smokers, HTP-only users, dual users, past smokers, and never smokers. The association between smoking group and the change in smoking consumption over a mean 5.6 years was examined. Differences in annual FEV1 change between smoking groups were examined in the resident population. Results: Prevalence of HTP-only and dual users in 2018–2019 was 0.8% and 0.6% in the resident population, and 5.0% and 1.9% in the worksite population, respectively. The overall number of tobacco products smoked=used increased in dual users compared to baseline, but not in others. Annual FEV1 decline in dual users tended to be greater than that in cigarette-only smokers (16; 95% confidence interval, −34 to 2 mL=year after full adjustment). Participants switching to HTP-only use 1.7 years before had a similar FEV1 decline as cigarette-only smokers. Conclusions: HTP use, including dual use, is prevalent even in a rural region of Japan. Dual users appear to smoke=use tobacco products more and have a greater FEV1 decline. Tobacco policy should consider dual use as high-risk.

Food intake biomarkers can be critical tools that can be used to objectively assess dietary exposure for both epidemiological and clinical nutrition studies. While an accurate estimation of food intake is essential to unravel associations between the intake and specific health conditions, random and systematic errors affect self-reported assessments. This study aimed to clarify how habitual food intake influences the circulating plasma metabolome in a free-living Japanese regional population and to identify potential food intake biomarkers. To achieve this aim, we conducted a cross-sectional analysis as part of a large cohort study. From a baseline survey of the Tsuruoka Metabolome Cohort Study, 7, 012 eligible male and female participants aged 40-69 years were chosen for this study. All data on patients' health status and dietary intake were assessed via a food frequency questionnaire, and plasma samples were obtained during an annual physical examination. Ninety-four charged plasma metabolites were measured using capillary electrophoresis mass spectrometry, by a non-targeted approach. Statistical analysis was performed using partial-least-square regression. A total of 21 plasma metabolites were likely to be associated with long-term food intake of nine food groups. In particular, the influential compounds in each food group were hydroxyproline for meat, trimethylamine- N-oxide for fish, choline for eggs, galactarate for dairy, cystine and betaine for soy products, threonate and galactarate for carotenoid-rich vegetables, proline betaine for fruits, quinate and trigonelline for coffee, and pipecolate for alcohol, and these were considered as prominent food intake markers in Japanese eating habits. A set of circulating plasma metabolites was identified as potential food intake biomarkers in the Japanese community-dwelling population. These results will open the way for the application of new reliable dietary assessment tools not by self-reported measurements but through objective quantification of biofluids.

The relation between chronic kidney disease (CKD) and cardiovascular disease (CVD) in the general population is well elucidated. In patients with CKD, anemia is associated with adverse outcomes. However, the effects of CKD and anemia on CVD in the general population remains poorly explored, especially in Asian populations. This study aimed to investigate the effect of CKD and/or anemia on CVD mortality in a long-term cohort study involving Japanese community dwellers. We assessed 7,339 participants (aged ≥30 years) with no CVD history. These participants were divided into 4 categories according to their CKD (estimated glomerular filtration rate <60 or urine protein >1+ by dipstick qualitative test) and/or anemia (hemoglobin: <13 g/100 ml [men], <12 g/100 ml [women]) statuses. For each category, we calculated the hazard ratios (HRs) of CVD mortality by using the Cox proportional hazards model after adjusting for age, body mass index, hypertension, diabetes, dyslipidemia, smoking, and alcohol drinking. Within 25 years of follow-up, 637 participants died because of CVD. The HRs of CVD in patients with CKD only, anemia only, and both were 1.27, 1.59, and 2.60 (95% confidence intervals [CI] 1.06 to 1.53, 1.34 to 1.90, and 1.80 to 3.76) in men and 1.42, 1.08, and 2.00 (95% CI 1.19 to 1.69, 0.99 to 1.18, and 1.54 to 2.60) in women, respectively. In conclusion, CKD with anemia is associated with an increased risk for CVD mortality in a general population in Japan.

