Evaluate Sex Differences Research Articles

Sex differences in in-hospital management and outcomes of patients with acute pulmonary embolism

Abstract Background Acute pulmonary embolism (PE) is a life-threatening disease with specific risk factors among women. Systematic evaluation of contemporary quality of care and outcomes in women hospitalized with acute PE is needed. Methods The COPE Registry (COntemporary management of acute Pulmonary Embolism) is a nationwide registry that was run in Internal Medicine, Cardiology and Emergency Departments in Italy. Using data from the COPE Registry, we evaluated sex differences in acute management, medical therapies, in-hospital and 30-day mortality and major bleeding in 5,213 patients admitted for acute PE at 182 hospitals in Italy from 2018 to 2020. Results Women (n=2,728) were older than men (71.2 versus 66.6 years, P<0.001) and had different distribution of comorbidities, with dementia and severe renal failure being more prevalent (13.6 vs 6.4% and 6.1 vs 3.0%, respectively) and cancer, COPD and recent bed-rest less prevalent (15.2 vs 18.5% and 11.1 vs 14.5% and 23.5 vs 20.2%) in women than men. At presentation, PE was more severe in women than men in terms of hemodynamic instability (4.1 vs 2.7%), prevalence of right ventricle overload at echocardiography (64.5 vs 57%) and prevalence of sPESI=0 (29.4 vs 38.5%). Concerning the likelihood to receive evidence-based acute treatments for PE, women were more likely than men to receive reperfusion in the case of hemodynamic compromise at presentation after adjusting for age and dementia (63.1 vs 50.0%; OR 1.934, 95% CI 1.01-3.71), and to receive direct oral anticoagulants during hospitalization after adjusting for age, dementia and severe renal failure (50.9 vs 48.6%; OR 1.14, 95% CI 1.01-1.28); similar proportions of low-risk women and men were managed as outpatients or by short hospital stay (1.4% vs 1.4% and 8.6 vs 6.0%, respectively). In-hospital and 30-day mortality rates were not different in women and in men (3.7% versus 3.1% and 5.5 vs 4.8%), but PE-related mortality was higher in women than in men (2.1 vs 1.3%). The sex difference in PE-related mortality was no longer observed in after adjusting for age, hemodynamic instability and dementia (adjusted HR 1.20; 95% CI 0.77-1.88; P=0.415). Similar rates of early and delayed major bleedings occurred in women and in men, both at univariate analysis and after adjusting for age, creatinine clearance and use of thrombolysis. None of 22 pregnant women and 1 out of 204 women with estro-progestin associated PE died or experienced major bleeding. Conclusions Women hospitalized for acute PE in Italy received evidence-based acute treatments more commonly than men. The observed sex differences in PE-related mortality were mainly attributable to worse clinical profiles and older age. Women with sex-related risk factor for PE had favorable prognosis.

Investigating the effect of chronic stress, depressive-like pathology and cognitive impairments on acute myocardial infarction: sex-differentiated effects

Abstract Background/Introduction Depression is an independent risk factor for cardiovascular disease (CVD) with the prevalence rates being higher in women than men in the general population and among patients with CVD. Furthermore, an association between myocardial infarction and cognitive deficits has been proposed, but the pathophysiological mechanisms that are responsible for the brain-heart axis interaction have not been elucidated. Purpose The present study aims to: 1) evaluate sex differences in the effect of chronic unpredictable stress (CUS) on myocardial infarct size (IS) and 2) determine the molecular pathways affected by CUS in the heart. Methods Adult male and female C57BL/6J mice, were randomly divided into 4 groups (n=7/group): CON (Control, sham surgery), iCON (Control, myocardial ischemia/reperfusion (IR)), STR (Stress, sham surgery) and iSTR (Stress, IR). Mice were intermittently exposed to the CUS protocol consisted of 4 different stressors for 6 consecutive weeks. Locomotor activity (open field-OF), anxiety-like alterations (OF, elevated plus-maze-EPM test), depressive-like pathology (tail suspension test- TST) and cognition (Y-maze and Novel Object Recognition-NOR tests) were evaluated. After behavioral evaluation, the animals were subjected to 30 min I followed by 24 h of R or sham surgery and infarct size (IS) was determined via double Evan’s Blue and triphenyltetrazolium chloride staining. In a second series of experiments (n=5/group), the ischemic part of the myocardium was collected at 24h R and subjected to label free proteomic analysis, in order to identify alterations associated with the effect of CUS and IR. Results CUS induced anxiety, depressive-like pathology and cognitive deficits as indicated by the increased time spent in the closed arms of the EPM (p<0.005), the increased immobility time (TST, p<0.05), the reduced preference for the novel object (NOR, p<0.05), and the significant body weight reduction (p<0.001), in both male and female mice. CUS significantly increased IS (p<0.001) in both male and female mice. Proteomic analysis revealed that CUS affected the heart proteome, related to endoplasmic reticulum stress, mitochondrial damage and apoptosis, of both sexes in the absence of IR. Female mice were more susceptible to IR damage in absence of CUS with 248 significant genes (FDR<0.05) being deregulated mainly belonging to Keap-Nrf2-ARE signaling pathway, in contrast to 168 significant genes in male mice. In male mice, CUS exacerbated the IR injury proteome changes mainly related to induction of apoptosis and mitochondrial dysregulation (292 significant genes, FDR<0.05 for males vs 102 for females). Conclusions Chronic exposure to stress increases depressive-like pathology and cognitive deficits, leading to heart proteome alterations and increased IS in both sexes. Sex differences were observed indicating that the coexistence of CUS and IR render the male heart more susceptible to myocardial damage.

