Sex-specific Analyses Research Articles

Association between diabetes mellitus and trochanteric bone mineral density in individuals with osteoporotic fractures: a retrospective study

BackgroundThe relationship between diabetes mellitus (DM) and bone mineral density (BMD) in patients with osteoporotic fractures (OPFs) remains complex and heterogeneous, specifically between the genders. This study aimed to explore the association between diabetes status and trochanteric BMD in a cohort of patients with OPFs and elucidate the differences between male and female patients.MethodsThis retrospective analysis was performed on 710 admitted patients aged 50 years or older with OPFs. In this study, the exposure variable was diabetes status. Trochanteric BMD comprised the dependent variable. While controlling for covariance influences, generalized estimating equations (GEE) were applied to examine the independent link between diabetes status and trochanteric BMD in OPFs patients. Moreover, a subgroup analysis was also conducted to validate the result’s stability.ResultsA substantial positive association was noted between diabetes status and trochanteric BMD in diabetic patients, as determined by the fully adjusted model (β = 0.017, 95% CI 0.001 to 0.033, p = 0.035). Furthermore, the sex-specific analysis showed a significant positive relationship between diabetes status and trochanteric BMD in male patients (β = 0.040, 95% CI 0.006 to 0.075, p = 0.022), whereas no significant relationship was observed in female patients (β = 0.010, 95% CI −0.008 to 0.028, p = 0.256).ConclusionThis study highlighted the significant sex differences in the impact of diabetes on trochanteric BMD among patients with OPFs. The male diabetic patients had higher trochanteric BMD than their non-diabetic counterparts; however, this association was not evident in female patients. Further research is necessary to understand the underlying mechanisms that contribute to these sex-specific differences and to evaluate the clinical implications of managing fracture risk in diabetic patients.

Sex differences in burnout and work-family conflict among Chinese emergency nurses: a cross-sectional study

IntroductionWork–family conflict and burnout have become pressing concerns in nursing profession. These factors negatively affect nurses' health and work performance and therefore negatively influence the quality and safety of patient care. Whereas, nursing is a female-dominated profession. Studies have found that male nurses have higher level of depersonalization dimension of burnout than female nurses. Female nurses present higher level of emotional exhaustion dimension of burnout than male nurse. This study aimed to apply sex-specific analyses to investigate the associations between dimensions of burnout and work–family role behavior conflict among Chinese emergency department nurses.MethodsThis was a cross-sectional research. A questionnaire comprising items on demographic characteristics, work–family role behavior conflict, and burnout information, was distributed among emergency department nurses from 30 tertiary hospitals across mainland China, between December 26, 2023, and January 18, 2024.ResultsThis study's sample comprised 1,540 nurses. The total work–family role behavior conflict scores were 42.23 and 43.4, and the total burnout scores were 11.14 and 11.63 for female and male nurses, respectively. Significant differences were observed in comparisions of age, marital status, fertility status, education level, job title, work experience, night shift frequency, smoking status, and drinking status by sex. Correlation analyses revealed that burnout and work–family role behavior conflicts were positively associated with both sexes. Multiple linear regression analyses indicated that three dimensions of burnout including emotional exhaustion, depersonalization, and reduced work accomplishment significantly affected work–family role behavior conflict in both sexes. Compared with emotional exhaustion and reduced work accomplishment dimensions, depersonalization dimension of burnout affected work–family role behavior conflicts the most in male emergency nurses. Emotional exhaustion and depersonalization dimensions of burnout explained more of the variance in work–family role behavior conflict compared with redeuced work accomplishment dimension for female emergency nurses.ConclusionReducing depersonalization among emergency department male nurses and emotional exhaustion and depersonalization for female emergency department nurses, are crucial for decreasing work–family role behavior conflicts. Future studies should explore differences in burnout level among male and female nurses for a long time.

Blood-based biomarkers for early frailty are sex-specific: validation of a combined in silico prediction and data-driven approach.

