Sex Differences Research Articles

UNRAVELING GENDER DISPARITIES AND PROGNOSTIC INSIGHTS IN MODERATE AORTIC STENOSIS: A RETROSPECTIVE STUDY

Abstract Aortic stenosis (AS) is the most prevalent valvular heart disease in developed countries, associated with reduced survival if severe AS remains untreated. Recent reports note unfavorable outcomes in moderate AS (mAS) patients, challenging optimal intervention timing. Variations in pathophysiology linked to sex differences, involving sex hormones, activation of the renin–angiotensin–aldosterone system, and dysregulation in collagen synthesis, have been observed. Yet, limited data exists on sex–specific differences in mAS outcomes. This single–center, retrospective study included 150 patients (median age 79±13 years, female sex 48%) diagnosed with mAS who underwent comprehensive echocardiography in IRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico of Milan from July 2022 to October 2023. Clinical data, encompassing demographics details and therapy, were obtained via record reviews and phone interviews. Death verification relied on the ‘Sistema Informativo Socio–Sanitario Regione Lombardia’ database. Echocardiographic records were digitally stored and post–processed by four independent investigators using Medimatic ComPACS workstation. Men were significantly younger than women (75±10 vs 79±9.7 years, p= 0.016). They exhibited lower left ventricular (LV) ejection fraction, larger LV end–systolic volume and stroke volume compared to women (54±7 vs 59±10%; p=0.028. 55±36 vs 31±13 ml; p<0.001. 83±18 vs 75±18 ml; p=0.030). Men had significantly smaller aortic valve (AV) area index to body surface area (BSA) (0.6±0.09 vs 0.7±0.1 cmq/mq; p<0.001) and lower doppler velocity index (0.32±0.07 vs 0.38±0.11; p<0.001) than women. Coronary artery disease and smoking were more frequent in men (53.3 vs 46.7%; p=0,002. 52.6 vs 47.4%; p<0.001). In survival analysis, 15% of women and 30.8% of men experienced events, with male gender independently associated with the composite outcome (all–cause mortality and AV replacement) over a mean follow–up time of 200 ± 133 days, showing a median survival of 244±16 vs 255±15 days for females (p–value=0.025). In multivariable analysis including relevant clinical variables (hemoglobin and AV index to BSA), male sex remained independently associated with the composite outcome (hazard ratio 2,01; CI 1.0–4.17; p=0.05). Women diagnosed with mAS exhibited a lower incidence of AV replacement and all–cause mortality. These findings may suggest the existence of different clinical and echocardiographic phenotypes among patients with AS.

REAL–WORLD SINGLE CENTER EXPERIENCE WITH THE WEARABLE CARDIOVERTER DEFIBRILLATOR: SEX DIFFERENCES IN RISK STRATIFICATION FOR SUDDEN CARDIAC DEATH

Abstract Background Wearable cardioverter defibrillator (WCD) demonstrated an important role for prevention of sudden cardiac death in patients with advanced heart failure and reduced left ventricular ejection fraction. Although in randomized trial there are no gender difference in WCD use and defibrillator (ICD) implantation rate, real world data in female patients is lacking. Purposes: We aimed to describe the sex differences in WCD use, the rate of cardiac events detected with WCD and the rate of ICD implantation after WCD use in women in a real–world single center experience with reduced left ventricular ejection fraction or prior ventricular tachyarrhythmia. Methods and Results According with the current guidelines indications, between August 2017 and June 2023 ninety–six consecutive patients (mean age 66.0±11.1 years) received a WCD at Piacenza Hospitals and were retrospectively included in this analysis. There were no differences in clinical characteristics between female (18 patients, 18,8%) and male: in particular baseline left ventricular ejection fraction (LV EF) were similar between the two groups (29.5±5.2 vs 27.9±7.9, p=0.23) and no differences were found in the rate of ischaemic cardiopathy (66,6% vs 69,2% p=0.51). After 3–months follow up with WCD use, a similar rate of ventricular arrhythmias were found in the two groups (5.5% vs 3.8%, p=0.48) and no ventricular fibrillation was detected. The WCD usage period and median daily wear time were not different between female and male (55.2±50.6 vs 56.2±34.8 days p=0.53, 21.0±6.4 vs 23.1±1.5 hours p=0.48, respectively). However women presented a better LV EF improvement (12.2±9.7 vs 7.2±6.8, p=0.01), with a significant lower ICD implantation rate at the end of WCD use (55.5% vs 43.8%; p< 0.01). Conclusions In this real word analysis women presented a nice compliance using WCD. In spite of a similar burden of ventricular arrhythmic events, women presented a better LV EF improvement with a significant lower ICD implantation rate.

Increasing precision during neuromodulator injections for frontal rhytids-Using ultrasound imaging to identify the line of convergence.