Sex differences in aortic prognosis in Marfan patients, a retrospective longitudinal study from the REPAG registry

Abstract Introduction Previous studies(1-4) have suggested a more favourable aortic outcome among women with Marfan syndrome (MFS), although the precise underlying mechanism remains not completely understood. In this retrospective longitudinal study, we aim to evaluate sex differences in aortic events in a large cohort of Marfan patients seen in 11 tertiary centres in Spain. Methods Patients with diagnosis of Marfan syndrome (MFS) were included. Data on aortic events (AE) including elective aortic surgeries, acute aortic syndrome or death were incorporated. Survival free of the combined endpoint of death or first aortic event (elective aortic surgery or acute aortic syndrome) was compared between male and female by the Kaplan-Meier curves, log-rank test and subsequent Cox regression analysis. Results A total of 442 patients with MFS where included, 48.2% female and 56.2% index cases. Although systemic score and proband proportion was not different between both sexes, the diagnosis was earlier in males (p=0.01) (Table). Furthermore, among adult patients, males exhibited greater height, weight, and body surface area (BSA). Absolute aortic root diameter at baseline was greater in males, but not BSA-indexed diameters or z-scores. Combined endpoint of death or aortic event was observed in 192 patients (120 male, 72 female, p=<0.00001). Female sex had better survival free of the combined endpoint in a multivariable Cox analysis (HR 0.41 95% CI=0.30–0.55) with a mean survival free of the combined endpoint of 41.3yrs in male and 61.4 years in females (p<0.0001) (Figure).Although a higher proportion of elective aortic interventions as first event was observed in males (66.7% vs 52.8%), the proportion of type A dissections was similar between both sexes (26.7 vs 26.4%) with increased frequency of type B dissections in females as first aortic event (4.2 vs 15.3%) (p=0.026) Conclusions Male patients with MFS present higher aortic root diameters but similar BSA-indexed and zscores than females. Survival free of first aortic event or death is reduced in male with MFS, with greater frequency of elective aortic intervention. Although this last is driven by absolute aortic diameter, no increase on type A dissection was observed in women. These findings might suggest a potentially less aggressive manifestation of proximal aortic disease in women with MFS.Table:Comparison male and female Marfan

Sleep quality and sex-related differences in an older adult population: a web-based cross-sectional study

Introduction: Aging has significant economic and social implications leading to an increase in chronic diseases and reduced autonomy of the elderly. Sleep disorders are common in the elderly, manifesting reduced sleep quality. Objective/Purpose: The study aimed to measure the prevalence of sleep disorders in older adults and assess sex differences in sleep quality and sleep problems. Method: A cross-sectional study based on an online survey was performed according to the STROBE checklist, using pre-validated questionnaires (Pittsburgh Sleep Quality Index) distributed to a sample of older adults. This is the first study evaluating sex differences in sleep quality and problems in the Italian population context using the Pittsburgh Sleep Quality Index assessment tool. The study was conducted in a university hospital in Rome from October 2020 to November 2020, on patients aged >65 years, independent in activities of daily living, with comorbidities and on treatment with up to 2 medications. Results: 59 patients were included in the study, with an average age of 71.12 years. The results show that among males, the prevalence of poor sleep quality was 51.9%, while among females, the prevalence of poor sleep quality was 62.5%. According to Shapiro-Wilk, the Pittsburgh Sleep Quality Index was not normally distributed. Pittsburgh Sleep Quality Index total scores in males did not differ significantly from females. Conclusions: Considering scientific literature, recent studies have highlighted the prevalence of sleep disorders in the elderly population and their underreporting. Providing early intervention not only improves the sleep quality of these people but may also reduce the risk of experiencing adverse health outcomes and susceptibility to frailty.

