Understanding Of Sex Differences Research Articles

Sex differences in transradial access failure in ST segment elevation myocardial infarction.

Transradial access (TRA) is now the default access site for PPCI, but technically is a more challenging approach mostly due to anatomic challenges connected to the RA. To assess the differences according to sex in radial artery (RA) access site characteristics during primary percutaneous coronary intervention (PPCI) for ST segment elevation myocardial infarction (STEMI). All 5092 consecutive STEMI patients from our center in the period from March 2011 until December 2017 were examined. The right proximal radial was the "intention-to-treat" access in all patients. Preprocedural RA angiography was performed in all patients. Clinical and procedure characteristics, type of radial anatomy variants, need to use another arterial access sites (the primary endpoint for this study), and procedure time were analyzed by sex. Using logistic regression, we selected predictors of radial crossover. Access site bleeding complications and vascular complications were also recorded. The STEMI population in this period included 1326 females and 3766 male patients. Females were older (65 ± 11 years) than males (59 ± 11 years, p < 0.0001). Among standard risk factors, hypertension and diabetes mellitus were more common in women and smoking less common. RA anomalies were more frequent in the females (8.8% vs. 6.5%, p < 0.0001), with complex RA loop and tortuous RA twice as frequent in women. Failure of TRA access as the initially chosen site occurred in 4.6% (61) of females versus 2.5% (97) of male STEMI patients (p = 0.0003). The most common subsequent access site was right ulnar access in both groups (57 and 61% respectively). Access site bleeding complications were more common in women 4.4% versus 3.2%, mirrored in hematomas with EASY score III to V. Clinical RA spasm (RAS) was significantly more frequent in females (5.7% vs. 2.2%, p < 0.0001). Multiple regression analysis identified 5 independent predictors for TRA access crossover: previous TRA, anomalous RA, RAS, along with female sex and diabetes. Female sex is a significant predictor of more complex TRA in STEMI. Understanding sex differences and predictors for TRA crossover will strengthen the use of different procedural modalities that can help in preserving a successful wrist access in female STEMI patients.

Association Between Obesity and Risk of Total and Obesity-Related Cancer in People With Incident Cardiovascular Disease.

Cardiovascular disease (CVD) and cancer frequently co-occur due to shared risk factors such as obesity, which is linked to CVD and 14 cancer types. This study explores whether CVD pathophysiologies, combined with obesity, increase cancer risk, impacting clinical management. Data from the ARIC (Atherosclerosis Risk in Communities) study, spanning 28 years, were analyzed. The cohort included 5127 participants with incident CVD (myocardial infarction, stroke, heart failure, coronary heart disease), of whom 1511 developed a first primary cancer. Follow-up began at CVD diagnosis after Visit 1. Obesity was assessed using body mass index, waist circumference, and waist-to-hip ratio. Incidence rate differences between obesity groups were adjusted for age, sex, and center, whereas the obesity-cancer association was estimated using Fine-Gray regression adjusted for shared risk factors including smoking. Cancer incidence in obese individuals with CVD (body mass index: rate differences=226.6/100 000 person-years) was higher than in those with normal weight. Although obesity was not linked to overall cancer after adjusting for shared risk factors, it was nominally associated with obesity-related cancers. Specifically, women with CVD and obesity had increased obesity-related cancer risk (body mass index: hazard ratio, 1.67 [95% CI, 1.17-2.31]). No significant associations were found in men, even after excluding prostate cancer. This study suggests that obesity is linked to higher obesity-related cancer risk in women with incident CVD, independent of shared risk factors. Further research is needed to eliminate residual confounding, understand sex differences, and explore how CVD pathophysiologies and obesity together influence cancer risk.

Evaluating the role of sex-related structure-function differences on airway aerosol transport and deposition.

