Reported Sex Differences Research Articles

Outcomes of CT- or CMR-guided TAVR according to sex: a secondary analysis of the randomized TAVR-CMR trial

Abstract Background Previous studies have reported sex differences in pre-procedural imaging characteristics of patients undergoing transcatheter aortic valve replacement (TAVR) evaluation. Whether these differences affect the outcome of computed tomography (CT)-guided or cardiac magnetic resonance (CMR)-guided TAVR has not been studied. Objectives This analysis aimed to evaluate sex-based differences in imaging findings and outcomes in patients undergoing TAVR for severe aortic valve stenosis. Methods This was a secondary analysis of the TAVR-CMR trial, a randomized clinical trial comparing TAVR planning by CT or CMR. Outcomes (based on the Valve Academic Research Consortium (VARC)–2 definition) with each imaging strategy were compared according to sex. Results Of 380 patient randomized into the TAVR-CMR trial, 194 (51.1%) were female and 186 (48.9%) were male. Of these, 267 patients eventually underwent TAVR (133 women (49.8%) and 134 men (50.2%), p=0.457). Imaging findings differed between the sexes for both imaging modalities. The comparison between CT and CMR to assess the access route and landing zone showed no difference in both women and men (all p>0.05). Implantation success was not significantly different between imaging strategies for both women (84.7% (CT group) vs. 93.2% (CMR group), p=0.11) and men (95.7% (CT group) vs. 93.8% (CMR group), p=0.61). All-cause mortality at 6 months was not significantly different between imaging strategies for both women (10.2% (CT group) vs. 8.1% (CMR group), p=0.68) and men (4.3% (CT group) vs. 9.4% (CMR group), p=0.24). Conclusions This secondary analysis has confirmed sex-related differences in pre-procedural imaging characteristics, with no influence of the imaging modality used. Similar outcomes were observed in both female and male patients when the TAVR was guided by either a CMR or a CT scan.

More similarity than difference: comparison of within- and between-sex variance in early adolescent brain structure.

Background Adolescent neuroimaging studies of sex differences in the human brain predominantly examine mean differences between males and females. This focus on between-groups differences without probing relative distributions and similarities may contribute to both conflation and overestimation of sex differences and sexual dimorphism in the developing human brain. Methods We aimed to characterize the variance in brain macro- and micro-structure in early adolescence as it pertains to sex at birth using a large sample of 9-11 year-olds from the Adolescent Brain Cognitive Development (ABCD) Study (N=7,723). Specifically, for global and regional estimates of gray and white matter volume, cortical thickness, and white matter microstructure (i.e., fractional anisotropy and mean diffusivity), we examined: within- and between-sex variance, overlap between male and female distributions, inhomogeneity of variance via the Fligner-Killeen test, and an analysis of similarities (ANOSIM). For completeness, we examined these sex differences using both uncorrected (raw) brain estimates and residualized brain estimates after using mixed-effects modeling to account for age, pubertal development, socioeconomic status, race, ethnicity, MRI scanner manufacturer, and total brain volume, where applicable. Results The overlap between male and female distributions was universally greater than the difference (overlap coefficient range: 0.585 - 0.985) and the ratio of within-sex and between-sex differences was similar (ANOSIM R range: -0.001 - 0.117). All cortical and subcortical volumes showed significant inhomogeneity of variance, whereas a minority of brain regions showed significant sex differences in variance for cortical thickness, white matter volume, fractional anisotropy, and mean diffusivity. Inhomogeneity of variance was reduced after accounting for other sources of variance. Overlap coefficients were larger and ANOSIM R values were smaller for residualized outcomes, indicating greater within- and smaller between-sex differences once accounting for other covariates. Conclusions Reported sex differences in early adolescent human brain structure may be driven by disparities in variance, rather than binary, sex-based phenotypes. Contrary to the popular view of the brain as sexually dimorphic, we found more similarity than difference between sexes in all global and regional measurements of brain structure examined. This study builds upon previous findings illustrating the importance of considering variance when examining sex differences in brain structure.