Recent research introduced the concept of the "line of convergence" as a guide for injectors to enhance precision and avoid complications when treating the frontalis muscle with toxins. However, currently, no pre-injection ultrasound scanning is employed to increase precision and reduce adverse events when searching for the line of convergence. To explore the feasibility and practicality of implementing pre-injection ultrasound scanning into aesthetic neuromodulator treatments of the forehead. The sample of this study consisted of n = 55 volunteers (42 females and 13 males), with a mean age of 42.24 (10.3) years and a mean BMI of 25.07 (4.0) kg/m2. High-frequency ultrasound imaging was utilized to measure the thickness, length, and contractility of the frontal soft tissue and to determine the precise location of the line of convergence during maximal frontalis muscle contraction. The results revealed that the line of convergence was located at 58.43% (8.7) of the total forehead height above the superior border of the eyebrow cilia without a statistically significant difference between sex, age, or BMI. With frontalis muscle contraction, the forehead shortens in males by 25.90% (6.5), whereas in females it shortens only by 21.74% (5.1), with p < 0.001 for sex differences. This study demonstrated the feasibility and practicality of pre-injection ultrasound scanning for facial aesthetic neuromodulator treatments. Knowing the location of the line of convergence, injectors can determine precisely and on an individual basis where to administer the neuromodulator deep or superficial or when the injection location is at risk to cause eyebrow ptosis.

Sex difference in the associations among risk factors with gastroesophageal reflux disease in a large Taiwanese population study

BackgroundGastroesophageal reflux disease (GERD) is a common global health issue. Previous studies have revealed a higher prevalence of GERD in females than in males, however few studies have investigated sex differences in the risk factors associated with GERD. Therefore, the aim of this population-based study was to examine sex differences in the risk factors for GERD in a large cohort of over 120,000 Taiwanese participants.MethodsWe enrolled 121,583 participants (male: 43,698; female: 77,885; mean age 49.9 ± 11.0 years) from the Taiwan Biobank. The presence of GERD was ascertained using self-reported questionnaires. Sex differences in the risk factors associated with GERD were examined using multivariable logistic regression analysis.ResultsThe overall prevalence of GERD was 13.7%, including 13.0% in the male participants and 14.1% in the female participants (p < 0.001). Multivariable analysis showed that older age, hypertension, smoking history, alcohol history, low fasting glucose, and low uric acid were significantly associated with GERD in the male participants. In the female participants, older age, diabetes, hypertension, smoking history, alcohol history, low systolic blood pressure, low fasting glucose, high hemoglobin, high total cholesterol, low high-density lipoprotein cholesterol (HDL-C), low low-density lipoprotein cholesterol, and low uric acid were significantly associated with GERD. Significant interactions were found between sex and age (p < 0.001), diabetes (p < 0.001), smoking history (p < 0.001), fasting glucose (p = 0.002), triglycerides (p = 0.001), HDL-C (p = 0.001), and estimated glomerular filtration rate (p = 0.002) on GERD.ConclusionsOur results showed a higher prevalence of GERD among females compared to males. Furthermore, sex differences were identified in the risk factors associated with GERD, and older age, diabetes, smoking history, and low HDL-C were more closely related to GERD in females than in males.

Modeling brain sex in the limbic system as phenotype for female-prevalent mental disorders

BackgroundSex differences exist in the prevalence and clinical manifestation of several mental disorders, suggesting that sex-specific brain phenotypes may play key roles. Previous research used machine learning models to classify sex from imaging data of the whole brain and studied the association of class probabilities with mental health, potentially overlooking regional specific characteristics.MethodsWe here investigated if a regionally constrained model of brain volumetric imaging data may provide estimates that are more sensitive to mental health than whole brain-based estimates. Given its known role in emotional processing and mood disorders, we focused on the limbic system. Using two different cohorts of healthy subjects, the Human Connectome Project and the Queensland Twin IMaging, we investigated sex differences and heritability of brain volumes of limbic structures compared to non-limbic structures, and subsequently applied regionally constrained machine learning models trained solely on limbic or non-limbic features. To investigate the biological underpinnings of such models, we assessed the heritability of the obtained sex class probability estimates, and we investigated the association with major depression diagnosis in an independent clinical sample. All analyses were performed both with and without controlling for estimated total intracranial volume (eTIV).ResultsLimbic structures show greater sex differences and are more heritable compared to non-limbic structures in both analyses, with and without eTIV control. Consequently, machine learning models performed well at classifying sex based solely on limbic structures and achieved performance as high as those on non-limbic or whole brain data, despite the much smaller number of features in the limbic system. The resulting class probabilities were heritable, suggesting potentially meaningful underlying biological information. Applied to an independent population with major depressive disorder, we found that depression is associated with male–female class probabilities, with largest effects obtained using the limbic model. This association was significant for models not controlling for eTIV whereas in those controlling for eTIV the associations did not pass significance correction.ConclusionsOverall, our results highlight the potential utility of regionally constrained models of brain sex to better understand the link between sex differences in the brain and mental disorders.