Several experimental studies have found that females have higher deposition of particles in the airways compared with males. This has implications for the delivery of aerosolized therapeutics and for understanding sex differences in respiratory system response to environmental exposures. This study evaluates several factors that potentially contribute to sex differences in particle deposition, using scale-specific structure-function models of 1D ventilation distribution, particle transport, and deposition. The impact of gravity, inhalation flow rate, and dead space are evaluated in 12 structure-based models (seven female; five male). Females were found to have significantly higher total, bronchial, and alveolar deposition than males across a particle size range from 0.01 to 10 . Results suggest that higher deposition fraction in females is due to higher alveolar deposition for smaller particle sizes, and higher bronchial deposition for larger particles. Females had higher alveolar deposition in the lower lobes, and slightly lower particle concentration in the left upper lobe. Males were found to be more sensitive to changes due to gravity, showing greater reduction in bronchial deposition fraction. Males were also more sensitive to change in inhalation flow rate, and to scaling of dead space due to the larger male baseline airway size. Predictions of sex differences in particle deposition - that are consistent with the literature - suggest that sex-based characteristics of lung and airway size interacting with particle size gives rise to differences in regional deposition.

Understanding sex differences in extinction retention: Pre-extinction stress and sex hormone status

Difficulties in fear regulation can sometimes result in maladaptive fear responses. To better understand how to improve fear regulation, it is important to determine how known factors, such as sex hormone status and stress, might interact to influence fear memory. Research has shown that women with high estradiol levels (mid-cycle) and men exhibit better extinction retention compared to women with low estradiol levels (women in the early follicular cycle or using oral contraceptives). Stress has also been demonstrated to affect both the learning and retention of extinction. Despite documented interactions between stress and sex hormones, their combined effects have not been thoroughly studied. This study aims to examine the impact of stress as a function of sex hormone status on extinction learning and retention.A total of 168 non-clinical participants were studied, including men (n = 46), women using oral contraceptives (n = 38), women in the early follicular phase (n = 40), and women in mid-cycle (n = 44). On Day 1, fear acquisition training was performed. On day 2, prior to extinction training, half of the participants were exposed to a psychosocial stressor, while the other half performed a non-stressful control task. On day 3, extinction retention was tested. Fear was quantified using skin conductance responses, while stress hormones were quantified through saliva samples.Exposure to stress prior to extinction training did not affect extinction learning, regardless of sex hormone status. In contrast, pre-extinction stress exposure had different effects on extinction retention depending on hormone status. Stressed men showed impairment in extinction retention compared to controls, while the experimental condition had no effect on naturally cycling women. Regardless of stress exposure, early follicular women exhibited a deficit in fear regulation, while mid-cycle women showed effective fear regulation. Among women using oral contraceptives, the stress group demonstrated better extinction retention compared to the control group.These results demonstrate the importance of considering sex hormone status and stress exposure during extinction learning, as both components may modulate extinction retention. These results could help identifying hormonal conditions that may enhance the effectiveness of extinction-based psychological therapies used in the treatment of fear-related disorders.

Operant ethanol self-administration behaviors do not predict sex differences in continuous access home cage drinking

Understanding sex differences in disease prevalence is critical to public health, particularly in the context of alcohol use disorder (AUD). The goal of this study was to understand sex differences in ethanol drinking behavior and define the precise conditions under which sex differences emerge. Consistent with prior work, C57BL/6J females drank more than males under continuous access two-bottle choice conditions. However, using ethanol self-administration - where an operant response results in access to an ethanol sipper for a fixed time period - we found no sex differences in operant response rates or ethanol consumption (volume per body weight consumed, as well as lick behavior). This remained true across a wide range of parameters including acquisition, when the ethanol sipper access period was manipulated, and when the concentration of the ethanol available was scaled. The only sex differences observed were in total ethanol consumption, which was explained by differences in body weight between males and females, rather than by sex differences in motivation to drink. Using dimensionality reduction approaches, we found that drinking behavior in the operant context did not cluster by sex, but rather clustered by high and low drinking phenotypes. Interestingly, these high and low drinking phenotypes in the operant context showed no correlation with those same categorizations in the home cage context within the same animals. These data underscore the complexity of sex differences in ethanol consumption, highlighting the important role that drinking conditions/context plays in the expression of these differences.

Sex differences in discrimination behavior and orbitofrontal engagement during context-gated reward prediction.