Failure to Rescue Female Patients Undergoing High-Risk Surgery

Female patients have higher mortality rates after high-risk surgery than male patients. It is unknown whether this mortality gap is due to different rates of postoperative complications or if complications are addressed differently by sex, causing complications to lead to death-so-called failure to rescue. To evaluate sex differences in failure to rescue across high-risk surgical procedures. This retrospective cohort study was conducted using data from Medicare beneficiaries from October 2015 to February 2020 who underwent high-risk vascular or cardiac surgical procedures, including abdominal aortic aneurysm repair, coronary artery bypass grafting, aortic valve replacement, and mitral valve replacement or repair. Data analysis was performed from August 2023 to March 2024. The primary exposure was patient sex. The primary outcomes were risk-adjusted rates of complications, 30-day mortality, and failure to rescue, which was defined as a death occurring after a serious complication. Categorical variables are presented as frequencies and proportions and compared using χ2 analysis. Continuous variables were tested for normality and compared using a t test. A total of 863 305 Medicare beneficiaries were included in this study cohort, of whom 304 176 (35.2%) were female. Mean (SD) age was slightly higher in female patients (74.8 [9.3] years) than male patients (73.4 [8.5] years), and female patients had more comorbidities than male patients (≥2 Elixhauser comorbidities, female: 262 809 [86.4%] vs male: 465 231 [83.2%]). Female patients were more likely to receive care at large hospitals and hospitals with a higher surgical case volume. Overall, female and male patients had similar rates of complications (female: 14.98% vs male: 14.37%; adjusted relative risk [aRR], 1.04; 95% CI, 1.03-1.05; P < .001). However, female patients had higher rates of 30-day mortality (female: 4.22% vs male: 3.34%; aRR, 1.26; 95% CI, 1.23-1.29; P < .001) and higher rates of failure to rescue (female: 10.71% vs male: 8.58%; aRR, 1.25; 95% CI, 1.22-1.28; P < .001). A similar pattern was observed when stratified by each procedure. In this cohort study among Medicare beneficiaries undergoing high-risk surgery, male and female patients experienced similar rates of serious complications, but female patients with complications were more likely to die. In other words, clinicians fail to rescue female patients with complications after high-risk surgery more often than male patients. Improving the recognition and management of female patients' complications postoperatively may narrow the sex disparity after high-risk surgery.

A Psychometric Evaluation of the Tend-and-Befriend Questionnaire

In response to Cannon’s widely accepted fight-or-flight system, Taylor et al. proposed the tend-and-befriend hypothesis to better capture variance in women’s stress response behaviors. The Tend-and-Befriend Questionnaire (TBQ) measures self-reported individual differences in the use of fight, flight, tend, and befriend. Several studies have used this scale to evaluate sex differences in these behaviors, yet it has not yet been rigorously evaluated. Using three samples (N = 1094), we first explore the factor structure of the TBQ to produce and validate a revised measure, the TBQ-Short Form (TBQ-SF). Next, we evaluate the claim that women use tend-and-befriend more than men. Results indicated that the TBQ-SF provided both reliable subscales and largely acceptable model fit, yet the factor structure and validity varied across the three samples. While men do report more fighting than women, both men and women report use tending and befriending more than fighting or fleeing. Finally, other variables—namely attachment—capture more variance in TBQ-SF factors than sex. While the TBQ-SF does capture differences in stress reactions (fight, flight, tend/befriend), we suggest that the scale is most reliable in measuring overall stress reactivity. Therefore, future research should aim to construct a better scale specific to tend-and-befriend using alternative methodologies.

Integrated large-scale metagenome assembly and multi-kingdom network analyses identify sex differences in the human nasal microbiome.