Sex-specific impacts of prenatal bisphenol A exposure on genes associated with cortical development, social behaviors, and autism in the offspring’s prefrontal cortex

BackgroundRecent studies have shown that prenatal BPA exposure altered the transcriptome profiles of autism-related genes in the offspring’s hippocampus, disrupting hippocampal neuritogenesis and causing male-specific deficits in learning. However, the sex differences in the effects of prenatal BPA exposure on the developing prefrontal cortex, which is another brain region highly implicated in autism spectrum disorder (ASD), have not been investigated.MethodsWe obtained transcriptome data from RNA sequencing analysis of the prefrontal cortex of male and female rat pups prenatally exposed to BPA or control and reanalyzed. BPA-responsive genes associated with cortical development and social behaviors were selected for confirmation by qRT-PCR analysis. Neuritogenesis of primary cells from the prefrontal cortex of pups prenatally exposed to BPA or control was examined. The social behaviors of the pups were assessed using the two-trial and three-chamber tests. The male-specific impact of the downregulation of a selected BPA-responsive gene (i.e., Sema5a) on cortical development in vivo was interrogated using siRNA-mediated knockdown by an in utero electroporation technique.ResultsGenes disrupted by prenatal BPA exposure were associated with ASD and showed sex-specific dysregulation. Sema5a and Slc9a9, which were involved in neuritogenesis and social behaviors, were downregulated only in males, while Anxa2 and Junb, which were also linked to neuritogenesis and social behaviors, were suppressed only in females. Neuritogenesis was increased in males and showed a strong inverse correlation with Sema5a and Slc9a9 expression levels, whereas, in the females, neuritogenesis was decreased and correlated with Anxa2 and Junb levels. The siRNA-mediated knockdown of Sema5a in males also impaired cortical development in utero. Consistent with Anxa2 and Junb downregulations, deficits in social novelty were observed only in female offspring but not in males.ConclusionThis is the first study to show that prenatal BPA exposure dysregulated the expression of ASD-related genes and functions, including cortical neuritogenesis and development and social behaviors, in a sex-dependent manner. Our findings suggest that, besides the hippocampus, BPA could also exert its adverse effects through sex-specific molecular mechanisms in the offspring’s prefrontal cortex, which in turn would lead to sex differences in ASD-related neuropathology and clinical manifestations, which deserves further investigation.

Does an Aspirin a Day Take the MASLD Away?

Although aspirin is deeply rooted in the most ancient history of medicine, the mechanism of action of this drug was only identified a few decades ago. Aspirin has several indications ranging from its long-known analgesic and antipyretic properties to the more recently discovered antithrombotic, chemopreventive and anti-eclampsia actions. In addition, a recent line of research has identified aspirin as a drug with potential hepatologic indications. This article specifically focuses on the nonalcoholic fatty liver disease/nonalcoholic metabolic dysfunction fatty liver disease/metabolic dysfunction-associated steatotic liver disease (NAFLD/MAFLD/MASLD) field. To this end, the most recently published randomized controlled trial on aspirin for non-cirrhotic MASLD is summarized and discussed. Moreover, previous epidemiologic evidence supporting the notion that aspirin exerts antisteatotic and antifibrotic hepatic effects, which may result in the primary prevention of hepatocellular carcinoma, is also addressed. Next, the putative mechanisms involved are examined, with reference to the effects on adipose tissue and liver and sex differences in the action of aspirin. It is concluded that these novel findings on aspirin as a "hepatologic drug" deserve additional in-depth evaluation.

13C-Stable isotope resolved metabolomics uncovers dynamic biochemical landscape of gut microbiome-host organ communications in mice

BackgroundGut microbiome metabolites are important modulators of host health and disease. However, the overall metabolic potential of the gut microbiome and interactions with the host organs have been underexplored.ResultsUsing stable isotope resolved metabolomics (SIRM) in mice orally gavaged with 13C-inulin (a tracer), we first observed dynamic enrichment of 13C-metabolites in cecum contents in the amino acids and short-chain fatty acid metabolism pathways. 13C labeled metabolites were subsequently profiled comparatively in plasma, liver, brain, and skeletal muscle collected at 6, 12, and 24 h after the tracer administration. Organ-specific and time-dependent 13C metabolite enrichments were observed. Carbons from the gut microbiome were preferably incorporated into choline metabolism and the glutamine-glutamate/GABA cycle in the liver and brain, respectively. A sex difference in 13C-lactate enrichment was observed in skeletal muscle, which highlights the sex effect on the interplay between gut microbiome and host organs. Choline was identified as an interorgan metabolite derived from the gut microbiome and fed the lipogenesis of phosphatidylcholine and lysophosphatidylcholine in host organs. In vitro and in silico studies revealed the de novo synthesis of choline in the human gut microbiome via the ethanolamine pathway, and Enterococcus faecalis was identified as a major choline synthesis species. These results revealed a previously underappreciated role for gut microorganisms in choline biosynthesis.ConclusionsMulticompartmental SIRM analyses provided new insights into the current understanding of dynamic interorgan metabolite transport between the gut microbiome and host at the whole-body level in mice. Moreover, this study singled out microbiota-derived metabolites that are potentially involved in the gut-liver, gut-brain, and gut-skeletal muscle axes.1fG1mJvQp124HCbb2HZFdqVideo

