Sex differences in DNA methylation across gestation: a large scale, cross-cohort, multi-tissue analysis.

Biological sex is a key variable influencing many physiological systems. Disease prevalence as well as treatment success can be modified by sex. Differences emerge already early in life and include pregnancy complications and adverse birth outcomes. The placenta is a critical organ for fetal development and shows sex-based differences in the expression of hormones and cytokines. Epigenetic regulation, such as DNA methylation (DNAm), may underlie the previously reported placental sexual dimorphism. We associated placental DNAm with fetal sex in three cohorts. Individual cohort results were meta-analyzed with random-effects modelling. CpG-sites differentially methylated with sex were further investigated regarding pathway enrichment, overlap with methylation quantitative trait loci (meQTLs), and hits from phenome-wide association studies (PheWAS). We evaluated the consistency of findings across tissues (CVS, i.e. chorionic villus sampling from early placenta, and cord blood) as well as with gene expression. We identified 10,320 epigenome-wide significant sex-differentially methylated probes (DMPs) spread throughout the epigenome of the placenta at birth. Most DMPs presented with lower DNAm levels in females. DMPs mapped to genes upregulated in brain, were enriched for neurodevelopmental pathways and significantly overlapped with meQTLs and PheWAS hits. Effect sizes were moderately correlated between CVS and placenta at birth, but only weakly correlated between birth placenta and cord blood. Sex differential gene expression in birth placenta was less pronounced and implicated genetic regions only marginally overlapped with those associated with differential DNAm. Our study provides an integrative perspective on sex-differential DNAm in perinatal tissues underscoring the possible link between placenta and brain.

Sex-specific cardiovascular remodeling leads to a divergent sex-dependent development of heart failure in aged hypertensive rats.

INTRODUCTION: The prevalence of heart failure with preserved ejection fraction (HFpEF) is continuously rising and predominantly affects older women often hypertensive and/or obese or diabetic. Indeed, there is evidence on sex differences in the development of HF. Hence, we studied cardiovascular performance dependent on sex and age as well as pathomechanisms on a cellular and molecular level. METHODS: We studied 15-week- and 1-year-old female and male hypertensive transgenic rats carrying the mouse Ren-2 renin gene (TG) and compared them to wild-type (WT) controls at the same age. We tracked blood pressure and cardiac function via echocardiography. After sacrificing the 1-year survivors we studied vascular smooth muscle and endothelial function. Isolated single skinned cardiomyocytes were used to determine passive stiffness and Ca2+-dependent force. In addition, Western blots were applied to analyse the phosphorylation status of sarcomeric regulatory proteins, titin and of protein kinases AMPK, PKG, CaMKII as well as their expression. Protein kinase activity assays were used to measure activities of CaMKII, PKG and angiotensin-converting enzyme (ACE). RESULTS: TG male rats showed significantly higher mortality at 1 year than females or WT male rats. Left ventricular (LV) ejection fraction was specifically reduced in male, but not in female TG rats, while LV diastolic dysfunction was evident in both TG sexes, but LV hypertrophy, increased LV ACE activity, and reduced AMPK activity as evident from AMPK hypophosphorylation were specific to male rats. Sex differences were also observed in vascular and cardiomyocyte function showing different response to acetylcholine and Ca2+-sensitivity of force production, respectively cardiomyocyte functional changes were associated with altered phosphorylation states of cardiac myosin binding protein C and cardiac troponin I phosphorylation in TG males only. Cardiomyocyte passive stiffness was increased in TG animals. On a molecular level titin phosphorylation pattern was altered, though alterations were sex-specific. Thus, also the reduction of PKG expression and activity was more pronounced in TG females. However, cardiomyocyte passive stiffness was restored by PKG and CaMKII treatments in both TG sexes. CONCLUSION: Here we demonstrated divergent sex-specific cardiovascular adaptation to the over-activation of the renin-angiotensin system in the rat. Higher mortality of male TG rats in contrast to female TG rats was observed as well as reduced LV systolic function, whereas females mainly developed HFpEF. Though both sexes developed increased myocardial stiffness to which an impaired titin function contributes to a sex-specific molecular mechanism. The functional derangements of titin are due to a sex-specific divergent regulation of PKG and CaMKII systems.

A Machine Learning Model for Identifying Sexual Health Influencers to Promote the Secondary Distribution of HIV Self-Testing Among Gay, Bisexual, and Other Men Who Have Sex With Men in China: Quasi-Experimental Study.

