Sex Disparities Research Articles

Sex differences in myocardial infarction care and outcomes: a longitudinal Scottish National Data-Linkage Study.

We investigate sex disparities in management and outcomes of myocardial infarction (MI) in contemporary practice in Scotland. This was a longitudinal cohort study including all MI admissions aged 45-80 years across Scotland between 2010-2016 and 2:1 age, sex, and general practice-matched general population controls. Participants were followed up until the end of 2021. We analysed in-hospital outcomes (percutaneous coronary intervention, secondary prevention and mortality) using Poisson regressions, adjusting for age, comorbidities, and ST-elevation. We used Royston-Parmar models for long-term outcomes (all-cause and cardiovascular mortality, incident cardiovascular events), adjusting for age, comorbidities, and secondary prevention. Of a total 47 063 MI patients, 15 776 (33.5%) were women. Median (inter-quartile range) age was 66 (57, 73) years. Compared to men, women were older and more comorbid, but were less likely to undergo percutaneous coronary intervention [risk ratio (95% confidence interval) - 0.87 (0.86 - 0.89)] or receive secondary prevention at discharge [0.94 (0.93-0.95)]. No in-hospital mortality difference was observed between sexes [1.06 (0.99-1.13) after adjustment]. Over a median follow-up of 8.2 (6.7, 10.1) years, women had higher crude rates of adverse outcomes. After full adjustment, this translated into a lower risk for women compared to men of all-cause mortality [hazard ratio, 0.92 (0.89-0.95)], cardiovascular mortality [0.82 (0.78-0.87)], and cardiovascular events [0.92 (0.88-0.95)]. The female survival advantage seen in general population controls was attenuated in MI patients. Women were undertreated compared to men after MI. Their survival and outcome benefits may be improved further. Poor outcomes in men despite better receipt of secondary prevention require further attention.

Sex differences in treatment strategies for pulmonary embolism in older adults: The SERIOUS-PE study of RIETE participants and US Medicare beneficiaries.

Sex differences exist in risk factors and comorbidities of older adults (aged ⩾ 65 years) with pulmonary embolism (PE). Clinically relevant sex-based treatment disparities for PE have not been adequately addressed. The few existing show conflicting results due to small sample size (type II error) and suboptimal methods (overreliance on p-value, which may detect differences of small clinical relevance). We assessed sex differences in anticoagulation and advanced therapies for PE in older adults, utilizing data from Registro Informatizado Enfermedad TromboEmbolica (RIETE), a large PE registry with predominant participation from Europe, and data from US Medicare beneficiaries. We prespecified a standardized difference (SRD) > 10% as clinically relevant. RIETE included 33,462 (57.7% female) and Medicare included 102,391 (55.0% female) older adults with PE. In RIETE, there were no overall sex differences in the use of anticoagulation (median: 181 vs 180 days, SRD < 1%), fibrinolysis (SRD < 3%), thrombectomy (SRD < 2%), or inferior vena cava (IVC) filters (SRD: 4.4%). However, fibrinolytic therapy (systemic or catheter-based) was less often used in female than male patients with intermediate-risk PE (8.0% vs 12.1%, SRD: 13.6%). No sex differences were noted with advanced PE therapies in Medicare beneficiaries. In unadjusted analyses, fibrinolysis and IVC filter placement were more frequent in Medicare than RIETE participants regardless of sex (p < 0.001). In a predominantly European PE registry and a US study of older adults, there were no overall sex differences in anticoagulation patterns or advanced therapy utilization. Future studies should determine if sex disparities in fibrinolytic therapy for intermediate-risk PE and greater use of advanced therapies in US older adults correlate with clinical outcomes.

Supplemental Material for Sex and Gender Disparities in Health Behaviors and Adherence in Patients Recovering From Percutaneous Coronary Intervention

Supplemental Material for Sex and Gender Disparities in Health Behaviors and Adherence in Patients Recovering From Percutaneous Coronary Intervention

An exploratory study on sex differences in musculoskeletal pain and its associated factors among the Santal indigenous people of West Bengal, India