Frailty is characterized by loss of physical function and is preferably diagnosed at an early stage (e.g., during pre-frailty). Unfortunately, sensitive tools that can aid early detection are lacking. Blood-based biomarkers, reflecting pathophysiological adaptations before physical symptoms become apparent, could be such tools. We identified candidate biomarkers using a mechanism-based computational approach which integrates a priori defined database-derived clinical biomarkers and skeletal muscle transcriptome data. Identified candidate biomarkers were used as input for a sex-specific correlation analysis, using individual gene expression data from female (n = 24) and male (n = 28) older adults (all 75 + years, ranging from fit to pre-frail) and three frailty-related physical parameters. Male and female groups were matched based on age, BMI, and Fried frailty index. The best correlating candidate biomarkers were evaluated, and selected biomarkers were measured in serum. In females, myostatin and galectin-1 and, in males, cathepsin B and thrombospondin-4 serum levels were significantly different between the physically weakest and fittest participants (all p < 0.05). Logistic regression confirmed the added value of these biomarkers in conjunction with age and BMI to predict whether the subjects belonged to the weaker or fittest group (AUC = 0.80 in females and AUC = 0.83 in males). In conclusion, both in silico and in vivo analyses revealed the sex-specificity of candidate biomarkers, and we identified a selection of potential biomarkers which could be used in a biomarker panel for early detection of frailty. Further investigation is needed to confirm these leads for early detection of frailty.

Phenome-wide diagnostic comparison among suicide deaths and living individuals with chronic pain diagnoses

BackgroundChronic pain, regardless of its type, is a significant risk factor for suicide. However, not all individuals with chronic pain also experience suicidal thoughts and behaviors. Better characterization of clinical risk profiles and comorbidities across the medical spectrum among people with chronic pain who die by suicide is urgently needed to aid treatment and prevention strategies.MethodsThis case–control study leverages population-based data from the Utah Suicide Mortality Risk Study. Specifically, we identify clinical phenotypes from diagnostic data that differentiate between individuals that died by suicide with chronic pain diagnoses (N = 1,410) and living control individuals who also had chronic pain diagnoses (N = 4,664). Medical diagnostic codes were aggregated via phecodes to perform a phenotype-based phenome-wide association study. Using multivariable logistic regression analysis adjusting for covariates and multiple testing, differences in 1,727 common clinical phenotypes (phecodes) were assessed between suicide deaths and controls with chronic pain diagnoses. Models were also stratified by sex.ResultsChronic pain diagnoses were nearly three times more prevalent in individuals who died by suicide compared with those who did not. Sixty-five phecodes were significantly overrepresented among suicide deaths with chronic pain diagnoses compared with controls with chronic pain diagnoses. Utah suicide deaths with chronic pain had significantly more psychiatric diagnoses (mood disorders, anxiety disorders, attention deficit hyperactivity disorder, posttraumatic stress disorder, personality disorders, schizophrenia/psychosis, substance use related traits and prior overdoses, and diagnoses related to previous suicidal thoughts and behaviors) in addition to insomnia and specific pain related diagnoses compared to Utah controls with chronic pain (odds ratios ranged from 1.40–7.10). Twenty-five phecodes were overrepresented in controls with chronic pain compared to suicides. These were related to preventative care, cancer, obesity and other conditions (odds ratios ranged from 0.16–0.73). Sex-specific analyses largely replicated the combined analyses, yet the strength of the association was stronger for women with phecodes related to prior self-harm.ConclusionsResults identified multiple clinical comorbidities with chronic pain that differentiate suicide deaths from living control individuals with a history of diagnosed chronic pain. Our findings may help discern individuals with chronic pain who may be at greater risk for suicide death.

The role of prenatal perceived stress and hair cortisol as they relate to toddler socioemotional outcomes over the first three years

Prenatal maternal psychological distress and physiological stress (hypothalamic-pituitary-adrenal [HPA] activity) can negative impact early child development. Research rarely examines the combined or interactive role of prenatal perceived stress and HPA activity on child outcomes. The current longitudinal study examined how prenatal distress and HPA activity impacted child socioemotional functioning from age 1–3. This sample (n=148) was followed from pregnancy, 15-, 24- and 35-months postpartum. During pregnancy, mothers reported their levels of perceived stress and hair samples were collected, reflecting cortisol secretion in the past 3 months. At each postpartum timepoint, mothers reported toddler socioemotional functioning using the Brief Infant–Toddler Social and Emotional Assessment. Multivariate regression results indicated that higher maternal perceived stress interacted with higher hair cortisol levels in association with greater socioemotional problems at 15 and 24 months. In addition, there was a main effect of higher prenatal perceived stress in relation to greater socioemotional problems at 36 months. Exploratory sex-specific moderation analyses indicated that sex interacted with hair cortisol, such that higher levels of prenatal cortisol were associated greater behaviour problems and lower socioemotional competence for females compared to males at 24-months. Findings indicated the importance of examining both physiological stress and psychological stress in pregnancy, as they interact to impact child socioemotional development. Findings also highlight sex-specific prenatal effects.