Sex disparities in the prevalence, incidence, and management of diabetes mellitus: an Australian retrospective primary healthcare study involving 668,891 individuals

BackgroundIn Australia, diabetes is the fastest growing chronic condition, with prevalence trebling over the past three decades. Despite reported sex differences in diabetes outcomes, disparities in management and health targets remain unclear. This population-based retrospective study used MedicineInsight primary healthcare data to investigate sex differences in diabetes prevalence, incidence, management, and achievement of health targets.MethodsAdults (aged ≥ 18 years) attending 39 general practices in Western Australia were included. Diabetes incidence and prevalence were estimated by age category. Health targets assessed included body mass index (BMI), blood pressure, blood lipids, and glycated haemoglobin (HbA1c) levels. Medical management of diabetes-associated conditions was also investigated. Time-to-incident diabetes was modelled using a Weibull regression. A multilevel mixed-effects logistic regression model investigated risk-adjusted sex differences in achieving the HbA1c health target (HbA1c ≤ 7.0% (≤ 53 mmol/mol)).ResultsRecords of 668,891 individuals (53.4% women) were analysed. Diabetes prevalence ranged from 1.3% (95% confidence interval (CI) 1.2%-1.3%) in those aged < 50 years to 7.2% (95% CI 7.1%-7.3%) in those aged ≥ 50 years and was overall higher in men. In patients younger than 30 years, incidence was higher in women, with this reversing after the age of 50. Among patients with diabetes, BMI ≥ 35 kg/m2 was more prevalent in women, whereas current and past smoking were more common in men. Women were less likely than men to achieve lipid health targets and less likely to receive prescriptions for lipid, blood pressure, or glucose-lowering agents. Men with incident diabetes were 21% less likely than women to meet the HbA1c target. Similarly, ever recorded retinopathy, nephropathy, neuropathy, hypertension, dyslipidaemia, coronary heart disease, heart failure, peripheral vascular disease and peripheral artery disease were higher in men than women.ConclusionsThis research underscores variations in diabetes epidemiology and management based on sex. Tailoring diabetes management should consider the patient's sex.

7053 Sex Differences in Endocrine-Related Pre-existing, COVID-19- and COVID-19 Vaccine-Related Health Conditions and Adverse Events

Abstract Disclosure: J. Knapp: Other; Self; Co-founder, Aseesa Inc. R. Karumanchi: None. C. Fee: None. S. Inslicht: None. A. Bhargava: Other; Self; Co-Founder, Aseesa Inc. COVID-19 illness-related symptoms and outcomes are highly variable, with reported sex differences. mRNA vaccines were deployed for the first-time on a large scale for COVID-19, and the endocrine effects of Pfizer’s and Moderna’s mRNA vaccines, remain to be elucidated. Associations between COVID-19 illness and/or COVID-19 vaccines and reproductive disturbances have been reported based on large nation-wide surveys and targeted studies. Yet, none of the studies have directly ascertained similarities and differences between reproductive adverse outcomes from COVID-19 illness in unvaccinated individuals versus COVID-19 mRNA vaccines in individuals without COVID-19 illness. Here, we report preliminary findings on endocrine systems from a global survey of ∼8,000-10,000 participants collected between February 2022 and October 2023. Approximately 62.5% of the participants were from the United States, and the remaining were international. Nearly 1.49% of respondents reported hospitalization after COVID-19, whereas 5.69% of the respondents reported hospitalization after vaccination in our cohort. SARS-CoV-2-related severe symptoms were reported by ∼9.3% of COVID-19 vaccinated versus 6.7% of unvaccinated individuals (p&amp;lt;0.001). Women reported more vaccine-related adverse events (AEs) than men; 30% of men and 19% of women reported no AEs after any vaccination dose. After the first dose, 60% women and 48% of men reported some AEs, whereas after the second dose, 46% of women and 40% of men reported experiencing several AEs. Sex differences were present in endocrine and autoimmune pre-existing health conditions, including thyroid disease (13%F vs 3%M), osteoporosis (6%F vs 1%M), elevated cholesterol (M&amp;gt;F), and hypertension (M&amp;gt;F). Nearly 5% of women reported pre-existing irregular menstrual cycle irregularities and hormonal changes, whereas only 2% of men reported hormonal irregularities. In unvaccinated individuals, after COVID-19 illness, nearly 6% of women reported experiencing hot flashes, whereas 7.5% reported irregular menstrual cycles. In COVID-19 vaccinated individuals without SARS-CoV-2 infection, 94.6% of men and 62.5% of women respondents reported no reproductive changes. Of those reporting reproductive AEs included hormonal changes in 5% of women and 3.5% men, hot flashes in 8.5% women and 1.9% men, heavy periods and/or dysmenorrhea in 16.7% of women, and irregular periods in17.1% of women. In summary, reproductive AEs in vaccinated individuals without COVID-19 illness were more frequent than in unvaccinated individuals with COVID-19 illness. A detailed and thorough follow-up is needed to better understand if pre-existing health conditions exacerbated vaccine-associated AEs. Presentation: 6/3/2024

Sexual Dimorphism in Sex Hormone Metabolism in Human Skeletal Muscle Cells in Response to Different Testosterone Exposure.