Animals, including humans, rely on contextual information to interpret ambiguous stimuli. Impaired context processing is a hallmark of several neuropsychiatric disorders, including schizophrenia, autism spectrum disorders, post-traumatic stress disorder, and addiction. While sex differences in the prevalence and manifestations of these disorders are well established, potential sex differences in context processing remain uncertain. Here, we examined sex differences in the contextual control over cue-evoked reward seeking and its neural correlates, in rats. Male and female rats were trained in a bidirectional occasion-setting preparation in which the validity of two auditory reward-predictive cues was informed by the presence, or absence, of a visual contextual feature (LIGHT: X+/DARK: X-/LIGHT: Y-/DARK: Y+). Females were significantly slower to acquire contextual control over cue-evoked reward seeking. However, once established, the contextual control over behavior was more robust in female rats; it showed less within-session variability (less influence of prior reward) and greater resistance to acute stress. This superior contextual control achieved by females was accompanied by an increased activation of the orbitofrontal cortex (OFC) compared to males. Critically, these behavioral and neural sex differences were specific to the contextual modulation process and not observed in simple, context-independent, reward prediction tasks. These results indicate a sex-biased trade-off between the speed of acquisition and the robustness of performance in the contextual modulation of cued reward seeking. The different distribution of sexes along the fast learning ↔ steady performance continuum might reflect different levels of engagement of the OFC, and might have implications for our understanding of sex differences in psychiatric disorders.

Sex differences in discrimination behavior and orbitofrontal engagement during context-gated reward prediction

Animals, including humans, rely on contextual information to interpret ambiguous stimuli. Impaired context processing is a hallmark of several neuropsychiatric disorders, including schizophrenia, autism spectrum disorders, post-traumatic stress disorder, and addiction. While sex differences in the prevalence and manifestations of these disorders are well established, potential sex differences in context processing remain uncertain. Here, we examined sex differences in the contextual control over cue-evoked reward seeking and its neural correlates, in rats. Male and female rats were trained in a bidirectional occasion-setting preparation in which the validity of two auditory reward-predictive cues was informed by the presence, or absence, of a visual contextual feature (LIGHT: X+/DARK: X−/LIGHT: Y−/DARK: Y+). Females were significantly slower to acquire contextual control over cue-evoked reward seeking. However, once established, the contextual control over behavior was more robust in female rats; it showed less within-session variability (less influence of prior reward) and greater resistance to acute stress. This superior contextual control achieved by females was accompanied by an increased activation of the orbitofrontal cortex (OFC) compared to males. Critically, these behavioral and neural sex differences were specific to the contextual modulation process and not observed in simple, context-independent, reward prediction tasks. These results indicate a sex-biased trade-off between the speed of acquisition and the robustness of performance in the contextual modulation of cued reward seeking. The different distribution of sexes along the fast learning ↔ steady performance continuum might reflect different levels of engagement of the OFC, and might have implications for our understanding of sex differences in psychiatric disorders.

Sex differences in patient-reported outcomes and the association with clinical factors in axial spondyloarthritis patients treated with tumour necrosis factor inhibitors.

To investigate sex differences in patient-reported outcome measures (PROMs) among axSpA patients initiating their first TNFi and identify factors contributing to these disparities over the follow-up. Data were included from 15 EuroSpA registries and consisted of axSpA patients initiating their first TNFi, with ≥2 measurements for each analysed PROM (BASDAI and BASFI, scale 0-100) taken at any time point. Linear mixed models were employed to analyse sex differences in PROMs over 24 months and to evaluate how baseline characteristics were related to the observed sex differences. We analysed 13 102 (38% women) in the BASDAI analyses and 10 623 (38% women) in the BASFI analyses. At follow-up, mean sex differences in BASDAI increased from 4.3 units at baseline (95% CI, 3.5-5.1)-8.0 (7.2-8.8) at 6 months, and in BASFI from 2.2 (1.4-3.1)-4.6 (3.6-5.5), with consistently worse scores in women. Baseline characteristics could not substantially account for the observed sex differences over time; however, the magnitude of the sex differences was reduced by HLA-B27 positivity, longer disease duration, and increased CRP levels, but increased by TNFi initiation in later years and peripheral arthritis. In axSpA patients initiating their first TNFi, baseline sex differences in BASDAI and BASFI increased two-fold after 6 months of treatment and persisted thereafter, with worse scores in women. Several baseline characteristics moderated the sex differences, though none could fully account for them. These findings improve our understanding of sex differences and underscore their importance in axSpA.