BACKGROUND: Sexual health influencers (SHIs) are individuals actively sharing sexual health information with their peers, and they play an important role in promoting HIV care services, including the secondary distribution of HIV self-testing (SD-HIVST). Previous studies used a 6-item empirical leadership scale to identify SHIs. However, this approach may be biased as it does not consider individuals' social networks. OBJECTIVE: This study used a quasi-experimental study design to evaluate how well a newly developed machine learning (ML) model identifies SHIs in promoting SD-HIVST compared to SHIs identified by a scale whose validity had been tested before. METHODS: We recruited participants from BlueD, the largest social networking app for gay men in China. Based on their responses to the baseline survey, the ML model and scale were used to identify SHIs, respectively. This study consisted of 2 rounds, differing in the upper limit of the number of HIVST kits and peer-referral links that SHIs could order and distribute (first round ≤5 and second round ≤10). Consented SHIs could order multiple HIV self-testing (HIVST) kits and generate personalized peer-referral links through a web-based platform managed by a partnered gay-friendly community-based organization. SHIs were encouraged to share additional kits and peer-referral links with their social contacts (defined as "alters"). SHIs would receive US $3 incentives when their corresponding alters uploaded valid photographic testing results to the same platform. Our primary outcomes included (1) the number of alters who conducted HIVST in each group and (2) the number of newly tested alters who conducted HIVST in each. We used negative binomial regression to examine group differences during the first round (February-June 2021), the second round (June-November 2021), and the combined first and second rounds, respectively. RESULTS: In January 2021, a total of 1828 men who have sex with men (MSM) completed the survey. Overall, 393 SHIs (scale=195 and ML model=198) agreed to participate in SD-HIVST. Among them, 229 SHIs (scale=116 and ML model=113) ordered HIVST on the web. Compared with the scale group, SHIs in the ML model group motivated more alters to conduct HIVST (mean difference [MD] 0.88, 95% CI 0.02-2.22; adjusted incidence risk ratio [aIRR] 1.77, 95% CI 1.07-2.95) when we combined the first and second rounds. Although the mean number of newly tested alters was slightly higher in the ML model group than in the scale group, the group difference was insignificant (MD 0.35, 95% CI -0.17 to -0.99; aIRR 1.49, 95% CI 0.74-3.02). CONCLUSIONS: Among Chinese MSM, SHIs identified by the ML model can motivate more individuals to conduct HIVST than those identified by the scale. Future research can focus on how to adapt the ML model to encourage newly tested individuals to conduct HIVST. TRIAL REGISTRATION: Chinese Clinical Trials Registry ChiCTR2000039632; https://www.chictr.org.cn/showprojEN.html?proj=63068. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s12889-021-11817-2.

The recipient metabolome explains the asymmetric ovarian impact on fetal sex development after embryo transfer in cattle.

In cattle, lateral asymmetry affects ovarian function and embryonic sex, but the underlying molecular mechanisms remain unknown. The plasma metabolome of recipients serves to predict pregnancy after embryo transfer (ET). Thus, the aim of this study was to investigate whether the plasma metabolome exhibits distinct lateral patterns according to the sex of the fetus carried by the recipient and the active ovary side (AOS), i.e., the right ovary (RO) or the left ovary (LO). We analyzed the plasma of synchronized recipients by 1H+NMR on day 0 (estrus, n = 366) and day 7 (hours prior to ET; n = 367). Thereafter, a subset of samples from recipients that calved female (n = 50) or male (n = 69) was used to test the effects of embryonic sex and laterality on pregnancy establishment. Within the RO, the sex ratio of pregnancies carried was biased toward males. Significant differences (P < 0.05) in metabolite levels were evaluated based on the day of blood sample collection (days 0, 7 and day 7/day 0 ratio) using mixed generalized models for metabolite concentration. The most striking differences in metabolite concentrations were associated with the RO, both obtained by multivariate (OPLS-DA) and univariate (mixed generalized) analyses, mainly with metabolites measured on day 0. The metabolites consistently identified through the OPLS-DA with a higher variable importance in projection score, which allowed for discrimination between male fetus- and female fetus-carrying recipients, were hippuric acid, l-phenylalanine, and propionic acid. The concentrations of hydroxyisobutyric acid, propionic acid, l-lysine, methylhistidine, and hippuric acid were lowest when male fetuses were carried, in particular when the RO acted as AOS. No pathways were significantly regulated according to the AOS. In contrast, six pathways were found enriched for calf sex in the day 0 dataset, three for day 7, and nine for day 7/day 0 ratio. However, when the AOS was the right, 20 pathways were regulated on day 0, 8 on day 7, and 13 within the day 7/day 0 ratio, most of which were related to amino acid metabolism, with phenylalanine, tyrosine, and tryptophan biosynthesis and phenylalanine metabolism pathways being identified throughout. Our study shows that certain metabolites in the recipient plasma are influenced by the AOS and can predict the likelihood of carrying male or female embryos to term, suggesting that maternal metabolism prior to or at the time of ET could favor the implantation and/or development of either male or female embryos.