Muscle tissue is an important target of sex steroids, and particularly, testosterone plays essential roles in muscle cell metabolism. Wide ranges of studies have reported sex differences in basal muscle steroidogenesis, and recently several genes have been identified to be regulated by androgen response elements that show innate sex differences in muscle. However, studies accounting for and demonstrating cell sexual dimorphism in vitro are still scarce and not well characterized. Here, we demonstrated the ability of 46XX and 46XY human primary skeletal muscle cells to differently activate steroidogenesis in vitro, likely related to sex-chromosome onset, and to differently induce hormone release after increasing doses of testosterone exposure. Cells were treated with testosterone at concentrations of 0.5, 2, 5, 10, 32, and 100 nmol/L for 24 h. Variations in 17β-HSD, 5α-R2, CYP-19 expression, DHT, estradiol, and androstenedione release, as well as IL6 and IL8 release, were analyzed, respectively, by RT-PCR, ELISA, and luminex-assay. Following testosterone treatments, and potentially at any concentration level, an increase in the expression of 17β-HSD, 5α-R2, and CYP-19 was observed in 46XY cells, accompanied by elevated levels of DHT, androstenedione, and IL6/IL8 release. Following the same treatment, 46XX cells exhibited an increase in 5α-R2 and CYP-19 expression, a conversion of androgens to estrogens, and a reduction in IL6 and IL8 release. In conclusion, this study demonstrated that sex-chromosome differences may influence in vitro muscle cell steroidogenesis and hormone homeostasis, which are pivotal for skeletal muscle metabolism.

Enhanced Ca2+-Driven Arrhythmogenic Events in Female Patients With AtrialFibrillation: Insights From Computational Modeling.

Substantial sex-based differences have been reported in atrial fibrillation (AF), but the underlying mechanisms are poorly understood. This study sought to gain a mechanistic understanding of Ca2+-handling disturbances and Ca2+-driven arrhythmogenic events in male vs female atrial cardiomyocytes and establish their responses to Ca2+-targeted interventions. We integrated reported sex differences and AF-associated changes (ie, expression and phosphorylation of Ca2+-handling proteins, cardiomyocyte ultrastructural characteristics, and dimensions) into our human atrial cardiomyocyte model that couples electrophysiology with spatially detailed Ca2+-handling processes. Sex-specific responses of atrial cardiomyocytes to arrhythmia-provoking protocols and Ca2+-targeted interventions were evaluated. Simulated quiescent cardiomyocytes showed increased incidence of Ca2+ sparks in female vs male myocytes inAF, in agreement with previous experimental reports. Additionally, our female model exhibited elevated propensity to develop pacing-induced spontaneous Ca2+ releases (SCRs) and augmented beat-to-beat variability in action potential (AP)-elicited Ca2+ transients compared with the male model. Sensitivity analysis uncovered distinct arrhythmogenic contributions of each component involved in sex and/or AF alterations. Specifically, increased ryanodine receptor phosphorylation emerged as the major SCR contributor in female AF cardiomyocytes, whereas reduced L-type Ca2+ current was protective against SCRs for male AF cardiomyocytes. Furthermore, simulated Ca2+-targeted interventions identified potential strategies (eg, t-tubule restoration, and inhibition of ryanodine receptor and sarcoplasmic/endoplasmic reticulum Ca2⁺-ATPase) to attenuate Ca2+-driven arrhythmogenic events in women, and revealed enhanced efficacy when applied in combination. Sex-specific modeling uncovers increased Ca2+-driven arrhythmogenic events in female vs male atria inAF, and suggests combined Ca2+-targeted interventions are promising therapeutic approaches in women.

More similarity than difference: comparison of within- and between-sex variance in early adolescent brain structure.