Respiratory diseases impose an immense health burden worldwide. Epidemiological studies have revealed extensive disparities in the incidence and severity of respiratory tract infections between men and women. It has been hypothesized that there might also be a nasal microbiome axis contributing to the observed sex disparities. Here, we study the nasal microbiome of healthy young adults in the largest cohort to date with 1593 individuals, using shotgun metagenomic sequencing. We compile the most comprehensive reference catalog for the nasal bacterial community containing 4197 metagenome-assembled genomes and integrate the mycobiome, to provide a valuable resource and a more holistic perspective for the understudied human nasal microbiome. We systematically evaluate sex differences and reveal extensive sex-specific features in both taxonomic and functional levels in the nasal microbiome. Through network analyses, we capture markedly higher ecological stability and antagonistic potentials in the female nasal microbiome compared to the male's. The analysis of the keystone bacteria reveals that the sex-dependent evolutionary characteristics might have contributed to these differences. In summary, we construct the most comprehensive catalog of metagenome-assembled-genomes for the nasal bacterial community to provide a valuable resource for the understudied human nasal microbiome. On top of that, comparative analysis in relative abundance and microbial co-occurrence networks identify extensive sex differences in the respiratory tract community, which may help to further our understanding of the observed sex disparities in the respiratory diseases.

Sex-Dependent Effects of Cardiometabolic Health and APOE4 on Brain Age: A Longitudinal Cohort Study.

The aging population is growing faster than all other demographic strata. With older age comes a greater risk of health conditions such as obesity and high blood pressure (BP). These cardiometabolic risk factors (CMRs) exhibit prominent sex differences in midlife and aging, yet their influence on brain health in females vs males is largely unexplored. In this study, we investigated sex differences in relationships between BP, body mass index (BMI), and brain age over time and tested for interactions with APOE ε4 genotype (APOE4), a known genetic risk factor of Alzheimer disease. The sample included participants from 2 United Kingdom-based longitudinal birth cohorts, the Lothian Birth Cohort (1936) and Insight 46 (1946). Participants with MRI data from at least 1 time point were included to evaluate sex differences in associations between CMRs and brain age. The open-access software package brainageR 2.1 was used to estimate brain age for each participant. Linear mixed-effects models were used to assess the relationships between brain age, BMI, BP, and APOE4 status (i.e., carrier vs noncarrier) in males and females over time. The combined sample comprised 1,120 participants (48% female) with a mean age (SD) of 73 (0.72) years in the Lothian Birth Cohort and 71 (0.68) years in Insight 46 at the time point 1 assessment. Approximately 30% of participants were APOE4 carriers. Higher systolic and diastolic BP was significantly associated with older brain age in females only (β = 0.43-0.56, p < 0.05). Among males, higher BMI was associated with older brain age across time points and APOE4 groups (β = 0.72-0.77, p < 0.05). In females, higher BMI was linked to older brain age among APOE4 noncarriers (β = 0.68-0.99, p < 0.05), whereas higher BMI was linked to younger brain age among carriers, particularly at the last time point (β = -1.75, p < 0.05). This study indicates sex-dependent and time-dependent relationships between CMRs, APOE4 status, and brain age. Our findings highlight the necessity of sex-stratified analyses to elucidate the role of CMRs in individual aging trajectories, providing a basis for developing personalized preventive interventions.

Global Sex Disparities in Bystander Cardiopulmonary Resuscitation After Out-of-Hospital Cardiac Arrest: A Scoping Review.

This scoping review collates evidence for sex biases in the receipt of bystander cardiopulmonary resuscitation (BCPR) among patients with out-of-hospital cardiac arrest patients globally. The MEDLINE, PsycINFO, CENTRAL, and Embase databases were screened for relevant literature, dated from inception to March 9, 2022. Studies evaluating the association between BCPR and sex/gender in patients with out-of-hospital cardiac arrest, except for pediatric populations and cardiac arrest cases with traumatic cause, were included. The review included 80 articles on BCPR in men and women globally; 58 of these studies evaluated sex differences in BCPR outcomes. Fifty-nine percent of the relevant studies (34/58) indicated that women are less likely recipients of BCPR, 36% (21/58) observed no significant sex differences, and 5% (3/58) reported that women are more likely to receive BCPR. In other studies, women were found to be less likely to receive BCPR in public but equally or more likely to receive BCPR in residential settings. The general reluctance to perform BCPR on women in the Western countries was attributed to perceived frailty of women, chest exposure, pregnancy, gender stereotypes, oversexualization of women's bodies, and belief that women are unlikely to experience a cardiac arrest. Most studies worldwide indicated that women were less likely to receive BCPR than men. Further research from non-Western countries is needed to understand the impact of cultural and socioeconomic settings on such biases and design customized interventions accordingly.

