Sex-stratified Analyses Research Articles

Abstract 14613: Sex Differences in Protein Biomarkers and Measures of Fat Distribution

Background: Sex differences in obesity and fat distribution have been well described and may explain differences in subsequent cardiovascular risk in men vs women. Underlying mechanisms are not fully elucidated and warrant further investigation. Objective: This study aims to examine sex differences in the associations of obesity and fat distribution measures with cardiovascular disease (CVD) protein biomarkers reflecting key pathways including inflammation, adiposity, fibrosis, and neurohormonal regulation. Methods: We measured 71 circulating protein biomarkers in 3,143 participants with available computed tomography measures of adiposity in the Framingham Heart Study. We examined whether sex modified the association of obesity (body mass index [BMI] and waist circumference [WC]) and fat distribution measures (visceral adipose tissue [VAT]) with protein biomarkers using multiplicative interaction terms in multivariable linear regression models. Sex-stratified analyses were performed as appropriate. Results: Among 3,143 participants (mean age 50 years, 48.7% women), we found that sex modified the association of BMI with 8 protein biomarkers including AGP-1, adipsin, IGFBP-1, IGFBP-2, ADM, KLKB1, MCP-1, and ucMGP (FDR-q int < 0.05 for all, Figure 1 ). For example, BMI was associated with higher MCP-1 levels in women, but not in men (ß 0.132, SE 0.025, p < 0.0001 in women vs ß 0.036, SE 0.028, p = 0.20 in men, FDR-q int 0.03). We found that sex also modified the association of WC and VAT with key CVD protein biomarkers including AGP-1 and A1M. Conclusions: We found that sex modified the association of obesity and adipose traits with cardiovascular risk as ascertained using biomarkers of CVD. These findings highlight potential biological pathways that may contribute to obesity-related cardiometabolic disease uniquely in men versus women.

Abstract 18025: Does Co-Morbid Depression Predict Worse In-Hospital Outcomes in Elderly Patients Primarily Hospitalized With Atrial Fibrillation?: A Nationwide Sex and Race Stratified Analysis

Introduction: Depression is an established risk factor for major adverse cardiac and cerebrovascular events (MACCE). However, the association between depression (DP) and all-cause mortality, as well as stroke in atrial fibrillation (AF) patients, remains understudied. We aim to establish a relationship between depression and MACCE in AF patients. Methods: Using the National Inpatient Sample (2019) and relevant international classification of disease (ICD-10) codes, we identified hospitalizations with AF among elderly patients (age >65) and categorized them into groups with and without depression (DP vs nDP). The primary outcome was all-cause inpatient mortality and stroke in AF-related hospitalizations. Results: The overall prevalence of depression (DP) among elderly patients hospitalized for AF was 10.6% (32810/310,005). The DP cohort contained less number of males (30.4% vs 44.38%), Blacks ( 2.91% vs 5.77%), Hispanics (4.11% vs 4.68%) while more females (69.59% vs 55.62%) and Whites ( 88.7% vs 83.82%). Stroke prevalence was not significantly different (0.8% vs 0.8% OR:0.97, CI:0.85-1.1 p=0.701) whereas all-cause mortality prevalence was lower in the DP cohort (0.9% vs 1%, OR: 0.85, CI:0.75-0.97 p=0.015). Surprisingly, the subgroup analysis revealed that depressed males exhibited significantly higher odds of stroke, and this association persisted even after multivariable analysis (aOR 1.184, CI: 1.12-3.02, p= 0.016)[Fig 1]. All-cause mortality was higher in depressed blacks(2.6% vs 1.4%, OR:1.84, CI:1.21-2.79, p=0.004) and lower in depressed females (0.8% vs 1.1%, OR:0.78 CI:0.67-0.91, p=0.001). Adjusted multivariable analysis revealed no significant all-cause mortality and stroke in depressed vs non-depressed except for subgroup analysis for elderly depressed males. Conclusion: Depression independently associated with stroke in elderly males hospitalized for AF.

Abstract 13953: A Genome-Wide European Ancestry Study Identifies Coronary Artery Disease-Associated Loci Through Gene-Sex Hormone Interaction

