Introduction: 45,X/46,XY mosaicism is a rare disorder of sex development characterized by marked phenotypic variability, ranging from typical male or female genitalia to significant genital ambiguity. Data describing long-term clinical outcomes in affected patients remain limited. This study aimed to characterize the phenotypic spectrum and longitudinal outcomes of patients with 45,X/46,XY mosaicism, focusing on growth, associated comorbidities, and gonadal pathology. Methodology: We conducted a retrospective longitudinal study at a tertiary paediatric endocrine referral centre between January 2006 and January 2025. Patients with cytogenetically confirmed 45,X/46,XY mosaicism or related variants were included. Clinical presentation, karyotype, anthropometry, hormonal profiles, imaging findings, and gonadal histology were reviewed. External genital phenotype was quantified using the External Masculinization Score (EMS). Height was expressed as standard deviation scores (SDS) relative to population norms and compared with genetic potential. Results: Fourteen patients (10 males, 4 females) with 45,X/46,XY mosaicism were identified. Ambiguous genitalia was the predominant presenting feature, observed in 11 of 12 patients with available phenotype data. Growth impairment was common; median height SDS was −2.62 (range −3.26 to −2.00) in females and −0.46 (range 0.13 to −1.70) in males, both below expected genetic potential. Associated congenital anomalies were present in 25% of patients, including cardiac and renal abnormalities. Male patients demonstrated variable degrees of undervirilization with a median EMS of 4.5 (3.75–7.25). Müllerian duct remnants were identified in 66% of patients on imaging. Testicular microlithiasis was observed in two males. During follow-up, two patients underwent gender reassignment. Histological analysis of 14 gonads obtained via gonadectomy or biopsy revealed abnormal gonadal architecture in all cases. All intra-abdominal gonads demonstrated streak gonads or dysgenetic testicular tissue. Conclusion 45,X/46,XY mosaicism demonstrates a broad phenotypic spectrum with frequent genital ambiguity, growth impairment, and abnormal gonadal development. The high prevalence of gonadal dysgenesis underscores the importance of careful surveillance and individualized multidisciplinary management guided by clinical, endocrine, and histopathological findings.
Child ; Longitudinal Studies ; Mosaicism

BACKGROUND: Studies have shown that married couples often share similar lifestyles, as well as lifestyle-associated conditions such as diabetes, hypertension, and hyperlipidemia. This study aims to prospectively investigate the association between an individual's development of a non-communicable disease and the subsequent development of the same condition in their spouse. METHODS: This population-based cohort study utilized 12 waves of annual prospective surveys from 2005 onwards in Japan, with a discrete-time design. A total of 9,417 middle-aged couples (18,834 participants; discrete-time observations = 118,876) were included. Each participant whose spouse had developed one of six conditions was propensity score-matched with five controls whose spouses had not been diagnosed with the condition: diabetes [n = 1374 vs n = 6870], hypertension [n = 2657 vs n = 13285], hypercholesterolemia [n = 3321 vs n = 16605], stroke [n = 567 vs n = 2835], coronary heart disease (CHD) [n = 1093 vs n = 5465] or cancer [n = 923 vs n = 4615]. Using conditional logistic regression, we assessed participants' development of the same condition within three years following their spouse's diagnosis. RESULTS: Participants whose spouses had developed diabetes, hypertension, hypercholesterolemia, or CHD were more likely to develop the same condition within three years. The odds ratios (ORs) and 95% confidence intervals (CIs) were: 1.96 (1.53-2.50), 1.20 (1.06-1.36), 1.63 (1.47-1.81) and 1.43 (1.05-1.95), respectively. No significant associations were observed in stroke [1.69 (0.80-3.58)] or cancer [1.08 (0.75-1.54)]. CONCLUSION Spouses of individuals recently diagnosed with certain metabolic conditions are at a higher risk of developing those conditions themselves. These findings may provide valuable guidance for targeting and personalizing chronic disease screening and prevention efforts.
Humans ; Spouses/statistics & numerical data* ; Male ; Female ; Middle Aged ; Aged ; Japan/epidemiology* ; Longitudinal Studies ; Noncommunicable Diseases/epidemiology* ; Prospective Studies ; Neoplasms/epidemiology* ; Diabetes Mellitus/epidemiology* ; Risk Factors ; Aged, 80 and over ; Adult ; Hypertension/epidemiology*