Correlation of the Upper Nasolabial Angle With Skeletal Patterns and Nasal Morphology in Indian Adults: An Observational Study.

The upper nasolabial angle (UNLA) is an important determinant in clinical diagnosis and treatment planning. Therefore, the primary objective of this study was to assess the correlation between various skeletal parameters and nasal morphology in an Indian cohort, particularly UNLA. The secondary objectives were to evaluate sex differences in nasal morphology, optimal cut-off values of the UNLA for skeletal malocclusions, and differences in nasal morphology in different skeletal malocclusions. This retrospective study used 162 pre-treatment lateral cephalometric records of patients with skeletal Class I, Class II, and Class III relationships. Group 1 consisted of 68 skeletal Class I patients (ANB angle of 2-40), Group 2 consisted of 68 skeletal Class II patients (ANB angle > 40), and Group 3 consisted of 26 skeletal Class III patients (ANB angle of less than 20). Each group was further subdivided according to the growth pattern into low (horizontal), average, and high (vertical) growers. The angle between the sella-nasion plane and mandibular plane (SN-GoGn angle) was used to further divide the groups according to their growth pattern into a horizontal growth pattern (SN-GoGn angle < 280), an average growth pattern (SN-GoGn angle of 28-360), and a vertical growth pattern (SN-GoGn angle > 360). The study sample was also divided into males and females to assess gender differences. Spearman's correlation coefficient, multinomial logistic regression analysis, Mann-Whitney U test, and Kruskal-Wallis tests were used. Receiver operating characteristic curves were used to obtain the optimal cut-off values for UNLA. The UNLA showed a positive correlation with the sagittal position of the maxilla and a negative correlation with the sagittal position of the mandible and palatal plane (PP) inclination angle. Statistically significant sex differences were observed in nasal length, nasal depth, and lower anterior facial height. The optimal cut-off values for the UNLA angle in the class II skeletal pattern were ≥ 200, 16-200 for skeletal class I, and ≤ 160 for skeletal class III patients. None of the skeletal and nasal parameters were reliable predictors of the skeletal pattern type. The present study showed that the UNLA increased in the skeletal class II pattern with the downward inclination of the PP. Patients with skeletal class III malocclusion had an upward-canted nasal tip.

Matching males and females undergoing non mesh primary unilateral inguinal hernia repair: evaluating sex differences in preoperative and acute postoperative pain.

The objective was to compare pain and related psychological factors during the preoperative and acute postoperative period between male and female patients, who underwent non mesh primary unilateral inguinal hernia repair. After ethics approval, informed consent was obtained, and data were collected. Male and female participants were compared by manually matching one-to-one on 10 variables. Descriptive statistics (mean ± standard deviation and frequency) as well as numerical rating scales from 0 to 10 were used. Comparison tests were performed using Chi-square or Fisher's Exact test for categorical data and independent samples t-test or non-parametric equivalent tests for numerical scores. p < 0.05 is reported as statistically significant. To control type I error, Bonferroni correction was used. 72 participants with 36 matched pairs were included. Sex differences were found for operation length (p = .006), side of operation (p = .002), and hernia type (p = .013). Significant differences between the sexes were not found at the preoperative or postoperative time for resilience, pain interference or pain severity related measures, postoperative hernia pain incidence, pain catastrophizing, depression and anxiety symptoms, or return to normal activities. When controlling for known confounders and using a conservative Type I error rate, pain and related factors between the sexes did not differ significantly.

Commentator Discussion: Evaluation of sex differences in the receipt of concomitant atrial fibrillation procedures during nonmitral cardiac surgery

Commentator Discussion: Evaluation of sex differences in the receipt of concomitant atrial fibrillation procedures during nonmitral cardiac surgery

Sex-specific differences in NAFLD development: effect of a high-sucrose diet on biochemical, histological, and genetic markers in C57bl/6N mice

ABSTRACT Sucrose intake is a potential risk factor for non-alcoholic fatty liver disease (NAFLD). Individual characteristics such as sex, play arole in the biological variation of the disease, potentially related to genetic regulation. This research evaluated sex differences in biochemical, histopathological, and gene expression responses associated with NAFLD in C57bl/6N mice on a high sucrose diet. Female and male mice were assigned to control or high sucrose diets (50% sucrose solution) for 20 weeks. After sacrifice, blood and hepatic tissue were collected for analysis. Female mice revealed moderate-to-high NAFLD, whereas male mice showed mild-to-moderate NAFLD. Sex-specific variations were observed in Cd36 gene expression, an upregulation in females compared with the male group, and Adipor1 gene expression showed significant downregulation in the female group in response to high sucrose diet compared with the control group. These findings highlight the importance of considering gender disparities in the treatment and management of NAFLD.