This study explored how the active ovary side (AOS, i.e., left or right) and the sex of the calf carried by the recipient relate to the plasma metabolome in blood. For this purpose, we analyzed blood samples from heifers at two specific times: the day of the estrus and the day of the embryo transfer. We found significant differences in the sex ratio of pregnancies carried in the right ovary, and in the levels of certain metabolites depending on whether the active ovary was on the right or left and whether the calf was male or female. As examples, the concentrations of hydroxyisobutyric acid, propionic acid, l-lysine, methylhistidine, and hippuric acid were lowest when male calves were carried, in particular when the right ovary was active. Interestingly, the calf sex also influenced certain metabolic pathways, especially in the right AOS, several of them related to amino acid metabolism. However, no significant metabolic pathway changes were observed based solely on which ovary was active. Overall, the study suggests that the metabolism of the recipient, influenced by the AOS, might play a role in the successful implantation and development of embryos of a certain sex. This insight could potentially help to predict and improve pregnancy outcomes in cattle through embryo transfer techniques.

"This is part of the body" - Student nurses' de-sexualisation of intimate care for patients.

BACKGROUND: Effective intimate care can significantly impact the clinical outcomes of patients. However, conducting intimate care, which involves exposing and touching sexually sensitive areas of the body, presents challenges and anxieties for student nurses, particularly when providing care for patients of the opposite sex. OBJECTIVES: This study aims to identify the challenges and struggles encountered by student nurses when providing intimate care for patients of the opposite sex, as well as to explore the coping strategies employed by the students. DESIGN: A constructivist grounded theory research approach. SETTINGS: The study was conducted in Macau, a Special Administrative Region of China. PARTICIPANTS: Twenty-six student nurses across various stages of their education, and three clinical mentors. METHODS: Purposive and theoretical sampling techniques were utilized to recruit participants. Semi-structured interviews were conducted. The data analysis was in line with the principles of constructivist grounded theory research. RESULTS: A two-stage adaptation model was established, demonstrating a dynamic pathway of student nurses toward intimate care. The first stage 'gendered confinement in intimate care' was characterized by student nurses' negative feelings and lack of nurse-patient interactions; the second stage 'emancipation to gendered confinement' was characterized by the development of constructive therapeutic nurse-patient relationships. The successful transfer was achieved through students' reconstructing the meaning of intimate care and nursing profession in three interplayed types: objectification of patients' body, moral authority of nursing care, and legitimisation of nursing profession. While the transfer process involved the students' intentional efforts to de-sexualize intimate care, clinical mentors facilitated the process. CONCLUSION: Student nurses' adaption to intimate care is a dynamic process which enhances the construction of the nursing professional identity. Support from nursing educators can facilitate student nurses' coping with intimate care-related challenges.

Out with the old, in with the new: Meiotic driving of sex chromosome evolution.

Chromosomal regions with meiotic drivers exhibit biased transmission (> 50 %) over their competing homologous chromosomal region. These regions often have two prominent genetic features: suppressed meiotic crossing over and rapidly evolving multicopy gene families. Heteromorphic sex chromosomes (e.g., XY) often share these two genetic features with chromosomal regions exhibiting meiotic drive. Here, we discuss parallels between meiotic drive and sex chromosome evolution, how the divergence of heteromorphic sex chromosomes can be influenced by meiotic drive, experimental approaches to study meiotic drive on sex chromosomes, and meiotic drive in traditional and non-traditional model organisms with high-quality genome assemblies. The newly available diversity of high-quality sex chromosome sequences allows us to revisit conventional models of sex chromosome evolution through the lens of meiotic drive.

Sex ratio shift after frozen single blastocyst transfer in relation to blastocyst morphology parameters.

The sex ratio shift was observed in peoples who underwent ART treatment. Moreover, there is limited evidence on differences in sex ratio between single frozen-thawed blastocyst morphology, insemination type and transfer days. So further research is needed in this area with regard to factors possibly affecting the sex ratio. Retrospective study based on multicenter including two large assisted reproduction centers in Shanghai and Wuhan in China. A total of 6361 singleton delivery offspring after frozen-thawed blastocyst transfer. Propensity score weighting and logistic regression models were used to estimate the associations between blastocyst morphology grading and child sex ratio. The main outcome measures is singleton sex ratio. In our study, the primary outcome measure was sex ratio which was calculated as the proportion of male newborns among all live births. Higher quality blastocysts resulted in a higher sex ratio than single poor-quality frozen-thawed blastocyst transfer. Among the three blastocyst morphological parameters of trophectoderm (TE), Grade A and B were significantly associated with a higher sex ratio than Grade C. The similar trend was observed in both IVF and ICSI treated subgroups. As compared with expansion (4 + 3), expansion degree 6 achieved a higher sex ratio in overall populations and IVF treated subgroup. Transferring blastocysts of day 6 had the highest sex ratio both in IVF group and ICSI group. A 6.95% higher sex ratio in transferring blastocysts of day 5 in IVF group than those in ICSI group. No significant association between inner cell mass degree and sex ratio was observed. However, as compared with IVF treatment, all morphology parameters achieved the similar or the biased sex ratio favoring female in ICSI treated subgroup. Quality of blastocysts was positively associated with sex ratio. TE score and expansion degree rather than ICM were significantly associated with sex ratio at birth. ICSI treatment promotes the biased sex ratio favoring female.