BACKGROUND: Mitochondria, which harbor their own genome (mtDNA), have attracted attention due to the potential of mtDNA copy number (mtDNA-CN) as an indicator of mitochondrial dysfunction. Although mtDNA-CN has been proposed as a simple and accessible biomarker for metabolic disorders such as metabolic dysfunction-associated steatotic liver disease, the underlying mechanisms and the causal relationship remain insufficiently elucidated. In this investigation, we combined longitudinal epidemiological data, animal studies, and in vitro assays to elucidate the potential causal relationship between reduced mtDNA-CN and the development of steatotic liver disease (SLD). METHODS: We conducted a longitudinal study using data from a health examination cohort initiated in 1981 in Yakumo, Hokkaido, Japan. Data from examinations performed in 2015 and 2022 were analyzed, focusing on 76 subjects without SLD at baseline (2015) to assess the association between baseline mtDNA-CN and subsequent risk of SLD development. In addition, 28-day-old SD rats were fed ad libitum on a 45% high-fat diet and dissected at 2 and 8 weeks of age. Blood and liver mtDNA-CN were measured and compared at each feeding period. Additionally, in vitro experiments were performed using HepG2 cells treated with mitochondrial function inhibitors to induce mtDNA-CN depletion and to examine its impact on intracellular lipid accumulation. RESULTS: Epidemiological analysis showed that the subjects with low mtDNA-CN had a significantly higher odds ratio for developing SLD compared to high (odds ratio [95% confidence interval]: 4.93 [1.08-22.50]). Analysis of the animal model showed that 8 weeks of high-fat diet led to the development of fatty liver and a significant decrease in mtDNA-CN. A further 2 weeks of high-fat diet consumption resulted in a significant decrease in hepatic mtDNA-CN, despite the absence of fatty liver development, and a similar trend was observed for blood. Complementary in vitro experiments revealed that pharmacologically induced mitochondrial dysfunction led to a significant reduction in mtDNA-CN and was associated with increases in intracellular lipid accumulation in HepG2 cells. CONCLUSIONS Our findings suggest that reduced mtDNA-CN may contribute causally to SLD development and could serve as a convenient, noninvasive biomarker for early detection and risk assessment.
Animals ; DNA, Mitochondrial/genetics* ; Humans ; Male ; DNA Copy Number Variations ; Female ; Fatty Liver/blood* ; Rats ; Middle Aged ; Longitudinal Studies ; Rats, Sprague-Dawley ; Adult ; Japan/epidemiology* ; Aged ; Biomarkers/blood* ; Hep G2 Cells ; Diet, High-Fat/adverse effects*

BACKGROUND: Cancer is a major public health concern, particularly among middle-aged and elderly populations, who are disproportionately affected by rising cancer incidence. Environmental pollution has been identified as a significant risk factor for cancer development. China's Carbon Emission Trading Policy (CETP), implemented in pilot regions since 2013, aims to reduce carbon emissions and improve air quality. This study evaluates the impact of CETP on pan-cancer incidence, with a focus on its effects on specific cancer types and vulnerable populations. METHODS: This quasi-natural experiment utilized data from the China Health and Retirement Longitudinal Study (CHARLS) and environmental data from the China National Environmental Monitoring Center (2011-2018). A staggered difference-in-differences (DID) model was employed to estimate the impact of CETP on cancer incidence. Robustness tests, including parallel trend tests, placebo analysis, and entropy balancing, validated the findings. Subgroup analyses were performed to assess the policy's heterogeneous effects based on gender, Body Mass Index (BMI), and smoking status. RESULTS: CETP implementation significantly reduced the incidence of six cancer types: endometrial, cervical, gastric, esophageal, breast, and lung cancers. Overall, pan-cancer incidence significantly declined post-policy implementation (CETP × POST: -47.200, 95% CI: [-61.103, -33.296], p < 0.001). The policy demonstrated stronger effects in highly polluted areas and among individuals with poorer mental health. Subgroup analysis revealed that females, individuals with lower BMI, and non-smokers experienced more substantial benefits. CONCLUSIONS CETP significantly reduces cancer incidence by improving environmental quality and influencing mental health, with particularly strong effects observed among high-risk populations. This study highlights the important role of environmental economic policies in mitigating cancer burden and promoting public health. Future research should further explore the long-term impacts of this policy and its applicability across different national and regional contexts.
Humans ; Incidence ; Neoplasms/epidemiology* ; China/epidemiology* ; Middle Aged ; Female ; Male ; Aged ; Air Pollution/legislation & jurisprudence* ; Carbon/analysis* ; Longitudinal Studies ; Air Pollutants/analysis* ; Environmental Exposure