Adolescent neuroimaging studies of sex differences in the human brain predominantly examine mean differences between males and females. This focus on between-groups differences without probing relative distributions and similarities may contribute to both conflation and overestimation of sex differences and sexual dimorphism in the developing human brain. We aimed to characterize the variance in brain macro- and micro-structure in early adolescence as it pertains to sex at birth using a large sample of 9-11 year-olds from the Adolescent Brain Cognitive Development (ABCD) Study (N=7,723). Specifically, for global and regional estimates of gray and white matter volume, cortical thickness, and white matter microstructure (i.e., fractional anisotropy and mean diffusivity), we examined: within- and between-sex variance, overlap between male and female distributions, inhomogeneity of variance via the Fligner-Killeen test, and an analysis of similarities (ANOSIM). For completeness, we examined these sex differences using both uncorrected (raw) brain estimates and residualized brain estimates after using mixed-effects modeling to account for age, pubertal development, socioeconomic status, race, ethnicity, MRI scanner manufacturer, and total brain volume, where applicable. The overlap between male and female distributions was universally greater than the difference (overlap coefficient range: 0.585 - 0.985) and the ratio of within-sex and between-sex differences was similar (ANOSIM R range: -0.001 - 0.117). All cortical and subcortical volumes showed significant inhomogeneity of variance, whereas a minority of brain regions showed significant sex differences in variance for cortical thickness, white matter volume, fractional anisotropy, and mean diffusivity. Inhomogeneity of variance was reduced after accounting for other sources of variance. Overlap coefficients were larger and ANOSIM R values were smaller for residualized outcomes, indicating greater within- and smaller between-sex differences once accounting for other covariates. Reported sex differences in early adolescent human brain structure may be driven by disparities in variance, rather than binary, sex-based phenotypes. Contrary to the popular view of the brain as sexually dimorphic, we found more similarity than difference between sexes in all global and regional measurements of brain structure examined. This study builds upon previous findings illustrating the importance of considering variance when examining sex differences in brain structure.

Sex-disaggregated analysis of acute kidney injury in hospitalized children with sickle cell anemia in Uganda.

A growing body of research is categorizing sex differences in both sickle cell anemia (SCA) and acute kidney injury (AKI); however, most of this work is being conducted in high-resource settings. Here, we evaluated risk factors and clinical parameters associated with AKI and AKI severity, stratified by sex, in a cohort of children hospitalized with SCA and vaso-occlusive pain crisis (VOC). The purpose of this study was to explore sex disparities in a high-risk, vulnerable population. This study was a secondary analysis of data collected from a cohort of Ugandan children between 2 and 18 yr of age prospectively enrolled. A total of 185 children were enrolled in the primary study; 41.6% were female and 58.4% were male, with a median age of 8.9 yr. Incident or worsening AKI (P = 0.026) occurred more frequently in female compared with male children, despite no differences in AKI on admission. Female children also had altered markers of renal function including higher creatinine levels at admission (P = 0.03), higher peak creatinine (P = 0.006), and higher urine neutrophil gelatinase-associated lipocalin (NGAL) at admission (P = 0.003) compared with male children. Female children had elevated total (P = 0.045) and conjugated bilirubin at admission (P = 0.02) compared with male children and higher rates of hematuria at admission (P = 0.004). Here, we report sex differences in AKI in children with SCA and VOC, including increased incidence and worsening of AKI in female pediatric patients, in association with an increase in biological indicators of poor renal function including creatinine, estimated glomerular filtration rate, and NGAL.NEW & NOTEWORTHY In this study, we report an increased risk of developing acute kidney injury (AKI) during hospitalization, worsening AKI, and death among females with sickle cell anemia (SCA) hospitalized with an acute pain crisis compared with males. The sex differences in AKI were not explained by socioeconomic differences, severity of pain, or disease severity among females compared with males. Together, these data suggest that female children with SCA may be at increased risk of AKI.

Gonadal sex and chromosome complement influence the gut microbiome in a mouse model of allergic airway inflammation.

Evidence abounds that gut microbiome components are associated with sex disparities in the immune system. However, it remains unclear whether the observed sex disparity in asthma incidence is associated with sex-dependent differences in immune-modulating gut microbiota, and/or its influence on allergic airway inflammatory processes. Using a mouse model of house dust mite (HDM)-induced allergic inflammation and the four core genotypes (FCGs) model, we have previously reported sex differences in lung inflammatory phenotypes. Here, we investigated associations of gut microbiomes with these phenotypes by challenging FCG mice [mouse with female sex chromosome and male gonad (XXM), mouse with female sex chromosome and female gonad (XXF), mouse with male sex chromosome and male gonad (XYM), and mouse with male sex chromosome and female gonad (XYF); n = 7/group] with HDM (25 μg) or PBS intranasally for 5 wk and collecting fecal samples. We extracted fecal DNA and analyzed the 16S microbiome via Targeted Metagenomic Sequencing. We compared α and β diversity across genotypes and assessed the Firmicutes/Bacteroidetes (F/B) ratio. When comparing baseline and after exposure for the FCG, we found that the gut F/B ratio was only increased in the XXM genotype. We also found that α diversity was significantly increased in all FCG mice upon HDM challenge, with the highest increase in the XXF, and the lowest in the XXM genotypes. Similarly, β diversity of the microbial community was also affected by challenge in a gonad- and chromosome-dependent manner. In summary, our results indicated that HDM treatment, gonads, and sex chromosomes significantly influence the gut microbial community composition. We concluded that allergic lung inflammation may be affected by the gut microbiome in a sex-dependent manner involving both hormonal and genetic influences.NEW & NOTEWORTHY Recently, the gut microbiome and its role in chronic respiratory disease have been the subject of extensive research and the establishment of its involvement in immune functions. Using the FCG mouse model, our findings revealed the influence of gonads and sex chromosomes on the microbial community structure before and after exposure to HDM. Our data provide a potential new avenue to better understand mediators of sex disparities associated with allergic airway inflammation.