Background: Genome-wide association studies (GWAS) have improved our understanding of the genetic basis of coronary artery disease (CAD). While sex-differences in CAD have been observed, little is known about the role of sex hormones in CAD genetics. Accounting for sex hormone levels may help identify CAD-risk loci and extend our knowledge of its genetic architecture. Methods: We performed a GWAS to identify CAD risk loci by incorporating gene-sex hormone interactions in 365,662 individuals of European ancestry enrolled in the UK Biobank (UKB). Genetic interactions of total testosterone (TT), bioavailable testosterone (BAT) and sex-hormone binding globulin (SHBG) were evaluated. GEM software was used to conduct sex-stratified genome-wide interaction analysis with prevalent CAD. Enrollment age and principal components 1-10 were model covariates. The online post-GWAS tool FUMA was used to annotate the biological functions of marginal, interaction, and joint effects summary statistics. Results: We identified 64 loci in males and 8 loci in females that reached genome-wide significance (p < 5х10 -8 ) for CAD ( Table 1 ). Among males, 3 significant loci were identified for BAT, one for TT and one for SHBG using joint effect model that did not overlap with those identified with marginal effect. Among females, 5 significant loci were identified, all for TT using joint effect that that did not overlap with those identified with marginal effect. Of these 5 loci, two loci were independently identified with significant SNP-TT interaction. These loci were mapped close to the TRDN and THADA genes that have been implicated in congenital ventricular tachycardia and polycystic ovarian syndrome, respectively. Conclusion: This Genome-wide gene-sex hormone interaction study identified genomic-risk loci that may contribute to the differential CAD risk between men and women, which would otherwise not have been discovered in traditional GWAS only including marginal genetic effect.

Abstract 12077: Temporal Trends in the Prevalence of Atrial Fibrillation and Atrial Flutter in Septic Patients From 2010 to 2019

Background: Increased awareness of the importance of timely treatment of sepsis has led to improved sepsis care and outcomes over time in the USA. Research question: We evaluated the prevalence of atrial fibrillation (AF) and atrial flutter (AFL) in septic patients over time. Aims: The primary objective was to evaluate temporal trends in the prevalence of AF and AFL in septic patients. The secondary objective was to evaluate these trends stratified by age, sex, and race and ethnicity. Methods: Using the National Inpatient Sample, we studied all adult patients hospitalized with sepsis in the USA from 2010 to 2019. The year 2015 was not included due to changes in ICD coding in the last quarter. Results: Of 18.4 million adult patients admitted with sepsis from 2010 to 2019 in the USA, with a mean age of 65±0.038 years, 50% were female. The risk-adjusted rates of AF and AFL in septic patients showed an increasing trend over time (Panel A) after accounting for differences in age, sex, and comorbidity burden. AF and AFL occurred more frequently in the elderly than the young (Panel B). Sex-stratified analysis showed consistently higher rates of AF and AFL in males than females throughout the study period (Panel C). Finally, the risk-adjusted rates of AF and AFL were consistently highest in White patients, followed by Asian patients, compared with other races and ethnicities throughout the study period (Panel D). Conclusion: Despite improved treatment of sepsis, as evidenced by improving outcomes shown by many studies, the prevalence of AF and AFL in patients with sepsis in the USA has increased over time. This is likely due to sicker patients with sepsis now than in the past or to residual confounding owing to an increase in the elderly and comorbid patient population, which is not captured completely by the comorbidity index. White and Asian patients with sepsis had higher rates of AF than other racial and ethnic groups.

Abstract 11912: Temporal Trends in the Incidence of Non-Shockable In-Hospital Cardiac Arrest in Septic Patients

Background: Owing to increased awareness of the timely recognition and treatment of sepsis in the USA, sepsis care has improved over time with better outcomes. Hypothesis: We hypothesized that the incidence of non-shockable in-hospital cardiac arrest (IHCA) has also improved over time with improving sepsis care. Aims: The primary objective was to evaluate temporal trends of non-shockable IHCA in septic patients. The secondary objective was to evaluate these trends stratified by age, sex, and race. Methods: Using the National Inpatient Sample, we studied all adult patients hospitalized with sepsis from 2005 to 2019. We used multivariate logistic regression for trend analysis. Results: Of 26 million adult patients admitted with sepsis from 2005 to 2019 in the USA, with a mean age of 66 ±0.043 years, 50% were females. The mean age decreased from 68 years in 2005 to 65 years in 2019. The risk-adjusted rates of non-shockable IHCA in septic patients decreased from 2.4% in 2005 to 1.1% in 2019 (Figure 1, Panel A) after accounting for differences in age, sex, and comorbidity burden. The risk-adjusted rates were highest in the age group 45-64 and lowest in the oldest age group ≥85 years (Panel B). Furthermore, the sex-stratified analysis showed consistently higher rates of non-shockable IHCA in males than in females throughout our study (Panel C). Finally, the risk-adjusted rates of non-shockable IHCA were consistently highest in Black patients compared to other races throughout our study period (Panel D). Conclusions: The incidence of non-shockable IHCA in septic patients has significantly improved with increased awareness and improved care of sepsis. Initiatives like Surviving Sepsis Campaign need continued implementation in hospitals, with constant monitoring of compliance with these guidelines to further improve the incidence of non-shockable IHCA in septic patients.

Association between the dietary antioxidant index and relative telomere length of leucocytes in the Chinese population.