BACKGROUND: Cardiovascular disease (CVD) is the predominant cause of mortality in China. However, the mechanisms linking sarcopenia to CVD remain poorly understood, particularly in normal-weight populations. Individuals with the absence of overweight or obesity may tend to experience missed opportunities for timely intervention. This study aimed to investigate the longitudinal association between sarcopenia and incidence of new-onset CVD in a normal-weight population, and to examine the mediating effect of functional limitation in this relationship. METHODS: We conducted a closed-cohort analysis using a nationwide sample of 4,147 middle-aged and older adults with normal weight in China. We performed Cox proportional hazards regression analysis to explore the associations of baseline sarcopenia with incident CVD. The difference method was applied to estimate the mediation proportion of functional limitation in this association. RESULTS: Over a mean follow-up period of 7.62 years, CVD occurred in 835 participants. In the multivariable-adjusted Cox model, individuals with sarcopenia exhibited a significantly higher likelihood of developing incident CVD compared to those without sarcopenia (adjusted hazard ratio [aHR] = 1.45, 95% confidence interval [CI]: 1.21-1.73, P < 0.001). Similar associations were observed for the incidence of heart disease and stroke. Functional limitation accounted for approximately 15.0% of the total effect of sarcopenia on incident CVD (P < 0.001). CONCLUSIONS Sarcopenia exerts both direct and indirect effects on incident CVD among middle-aged and older adults who are normal weight, with functional limitation serving as a significant mediator. Interventions targeting both sarcopenia and functional limitation may offer a promising strategy for enhancing cardiovascular health in this population.
Humans ; Sarcopenia/complications* ; China/epidemiology* ; Male ; Female ; Middle Aged ; Cardiovascular Diseases/etiology* ; Aged ; Incidence ; Cohort Studies ; Proportional Hazards Models ; Risk Factors ; Aged, 80 and over ; Longitudinal Studies

BACKGROUND: Depression among older adults is an important public health issue, and air and noise pollution have been found to contribute to exacerbation of depressive symptoms. This study examined the association of exposure to air and noise pollutants with clinically-newly-diagnosed depressive disorder. The mediating role of individual pro-inflammatory markers was explored. METHODS: We linked National Health Insurance claim data with 2998 healthy community-dwellers aged 55 and above who participated in the Healthy Aging Longitudinal Study between 2009 and 2013. Newly diagnosed depressive disorder was identified using diagnostic codes from the medical claim data. Pollutants were estimated using nationwide land use regression, including PM_2.5 and PM₁₀, carbon monoxide, ozone, nitrogen dioxide, sulfur dioxide, and road traffic noise. Cox proportional hazard models were employed to examine the association between pollutants and newly developed depressive disorders. The mediating effect of serum pro-inflammatory biomarkers on the relationship was examined. RESULTS: Among the 2998 participants, 209 had newly diagnosed depressive disorders. In adjusted Cox proportional hazard models, one interquartile range increase in PM_2.5 (8.53 µg/m³) was associated with a 17.5% increased hazard of developing depressive disorders. Other air pollutants and road traffic noise were not linearly associated with depressive disorder incidence. Levels of serum tumor necrosis factor receptor 1 mediated the relationship between PM_2.5 and survival time to newly onset depressive disorder. CONCLUSION PM_2.5 is related to an increased risk of newly developed depressive disorder among middle-aged and older adults, and the association is partially mediated by the pro-inflammatory marker TNF-R1.
Humans ; Particulate Matter/analysis* ; Male ; Female ; Middle Aged ; Longitudinal Studies ; Aged ; Incidence ; Air Pollutants/analysis* ; Environmental Exposure/adverse effects* ; Taiwan/epidemiology* ; Receptors, Tumor Necrosis Factor, Type I/blood* ; Proportional Hazards Models ; Biomarkers/blood* ; Depression/epidemiology* ; Aged, 80 and over ; Depressive Disorder/chemically induced* ; Risk Factors ; Air Pollution/adverse effects*