BackgroundMusculoskeletal pain is a global health concern affecting both sexes. However, recent insights highlighted significant sex differences in its occurrence and experience, which are influenced by various factors. The present study sought to examine sex differences in musculoskeletal pain and, subsequently, explore the factors associated with its occurrence, separately for both adult males and females belonging to the Santal indigenous community.MethodsThe present cross-sectional study was conducted in a Santal indigenous community inhabiting Purba Bardhaman District, West Bengal, India. It comprised 278 adult individuals, including 112 males and 166 females. Data on socio-demographic, lifestyle, anthropometric, reproductive (only for females), and pain-related variables were collected using appropriate tools and protocols.ResultsFemales exhibited a significantly higher incidence of musculoskeletal pain, with nearly half experiencing chronic pain, particularly back pain. Pain intensity and interference of pain were notably higher in females compared to males. Males were less inclined to use treatment for their pain. Hierarchical binary logistic regression revealed that for males, involvement in white-collar jobs showed an inverse association, while engaging in vigorous physical activities demonstrated a positive link with the incidence of musculoskeletal pain. In females, advanced age and a higher number of childbirths were associated with a greater likelihood of experiencing musculoskeletal pain.ConclusionThe study reveals significant sex disparities in musculoskeletal pain concerning its prevalence, severity, interference, and treatment-seeking behavior. Additionally, marked differences were observed in the risk factors contributing to musculoskeletal pain between the sexes. These findings underscore the importance for public health researchers to tailor interventions addressing sex-specific risk factors and experiences, aiming to enhance overall musculoskeletal health and reduce pain-related interference.

Abstract PR003: Sex-dependent changes in the aged melanoma tumor microenvironment influence metastasis and therapeutic responses

Abstract There is documented sex disparity in cutaneous melanoma incidence and mortality, increasing disproportionately with age and in the male sex. However, the underlying mechanisms remain unclear; while biological sex differences and inherent immune response variability have been assessed in tumor cells, the role of the tumor-surrounding microenvironment, contextually in aging, has been overlooked. Dermal fibroblasts are known to have profound impact on melanoma progression. We examined if both sex-dependent and age-related changes in these fibroblasts can alter the course of melanoma tumor growth, visceral metastasis, and responses to therapy. We find that skin fibroblasts undergo age-mediated sex-differential changes in their proliferation, senescence, ROS production and stress response. We find that aged male fibroblasts drive an invasive, therapy-resistant phenotype in melanoma cells and promote metastasis in aged male mice by increasing AXL expression. Intrinsic aging promotes sex- dimorphic BMP2 secretion exclusively by aged male fibroblasts, which in turn drives the slower-cycling, highly invasive, and therapy-resistant melanoma cell phenotype, characteristic of the aged male TME. Inhibition of BMP2 activity blocks the emergence of invasive phenotype and sensitizes melanoma cells to BRAF/MEK inhibition. Our data provide an integrated view of how host factors such as advancing age and biological sex alter the tumor microenvironment and contribute to disease progression. Bridging this knowledge gap will improve patient stratification and assist in tailoring the therapy and achieve gender-equitable healthcare. Citation Format: Yash Chhabra, Ashani T. Weeraratna. Sex-dependent changes in the aged melanoma tumor microenvironment influence metastasis and therapeutic responses [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr PR003.

“A call to action: amplifying the role of men in bridging the gender gap in live kidney donations"- A Letter to the Editor

Dear Editor, We are writing this letter to expound upon an underreported and rarely talked about issue referencing the gender bias invloving the live kidney donations. That being said, the purpose of this letter is purely to underscore the fact that women are less likely to receive a living donor transplant as compared to men. However, they are more likely to serve as living donors for kidney transplantation. [1] Multiple contributory factors including societal stigmas and cultural biases can be attributed to this approach. The evidence of this sex disparity is much more prominent in south Asian countries where men have a 10 times more likely chance to receive a kidney transplant than women. [2] Apart from the male dominance influenced by the socioeconomic reason, this gender imbalance is difficult to quantify. Many women feel obliged to accept the traditional role to care for sick family members. They are less able to refuse the appeal for help within the family compared to men. This is especially true for mothers and spouses. [3] When it comes to men, documented instance in literature show that men in situations where they needed to donate silently disappear from the scene and only show up once the transplantation is over, leaving the women to step forward in this situation. This, cowardice of men is cemented by a recent story of a 36-year-old man with end- stage renal failure. Although one of his healthy brothers was a perfect match, the burden of the transplant still befelled on their old mother. [4] Kidney donation is an act of altruism and devotion. As evidenced by the statistics, the local literature also have frequently portray that women are the frontrunners in this race, while the men are falling far behind. Here the authors need to make it very clear that our purpose is not to say that all men would react this way, but it is to highlight the huge contrast between men and women stepping up as donors for their families. The primary objective of this letter is to accentuate the importance of enhanced access to care for women requiring transplantation while fostering within the male population a deeper understanding of the myths surrounding organ donation and the vital importance of supporting the women in their lives during such critical moments.