Impact of gender in patients with device-related thrombosis after left atrial appendage closure - A sub-analysis from the multicenter EUROC-DRT-registry.

Device-related thrombosis (DRT) is a common finding after left atrial appendage closure (LAAC) and is associated with worse outcomes. As women are underrepresented in clinical studies, further understanding of sex differences in DRT patients is warranted. This sub-analysis from the EUROC-DRT-registry compromises 176 patients with diagnosis of DRT after LAAC. Women, who accounted for 34.7% (61/176) of patients, were older (78.0±6.7vs. 74.9±9.1 years, p=.06) with lower rates of comorbidities. While DRT was detected significantly later in women (173±267vs. 127±192 days, p=.01), anticoagulation therapy was escalated similarly, mainly with initiation of novel oral anticoagulant (NOAC), vitamin K antagonist (VKA) or heparin. DRT resolution was achieved in 67.5% (27/40) of women and in 75.0% (54/72) of men (p=.40). In the remaining cases, an intensification/switch of anticoagulation was conducted in 50.% (9/18) of men and in 41.7% (5/12) of women. Final resolution was achieved in 72.5% (29/40) cases in women, and in 81.9% (59/72) cases in men (p=.24). Women were followed-up for a similar time as men (779±520vs. 908±687 days, p=.51). Kaplan-Meier analysis revealed no difference in mortality rates in women (Hazard Ratio [HR]: 1.73, 95%-Confidence interval [95%-CI]:.68-4.37, p=.25) and no differences in stroke (HR:.83, 95%-CI:.30-2.32, p=.72) within 2 years after LAAC. Evaluation of risk factors and outcome revealed no differences between men and women, with DRT in women being diagnosed significantly later. Women should be monitored closely to assess for DRT formation/resolution. Treatment strategies appear to be equally effective.

Sex Differences in Physiological Responses to a National Collegiate Athletic Association Division I Soccer Season.

McFadden, BA, Walker, AJ, Cintineo, HP, Bozzini, BN, Sanders, DJ, Chandler, AJ, and Arent, SM. Sex differences in physiological responses to a national collegiate athletic association division I soccer season. J Strength Cond Res XX(X): 000-000, 2024-Identifying physiological changes that occur in response to workload demands can help to elucidate athlete management and recovery strategies. The purpose of this study was to compare the physical and physiological demands between men and women throughout the course of a collegiate soccer season. Men (N = 23) and women (N = 26) soccer players participated in blood draws before preseason (T1) and every 4 weeks thereafter (T2-T4). Workload was determined at all practices and games via heart rate and global positioning satellite monitoring systems. Repeated measures multivariate analysis of variance and linear mixed models were used to assess workload and biomarker responses throughout the season (p < 0.05). Both teams experienced the highest workloads during the first 4 weeks of the season (p < 0.05), which was followed by several biomarker perturbations. Sex-by-Time interactions were observed for total cortisol, growth hormone, insulin-like growth factor-1, thyroxine, thyroid-stimulating hormone, vitamin D, and omega 3 fatty acid index (p < 0.05). Additional Sex effects were observed for free and total testosterone, estrogen, prolactin, sex-hormone binding globulin, creatine kinase, and iron levels (p < 0.05). Women soccer players experienced further Time effects for free cortisol, iron, ferritin, and percent transferrin saturation (p < 0.05). Male soccer players experienced additional Time effects for total testosterone, estrogen, creatine kinase, interleukin-6, triiodothyronine, and ferritin (p < 0.05). Despite similar patterns of change in workloads, differential fluctuations in physiological markers were observed between the sexes. Understanding sex differences in response to comparable workloads may enhance exercise prescriptions for better athlete management plans. Additional strategies to increase iron may be warranted in female athletes.