Dietary antioxidant indices (DAI) may be potentially associated with relative telomere length (RTL) of leucocytes. This study aimed to investigate the relationship between DAI and RTL. A cross-sectional study involving 1656 participants was conducted. A generalised linear regression model and a restricted cubic spline model were used to assess the correlation of DAI and its components with RTL. Generalised linear regression analysis revealed that DAI (β = 0·005, P = 0·002) and the intake of its constituents vitamin C (β = 0·043, P = 0·027), vitamin E (β = 0·088, P < 0·001), Se (β = 0·075, P = 0·003), and Zn (β = 0·075, P = 0·023) were significantly and positively correlated with RTL. Sex-stratified analysis showed that DAI (β = 0·006, P = 0·005) and its constituents vitamin E (β = 0·083, P = 0·012), Se (β = 0·093, P = 0·006), and Zn (β = 0·092, P = 0·034) were significantly and positively correlated with RTL among females. Meanwhile, among males, only vitamin E intake (β = 0·089, P = 0·013) was significantly and positively associated with RTL. Restricted cubic spline analysis revealed linear positive associations between DAI and its constituents' (vitamin E, Se and Zn) intake and RTL in the total population. Sex-stratified analysis revealed a linear positive correlation between DAI and its constituents' (vitamin E, Se and Zn) intake and RTL in females. Our study found a significant positive correlation between DAI and RTL, with sex differences.

Genetic relationship between the immune system and autism

Autism spectrum disorder (ASD) is a common and complex neurodevelopmental condition. The pathophysiology of ASD is poorly defined; however, it includes a strong genetic component and there is increasing evidence to support a role of immune dysregulation. Nonetheless, it is unclear which immune phenotypes link to ASD through genetics. Hence, we investigated the genetic correlation between ASD and diverse classes of immune conditions and markers; and if these immune-related genetic factors link to specific autistic-like traits in the population.We estimated global and local genetic correlations between ASD (n = 55,420) and 11 immune phenotypes (n = 14,256–755,406) using genome-wide association study summary statistics. Subsequently, polygenic scores (PGS) for these immune phenotypes were calculated in a population-based sample (n = 2487) and associated to five autistic-like traits (i.e., attention to detail, childhood behaviour, imagination, rigidity, social skills), and a total autistic-like traits score. Sex-stratified PGS analyses were also performed.At the genome-wide level, ASD was positively correlated with allergic diseases (ALG), and negatively correlated with lymphocyte count, rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE) (FDR-p = 0.01–0.02). At the local genetic level, ASD was correlated with RA, C-reactive protein, and granulocytes and lymphocyte counts (p = 5.8 × 10−6–0.002). In the general population sample, increased genetic liability for SLE, RA, ALG, and lymphocyte levels, captured by PGS, was associated with the total autistic score and with rigidity and childhood behaviour (FDR-p = 0.03).In conclusion, we demonstrated a genetic relationship between ASD and immunity that depends on the type of immune phenotype considered; some increase likelihood whereas others may potentially help build resilience. Also, this relationship may be restricted to specific genetic loci and link to specific autistic dimensions (e.g., rigidity).

Anticoagulant treatment and COVID-19 mortality among older adults living in nursing homes in Sweden.

Anticoagulants (AC) were introduced in March 2020 as standard of care in nursing home (NH) residents affected with COVID-19 in the Stockholm region, Sweden. ACs are proven to reduce the risk of complications and mortality from COVID-19 among patients of other ages and settings, but there is limited scientific evidence underpinning this practice in the NH setting. This matched cohort study included 182 NH residents in the Stockholm Region diagnosed with COVID-19 in March-May 2020. The main exposure was any AC treatment. Exposed (n = 91), 49% prevalent (pre-COVID-19 diagnosis) AC and 51% incident AC were compared with unexposed controls (n = 91). The outcome was 28-days all-cause mortality after COVID-19 infection. The mortality odds ratios (OR) were assessed using logistic regression, adjusted for age, sex, multimorbidity, and mobility, also stratified by incident or prevalent AC-type, age group, and sex. Of the 182 individuals diagnosed with COVID-19 (median age 88 years, 68% women), 39% died within 28 days after diagnosis. Use of either incident or prevalent AC was associated with a reduced, adjusted 28-day mortality (OR[95% CI]: 0.31[0.16-0.62]). In stratified analyses, the association was significant in both age groups: 70-89 (OR: 0.37 [0.15-0.89]) and 90-99 years of age (OR: 0.22 [0.07-0.65]. In sex-stratified analysis, the AC-lowering effect was significant in women only (OR: 0.28[0.11-0.67]). In the analyses stratified by AC type, the mortality-lowering effect was observed for both prevalent AC (OR: 0.35[0.12-0.99]) and incident AC (OR: 0.29[0.11-0.76]). Both prevalent and incident use of ACs in prophylactic dosing was associated with reduced 28-day mortality among older individuals with COVID-19 in a NH setting. The effect was seen across age-strata and in women. The findings present new insight in best practice for individuals diagnosed with COVID-19 in the NH setting.