Abstract 4135444: Sex Disparities in Enrollment of Cardiovascular Trials: A Meta-Analysis of ClinicalTrials.gov Listings

Background: Despite increasing recognition of sex differences in the burden of cardiovascular (CV) diseases, women have historically been underrepresented in clinical trials. Aims: The study aimed to systematically quantify the extent of sex disparity in the enrollment of CV trials and explore the annual enrollment trends of women in CV trials. Methods: The analysis included studies that: (1) were registered in ClinicalTrials.gov up to February 2024; (2) were randomized trials involving ≥1 intervention; (3) investigated ≥1 CV condition, as determined by Medical Subject Heading descriptors. The exclusion criteria were: (1) studies without available enrollment information; (2) studies exclusively enrolling men or women; and (3) studies with ≤100 participants. We computed enrollment disparity difference (EDD), defined as the difference between the proportion of women in trial participants and the proportion of women with CV diseases in the general population, based on the Global Burden of Disease estimates matched by country/geographic region and enrollment period. Random-effects meta-analysis was performed to summarize the overall enrollment disparity. Subgroup analysis by trial characteristics was conducted. Meta-regression was used to assess the association of enrollment disparity with the start year of the trials. Results: A total of 1,687 CV trials were identified from 484,781 studies. Among 2,198,317 trial participants for whom sex was reported, 819,570 (37.3%) were women. EDD in CV trials was -0.105 (95% CI, -0.113 to -0.097), indicating that women were under-enrolled by 10.5% (Figure 1). Except for valvular heart disease trials, disparities were evident across other CV disease trials, with the most remarkable under-enrollment of women in peripheral artery disease trials (-0.302 [95% CI, -0.324 to -0.279]). Disparities were more prominent in trials with larger sample sizes, longer study durations, device or procedural interventions, and data monitoring committee oversight (p&lt;0.001 for subgroup differences; Figure 2). There was a significant yet modest improvement in the representation of women over time (increase of 0.0028 [95% CI, 0.0011 to 0.0045] in EDD per start year of trials; p=0.001; Figure 3). Conclusion: Women remain substantially underrepresented in CV trials, particularly in peripheral artery disease trials. The findings underscore the imperative for interventions to mitigate sex inequity in the enrollment of CV trials.

Abstract 4136767: Racial/Ethnic and Sex Disparities in the Outcomes and Treatment of In-Hospital Cardiac Arrest: A Nationwide Analysis From the United States

Background: In-hospital cardiac arrest (IHCA) is associated with significant morbidity and mortality. The relationships of race/ethnicity and sex to outcomes and treatment patterns among patients with IHCA remain poorly understood. Methods: We conducted a retrospective cohort study using the National Inpatient Sample database from 2016 to 2020 to identify adult patients with IHCA and compare in-hospital outcomes stratified by race/ethnicity (White, Black, Hispanic) and sex. The primary outcome was in-hospital mortality. Secondary outcomes included rates of in-hospital procedures. Multivariable logistic regression was used to adjust for potential confounders. Results: Among 207,770 patients with IHCA, 26.6% had ventricular tachycardia/fibrillation (VT/VF) and 73.4% had pulseless electrical activity (PEA)/asystole. In the VT/VF subgroup, Black males (aOR 1.42, 95% CI 1.21-1.66), Black females (aOR 1.25, 95% CI 1.05-1.50), and Hispanic females (aOR 1.30, 95% CI 1.01-1.66) had higher odds of mortality compared to White males (Figure 1). In the PEA/asystole subgroup, Black males (aOR 1.25, 95% CI 1.11-1.39) and Hispanic males (aOR 1.22, 95% CI 1.07-1.40) had higher odds of mortality, while White females had lower odds (aOR 0.88, 95% CI 0.82-0.94) compared to White males (Figure 2). Black patients were less likely to receive percutaneous coronary intervention (aOR 0.53, 95% CI 0.43-0.66 for males; aOR 0.54, 95% CI 0.42-0.69 for females) and coronary artery bypass grafting (aOR 0.50, 95% CI 0.30-0.82 for males; aOR 0.47, 95% CI 0.27-0.81 for females) compared to White males in VT/VF arrests. Additionally, Black males had the highest adjusted odds of renal replacement therapy in VT/VF arrests (aOR 1.47, 95% CI 1.21-1.80), while Hispanic males had the highest adjusted odds in PEA/asystole arrests (aOR 1.49, 95% CI 1.27-1.74) compared to White males. The remaining outcomes of interest in both VT/VF and PEA/asystole arrests are shown in Figure 1 and Figure 2 respectively. Conclusion: Significant racial/ethnic and sex disparities exist in outcomes and treatment patterns among patients with IHCA, with differences observed in both VT/VF and PEA/asystole subgroups. Targeted efforts and further studies are needed to better understand and address these disparities and improve outcomes in these severely ill patients.

