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The rare decay K_{L}→π^{0}νν[over ¯] was studied with the dataset taken at the J-PARC KOTO experiment in 2016, 2017, and 2018. With a single event sensitivity of (7.20±0.05_{stat}±0.66_{syst})×10^{-10}, three candidate events were observed in the signal region. After unveiling them, contaminations from K^{±} and scattered K_{L} decays were studied, and the total number of background events was estimated to be 1.22±0.26. We conclude that the number of observed events is statistically consistent with the background expectation. For this dataset, we set an upper limit of 4.9×10^{-9} on the branching fraction of K_{L}→π^{0}νν[over ¯] at the 90% confidence level.

Purpose: To examine the discrepancy in breast density assessments by radiologists, LIBRA software, and AI algorithm and their association with breast cancer risk., Methods: Among 74,610 Korean women aged ≥ 34 years, who underwent screening mammography, density estimates obtained from both LIBRA and the AI algorithm were compared to radiologists using BI-RADS density categories (A-D, designating C and D as dense breasts). The breast cancer risks were compared according to concordant or discordant dense breasts identified by radiologists, LIBRA, and AI. Cox-proportional hazards models were used to determine adjusted hazard ratios (aHRs) [95% confidence intervals (CIs)]., Results: During a median follow-up of 9.9 years, 479 breast cancer cases developed. Compared to the reference non-dense breast group, the aHRs (95% CIs) for breast cancer were 2.37 (1.68-3.36) for radiologist-classified dense breasts, 1.30 (1.05-1.62) for LIBRA, and 2.55 (1.84-3.56) for AI. For different combinations of breast density assessment, aHRs (95% CI) for breast cancer were 2.40 (1.69-3.41) for radiologist-dense/LIBRA-non-dense, 11.99 (1.64-87.62) for radiologist-non-dense/LIBRA-dense, and 2.99 (1.99-4.50) for both dense breasts, compared to concordant non-dense breasts. Similar trends were observed with radiologists/AI classification: the aHRs (95% CI) were 1.79 (1.02-3.12) for radiologist-dense/AI-non-dense, 2.43 (1.24-4.78) for radiologist-non-dense/AI-dense, and 3.23 (2.15-4.86) for both dense breasts., Conclusion: The risk of breast cancer was highest in concordant dense breasts. Discordant dense breast cases also had a significantly higher risk of breast cancer, especially when identified as dense by either AI or LIBRA, but not radiologists, compared to concordant non-dense breast cases., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no conflict of interest. Ethical approval: This study was approved by the Institutional Review Board of Kangbuk Samsung Hospital (2023-02-004), and the need for informed consent was waived due to the use of de-identified retrospective data collected during the health screening process. Consent to participate: Not applicable. Consent for publication: Not applicable., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: This large cohort study aimed to examine the overall associations of physical activity (PA) and estimated cardiorespiratory fitness (eCRF) with incident chronic kidney disease (CKD)., Methods: This study included a total of 274,292 participants (mean age, 37.9±8.0 years; 41% women) using data collected from the Kangbuk Samsung Health Study. The participants were categorized into three groups: PA (Inactive, Insufficiently active, and Active) and eCRF(Low, Middle, High). Furthermore, subgroup analyses were conducted to examine the differences in the risks of CKD incidence by age and sex. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs)., Results: A total of 932 participants (0.34%) developed CKD. Physical activity level was not associated with CKD risk in the overall cohort. However, younger participants (<45 years) showed lower CKD risks, with hazard ratios (HRs) of 0.53 (95% CI: 0.36-0.79) and 0.73 (95% CI: 0.53-1.00) for insufficiently active and active individuals, respectively. Similarly, men exhibited reduced CKD risks, with HRs of 0.77 (95% CI: 0.59-1.00) and 0.81 (95% CI: 0.66-1.00) in these groups. Additionally, those in the high eCRF group had a 20% reduced CKD risk (HR, 0.80; 95% CI: 0.67-0.96) compared to the low eCRF group., Conclusions: The associations between PA or eCRF and incident CKD showed differences according to age and sex., (Copyright © 2025. Published by Elsevier Inc.)

In recent years salinomycin has emerged as a promising anticancer drug. Many literature reports have proved its remarkable antiproliferative activity. Moreover, chemical modifications of salinomycin lead to analogues with even higher cytotoxicity against cancer cell lines and a better selectivity index for malignant cells than those of the unmodified compound or a standard anticancer drug such as doxorubicin. In this paper we report the synthesis of a series of twelve novel salinomycin conjugates and their characterization by spectroscopic and spectrometric methods. Salinomycin was conjugated with different triphenylphosphonium cations in order to find out whether the conjugation with mitochondrial targeting vectors would have a beneficial impact on biological properties. Salinomycin and its novel conjugates were tested to determine their in vitro antiproliferative and antimicrobial activity. Taking into account the presence of triphenylphosphonium moiety, the impact of the obtained analogues on mitochondria activity was evaluated by MitoTrackers dyes, furthermore their apoptosis effect and cell cycle arrest were assessed. In addition, the changes in the mitochondrial membrane potential were measured and the ability to generate reactive oxygen species was assessed. Finally, we conducted biophysical studies to investigate the impact of the obtained salinomycin analogues on mitochondrial respiration rates and their electrophysiological properties. Results of this study have proved that conjugation of salinomycin with phosphonium cations leads to promising results in the search for promising anticancer agents., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Selol is a semi-synthetic mixture of selenized triglycerides. The results of biological studies revealed that Selol exhibits several anticancer effects. However, studies on its potential anti-inflammatory activity are scarce, and underlying signaling pathways are unknown. The aim of our study was to investigate the ability of Selol to exert anti-inflammatory effects in a RAW 264.7 cell line model of LPS (lipopolysaccharide)-induced inflammation. Cells were treated either with Selol 5% (4 or 8 µg Se/mL) or LPS (1 µg/mL) alone or with Selol given concomitantly with LPS. The parameters studied were reactive oxygen species (ROS) production, glutathione and thioredoxin (Txn) levels, and nuclear factor kappa B (NF-κB) activation, as well as nitric oxide/prostaglandin E 2 (NO/PGE 2 ) production. The presented research also included the effect of Selol and/or LPS on glucose (Glc) catabolism; for this purpose, the levels of key enzymes of the glycolysis pathway were determined. The results showed that Selol exhibited pro-oxidative properties. It induced ROS generation with a significant increase in the level of Txn; however, it did not affect the reduced glutathione/oxidized glutathione (GSH/GSSG) ratio. Selol moderately activated NF-κB but failed to affect NO/PGE 2 production. The effect of Selol on glucose catabolism was not significant. However, the simultaneous administration of Selol with LPS exerted a statistically significant anti-inflammatory effect via a decrease in the production of pro-inflammatory mediators and NF-κB activation. Our study also showed that as a result of LPS action in cells, the anaerobic glycolysis activity was increased, and incubation with Selol caused a partial reprogramming of Glc metabolism towards aerobic metabolism. This may indicate different pharmacological and molecular effects of Selol action in physiological and pathological conditions.