17 Education Moderates the Association Between Hippocampal CBF and Memory in Women but Not Men

Objective:Higher educational attainment is associated with reduced risk for Alzheimer's disease (AD) dementia, and its protective effect may act through alterations in cerebral blood flow (CBF) that allow for better coping with accumulating neuropathology. Additionally, there are sex differences in both the risk of developing AD as well as the potential protective effects of education. We therefore sought to investigate whether education moderates the association of hippocampal CBF and memory in cognitively unimpaired older adults, and to examine if these interactions were moderated by sex.Participants and Methods:Cognitively unimpaired older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI; 51 men, 50 women) underwent neuropsychological evaluation and arterial spin labeling MRI, which was used to quantify bilateral hippocampal CBF. Sex was defined as sex at birth. Multiple linear regressions assessed (1) the independent associations among education, CBF, and memory performance separately in men and women and (2) the three-way interactions among CBF, sex, and education, followed by sex-stratified analyses. Three outcome measures were examined: Logical Memory Story A immediate and delayed recall, and Rey Auditory Verbal Learning Test (RAVLT) intrusions. All models adjusted for age and APOE epsilon-4 allele frequency, and all models with CBF additionally adjusted for cerebral metabolism (baseline FDG-PET composite) and pulse pressure.Results:CBF was not associated with education or memory in either women or men. There was a positive association between education and delayed memory in women (ß=0.14, t=2.64, p=0.008) as well as trending, positive associations between education and immediate memory in women (ß=0.09, t=1.79, p=0.074) and education and delayed memory in men (ß=0.09, t=1.94, p=0.054). Three-way interactions among sex, CBF, and education were significant on immediate recall (ß=2.55, t=2.53, p=0.013), delayed recall (ß=2.56, t=2.44, p=0.017), and RAVLT intrusions (ß=-2.28, t=-2.27, p=0.026). In women, there were interactions between education and hippocampal CBF on both immediate (ß=2.49, t=2.90, p=0.006) and delayed recall (ß=2.30, t=2.78, p=0.009), such that as education increased, the strength of the association between CBF and immediate memory increased. There was also an interaction between education and hippocampal CBF on RAVLT intrusions in women (ß=-2.42, t=-3.05, p=0.004), such that as education increased, the strength of the association between CBF and number of intrusions decreased; there was a main effect where in women with lower education, as CBF increased, the number of intrusions increased (ß=0.76, t=2.59, p=0.032); in women with higher education, there was no association between CBF and intrusions. In men, none of these two-way interactions were significant.Conclusions:These results suggest that, in cognitively unimpaired older women, the relationship between hippocampal CBF and memory is moderated by education level, even when adjusting for several other factors. Specifically, higher education may serve as a protective factor in the hippocampal CBF-memory relationship, and this relationship was sex-dependent, occurring in women only. Further research is needed to examine these relationships longitudinally across the clinical continuum of AD. Additionally, this work needs to be conducted in more diverse samples to allow for analyses investigating the impact of education on the intersection of race/ethnicity and sex/gender.

Benefits of a Postoperative Hip Orthosis After Routine Arthroscopy of the Hip: A Retrospective Cohort Study.

No consensus currently exists among orthopaedic surgeons regarding the benefits of hip orthosis after routine hip arthroscopy. To compare patient-reported outcome measures (PROMs) and reoperation rates between patients who were braced versus those who were not braced after routine hip arthroscopy. Cohort study; Level of evidence, 3. A retrospective review was conducted of 193 patients who underwent hip arthroscopy for femoroacetabular impingement (FAI) from January 1, 2018, to December 31, 2021, by 2 orthopedic surgeons at a single institution. Patients before July 1, 2019, were immobilized in a hip orthosis after hip arthroscopy (braced group; n = 101), whereas those after July 1, 2019, were not (nonbraced group; n = 92). Baseline PROMs (visual analog scale for pain, modified Harris Hip Score, Single Assessment Numeric Evaluation, and Veterans Rand 12-Item Health Survey [VR-12] Physical Component Summary and Mental Component Summary) were obtained for all patients and were repeated postoperatively at 2 weeks, 4 weeks, 3 months, 6 months, 1 year, and 2 years. The study groups were compared to evaluate differences in PROMs over time and 2-year postoperative reoperation rates. Group comparisons were also stratified by patient sex. There were no significant differences on any PROM between the braced and nonbraced cohorts at any timepoint. There were also no significant group differences in reoperation rates, with 8 braced patients (7.9%) undergoing reoperation and 1 nonbraced patient (2.3%) undergoing reoperation (P = .208). In the sex-stratified analyses, nonbraced male patients had significantly higher VAS pain and lower VR-12 Mental Component Summary scores at 6 months postoperatively compared with braced male patients (P = .043 and .026, respectively). The study findings suggested that the use of an orthosis after routine hip arthroscopy for FAI does not improve patient-reported outcomes or negatively affect the 2-year reoperation rate. Postoperative bracing increases perioperative cost, and by foregoing routine bracing, patients may avoid the morbidity associated with wearing a brace for a prolonged period.