Prevalence of Elevated Blood Triglycerides and Associated Risk Factors: Findings from a Nationwide Health Screening in Mongolia

Background: This study aims to assess the demographic, lifestyle, and clinical characteristics associated with varying levels of triglycerides (TGs) in a large population sample. Methods: This cross-sectional study utilized data from a nationwide health screening program in Mongolia. A total of 125,330 participants (mean age: 43.8 ± 15.3 years) were included. TG levels were categorized into normal, borderline high, high, and very high. Due to the small number of participants in the very high TG group, they were combined with the high TG category for analysis. Multivariate logistic regression was performed to identify independent predictors of elevated TG levels. Results: The majority of participants (80.3%) had normal TG levels, while 10.3% had borderline high, 8.7% had high, and 0.7% had very high TG levels. Significant predictors of elevated TG levels included age (OR 1.013, 95% CI 1.012–1.014), male (OR 2.328, 95% CI 2.251–2.408), obesity (OR 1.920, 95% CI 1.855–1.987), central obesity (OR 1.866, 95% CI 1.801–1.933), smoking (OR 1.399, 95% CI 1.347–1.453), alcohol use (OR 1.233, 95% CI 1.176–1.292), and non-regular exercise (OR 1.144, 95% CI 1.118–1.171). Sex-specific analysis revealed that elevated TG levels were more prevalent among males, regardless of other risk factors such as obesity and smoking. Conclusions: Male sex, obesity, and smoking were the strongest predictors of elevated TG levels.

Heavy metal exposure and its effects on APOC3, CFAI, and ZA2G

Despite increasing heavy metal pollution, traditional epidemiology often fails to link exposure to health outcomes. This study used multi-omics to investigate associations between heavy metal exposure and health. Blood and urine samples from 294 participants in heavy metal-exposed and control areas were analyzed, revealing key biomarkers. Meta P analysis revealed consistent trends in apolipoprotein C3 (APOC3) expression, and mediation analysis showed significant effects of APOC3 and zinc-alpha-2-glycoprotein (ZA2G) on metabolites: the mediating effect of APOC3 from blood cadmium to serotonin was 0.023 (P < 0.001) and that to 3-phosphoglyceric acid (3PG) was 0.0125 (P = 0.002). Mendelian randomization confirmed the positive impact of APOC3 and Complement Factor I (CFAI) and the negative effect of ZA2G on metabolites, with apolipoprotein H (APOH) methylation significantly altering APOC3 (β = −0.22, P = 0.017), CFAI (β = 0.176, P = 0.035), and ZA2G (β = 0.139, P = 0.048) protein levels. Liver function variables, including albumin, total protein, calcium, and lactate dehydrogenase, correlated with 3PG and serotonin levels in the exposed areas. Sex-specific analysis showed that men exhibited stronger compensatory mechanisms via CFAI and myo-inositol, while women’s greater vulnerability to heavy metal exposure highlighted the need for targeted interventions. These findings suggest APOH methylation affects APOC3, CFAI, and ZA2G levels, elevating 3PG, inosine monophosphate, and serotonin levels and harming liver function via lipolysis, supporting the use of these markers in health monitoring, therapies, and policies to limit heavy metal risks.

Sex-specific associations of cigarettes and e-cigarettes use with self-reported premature atherosclerotic cardiovascular disease among adults aged 18–54 in the United States

BackgroundPremature atherosclerotic cardiovascular disease (ASCVD) is increasing in young adults (<55 years old). While research suggests females who smoke cigarettes have a higher risk of ASCVD than males, studies on the impact of exclusive e-cigarette and dual use on premature ASCVD are limited. This study investigated the association between tobacco use and self-reported premature ASCVD and explored potential sex differences. MethodsUsing pooled data from 480,317 adults (ages 18–54; ∼50 % female) from the 2020–2022 Behavioral Risk Factor Surveillance System from the United States, logistic regression models assessed associations between cigarette and e-cigarette use patterns and self-reported premature ASCVD. Tobacco use categories were defined as: non-use, former use (cigarettes, e-cigarettes), and current use (cigarettes, e-cigarettes) and dual use. Self-reported premature ASCVD was defined as self-reported angina or coronary heart disease, heart attack, or stroke. Weighted analyses were conducted for the overall sample and stratified by sex. ResultsAfter controlling for potential confounders, former exclusive cigarette (adjusted OR: 1.47 [95 % CI 1.29, 1.67]), current exclusive cigarette (1.68 [1.47–1.94]) and current dual (2.03 [1.69–2.44]) use were associated with higher odds of self-reported premature ASCVD. There was no significant association for e-cigarette use. Sex-specific analyses revealed similar patterns but the magnitude of these associations varied between males and females. ConclusionBoth sexes showed higher odds of self-reported premature ASCVD for dual and exclusive cigarette use. Although the cross-sectional design precludes causal inferences, the findings suggest comprehensive tobacco cessation programs tailored to diverse use patterns are needed to reduce the burden of premature ASCVD.

