Published papers

Age-related disease burden accumulates heterogeneously from later midlife to older age, but the biology underlying these divergent trajectories is poorly understood. We analysed 7199 adults aged 40 years and over in the Tsuruoka Metabolomics Cohort Study, Japan, with baseline fasting plasma metabolomics (94 metabolites measured by capillary electrophoresis–mass spectrometry) and linked health insurance claims. Monthly cumulative Charlson Comorbidity Index scores were constructed from aligned cohort entry to 60 months to capture accumulation of newly documented Charlson conditions after follow-up start. K-means clustering identified six trajectories of claims-recorded disease burden, and ordinal logistic regression related metabolites to ordered trajectory severity with adjustment for demographic and lifestyle factors. Six trajectories ranged from minimal accumulation to rapid progression. Nineteen metabolites were associated with greater trajectory severity after false discovery rate correction. Glutamate showed the strongest positive association (odds ratio, 1.18 per standard deviation; 95% confidence interval, 1.12–1.24), whereas cysteine–glutathione disulfide showed the strongest inverse association (odds ratio, 0.89; 95% confidence interval, 0.86–0.93). Eighteen of these metabolites were also associated with time to first newly documented Charlson disease. Disease-specific analyses linked glutamate to diabetes with complications, mild liver disease, and cerebrovascular disease. Exploratory cluster-specific analyses identified hippurate as a distinctive marker of a late-acceleration trajectory. These findings implicate amino acid metabolism, redox balance, and microbiome-host interactions as candidate biological pathways underlying heterogeneous patterns of age-related disease accumulation, and warrant replication in independent cohorts. These signals may inform biomarker development for accelerated disease-burden accumulation.

Background & Aims: Aminotransferases are widely used for metabolic dysfunction-associated steatotic liver disease (MASLD) evaluation, especially in type 2 diabetes mellitus (T2DM). Whether within-person seasonal variation affects classification near commonly used thresholds or relates to long-term metabolic outcomes remains unclear. Methods: This registry-based cohort analysed monthly aspartate aminotransferase (AST) and alanine aminotransferase (ALT) measurements from 6039 adults with T2DM in the Japan Diabetes Clinical Data Management registry (2014–2020). Classification discordance across the 30 IU/L threshold was compared between winter-mean and summer-mean values. Individual seasonal amplitude was derived from seasonal-trend decomposition of multiply imputed monthly time series. Final glycated haemoglobin (HbA1c) and non-achievement of HbA1c < 7% were analysed using multivariable regression. Results: Both AST and ALT showed significant seasonal variation, with the highest values in late autumn to early winter and the lowest in summer (p < 0.001). Approximately one in nine patients with borderline ALT values showed discordant winter-summer classification. Each 1-SD increase in AST amplitude was associated with 0.06 percentage points higher final HbA1c (95% CI, 0.04–0.08) and higher odds of not achieving HbA1c < 7% (odds ratio, 1.14; 95% CI, 1.08–1.21; p < 0.001). ALT amplitude showed a similar but weaker, less consistent association. Conclusions: AST and ALT exhibited reproducible seasonal variation peaking in late autumn to early winter, with approximately one in nine patients near the MASLD screening threshold reclassified depending on season. Greater seasonal amplitude, especially AST, was independently associated with poorer glycemic control, supporting season-aware interpretation in routine clinical practice.

AIMS: Nonalcoholic fatty liver disease (NAFLD) is known to be associated with atherosclerosis. This study focused on upstream changes in the process by which NAFLD leads to atherosclerosis. The study aimed to confirm the association between NAFLD and the cardio-ankle vascular index (CAVI), an indicator of subclinical atherosclerosis, and explore metabolites involved in both by assessing 94 plasma polar metabolites. METHODS: A total of 928 Japanese community-dwellers (306 men and 622 women) were included in this study. The association between NAFLD and CAVI was examined using a multivariable regression model adjusted for confounders. Metabolites commonly associated with NAFLD and CAVI were investigated using linear mixed-effects models in which batch numbers of metabolite measurements were used as a random-effects variable, and false discovery rate-adjusted p-values were calculated. To determine the extent to which these metabolites mediated the association between NAFLD and CAVI, mediation analysis was conducted. RESULTS: NAFLD was positively associated with CAVI (coefficients [95% Confidence intervals (CI)]=0.23 [0.09-0.37]; p=0.001). A total of 10 metabolites were involved in NAFLD and CAVI, namely, branched-chain amino acids (BCAAs; valine, leucine, and isoleucine), aromatic amino acids (AAAs; tyrosine and tryptophan), alanine, proline, glutamic acid, glycerophosphorylcholine, and 4-methyl-2-oxopentanoate. Mediation analysis showed that BCAAs mediated more than 20% of the total effect in the association between NAFLD and CAVI. CONCLUSIONS: NAFLD was associated with a marker of atherosclerosis, and several metabolites related to insulin resistance, including BCAAs and AAAs, could be involved in the process by which NAFLD leads to atherosclerosis.