Sex differences in the presentation and outcomes of patients with acute myocardial infarction complicated by cardiogenic shock: a critical review of contemporary data and a look towards future directions.

Cardiogenic shock (CS) is a devasting complicating of acute myocardial infarction (AMI), associated with significant mortality. Prior studies have reported sex differences in the presentation, management and outcomes of patients with AMI and CS. These differences are likely due to a variety of factors influencing therapeutic decision-making and impacting survival. This review highlights the more contemporary studies exploring differences in women and men with AMI-CS, providing a critical perspective towards understanding the factors that might lead to these differences and outlining potential opportunities to reduce disparities in treatment and improve survival for women with AMI-CS. Recent reports demonstrate that women with AMI-CS are older than men and have more cardiovascular comorbidities. When examining an unselected population of patients with AMI-CS, women receive less aggressive treatment compared to men and have poorer outcomes. However, when examining a selected population of patients with AMI-CS treated with mechanical circulatory support (MCS) and/or admitted to centers that implement CS protocols to manage AMI-CS, these sex-based differences in outcomes are largely mitigated. Standardizing protocols for the diagnosis and treatment of patients with AMI-CS, with an emphasis on early revascularization and appropriate invasive therapies, can improve outcomes in women and narrow the gender gap.

#1905 Sex differences in primary distal renal tubular acidosis: a single-centre retrospective study

Abstract Background and Aims The kidney has been described as one of the most estrogen-responsive organs after reproductive ones. Many non-X-linked renal diseases present with sex differences. Although not completely elucidated, an influence of estrogens has been described in several transporters along the renal tubule such as the Na+/phosphate cotransporter (NaPi-IIa) in the proximal tubule, the Na+/K+/2Cl⁻ cotransporter (NKCC) in the thick ascending limb of the loop of Henle, the thiazide-sensitive Na+/Cl⁻ cotransporter (NCC) in the distal convoluted tubule and the epithelial sodium channel (ENaC) expressed by the principal cells of the collecting duct. Our study aimed to investigate possible phenotypic sex differences over the natural history of primary distal renal tubular acidosis (dRTA), a rare genetic condition characterized by impaired urinary acidification in the collecting duct that results in non-anion gap metabolic acidosis, hypokalemia, hypercalciuria, nephrolithiasis and nephrocalcinosis, which can lead to chronic kidney disease (CKD). Method We included a cohort of 31 genetically confirmed dRTA patients (19 women and 12 men) followed at the London Tubular Centre. We retrospectively collected data from 2012 to 2023. Estimated glomerular filtration rate (eGFR) was calculated with the CKD-EPIcr formula. Hypokalemia was defined as serum potassium &amp;lt; 3.5 mmol/L, hypercalciuria was defined as urinary calcium/creatinine (uCa/Cr) &amp;gt; 0.7 mmol/mmol and acidosis was defined as HCO3− ≤ 22 mmol/L. Data were analyzed using non-parametric Mann-Whitney as appropriate (Prism GraphPad 8.0.2). A p value &amp;lt; 0.05 was considered as statistically significant. Results Baseline characteristics and prevalence of different mutations are shown in Table 1. At baseline, both cohorts were young, with preserved kidney function. 60% of women were acidotic compared to 50% of men, and 30% of men were hypokalemic compared to 8% of women. The majority of patients in both cohorts presented with overt hypercalciuria (60% of women vs 90% of men). Prevalence of nephrolithiasis and nephrocalcinosis was similar among women and men. At baseline, no statistically significant difference between sexes was found for serum or urinary parameters. Interestingly, men exhibited a tendency towards higher annual mean slope of eGFR (−3.3 ± 2.5 mL/min/1.73 m2) compared to women (−0.5 ± 1.5 mL/min/1.73 m2) in a statistically significant fashion (Fig. 1a). Although not statically significant, we noticed a tendency towards higher fractional excretion of phosphate (FEPO4) (Fig. 1b) and dyslipidemia in men (Fig. 1c). There was no difference in PTH between the two groups (Fig. 1c). Conclusion Men affected by primary dRTA are at increased risk of CKD progression, tend to have a more severe phenotype at baseline and appear to be more dyslipidemic than women. This is consistent with findings in the literature that report accelerated CKD progression and higher cardiovascular morbidity and mortality in men. To our knowledge, this is the first study reporting sex differences in primary dRTA.