Abstract 4134990: Body Fat Quantitation Predicts Progressive Cardiac Dysfunction with Age: Sex-Dependent Variations And Clinical Outcomes

Background: Among older adults whose body mass index (BMI) readings may be spuriously reduced due to loss of skeletal muscle, BMI alone may lack specificity for body fat quantitation. In addition, sex-based hormones differentially influence body fat composition between the sexes with aging. To evaluate the cardiometabolic effect of body fat on older adults, we hypothesize that sex would exert differential effects on baseline and progression of cardiac dysfunction in older adults. Methods: Community older adults without cardiovascular disease (CVD) underwent prospective transthoracic echocardiography with simultaneous body fat quantitation (body fat mass (BFM), percentage body fat (PBF), and waist-hip ratio (WHR) by bioimpedance, at baseline and five-year intervals. Mitral early diastolic inflow velocity to early diastolic annular tissue velocity (E/e') and early to late diastolic inflow velocity (E/A) ratios were recorded. Multivariable regression models were adjusted for significant clinical variables. Adverse clinical outcomes were defined as mortality or hospitalization during follow-up. Results: Baseline and interval annotation of 409 older adults (mean age 61±12.7 years, 52% females) demonstrated deteriorations in E/A ratios of -0.1 ± 0.3 and E/e' ratios of 1.8 ± 2.8, over a mean duration of 4.9 ± 0.4 years. Baseline BFM (β -0.01, p&lt;0.001; β 0.023, p=0.352) and PBF (β -0.008, p=0.002; β -0.007, p=0.759) predicted interval changes in E/A but not E/e' respectively independent of covariates (Table 1). In sex-specific analyses, higher baseline PBF was associated with deteriorations in E/A (β 0.010, p=0.028) among women and E/e' among men (β -0.069, p=0.020). Increases in PBF over time were particularly associated with reductions in E/A among women (β -0.005, p=0.047) independent of higher baseline PBF, in addition to significant interactions between sex and PBF in predicting changes in E/A. (Figure 1). Higher baseline WHR predicted adverse clinical outcomes [w1] among women (HR 1.09, 95%CI 1.03-1.16, p=0.005). Conclusion: Baseline and longitudinal increases in fat quantity defined a trajectory of deteriorations in cardiac function among older adults, and prognosticated poorer future outcomes, particularly among women with central adiposity as represented by WHR. Refining CVD risk based upon quantitative sex-specific fat targets for older adults may be a strategy in the future.

Abstract 4116975: Safety signals with SGLT2 inhibitor use in diabetic males with erythrocytosis, but not in females: Findings from the CANVAS Program and CREDENCE trial

Backgrounds: Mediation analyses have shown that an increase in hematocrit (Hct) levels significantly contributes to the cardiorenal benefits of SGLT2 inhibitors (SGLT2i). However, given the link between erythrocytosis and poor prognosis, concerns remain about whether SGLT2i-induced erythropoiesis in patients with erythrocytosis may increase thromboembolic events (TE) including myocardial infarction (MI). Methods: We conducted a pooled analysis utilizing individual participant data from the CANVAS Program and the CREDENCE trial, both aimed to evaluate the efficacy and safety of canagliflozin versus placebo in diabetic patients. The primary outcome was a composite of MI, stroke, or any other TE. Sex-specific Cox analyses were performed to assess effect modifications by baseline Hct levels, treated as categorical (anemia, normal, and erythrocytosis) or continuous variable. Results: Of the participants for whom baseline Hct values were available (98.5% [14,321/14,543]), 35% were female. Canagliflozin significantly increased the percentage of erythrocytosis from baseline to 1 year in males (5.6% to 16.9%) and females (1.9% to 5.2%), unlike placebo. Overall, canagliflozin did not alter the risk of the primary outcome for either male (HR 0.97; 95% CI, 0.86–1.10) or female (HR 0.95; 95% CI, 0.78–1.15). In males, baseline Hct levels modified treatment effect on the primary outcome, whether treated as categorical or continuous variables (Pinteraction &lt;0.05), with benefits in anemic patients and harm in those with erythrocytosis (Figure). Meanwhile, no effect modifications were noted in females. In analyses for each component of the primary outcome, canagliflozin consistently reduced the risk of MI, stroke, and any TE in anemic male patients (HR 0.53, 0.49, and 0.71, respectively). However, mixed results were observed in those with erythrocytosis (HR 1.77, 0.62, and 1.11, respectively), suggesting detrimental effects on the primary outcome in these patients were primarily driven by MI. No heterogeneity by Hct was found for heart failure hospitalization or kidney outcome in both sexes. Conclusion: Canagliflozin may pose a safety concern regarding the risk of TE in diabetic male patients with erythrocytosis.