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.

Ureteral injuries are well-known complications of gynecologic surgery, with a higher prevalence in laparoscopic surgery than in laparotomy [1]. The use of near-infrared fluorescent imaging navigation is currently being considered a novel method to identify the ureters intraoperatively and prevent ureteral injuries [2]. The Near-Infrared Ray Catheter (NIRC) fluorescent ureteral catheter is a newly developed device, containing a fluorescent resin that can be recognized by near-infrared irradiation. We found few reports on the use of this catheter in laparoscopic surgery for colon and rectal cancer [3, 4], but no reports in gynecologic surgery. We demonstrate the feasibility, safety, and potential usefulness of the real-time intraoperative visualization of the ureters using a novel NIRC fluorescent ureteral catheter in laparoscopic hysterectomy for endometrial cancer. A 30-year-old woman with early grade 1 endometrioid carcinoma was treated with medroxyprogesterone acetate for fertility preservation. After achieving complete response, she got pregnant and underwent cesarean section. The recurrence of atypical endometrial hyperplasia one year post-delivery prompted a total laparoscopic hysterectomy. Before the laparoscopic surgery began, the NIRC fluorescent ureteral catheters were placed in the ureters under the obtainment of informed consent from the patient. During the surgery, the catheters were successfully visualized by near-infrared fluorescence observation, which helped identify the ureters clearly and prevent ureteral injuries. This novel ureteral imaging navigation is expected to be an effective tool in cases of obesity, severe pelvic adhesion, deep infiltrating endometriosis, and malignancy in gynecologic laparoscopic surgery to clearly identify the ureter and to reduce the risk of ureteral injury.

The Tsuruoka Metabolomics Cohort Study (TMCS) is an ongoing population-based cohort study being conducted in the rural area of Yamagata Prefecture, Japan. This study aimed to enhance the precision prevention of multi-factorial, complex diseases, including non-communicable and aging-associated diseases, by improving risk stratification and prediction measures. At baseline, 11,002 participants aged 35-74 years were recruited in Tsuruoka City, Yamagata Prefecture, Japan, between 2012 and 2015, with an ongoing follow-up survey. Participants underwent various measurements, examinations, tests, and questionnaires on their health, lifestyle, and social factors. This study uses an integrative approach with deep molecular profiling to identify potential biomarkers linked to phenotypes that underpin disease pathophysiology and provide better mechanistic insights into social health determinants. The TMCS incorporates multi-omics data, including genetic and metabolomic analyses of 10,933 participants, and comprehensive data collection ranging from physical, psychological, behavioral, and social to biological data. The metabolome is used as a phenotypic probe because it is sensitive to changes in physiological and external conditions. The TMCS focuses on collecting outcomes for cardiovascular disease, cancer incidence and mortality, disability and functional decline due to aging and disease sequelae, and the variation in health status within the body represented by omics analysis that lies between exposure and disease. It contains several sub-studies on aging, heated tobacco products, and women's health. This study is notable for its robust design, high participation rate (89%), and long-term repeated surveys. Moreover, it contributes to precision prevention in Japan and East Asia as a well-established multi-omics platform.

We describe a successful surgical technique of abdominal trachelectomy and re-vaginoplasty for cervico-vaginal stenosis following unsuccessful uterovaginal anastomosis and vaginoplasty in a patient with congenital cervical and vaginal aplasia. After the surgical procedure, cervico-vaginal stenosis was resolved and periodic menstruation without dysmenorrhoea resumed. While long-term follow-up is essential to ensure successful pregnancy and delivery, we conclude that this novel surgical procedure is a promising alternative for improvement of the quality of life and normal sexual function, and for preservation of fertility in patients with cervical and vaginal aplasia.