Cortical gyrification in women and men and the (missing) link to prenatal androgens.

Previous studies have reported sex differences in cortical gyrification. Since most cortical folding is principally defined in utero, sex chromosomes as well as gonadal hormones are likely to influence sex-specific aspects of local gyrification. Classic congenital adrenal hyperplasia (CAH) causes high levels of androgens during gestation in females, whereas levels in males are largely within the typical male range. Therefore, CAH provides an opportunity to study the possible effects of prenatal androgens on cortical gyrification. Here, we examined the vertex-wise absolute mean curvature-a common estimate for cortical gyrification-in individuals with CAH (33 women and 20 men) and pair-wise matched controls (33 women and 20 men). There was no significant main effect of CAH and no significant CAH-by-sex interaction. However, there was a significant main effect of sex in five cortical regions, where gyrification was increased in women compared to men. These regions were located on the lateral surface of the brain, specifically left middle frontal (rostral and caudal), right inferior frontal, left inferior parietal, and right occipital. There was no cortical region where gyrification was increased in men compared to women. Our findings do not only confirm prior reports of increased cortical gyrification in female brains but also suggest that cortical gyrification is not significantly affected by prenatal androgen exposure. Instead, cortical gyrification might be determined by sex chromosomes either directly or indirectly-the latter potentially by affecting the underlying architecture of the cortex or the size of the intracranial cavity, which is smaller in women.

Sex differences in extinction and reinstatement of nicotine discrimination in rats: The effects of reinforcer devaluation.

Nicotine functions effectively as an interoceptive operant discriminative stimulus (SD) that sets the occasion for voluntarily emitted behavior to be reinforced by biologically relevant outcomes (e.g., food). This has been demonstrated primarily with male rats. Far less is known about nicotine's operant SD functions in female rats. There are no reports of sex differences in extinction and recovery of the SD functions of nicotine, which may elucidate smoking cessation and relapse. In view of this, eight male and eight female rats were trained to nose poke differentially among quasirandomly intermixed sessions of food reinforcement variable interval (VI-30 s) and nonreinforcement in a go/no-go across session one-manipulanda operant drug discrimination procedure. For half the rats, presession administration of nicotine (0.30 mg/kg, subcutaneous) occasioned reinforcement sessions of nose pokes (i.e., SD); for the remaining rats, it occasioned nonreinforcement (SΔ). Saline sessions occasioned the opposite contingencies. Training was conducted first under feeding restriction and then under free feeding, which was then followed by extinction sessions that were also conducted with free feeding. During discrimination training, response rates for females did not differ from males when conducted under restricted feeding but did so during training and later extinction conducted under free feeding. Females also exhibited greater reinstatement of responding under the nicotine SD but not the SΔ. These data provide additional evidence for sex differences in rats with the discriminative stimulus functions of nicotine under low, but not high, food-drive states-and may have implications for sex/gender differences in smoking cessation and relapse. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Renal epithelial-derived miR-17~92 inhibits STAT3 signaling, serving a sex-specific and renoprotective role in the development of AKI