Left ventricular mass as a modulator of ventricular arrhythmia risk and sex differences after CRT for nonischemic cardiomyopathy and LBBB

BackgroundThe risk of ventricular arrhythmias (VAs) after cardiac resynchronization therapy (CRT) has been associated with ischemic disease/scar, sex, and possibly left ventricular mass (LVM). ObjectiveThe purpose of this study was to evaluate sex differences and baseline/postimplant change in LVM on VA risk after CRT implantation in patients with nonischemic cardiomyopathy and left bundle branch block. MethodsIn patients meeting the criteria, baseline and follow-up echocardiographic images were obtained for LVM assessment. VA events were reported from device diagnostics and therapies. VA risk was stratified by receiver operating characteristic (Youden index cutoff point) for baseline LVM and baseline/postimplant change in LVM. Multivariate Cox regression model was also used for VA risk stratification. ResultsOne hundred eighteen patients (71 female patients [60.2%]; mean age 60.5 ± 11.3 years; left ventricular ejection fraction 19.2% ± 7.0%; QRS duration 165.6 ± 20 ms; LVM 313.9 ± 108.8 g) were enrolled and followed up for a median of 90 months (interquartile range 44–158 months). Thirty-five patients (29.6%) received appropriate shocks or antitachycardia pacing at a median of 73.5 months (interquartile range 25–130 months) postimplantation. Males had a higher VA incidence (male patients 18 of 47 [38.3%] vs female patients 17 of 71 [23.9%]; P = .02). Baseline LVM > 308.9 g separated patients with higher VA risk (P = .001). Less than a 20% decrease in LVM increased VA risk (P < .001). Baseline LVM was the only baseline characteristic predicting VA events in the Cox regression model (hazard ratio 1.01; 95% confidence interval 1.001–1.009; log-rank, P = .003). Sex differences in VA risk were eliminated by the baseline LVM parameters. ConclusionVA risk after CRT implantation in nonischemic cardiomyopathy was associated with baseline LV > 308.9 g and a decrease in LVM ≤ 20%, without sex differences.

Sex inequalities in cardiovascular risk prediction.

Evaluate sex differences in cardiovascular disease (CVD) risk prediction, including use of i) optimal sex-specific risk predictors and ii) sex-specific risk thresholds. Prospective cohort study using UK Biobank, including 121,724 and 182,632 healthy men and women, respectively, aged 38-73 years at baseline. There were 11,899 (men) and 9,110 (women) incident CVD cases (hospitalization or mortality) with median 12.1 years follow-up. We used recalibrated Pooled Cohort Equations (PCE, 7.5% 10-year risk threshold as per US guidelines), QRISK3 (10% 10-year risk threshold as per UK guidelines) and Cox survival models using sparse sex-specific variable sets (via LASSO stability selection) to predict CVD risk separately in men and women. LASSO stability selection included 12 variables in common between men and women, with three additional variables selected for men and one for women. C-statistics were slightly lower for PCE than QRISK3 and models using stably-selected variables, but were similar between men and women: 0.67 [0.66-0.68], 0.70 [0.69-0.71], and 0.71 [0.70-0.72] in men and 0.69 [0.68-0.70], 0.72 [0.71-0.73], and 0.72 [0.71-0.73] in women for PCE, QRISK3 and models using stably-selected variables, respectively. At current clinically implemented risk thresholds, test sensitivity was markedly lower in women than men for all models: at 7.5% 10-year risk, sensitivity was 65.1% and 68.2% in men and 24.0% and 33.4% in women for PCE and models using stably-selected variables, respectively; at 10% 10-year risk, sensitivity was 53.7% and 52.3% in men and 16.8% and 20.2% in women for QRISK3 and models using stably-selected variables, respectively. Specificity was correspondingly higher in women than men. However, the sensitivity in women at 5% 10-year risk threshold increased to 50.1%, 58.5% and 55.7% for PCE, QRISK3 and models using stably-selected variables, respectively. Use of sparse sex-specific variables improved CVD risk prediction compared with PCE but not QRISK3. At current risk thresholds, PCE and QRISK3 work less well for women than men but sensitivity was improved in women using a 5% 10-year risk threshold. Use of sex-specific risk thresholds should be considered in any re-evaluation of CVD risk calculators. Cardiovascular disease (CVD) risk prediction is an important component of clinical risk management and disease prevention. We find that at risk prediction thresholds used by currently applied risk prediction algorithms (PCE 7.5% 10-year risk threshold in the US and QRISK3 10% risk threshold in the UK), sensitivity of these risk prediction tools is markedly lower in women than in men. This sex inequality implies that women are proportionately less likely to receive appropriate clinical management including lipid-lowering therapy. If the risk prediction threshold is lowered to 5% 10-year risk in women, then sensitivity in women is substantially increased.