Background: Patients with estrogen receptor (ER)-positive breast cancer (BC) can be treated with endocrine therapy targeting ER, however, metastatic recurrence occurs in 25% of the patients who have initially been treated. Secreted proteins from tumors play important roles in cancer metastasis but previous methods for isolating secretory proteins had limitations in identifying novel targets., Methods: We applied an in situ secretory protein labeling technique using TurboID to analyze secretome from tamoxifen-resistant (TAMR) BC. The increased expression of LGALS3BP was validated using western blotting, qPCR, ELISA, and IF. Chromatin immunoprecipitation was applied to analyze estrogen-dependent regulation of LGALS3BP transcription. The adhesive and angiogenic functions of LGALS3BP were evaluated by abrogating LGALS3BP expression using either shRNA-mediated knockdown or a neutralizing antibody. Xenograft mouse experiments were employed to assess the in vivo metastatic potential of TAMR cells and the LGALS3BP protein. Clinical evaluation of LGALS3BP risk was carried out with refractory clinical specimens from tamoxifen-treated ER-positive BC patients and publicly available databases., Results: TAMR secretome analysis revealed that 176 proteins were secreted at least 2-fold more from MCF7/TAMR cells than from sensitive cells, and biological processes such as cell adhesion and angiogenesis were associated with the TAMR secretome. Galectin-3 binding protein (LGALS3BP) was one of the top 10 most highly secreted proteins in the TAMR secretome. The expression level of LGALS3BP was suppressed by estrogen signaling, which involves direct ERα binding to its promoter region. Secreted LGALS3BP in the TAMR secretome helped BC cells adhere to the extracellular matrix and promoted the tube formation of human umbilical vein endothelial cells. Compared with sensitive cells, xenograft animal experiments with MCF7/TAMR cells showed increased pulmonary metastasis, which completely disappeared in LGALS3BP-knockdown TAMR cells. Finally, higher levels of LGALS3BP were associated with poor prognosis in ER-positive BC patients treated with adjuvant tamoxifen in the clinic., Conclusion: TAMR secretome analysis identified secretory proteins, such as LGALS3BP, that are involved in biological processes closely related to metastasis. Secreted LGALS3BP from the TAMR cells promoted adhesion of the cells to the extracellular matrix and vasculature formation, which may support metastasis of TAMR cells., Competing Interests: Declarations. Ethics approval: The animal experiments were performed in accordance with the guidelines of the Seoul National University Animal Care and Use Committee (SNU-210906-2-3 and SNU-240124-3). Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Understanding the association between the menopausal transition and declining sleep quality can guide optimal timing for preventive interventions in transitioning women. However, studies lack representation of Asian women and sufficient data on the progression of menopausal stages and sleep quality changes over time in this population., Methods: This study included 3305 women in the pre-menopause stage at baseline. The sleep quality and its components were assessed using the Pittsburgh Sleep Quality Index (PSQI). Menopausal stages were classified as pre-menopause, early transition, late transition, and post-menopause according to the Stages of Reproductive Aging Workshop+10 (STRAW+10) criteria. We estimated the longitudinal association between menopausal stage changes over time and the PSQI score, and examined the effect of being overweight., Results: The trends in the PSQI scores and its components according to the menopausal stage changes over time showed that with the exception of sleep duration and habitual sleep efficiency, an overall decline was noted in sleep health during late transition and post-menopause compared to pre-menopause. These associations were independent of time-variant annual chronological aging, which was not significantly associated with sleep deterioration. Additionally, although the associations between menopausal stages and sleep quality did not significantly differ by adiposity level, the overweight group exhibited worse PSQI scores and components than did the non-overweight group., Limitation: Sleep quality and menopausal stage were assessed using self-reported questionnaires without objective measures., Conclusion: Our study underscores the importance of screening for sleep quality deterioration and implementing appropriate measures for women experiencing menopausal transition., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To examine the prevalence of overactive bladder (OAB) according to menopausal stages in middle-aged women., Design: Cross-sectional study., Setting: Total Healthcare Center in South Korea., Population: Middle-aged Korean women (n=3469, mean age, 49.5 ± 2.9 years)., Methods: Menopausal stages were defined according to the Stages of Reproductive Aging Workshop +10 criteria, and menopausal symptoms were assessed using the Korean version of Menopause-Specific Quality of Life (MENQOL). Logistic regression models were used to estimate prevalence ratios with 95% confidence intervals for OAB according to menopausal stage and to assess the associations with menopausal symptoms., Main Outcome Measures: OAB symptoms were evaluated using the Overactive Bladder Symptom Score (OABSS)., Results: The prevalence of OAB increased with menopausal stage; however, the multivariable-adjusted prevalence ratios for women in menopausal transition and postmenopausal stage were insignificant (p trend  = 0.160) compared to those for premenopausal women. Among individual OAB symptoms, the multivariable-adjusted prevalence ratios for nocturia increased with menopausal stage in a dose-response manner (p trend  = 0.005 for 1 time/day; p trend  < 0.001 for ≥2 times/day). The association between menopausal stages and nocturia occurring ≥2 times/day was evident in women without OAB and with relatively high MENQOL scores, vasomotor symptoms and difficulty sleeping., Conclusions: The prevalence of OAB, particularly nocturia, increased with menopausal stage, and the association was obvious in women with other menopausal symptoms. This finding underscores the importance of addressing nocturia as a potential menopausal symptom in middle-aged women. Further studies are required to understand the mechanisms linking OAB with menopausal symptoms in middle-aged women., (© 2024 John Wiley & Sons Ltd.)

Background: Taller women are at an increased risk of breast cancer; however, evidence regarding this in younger women is limited. This study investigated the association between body height and breast cancer risk in premenopausal Korean women aged <40 years., Methods: Premenopausal women aged <40 years enroled in the Kangbuk Samsung Health Study (KSHS) and National Health Insurance Service-National Health Information Database (NHIS-NHID) were included in the analysis. Trained staff members performed anthropometry, including height measurements. Breast cancer incidence was followed up until December 2019. Cox regression model and restricted cubic- spline regression were applied., Results: The mean (standard deviation [SD]) age was 33.3 (3.6) years and 32.9 (4.2) in KSHS and NHIS-NHID cohorts, respectively. After adjusting for age at baseline and other confounders, every 10 cm of height was associated with a 1.44-fold increased risk of developing breast cancer (adjusted hazard ratio [aHR], 1.44; 95% confidence interval [CI], 1.17-1.78) in the KSHS. The restricted cubic spline regression showed an almost linear association between height and breast cancer risk. Compared to women with height <155 cm, aHRs (95% CI) among those with height 160-165 cm, 165-170 cm, and ≥170 cm were 1.67 (1.07-2.60), 1.75 (1.09-2.81), and 2.31 (1.18-3.86), respectively (P = 0.009). Results were similar in the NHIS-NHID cohort (aHR, 1.20 [95% CI, 1.10-1.31] per 10-cm increase in height)., Conclusion: In young Korean women, greater body height was associated with increased breast cancer risk., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Objectives: The association between occupational psychosocial factors and mental health has been studied in several systematic reviews. However, few systematic reviews exist that specifically address suicidal ideation. Therefore, this systematic review and meta-analysis aimed to examine the associations between long working hours, shift work, and suicidal ideation., Methods: We systematically screened and collected studies published between January 1970 and September 2022 from three electronic databases and Google Scholar. We conducted a meta-analysis using a random-effects model and assessed the risk of bias using a navigation guide. Additionally, the grading of recommendations assessment, development and evaluation (GRADE) approach was used to consider five items, including the risk of bias and publication bias., Results: Twenty-eight articles were included in this meta-analysis. After adjusting for covariates, the overall odds ratio (OR) for long working hours and shift work were 1.44 [95% confidence interval (CI) 1.26-1.63] and 1.34 (95% CI 1.22-1.47), respectively. Compared with those who worked <40 hours per week, those who worked >55 hours per week had a 1.65 (95% CI 1.37-1.98) higher risk of suicidal ideation, and fixed night shift workers had 1.37 (95% CI 1.03-1.83) higher risk than non-shift workers., Conclusions: Evidence has shown associations between long working hours, shift work, and suicidal ideation. Implementing evidence-based interventions to address these risk factors may help prevent the progression of suicidal ideation. However, further studies are critically needed, especially those using standardized exposure definitions and longitudinal data.