Low-birthweight (LBW; <2,500 g) babies are at a higher risk of poor educational achievement, disability, and metabolic diseases than normal-birthweight babies in the future. However, reliable data on factors that contribute to LBW have not been considered previously. Therefore, we aimed to examine the distribution of the causes for LBW. A retrospective review of cases involving 4,224 babies whose mothers underwent perinatal care at Keio University Hospital between 2013 and 2019 was conducted. The LBW incidence was 24% (1,028 babies). Of the 1,028 LBW babies, 231 babies were from multiple pregnancies. Of the 797 singleton LBW babies, 518 (65%) were born preterm. Obstetric complications in women with preterm LBW babies included premature rupture of membrane or labor onset (31%), hypertensive disorders of pregnancy (HDP, 64%), fetal growth restriction (24%), non-reassuring fetal status (14%), and placental previa/vasa previa (8%). Of the 279 term LBW babies, 109 (39%) were small for gestational age. Multiple logistic regression analyses revealed the following factors as LBW risk factors in term neonates: low pre-pregnancy maternal weight, inadequate gestational weight gain, birth at 37 gestational weeks, HDP, anemia during pregnancy, female sex, and neonatal congenital anomalies. HDP was an LBW risk factor not only in preterm births but also in term births. Our results suggest that both modifiable and non-modifiable factors are causes for LBW. It may be appropriate to consider a heterogeneous rather than a simple classification of LBW and to evaluate future health risks based on contributing factors.

Premenstrual disorders (PMDs) in working women are reported to be associated with absenteeism and presenteeism, but few studies have considered their severity from a broad range of manifestations and investigated its impact on absenteeism and presenteeism simultaneously within the same population consisting of various occupations. Thus, we conducted a cross-sectional study of 2,987 premenopausal women working across Japan using a self-administered survey that included items on absenteeism and presenteeism due to premenstrual symptoms and symptom severity. Multivariate analyses were used to examine the association between PMD severity, absenteeism (being away from work) and presenteeism (decreased work performance). Results demonstrated that PMD severity was strongly associated with both absenteeism and presenteeism irrespective of age, socioeconomic background, and work-related factors. Those with moderate to severe forms of PMDs had a two-fold risk of absenteeism and 18-30% worse presenteeism compared to a milder group. Furthermore, two-thirds of women with severe PMDs reported ≥30% performance reduction without absenteeism, indicating that the impact of PMDs was more significant for presenteeism than absenteeism. Our study results suggest the importance of widely promoting education and treatment of PMDs regardless of sociodemographic factors and working conditions for securing the workforce through the advancement of working women.

Objectives: Underweight or obesity is associated with infertility in women, but large cohort studies with a life course perspective are rare. We explored the association between body mass index (BMI) at age 18 and subsequent infertility among Japanese women. Study design: In total, 15,907 married women aged 30–44 years who participated in a prospective cohort baseline survey during 2001–2007 were cross-sectionally analyzed. Those with a history of cancer, and those with a partner with infertility or missing data were excluded. All data were obtained from self-reported questionnaires. Main outcome measures: The main outcome measure was infertility, defined as a self-reported history of infertility for at least 2 years. Age and cause of infertility were also recorded. Results: Overall, 2825 participants (17.8 %) reported being infertile. The proportions of women who were underweight (BMI <18.5 kg/m2), overweight (BMI ≥25 and < 30 kg/m2), and obese (BMI ≥ 30 kg/m2) at age 18 were 12.8 %, 4.5 %, and 0.4 %, respectively. Multiple logistic regression analysis revealed a 1.31-fold and a 1.82-fold increase in the rate of infertility in those women who were underweight or obese during adolescence, respectively, compared with those of normal weight. Further analysis by cause of infertility revealed no significant associations with overweight or obesity at age 18, but being underweight was positively associated with infertility of unknown cause. Conclusions: Being underweight or obese at adolescence is a potential risk factor for subsequent infertility among Japanese women. In particular, being underweight during adolescence may be a contributing factor to unexplained infertility later in life.

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.