Sex Differences during Influenza A Virus Infection and Vaccination and Comparison of Cytokine and Antibody Responses between Plasma and Serum Samples.

In this study, we evaluated sex differences during infection with mouse-adapted H1N1 and H3N2 influenza A viruses (IAVs) in the C57BL/6J mouse model and compared the cytokine and antibody responses between plasma and serum samples during IAV infection and vaccination. Lethal doses for both H1N1 and H3N2 IAVs were lower for adult females and they suffered with greater morbidity than adult males when infected with sublethal doses. In influenza virus-infected mice, cytokine responses differed between plasma and serum samples. After inactivated influenza virus vaccination and drift variant challenge, adult female mice had greater antibody responses and were better protected. In influenza-vaccinated and challenged mice, binding antibodies were unaffected between paired plasma or serum samples. However, functional antibody assays, including hemagglutination inhibition, microneutralization, and antibody-dependent cellular cytotoxicity assays, were affected by the use of plasma and serum sample types. Our results indicate that careful consideration is required while selecting plasma versus serum samples to measure cytokine and antibody responses during IAV infection and vaccination.

Sex Differences in Time to Initiate Nonsteroidal Anti-Inflammatory Drugs or Biologic Disease-Modifying Antirheumatic Drugs Among Patients With Axial Spondyloarthritis.

We evaluated sex differences in time to initiation of receiving nonsteroidal anti-inflammatory drugs (NSAIDs) or biologic disease-modifying antirheumatic drugs (bDMARDs) among patients with axial spondyloarthritis (axSpA). Using the 2013 to 2018 IBM MarketScan Database, we identified 174,632 patients with axSpA aged ≥18 years. We evaluated the time between axSpA diagnosis and the first prescription NSAID dispensing (among those with no baseline NSAIDs reception) or bDMARDs infusion/procedure claim (among those who were dispensed two or more different prescription NSAIDs in the baseline period). Adjusted hazard ratios (aHRs) for time to initiation of patients receiving NSAIDs or bDMARDs were computed using survival analyses. Cox proportional hazard models estimated associations between sex and predictors of treatment initiation. Average age at diagnosis was 48.2 years, 65.7% were female, and 37.8% were dispensed one or more NSAIDs before axSpA diagnosis. Of those who did not receive two or more different prescription NSAIDs before diagnosis, NSAID reception was initiated earlier in female patients than in male patients (NSAID reception initiators: female patients (32.9%), male patients (29.3%); aHR 1.14, 95% confidence interval [CI] 1.11-1.16). Among those who received two or more different prescription NSAIDs in the baseline period, 4.2% received a bDMARD, whereas 77.9% continued receiving NSAIDs after diagnosis. Time to bDMARD reception initiation was longer for female patients than for male patients (aHR 0.61, 95% CI 0.52-0.72), but bDMARDs were received sooner among those who received NSAIDs in the baseline period. Prescription NSAID reception was more common than initiation of receiving bDMARDs among patients newly diagnosed with axSpA. Female patients appeared more likely to continue receiving NSAIDs after diagnosis, and the time to initiation of receiving bDMARDs was longer for female patients than for male patients.

Gastric emptying is slower in women than men with type 2 diabetes and impacts on postprandial glycaemia.

