Judith G. Regensteiner

The Ludeman Family Center for Women’ s Health Research (Ludeman Center) at the University of Colorado ( cwhr@ucdenver.edu ) organized its 4th National Conference at The Broadmoor Hotel in Colorado Springs, CO. The research presentations and discussions from the three-day October 2024 conference addressed sex differences across the life span with a focus on cardio-metabolism and mental health. Over one hundred thirty participants, including scientists, clinicians, policy makers, advocacy group leaders and federal agency representatives participated in the meeting. In this manuscript, we briefly summarize the conference scientific presentations made at the 2024 meeting which were organized into 3-day sessions as well as poster sessions.

This study aimed to assess the impacts of overweight and type 2 diabetes (T2D) on early hemodynamic and left ventricular (LV) changes using comprehensive c

Background: Type 2 diabetes (T2D) is associated with reduced cardiorespiratory fitness (CRF), a critical predictor of cardiovascular disease and all-cause mortality. CRF relies upon the coordinated action of multiple systems including the skeletal muscle where the mitochondria metabolize oxygen and substrates to sustain ATP production. Yet, previous studies have shown that impairments in muscle bioenergetics in T2D are not solely due to mitochondrial deficits. This finding indicates that factors outside the mitochondria, particularly within the local tissue microenvironment, may contribute to reduced CRF. One such factor is the extracellular matrix (ECM), which plays structural and regulatory roles in metabolic processes. Despite its potential regulatory role, the contribution of ECM remodeling to metabolic impairment in T2D remains poorly understood. We hypothesize that pathological remodeling of the skeletal muscle ECM in overweight individuals with and without T2D impairs bioenergetics and insulin sensitivity, and that exercise may help to ameliorate these effects. Methods: Participants with T2D (n = 21) and overweight controls (n = 24) completed a 10-day single-leg exercise training (SLET) intervention. Muscle samples obtained before and after the intervention were analyzed for ECM components, including collagen, elastin, hyaluronic acid, dystrophin, and proteoglycans, using second harmonic generation imaging and immunohistochemistry. Results: Positive correlations were observed with elastin content and both glucose infusion rate (p = 0.0010) and CRF (0.0363). The collagen area was elevated in participants with T2D at baseline (p = 0.0443) and showed a trend toward reduction following a 10-day SLET (p = 0.0867). Collagen mass remained unchanged, suggesting differences in density. Dystrophin levels were increased with SLET (p = 0.0256). Conclusions: These findings identify that structural proteins contribute to aerobic capacity and identify elastin as an ECM component linked to insulin sensitivity and CRF.

Introduction: Diabetes mellitus (DM) is increasingly recognized as a possible consequence of statin therapy. Secondary analysis of randomized clinical trials and limited observational cohort analyses have suggested that women may be more likely than men to experience statin-associated DM. No analyses of real-world drug safety data addressing this question have been published.Research design and methods: This was a retrospective pharmacovigilance analysis of spontaneously reported adverse drug events (ADEs) submitted to the Food and Drug Administration Adverse Event Reporting System between January 1997 through December 2023. We analyzed cases that mentioned atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin in aggregate as well as cases reporting atorvastatin, pravastatin, rosuvastatin, simvastatin individually. DM events were identified using the Medical Dictionary for Regulatory Activities. We used the proportional reporting ratio to identify increased rates of statin-associated DM events in women and men compared with all other medications, and the reporting OR to compare reporting rates in women versus men.Results: A total of 18,294,814 ADEs were reported during the study period. Among statin-associated ADEs, 14,874/519,209 (2.9%) reports mentioned DM in women compared with 7,411/489,453 (1.5%) in men, which were both significantly higher than background (0.6%). Statins were the primary-suspected or secondary-suspected cause of the ADE significantly more often in women than men (60 vs 30%), and reporting rates were disproportionately higher in women than in men for all statins. (reporting OR 1.9 (95% CI 1.9 to 2.0)). The largest difference in reporting of statin-associated DM between women and women was observed with atorvastatin.Conclusions: Analysis of post-marketing spontaneous ADE reports demonstrated a higher reporting rate of DM-associated with statin use compared with other medications with a significantly higher reporting rate in women compared with men. Future studies should consider mechanisms of statin-associated DM moderated by sex.

JBJS convened a symposium to discuss the reporting of sex and gender in research studies as an imperative to improve research methods and results to benefit all patients. Barriers to improved reporting include a lack of societal and cultural acceptance of its need; a lack of education regarding appropriate terminology and appropriate statistical methods and efficient study designs; a need for increased research funding to support larger group sizes; unknown concordance of cell and animal models with humans to reflect biologic variables such as sex; and a lack of understanding of key considerations of gender, race, and other social determinants of health and how these factors intersect. Attention to developing and disseminating best-practice statistical methods and to educating investigators (at all career levels), reviewers, funders, editors, and staff in their proper implementation will aid reporting. Concomitantly, well-designed studies with sufficient rigor and adequate resources are essential to enable meaningful and reproducible research. Existing recommendations, such as the Sex and Gender Equity in Research (SAGER) guidelines, provide valuable guidance that can be applied across the research ecosystem. Academic institutions and private foundations are likely groups to assist in scientific and institutional review board guidance and study recruitment and pilot funding to generate meaningful power estimates, and to serve as sources for additional funding and presentation of workshops, educational events, and seminars. All of this needs to be conducted on an ongoing basis to ensure that sex and gender are considered in scientific analyses, where relevant.

Until recently, sex differences in human health (defined as a set of biological attributes associated with physical and physiological features “including

➢ Sex-based differences are understudied, which has potential consequences for the health of everyone. ➢ Women’s health is particularly affected given a lack of sex-specific data across many disease states. ➢ Journals do not consistently require the inclusion of both sexes and the disaggregation of data by sex in cell, animal model, and human studies. ➢ Instructions for investigators and journals regarding the inclusion of sex-specific data are found in guidelines such as those by the Sex and Gender Equity in Research (SAGER) group, but these guidelines are underutilized. ➢ Consistency in the inclusion of both sexes in studies (except in studies on diseases affecting only 1 sex), as well as in the disaggregation and reporting of results by sex, has the potential to improve health for all people.

Objective Determine whether statin-associated DM is reported more frequently in women than men in post-marketing adverse drug event (ADE) surveillance. Design Retrospective pharmacovigilance analysis Data source Publicly available FDA Adverse Event Reporting System (FAERS) from January 1997 through December 2023. Setting Real-world spontaneously reported ADEs in the United States. Participants Community patients reporting statin ADEs during the study period. Interventions/exposures Adverse drug event reports that included at least one statin. Main outcome measures Proportional reporting ratio to identify increased rates of statin-associated DM events in women and men compared with all other medications, and reporting odds ratio to compare reporting rates in women vs. men. Results A total of 18,294,814 ADEs were reported during the study period. Among statin-associated ADEs, 14,897/519,209 (2.9%) reports mentioned DM in women compared with 7,412/489,453 (1.5%) in men, which were both significantly higher than background (0.6%). Statins were primary-or secondary-suspected cause of the ADE significantly more often in women than men (59.8 vs. 28.7%), and reporting rates were disproportionately higher in women than in men for all statins. (reporting odds ratio 1.9 [95% CI 1.9-2.0]). The largest difference in reporting of statin-associated DM between women and women was observed with atorvastatin. Conclusions Analysis post-marketing spontaneous ADE reports demonstrated a higher reporting rate of DM-associated with statin use compared to other medications with a significantly higher reporting rate in women compared to men. Future studies should consider mechanisms of statin-associated DM moderated by sex.