Aims/Introduction: Obesity is a known risk factor for several chronic diseases, including type 2 diabetes mellitus, which results from increased insulin resistance and impaired insulin secretion. However, the association between obesity and insulin resistance in Asian populations has not yet been fully elucidated. Therefore, we aimed to investigate the causal relationship between body mass index (BMI) and glycemic traits using Mendelian randomization (MR). Materials and Methods: We performed individual-level MR analyses using genetic risk scores based on BMI-related variants in 3,745 individuals without diabetes mellitus from a Japanese cohort. We examined heterogeneity through subgroup analyses based on potential modifiers and determined the shape of the causal relationship using nonlinear MR analyses to further assess the impact of BMI on the homeostasis model assessment of insulin resistance (HOMA-IR). Results: MR analyses revealed a significant positive association between BMI and HOMA-IR (β = 0.077; 95% confidence interval, 0.014–0.141; P = 0.016; outcome variable was log-transformed and standardized). Additional analyses revealed heterogeneity among subgroups differentiated by age, sex, lifestyle habits, and cardiometabolic traits. Nonlinear MR analyses suggested a potential J-shaped causal relationship between BMI and HOMA-IR. Conclusions: Our findings demonstrated that obesity and low BMI may contribute to increased insulin resistance. Furthermore, the impact of BMI on insulin resistance could vary owing to effect modification. Managing BMI is crucial in individuals at high risk of increased insulin resistance and may have important implications for preventing type 2 diabetes, especially given the low insulin secretory capacity observed in East Asian populations.

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.

Objective: This study aimed to develop and validate a screening tool tailored for working women to comprehensively assess premenstrual symptoms—including physical, psychological, and work-related domains—and to examine its reliability, validity, and association with absenteeism. Methods: In October 2021, a multidisciplinary expert panel comprising a gynecologist, a psychosomatic physician, a psychologist, occupational health specialists, and data scientists developed a set of 47 original items. We then recruited 3,239 working women with menstruation via an internet research company and administered these items to assess PMS-related symptoms. For scale development, we conducted exploratory and confirmatory factor analyses, along with evaluations using Cronbach’s alpha, receiver operating characteristic analysis, and logistic regression analysis. Results: Of the participants, 331 women had experienced PMS (10%), and 393 women had taken sick leave because of PMS-associated symptoms (12%). Exploratory factor analyses with maximum likelihood and Promax rotation identified four domains with 27 items, including “Somatic symptoms’’ (Cronbach’s α = 0.93), “Psychological symptoms” (Cronbach’s α = 0.94), “Lack of work efficiency” (Cronbach’s α = 0.93), and “Abdominal symptoms” (Cronbach’s α = 0.95). Using a split-half sample for the confirmatory factor analysis, the four-factor solution demonstrated acceptable model fit (RMSEA = 0.077, CFI = 0.928). The Average Variance Extracted values ranged from 0.54 to 0.68 across the four domains, and in all cases, the square root of AVE exceeded the corresponding inter-factor correlations, supporting the discriminant validity using the Fornell–Larcker criterion. We also confirmed the developed scale’s criterion validity using existing PMS screening criteria and its concurrent validity through moderate correlation coefficients with Copenhagen Burnout Inventory scores. The receiver operating characteristic curve yielded a moderate construct ability for work absenteeism, including a sensitivity of 78%, a specificity of 57%, and an area under the curve of 0.735. Conclusion: A moderately reliable and valid new scale for PMS for working women was developed with efficacy for screening for work absenteeism.

Objectives: To develop a Workplace Health Initiatives Checklist for Women (WHIC‑W), we assessed content validity (expert) and provided initial evidence for construct validity by examining hypothesized cross-sectional associations with burnout, productivity, and job satisfaction. Methods: A multidisciplinary expert panel comprising gynecologists, occupational physicians, nurses, industrial hygienists, and psychosomatic specialists created 26 items for the WHIC‑W. A survey was conducted in October 2023 with 3343 working women aged 20-69 years. The checklist includes 2 domains: Domain 1 (15 items on work environment) and Domain 2 (11 items on pregnancy, child/elderly care, and support for balancing illness and work). The outcome included the Copenhagen Burnout Inventory, work productivity using presenteeism (WHO Health and Work Performance Questionnaire) and absenteeism (health-related days off in the past 28 days), satisfaction rated on a visual analog scale (0-10), and intention to resign over the past year. Results: The checklist was scored on a 26-point scale, with a median score of 3 (interquartile range: 1-9), indicating limited workplace support for women. Higher checklist total scores were associated with lower personal burnout (β = −0.32, 95% CI: −0.435 to −0.196), work-related burnout (β = −0.30, 95% CI: −0.395 to −0.207), and client-related burnout (β = −0.17, 95% CI: −0.276 to −0.065), and higher absolute presenteeism (β = 0.43, 95% CI: 0.336-0.516; higher score = less performance loss), absenteeism (OR = 1.01, 95% CI: 1.001-1.021), and satisfaction (OR = 1.07, 95% CI: 1.055-1.079). Conclusions: This study provides preliminary construct validity evidence supporting WHIC-W as a formative checklist, with higher scores showing hypothesized cross-sectional associations with lower burnout, better productivity, and job satisfaction.

