Supplementary Table S9 presents breast cancer incidence in relation to ferritin level, menopausal status, and obesity.

Supplementary Table S4 presents breast cancer incidence in relation to ferritin level and menopausal status after further adjustment for parity, age at menarche, age at menopause, and hormone medication use.

Importance:Among individuals who meet the diagnostic threshold for type 2 diabetes (T2D), timely initiation of antidiabetic medication (ADM) is essential for lowering long-term cardiovascular risk. Objective:To estimate the association between ADM initiation timing-specifically within 3, 6, or 12 months-and the risk of major adverse cardiovascular events (MACE) and all-cause mortality among individuals newly meeting diagnostic criteria for T2D. Design, Setting, and Participants:This cohort study used target trial emulation to analyze health screening data linked to health insurance claims in Korea (2013-2022) using a clone-censor-weight approach. Participants were adults with newly detected glycated hemoglobin (HbA1c) of 6.5% or greater or fasting plasma glucose of 126 mg/dL or greater. Data analysis was conducted from January to August 2025. Exposures:Eligible participants were cloned into 4 treatment strategies: ADM initiation within 3, 6, or 12 months or no initiation within 12 months (strategy 1, 2, 3, and control, respectively). Main outcomes and Measures:Five-year absolute risk difference (RD) and risk ratio (RR) of 3-point MACE (stroke, myocardial infarction, and all-cause mortality) and all-cause mortality were estimated using Kaplan-Meier survival probabilities along with 95% CIs from 1000-sample nonparametric bootstrapping. Results:A total of 23 452 eligible participants (mean [SD] age, 48.2 [11.1] years; 5790 [24.7%] female; mean [SD] HbA1c, 6.9% [1.1%]) were cloned into 4 treatment strategies. Earlier ADM initiation compared with the control showed progressively lower point estimates for 3-point MACE (RR, 0.32; 95% CI, 0.15 to 1.11 for strategy 1; RR, 0.65; 95% CI, 0.41 to 1.29 for strategy 2; RR, 0.93; 95% CI, 0.70 to 1.41 for strategy 3), though it did not achieve statistical significance. Corresponding RDs were -0.97% (95% CI, -1.26% to 0.14%), -0.49% (-0.84% to 0.40%), and -0.10% (-0.44% to 0.57%), respectively. ADM initiation within 3 months yielded significant risk reduction for all-cause mortality compared with the control in both relative (RR, 0.31; 95% CI, 0.10-0.98) and absolute (RD, -0.40%; 95% CI, -0.57% to -0.01%) scales. Conclusions and Relevance:In this cohort study, earlier ADM initiation following the diagnostic threshold for T2D showed a lower risk of mortality, suggesting a potential cardiovascular benefit of early glycemic control; however, given the low event counts and the observational nature of the study, further evaluation in larger studies is warranted before definitive conclusions can be drawn.

BACKGROUND:Deep learning-derived chest radiographic age may capture subclinical structural changes associated with spirometric impairment. RESEARCH QUESTION:Is chest radiograph (CXR)-based accelerated aging associated with the prevalence and incidence of preserved ratio impaired spirometry (PRISm) and obstructive lung disease (OLD)? STUDY DESIGN AND METHODS:This retrospective study included Korean adults who underwent CXRs and spirometry during regular health checkups between 2006 and 2019. Participants were categorized into decelerated (< -2.0 years), reference (-2.0 to 1.9 years), or accelerated (≥ 2.0 years) aging groups according to CXR-Lung-Risk scores relative to chronological age derived from baseline CXRs. Prevalent PRISm (FEV1 < 80% predicted with FEV1/FVC ≥ 0.70) and OLD (FEV1/FVC < 0.70) were defined based on baseline spirometry and assessed using multivariable multinomial logistic regression. Incident PRISm and OLD were evaluated among participants with normal baseline spirometry using follow-up spirometry data through December 31, 2022, and associations were estimated using multivariable Cox proportional hazards models. RESULTS:Among 231,278 participants (mean age, 50.7 ± 8.8 years; 55.0% male), the prevalence of PRISm and OLD was 2.2% (5,161 of 231,278) and 4.6% (10,557 of 231,278), respectively. Compared with those in the reference group, participants with accelerated aging had higher odds of prevalent PRISm (adjusted OR; 1.37; 95% CI, 1.28-1.46) and OLD (adjusted OR, 1.58; 95% CI, 1.51-1.65). In the longitudinal analysis including 104,158 participants (median follow-up, 4.3 years), accelerated aging was associated with higher risks of incident PRISm (adjusted hazard ratio, 1.37; 95% CI, 1.27-1.48) and OLD (adjusted hazard ratio, 1.28; 95% CI, 1.20-1.37). Associations were directionally consistent across subgroups defined by age, sex, smoking status, and BMI, with most subgroup analyses remaining statistically significant. INTERPRETATION:Our results show that CXR-derived accelerated aging was associated with both current and future PRISm and OLD. These findings support a potential complementary role for routine CXRs in opportunistic identification of pulmonary dysfunction.