A retrospective analysis of the role of age and sex in outcomes of non-surgical periodontal therapy at a single academic dental center.

The present study examined the role of age and sex in the outcomes of non-surgical periodontal therapy (NSPT). De-identified demographic and periodontal characteristics of patients who presented for baseline periodontal evaluation, NSPT, and periodontal re-evaluation were abstracted from electronic health records. Independent associations of age and sex with severe periodontitis defined as ≥ 5 mm clinical attachment loss (CAL) and ≥ 6 mm probing depth (PD) were determined using multinomial logistic regression. The null hypothesis was rejected at α < 0.05. A total of 2866 eligible subjects were included in the analysis. Significantly lower odds of CAL ≤ 4 mm than CAL ≥ 5 mm (reference) were observed in adults aged 35-64 (odds ratio, OR, 0.19; 95% confidence interval, CI 0.13, 0.29) and ≥ 65 years (OR 0.13; 95% CI 0.07, 0.25) compared to those aged 18-34 years. Odds of PD < 4 mm versus PD ≥ 6 mm (reference) were lower in adults aged 35-64 years than those aged 18-34 years (OR 0.71; 95% CI 0.55, 0.90) and higher in females compared to males (OR 1.67; 95% CI 1.14, 2.44). These results suggest more compromised post-NSPT outcomes in older adults and males compared to the respective populations and highlight the need for personalized therapeutic strategies in these populations.

Lack of detectable sex differences in the mitochondrial function of Caenorhabditis elegans.

BACKGROUND: Sex differences in mitochondrial function have been reported in multiple tissue and cell types. Additionally, sex-variable responses to stressors including environmental pollutants and drugs that cause mitochondrial toxicity have been observed. The mechanisms that establish these differences are thought to include hormonal modulation, epigenetic regulation, double dosing of X-linked genes, and the maternal inheritance of mtDNA. Understanding the drivers of sex differences in mitochondrial function and being able to model them in vitro is important for identifying toxic compounds with sex-variable effects. Additionally, understanding how sex differences in mitochondrial function compare across species may permit insight into the drivers of these differences, which is important for basic biology research. This study explored whether Caenorhabditis elegans, a model organism commonly used to study stress biology and toxicology, exhibits sex differences in mitochondrial function and toxicant susceptibility. To assess sex differences in mitochondrial function, we utilized four male enriched populations (N2 wild-type male enriched, fog-2(q71), him-5(e1490), and him-8(e1498)). We performed whole worm respirometry and determined whole worm ATP levels and mtDNA copy number. To probe whether sex differences manifest only after stress and inform the growing use of C. elegans as a mitochondrial health and toxicologic model, we also assessed susceptibility to a classic mitochondrial toxicant, rotenone. RESULTS: We detected few to no large differences in mitochondrial function between C. elegans sexes. Though we saw no sex differences in vulnerability to rotenone, we did observe sex differences in the uptake of this lipophilic compound, which may be of interest to those utilizing C. elegans as a model organism for toxicologic studies. Additionally, we observed altered non-mitochondrial respiration in two him strains, which may be of interest to other researchers utilizing these strains. CONCLUSIONS: Basal mitochondrial parameters in male and hermaphrodite C. elegans are similar, at least at the whole-organism level, as is toxicity associated with a mitochondrial Complex I inhibitor, rotenone. Our data highlights the limitation of using C. elegans as a model to study sex-variable mitochondrial function and toxicological responses.

Sex-specific disparities in disease activity scores among patients with axial spondyloarthritis and their implications for evaluating the response to tumor necrosis factor alpha inhibitor therapy.