Abstract 4129397: Cardiovascular Risk Models Using Large-Scale Physical Examination Data

Background: Physical examination (PE) data offer more potential key risk factors that can enhance the development of risk models. Additionally, the latest CVD risk model, PREVENT, developed from an American population, necessitates validation within China. Objectives: This study aimed to develop CVD risk models based on large-scale PE records and compare them with PREVENT model in Chinese adults. Methods: Data were collected from a China national database (2016-2024), including 929682 participants aged 30-79 years without previous CVD (Table I). The variables covered demographics, comorbidities, and PE items, resulting in 59 features as input. The endpoint events were defined as total CVD and its subtypes, ASCVD and heart failure (HF). Sex-specific survival analysis was developed based on age-scale, utilizing Cox Proportional Hazards and Random Survival Forests (RSF). Feature importance was assessed using the average minimal depth in RSF. The performance was evaluated by the Harrell C-statistic in the validation set. Results: The results showed that our RSF model achieved the best performance in total CVD, with the highest C-index of 0.82 (Table II). The top 15 predictive risk factors for each gender are presented in Figure 1. Additionally, validation of the PREVENT model in our Chinese population dataset showed its great generalizability, particularly for HF events. Conclusions: Overall, this research underscores the importance of leveraging large-scale PE data and advanced modeling techniques to improve CVD risk prediction. Beyond traditional risk factors, greater emphasis should be placed on more demographic characteristics, comorbidities, urinalysis, and ECG features.

Smad4 Heterozygous Knockout Effect on Pancreatic and Body Weight in F1 Population Using Collaborative Cross Lines.

Smad4, a critical tumor suppressor gene, plays a significant role in pancreatic biology and tumorigenesis. Genetic background and sex are known to influence phenotypic outcomes, but their impact on pancreatic weight in Smad4-deficient mice remains unclear. This study investigates the impact of Smad4 deficiency on pancreatic weight in first-generation (F1) mice from diverse collaborative cross (CC) lines, focusing on the influence of genetic background and sex. F1 mice were generated by crossbreeding female CC mice with C57BL/6J-Smad4tm1Mak males. Genotyping confirmed the presence of Smad4 knockout alleles. Mice were housed under standard conditions, euthanized at 80 weeks, and their pancreatic weights were measured, adjusted for body weight, and analyzed for effects of Smad4 deficiency, sex, and genetic background. The overall population of F1 mice showed a slight but non-significant increase in adjusted pancreatic weights in heterozygous knockout mice compared to wild-type mice. Sex-specific analysis revealed no significant difference in males but a significant increase in adjusted pancreatic weights in heterozygous knockout females. Genetic background analysis showed that lines CC018 and CC025 substantially increased adjusted pancreatic weights in heterozygous knockout mice. In contrast, other lines showed no significant difference or varied non-significant changes. The interplay between genetic background and sex further influenced these outcomes. Smad4 deficiency affects pancreatic weight in a manner significantly modulated by genetic background and sex. This study highlights the necessity of considering these factors in genetic research and therapeutic development, demonstrating the value of the collaborative cross mouse population in dissecting complex genetic interactions.

Relationship between bullying victimization and murderous behaviors and impulsivity's mediating role: Evidence from Chinese early adolescents.

Evidence suggests a robust relationship between experiencing bullying victimization (BV) and engaging in murderous behaviors among adolescents. However, the potential mediating effect of impulsivity on the relationship between BV and murderous behaviors in early adolescents remains underexplored. A total of 5724 adolescents, with a mean age of 13.5years, were enrolled from three middle schools in Anhui Province, China. Participants completed self-report questionnaires detailing their experiences with bullying, impulsiveness, and murderous behaviors. To assess the relationship between BV and murderous behaviors, multivariate logistic regression and Poisson regression analyses were conducted. Mediation analysis was performed using structural equation modeling. After controlling for confounding factors, a positive association was found between experiencing BV and engaging in murderous behaviors (p<0.05). Mediation analysis revealed a significant indirect effect of BV on the occurrence of murderous behaviors through impulsivity (indirect effect=0.027, 95% CI: 0.021, 0.033). BV appears to heighten levels of impulsivity, which in turn increases the likelihood of murderous behaviors. Additionally, sex-specific analysis indicated that impulsivity played a greater mediating role in the link between verbal and relational BV and murderous behaviors in females, while physical and cyber BV were more significant in males. Our findings underscore the necessity of early targeted interventions for adolescents experiencing BV and exhibiting high levels of impulsivity to mitigate their risk of engaging in murderous behaviors.