Abstract 4121359: Heart Disease and Heart Failure: Trends and Disparities in Mortality Rates in the United States from 2000 to 2020

Background: The remarkable decline in the overall prevalence and mortality rates of cardiovascular diseases (CVD) in the United States (US) over the past few decades has not been consistent across all age groups, sexes, races, and types of cardiovascular diseases. Heart disease (HD) and heart failure (HF) still pose a significant burden to the healthcare system. Objectives: This study sought to describe the age, sex and racial disparities in the trends in mortality rates for these two outcomes in the US over the past two decades. Methods: This was an ecological study with trend analysis of the mortality from heart disease and heart failure in the US between 2000 and 2020. Data on CVD was obtained from the National Centers for Disease Control and Prevention (CDC) surveillance databases and analyzed. Binomial regression models were used to evaluate trends in outcomes. Statistical significance was considered for p-values &lt; 0.05. Results: There was a significant decrease in the age-standardized mortality for HD over the past two decades (from 343.5 per 100,000 cases to 215.1 per 100,000 cases (p&lt;0.001)). Mortality rates were significantly higher in males (p&lt;0.001, R2 = 0.92), non-Hispanic blacks (p&lt;0.001) and non-Hispanic whites (p&lt;0.001) compared to Hispanics, (R2 = 0.94) and in adults aged 65+ (p&lt;0.001) and 75+ (p&lt;0.001) (R2 = 0.98). There was no significant decrease in the age-standardized mortality for HF (from 26.9 per 100,000 cases to 25.7 per 100,000 cases (p=0.706)) due to a reversal in the trend after 2011. Though the rates were significantly lower in males overall (p=0.001, R2 = 0.27), these rates became higher in males and in non-Hispanic Blacks compared to non-Hispanic Whites beyond 2016. Mortality rates due to HF were highest in the 65+ and 75+ age groups. Conclusions: This study on national trends in heart disease and heart failure across age groups, sexes and races over the past two decades confirmed a significant reduction in heart disease mortality rates over this period, but with persistent disparities between males and females, non-Hispanic Blacks and other races and the older age groups. This study also highlights important reversals of heart failure mortality rates trends in more recent years in males and females, and non-Hispanic Blacks and Whites, the reasons for which are amenable to further research.

Abstract 4124005: Sex, ethnic and social determinants of health differences in high-potency P2Y12 inhibitors prescription among patients with acute coronary syndrome: An analysis of the American Heart Association Get With The Guidelines®–Coronary Artery Disease Registry

Background: Sex and racial differences in the outcomes of patients with acute coronary syndrome (ACS) persist and could be related to the differences in management including high-potency P2Y12 inhibitors. Aim: This study aims to examine the contribution of social determinants of health on the association between sex and racial differences in the prescription of high-potency P2Y12 inhibitor upon discharge. Methods: Patients with ACS undergoing percutaneous coronary intervention (PCI) from the American Heart Association Get With The Guidelines®–Coronary Artery Disease Registry between October 2019 to December 2022 were included. Multivariable hierarchical models were used to assess whether there are differences in high-potency P2Y12 inhibitors (i.e., ticagrelor or prasugrel) prescription at discharge adjusting for race/ethnicity, insurance, age, social vulnerability index (SVI), zip code designation, and medical history. Analyses were performed in women and men separately. Results: Among 135,153 patients with ACS who underwent PCI, 59.8% were discharged on a high-potency P2Y12 inhibitor. Compared with men, women were less likely prescribed high-potency P2Y12 inhibitor (66.9% vs 72%), and this pattern did not change during the study period (P=0.50) (Figure). There was a significant interaction between sex and race for high-potency P2Y12 inhibitor prescription (P&lt; 0.05). Among women, the likelihood of high-potency P2Y12 inhibitors prescription was not significantly different across different race/ethnicities. However, in men, non-Hispanic Blacks and Hispanics had lower odds of high-potency P2Y12 inhibitors prescription compared with non-Hispanic Whites among men after adjusting for all covariates. Conclusions: In this large contemporary observational analysis of patients with AMI undergoing PCI, women were less likely prescribed a high-potency P2Y12 inhibitor upon discharge. Among women, the likelihood of high-potency P2Y12 inhibitors prescription was not significantly different across different race/ethnicities; however, in men, non-Hispanic Blacks and Hispanics had lower odds of high-potency P2Y12 inhibitors prescription. Further efforts should be directed to minimize these sex and racial disparities.