BACKGROUND: We aimed to investigate whether there are sex differences in disease activity measures among patients with axial spondyloarthritis (axSpA) and to determine any potential impact on the assessment of treatment responses to tumor necrosis factor alpha inhibitors (TNFi). METHODS: Using the Korean College of Rheumatology Biologics and Targeted Therapy (KOBIO) registry data, we compared sex differences in changes in the Bath Ankylosing Spondylitis Disease Activity Score (BASDAI) and Ankylosing Spondylitis Disease Activity Score (ASDAS) levels at baseline and one year after TNFi initiation in patients with axSpA. RESULTS: This study included 1,753 patients with axSpA who started or changed TNFi, of whom 1,343 (76.6%) were male. At baseline, the mean BASDAI and ASDAS scores of all patients were 5.98 and 3.6, respectively. The BASDAI changes between baseline and the one-year follow-up were independently associated with sex (𝛽 = 0.343, p = 0.011), whereas ASDAS was not (𝛽 = 0.079, p = 0.235). When judging the effect of TNFi at one-year of treatment, male patients were more likely to be assessed as effective by the BASDAI-based criterion (ΔBASDAI ≥ 50% or ≥ 2; OR 1.700, 95% CI 1.200-2.406), while the ASDAS-based criterion (ΔASDAS ≥ 1.1) showed no significant difference between sexes (OR 0.993, 95% CI 0.678-1.455), after adjusting for other baseline characteristics. CONCLUSIONS: The changes in disease activity before and after TNFi use were significantly different between sexes when measured by BASDAI, but not ASDAS. TNFi treatment effects may be interpreted differently between sexes depending on the disease activity measure used.

Sex-dependent effects of chronic intermittent hypoxia: implication for obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea (OSA) affects 10-26% of adults in the United States with known sex differences in prevalence and severity. OSA is characterized by elevated inflammation, oxidative stress (OS), and cognitive dysfunction. However, there is a paucity of data regarding the role of sex in the OSA phenotype. Prior findings suggest women exhibit different OSA phenotypes than men, which could result in under-reported OSA prevalence in women. To examine the relationship between OSA and sex, we used chronic intermittent hypoxia (CIH) to model OSA in rats. We hypothesized that CIH would produce sex-dependent phenotypes of inflammation, OS, and cognitive dysfunction, and these sex differences would be dependent on mitochondrial oxidative stress (mtOS). METHODS: Adult male and female Sprague Dawley rats were exposed to CIH or normoxia for 14 days to examine the impact of sex on CIH-associated circulating inflammation (IL-1ß, IL-6, IL-10, TNF-α), circulating steroid hormones, circulating OS, and behavior (recollective and spatial memory; gross and fine motor function; anxiety-like behaviors; and compulsive behaviors). Rats were implanted with osmotic minipumps containing either a mitochondria-targeting antioxidant (MitoTEMPOL) or saline vehicle 1 week prior to CIH initiation to examine how inhibiting mtOS would affect the CIH phenotype. RESULTS: Sex-specific differences in CIH-induced inflammation, OS, motor function, and compulsive behavior were observed. In female rats, CIH increased inflammation (plasma IL-6 and IL-6/IL-10 ratio) and impaired fine motor function. Conversely, CIH elevated circulating OS and compulsivity in males. These sex-dependent effects of CIH were blocked by inhibiting mtOS. Interestingly, CIH impaired recollective memory in both sexes but these effects were not mediated by mtOS. No effects of CIH were observed on spatial memory, gross motor function, or anxiety-like behavior, regardless of sex. CONCLUSIONS: Our results indicate that the impact of CIH is dependent on sex, such as an inflammatory response and OS response in females and males, respectively, that are mediated by mtOS. Interestingly, there was no effect of sex or mtOS in CIH-induced impairment of recollective memory. These results indicate that mtOS is involved in the sex differences observed in CIH, but a different mechanism underlies CIH-induced memory impairments.

Sleep apnea is a common sleeping condition in adults with a wide range of symptoms that include inflammation, oxidative stress, memory problems, anxiety, and compulsivity. Men are diagnosed with sleep apnea more often than women. Although there is limited information on how sleep apnea affects men and women differently, previous studies suggest that women may exhibit different sleep apnea symptoms than men. To examine the impact of male and female sex on common sleep apnea symptoms, we exposed adult male and female rats to a model of sleep apnea called chronic intermittent hypoxia (CIH). We found that many effects of CIH were different in males and females. CIH females had increased inflammation and motor problems, whereas CIH males had increased oxidative stress and compulsivity. To investigate the reason for these CIH sex differences, we blocked mitochondrial oxidative stress. Blocking mitochondrial oxidative stress decreased CIH associated sex differences. However, blocking mitochondrial oxidative stress had no impact on CIH-induced memory impairment that was observed in male and female rats. Our findings support previous reports that suggest that women exhibit different sleep apnea symptoms than men. Further, we extend these findings by showing that mitochondrial oxidative stress is involved in these sex differences. Clinically, patients diagnosed with sleep apnea are typically treated with continuous positive airway pressure (CPAP) machines, which have high rates of non-compliance (15­40%). Therefore, understanding why sleep apnea is causing these symptoms will be important in developing therapeutics.