Region-Based Analyses of Existing Genome-Wide Association Studies Identifies Novel Potential Genetic Susceptibility Regions for Glioma.

Further investigation of the potential susceptibility regions identified in our study may lead to a better understanding of glioma genetic risk and the underlying biological etiology of glioma. Our study suggests sex may play a role in genetic susceptibility and highlights the importance of sex-specific analysis in future glioma research.

Gastrointestinal helminths of Cattle slaughtered at Gwagwalada abattoir, federal capital territory, Nigeria

Gastrointestinal parasites are widespread in cattle worldwide, causing both clinical and sub-clinical infections that can lead to significant financial losses. This study investigated the prevalence of gastrointestinal helminths infection in cattle slaughtered in the abattoir at Gwagwalada area council, federal capital territory, Nigeria. A total of 120 faecal samples were collected and analysed by flotation and sedimentation methods. The results revealed an overall prevalence of 26.67%. The helminths identified were Toxocara sp (5.00%), Schistosoma sp (10.83%), and Fasciola sp (10.83%). These findings were compared to existing studies, with variations attributed to differences in climatic conditions, management practices, and seasonal factors. Age, breed, and sex-specific analyses revealed significant differences in infection rates. While no helminth infection was found in young adult cattle (1≤3 years), a 31.37% prevalence was recorded in older adult cattle (≥3 years). Among the breeds examined, Sokoto Gudali showed the highest prevalence (100%), followed by White Fulani (26.42%) and Red Fulani (16.67%). A significant breed-related difference (p = 0.0001) was recorded. Additionally, male cattle exhibited a higher prevalence (31.37%) compared to (0.00%) in females. The study highlighted the impact of geographical, ecological, and environmental factors on helminths infection, as well as the need for strategic anthelmintic treatment, improved livestock management, and educational programs to control these infections. Regular monitoring and selective breeding may further contribute to long-term infection control in cattle populations.

Type 2 diabetes risk is associated with poorer general health and mental health in women and men

Abstract Background Increasing evidence points to a relation between cardiometabolic and mental health, but population-based data are scarce. We investigated the association of type 2 diabetes (T2D) risk to general and mental health with a focus on potential differences between women and men. Methods The study population comprised 5,192 adults (18+ years) without known diabetes based on data of the German Health Update (GEDA) 2022. T2D risk was assessed by the German Diabetes Risk Score (GDRS), that estimates the 5-year probability of developing T2D and was categorized into low, still low, elevated, and high risk. Sex-specific Poisson regression analyses were conducted including self-rated health (SRH), self-rated mental health (SRMH), depressive symptoms (PHQ-2) and anxiety symptoms (GAD-2) as dichotomous dependent variables and age, educational level, living alone, region of residence, and social support as covariables. Results Women had a higher prevalence of low T2D risk (66.1%) and a lower prevalence of high T2D risk (9.4 %) than men (55.3% vs. 16.3%). Compared to those with low T2D risk, women and men with a high T2D risk were less likely to report very good/good SRH (women: prevalence ratio: 0.63; 95% confidence interval: 0.51-0.79; men: 0.69; 0.57-0.84) or excellent/very good SRMH (women: 0.53, 0.39-0.73; men: 0.85, 0.63-1.15). Further, those with a high T2D risk had a higher risk of depressive symptoms (women: 1.71, 1.05-2.81; men: 2.23, 1.22-4.05) and anxiety symptoms (women: 1.84, 1.03-3.29; men: 2.73, 1.09-6.81). No statistically significant interactions between sex and T2D risk were observed regarding the included health outcomes. Conclusions A high T2D risk is associated with a lower probability of a favourable SRH and SRMH and a higher risk of depressive and anxiety symptoms in men and women. The underlying mechanisms need further identification, in order to design synergistically beneficial health promotion for cardiometabolic and mental health. Key messages • No sex-specific differences in general and mental health were found in people at high T2D risk. • Further research is needed to identify the underlying mechanism to improve general and mental health.