Sex differences in postconcussive symptom reporting in those with history of concussion: Findings from the federal interagency traumatic brain injury research (FITBIR) database

Objective: This study investigated influence of biological sex on postconcussive symptoms (PCS) following concussion using the Federal Interagency Traumatic Brain Injury Research (FITBIR) database. Method: All studies with publicly released data as of 4/7/21 that included both males and females, enough information to determine severity of injury consistent with concussion, a measure of PCS, and objective measures of neurocognitive functioning were used. This resulted in 6 studies with a total of 9890 participants (3206 females, 6684 males); 815 participants completed the Neurobehavioral Symptom Inventory (NSI), 471 completed the Rivermead Post-Concussion Symptoms Questionnaire (RPSQ), and 8604 completed the Sport Concussion Assessment Tool–3rd Edition (SCAT 3). Questionnaires were harmonized and the following symptom composite scores were computed: total score, somatic, cognitive, and affective. Data were analyzed using linear mixed-effects models. Results: Females endorsed higher total symptoms relative to males and that military personnel endorsed higher symptoms relative to civilians. Additionally, there was a small but significant interaction effect, such that female military personnel endorsed even higher symptoms than would be predicted by the main effects. Similar patterns were observed for somatic, cognitive, and affective symptom domains. Conclusions: Further understanding sex differences in PCS reporting is key to informing the most appropriate treatment options. Future work will need to examine whether sex differences in symptom reporting is due to sex differences in endorsement styles or genuine differences in symptom presentation, as well as the relationship between study population (e.g., military, civilian, sport) and sex on objective cognitive functioning and other functional outcomes.

Sex Differences in Energy Metabolism: A Female-Oriented Discussion.

The purpose of this review is to delineate aspects of energy metabolism at rest and during exercise that may be subject to sex differences and the potential underlying mechanisms involved. It focuses on distinct aspects of female physiology with an oriented discussion following the reproductive life stages of healthy, eumenorrheic females, including premenopausal time frames, pregnancy, perimenopause, and menopause. Finally, this review aims to address methodological challenges surrounding sexual dimorphism in energy metabolism investigations and confounding factors in this field. During resting conditions, females tend to have higher rates of non-oxidative free fatty acid clearance, which could contribute to lower respiratory exchange ratio measures. At the same time, carbohydrate energy metabolism findings are mixed. In general, females favor lipid energy metabolism during moderate-intensity exercise, while men favor carbohydrate energy metabolism. Factors such as age, dietary intake, genetics, and methodological decisions confound study findings, including properly identifying and reporting the menstrual cycle phase when female subjects are eumenorrheic. Pregnancy presents a unique shift in physiological systems, including energy metabolism, which can be observed at rest and during exercise. Changes in body composition and hormonal levels during the post-menopausal period directly impact energy metabolism, specifically lipid metabolism. This change in physiological state factors into the evidence showing a reduction in our understanding of sex differences in lipid metabolism during exercise in older adults. This review reveals a need for a focused understanding of female energy metabolism that could help exercise and nutrition professionals optimize female health and performance across the lifespan.

Advanced subject-specific neck musculoskeletal modeling unveils sex differences in muscle moment arm and cervical spine loading

Neck pain and injuries are growing healthcare burdens with women having a higher incidence rate and poorer treatment outcomes than males. A better understanding of sex differences in neck biomechanics, foundational for more targeted, effective prevention or treatment strategies, calls for more advanced subject-specific musculoskeletal modeling. Current neck musculoskeletal models are based on generic anatomy, lack subject specificity beyond anthropometric scaling, and are unable to accurately reproduce neck strengths exhibited in vivo without arbitrary muscle force scaling factors or residual torque actuators. In this work, subject-specific neck musculoskeletal models of 23 individuals (11 male, 12 female) were constructed by integrating multi-modality imaging and biomechanical measurements. Each model simulated maximal voluntary neck static exertions in three postures: neck flexion in a neutral posture, flexion in a 40° extended posture, and extension in a 40° flexed posture. Quantitative model validation showed close agreement between model-predicted muscle activation and EMG measurement. The models unveiled that (1) males have greater moment arms in one flexor muscle group and five extensor muscle groups, (2) females exhibited higher cervical spinal compression per unit exertion force in the flexed posture, and (3) the variability of compression force was much greater in females in all three exertions but most notably in the extension with a flexed “dropped head” position. These insights illuminated a plausible pathway from sex differences in neck biomechanics to sex disparities in the risk and prevalence of neck pain.