Supplementary Table S1 presents breast cancer incidence in relation to iron level and menopausal status.

Supplementary Figure S1 shows the risk of breast cancer in relation to serum ferritin level for the whole cohort (A), premenopausal women (B), and postmenopausal women (C), with hazard ratios and 95% confidence intervals estimated using restricted cubic spline models treating ferritin as a continuous variable.

Supplementary Figure S4 shows the risk of breast cancer in relation to serum transferrin saturation (TSAT) for the whole cohort (A), premenopausal women (B), and postmenopausal women (C), with hazard ratios and 95% confidence intervals estimated using restricted cubic spline models treating TSAT as a continuous variable.

Supplementary Figure S2 shows the risk of breast cancer in relation to serum iron level for the whole cohort (A), premenopausal women (B), and postmenopausal women (C), with hazard ratios and 95% confidence intervals estimated using restricted cubic spline models treating iron as a continuous variable.

Supplementary Table S2 presents breast cancer incidence in relation to TIBC level and menopausal status.

OBJECTIVES The purpose of this study is to analyze whether the association between physical activity and perceived stress differs across urbanicity levels among Korean adolescents. METHODS This study utilized data from the Korea Youth Risk Behavior Survey (KYRBS), collected between 2018 and 2023. Physical activity was dichotomized based on engaging in ≥60 minutes of activity per day for seven consecutive days. Perceived stress was categorized into high and low levels based on survey responses. Urbanicity was classified into metropolitan, mid-sized city, or rural. Complex-sample logistic regression analyses were performed to assess the association between physical activity and perceived stress by urbanicity level, adjusting for age, sex, economic status, academic performance, school type, height, and weight. RESULTS A total of 322,978 adolescents were included in the analysis. The association between physical activity and perceived stress differed by urbanicity level. Adolescents in mid-sized cities who engaged in physical activity for seven consecutive days were more likely to report lower perceived stress (OR = 1.087, 95% CI = 1.035-1.142). However, no significant associations were observed among adolescents residing in metropolitan areas (OR = 1.048, 95% CI = 0.996-1.103) or rural areas (OR = 1.079, 95% CI = 0.950-1.225). CONCLUSIONS This study confirmed that the association between physical activity and perceived stress among adolescents varies by urbanicity level. Significant associations were observed only in mid-sized cities, suggesting that the stress-reducing benefits of physical activity may be influenced by contextual environmental factors. These findings highlight the need for region-specific physical activity promotion strategies to support adolescent mental health.

BackgroundPhysical activity and diet quality are key determinants of chronic disease prevention and overall health. However, their population-level time trends and between-year differences in cross-sectional associations remain underexplored.AimsThis study examined secular trends in physical activity and diet quality among Korean adults from 2018 to 2021 and assessed whether the cross-sectional association between adherence to WHO physical activity guidelines and diet quality varied across survey years.MethodsData were drawn from 18,976 adults aged 19-79 years participating in the Korea National Health and Nutrition Examination Survey. Physical activity was assessed using the Korean version of the International Physical Activity Questionnaire-Short Form and classified according to the WHO guideline (≥150 min/week). Diet quality was measured using the Korean Healthy Eating Index (KHEI). Logistic regression was used to examine the association between physical activity adherence and higher diet quality, adjusting for age, gender, smoking, alcohol use, and body mass index. Meta-regression evaluated the between-year variation in the cross-sectional association.ResultsPhysical activity levels remained stable across survey years, whereas diet quality significantly declined (Plinear = 0.04), particularly among women, non-smokers, alcohol consumers, and individuals with underweight or overweight. In year-specific cross-sectional models, meeting the physical activity recommendation was associated with 31% higher odds of higher diet quality (OR = 1.31, 95% CI = 1.16-2.48, p < 0.001). This association did not significantly change over time.ConclusionsFrom 2018 to 2021, diet quality declined among Korean adults despite stable physical activity levels. Although physical activity adherence was consistently associated with higher diet quality, no significant temporal trends were observed in this relationship.