Sex differences in RNA transcripts in dilated cardiomyopathy

Abstract Introduction Dilated cardiomyopathy (DCM) is the most common cardiomyopathy and a major cause of heart failure. Differences in clinical presentation and phenotype exist in men and women but the reason for this is not clear. The analysis of the RNA transcripts (mRNA sequencing) offers an opportunity to provide a link between the genome, the proteome, and the phenotype. The aim of this study was to explore sex differences using mRNA sequencing in patients with DCM. Method Our database, an observational prospective cohort study, includes patients referred for suspected cardiomyopathy. The database includes data on patients’ characteristics, symptoms, diagnostic procedures, treatments, cardiac devices, and outcome. Endomyocardial biopsy from the right ventricle was collected and total RNA, including miRNA and other small RNA, was isolated. RNA sequencing and library preparation was performed. Following quality check, reads were aligned to GRCh38 reference genome by STAR (v2.7.10a). Sex-specific differential expression analysis between individuals diagnosed with DCM (cases) versus non-confirmed cardiomyopathy (controls) was performed using DESeq2 (v.1.38.3) adjusting for age, RNA integrity number and systolic blood pressure. After controlling for multiple testing using the Benjamini-Hochberg method, genes with a corrected P-value &amp;lt; 0.05 were considered as being differentially expressed. Gene-set enrichment analysis on differentially expressed genes was performed via Enrichr tool using Descartes cell types and tissues, KEGG biological pathways, DisGeNET, and Gene Ontology Biological Processes (GOBP). Results Patients´characteristics in women and men with DCM is presented in table 1. There was no difference in outcome in men and women (data not shown). Differential expression analyses with transcriptomic data comparing DCM (n=43) versus controls (n=22) stratified by sex (DCM n= 9, (20.9%) women and controls n=7, (30.4%) women) was performed. There was no overlap between differentially expressed genes between sexes (Figure 1). In men gene set enrichment analyses showed that differentially expressed genes were related to pathways involved in dilated and hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy (KEGG). Interestingly, these analyses revealed an enrichment of genes related to platelet biology, namely precursors (Descartes), activation (GOBP, KEGG) and platelet disorder (DisGeNET). In women, HLA-DQB1 was more expressed in DCM. HLA-DQB1 is associated with celiac disease, narcolepsy, and type 1 diabetes. Consistently, the enrichment analyses showed an enrichment of genes involved in autoimmune diseases (DisGeNET). Conclusion Women and men with DCM exhibit differently activated RNA transcripts although no difference in phenotype was observed. This may indicate that although DCM can be caused by similar factors in women and men the transcriptome is differently activated which warrants further investigation.Table 1.

Picking a bone with fluoride – dose-response meta-analysis on exposure to fluoride and bone density

Abstract There are still uncertainties around the effects, beneficial and adverse, of water fluoride exposure on bone density and strength. We selected bone mineral density (BMD) for investigation as it is recognized as the major non-invasive indicator of bone strength, representing its clinical assessment standard. The aim of this systematic review and meta-analysis was to characterize for the first time the relation between fluoride exposure and BMD through a dose-response approach, using a one-stage dose-response meta-analysis based on a cubic spline random-effects model. Out of 1201 potentially relevant literature records retrieved, after removing duplicates, title/abstract screening, and full-text evaluation, 16 studies were eligible for this review, 12 of which were also suitable for the dose-response meta-analysis. We observed an almost linear association between fluoride and BMD, yielding a mean difference of 2.60 (95% CI 0.17 to 0.40) at 4 mg/L of fluoride exposure. This pattern was also confirmed for hip BMD (MD = 2.83; 95% CI 0.11 to 0.40 at 4 mg/L). However, sex-specific analyses showed different patterns of association. In males, the relation between fluoride exposure and BMD was almost linear until 0.75 mg/L (MD = 0.24; 95% CI -0.22to 0.37), after which it plateaued. Females showed a slight increased BMD at 1 mg/L (MD = 0.05; 95% CI -0.02 to 0.16) but decreasing values above 2.5 mg/L (MD=-0.22; 95% CI -2.72 to 2.38 at 4 mg/L), with an indication of an inverted U-shaped association. This pattern was clearer when we restricted our analysis to hip BMD (MD=-0.56; 95% CI -2.98 to 1.85 at 4 mg/L). Sensitivity analyses examining both bone-specific BMD and conducting risk of bias assessments are currently underway. Moreover, imprecision of the estimates, especially in stratified analyses, and potential for residual confounding, underscore the need for further prospective studies, to more adequately assess the relation between fluoride exposure and bone density and strength. Key messages • At fluoride exposure below 1 mg/L, we observed a linear correlation between fluoride exposure and increase bone density in the overall pooled dose-response analysis of eligible studies. • Sex-specific patterns: males show positive response until certain exposure threshold; while females demonstrate an increase only at low doses of exposure and a downward trend at higher exposures.