Understanding sex differences and the translational value of models of persistent substance use despite negative consequences

Persistent substance use despite negative consequences is a key facet of substance use disorder. The last decade has seen the preclinical field adopt the use of punishment to model adverse consequences associated with substance use. This has largely involved the pairing of drug use with either electric foot shock or quinine, a bitter tastant. Whilst at face value, these punishers may model aspects of the physical and psychological consequences of substance use, such models are yet to assist the development of approved medications for treatment. This review discusses progress made with animal models of punishment to understand the behavioral consequences of persistent substance use despite negative consequences. We highlight the importance of examining sex differences, especially when the behavioral response to punishment changes following drug exposure. Finally, we critique the translational value these models provide for the substance use disorder field.

Swimming training induced sex-specific differences in cardiac hypertrophy and blood levels of the renin-angiotensin system

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): FNS Background Exercise promotes physiological cardiac hypertrophy that is adaptive and reversible and influenced by age, genetics, sex, exercise intensity and type. The renin-angiotensin system (RAS) plays a crucial role in cardiovascular remodelling at both systemic and tissue levels. However, a significant gap exists in our understanding of sex differences in response to physical activity. Our objective is to characterise swimming-induced cardiac remodelling in female and male rats and RAS at both the cardiac tissue and systemic levels. Methods Male and female Lewis rats swam in a container filled with tap water at 32° C for 1 hour per day for 4 weeks or up to 8 weeks, respectively. Sedentary animals served as control. Echocardiography and immunostaining of RAS components, including angiotensin-converting enzyme 2 (ACE2) on cardiac sections' staining were performed. Cardiomyocyte (CM) size was measured. Cardiac RAS receptors were quantified with RT-PCR. Blood levels of Angiotensinogen, Angiotensins (Ang) were measured with Mass Spectrometry. Renin activity was calculated by the ratio Ang1/Angiotensinogen. Results After 4 weeks, an increase in ventricle diameter was shown in exercised male rats compared to the control. The cardiac hypertrophy was confirmed by increased heart/body weight (H/BW= 3x10-3±1.3x10-4vs2.5x10-3±3.10-5mg/g p&amp;lt;0.0001) and CM size (288±23 vs 198±1μm2 p=0.0028) associated with increased intra-CM immunostained ACE2 (AC2 area fraction: 38.5%±2.8%vs20%±5 p=0.0001). In females, ventricle diameter was unchanged, but wall thickness increased. Exercise was pursued for up to 8 weeks. At 6 and 8 weeks, echocardiography measurements remained similar as at 4 weeks. Hypertrophy was then confirmed by increased H/BW (3.2x10-3±1.7x10-4vs control:2.7x103 ±1.8x104mg/g p&amp;lt;0.0001) and CM size (335±47vs233±25μm2 p= 0.0019). An increased intra-CM-ACE2 was characterised by immunostaining (55.8%±6vs32.5%±6.6% p&amp;lt;0.0001) and confirmed by the increased ACE2 gene expression in cardiac tissue. At 4 weeks, the blood levels of RAS components were similar in trained and control males as well as renin activity. On contrary, exercised female rats showed increased blood levels of Angiotensinogen (4.2x10-4±7x10-5 vs 3x10-4±7x10-5au p=0.0288), Ang1 (2±1.9vs0.0±0.9au p=0.0151), Ang2 (1.2±1.5vs0.0±0.9au p=0.0204), and Ang1-7 (3.4±2.9vs 0.0±0.9au p=0.0058). The blood levels of these RAS compounds returned to the control levels after 6 and 8 weeks. In addition, a sex-distinct blood proteome was identified. Conclusion Our results showed a sex-distinct RAS regulation post-exercise and suggested a sex difference in the timing of adaptive responses at the system and cardiac tissue levels.

Skeletal Muscle Mitochondrial Function and Mitochondria-related Protein Expression in Men and Women During Acute Exercise-Heat Stress and Acclimation