Supplementary Figure S3 shows the risk of breast cancer in relation to serum total iron-binding capacity (TIBC) for the whole cohort (A), premenopausal women (B), and postmenopausal women (C), with hazard ratios and 95% confidence intervals estimated using restricted cubic spline models treating TIBC as a continuous variable.

Supplementary Table S3 presents breast cancer incidence in relation to transferrin saturation level and menopausal status.

Purpose To evaluate breast density changing trajectories in women age 60 years or older and identify their associated factors. Materials and Methods Data were obtained from the Korean National Health Insurance Service Database, which includes six biennial mammography screenings from January 2009 to December 2020. Women age 60 years or older who participated in screenings in 2009-2010 and 2019-2020 and at least two screenings in between were included. Breast density was classified using the Breast Imaging Reporting and Data System (BI-RADS). Group-based trajectory modeling was used to identify patterns of breast density changes across the six screening cycles. Logistic regression was used to examine breast cancer risk factors associated with the increasing or decreasing breast density trajectories. Results Among 674 993 women (mean age, 65.0 years ± 4.3 [SD]; 51% BI-RADS 1 at baseline), five distinct breast density change trajectories were identified: persistent fatty (20.5%), persistent BI-RADS 2 (36.1%), and persistent BI-RADS 3 (15.4%). Group 2 (17.2%) showed increased density, and group 3 (10.8%) demonstrated decreased density. Several breast cancer risk factors were associated with the breast density trajectories. For example, older women (adjusted odds ratio, 0.98; 95% CI: 0.97, 0.98; P < .001) and women with a higher baseline body mass index and a greater increase in body mass index over time were less likely to have increased breast density. Conclusion Five distinct breast density change trajectories were identified among Korean women who were age 60 years or older. Women with initially low breast density and more breast cancer risk factors were more likely to show increasing trajectory, whereas those with initially high density and fewer risk factors tended to show decreasing density. Keywords: Breast Density, Breast Density Change, Older Women, Reproductive Factors, Breast Cancer © RSNA, 2026.

Loss of muscle mass and quality (myopenia and myosteatosis) are hallmarks of aging and predictors of disability, yet their relationship with biological aging in younger adults is unclear. This prospective cohort study included 165,015 adults (mean age 39.9) who underwent low-dose chest computed tomography (CT) between 2010 and 2020. A longitudinal subset of 61,669 participants had repeated scans (median follow-up 4.1 years). We adopted blood-based Phenotypic Age acceleration (PhenoAgeAccel) and chest radiograph-based biological age acceleration (CXR-AgeAccel). Myopenia and myosteatosis were defined as muscle area and density values more than two standard deviations below young sex-specific reference means. Multivariable multinomial logistic and Cox proportional hazard models estimated associations between biological age acceleration and prevalent or incident muscle abnormalities, adjusting for sociodemographic, lifestyle, and clinical factors. PhenoAgeAccel was associated with higher odds of myopenia (OR 1.16, 95

Dyslipidemia, characterized by abnormal blood lipid levels, constitutes a significant risk factor for cardiovascular disease. Emerging evidence indicates that the gut microbiota influences lipid metabolism, although findings across studies have been inconsistent. In this cross-sectional investigation, we analyzed the composition of gut microbiota, associated metabolic pathways, predicted gut metabolites, and the resistome in 1,384 participants (including 895 individuals with dyslipidemia and 489 controls) through shotgun metagenomic sequencing. Our findings demonstrated that Bacteroides caccae was enriched among dyslipidemia cases, potentially contributing to inflammation and altered lipid metabolism. Conversely, Coprococcus eutactus and Coprococcus catus, recognized producers of short-chain fatty acids (SCFAs) involved in lipid regulation, as well as Blautia obeum, known to be positively affected by SCFAs, were more prevalent in the control group. Additionally, we identified an enrichment of the gene family responsible for dTDP-beta-D-fucofuranose biosynthesis, associated with bacterial pathogenicity, in dyslipidemia cases, with Bacteroides stercoris serving as a major contributor. Dyslipidemia cases also exhibited depletion of glycogen and peptidoglycan biosynthesis pathways, which may compromise energy storage and immune function, alongside decreased levels of pseudouridine, a molecule involved in RNA metabolism. Furthermore, a marginal increase in abundance of antibiotic-resistance genes, tetQ, was observed in dyslipidemia cases, suggesting a potential link between the gut resistome and metabolic dysregulation. These results offer novel insights into the role of gut microbiota in the pathophysiology of dyslipidemia and underscore potential microbiome-targeted interventions for metabolic disease management.IMPORTANCEDyslipidemia, characterized by abnormal blood lipid levels, is a significant risk factor for cardiovascular disease. Emerging evidence suggests that the gut microbiota plays a role in lipid metabolism, although findings across studies have varied. This study analyzed the gut microbiota, metabolic pathways, predicted gut metabolites, and antimicrobial resistance genes in 1,384 participants using shotgun metagenomic sequencing. Individuals with dyslipidemia exhibited an imbalance in gut bacteria, including an increase in Bacteroides caccae, a species associated with inflammation, and a decrease in short-chain fatty acid-producing bacteria such as Coprococcus eutactus and Blautia obeum, which support metabolic health. Furthermore, we identified significant changes in microbial metabolic pathways related to energy storage and immune function, as well as an increased abundance of tetracycline resistance genes (tetQ), suggesting a potential link between dyslipidemia and antimicrobial resistance. Our study provides a comprehensive overview of dyslipidemia-associated gut microbial alterations, highlighting potential mechanistic links and therapeutic targets.