Understanding Female and Male Insights in Psychology: Who Thinks What?

Evolutionary psychology is the study of human psychological behavior. During childhood, men and women behave similarly; however, as a child approaches puberty, new physical and behavioral changes emerge. Behavioral psychology focuses on understanding the functioning and thought processes of the human mind. The general population lacks knowledge of basic behavioral differences between men and women, leaving them unaware of their role, limitations, societal responsibilities, resulting in an underestimation of their own natural talents and biology. Thus, people tend to follow societal norms rather than exploring and utilizing their natural talents. The current review was designed and conducted to enforce compression on behavioral psychology in both genders as well as to identify variations in hormonal activity and sexual preferences.

A P2RY12 deficiency results in sex-specific cellular perturbations and sexually dimorphic behavioral anomalies.

Microglia are sexually dimorphic, yet, this critical aspect is often overlooked in neuroscientific studies. Decades of research have revealed the dynamic nature of microglial-neuronal interactions, but seldom consider how this dynamism varies with microglial sex differences, leaving a significant gap in our knowledge. This study focuses on P2RY12, a highly expressed microglial signature gene that mediates microglial-neuronal interactions, we show that adult females have a significantly higher expression of the receptor than adult male microglia. We further demonstrate that a genetic deletion of P2RY12 induces sex-specific cellular perturbations with microglia and neurons in females more significantly affected. Correspondingly, female mice lacking P2RY12 exhibit unique behavioral anomalies not observed in male counterparts. These findings underscore the critical, sex-specific roles of P2RY12 in microglial-neuronal interactions, offering new insights into basal interactions and potential implications for CNS disease mechanisms.

Treating sex and gender differences as a continuous variable can improve precision cancer treatments.

BACKGROUND: The significant sex and gender differences that exist in cancer mechanisms, incidence, and survival, have yet to impact clinical practice. One barrier to translation is that cancer phenotypes cannot be segregated into distinct male versus female categories. Instead, within this convenient but contrived dichotomy, male and female cancer phenotypes are highly overlapping and vary between female- and male- skewed extremes. Thus, sex and gender-specific treatments are unrealistic, and our translational goal should be adaptation of treatment to the variable effects of sex and gender on targetable pathways. METHODS: To overcome this obstacle, we profiled the similarities in 8370 transcriptomes of 26 different adult and 4 different pediatric cancer types. We calculated the posterior probabilities of predicting patient sex and gender based on the observed sexes of similar samples in this map of transcriptome similarity. RESULTS: Transcriptomic index (TI) values were derived from posterior probabilities and allowed us to identify poles with local enrichments for male or female transcriptomes. TI supported deconvolution of transcriptomes into measures of patient-specific activity in sex and gender-biased, targetable pathways. It identified sex and gender-skewed extremes in mechanistic phenotypes like cell cycle signaling and immunity, and precisely positioned each patient's whole transcriptome on an axis of continuously varying sex and gender phenotypes. CONCLUSIONS: Cancer type, patient sex and gender, and TI value provides a novel and patient- specific mechanistic identifier that can be used for realistic sex and gender-adaptations of precision cancer treatment planning.

Some efforts to improve cancer therapy involve the idea of personalizing treatments to who a patient is and how their cancer operates. Personalizing treatment can involve straighforward features like a patient's age, family cancer history, personal disease and surgical histories, as well as more complex features like analysis of their specific cancer's mechanisms of growth and spread throughout the body. One glaring omission in common personalization schemes is the sex and gender of the patient. While patient sex and gender is known to substantially affect cancer rates and response to treatment, we do not yet use this information in treatment planning. There are multiple reasons for this but among them is that we tend to think about sex and gender as an either/or categorization. You are either a male/man or a female/woman. This is not accurate as there are many variables that contribute to who an individual is as a male/man or female/woman. This variability is a challenge to incorporating these features into personalized treatment planning. Here, we have developed a method to address this challenge. It is our great hope that this will enable the use of this critically important element of personalization in cancer treatment planning and improve survival rates for all patients.

Acute stress differentially alters reward-related decision making and inhibitory control under threat of punishment.