INTRODUCTION: Military personnel can exhibit improved performance and reduced physiological strain in hot environments with the induction of heat adaptations. Mild heat exposure at 40°C heat serves therapeutic purposes, enhancing metabolic flexibility, and promoting positive muscle adaptations. Research indicates that heat acclimation (HA) leads to increased mitochondrial biogenesis and reduced reactive oxygen species in skeletal muscle, improving thermal tolerance. However, understanding sex differences in mitochondrial function and related protein expression affected by heat acclimation remain limited. Therefore, this study aimed to explore mitochondrial respiration and the expression of mitochondria-related proteins to better understand the impact of heat stress on mitochondrial adaptations in skeletal muscle in both males and females. METHODS: Healthy men (M:n = 7, 22±2yo, VO2max 52.86±2.35ml·kg−1·min−1) and women (F:n = 7, 24±1yo, VO2max 45.97±2.57 ml·kg−1·min−1) participated in a 5-day heat acclimation (HA) at 40°C and 40% relative humidity. Before and after HA, participants completed a heat tolerance test (HTT) measuring time to reach a rectal temperature of 39.5°C or volitional failure. Biopsies from the vastus lateralis were taken immediately post-HTT for musculoskeletal analysis. Mitochondrial respiratory function was assessed using Oroboros O2K, employing high-resolution respirometry. Paired sample t-tests were used to determine statistical significance between groups (p&lt;0.05). Proteomics data were mined for Gene Ontology (GO) terms related to mitochondrial function (STRING V.12.0) (adjusted p&lt;0.05). RESULTS: Both men and women exhibited significant enhancements in complex I-mediated respiration and complex I+II maximal coupled respiration after HA (PRE-HA: M:P=0.009, P=0.026; F:P=0.016, P=0.011). No sex differences in mitochondria respiration were observed before or after HA. Before HA, skeletal muscle from women showed higher expression in 4 proteins (ND61, NDUFB1, COX1, ATP5MF) associated with 9 GO terms related to mitochondrial function compared to men. However, after HA, men exhibited higher expression in 14 proteins (MTX2, APOOL, DNAJC11, TIMM13, NDUFAB1, DNAJC11, MAVS, CHCHD4, NDUFAF4, ATP5PF, NDUFAS, UQCRH, SSBP1, ND3) associated with 21 mitochondria-related GO terms compared to women. CONCLUSION: Acclimation to heat stress is associated with positive mitochondrial adaptation in both men and women. Although enhancements in mitochondrial respiratory function in both men and women after HA, there were different skeletal muscle responses between men and women regarding the regulation of mitochondria-related proteins after a bout of exercise-heat stress. Funding: DoD BA200299. 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.

Sex Differences in Youth with Chronic Tic Disorder and Tourette Syndrome: Evaluation of Tic Severity, Psychological Profiles, and Quality of Life.

Background: Tourette syndrome (TS) and Chronic Tic Disorder (CT) are neurodevelopmental conditions involving motor and/or phonic tics. Youth with tics may encounter feelings of isolation, diminished self-esteem and quality of life, and academic difficulties. A growing body of scientific literature suggests sex differences in youth with tics, but findings have been mixed so far. Because symptom severity peaks around puberty, understanding sex differences in tic manifestations and associated symptoms during this critical period is essential. Therefore, we aimed to assess sex differences related to tic symptoms, action planning styles, quality of life, and externalizing/internalizing symptoms in youth with tics. Methods: Our sample consisted of 66 youths with tics (19 girls) aged 7-14 (mean = 10 years). Youths were assessed with clinical interviews, as well as self- and parent-reported inventories evaluating tic symptoms, psychological profiles, and quality of life. Results: While no differences in tic symptoms were found, girls exhibited lower functional inflexibility, reduced overall functional planning effectiveness, and higher impairment in the psychological well-being subscale than boys. Additionally, girls had reduced general life satisfaction and social self-esteem. Boys reported more explosive outbursts, higher levels of hyperactivity, and more difficulties with self-concept. Conclusions: Our analyses suggested differences in several manifestations associated with tics. This introduces new perspectives that refine our understanding of sex differences. A better understanding of sex differences in tic disorders may eventually improve outcomes for all individuals living with these conditions.

Transcriptomic analysis reveals sex-specific patterns in the hippocampus in Alzheimer's disease.