Abstract 4117640: Thirty-Year Prevalence and Prognosis of the Cardiovascular-Kidney-Metabolic Syndrome in U.S. Females and Males

Background: The American Heart Association recently published guidelines on how to clinically identify and categorize individuals with cardiovascular-kidney-metabolic (CKM) syndrome. The extent to which CKM syndrome prevalence and prognosis differ by sex remain unknown. This study aimed to examine the impact of sex on trends in prevalence over 30 years and long-term prognosis of the CKM syndrome in the US. Methods: We analyzed nationally representative NHANES 1988-2018 data collected from 33,868 US adults (age ≥20 years) who were under surveillance for all-cause mortality through December 31, 2019. We examined sex-specific prevalence of CKM syndrome, and sex-specific CKM associations with all-cause mortality. Results: Of the 33,868 adults studied, the mean±SD age was 48.4±18.3 years with 52% female and 56% non-White. Overall prevalence of CKM syndrome increased steadily from 1988 to 2018 in both sexes, with a larger temporal rise in prevalent Stage 3 CKM seen for males (from 18.9% to 22.4%) compared to females (from 13.9% to 15.2%) ( Figure 1 ). Over a median follow-up of 13.3 years, there were 8745 deaths. In multivariable cox-regression analysis, worsening CKM severity was associated with all-cause mortality (P&lt;0.001 for both sexes), with greater magnitudes of risk seen in females (HR=1.24 to 3.33) compared to males (HR=0.85 to 2.60) across all stages (LRT χ 2 =19.0, P interaction &lt;0.001); results were similar for cardiovascular mortality (LRT χ 2 =22.3, P interaction &lt;0.001) ( Table 1 ). Conclusions: Females, compared with males, exhibited a lower prevalence of CKM stage 3 but experienced excess mortality risk across the spectrum of multi-system CKM dysfunction. These findings underscore the importance of identifying mechanisms underlying joint cardiovascular, renal, and metabolic systems pathophysiology to close a potentially widening sex disparities gap in multi-organ disease risk.

Racial/Ethnic and Sex Disparities in the Outcomes and Treatment of In-Hospital Cardiac Arrest: A Nationwide Analysis From the United States.

In-hospital cardiac arrest (IHCA) is associated with significant morbidity and mortality. The relationships of race/ethnicity and sex to outcomes and treatment patterns among patients with IHCA remain poorly understood. We conducted a retrospective study using the National Inpatient Sample (NIS) database from 2016 to 2020 to identify adult patients with IHCA and examine associations between in-hospital outcomes and race/ethnicity (White, Black, Hispanic) and sex. The primary outcome was in-hospital mortality. Secondary outcomes included rates of in-hospital procedures. Multivariable logistic regression analysis was used to adjust for potential confounders. Among 207,770 patients with IHCA, 26.6% had ventricular tachycardia/fibrillation (VT/VF) and 73.4% had pulseless electrical activity (PEA)/asystole. For VT/VF arrest, Black males (aOR 1.42, 95% CI 1.21-1.66), Black females (aOR 1.25, 95% CI 1.05-1.50), and Hispanic females (aOR 1.30, 95% CI 1.01-1.66) had higher odds of mortality compared to White males (corresponding adjusted risk ratios (aRRs): 1.10 (CIs 1.06-1.14), 1.06 (1.02-1.11), and 1.08 (1.01-1.14), respectively). In the PEA/asystole arrest subgroup, Black males (aOR 1.25, 95% CI 1.11-1.39) and Hispanic males (aOR 1.22, 95% CI 1.07-1.40) had higher odds of mortality (corresponding aRRs 1.04 (1.02-1.06) and 1,04 (1.01-1.06), respectively). Black patients with IHCA were less likely to receive percutaneous coronary intervention, coronary artery bypass grafting, and mechanical circulatory support compared to White males. Significant racial/ethnic and sex disparities exist in outcomes and treatment patterns among patients with IHCA. Targeted efforts and further studies are needed to better understand and address these disparities and improve outcomes.