Acute stress has various effects on cognition, executive function and certain forms of cost/benefit decision making. Recent studies in rodents indicate that acute stress differentially alters reward-related decisions involving particular types of costs and slows choice latencies. Yet, how stress alters decisions where rewards are linked to punishment is less clear. We examined how 1 h restraint stress, followed by behavioral testing 10 min later altered action-selection on two tasks involving reward-seeking under threat of punishment in well-trained male and female rats. One study used a risky decision-making task involving choice between a small/safe reward and a large/risky one that could coincide with shock, delivered with a probability that increased over blocks of trials. Stress increased risk aversion and punishment sensitivity, reducing preference for the larger/risky reward, while increasing decision latencies and trial omissions in both sexes, when rats were teste. A second study used a "behavioral control" task, requiring inhibition of approach towards a readily available reward associated with punishment. Here, food pellets were delivered over discrete trials, half of which coincided with a 12 s audiovisual cue, signalling that reward retrieval prior to cue termination would deliver shock. Stress exerted sex- and timing-dependent effects on inhibitory control. Males became more impulsive and received more shocks on the stress test, whereas females were unaffected on the stress test, and were actually less impulsive when tested 24 h later. None of the effects of restraint stress were recapitulated by systemic treatment with physiological doses of corticosterone. These findings suggest acute stress induces qualitatively distinct and sometimes sex-dependent effects on punished reward-seeking that are critically dependent on whether animals must either choose between different actions or withhold them to obtain rewards and avoid punishment.

Discriminatory experiences among gay, bisexual, and other men who have sex with men, and transgender and non-binary individuals: a cross sectional analysis.

Background: Several systems of oppression combine in complex ways to impact the lives of minority populations. Following an intersectionality framework, we assessed the frequency and perceived reasons for discrimination among gay, bisexual, and other cisgender men who have sex with men (MSM) and transgender and non-binary individuals (TGNB), stratified by race. Methods: Online survey among MSM and TGNB ≥18 years living in Brazil, between November/2021 and January/2022. We used the 18-item Explicit Discrimination Scale to assess day-to-day experiences of differential treatment, and perceived discrimination. For each item, participants indicated their perceived reasons for differential treatment using 14 pre-defined options. Negative binomial regression models assessed if race was a significant predictor of discrimination. Subsequent models, stratified by race, examined associations of perceived reasons and number of reasons with perceived discrimination. Findings: Of 8464 MSM and TGNB, 4961 (58.6%) were White, 2173 (25.7%) Pardo (Brazil's official term for admixed populations), and 1024 (12.1%) Black. Black participants' scores for perceived discrimination (mean, standard deviation) were higher (10.2, 8.8) [Pardo (6.5, 6.8), White (5.2, 5.7)], and race was both the main reason for and the strongest predictor of perceived discrimination. The number of reasons participants used to interpret their discriminatory experiences was also a predictor of discrimination score among White, Pardo, and Black participants. Interpretation: LGBTQIA+phobia was highly prevalent among all participants. Additionally, our results indicated that Black MSM and TGNB participants were more frequently discriminated against than other racial groups, with racial discrimination uniquely contributing these experiences. Funding: Fundação Oswaldo Cruz, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro.

Secular trends of population-attributable fractions of obesity for hypertension among US population by sex and race/ethnicity: Analysis from NHANES 1999-2018.

Obesity is a major risk factor of hypertension, therefore quantifying the contribution of obesity to hypertension is necessary. The current study aimed to investigate the changes in population-attributable fractions (PAFs) of hypertension associated with general obesity and abdominal obesity over the recent 2 decades among the US population, as well as important sub-populations. This report was performed based on national-level cross-sectional data for 46,535 adults aged 18 years and older and 20,745 children aged 8-17 from the US National Health and Nutrition Examination Survey 1999-2018. The PAFs of hypertension due to general obesity and abdominal obesity were calculated by sex, race/ethnicity, and survey year. The linear regression analysis was used to evaluate the secular trends of PAFs over the years. The prevalence of general obesity and abdominal obesity presented significantly increasing trends during the past 2 decades in the US. The PAFs of hypertension due to general obesity increased steadily from 11.9 % to 15.1 % in women with a slope of 0.38 % (95 % CI: 0.31 - 0.45 %) and from 8.4 % to 13.4 % in men with a slope of 0.46 % (95 % CI: 0.36 - 0.56 %). Similar increasing trends were also observed for the PAFs due to abdominal obesity in both women and men. Additionally, there were significantly different trends of PAFs in various races/ethnicities. Over the past 2 decades, the contributions of obesity to hypertension were gradually rising among US population, which emphasizes the importance of controlling weight to further reduce the burden of hypertension.

Comparison of enjoyment and energy expenditure of exergame with and without blood flow restriction in men and women.