Background: Overactive bladder (OAB) is a common condition in middle-aged and older women. It has been reported to be potentially linked to cognitive decline, particularly in older adults. This study investigated the association between OAB symptoms and cognitive impairment in middle-aged women., Materials and Methods: This cross-sectional study had a sample of 1652 women (mean age 49.3 ± 2.8 years) who were not taking medication for either urinary tract infection or OAB. OAB symptoms and cognitive function were evaluated by self-administered questionnaires: the Overactive Bladder Symptom Score and the Alzheimer's disease 8. Logistic regression models estimated prevalence ratios (PRs) with 95 % confidence intervals (CI) for cognitive impairment according to the presence/absence of OAB. Mediation analyses assessed the impact of poor sleep quality on this association., Results: Cognitive impairment was more prevalent in women with OAB than in those without OAB (multivariable-adjusted PR: 1.88 [95 % CI: 1.52-2.24]). Women experiencing nocturia (≥twice a night), urinary urgency at least once a week, and urgency urinary incontinence at least once a week had multivariable-adjusted PRs (95 % CI) for cognitive impairment of 2.08 (1.50-2.65), 2.12 (1.66-2.58), and 1.75 (1.17-2.34), respectively. Poor sleep quality mediated 10.81 % [95 % CI: 4.55-19.44 %] of the relationship between OAB and cognitive impairment., Conclusions: Among middle-aged women not taking OAB medications, OAB symptoms were associated with cognitive impairment, partly because of poor sleep quality. Further research is needed to determine whether early screening of patients with OAB can help identify those susceptible to cognitive impairment associated with OAB medication and if preventive measures should be targeted at this group., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background CT performed for various clinical indications has the potential to predict cardiometabolic diseases. However, the predictive ability of individual CT parameters remains underexplored. Purpose To evaluate the ability of automated CT-derived markers to predict diabetes and associated cardiometabolic comorbidities. Materials and Methods This retrospective study included Korean adults (age ≥ 25 years) who underwent health screening with fluorine 18 fluorodeoxyglucose PET/CT between January 2012 and December 2015. Fully automated CT markers included visceral and subcutaneous fat, muscle, bone density, liver fat, all normalized to height (in meters squared), and aortic calcification. Predictive performance was assessed with area under the receiver operating characteristic curve (AUC) and Harrell C-index in the cross-sectional and survival analyses, respectively. Results The cross-sectional and cohort analyses included 32166 (mean age, 45 years ± 6 [SD], 28833 men) and 27 298 adults (mean age, 44 years ± 5 [SD], 24 820 men), respectively. Diabetes prevalence and incidence was 6% at baseline and 9% during the 7.3-year median follow-up, respectively. Visceral fat index showed the highest predictive performance for prevalent and incident diabetes, yielding AUC of 0.70 (95% CI: 0.68, 0.71) for men and 0.82 (95% CI: 0.78, 0.85) for women and C-index of 0.68 (95% CI: 0.67, 0.69) for men and 0.82 (95% CI: 0.77, 0.86) for women, respectively. Combining visceral fat, muscle area, liver fat fraction, and aortic calcification improved predictive performance, yielding C-indexes of 0.69 (95% CI: 0.68, 0.71) for men and 0.83 (95% CI: 0.78, 0.87) for women. The AUC for visceral fat index in identifying metabolic syndrome was 0.81 (95% CI: 0.80, 0.81) for men and 0.90 (95% CI: 0.88, 0.91) for women. CT-derived markers also identified US-diagnosed fatty liver, coronary artery calcium scores greater than 100, sarcopenia, and osteoporosis, with AUCs ranging from 0.80 to 0.95. Conclusion Automated multiorgan CT analysis identified individuals at high risk of diabetes and other cardiometabolic comorbidities. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Pickhardt in this issue.