Aims: The association between alcohol consumption and the risk of cardiovascular disease (CVD) varies according to the presence of underlying cardiovascular risk factors. Incorporating such risk factors may be important to effectively reduce harmful alcohol use through health guidance. However, whether the risk of alcohol consumption is affected due to renal impairment remains unclear. Methods: A total of 10,583 community-dwelling Japanese adults (mean age 59.4 (SD 10.1) years; 46% men) were followed for 10 years. Alcohol consumption was categorized into five groups for men: never drinkers, former drinkers, light drinkers (＜20 g/day), moderate drinkers (20-39 g/day), and heavy drinkers (≥ 40 g/day), and four groups for women with moderate and heavy combined. Cox proportional hazards models estimated hazard ratios for incident CVD stratified by the presence or absence of reduced estimated glomerular filtration rate (eGFR) (＜60 mL/min/1.73m2) and proteinuria, with adjustment for confounders. Results: Among men with proteinuria, alcohol consumption was associated with a higher risk of atherosclerotic CVD, whereas an inverse association was observed in men without proteinuria [hazard ratio (95% confidence interval): moderate drinkers without proteinuria, 0.58 (0.34-0.97); moderate drinkers with proteinuria, 3.49 (1.15-10.56)]. Moderate to heavy drinking increased the risk of intracerebral hemorrhage irrespective of the renal status. In women, moderate to heavy drinking was associated with an increased CVD risk only when proteinuria was present. In contrast, a reduced eGFR did not clearly affect the association in either sex. Conclusions: The CVD risk associated with alcohol consumption may differ according to the renal status, particularly depending on the presence or absence of proteinuria.

Objectives: To examine changes in rheumatoid arthritis (RA) medication prescriptions during the peri-delivery period, and to explore recent RA prescription trends using a Japanese claims database. Methods: This retrospective observational cohort study used an insurance claims database provided by JMDC Inc. We identified pregnant women with RA who delivered between April 2018 and October 2023. The outcome was the initiation or resumption of intensive treatment after delivery, defined as new or restarting of biologic disease modifying anti-rheumatic drugs (DMARDs), targeted synthetic DMARDs, oral corticosteroids (OCS), or methotrexate. Results: We identified 229 mothers with RA and 246 deliveries. Intensive treatment was initiated in 55 (22.4%) deliveries. Continuation of the same prescription from before delivery was observed in 106 (43.1%) deliveries. The most frequent new prescription postpartum was methotrexate in 18 (7.3%) deliveries. OCS were the most commonly prescribed medications throughout the observation period. Tumour necrosis factor alpha inhibitors were prescribed at similar rates as OCS before pregnancy and in the first trimester, but declined during the second and third trimesters, and returned postpartum. Conclusions: The number of deliveries that required intensive treatment postpartum was lower than in previous studies. Our results suggest that the latest guidelines for pregnant women with RA help control disease activity.

Background: Competency-based education defines competencies as educational outcomes and guiding instruction and assessment. In Japan, standardised competency frameworks for medical laboratory scientists in clinical settings are underdeveloped. This study aimed to develop and validate a competency scale for novice medical laboratory scientists with less than 3 years of clinical experience into an assessment tool. Methods: This study involved scale development and validation conducted in four phases: a preliminary study to test content validity for exploratory purposes, a pilot survey to examine the feasibility of the evaluation sheet under conditions similar to those of the main survey, a main survey to verify reliability and validity and a final phase to establish the completed scale. In the main survey, each novice medical and biomedical laboratory scientist (self-evaluator) was paired with two supervising evaluators from the same institution. The supervising evaluators, comprising educational supervisors, senior medical laboratory scientists or managers, were directly involved in the guidance and assessment of the corresponding novice. Results: Exploratory factor analysis of the self-evaluation dataset identified four factors with 51 items using a five-point Likert scale. The cumulative variance explained by the four factors was 52%, and Cronbach’s alpha ranged from 0.78 to 0.94 for each factor. The validity of the scale was confirmed through confirmatory factor analysis with the supervisory evaluation dataset. Conclusions: The Japan Medical Laboratory Scientists Competency Scale demonstrated robust psychometric properties, establishing it as an effective tool for assessing novice medical laboratory scientists in Japan through self- and supervisory evaluation. Those findings would support enhancements in workforce development and competency-based education in this field.