This study compared the effects of blood flow restriction (BFR) on intensity and perceived enjoyment during an exergame. Fourteen healthy young participants engaged in a boxing exergame for 20 min, with or without BFR, across two sessions. Perceived enjoyment levels were assessed using the Physical Activity Enjoyment Scale. Heart rate was monitored, and energy expenditure (EE) during exercise was calculated. A mixed model analysis of variance with repeated measures was used to evaluate differences in EE and enjoyment between exergame conditions (with and without BFR) as well as the interaction effects of these protocols with gender. Although not statistically significant, perceived enjoyment decreased with BFR inclusion for both genders. No significant differences were observed between men and women for both protocols. Regarding EE, there was no significant difference between the two groups (with and without BFR). However, a significant main effect of gender was found, with men exhibiting higher EE values in both protocols compared to women. In conclusion, exergames incorporating BFR impact perceptual responses, particularly perceived enjoyment. Furthermore, significant gender differences in EE were found, with men displaying higher values.

Days alive and out of hospital for adult female and male cardiac surgery patients: a population-based cohort study.

BACKGROUND: Research shows women experience higher mortality than men after cardiac surgery but information on sex-differences during postoperative recovery is limited. Days alive and out of hospital (DAH) combines death, readmission and length of stay, and may better quantify sex-differences during recovery. This main objective is to evaluate (i) how DAH at 30-days varies between sex and surgical procedure, (ii) DAH responsiveness to patient and surgical complexity, and (iii) longer-term prognostic value of DAH. METHODS: We evaluated 111,430 patients (26% female) who underwent one of three types of cardiac surgery (isolated coronary artery bypass [CABG], isolated non-CABG, combination procedures) between 2009 - 2019. Primary outcome was DAH at 30 days (DAH30), secondary outcomes were DAH at 90 days (DAH90) and 180 days (DAH180). Data were stratified by sex and surgical group. Unadjusted and risk-adjusted analyses were conducted to determine the association of DAH with patient-, surgery-, and hospital-level characteristics. Patients were divided into two groups (below and above the 10th percentile) based on the number of days at DAH30. Proportion of patients below the 10th percentile at DAH30 that remained in this group at DAH90 and DAH180 were determined. RESULTS: DAH30 were lower for women compared to men (22 vs. 23 days), and seen across all surgical groups (isolated CABG 23 vs. 24, isolated non-CABG 22 vs. 23, combined surgeries 19 vs. 21 days). Clinical risk factors including multimorbidity, socioeconomic status and surgical complexity were associated with lower DAH30 values, but women showed lower values of DAH30 compared to men for many factors. Among patients in the lowest 10th percentile at DAH30, 80% of both females and males remained in the lowest 10th percentile at 90 days, while 72% of females and 76% males remained in that percentile at 180 days. CONCLUSION: DAH is a responsive outcome to differences in patient and surgical risk factors. Further research is needed to identify new care pathways to reduce disparities in outcomes between male and female patients.

Dimorphic effect of TFE3 in determining mitochondrial and lysosomal content in muscle following denervation.

BACKGROUND: Muscle atrophy is a common consequence of the loss of innervation and is accompanied by mitochondrial dysfunction. Mitophagy is the adaptive process through which damaged mitochondria are removed via the lysosomes, which are regulated in part by the transcription factor TFE3. The role of lysosomes and TFE3 are poorly understood in muscle atrophy, and the effect of biological sex is widely underreported. METHODS: Wild-type (WT) mice, along with mice lacking TFE3 (KO), a transcriptional regulator of lysosomal and autophagy-related genes, were subjected to unilateral sciatic nerve denervation for up to 7 days, while the contralateral limb was sham-operated and served as an internal control. A subset of animals was treated with colchicine to capture mitophagy flux. RESULTS: WT females exhibited elevated oxygen consumption rates during active respiratory states compared to males, however this was blunted in the absence of TFE3. Females exhibited higher mitophagy flux rates and greater lysosomal content basally compared to males that was independent of TFE3 expression. Following denervation, female mice exhibited less muscle atrophy compared to male counterparts. Intriguingly, this sex-dependent muscle sparing was lost in the absence of TFE3. Denervation resulted in 45% and 27% losses of mitochondrial content in WT and KO males respectively, however females were completely protected against this decline. Decreases in mitochondrial function were more severe in WT females compared to males following denervation, as ROS emission was 2.4-fold higher. In response to denervation, LC3-II mitophagy flux was reduced by 44% in females, likely contributing to the maintenance of mitochondrial content and elevated ROS emission, however this response was dysregulated in the absence of TFE3. While both males and females exhibited increased lysosomal content following denervation, this response was augmented in females in a TFE3-dependent manner. CONCLUSIONS: Females have higher lysosomal content and mitophagy flux basally compared to males, likely contributing to the improved mitochondrial phenotype. Denervation-induced mitochondrial adaptations were sexually dimorphic, as females preferentially preserve content at the expense of function, while males display a tendency to maintain mitochondrial function. Our data illustrate that TFE3 is vital for the sex-dependent differences in mitochondrial function, and in determining the denervation-induced atrophy phenotype.