Objective: Optimal metabolically healthy status is important to prevent various chronic diseases. This study investigated the association between lifelog-derived physical activity and metabolically healthy status., Methods: This cross-sectional study included 51 Korean adults aged 30-40 years with no history of chronic diseases. Physical activity data were obtained by the International Physical Activity Questionnaire-Short Form (IPAQ-SF). Lifelog-derived physical activity was defined by step counts and walking speed for 1 week, as recorded by the Samsung Health application on both the Samsung Galaxy Fit2 and mobile phones. Participants without metabolic syndrome components were categorized as the metabolically healthy group ( n  = 31) and the remaining participants as the metabolically unhealthy group ( n  = 20). Prevalence ratios and 95% confidence intervals were estimated using Poisson regression models. The predictive ability of each physical activity measure was evaluated according to the area under the curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI) values., Results: Among the physical activity measures, lifelog-derived walking speed was significantly inversely associated with prevalent metabolically unhealthy status. The lifelog component model including walking speed, age, and sex had the highest AUC value for metabolically unhealthy status. Adding lifelog-derived step counts to the IPAQ-SF-derived metabolic equivalent (MET) model (including age, sex, and IPAQ-SF-METs) yielded 37% and 13% increases in the NRI and IDI values, respectively. Incorporating walking speed into the IPAQ-SF-derived MET model improved metabolically unhealthy status prediction by 42% and 21% in the NRI and IDI analyses, respectively., Conclusions: Slow walking speed derived from the lifelog was associated with a higher prevalence of metabolically unhealthy status. Lifelog-derived physical activity information may aid in identifying individuals with metabolic abnormalities., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Background: We investigated the association between vasomotor symptoms (VMSs) and the onset of depressive symptoms among premenopausal women., Methods: This cross-sectional study included 4376 premenopausal women aged 42-52 years, and the cohort study included 2832 women without clinically relevant depressive symptoms at baseline. VMSs included the symptoms of hot flashes and night sweats. Depressive symptoms were evaluated using the Center for Epidemiological Studies Depression Scale; a score of ≥16 was considered to define clinically relevant depressive symptoms., Results: Premenopausal Women with VMSs at baseline exhibited a higher prevalence of depressive symptoms compared with women without VMSs at baseline (multivariable-adjusted prevalence ratio 1.76, 95 % confidence interval [CI] 1.47-2.11). Among the 2832 women followed up (median, 6.1 years), 406 developed clinically relevant depressive symptoms. Women with versus without VMSs had a significantly higher risk of developing clinically relevant depressive symptoms (multivariable-adjusted hazard ratio, 1.72; 95 % CI 1.39-2.14). VMS severity exhibited a dose-response relationship with depressive symptoms (P for trend <0.05)., Limitations: Self-reported questionnaires were only used to obtain VMSs and depressive symptoms, which could have led to misclassification. We also could not directly measure sex hormone levels., Conclusions: Even in the premenopausal stage, women who experience hot flashes or night sweats have an increased risk of present and developed clinically relevant depressive symptoms. It is important to conduct mental health screenings and provide appropriate support to middle-aged women who experience early-onset VMSs., Competing Interests: Declaration of competing interest All authors declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Artificial intelligence (AI) algorithms for the independent assessment of screening mammograms have not been well established in a large screening cohort of Asian women. We compared the performance of screening digital mammography considering breast density, between radiologists and AI standalone detection among Korean women., Methods: We retrospectively included 89,855 Korean women who underwent their initial screening digital mammography from 2009 to 2020. Breast cancer within 12 months of the screening mammography was the reference standard, according to the National Cancer Registry. Lunit software was used to determine the probability of malignancy scores, with a cutoff of 10% for breast cancer detection. The AI's performance was compared with that of the final Breast Imaging Reporting and Data System category, as recorded by breast radiologists. Breast density was classified into four categories (A-D) based on the radiologist and AI-based assessments. The performance metrics (cancer detection rate [CDR], sensitivity, specificity, positive predictive value [PPV], recall rate, and area under the receiver operating characteristic curve [AUC]) were compared across breast density categories., Results: Mean participant age was 43.5 ± 8.7 years; 143 breast cancer cases were identified within 12 months. The CDRs (1.1/1000 examination) and sensitivity values showed no significant differences between radiologist and AI-based results (69.9% [95% confidence interval [CI], 61.7-77.3] vs. 67.1% [95% CI, 58.8-74.8]). However, the AI algorithm showed better specificity (93.0% [95% CI, 92.9-93.2] vs. 77.6% [95% CI, 61.7-77.9]), PPV (1.5% [95% CI, 1.2-1.9] vs. 0.5% [95% CI, 0.4-0.6]), recall rate (7.1% [95% CI, 6.9-7.2] vs. 22.5% [95% CI, 22.2-22.7]), and AUC values (0.8 [95% CI, 0.76-0.84] vs. 0.74 [95% CI, 0.7-0.78]) (all P < 0.05). Radiologist and AI-based results showed the best performance in the non-dense category; the CDR and sensitivity were higher for radiologists in the heterogeneously dense category (P = 0.059). However, the specificity, PPV, and recall rate consistently favored AI-based results across all categories, including the extremely dense category., Conclusions: AI-based software showed slightly lower sensitivity, although the difference was not statistically significant. However, it outperformed radiologists in recall rate, specificity, PPV, and AUC, with disparities most prominent in extremely dense breast tissue., (© 2024. The Author(s).)

Objective: To investigate the association between body composition parameters and breast cancer (BC) risk in premenopausal women., Design, Setting, and Participants: Prospective cohort study using data from the Kangbuk Samsung Cohort Study. Participants were women aged 20 to 54 years who were enrolled from 2011 to 2019 and followed up for BC development until December 31, 2020. Data were analyzed from June to August 2023., Exposures: Trained nurses conducted anthropometric measurements and assessed body composition using segmental bioelectric impedance analysis. The analysis encompassed adiposity measures such as body mass index (BMI), waist circumference, and body composition parameters, including muscle mass, fat mass, ratio of muscle mass to weight, ratio of fat mass to weight, and fat mass index., Main Outcomes and Measures: Adjusted hazard ratios (aHR) for BC during the follow-up period., Results: Among 125 188 premenopausal women, the mean (SD) age was 34.9 (6.3) years. During a mean (range) follow-up of 6.7 (0.5-9.9) years, 1110 incident BC cases were identified. The mean (SD) BMI and waist circumference were 21.6 (3.1) and 75.3 (8.2) cm, respectively. Higher BMI and waist circumference were associated with decreased risk, with an aHR of 0.89 (95% CI, 0.84-0.95) per SD increase in BMI and 0.92 (95% CI, 0.86-0.98) per SD increase in waist circumference. A higher ratio of fat mass to weight was associated with decreased BC risk (aHR, 0.92; 95% CI, 0.86-0.99 per SD increase), whereas the opposite trend was observed for the ratio of muscle mass to weight, with an aHR of 1.08 (95% CI, 1.02-1.15) per SD increase. The results remained consistent even after additional adjustments for height in the model. The fat mass index was also inversely associated with BC risk, with an HR of 0.90 (95% CI, 0.85-0.97) per SD increase., Conclusions and Relevance: In this cohort study of premenopausal women, a higher level of adiposity, represented by increased BMI, waist circumference, and fat mass, was consistently associated with decreased breast cancer risk. Conversely, muscle mass and its ratio to weight displayed opposite or inconsistent patterns. These findings suggest an inverse association between excess adiposity and the risk of BC in premenopausal women, confirming earlier findings that BMI is an indirect measure of adiposity.