Relationship between phase angle and lower-extremity function in older adults: Itabashi Longitudinal Study on Aging

ObjectiveEvaluating muscle quality instead of its mass has gained attention in diagnosing sarcopenia. The aim of this study was to examine whether phase angle (PhA) as a bioelectrical impedance analysis (BIA)-derived muscle quality indicator is associated with overall lower extremity function better than appendicular skeletal muscle mass index (ASMI) in community-dwelling older adults. MethodsThis cross-sectional study used data from the Itabashi Longitudinal Study on Aging, a community-based cohort study. A sex-stratified multivariate logistic regression analysis was conducted using PhA and ASMI as exposures, and low physical function defined as short physical performance battery score <10 as the outcome, adjusted for age, being overweight, knee pain, and non-communicable diseases. Discrimination of low physical function was compared using the receiver operating characteristic curve. ResultsThis study included 1464 participants (age 76 [73–80] y; 757 women), with 58 men (8%) and 66 women (9%) exhibiting low physical function. The multivariate odds ratio (OR; 95% confidence interval [CI]) for low physical function among the highest quartile, compared with the lowest quartile were significant in PhA in multiple sites (e.g., OR, 0.09; 95% CI, 0.03–0.32] for men and 0.12; 95% CI, 0.04–0.33 for women in the left leg) but not in ASMI (OR, 0.51; 95% CI, 0.19–1.34 for men and 0.56; 95% CI, 0.21–1.47 for women). Legs and whole-body PhA outperformed the ASMI in discriminating low physical function (P < 0.001). ConclusionPhA reflected physical function better than ASMI; using PhA instead of ASMI in BIA-based morphometric evaluation may add information on low physical function and enhance the diagnostic value of sarcopenia.

Functional principal component analysis and sparse-group LASSO to identify associations between biomarker trajectories and mortality among hospitalized SARS-CoV-2 infected individuals

BackgroundA substantial body of clinical research involving individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evaluated the association between in-hospital biomarkers and severe SARS-CoV-2 outcomes, including intubation and death. However, most existing studies considered each of multiple biomarkers independently and focused analysis on baseline or peak values.MethodsWe propose a two-stage analytic strategy combining functional principal component analysis (FPCA) and sparse-group LASSO (SGL) to characterize associations between biomarkers and 30-day mortality rates. Unlike prior reports, our proposed approach leverages: 1) time-varying biomarker trajectories, 2) multiple biomarkers simultaneously, and 3) the pathophysiological grouping of these biomarkers. We apply this method to a retrospective cohort of 12, 941 patients hospitalized at Massachusetts General Hospital or Brigham and Women’s Hospital and conduct simulation studies to assess performance.ResultsRenal, inflammatory, and cardio-thrombotic biomarkers were associated with 30-day mortality rates among hospitalized SARS-CoV-2 patients. Sex-stratified analysis revealed that hematogolical biomarkers were associated with higher mortality in men while this association was not identified in women. In simulation studies, our proposed method maintained high true positive rates and outperformed alternative approaches using baseline or peak values only with respect to false positive rates.ConclusionsThe proposed two-stage approach is a robust strategy for identifying biomarkers that associate with disease severity among SARS-CoV-2-infected individuals. By leveraging information on multiple, grouped biomarkers’ longitudinal trajectories, our method offers an important first step in unraveling disease etiology and defining meaningful risk strata.

Individual-level risk factors for suicide mortality in the general population: an umbrella review