IMMU-64. SEX-SPECIFIC ROLES OFYAP1 AND CD276/B7-H3 IN MEDULLOBLASTOMA IMMUNE SUPPRESSION

Abstract The molecular mechanism governing sex disparities in cancer prevalence, progression, and treatment outcomes represents an important yet understudied area of research with significant implications for cancer treatment. Medulloblastoma (MB), the most prevalent pediatric brain malignancy, exhibits a notable sex bias in incidence and survival rates. Males have a higher incidence rate across all age groups and have worse prognoses than their females for age groups over three years old. Here, we report an unanticipated sex-biased role of the oncogene Yap1 in SHH medulloblastoma. Our results reveal that Yap1 deletion significantly prolongs survival in male, but not female mice with SmoM2-driven SHH MB. Employing an integrated multi-omics approach, we demonstrate that YAP1 is required to maintain cancer stem cells simultaneously activating stemness genes (such as Sox2) and repressing differentiation genes (such as Neurod1 and Zic1/2) in both sexes. In contrast, Yap1 plays a more critical role in immune evasion in males than in females. Specifically, YAP1 regulates the expression of the immune checkpoint molecule Cd276/B7-H3, which suppresses cytotoxic T cell function. In males, CD276 blockade or Yap1 deletion in MB cells is enough to reverse T cell suppression effectively. In females, neither CD276 blockade nor Yap1 deletion alone in MB cells can reverse T cell suppression. Furthermore, YAP1’s direct transcriptional target gene signatures, including CD276, predict survival across multiple human cancers in male patients. These findings suggest broader implications of our findings beyond medulloblastoma and indicate a highly conserved mechanism across species. Our study provides compelling evidence for the male-biased efficacy of Yap1 or CD276 inhibitors and presents novel insights into sex-specific mechanisms of cancer immune evasion.

Quantifying the Strain: A Global Burden of Disease (GBD) Perspective on Musculoskeletal Disorders in the United States Over Three Decades: 1990-2019.

Background: Musculoskeletal (MSK) disorders significantly contribute to global disability, especially in high-income countries. Yet, comprehensive studies on their epidemiological burden in the United States (US) are limited. Our study aims to fill this gap by characterizing the MSK disease burden in the US using Global Burden of Disease (GBD) data from 1990 to 2019. Methods: We conducted an ecological study using descriptive statistical analyses to examine age-standardized prevalence and disability-adjusted life years (DALY) rates of MSK disorders across different demographics and states. The study also assessed the impact of risk factors segmented by age and sex. Results: From 1990 to 2019, the burden of MSK disorders in the US increased significantly. Low back pain was the most prevalent condition. Age-standardized prevalence and DALY rates increased by 6.7% and 17.6%, respectively. Gout and other MSK disorders saw the most significant rise in DALY rates. Females experienced higher rates than males, and there were notable geographic disparities, with the District of Columbia having the lowest and North Dakota and Iowa the highest DALY rates. Smoking, high BMI, and occupational risks emerged as primary risk factors. Conclusions: Our study highlights the escalating burden of MSK disorders in the US, revealing significant geographic and sex disparities. These findings highlight the urgent need for targeted health interventions, policy formulation, and public health initiatives focusing on lifestyle and workplace modifications. Region- and sex-specific strategies are crucial in effectively managing MSK conditions, considering the influence of various risk factors.

A case-control study of reaction time deficits in a 3D virtual reality in patients with Post-COVID syndrome

Following the Coronavirus disease 2019 (COVID-19) pandemic, a large number of people continue to report Post-COVID symptoms (PCS). A wide variety of symptoms are described, including fatigue, post-exertional malaise and cognitive impairment. However, adequate objective diagnostic tests for PCS are not yet available. Since the neurotropism of SARS-CoV-2 could be a possible factor for cognitive impairment, the aim of this study was to clarify whether visual reaction time (RT) in a stereoscopic setting can be a marker in PCS diagnostics. The Virtual-Reality-Oculomotor-Test-System (VR-OTS) was used testing binocular vision in 9 gaze directions via stereoscopic stimuli displayed in a virtual reality (VR)-environment (disparity: 275″, 550″, 1100″) in 179 individuals: 130 patients with PCS and 49 healthy controls. The results from the generalized linear models indicated that both group membership (PCS vs. control) and covariates (age and sex) yielded statistically significant different RT across the models. Accounting for the effect of covariates a statistically significant difference of RT was observed between patients with PCS and controls (disparity 275″ p-value = 0.001; 550″ p-value = 0.001; 1100″ p-value = 0.003). Patients with PCS performed worse in RT in all gaze directions, respectively. Adjusting for the influence of covariates, correct responses (CR) differed significantly between patients with PCS and controls (disparity 275″ p-value < 0.001; 550″ p-value = 0.003; 1100″ p-value = 0.019). Statistically significant effects of covariates on RT were observed for sex (disparity 275″ p-value = 0.047; 550″ p-value = 0.012; 1100″ p-value = 0.005) and age (disparity 275″ p-value < 0.001; 550″ p-value < 0.001; 1100″ p-value < 0.001). However, regarding covariates, no significant effects were found for CR, except for age at disparity 275″ (p-value = 0.035). The present data suggested that the mentioned variables uniquely contributed to explain the variation of the response variable (RT, CR). RT and CR detecting 3D-stimuli in a virtual 3D- environment might offer novel functional diagnostic approaches in PCS.