BACKGROUND: Although serum carotene may contribute to dementia prevention, there is a lack of longitudinal evidence for early cognitive decline before dementia symptoms. The aim of this study was to examine whether serum carotene levels were associated with annually evaluated cognitive trajectories among the Japanese general population. METHODS: Among 581 baseline participants, 199 individuals (83 males; mean age [min, max], 62.7 [39, 90] years) who underwent cognitive assessments more than twice after baseline were analyzed. "Attention" levels were assessed using one- and three-target Digit Cancellation Tests (D-CAT1 and D-CAT3). "General cognitive ability" was assessed by the short version of Mini-Mental State Examination (SMMSE). Serum carotenes (α-carotene, β-carotene and lycopene) were measured by high-performance liquid chromatography. After the measurements, we calculated total carotene levels by summing up the levels of all measured carotene. Carotene levels were categorized into three groups for analysis (low: 0%-25%, middle: 25%-75%, and high: 75%-100%). A linear mixed model was used to estimate the slope of the D-CAT score trajectory and to compare it between three categories. RESULTS: Compared with the middle carotene group, decline of attention was faster in the D-CAT1 for low β-carotene (β = -3.48, p = 0.035), lycopene (β = -3.10, p = 0.062), and total carotene (β = -4.75, p = 0.003), but not for α-carotene (β = -2.60, p = 0.111). For the D-CAT3, decline of attention was faster in the group of low lycopene (β = -3.17, p = 0.002) and total carotene (β = -2.17, p = 0.037) compared with the middle carotene group, while no clear association for α-carotene (β = -0.67, p = 0.521) and β-carotene (β = -0.64, p = 0.639). There were no clear associations between serum carotene and the SMMSE score. CONCLUSIONS These findings suggest low levels of serum lycopene are associated with a decline of attention in the setting of the general population.
Humans ; Male ; Carotenoids/blood* ; Female ; Longitudinal Studies ; Middle Aged ; Japan ; Aged ; Adult ; Aged, 80 and over ; Attention ; Lycopene ; East Asian People

BACKGROUND: Exposure to air pollution and adherence to a healthy lifestyle have been identified to be related to sarcopenia. However, the interactive effects between these two factors remain insufficiently elucidated. The present study was designed to investigate the potential interaction exposure to air pollution with healthy lifestyle on the risk of developing sarcopenia. METHODS: In the retrospective cohort study, all data was extracted from China Health and Retirement Longitudinal Study. Household air pollution was assessed based on the utilization of solid fuels for cooking and heating. A lifestyle score was constructed comprising information on physical activity, smoking, drinking and sleeping time. Multivariate logistic regression model was used to assess the effects of household air pollution and healthy lifestyle score on sarcopenia, separately. We further explored the additive interaction between household air pollution and healthy lifestyle score to sarcopenia using the interaction table developed by T Anderson. Relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (SI) were used to evaluate the additive interactive effect. RESULTS: 2,114 participants were included in this study. The result indicated that exposed to household air pollution [adjusted relative risk (RR) = 1.80, 95% confidence interval (CI): 1.15-2.94] and unhealthy lifestyle (adjusted RR = 1.46, 95%CI: 1.04-2.03) were both significantly associated with increased risk of sarcopenia. Furthermore, participants exposed to both household air pollution and an unhealthy lifestyle exhibited a significantly higher risk of sarcopenia relative to those without household air pollution exposure and maintaining a healthy lifestyle (adjusted RR = 2.44). But RERI, AP, and SI suggested that there is no statistically significant additive interaction between household air pollution exposure and healthy lifestyle factors in relation to sarcopenia risk. CONCLUSION Household air pollution in conjunction with an unhealthy lifestyle confers a significantly higher risk of sarcopenia compared to either factor in isolation, with no evidence of a significant additive interaction between these two risk factors.
Humans ; China/epidemiology* ; Male ; Sarcopenia/etiology* ; Female ; Longitudinal Studies ; Middle Aged ; Aged ; Air Pollution, Indoor/adverse effects* ; Retrospective Studies ; Healthy Lifestyle ; Risk Factors ; Environmental Exposure/adverse effects* ; Cooking ; Aged, 80 and over