Aims: Mammography, commonly used for breast cancer screening in women, can also predict cardiovascular disease. We developed mammography-based deep learning models for predicting coronary artery calcium (CAC) scores, an established predictor of coronary events., Methods and Results: We evaluated a subset of Korean adults who underwent image mammography and CAC computed tomography and randomly selected approximately 80% of the participants as the training dataset, used to develop a convolutional neural network (CNN) to predict detectable CAC. The sensitivity, specificity, area under the receiver operating characteristic curve (AUROC), and overall accuracy of the model's performance were evaluated. The training and validation datasets included 5235 and 1208 women, respectively [mean age, 52.6 (±10.2) years], including non-zero cases (46.8%). The CNN-based deep learning prediction model based on the Resnet18 model showed the best performance. The model was further improved using contrastive learning strategies based on positive and negative samples: sensitivity, 0.764 (95% CI, 0.667-0.830); specificity, 0.652 (95% CI, 0.614-0.710); AUROC, 0.761 (95% CI, 0.742-0.780); and accuracy, 70.8% (95% CI, 68.8-72.4). Moreover, including age and menopausal status in the model further improved its performance (AUROC, 0.776; 95% CI, 0.762-0.790). The Framingham risk score yielded an AUROC of 0.736 (95% CI, 0.712-0.761)., Conclusion: Mammography-based deep learning models showed promising results for predicting CAC, performing comparably to conventional risk models. This indicates mammography's potential for dual-risk assessment in breast cancer and cardiovascular disease. Further research is necessary to validate these findings in diverse populations, with a particular focus on representation from national breast screening programmes., Competing Interests: Conflict of interest: All authors report no conflict of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: This study evaluated the prevalence and types of intracranial lesions through dedicated imaging analysis of primary headaches in children and compared them between patients with and without migraine., Methods: This study included 190 children diagnosed with primary headache who underwent neuroimaging, including brain computed tomography (CT), CT angiography (CTA), and brain magnetic resonance imaging (MRI). All patients with primary headaches was divided into two groups, namely, the migraine and non-migraine groups, on the basis of data from electronic medical records. Clinical characteristics and imaging findings were evaluated and compared between the two groups., Results: Patients with migraine were old and had a longer period from symptom onset to diagnosis. CT was normal in 71 of 95 patients, whereas 7 of 29 patients who underwent CTA had vascular lesions; the migraine group (n = 6/20, [30%]) had higher incidence of vascular lesions than the non-migraine group (n = 1/9, [11.1%]); however, there was no statistically significant difference (p = 0.382). Furthermore, 57.5% (61/106) of children showed normal brain MRI. The most common brain MRI finding was dilated perivascular space (n = 18, [16.8%]). Most perivascular spaces were located in the basal ganglia (n = 72, [75.8%]) and were in linear patterns (n = 58, [63.0%]). There was no statistically significant difference between the two groups., Conclusion: A low prevalence of significant abnormalities was found in children with primary headaches. Dilated perivascular space was the most common finding in both groups on MRI. CTA showed more vascular lesions in the migraine group than in the non-migraine group. Therefore, further evaluations are needed to reveal the relationship between vascular lesions or dilated perivascular space and pediatric primary headaches., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Potentiating antitumor immunity is a promising therapeutic approach for treating a variety of cancers, including breast cancer. One potential strategy to promote antitumor immunity is targeting DNA damage response. Given that the nuclear receptor NR1D1 (also known as REV-ERBα) inhibits DNA repair in breast cancer cells, we explored the role of NR1D1 in antitumor CD8+ T-cell responses. First, deletion of Nr1d1 in MMTV-PyMT transgenic mice resulted in increased tumor growth and lung metastasis. Orthotopic allograft experiments suggested that loss of Nr1d1 in tumor cells rather than in stromal cells played a prominent role in increasing tumor progression. Comprehensive transcriptome analyses revealed that biological processes including type I IFN signaling and T cell-mediated immune responses were associated with NR1D1. Indeed, the expression of type I IFNs and infiltration of CD8+ T cells and natural killer cells in tumors were suppressed in Nr1d1-/-;MMTV-PyMT mice. Mechanistically, NR1D1 promoted DNA damage-induced accumulation of cytosolic DNA fragments and activated cGAS-STING signaling, which increased the production of type I IFNs and downstream chemokines CCL5 and CXCL10. Pharmacologic activation of NR1D1 by its ligand, SR9009, enhanced type I IFN-mediated antitumor immunity accompanied by the suppression of tumor progression and lung metastasis. Taken together, these findings reveal the critical role of NR1D1 in enhancing antitumor CD8+ T-cell responses, suggesting that NR1D1 may be a good therapeutic target for breast cancer., Significance: NR1D1 suppresses breast cancer progression and lung metastasis by enhancing antitumor immunity via cGAS-STING pathway activation, which provides potential immunotherapeutic strategies for breast cancer., (©2023 The Authors; Published by the American Association for Cancer Research.)

Aims: In this study, we aimed to investigate previously unrecognized lipid metabolic perturbations in tamoxifen-resistant breast cancer (BC) by conducting comprehensive metabolomics and transcriptomics analysis. We identified the role of 3-hydroxy-3-methylglutary-coenzyme-A-synthase 2 (HMGCS2), a key enzyme responsible for ketogenesis, in tamoxifen-resistant BC growth., Main Methods: Comprehensive metabolomics (CE-TOFMS, LC-TOFMS) and transcriptiomics analysis were performed to characterize metabolic pathways in tamoxifen-resistant BC cells. The upregulation of HMGCS2 were verified thorugh immunohistochemistry (IHC) in clinical samples obtained from patients with recurrent BC. HMGCS2 inhibitor was discovered through surface plasmon resonance analysis, enzyme assay, and additional molecular docking studies. The effect of HMGCS2 suppression on tumor growth was studied thorugh BC xenograft model, and intratumoral lipid metabolites were analyzed via MALDI-TOFMS imaging., Key Findings: We revealed that the level of HMGCS2 was highly elevated in both tamoxifen-resistant T47D sublines (T47D/TR) and clinical refractory tumor specimens from patients with ER+ breast cancer, who had been treated with adjuvant tamoxifen. Suppression of HMGCS2 in T47D/TR resulted in the accumulation of mitochondrial reactive oxygen species (mtROS) and apoptotic cell death. Further, we identified alphitolic acid, a triterpenoid natural product, as a novel HMGCS2-specific inhibitor that elevated mtROS levels and drastically retarded the growth of T47D/TR in in vitro and in vivo experiments., Significance: Enhanced ketogenesis with upregulation of HMGCS2 is a potential metabolic vulnerability of tamoxifen-resistant BC that offers a new therapeutic opportunity for treating patients with ER+ BC that are refractory to tamoxifen treatment., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

Despite the increasing prevalence of lean nonalcoholic fatty liver disease (NAFLD), its risk factors are not well established. We examined the association between long working hours and incident NAFLD in lean Korean workers with emphasis on sex-based effect modification. This cohort study involved 46,113 non-overweight (BMI < 23 kg/m 2 ) and NAFLD-free Korean workers (mean age, 35.5 years). Working hours were categorized into 35-40 (reference), 41-52, and ≥ 53 h. The presence of fatty liver and its severity were determined using ultrasonography and NAFLD fibrosis score (NFS), respectively. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using parametric proportional hazards models. Incident cases of 5901 lean NAFLD developed over a median follow-up of 3.8 years. The incidence of lean NAFLD increased with increasing working hours with a stronger association in men than in women (P for interaction < 0.001). For men, multivariable-adjusted HRs (95% CIs) for lean NAFLD in time-dependent models comparing working hours of 41-52 and ≥ 53 h compared to the reference category were 1.17 (1.07-1.28) and 1.25 (1.12-1.39), respectively. The excess relative risk of developing lean NAFLD with intermediate/high NFS was observed in working hours of 41-52 and ≥ 53 h with a corresponding HR of 1.66 (1.13-2.43) and 1.54 (0.94-2.51), respectively. Conversely, no significant associations were found between working hours and incidence of lean NAFLD in women. In conclusion, long working hours were significantly associated with an increased incidence of lean NAFLD and its severe form in men but not in women., (© 2023. The Author(s).)

In tumor microenvironment (TME), macrophages trigger and maintain inflammatory responses that promoting tumor progression. Many cellular proteins are secreted from tumors and modulate their own TME by modulating macrophage phenotypes. Recently, we reported that interferon-γ-inducible protein 16 (IFI16), which was identified as an innate immune DNA sensor recognizing foreign DNA, triggered type Ⅰ interferon responses in breast cancer (BC). However, whether IFI16 was released from BC and affects TME has not been studied. Here, we report that IFI16 and its mouse homolog Ifi202 were released from BC cells, but not from normal epithelial cells. Ifi202 induced secretion of proinflammatory cytokines such as Interleukin (IL)-1β, IL-6, and Tumor necrosis factor-α from macrophages via binding toll-like receptor 2 and activating downstream signaling pathway. Growth of allografted mouse BC 4T1 lacking Ifi202 was suppressed and accompanied with increased infiltration and cytotoxic activity of CD8+ T lymphocytes. Further, IFI16 was detected in sera of patients with BC. High expression level of IFI16 was associated with poor prognosis in patients with BC. Taken together, our findings suggest a novel role of IFI16/Ifi202 in TME, that elicits tumor promoting inflammation and thereby shaping immunosuppressive TME in BC., (© 2023 Wiley Periodicals LLC.)