The hippocampus, vital for memory and learning, is among the first brain regions affected in Alzheimer's Disease (AD) and exhibits adult neurogenesis. Women face twice the risk of developing AD compare to men, making it crucial to understand sex differences in hippocampal function for comprehending AD susceptibility. We conducted a comprehensive analysis of bulk mRNA postmortem samples from the whole hippocampus (GSE48350, GSE5281) and its CA1 and CA3 subfields (GSE29378). Our aim was to perform a comparative molecular signatures analysis, investigating sex-specific differences and similarities in the hippocampus and its subfields in AD. This involved comparing the gene expression profiles among: (a) male controls (M-controls) vs. female controls (F-controls), (b) females with AD (F-AD) vs. F-controls, (c) males with AD (M-AD) vs. M-controls, and (d) M-AD vs. F-AD. Furthermore, we identified AD susceptibility genes interacting with key targets of menopause hormone replacement drugs, specifically the ESR1 and ESR2 genes, along with GPER1. The hippocampal analysis revealed contrasting patterns between M-AD vs. M-controls and F-AD vs. F-controls, as well as M-controls vs. F-controls. Notably, BACE1, a key enzyme linked to amyloid-beta production in AD pathology, was found to be upregulated in M-controls compared to F-controls in both CA1 and CA3 hippocampal subfields. In M-AD vs. M-controls, the GABAergic synapse was downregulated, and the Estrogen signaling pathway was upregulated in both subfields, unlike in F-AD vs. F-controls. Analysis of the whole hippocampus also revealed upregulation of the GABAergic synapse in F-AD vs. F-controls. While direct comparison of M-AD vs. F-AD, revealed a small upregulation of the ESR1 gene in the CA1 subfield of males. Conversely, F-AD vs. F-controls exhibited downregulation of the Dopaminergic synapse in both subfields, while the Calcium signaling pathway showed mixed regulation, being upregulated in CA1 but downregulated in CA3, unlike in M-AD vs. M-controls. The upregulated Estrogen signaling pathway in M-AD, suggests a compensatory response to neurodegenerative specifically in males with AD. Our results also identified potential susceptibility genes interacting with ESR1 and ESR2, including MAPK1, IGF1, AKT1, TP53 and CD44. These findings underscore the importance of sex-specific disease mechanisms in AD pathogenesis. Region-specific analysis offers a more detailed examination of localized changes in the hippocampus, enabling to capture sex-specific molecular patterns in AD susceptibility and progression.

Sex differences in CD8+ T cell responses during adaptive immunity.

Biological sex is an important variable that influences the immune system's susceptibility to infectious and non-infectious diseases and their outcomes. Sex dimorphic features in innate and adaptive immune cells and their activities may help to explain sex differences in immune responses. T lymphocytes in the adaptive immune system are essential to providing protection against infectious and chronic inflammatory diseases. In this review, T cell responses are discussed with focus on the current knowledge of biological sex differences in CD8+ T cell mediated adaptive immune responses in infectious and chronic inflammatory diseases. Future directions aimed at investigating the molecular and cellular mechanisms underlying sex differences in diverse T cell responses will continue to underscore the significance of understanding sex differences in protective immunity at the cellular level, to induce appropriate T cell-based immune responses in infection, autoimmunity, and cancer. This article is categorized under: Immune System Diseases > Molecular and Cellular Physiology Infectious Diseases > Molecular and Cellular Physiology.

Gender-specific genetic and epigenetic signatures in cardiovascular disease.

Cardiac sex differences represent a pertinent focus in pursuit of the long-awaited goal of personalized medicine. Despite evident disparities in the onset and progression of cardiac pathology between sexes, historical oversight has led to the neglect of gender-specific considerations in the treatment of patients. This oversight is attributed to a predominant focus on male samples and a lack of sex-based segregation in patient studies. Recognizing these sex differences is not only relevant to the treatment of cisgender individuals; it also holds paramount importance in addressing the healthcare needs of transgender patients, a demographic that is increasingly prominent in contemporary society. In response to these challenges, various agencies, including the National Institutes of Health, have actively directed their efforts toward advancing our comprehension of this phenomenon. Epigenetics has proven to play a crucial role in understanding sex differences in both healthy and disease states within the heart. This review presents a comprehensive overview of the physiological distinctions between males and females during the development of various cardiac pathologies, specifically focusing on unraveling the genetic and epigenetic mechanisms at play. Current findings related to distinct sex-chromosome compositions, the emergence of gender-biased genetic variations, and variations in hormonal profiles between sexes are highlighted. Additionally, the roles of DNA methylation, histone marks, and chromatin structure in mediating pathological sex differences are explored. To inspire further investigation into this crucial subject, we have conducted global analyses of various epigenetic features, leveraging data previously generated by the ENCODE project.