Objectives To date, the association between accumulated unhealthy behaviours and insomnia in individuals stratified according to the presence or absence of major cardiovascular risk factors is unclear. This study aimed to examine the effect of accumulated unhealthy behaviours on insomnia in Japanese dwellers. Design Cross-sectional study. Setting Baseline data between April 2012 and March 2015. Participants Our study used cross-sectional data among Japanese aged 35-74 years in a rural community (N=9565), the attendees of annual municipal or work site health check-up programmes. Main outcome measures Insomnia was assessed by Athens Insomnia Scale, which was set at 6 points and greater; other scales were given. Participants were categorised into three groups by their number of unhealthy behaviours (no exercise habit, smoking, alcohol drinking, skipping breakfast and obesity): 0-1, 2-3, 4 or more. The association between accumulated unhealthy behaviours and insomnia was estimated by logistic regression analysis. Further analysis was done after stratification of cardiovascular risk factors assessed by anthropometrics and clinical biochemistry measurements. Results The overall prevalence of insomnia was 13.3% for men and 19.3% for women. Men with unhealthy behaviour factors were more likely to have insomnia after adjusting for potential confounders, compared with the least unhealthy group (trend p=0.013). Women with four or more unhealthy behaviour factors were more likely to have insomnia, compared with the lowest groups (OR 1.175, 95% CI 1.077 to 1.282). Insomnia has an association with the unhealthy behaviours among men without cardiovascular risk factors (lowest groups: OR 1.133, 95% CI 1.037 to 1.238, trend p=0.026). Women without hypertension were more likely to have suspected insomnia, compared with the lowest group (OR 1.215, 95% CI 1.101 to 1.341). Conclusion The results showed accumulated unhealthy behaviours were associated with increased risk of insomnia in Japanese dwellers. For healthy population without cardiovascular risk factors, unhealthy behaviours should be considered as background conditions for insomnia.

Little is known about the associations between changes in the urinary sodium-to-potassium (Na/K) ratio and blood pressure (BP) in healthy individuals. Using survey data, urinary data, and BP data from the KOBE Study, this longitudinal study aimed to assess the associations between changes in the urinary Na/K ratio and BP in a healthy Japanese population over an 8-year follow-up period. We analyzed 567 participants aged 40–74 years who did not initiate antihypertensive or cardiovascular disease treatment during follow-up. Changes in the spot urinary Na/K ratio and BP were calculated by subtracting the baseline values from the follow-up measurements, and their associations were examined using a multivariable linear regression analysis that adjusted for sex, age, body mass index, baseline Na/K ratio and BP, low-density lipoprotein, hemoglobin A1c, ethanol intake, smoking status, salt taste sensitivity, years of education, employment status, baseline survey season, and 8-year follow-up survey season. The study cohort had a mean spot urinary Na/K ratio of 2.1 at baseline. While BP increased significantly over the 8-year follow-up period, the urinary Na/K ratio remained unchanged. However, urinary Na/K ratio changes were positively associated with changes in systolic BP (β = 1.48, p = 0.001) and diastolic BP (β = 0.76, p = 0.004). In conclusion, increases in spot urinary Na/K ratios were predictive of long-term BP elevation in a healthy, normotensive population with near-optimal urinary Na/K ratios at baseline. These findings indicate that maintaining a low urinary Na/K ratio is important for BP control, even among healthy individuals. (Figure presented.)