Deaths by suicide remain a major public health challenge worldwide. Identifying and targeting risk factors for suicide mortality is a potential approach to prevention. We aimed to summarise current knowledge on the range and magnitude of individual-level risk factors for suicide mortality in the general population and evaluate the quality of the evidence. In this umbrella review, five bibliographic databases were systematically searched for articles published from database inception to Aug 31, 2022. We included meta-analyses of observational studies on individual-level risk factors for suicide mortality in the general population. Biological, genetic, perinatal, and ecological risk factors were beyond the scope of this study. Effect sizes were synthesised and compared across domains. To test robustness and consistency of the findings, evidence for small-study effects and excess significance bias (ie, the ratio between the overall meta-analysis effect size and that of its largest included study) was examined, and prediction intervals were calculated. Risk of bias was assessed by the Risk of Bias in Systematic Reviews instrument. The protocol was pre-registered with PROSPERO (CRD42021230119). We identified 33 meta-analyses on 38 risk factors for suicide mortality in the general population. 422 (93%) of the 454 primary studies included in the meta-analyses were from high-income countries. A previous suicide attempt and suicidal ideation emerged as strong risk factors (with effect sizes ranging from 6 to 16). Psychiatric disorders were associated with a greatly elevated risk of suicide mortality, with risk ratios in the range of 4-13. Suicide risk for physical illnesses (such as cancer and epilepsy) and sociodemographic factors (including unemployment and low education) were typically increased two-fold. Contact with the criminal justice system, state care in childhood, access to firearms, and parental death by suicide also increased the risk of suicide mortality. Among risk factors for which sex-stratified analyses were available, associations were generally similar for males and females. However, the quality of the evidence was limited by excess significance and high heterogeneity, and prediction intervals suggested poor replicability for almost two-thirds of identified risk factors. A wide range of risk factors were identified across various domains, which underscores suicide mortality as a multifactorial phenomenon. Prevention strategies that span individual and population approaches should account for the identified factors and their relative strengths. Despite the large number of risk factors investigated, few associations were supported by robust evidence. Evidence of causal inference will need to be tested in high-quality study designs. Wellcome Trust.

Impact of PFAS exposure on immune-mediated diseases and immune transcriptome in Czech adults

Abstract Background Per- and polyfluoroalkyl substances (PFASs) are emerging environmental contaminants with multiple hazardous properties including immunomodulation potency. We aimed to investigate 1) the association between PFAS exposure and immune-mediated diseases (IMDs) and 2) the expression of genes associated with PFAS exposure in a population of Czech adults. Methods This study involved 309 adults from the Czech CELSPAC:YA cohort. The associations of serum concentrations of 9 PFAS with 9 IMDs were assessed by logistic regression. Furthermore, Bayesian kernel machine regression (BKMR) was used to estimate the effect of the PFAS mixture on IMDs. In cases of a statistically significant interaction of PFASs and sex, sex-stratified analyses were performed. To identify transcriptomic profiles, isolated RNA from peripheral mononuclear blood cells was sequenced (QuantSeq) and analysed. Significantly expressed genes associated with multiple PFASs (at least with 4 PFASs) were employed for enrichment analysis by Pathway Studio. All analyses were adjusted for relevant confounders (i.e., sex, age, BMI, smoking, education, and family history of IMDs). Results PFOA, PFOS, and PFUnDA were negatively associated with allergies. Similarly, BKMR modeling showed a negative tendency in the overall effect of PFAS mixture on IMDs. Results of the stratified analysis suggest sex to be an effect modifier in the association of PFOS and atopic eczema. Regarding transcriptomic analysis, 166 statistically significant genes were associated with multiple PFAS exposure. Enrichment analysis of these genes showed involvement of B cell signaling, specifically mechanisms involved in the production of antibody-secreting plasma cells. Conclusions Our results contribute to the body of literature that observes the immunomodulatory effect of PFAS exposure on the level of disease prevalence and further brought new information about underlying deregulatory mechanisms. Key messages • Our study showed an immunosuppressive effect of PFAS exposure on the level of prevalence of immune-mediated diseases, both for PFASs individually and as a mixture. • Genome-wide transcriptomic analysis revealed the involvement of plasma cells as a potential key event of PFAS-induced immunomodulation.

Perceived stress and psychosomatic complaints in Swedish youth

Abstract Background Psychosomatic complaints are common in youth, and are often assumed to reflect stress. Previous studies have reported associations between perceived stress and psychosomatic complaints. The current study extends this research by examining the longitudinal links between perceived stress and psychosomatic complaints. Methods The data was derived from two survey waves of the Swedish cohort study Futura01, with participants aged ∼17-18 in 2019 (t1) who were followed up in 2022 (t2; n = 2708). Perceived stress was measured by Cohen's Perceived Stress Scale (PSS-4). Psychosomatic complaints were captured by three items on the frequency of stomach ache, headache and sleeping problems, which were added to an index. Sex stratified linear regression analyses were performed, controlling for parental education and parental country of birth, based on information from official registers. The longitudinal analyses were carried out using the first difference (FD) approach, regressing the change in psychosomatic complaints on the change in perceived stress. Results Females reported higher levels of stress and of psychosomatic complaints than males at both time points. There were cross-sectional associations between perceived stress and psychosomatic complaints at t1 (females: b = 0.40, 95% CI 0.36, 0.45; males: b = 0.33, 95% CI 0.29, 0.38) and at t2 (females: b = 0.40, 95% CI 0.36, 0.45; males: b = 0.33, 95% CI 0.29, 0.38). The FD analyses showed that increases in perceived stress were associated with increases in psychosomatic complaints (females: b = 0.19, 95% CI 0.15, 0.23; males: b = 0.19, 95% CI 0.14, 0.23). Conclusions This study provides further empirical support for the assumption that psychosomatic complaints can be regarded as stress-related. Decreasing stress and strengthening young people's resources and strategies to cope with stress may thereby help to reduce the risk of developing psychosomatic complaints. Key messages • Psychosomatic complaints are responsive to perceived stress and can thus be regarded as stress-related. • Reducing stress and strengthening coping resources may increase well-being in youth.