BackgroundEndocrine therapy (ETx) for hormone receptor–positive breast cancer frequently induces menopausal symptoms that may compromise treatment adherence. However, longitudinal symptom trajectories compared with natural menopausal progression remain unclear.MethodsThis longitudinal cohort study included 5,734 women from two prospective cohorts. Menopausal symptoms were assessed using the Menopause Rating Scale (MRS). Women with breast cancer (n=2,583) were recruited from the Breast Cancer Information Grand Round for Survivorship cohort, and women without breast cancer (n=3,151) from the Kangbuk Samsung Health Study. Linear mixed-effects models estimated longitudinal changes in MRS scores according to breast cancer status, menopausal status, and ETx use. Difference-in-differences (DiD) analyses used premenopausal women without breast cancer as the reference group.ResultsAmong premenopausal women, ETx was associated with greater increases in total MRS scores compared with women without breast cancer (DiD 3.30; 95% CI, 2.04–4.58 at 1 year). Premenopausal women receiving ETx experienced sustained symptom increases over 3 years, particularly those receiving ovarian function suppression. Regimens including gonadotropin-releasing hormone agonists were associated with the greatest increases in symptom burden. Among postmenopausal women, ETx was associated with modest changes in total MRS scores but a significant increase in urogenital symptoms (DiD 0.71; 95% CI, 0.26–1.16).ConclusionsETx for breast cancer is associated with sustained increases in menopausal symptoms beyond those observed during natural menopause. The excess symptom burden is most pronounced among premenopausal women receiving ovarian function suppression. These findings highlight the importance of proactive symptom monitoring and supportive care strategies to improve long-term adherence to endocrine therapy.

OBJECTIVES The purpose of this study was to examine temporal trends in physical activity and metabolic syndrome (MetS) among Korean adults, and to evaluate secular trends in the association between physical activity and MetS from 2018 to 2023. METHODS This study utilized data from the Korea National Health and Nutrition Examination Survey (KNHANES) collected between 2018 and 2023. A total of 32,639 adults aged ≥ 19 years were included. Physical activity was dichotomized based on meeting the World Health Organization guidelines (≥ 150 minutes/week of moderate to vigorous physical activity). MetS was defined according to the National Cholesterol Education Program Adult Treatment Panel III criteria with Asian-specific waist circumference cutoffs, as the presence of ≥ 3 of 5 metabolic components based on measured component values. All analyses accounted for the complex sampling design of KNHANES by applying survey weights and primary sampling units and strata. Temporal trends were tested using orthogonal polynomial contrasts. Secular changes in the association between physical activity and MetS were evaluated using random-effects meta-regression. RESULTS Physical activity levels showed no significant temporal trends from 2018 to 2023. Among MetS components, waist circumference and HDL-C showed significant linear and quadratic trends, fasting plasma glucose demonstrated a significant quadratic pattern peaking in 2021, and both triglycerides and diastolic blood pressure showed significant negative linear trends, whereas systolic blood pressure showed no significant temporal trend. Pooled analyses revealed that meeting physical activity guidelines was associated with a 25% lower odds of MetS (pooled OR = 0.75, 95% CI = 0.70–0.80). Meta-regression indicated no significant secular change in this association across survey years. CONCLUSIONS Meeting physical activity guidelines was consistently associated with lower odds of MetS among Korean adults from 2018 to 2023, with no evidence of secular change in this association. Despite stable physical activity, several MetS components showed partially unfavorable temporal trends, underscoring the need for prevention strategies beyond physical activity alone.

Supplementary Table S5 presents breast cancer incidence in relation to ferritin level and menopausal status after further adjustment for WBC and hsCRP.