The relationship between serum osmolarity and cognitive function has not been fully characterized. This study aimed to examine the cross-sectional association between repeated high serum osmolarity and cognitive performance among elderly community residents. We performed a subanalysis of the Kobe Orthopedic and Biomedical Epidemiological Study, including residents aged ≥ 75 years who completed the Japanese Montreal Cognitive Assessment (MoCA-J) in 2016–2017 (n = 127), 2018–2019 (n = 71), and 2020 (n = 16). Serum osmolarity was obtained from the data in the 2012–2013 survey and in the 2016–2017 survey. MoCA-J scores were dichotomized at ≤ 22 versus > 22. Multivariate logistic regression adjusted for demographic, lifestyle including daily non-alcohol drink intake, seasonal, and clinical covariates to assess associations between osmolarity status and cognitive group. Among 214 participants (mean age 76.2 ± 1.3 years; 56% female), high osmolarity (≥ 300 mOsm/L) in 2012–2013 was associated with MoCA-J ≤ 22 (OR 2.67, 95% CI 1.29–5.53, p = 0.008). A similar association emerged for 2016–2017 measurements (OR 6.12, 95% CI 1.46–25.61, p = 0.013). Participants with high serum osmolarity at both time points showed a stronger cross-sectional association with lower MoCA-J scores (OR 17.64, 95% CI = 1.8–184.83, p = 0.017). No significant association was observed between daily non-alcoholic drink (NAD) intake and either MoCA-J scores or serum osmotic pressure. Repeated high serum osmolarity was cross-sectionally associated with lower cognitive performance in Japanese community-dwelling older adults. While NAD intake showed no significant association, further research is needed to explore the potential role of serum osmolarity in cognitive health. These findings warrant confirmation in larger prospective studies.

Background: Although self-reported questionnaires are widely employed in epidemiologic studies, their validity has not been sufficiently assessed. The aim of this study was to evaluate the validity of a self-reported questionnaire on medication use by comparison with health insurance claims and to identify individual determinants of discordance in the Tsuruoka Metabolomics Cohort Study. Methods: Participants were 2,472 community-dwellers aged 37 to 78 years from the Tsuruoka Metabolomics Cohort Study. Information on lifestyle and medications was collected through a questionnaire. Sensitivity and specificity were determined using health insurance claims from November 2014 to March 2016, which were used as a standard. Potential determinants of discordance were assessed using multivariable logistic regression. Results: The self-reported questionnaire on medication use showed high validity. Sensitivity and specificity were 0.95 (95% CI, 0.93–0.96) and 0.97 (95% CI, 0.96–0.98) for antihypertensive medications, 0.94 (95% CI, 0.91–0.97) and 0.98 (95% CI, 0.98–0.99) for diabetes medications, and 0.84 (95% CI, 0.82–0.87) and 0.98 (95% CI, 0.97–0.99) for dyslipidemia medications, respectively. Males without high education and those who currently smoke cigarettes were found to be associated with discordant reporting which affected sensitivity, especially those with medication use for dyslipidemia. Conclusions: In this population-based cohort study, we found that the self-reported questionnaire on medication use was a valid measure to capture regular medication users. Sensitivity for dyslipidemia medications was lower than those for the other medications. Type of medication, sex, education years, and smoking status influenced discordance, which affected sensitivity in self-reporting.

The mRNA-1273 Moderna COVID-19 vaccine was introduced to combat the COVID-19 global pandemic in 2020. Although the safety of the vaccine has been investigated worldwide, real-world safety data is scarce in Japan. An online, real-time survey of adverse events following immunization (AEFIs) with mRNA-1273 was conducted in the setting of a workplace vaccination program at the School of Pharmacy, Keio University from 26 June 2021, to 11 June 2022. Participants were requested to take four surveys during a seven-day follow-up period after each of the first, second, and third booster doses. The maximum number of responses, from 301 respondents, was obtained on day 0 (vaccination date) for the first dose. 98% of respondents reported local and systemic AEFIs for the second dose on day 1. No noticeable difference in local reactions was seen among the three doses. Females reported more AEFIs than males, and the young group (18–29 years) reported a higher rate than the middle age group (≥30 years) after the first dose. Age and gender differences in rates decreased at the second and third doses. This survey confirmed that the safety profile of mRNA-1273 in a real-world setting was similar to that derived from the clinical trials, and that the agent was well-tolerated.