Objective: We examined the association between menopause symptoms and the prevalence of ideal cardiovascular health (CVH) metrics among premenopausal women., Methods: This cross-sectional study comprised 4,611 premenopausal women aged 42 to 52 years. Data for CVH metrics were collected during health screening examinations. Menopause symptoms were measured using the Korean version of the Menopause-Specific Quality of Life questionnaire. For vasomotor, psychosocial, physical, and sexual symptoms, participants were divided into absent or symptomatic groups, further divided into tertiles (range, 0-7; 7 being the most bothersome). Ideal CVH metrics were defined according to the American Heart Association Life Simple 7 metrics, except dietary component. Cardiovascular health metrics were scored from 0 (unhealthy) to 6 (healthy) and classified as poor (0-2), intermediate (3-4), and ideal (5-6). Multinomial logistic regression models were used to estimate the prevalence ratios for intermediate and poor CVH metrics using ideal CVH as the reference., Results: The overall and 4 menopause-specific quality of life domain scores were significantly associated with poorer CVH metrics scores in a dose-response manner ( P < 0.05). After adjusting for age, parity, education level, anti-Mullerian hormone levels, and alcohol intake, women with the most bothersome degree for vasomotor, psychosocial, physical, and sexual symptoms had significantly higher prevalence of poor CVH metrics, with corresponding prevalence ratios (95% confidence interval) of 2.90 (1.95-4.31), 2.07 (1.36-3.15), 3.01 (1.19-7.65), and 1.66 (1.15-2.39), respectively, compared with those without each vasomotor, psychosocial, physical, and sexual symptom., Conclusions: Premenopausal stage women with either vasomotor or nonvasomotor menopausal symptoms have significantly higher prevalence of poor CVH metrics, compared with those without any menopausal symptoms., Competing Interests: Financial disclosure/conflicts of interest: None reported., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The North American Menopause Society.)

Krukenberg tumours are unusual metastatic tumours of the ovary with primary tumours from the stomach, breast and gastrointestinal malignancies. Krukenberg tumour from pulmonary malignancy represents an extremely rare situation. This is an elaboration of a case of young women with Krukenberg tumour rising from lung adenocarcinoma. A 38-year-old woman presented with progressive abdominal distention for the past 2-years. Computed tomography (CT) of thorax, abdomen and pelvis revealed a huge ovarian mass with left lung nodules and left-sided pleural effusion. A detailed immunohistochemical staining on pleural fluid cytology confirmed the diagnosis of metastatic adenocarcinoma of lung origin. She underwent doublet platinum chemotherapy as molecular testing for oncogenic mutation was negative. The patient responded well to chemotherapy with a significant reduction in ovarian tumour size. Early identification of the primary source of Krukenberg tumour is paramount to avoid invasive diagnostic surgical intervention for ovarian metastasis., Competing Interests: None declared., (© 2023 The Authors. Respirology Case Reports published by John Wiley & Sons Australia, Ltd on behalf of The Asian Pacific Society of Respirology.)

We present the first search for the pair production of dark particles X via K&#95;{L}^{0}→XX with X decaying into two photons using the data collected by the KOTO experiment. No signal was observed in the mass range of 40-110  MeV/c^{2} and 210-240  MeV/c^{2}. This sets upper limits on the branching fractions as B(K&#95;{L}^{0}→XX)<(1-4)×10^{-7} and B(K&#95;{L}^{0}→XX)<(1-2)×10^{-6} at the 90% confidence level for the two mass regions, respectively.

Purpose: The purpose of this study was to compare the image quality of the 3D T2-weighted images accelerated using conventional method (CAI-SPACE) with the images accelerated using compressed sensing (CS-SPACE) in pediatric brain imaging., Methods: A total of 116 brain MRI (53 with CAI-SPACE and 63 with CS-SPACE) were obtained from children 16 years old or younger. Quantitative image quality was evaluated using the apparent signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR). The sequences were qualitatively evaluated for overall image quality, general artifact, cerebrospinal fluid (CSF)-related artifact, and grey-white matter differentiation. The two sequences were compared for the total and two age groups (< 24 months vs. ≥ 24 months)., Results: Compressed sensing application in 3D T2-weighted imaging resulted in 8.5% reduction in scanning time. Quantitative image quality analysis showed higher apparent SNR (median [Interquartile range]; 29 [25] vs. 23 [14], P = 0.005) and CNR (0.231 [0.121] vs. 0.165 [0.120], P = 0.027) with CS-SPACE compared to CAI-SPACE. Qualitative image quality analysis showed better image quality with CS-SPACE for general (P = 0.024) and CSF-related artifact (P < 0.001). CSF-related artifacts reduction was prominent in the older age group (≥ 24 months). Overall image quality (P = 0.162) and grey-white matter differentiation (P = 0.397) were comparable between CAI-SPACE and CS-SPACE., Conclusion: Compressed sensing application in 3D T2-weighted images modestly reduced acquisition time and lowered CSF-related artifact compared to conventional images of the pediatric brain., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To examine the relationship between metabolically healthy and unhealthy obesity phenotypes and risk of vasomotor symptoms (VMS) in premenopausal women., Design: Prospective cohort study., Setting: Middle-aged women in a cohort based on regular health screening examinations., Population: Premenopausal Korean women aged 42-52 years were recruited and were followed up for a median of 4.2 years. The cross-sectional and cohort studies comprised 4672 women and 2590 women without VMS at baseline, respectively., Methods: Adiposity measures included body mass index (BMI), waist circumference and percentage body fat. Being metabolically healthy was defined as not having any metabolic syndrome components or a homeostasis model assessment of insulin resistance of 2.5 or more., Main Outcomes Measures: VMS (hot flushes and night sweats) assessed using the questionnaire., Results: All adiposity measures were positively associated with an increased risk of VMS in both cross-sectional and longitudinal studies. The multivariable-adjusted prevalence ratio (95% confidence interval [CI]) for VMS comparing percentage body fat of 35% or more with the reference was 1.47 (95% CI 1.14-1.90) in metabolically healthy women, and the corresponding prevalence ratio was 2.32 (95% CI 1.42-3.78) in metabolically unhealthy women (P interaction  = 0.334). The multivariable-adjusted hazard ratio for incident VMS comparing percentage body fat of 35% or more with the reference was 1.34 (95% CI 1.00-1.79) in metabolically healthy women, whereas the corresponding hazard ratio was 3.61 (95% CI 1.81-7.20) in metabolically unhealthy women (P interaction  = 0.036). The association between BMI, waist circumference and VMS did not significantly differ by metabolic health status., Conclusions: Maintaining normal weight and being metabolically healthy may help to prevent VMS in premenopausal women., Tweetable Abstract: Avoiding obesity and a metabolically unhealthy status may help reduce vasomotor symptoms in premenopausal women., (© 2022 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