AI-ECG sex-estimation discordances predict cardiovascular events

Abstract Background Cardiovascular disease remains the leading cause of death and burden globally, warranting the need to explore novel predictors of major adverse cardiovascular events (MACE) using new technologies. Artificial Intelligence (AI)-enhanced ECG (AI-ECG) algorithms can provide information on cardiovascular health of individuals, independent of conventional risk factors. Purpose The current study aimed to understand whether a previously described AI-ECG sex estimation algorithm could be applied for risk stratification of major adverse cardiovascular events (MACE), with a focus on a population without previous history of MACE. Methods Patients having 12-lead ECGs between 2018-2019 were included and followed up until August 2023. Exclusion criterion was a prior history of MACE. AI-ECG sex estimation was determined using a previously described algorithm predicting sex based on 12-lead ECGs. The algorithm generates outputs ranging from 0 to 1, representing the estimated probability of being male. Outputs above 0.5 were considered as AI-ECG-estimated male, and below as AI-ECG-estimated female. This was compared with biological sex to determine whether the two matched. Inconsistency between AI-ECG estimated sex and biological sex was defined as discordance. MACE was defined as myocardial infarction, coronary revascularization, non-fatal stroke, and all-cause death. Results Among 80,578 subjects (mean age 59.1 ± 16.1 years, 52.4% female), 9.7% exhibited sex discordance in AI-ECG estimation. Discordance was associated with a 56% higher risk of MACE (HR, 1.56, 95% CI 1.46-1.65, p &amp;lt;0.001), and remained significant in multivariable analysis with traditional risk factors (HR 1.35, 95% CI 1.27-1.43, p &amp;lt;0.001) (Figure 1). Sex-specific analysis showed increased MACE risk in both discordant males and females (Figure 2). Conclusion In patients with no history of MACE, discordance in AI-ECG sex estimation is associated with increased risk of MACE. These findings suggest the potential of AI-ECG sex estimation algorithm for risk assessment, especially in patients with no history of MACE.Figure 1.Cox proportional hazard modelFigure 2.Kaplan-Meier of MACE by sex

Gestational diabetes and future cardiovascular diseases: associations by sex-specific genetic data.

Observational studies have highlighted that gestational diabetes mellitus is associated with a higher risk of cardiovascular diseases, but the causality remains unclear. Herein, the causality between genetic predisposition to gestational diabetes mellitus and the risk of cardiovascular diseases was investigated using sex-specific Mendelian randomization analysis. Linkage disequilibrium score regression analysis and two-sample Mendelian randomization analysis were applied to infer the genetic correlation and causality, respectively. Mediation analysis was conducted using a two-step Mendelian randomization approach. Sensitivity analyses were performed to differentiate causality from pleiotropy. The genome-wide association study summary statistics for gestational diabetes mellitus were obtained from FinnGen consortium, while for cardiovascular diseases were generated based on individual-level genetic data from the UK Biobank. Linkage disequilibrium score regression analyses revealed that gestational diabetes mellitus had a significant genetic correlation with coronary artery disease and myocardial infarction after Benjamini-Hochberg correction in ever-pregnant women. In Mendelian randomization analyses, odds ratios (95% confidence interval) for coronary artery disease and myocardial infarction were 1.09 (1.01-1.17) and 1.12 (.96-1.31) per unit increase in the log-odds of genetic predisposition to gestational diabetes mellitus in ever-pregnant women, respectively. Further, Type 2 diabetes and hypertension were identified as mediators for the causality of genetic predisposition to gestational diabetes mellitus on coronary artery disease. In sensitivity analyses, the direction of odds ratio for the association between instrumental variables with gestational diabetes mellitus-predominant effects and the risk of coronary artery disease was consistent with the primary results in ever-pregnant women, although not statistically significant. This study demonstrated a suggestive causal relationship between genetic predisposition to gestational diabetes mellitus and the risk of coronary artery disease, which was mainly mediated by Type 2 diabetes and hypertension. These findings highlight targeting modifiable cardiometabolic risk factors may reduce the risk of coronary artery disease in women with a history of gestational diabetes mellitus.