Prerenal acute kidney injury (AKI) is a sudden loss of kidney excretory function from reduced blood flow to the kidney. Sex differences in the degree of injury have been recognized, the causes of which are ill-defined. While a role for miRs (microRNAs) in AKI has been recognized, there are no reports of sex differences in miR regulation after injury. Here we investigated sex differences in miR regulation in proximal tubular epithelial cells during AKI with IRI (ischemia reperfusion injury) in vivo and miR regulation of signal transducer and activator of transcription 3 (STAT3) signaling in vitro. We hypothesize that sex-differentially expressed miR-17~92 serves as a negative regulator of STAT3 signaling, repressing proinflammatory signaling in tubular epithelium during AKI. We recapitulated the phenotype that males have a higher level of injury compared to females with proportional intensity and duration of IRI in a murine AKI model. C57BL/6J mice underwent 25 minutes of unilateral IRI with a contralateral nephrectomy and sacrificed 18 hours post-reperfusion. Injured male tubules showed a significant increase in Kidney injury molecule-1 (Kim-1) expression (n³3, fold change=75.28 ± 35.92) whereas injured females showed no change, confirming that injured males experience a higher level of tubular injury than females with a matched degree of ischemia. Control female tubules showed significantly higher baseline expression of miR-17~92 compared to control males (n ³ 5, difference between means ± SEM: miR-17a, 2.337 ± 0.6322; miR-18a, 5.841 ± 2.008; miR-19a, 5.041 ± 1.232; miR- 19b, 3.826 ± 0.9791; miR-20a, 3.826 ± 1.053; miR-92a, 5.627 ± 1.588). MiR-17~92 expression in injured male tubules significantly increased compared to male controls. Even after this increase, miR-17~92 expression in male tubules was lower compared to miR-17~92 in injured females. Mir-17~92 is predicted to target STAT3 and components of the interleukin-6 (IL6)/STAT3 pathway. qPCR showed a significant increase in Stat3 expression after IRI in both sexes, but only a significant increase in IL6 and heme oxygenase-1 in injured males. To investigate miR regulation of STAT3 in vitro, we used a human proximal tubule cell line (HK2) model. Recombinant IL6 induced STAT3 protein expression and phosphorylation, and increased miR-17~92 expression. By altering miR-17~92 expression in HK2 cells we demonstrated that expression of STAT3 in response to IL6 is regulated, in part, by these miRs. These data provide the first example of sex-differential miR regulation in response to IRI. The elevated baseline expression of miR-17~92 in the female mice may provide a novel mechanism to account for sex-differences in IRI-AKI and may form part of the mechanism to protect female kidney epithelia from IRI and AKI. This work is supported by the NIH (DK102843 to MBB), (NIH R01DK102843-08S1 to AS), NIH (DK137419 and DK125015 to JH) and NIH (5R01DK131991 and 5R01DK064005 to RT). 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.

Acute pharmacodynamic responses to sitagliptin: Drug-induced increase in early insulin secretion in oral glucose tolerance test.

DPP4 inhibitors are widely prescribed as treatments for type 2 diabetes. Because drug responses vary among individuals, we initiated investigations to identify genetic variants associated with the magnitude of drug responses. Sitagliptin (100 mg) was administered to 47 healthy volunteers. Several endpoints were measured to assess clinically relevant responses - including the effect of sitagliptin on glucose and insulin levels during an oral glucose tolerance test (OGTT). This pilot study confirmed that sitagliptin (100 mg) decreased the area under the curve for glucose during an OGTT (p = 0.0003). Furthermore, sitagliptin promoted insulin secretion during the early portion of the OGTT as reflected by an increase in the ratio of plasma insulin at 30 min divided by plasma insulin at 60 min (T30:T60) from mean ± SEM 0.87 ± 0.05 to 1.62 ± 0.36 mU/L (p = 0.04). The magnitude of sitagliptin's effect on insulin secretion (as judged by the increase in the T30:T60 ratio for insulin) was correlated with the magnitude of sitagliptin-induced increase in the area under the curve for intact plasma GLP1 levels during the first hour of the OGTT. This study confirmed previously reported sex differences in glucose and insulin levels during an OGTT. Specifically, females exhibited higher levels of glucose and insulin at the 90-180 min time points. However, we did not detect significant sex-associated differences in the magnitude of sitagliptin-induced changes in T30:T60 ratios for either glucose or insulin. In conclusion, T30:T60 ratios for insulin and glucose during an OGTT provide useful indices to assess pharmacodynamic responses to DPP4 inhibitors.

Outcome differences by sex in oncology clinical trials

Identifying sex differences in outcomes and toxicity between males and females in oncology clinical trials is important and has also been mandated by National Institutes of Health policies. Here we analyze the Trialtrove database, finding that, strikingly, only 472/89,221 oncology clinical trials (0.5%) had curated post-treatment sex comparisons. Among 288 trials with comparisons of survival, outcome, or response, 16% report males having statistically significant better survival outcome or response, while 42% reported significantly better survival outcome or response for females. The strongest differences are in trials of EGFR inhibitors in lung cancer and rituximab in non-Hodgkin’s lymphoma (both favoring females). Among 44 trials with side effect comparisons, more trials report significantly lesser side effects in males (N = 22) than in females (N = 13). Thus, while statistical comparisons between sexes in oncology trials are rarely reported, important differences in outcome and toxicity exist. These considerable outcome and toxicity differences highlight the need for reporting sex differences more thoroughly going forward.