To evaluate sex differences in gastric emptying and the glycaemic response to a glucose drink and a high carbohydrate meal in type 2 diabetes (T2D). In cohort 1, 70 newly diagnosed, treatment-naïve Chinese patients with T2D (44 men) recruited from a diabetes outpatient clinic ingested a 75-g glucose drink containing 150 mg 13C-acetate. In cohort 2, 101 Australian patients with T2D (67 male) recruited from the community, managed by diet and/or metformin monotherapy, ingested a semi-solid mashed potato meal, labelled with 100 μl 13C-octanoic acid. Breath samples were collected over 3 and 4 h, respectively, for assessment of gastric emptying, and venous blood was sampled for evaluation of glycaemia (with and without adjustment for each participant's estimated total blood volume). Gastric emptying was slower in female than male subjects in both cohorts (both p < .01). Multiple linear regression analyses revealed that gastric emptying was independently associated with sex (both p < .05). Without adjustment for blood volume, the glycaemic responses to oral glucose and the mixed meal were greater in female subjects (both p < .001). However, after adjustment for blood volume, the glycaemic responses were greater in men (both p < .05). Gastric emptying is slower in women than men with T2D, associated with a reduced blood volume-adjusted glycaemic response to oral glucose and a mixed meal in women. These observations highlight the sex difference in postprandial glucose handling, which is relevant to the personalized management of postprandial glycaemia in T2D.

Evaluation of Sex Differences in DNA Methylation and Lung Tissue Gene Expression in a Mouse Model of E-cigarette Exposure

Evaluation of Sex Differences in DNA Methylation and Lung Tissue Gene Expression in a Mouse Model of E-cigarette Exposure

Macrophage Targeted Dendrimer-Tesaglitazar Therapy for Atherosclerosis

Background: Atherosclerosis is a leading contributor to cardiovascular disease, the number one cause of death globally. Although atherosclerosis is clearly a multicellular disease that also affects endothelial cells as well as smooth muscle cells of arteries, it is increasingly recognized as an inflammatory disease. Our goal is to determine if targeting immune cells implicated in atherosclerosis can halt plaque accumulation and resulting derangement of vascular cells in the aorta. Peroxisome proliferator activated receptors (PPARs) within macrophages present a promising therapeutic target as PPAR-α and PPAR-γ agonists have been shown to improve lipid metabolism and inhibit macrophage foam cell formation. However, due to high doses required and associated side effects, clinical translation was halted. We target anti-atherogenic pathways in immune cells using the novel treatment D-Tesa, a dendrimer conjugate of a dual PPAR-α/γ agonist, Tesaglitazar. Methods: 25-week-old, male, apolipoprotein E knockout (ApoE−/−) mice were fed high fat diet (HFD) for 16 weeks to induce atherosclerosis and randomized into two groups: 1) treatment group: D-Tesa for 6 weeks (20μg/kg twice weekly by oral gavage and 2) untreated group. HFD was continued for the duration of the study. Pulse wave velocity (PWV: Doppler), blood pressure (BP: tail cuff on trained, conscious mice), and body weight were monitored. Dendrimer mediated delivery of drug payload to plaque macrophages was studied using D-Cy5, a fluorescently labeled dendrimer, in an atherosclerotic mouse. Aortas were isolated and used for vasoreactivity studies and western blot analysis. THP-1 cell derived foam cells were used to study D-Tesa’s mechanism of action in vitro. Results: Immunofluorescence staining and confocal microscopy revealed that D-Cy5 localized in macrophages within the atherosclerotic plaque in ApoE−/− mice on HFD, indicating that the dendrimer can deliver drugs specifically into the plaque. D-Tesa slowed plaque progression, preserved endothelial function, and decreased arterial stiffness. BP was similar and unchanged between groups. D-Tesa surprisingly decreased body weight, which was the opposite effect observed from the free drug in clinical trials. Western blotting of aorta revealed that D-Tesa treated mice experienced an upregulation of PPAR-α, PPAR-γ, and ABCA1. The in vitro studies with THP-1 derived foam cells confirmed the upregulation of the cholesterol efflux pathway and anti-inflammatory benefit of D-Tesa. Conclusion: D-Tesa offers a novel therapy to ameliorate multiple damaging consequences of atherosclerosis on the cardiovascular system including improvements in plaque burden, endothelial function, arterial stiffness, and body weight in an ApoE−/− model of atherosclerosis. Excitingly, these effects were seen at 2-15 times lower doses despite continued HFD than those reported in literature with a combination of free Tesa and low-fat diet. Thus, D-Tesa offers great translational relevance because of potential reduction in negative side effects and higher patient benefit due to noted lack of compliance with dietary changes in the clinic. Further research is ongoing to evaluate sex differences, dose response, and long-term effects of this highly promising therapy. This work was supported by a NHLBI grant R01HL148112 01 (L.S.) and the Traystman Endowment (S.K.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.