Purpose: Hypertension (HT), dyslipidemia (DL), and diabetes mellitus (DM) are major risk factors for cardiovascular diseases. Despite the wide availability of medications to reduce this risk, poor adherence to medications remains an issue. The aim of this study is to evaluate medication adherence of prevalent users in these disease medications (HT, DL, DM) using claims data. Factors associated with non-adherence were also examined. Methods: Of 7538 participants of the Tsuruoka Metabolomics Cohort Study, 3693 (HT: 2702, DL: 2112, DM: 661) were identified as prevalent users of these disease medications. Information on lifestyle was collected through a questionnaire. Adherence was assessed by a proportion of days covered (PDC) and participants with PDC ≥0.8 were defined as adherent. Predictors of non-adherence were determined by performing multivariable logistic regression. Results: Medication adherence differed by treatment status. Among those without comorbidities, those with HT-only showed the highest adherence (90.2%), followed by those with DM-only (81.2%) and those with DL-only (80.8%). Factors associated with non-adherence in each medication group were skipping breakfast and poor understanding of medications among those with HT medications, females, having comorbidities, having a history of heart disease, and drinking habit among those with DL medications, and good sleep quality and skipping breakfast among those with DM medications. Conclusion: While participants showed high medication adherence, differences were observed across medication groups. The identified predictors of non-adherence could help target those in need of adherence support.

Plasma amino acids (AAs) have emerged as promising biomarkers for metabolic disorders, yet their causality remains unclear. We aimed to investigate the genetic determinants of AA levels in a cohort of 10,333 individuals and their causal effects on cardiometabolic traits using Mendelian randomization (MR). Plasma levels of 20 AAs were quantified using capillary electrophoresis mass spectrometry. Genome-wide association studies were conducted using BOLT-LMM and heritability estimation via LDSC analysis. Causal effects of AAs on 11 cardiometabolic traits were examined using two-sample MR analyses. We identified 85 locus-metabolite associations across 43 genes for 18 AAs, including 44 novel loci linked to metabolic genes. Heritability for AAs was estimated at 16%. MR analysis demonstrated cystine to positively associate with systolic blood pressure (SBP) (β = 0.056, SE = 0.010), while serine indicated protective effects on SBP (β = − 0.040, SE = 0.011), diastolic BP (β = − 0.044, SE = 0.010), and coronary artery disease (odds ratio 0.888, SE = 0.028). We identified potentially novel genetic loci associated with AA levels and demonstrated robust causal associations between several AAs and cardiometabolic traits. These findings reinforce the importance of AAs as potential biomarkers and therapeutic targets in cardiometabolic health.

Aim: This study investigated the current clinical status, structural barriers, and perceived outcomes of menopausal care provided by gynecologists in Japan, with a specific focus on the management of menopausal disorders among working women. Methods: A web-based survey was conducted among 919 gynecologists in December 2025. Participants were categorized by weekly menopausal patient volume (none/minimal, 1–19, or ≥ 20 patients/week). A mixed-methods approach was employed, including adjusted multivariable logistic regression analyses. Results: Most gynecologists (89.4%) encountered patients with decreased work performance, and 29.8% reported managing patients who had resigned owing to menopausal symptoms. Meanwhile, 82.4% of respondents perceived improvements in work performance following treatment. Adjusted multivariable analyses confirmed weekly patient volume as an independent predictor of occupational outcomes and willingness to continue menopausal care. While nearly all gynecologists prescribed hormone replacement therapy and Kampo (Japanese herbal) medicine, the variety of additional treatments increased significantly with patient volume. Furthermore, 66.4% of gynecologists reported that their residency training in menopausal disorders was insufficient. Consultations for menopausal disorders required significantly more time than those for dysmenorrhea, regardless of patient volume. Qualitative analysis identified inadequate reimbursement as the most frequently cited systemic concern. Conclusions: Gynecologists frequently encounter menopause-related work performance impairment but perceive treatment as beneficial. After adjustment for physician characteristics, higher patient volume remained an independent predictor of severe occupational consequences and willingness to continue menopausal care. Addressing time-intensive consultations, insufficient reimbursement, and limited postgraduate education is essential to support working women with menopausal symptoms.

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.