Background: Co-administration of Piperacillin/Tazobactam (PIPC/TAZ) and Vancomycin (VCM) as an antibiotic therapy for severe infectious diseases increases the risk of nephrotoxicity. We retrospectively investigated the utility of monitoring VCM trough concentration in early stage of developing acute kidney injury (AKI) on this combination therapy. Methods: We enrolled all infectious disease patients who were managed with concurrent PIPC/TAZ and VCM. The record of dosage and the administration interval of each antibiotic and its clinical parameters, as well as the VCM trough concentrations, blood culture for bacteria, and serum creatinine values, were collected. VCM trough concentration was measured during the initial 48–72 h of VCM administration. Nephrotoxicity was evaluated as the degree of AKI. Results: A total of 47 patients fulfilling the criteria were registered, and AKI developed in 10 patients. There was no statistical difference between the AKI and non-AKI groups with regard to age, height, weight, basal creatinine level, body surface area, body mass index, PIPC/TAZ dose, VCM dose, gender, artificial management, and death within around 30 days. The VCM trough level was increased significantly in the AKI group (mean [standard deviation {SD}]: 25.9 [7.8] μg/mL) compared to that in the non-AKI group (mean [SD]: 15.7 [6.9] μg/mL) (p = 0.003). During the clinical course, renal function returned to normal levels in three out of four AKI stage 2 patients, whereas only partial recovery was achieved in all AKI stage 3 patients. Conclusions: A high VCM trough concentration may have an influence on the occurrence of AKI during combination therapy of PIPC/TAZ and VCM. Careful monitoring of VCM trough concentration will be required to prevent AKI progression.

Studies examining long-term longitudinal metabolomic data and their reliability in large-scale populations are limited. Therefore, we aimed to evaluate the reliability of repeated measurements of plasma metabolites in a prospective cohort setting and to explore intra-individual concentration changes at three time points over a 6-year period. The study participants included 2999 individuals (1317 men and 1682 women) from the Tsuruoka Metabolomics Cohort Study, who participated in all three surveys—at baseline, 3 years, and 6 years. In each survey, 94 plasma metabolites were quantified for each individual and quality control (QC) sample. The coefficients of variation of QC, intraclass correlation coefficients, and change rates of QC were calculated for each metabolite, and their reliability was classified into three categories: excellent, fair to good, and poor. Seventy-six percent (71/94) of metabolites were classified as fair to good or better. Of the 39 metabolites grouped as excellent, 29 (74%) in men and 26 (67%) in women showed significant intra-individual changes over 6 years. Overall, our study demonstrated a high degree of reliability for repeated metabolome measurements. Many highly reliable metabolites showed significant changes over the 6-year period, suggesting that repeated longitudinal metabolome measurements are useful for epidemiological studies.

Background: Dehydration, a risk factor for ischemic cerebrovascular diseases, is common in summer; however, the incidence of ischemic diseases is not necessarily higher in summer. Therefore, this study aimed to clarify the relationships between serum osmolarity, hematocrit, daily non-alcohol drink (NAD) intake and factors such as season and age as risk factors for dehydration. Method: Participants (703 women and 306 men) in the follow-up survey, in 2012 and 2013, of the Kobe Orthopedic and Biomedical Epidemiologic (KOBE) Study, consisting of healthy individuals living in Kobe, Japan, were categorized into two groups based on the examination month: the warmer and colder seasons. Multivariate analyses were conducted to examine disparities in serum osmolarity, hematocrit, and NAD intake between these two groups. Results: The colder season was found to be negatively correlated with serum osmolarity and NAD intake, but positively correlated with hematocrit, even after adjusting for relevant factors. Age was independently associated with serum osmolarity, but not with hematocrit and NAD intake. Conclusions: This study suggests that intra-vascular volume depletion is more likely in the colder season despite lower serum osmolarity compared to the warmer season. Age-related increases in serum osmolarity without a corresponding rise in water intake may contribute to this. These findings support the importance of addressing dehydration in the colder season, particularly in older adults.