Violence against children and substance abuse: A pooled study of 8 low- and middle-income countries

Abstract Introduction Violence against children (VAC) has been linked to substance abuse later in life. However, most evidence of this association comes from high-income countries (HICs) and is understudied in the context of low- and middle-income countries (LMICs). Methods This study used the latest Violence Against Children Surveys (VACS) data from 2017-2019 across eight LMICs. The main exposure variable was defined as having experienced at least one type of violence (physical, sexual, or emotional) from any perpetrator before age 18. With the pooled dataset of 32,326 adolescents aged 13-24 years, a series of logistic regressions with country-fixed effects were estimated to examine the association between VAC and three substance abuse outcomes: smoking daily, binge drinking (i.e., more than four drinks a week) and use of illegal drugs in the last 30 days. Further, analyses based on the types of violence and whether the association differs by sex were performed. Results After adjusting for all covariates, any VAC experience was significantly associated with all three substance abuse outcomes: daily smoking (OR: 1.5, 95% CI 1.2,1.8), binge drinking (OR: 1.8, 95% CI 1.5, 2.2), and drug use (OR:1.9, 95% CI 1.5-2.3). Sexual violence, in particular, had the strongest association. Sex-stratified analyses revealed that women who experienced sexual violence in childhood were more likely (OR range 3.3-3.7) to engage in substance abuse than sexually abused men (OR range 1.2-2.1). Conclusions The findings highlight the need for interventions to prevent childhood violence and to address its consequences on substance abuse in LMICs. Key messages • Experience of any type of violence during childhood is significantly associated with daily smoking, binge drinking of alcohol, and drug use in later life. • Women who experience sexual violence in childhood are more likely to abuse substances than men who were sexually abused.

Sex-Specific Associations Between Preoperative Hemoglobin and Outcomes After Major Noncardiac Surgery: A Retrospective Cohort Study.

Preoperative anemia is an established risk factor for morbidity and mortality after surgery. Men and women have different hemoglobin concentrations and are at different risks of postoperative complications. However, sex-stratified analysis on the association between preoperative hemoglobin and outcomes after noncardiac surgery has been limited in previous studies. This was a retrospective cohort study of adult patients undergoing elective major noncardiac surgery in a large academic hospital. The primary outcome was a collapsed composite of postoperative mortality or cardiovascular, renal, pulmonary, and infectious complications during hospitalization. Sex-specific univariable associations between preoperative hemoglobin and the composite outcome were visualized using moving-average and cubic-spline smoothing plots. Multivariable regression models adjusting for patient demographics, comorbidities, medication uses, laboratory tests, and anesthesia/surgery features were used to estimate confounder-adjusted associations. Restricted cubic spline and piecewise linear functions were used to assess the possible nonlinear relationships between preoperative hemoglobin and the outcomes. The interaction between patient sex and hemoglobin on outcomes was assessed using a likelihood-ratio test. We included 22,550 patients, with 6.7% (622 of 9268) of women and 9.7% (1293 of 13,282) of men developing the primary outcome. Lower preoperative hemoglobin was associated with a higher incidence of the primary composite outcome in both men and women. Nonlinearity for the association was not statistically significant in either women (P = .539) or men (P = .165). The multivariable-adjusted odds ratios per 1 g/dL increase in hemoglobin were 0.93 (95% confidence interval [CI], 0.87-0.98; P = .013) for women and 0.94 (95% CI, 0.90-0.97; P < .001) for men, with no interaction by sex (Pinteraction = .923). No hemoglobin thresholds were confirmed at which the associations with the primary outcome changed significantly. Low preoperative hemoglobin was associated with a higher risk of complications or mortality after elective noncardiac surgery in both men and women. No differences in the strength of associations between sexes were found. Further studies are needed to assess whether these associations are linear or there are sex-specific thresholds of preoperative hemoglobin concentrations below which postoperative risks begin to increase.