Sex disparities in outcomes among hospitalizations for heart failure

This study investigated sex differences in clinical characteristics and in-hospital outcomes of heart failure (HF) hospitalizations using the National Inpatient Sample data, 2016–2019. HF hospitalizations ≥ 41 years of age were included and stratified by sex. Study outcomes were in-hospital mortality, prolonged length of stay, mechanical ventilation, mechanical circulatory support, vasopressor use, and disposition other than home. Propensity score matched regression analysis was done to compare outcomes between sex. A total of 4,704,684 primary HF hospitalizations were included in the analysis. Of these, 2,447,784 (52.0%) were males and 2,256,899 (48.0%) were females. Regression analysis showed that females had significantly lower odds for mortality (aOR, 0.92, 95% CI: 0.89–0.94), mechanical ventilation (aOR, 0.89, 95% CI: 0.86–0.92), mechanical circulatory support (aOR, 0.54, 95% CI: 0.51–0.58), and vasopressor use (aOR, 0.71, 95% CI: 0.66–0.74), compared to males. However, the odds for prolonged length of stay (aOR, 1.05, 95% CI: 1.04–1.06) and disposition other than home (aOR, 1.32, 95% CI: 1.31–1.34) were significantly higher among females, compared to males. There were significant differences in outcomes between males and females hospitalized for HF. Further research is required to delineate how sex affects several aspects of HF, including epidemiology, risk factors, pathogenesis, and response to medications.

Sex Disparities in Cancer Immunotherapy: A Review

Cancer immunotherapy has revolutionized cancer treatment, particularly through immune checkpoint inhibitors (ICIs) targeting proteins like PD-1, PD-L1, and CTLA-4. While these therapies have shown significant survival benefits across various cancers, sex-based disparities in treatment response and outcomes have emerged. This review explores the mechanisms behind these differences, focusing on genetic, hormonal, and immune system variations between male and female patients. Women tend to exhibit stronger immune responses due to the presence of two X chromosomes and the immunostimulatory effects of estrogen, which enhances immune activity. Conversely, men’s single X chromosome and the immunosuppressive effects of testosterone contribute to a less vigorous immune response. These biological differences manifest in clinical outcomes, with men generally experiencing better overall survival rates from ICIs, while women are more prone to immune-related adverse events (irAEs), including autoimmune toxicities. However, in certain cases, women may demonstrate more robust long-term survival benefits from treatments such as CTLA-4 inhibitors, despite higher toxicity risks. Beyond ICIs, sex disparities also extend to adoptive cell therapies (ACT) and cancer vaccines, where female patients often display stronger immune responses but face increased risks of side effects, necessitating personalized approaches to therapy. The review also discusses emerging research on the tumor microenvironment (TME), gut microbiome, and sex-specific pharmacokinetics and pharmacodynamics as contributing factors to these disparities. Understanding these mechanisms is critical for improving cancer immunotherapy outcomes for both sexes. Future research should focus on investigating the role of sex hormones, the microbiome, and developing biomarkers to better predict responses to immunotherapy. Clinically, the findings highlight the need for tailored treatment strategies that account for sex-specific differences, aiming for more equitable and effective cancer care. Keywords: Cancer immunotherapy, Immune checkpoint inhibitors (ICIs), Sex-based disparities, PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors

Estrogen receptors regulate sex disparity in the immune responses during zebrafish liver regeneration following partial hepatectomy

Immune responses play crucial roles in liver regeneration following partial hepatectomy (PH). Previous studies using the rodent PH models have shown that liver regeneration following PH has sex disparity. However, the sex disparity in the immune responses to PH and its relationship with sex-biased liver regeneration has not been investigated yet. In the current study, we applied the zebrafish PH model to study these issues and found that male zebrafish have earlier immune responses than female zebrafish following PH. By depleting macrophages before PH, we confirmed that liver regeneration following PH in zebrafish requires the participation of macrophages. In addition, activation of estrogen receptors inhibited the upregulation of inflammatory factors in male livers and reduced hepatocyte proliferation at the early stage of PH-induced liver regeneration. Therefore, the male-biased liver regeneration and immune responses in zebrafish following PH could be regulated by estrogen receptor activities.