BACKGROUND: Heated tobacco products (HTPs) are widely used in Japan, following cigarettes, but their health effects remain unclear. HTPs are often considered a less harmful alternative to cigarettes and are commonly used by adults with asthma, even though smoking is one of the most obvious and treatable factors in asthma. We aimed to elucidate the association between HTP use and asthma symptoms in adults with asthma. METHODS: A total of 3,787 individuals with asthma were extracted from the data in the Japan COVID-19 and Society Internet Survey 2023, an ongoing longitudinal internet-based cohort study conducted by a nationwide internet research company in Japan. They were categorized into three groups (never, past, and current smokers) based on cigarette use. The association between HTP use and worsening of asthma symptoms within the previous 2 months in each group was analyzed using univariate and multivariate logistic regression analyses. Both exposure and outcomes were assessed by self-reporting. RESULTS: Among the participants, 2,470 (65.2%) were never smokers, 845 (22.3%) were past smokers, and 472 (12.5%) were current smokers. Overall, the proportion of HTP users was 429 (11.3%), and worsened asthma symptoms were observed in 400 (10.6%) individuals. The total proportion of HTP users and worsened asthma symptoms was 70 (2.8%) and 259 (10.5%) among never smokers, 180 (21.3%) and 72 (8.5%) among past smokers, and 179 (37.9%) and 69 (14.6%) among current smokers. After adjusting for confounders, the odds ratio (OR) was 3.25 (95% confidence interval [CI] 1.86-5.68, p < 0.001), 1.47 (95% CI 0.93-2.34, p = 0.1), and 2.23 (95% CI 1.46-3.43, p < 0.001) for never, past, and current cigarette smokers with HTP use, respectively, where never smokers without HTP use were set as the standard. CONCLUSION The use of HTPs, not only cigarette smoking, was associated with worsening of asthma symptoms in adults with asthma. Therefore, people need to understand the harmful effects of HTPs on asthma symptoms.
Humans ; Japan/epidemiology* ; Asthma/etiology* ; Male ; Female ; Middle Aged ; Adult ; Aged ; Tobacco Products/adverse effects* ; Internet ; Surveys and Questionnaires ; Young Adult ; Hot Temperature ; Longitudinal Studies

BACKGROUND: Difficulty awakening is a common concern among adolescents and contributes to school absenteeism. Although cross-sectional studies suggest that commuting times, internet usage, and sleep disturbances are associated with school attendance problems, few have specifically focused on adolescents. We aimed to examine the factors contributing to school absenteeism due to difficulty awakening in Japanese high school students. METHODS: In this longitudinal cohort study, data were prospectively collected between 2016 and 2018 from 54 high schools in a prefecture of Western Japan. Tenth-grade students (n = 6,121) without tardiness (n = 5,812) or absences (n = 5,946) at baseline were recruited. The outcome of interest was school absenteeism due to difficulty awakening, which included both tardiness and absences (≥2 days/month). Cox proportional hazards models were used to assess the associations between commuting time and lifestyle factors after adjusting for confounders. RESULTS: The incidence rates of tardiness and absences due to difficulty awakening were 19.3 and 9.6 per 1,000 person-years, respectively. Common risk factors for absenteeism included prolonged internet usage (≥5 h) and dissatisfaction with school. Protective factors for school tardiness included study time and participation in extracurricular sports activities (both ≥2 h). Long commuting time (≥1 h) was associated with a higher risk of school absences. CONCLUSIONS Long commuting times, prolonged internet usage, and poor school satisfaction increased the risk of school absenteeism due to difficulty awakening. Promoting academic engagement and extracurricular activities may help reduce absenteeism. Interventions that increase school satisfaction, such as providing learning opportunities outside of school, supporting extracurricular activities, and improving the school environment, may be effective prevention strategies.
Humans ; Absenteeism ; Japan/epidemiology* ; Adolescent ; Male ; Female ; Prospective Studies ; Schools/statistics & numerical data* ; Students/psychology* ; Longitudinal Studies ; Risk Factors ; Transportation/statistics & numerical data* ; East Asian People