We investigated the associations between serum lipid profiles and risk of early-onset vasomotor symptoms (VMSs) in premenopausal women. This cohort study comprised 2,540 premenopausal women aged 42-52 years without VMSs at baseline (median follow-up: 4.4 years). VMSs, including hot flashes and night sweats, were assessed using the Menopause-Specific Quality of Life questionnaire (Korean version). Early-onset VMSs were defined as VMSs that occurred premenopause; moderate/severe VMSs were defined as a score of ≥ 3 points (range: 0 to 6, 6 being most bothersome). Cox proportional hazard regression models were used to estimate hazard ratios with 95% confidence intervals (CI) for the development of VMSs across the lipid levels. Higher low-density lipoprotein (LDL) cholesterol levels were positively associated with increased risk of early-onset VMSs. Compared to the < 100 mg/dL LDL group, the multivariable-adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for incident VMSs were 1.19 (1.03-1.37) and 1.20 (1.03-1.40) in participants with LDL cholesterol levels of 100-129 mg/dL and ≥ 130 mg/dL, respectively (P for trend = 0.027). The multivariable-adjusted HR for incident moderate/severe VMSs was 1.37 (95% CI: 1.08-1.73) in participants with LDL ≥ 130 mg/dL, compared to those with LDL < 100 mg/dL. Meanwhile, triglycerides and total and high-density lipoprotein cholesterol levels were not significantly associated with early-onset VMSs risk in premenopausal women. Premenopausal women with high serum LDL cholesterol concentrations had a higher risk of incident early-onset VMSs. Further studies should confirm our findings and examine whether LDL-lowering interventions reduce the risk of early-onset VMSs among women during menopause transition., (© 2022. The Author(s).)

Aims: There has been increasing evidence of hormonal changes during reproductive events that lead to mood changes. However, studies on the severity of psychological problems according to the menopausal stage are limited. Thus, this study aimed to investigate the association between menopausal stages, depression and suicidality., Methods: A total of 45 177 women who underwent regular health check-ups between 2015 and 2018 at Kangbuk Samsung Hospital were included. Participants were stratified into four groups (pre-menopause, early transition, late transition and post-menopause) based on the Stages of Reproductive Aging Workshop Criteria. The Center for Epidemiological Studies-Depression scale (CESD) was used to evaluate depressive symptoms, and the degree of depressive symptoms was classified as moderate (CESD score 16-24) or severe (CESD score ⩾ 25). To measure suicide risk, we administered questionnaires related to suicidal ideation., Results: Overall, the prevalence of CESD scores of 16-24 and ⩾ 25 was 7.6 and 2.8%, respectively. Menopausal stages were positively associated with depressive symptoms in a dose-dependent manner. Multivariable-adjusted prevalence ratios (PRs, 95% confidence intervals) for CESD scores of 16-24 comparing the stages of the early menopausal transition (MT), late MT and post-menopause to pre-menopause was 1.28 (1.16-1.42), 1.21 (1.05-1.38) and 1.58 (1.36-1.84), respectively. The multivariable-adjusted PRs for CESD scores ⩾ 25 comparing the stages of the early MT, late MT and post-menopause to pre-menopause were 1.31 (1.11-1.55), 1.39 (1.12-1.72), 1.86 (1.47-2.37), respectively. In addition, the multivariable-adjusted PRs for suicidal ideation comparing the early MT, late MT and post-menopause stages to the pre-menopause stage were 1.24 (1.12-1.38), 1.07 (0.93-1.24) and 1.46 (1.25-1.70) ( p for trend <0.001), respectively., Conclusions: These findings indicate that the prevalence of depressive symptoms and suicidal ideation increases with advancing menopausal stage, even pre-menopause.

Context: The relationship of ideal cardiovascular health (CVH) behaviors with preventing early-onset vasomotor symptoms (VMSs) is unknown., Objective: We investigated the association between CVH metrics and the development of early-onset VMSs in premenopausal women., Methods: This cohort study included 2541 premenopausal women aged 42 to 52 years without VMSs at baseline. CVH metrics were defined according to the American Heart Association Life Simple 7 metrics. Owing to limited availability of dietary information, CVH metrics were scored from 0 (unhealthy) to 6 (healthy) and classified into 3 groups: poor (0-2), intermediate (3-4), and ideal (5-6) CVH. VMSs, including hot flashes and night sweats, were assessed using the Menopause-Specific Quality of Life questionnaire. Moderate/severe VMSs was defined as a score of 3 or more points (range, 0 to 6; 6 being most bothersome)., Results: During a median follow-up of 4.5 years, 1241 women developed VMSs before menopause. After adjustment for age, parity, education level, and alcohol consumption, the hazard ratio (HR) (95% CI) for developing early-onset VMSs comparing poor CVH group to the ideal group was 1.41 (1.07-1.86). CVH scores were also inversely associated with moderate/severe VMSs in a dose-response manner (P for trend = .004); specifically, multivariable-adjusted HRs comparing intermediate and poor CVH groups to the ideal group were 1.20 (95% CI, 1.02-1.43) and 1.57 (95% CI, 1.08-2.29), respectively., Conclusion: Unfavorable CVH metrics were significantly associated with an increased risk of early-onset VMSs and its more severe forms among premenopausal women., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

The role of anti-Müllerian hormone (AMH) levels in incident vasomotor symptoms (VMS) is largely unknown. This study aimed to investigate the relationship between AMH levels and the development of early-onset VMS among premenopausal women. Our cohort study comprised 2041 premenopausal women aged 42-52 years free of VMS at baseline whose AMH levels were measured. VMS, including hot flushes and night sweats, were assessed using the Korean version of the Menopause-specific Quality of Life questionnaire. Early-onset VMS was defined as the occurrence of VMS prior to menopause. Parametric proportional hazards models were used to estimate adjusted hazard ratios (HRs) and 95% CI. During a median follow-up of 4.4 years, 708 premenopausal women developed early-onset VMS (incidence rate, 8.0 per 100 person-years). Lower AMH levels were statistically significantly associated with an increased risk of early-onset VMS. After adjusting for age and other confounders, multivariable-adjusted HRs (95% CI) for incident VMS comparing AMH quintiles 4-1 to the highest quintile were 1.02 (0.78-1.33), 1.37 (1.06-1.76), 1.36 (1.04-1.76), and 2.38 (1.84-3.08), respectively (P for trend < 0.001). Our results support an independent role of serum AMH levels in predicting incident early-onset VMS among premenopausal women in the late reproductive stage., (© 2022. The Author(s).)

The role of nonalcoholic fatty liver disease (NAFLD) in vasomotor symptom (VMS) risk in premenopausal women is unknown. We examined the prevalence of early-onset VMSs according to NAFLD status in lean and overweight premenopausal women. This cross-sectional study included 4242 premenopausal Korean women (mean age 45.4 years). VMSs (hot flashes and night sweats) were assessed using the Korean version of the Menopause-Specific Quality of Life questionnaire. Hepatic steatosis was determined using liver ultrasound; lean was defined as a body mass index of <23 kg/m2. Participants were categorized into four groups: NAFLD-free lean (reference), NAFLD-free overweight, lean NAFLD, and overweight NAFLD. Compared with the reference, the multivariable-adjusted prevalence ratios (PRs) (95% confidence intervals (CIs)) for VMSs in NAFLD-free overweight, lean NAFLD, and overweight NAFLD were 1.22 (1.06−1.41), 1.38 (1.06−1.79), and 1.49 (1.28−1.73), respectively. For moderate-to-severe VMSs, the multivariable-adjusted PRs (95% CIs) comparing NAFLD-free overweight, lean NAFLD, and overweight NAFLD to the reference were 1.38 (1.10−1.74), 1.73 (1.16−2.57), and 1.74 (1.37−2.21), respectively. NAFLD, even lean NAFLD, was significantly associated with an increased risk of prevalent early-onset VMSs and their severe forms among premenopausal women. Further studies are needed to determine the longitudinal association between NAFLD and VMS risk.