Somatic mutational landscape reveals mutational signatures and significantly mutated genes of cancer immunotherapeutic outcome and sex disparities.

Currently developed molecular markers can predict the effectiveness of cancer immunotherapy and screen beneficiaries to some extent, but they are not stable enough. Therefore, there is an urgent need for discovering novel biomarkers. At the same time, sex factor plays a vital role in the response to immunotherapy, so it is particularly important to identify sex-related molecular indicators. We integrated a pan-cancer cohort consisting of 2348 cancer patients who received immune checkpoint inhibitors and targeted sequencing. Using somatic mutation profiles, we identified mutational signatures, molecular subtypes, and frequently mutated genes, and analyzed their relationships with immunotherapeutic outcomes. We also explored sex disparities of determined biomarkers in response to treatments. We found that male patients exhibited better immunotherapy outcomes and higher tumor mutational burden. A total of seven mutational signatures were identified, among which signatures 1 and 3 were associated with worse immunotherapy outcomes, while signatures 2 and 6 correlated with better outcomes. Gender-based analysis revealed that mutational signature 1 continued to show a worse immunotherapy outcome in female patients, whereas signature 6 demonstrated a better outcome in male patients. Based on mutational activities, we identified four potential molecular subtypes with gender differences and relevance to treatment outcomes. PI3K-AKT, RAS signaling pathways, and 68 significantly mutated genes were identified to be associated with immunotherapy outcomes, with nine genes (i.e., ATM, ATRX, DOT1L, EP300, EPHB1, NOTCH1, PBRM1, RBM10, and SETD2) exhibiting gender differences. Finally, we discovered co-mutated gene pairs and TP53 p.R282W mutations related to treatment outcomes, highlighting their gender-specific differences. This study identified several molecular biomarkers related to cancer immunotherapy outcomes in terms of mutational signatures, molecular subtypes, and mutated genes, and explored their gender-relatedness in order to provide clues and basis for clinical treatment efficacy evaluation and patient selection.

Sex differences in tobacco use, attempts to quit smoking, and cessation among dual users of cigarettes and e-cigarettes: Longitudinal findings from the US Population Assessment of Tobacco and Health Study

SignificanceA growing number of adults use more than one tobacco product, with dual use of cigarettes and e-cigarettes being the most common combination. Monitoring sex disparities in tobacco use is a public health priority. However, little is known regarding whether dual users differ by sex. MethodsData came from Waves 4–6 (12/2016–11/2021) of the Population Assessment of Tobacco and Health Study, a US nationally-representative longitudinal survey. This analysis included current adult dual users of cigarettes and e-cigarettes. We used weighted generalized estimating equations to assess the association between sex and (1) making a cigarette quit attempt (n = 1882 observations from n = 1526 individuals) and (2) smoking cessation (n = 2081 observations from n = 1688 individuals) across two wave pairs, adjusting for age, education, ethnicity, time-to-first cigarette after waking, and e-cigarette use frequency. ResultsAmong US dual users, 14.1% (95% Confidence Intervals [Cl] = 11.9–16.4) of females and 23.4% (20.0–26.9) of males were young adults (aged 18–24), 11.7% (9.2–14.2) of females and 14.4% (11.6–17.2) of males had <high school education, and 82.2% (79.4–84.5) of females and 78.7% (75.1–82.4) of males were white. Overall, 44.9% (41.6–48.1) of females compared with 37.4% (33.5–41.3) of males made an attempt to quit smoking between a baseline and follow-up wave (Adjusted Risk Ratio [ARR] = 1.23, 1.05–1.45). In contrast, there were no apparent differences between females (22.1%, 19.0–25.2) and males (24.3%, 21.5–27.1) in smoking cessation (ARR = 1.06, 0.84–1.35). ConclusionUS females who dually use e-cigarettes and cigarettes were more likely to attempt to quit smoking, but not more likely to succeed at quitting, than males.