Plasma Expression of Carotid Plaque Presence-Related MicroRNAs Is Associated with Inflammation in Patients with Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is associated with problems beyond the joints such as cardiovascular (CV) disease. MicroRNA-24, -146 and -Let7a are associated with carotid plaque presence in RA patients. We evaluated whether these microRNAs were involved in the inflammatory state of RA, and we studied their gene targets to understand their role in inflammation and atherosclerosis. A total of 199 patients with RA were included. Inflammatory variables such as disease activity score 28 (DAS28) and erythrocyte sedimentation rate (ESR) were quantified. MicroRNAs were extracted from plasma and quantified with qPCR. Multivariate models and classification methods were used for analysis. The multivariate models showed that diminished expression of microRNA-146 was associated with inferior levels of DAS28-ESR, and the decreased expression of microRNA-24, -146 and -Let7a were associated with lowered ESR in the overall cohort. When microRNAs were evaluated globally, a global increase was associated with increased DAS28-ESR and ESR in the overall cohort. Sex-stratified analyses showed different associations of these microRNAs with the inflammatory variables. Finally, random forest models showed that microRNAs have a pivotal role in classifying patients with high and low inflammation. Plasmatic expressions of microRNA-24, -146 and -Let7a were associated with inflammatory markers of RA. These microRNAs are associated with both inflammation and atherosclerosis and are potential therapeutic targets for RA.

Social media and e-cigarette use: The mediating role of mental health conditions

BackgroundIn recent years, youth social media use, youth e-cigarette use, and youth mental health conditions have become major public health concerns. We examined the role of mental health condition indicators in the link between youth social media use and e-cigarette use. MethodsWe used data from the 2022 National Youth Tobacco Survey (N = 23,445) to measure social media use by time spent, anxiety and depression symptoms by the Patient Health Questionnaire-4, and past-30-day e-cigarette use. We applied the potential outcomes framework to examine the relationship between social media use and e-cigarette use mediated by mental health condition indicators. ResultsMental health condition indicators mediated the relationship between social media use and e-cigarette use in a dose-response manner, with higher levels of social media use associated with higher odds of e-cigarette use. With mental health condition indicators as a mediator, those who used social media for 4+ hours/day or 3–4 h/day had significantly higher odds of e-cigarette use than those who used social media sometimes or never. In the sex-stratified analysis, we found that very often social media use was associated with higher odds of e-cigarette use for both males and females, compared to sometimes users (OR = 1.53, 95 % CI [1.18,1.96] for males; OR = 2.27, 95 % CI [1.76,2.92] for females). LimitationsAnxiety and depression symptoms were self-reported. ConclusionsThis study shows that anxiety and depression symptoms mediate the relationship between social media and e-cigarette use among youth and support the growing concern that frequent social media use may negatively affect youth health.

Association of Blood-Based DNA Methylation Markers With Late-Onset Alzheimer Disease: A Potential Diagnostic Approach.

There is an urgent need to identify novel noninvasive biomarkers for Alzheimer disease (AD) diagnosis. Recent advances in blood-based measurements of phosphorylated tau (pTau) species are promising but still insufficient to address clinical needs. Epigenetics has been shown to be helpful to better understand AD pathogenesis. Epigenetic biomarkers have been successfully implemented in other medical disciplines, such as oncology. The objective of this study was to explore the diagnostic accuracy of a blood-based DNA methylation marker panel as a noninvasive tool to identify patients with late-onset Alzheimer compared with age-matched controls. A case-control study was performed. Blood DNA methylation levels at 46 cytosine-guanine sites (21 genes selected after a comprehensive literature search) were measured by bisulfite pyrosequencing in patients with "probable AD dementia" following National Institute on Aging and the Alzheimer's Association guidelines (2011) and age-matched and sex-matched controls recruited at Neurology Department-University Hospital of Navarre, Spain, selected by convenience sampling. Plasma pTau181 levels were determined by Simoa technology. Multivariable logistic regression analysis was performed to explore the optimal model to discriminate patients with AD from controls. Furthermore, we performed a stratified analysis by sex. The final study cohort consisted of 80 patients with AD (age: median [interquartile range] 79 [11] years; 58.8% female) and 100 cognitively healthy controls (age 77 [10] years; 58% female). A panel including DNA methylation levels at NXN, ABCA7, and HOXA3 genes and plasma pTau181 significantly improved (area under the receiver operating characteristic curve 0.93, 95% CI 0.89-0.97) the diagnostic performance of a single pTau181-based model, adjusted for age, sex, and APOE ɛ4 genotype. The sensitivity and specificity of this panel were 83.30% and 90.00%, respectively. After sex-stratified analysis, HOXA3 DNA methylation levels showed consistent association with AD. These results highlight the potential translational value of blood-based DNA methylation biomarkers for noninvasive diagnosis of AD. Research Ethics Committee of the University Hospital of Navarre (PI17/02218).