No significant sex differences in incidence or phenotype for the SMNΔ7 mouse model of spinal muscular atrophy

Spinal muscular atrophy (SMA) is an autosomal recessive disease that affects 1 out of every 6,000-10,000 individuals at birth, making it the leading genetic cause of infant mortality. In recent years, reports of sex differences in SMA patients have become noticeable. The SMNΔ7 mouse model is commonly used to investigate pathologies and treatments in SMA. However, studies on sex as a contributing biological variable are few and dated. Here, we rigorously investigated the effect of sex on a series of characteristics in SMA mice of the SMNΔ7 model. Incidence and lifespan of 23 mouse litters were tracked and phenotypic assessments were performed at 2-day intervals starting at postnatal day 6 for every pup until the death of the SMA pup(s) in each litter. Brain weights were also collected post-mortem. We found that male and female SMA incidence does not differ significantly, survival periods are the same across sexes, and there was no phenotypic difference between male and female SMA pups, other than for females exhibiting lesser body weights at early ages. Overall, this study ensures that sex is not a biological variable that contributes to the incidence ratio or disease severity in the SMNΔ7 mouse model.

The anterior retrosplenial cortex is required for short-term object in place recognition memory retrieval: Role of ionotropic glutamate receptors in male and female Long-Evans rats.

The anterior retrosplenial cortex (aRSC) integrates multimodal sensory information into cohesive associative recognition memories. Little is known about how information is integrated during different learning phases (i.e., encoding and retrieval). Additionally, sex differences are observed in performance of some visuospatial memory tasks; however, inconsistent findings warrant more research. We conducted three experiments using the 1-h delay object-in-place (1-h OiP) test to assess recognition memory retrieval in male and female Long-Evans rats. (i) We found both sexes performed equally in three repeated 1-h OiP test sessions. (ii) We showed infusions of a mixture of muscimol/baclofen (GABAA/B receptor agonists) into the aRSC ~15-min prior to the test phase disrupted 1-h OiP in both sexes. (iii) We assessed the role of aRSC ionotropic glutamate receptors in 1-h OiP retrieval using another squad of cannulated rats and confirmed that infusions of either the competitive AMPA/Kainate receptor antagonist CNQX (3 mM) or competitive NMDA receptor antagonist AP-5 (30 mM) (volumes = 0.50 uL/side) significantly impaired 1-h OiP retrieval in both sexes compared to controls. Taken together, findings challenge reported sex differences and clearly establish a role for aRSC ionotropic glutamate receptors in short-term visuospatial recognition memory retrieval. Thus, modulating neural activity in the aRSC may alleviate some memory processing impairments in related disorders.

Sex differences in mouse placental metabolite profiles: an NMR metabolomics study

A proper functioning placenta is essential for normal fetal development. The placenta has a vital function as a protective barrier and is critical for nutrient and waste exchange for the developing fetus. Our group and others have reported sex differences in both placental structure and function; however, differences in the placental metabolome between female and male fetuses have been understudied. Here, placental tissue samples were collected from healthy pregnant CD-1 mice in late gestation ( n = 26 female and n = 27 male placentas from 17 dams at embryonic day 17.5). Metabolite profiles were determined using 1H magic angle spinning nuclear magnetic resonance. The relative concentration of alanine was significantly higher in male placentas whereas, threonine was higher in female placentas ( p &lt; 0.05). This study adds to the growing literature demonstrating sex differences in healthy placental function and emphasizes the importance of examining both female and male placentas in metabolomics studies.

Sex-specific grey matter abnormalities in individuals with chronic insomnia.

Previous studies have reported sex differences in altered brain function in patients with chronic insomnia (CI). However, sex-related alterations in brain morphology have rarely been investigated. This study aimed to investigate sex-specific grey matter (GM) alterations in patients with CI and to examine the relationship between GM alterations and neuropsychological assessments. Ninety-three (65 females and 28 males) patients and 78 healthy (50 females and 28 males) controls were recruited. Structural magnetic resonance imaging data were analysed using voxel-based morphometry to test for interactions between sex and diagnosis. Spearman's correlation was used to assess the associations among structure, disease duration, and sleep-, mood-, and cognition-related assessments. Males with CI showed reduced GM volume in the left inferior parietal lobe, left middle cingulate cortex, and right supramarginal gyrus. Females with CI showed increased GM volume in the right Rolandic operculum. Moreover, mood-related assessments were negatively correlated with GM volumes in the right supramarginal gyrus and left inferior parietal lobe in the male patients, and cognitive-related assessments were positively correlated with GM volumes in the Rolandic operculum in the female patients. Our findings indicate sex-specific alterations in brain morphology in CI, thereby broadening our understanding of sex differences in CI and potentially providing complementary evidence for the development of more effective therapies and individual treatments.