Background: Women are more likely to experience thyroid diseases than men. However, thyroid dysfunction risk in women undergoing the menopausal transition remains largely unknown. We explored the prevalence of thyroid dysfunction across menopausal stages. Methods: We conducted a cross-sectional study of 53,230 women aged 40 years or older who underwent health screening between 2014 and 2018. Menopausal stages were categorized into 4 based on the Stages of Reproductive Aging Workshop +10 criteria. A multinomial logistic regression model was used to estimate the prevalence ratios (PRs) with confidence intervals [CIs] for thyroid dysfunction in menopausal stages compared with that in premenopause. Results: The prevalence of overt hypothyroidism was significantly increased during late transition and postmenopause; it remained significant after further adjustments for potential confounders (age, center, year of examination, age at menarche, parity, education level, smoking status, alcohol consumption, physical activity, and body mass index) with corresponding multivariable-adjusted PRs [CI] of 1.61 [1.12-2.30] and 1.66 [1.16-2.37] in the late transition and postmenopausal stages, respectively. A significant increase in the prevalence of subclinical hypothyroidism was also observed in the late transition and postmenopausal stage with multivariable-adjusted PRs [CI] of 1.22 [1.06-1.40] and 1.24 [1.07-1.44], respectively. In contrast, subclinical and overt hyperthyroidism were not significantly associated with menopausal stages. Conclusions: In this study of pre- and perimenopausal Korean women, the prevalence of overt and subclinical hypothyroidism was significantly elevated in the late menopausal transition. Future prospective studies are warranted to investigate the clinical and prognostic significance of thyroid dysfunction in women during menopausal transition.

The role of alcohol consumption in the risk of vasomotor symptoms (VMS), the most cardinal climacteric symptoms, is not well established. We examined their relationship with early-onset VMS among premenopausal women. Moderately-to-severely bothersome VMS, the primary outcome, was assessed using the Korean version of the Menopause-Specific Quality of Life questionnaire. The alcohol consumption categories included lifetime abstainer, former drinker, or current drinker, categorized as light, moderate, heavy, and very heavy. Compared with the lifetime-abstinence (reference), the multivariable-adjusted odds ratio (95% CIs) for prevalent VMS in alcohol consumption of <10, 10−19, 20−39, and ≥40 g/day were 1.42 (1.02−1.99), 1.99 (1.27−3.12), 2.06 (1.19−3.57), and 3.52 (1.72−7.20), respectively (p trend <0.01). Compared with the lifetime-abstinence, the multivariable-adjusted hazard ratios (95% CIs) for incident bothersome VMS among average alcohol consumption of <10, 10−19, 20−39, and ≥40 g/day were 1.10 (0.85−1.41), 1.03 (0.70−1.51), 1.72 (1.06−2.78), and 2.22 (1.16−4.23), respectively (p trend = 0.02). Increased alcohol consumption positively and consistently showed a relationship with increased risk of both prevalent and incident early-onset VMS. Refraining from alcohol consumption may help prevent bothersome VMS in premenopausal women.

Although type I interferons (IFNs) play multifaceted roles during tumorigenesis and cancer treatment, the interplay between type I IFNs and estrogen signaling in breast cancer (BC) microenvironment is not well understood. Here, we report a novel function of type I IFNs in inducing aromatase expression in adipose tissues surrounding BC, which potentiates the E 2 -dependent growth of estrogen receptor (ER)-positive BC. First, we found that expression levels of type I IFNs correlate negatively with clinical outcome but positively with tumor grade in patients with ER-positive BC. Levels of type I IFNs were elevated in cocultured media of immune cells and BC cells, which increased aromatase expression and E 2 production in Simpson-Golabi-Behmel syndrome preadipocytes. The type I IFN-induced aromatase expression was dependent on IFN-γ-inducible protein 16 (IFI16), which is encoded by an interferon-stimulated gene. At the molecular level, type I IFNs led to recruitment of HIF1α-IFI16-PRMT2 complex to the hypoxia-response element located in the aromatase PI.3/PII promoter. Next, we generated an adipocyte-specific Ifi204, which is a mouse ortholog of human IFI16, knockout mouse (Ifi204-AKO). IFNβ induced E 2 production in the preadipocytes isolated from the control mice, but such E 2 production was far lower in the Ifi204-AKO preadipocytes. Importantly, the growth of orthotopically inoculated E0771 ER-positive mammary tumors was reduced significantly in the Ifi204-AKO mice. Taken together, our findings provide novel insights into the crosstalk between type I IFNs and estrogen signaling in the progression of ER-positive BC., (© 2022. The Author(s).)

Background: Although unintentional pregnancy loss is common, national representative statistics are lacking in high-income East Asian countries undergoing rapid demographic changes. It is necessary to confirm the income inequality of pregnancy loss even in universal national health insurance., Method: Using National Health Insurance Service data between 2008 and 2014, the annual prevalence of pregnancy loss was enumerated, and differences in pregnancy loss according to age and income levels were assessed by multivariable Poisson regression. Joint-point regression was used to examine the trend of pregnancy loss., Result: On average, there was a 15.0% annual pregnancy loss among 3,941,020 pregnancy cases from 2008 to 2014. Pregnancy loss inequality increased stepwise with income levels except for the highest income group. After adjusting for income levels, the annual percent change of age-standardized prevalence significantly increased by 2.6% every year since 2011., Conclusion: Even in high-income countries with universal national health insurance, income inequality in pregnancy loss is observed. Further appraisal is needed to explain the increasing trend of pregnancy loss between 2011 and 2014 even after adjusting income., (© 2022. The Author(s).)

Tumor DNA-damage response (DDR) has an important role in driving type-I interferon (IFN)-mediated host antitumor immunity, but it is not clear how tumor DNA damage is interconnected with the immune response. Here, we report the role of IFN-γ-inducible protein 16 (IFI16) in DNA repair, which amplifies the stimulator of IFN genes (STING)-type-I IFN signaling, particularly in triple-negative breast cancer (TNBC). IFI16 is rapidly induced and accumulated to the histone-evicted DNA at double-stranded breakage (DSB) sites, where it inhibits recruitment of DDR factors. Subsequently, IFI16 increases the release of DNA fragments to the cytoplasm and induces STING-mediated type-I IFN production. Synergistic cytotoxic and immunomodulatory effects of doxorubicin and type-I IFNs are decreased upon IFI16 depletion in vivo. Furthermore, IFI16 expression correlates with improved clinical outcome in patients with TNBC treated with chemotherapy. Together, our findings suggest that type-I IFNs and IFI16 could offer potential therapeutic strategies for TNBC., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)