Effects of Obesity and Sex on Ventilatory Constraints during a Cardiopulmonary Exercise Test in Children.

Ventilatory constraints are common during exercise in children, but the effects of obesity and sex are unclear. The purpose of this study was to investigate the effects of obesity and sex on ventilatory constraints (i.e., expiratory flow limitation (EFL) and dynamic hyperinflation) during a maximal exercise test in children. Thirty-four 8-12-year-old children without obesity (18 females) and 54 with obesity (23 females) completed pulmonary function testing and maximal cardiopulmonary exercise tests. EFL was calculated as the overlap between tidal flow-volume loops during exercise and maximal expiratory flow-volume loops. Dynamic hyperinflation was calculated as the change in inspiratory capacity from rest to exercise. Maximal minute ventilation was not different between children with and without obesity. Average end-inspiratory lung volumes (EILV) and end-expiratory lung volumes (EELV) were significantly lower during exercise in children with obesity (EILV: 68.8 ± 0.7%TLC; EELV: 41.2 ± 0.5%TLC) compared with children without obesity (EILV: 73.7 ± 0.8%TLC; EELV: 44.8 ± 0.6%TLC; P < 0.001). Throughout exercise, children with obesity experienced more EFL and dynamic hyperinflation compared with those without obesity (P < 0.001). Also, males experienced more EFL and dynamic hyperinflation throughout exercise compared with females (P < 0.001). At maximal exercise, the prevalence of EFL was similar in males with and without obesity, however the prevalence of EFL in females was significantly different with 57% of females with obesity experiencing EFL compared with 17% of females without obesity (P < 0.05). At maximal exercise, 44% of children with obesity experienced dynamic hyperinflation compared with 12% of children without obesity (P = 0.002). Obesity in children increases the risk of developing mechanical ventilatory constraints such as dynamic hyperinflation and EFL. Sex differences were apparent with males experiencing more ventilatory constraints compared with females.

A practical, step-by-step, guide to taxonomic comparisons using Procrustes geometric morphometrics and user-friendly software (part B): group comparisons

In this second part of the study, using a ‘clean’ dataset without very low precision landmarks and outliers, I describe how to compare mandibular size and shape using Procrustes methods in adult North American marmots. After demonstrating that sex differences are negligible, females and males are pooled together with specimens of unknown sex and species are compared using a battery of tests, that estimate both statistical significance and effect size. The importance of allometric variation and its potential effect on shape differences is also explored. Finally, to provide potential clues on founder effects, I compare the magnitude of variance in mandibular size and shape between the Vancouver Island marmot (VAN) and the hoary marmot, its sister species on the mainland. In almost all main analyses, I explore the sensitivity of results to heterogeneous sample size and small samples using subsamples and randomized selection experiments. For both size and shape, I find a degree of overlap among species variation but, with very few exceptions, mean interspecific differences are well supported in all analyses. Shape, in particular, is an accurate predictor of taxonomic affiliation. Allometry in adults, however, explains a modest amount of within-species shape change. Yet, there is a degree of divergence in allometric trajectories that seems consistent with subgeneric separation. VAN is the most distinctive species for mandibular shape and mandibular morphology suggests a long history of reduced variation in this insular population. Geometric morphometrics (GMM) is a powerful tool to aid taxonomic research. Regardless of the effectiveness of this family of methods and the apparent robustness of results obtained with GMM, however, large samples and careful measurements remain essential for accuracy. Even with excellent data, morphometrics is important, but its findings must be corroborated with an integrative approach that combines multiple lines of evidence to taxonomic assessment. The analytical protocol I suggest is described in detail, with a summary checklist, in the Appendix, not to miss important steps. All the analyses can be replicated using the entire dataset, which is freely available online. Beginners may follow all the steps, whereas more experienced researchers can focus on one specific aspect and read only the relevant chapter. There are limitations, but the protocol is flexible and easy to improve or implement using a programming language such as R.

Gut–Brain Axis: Focus on Sex Differences in Neuroinflammation

In recent years, there has been a growing interest in the concept of the “gut–brain axis”. In addition to well-studied diseases associated with an imbalance in gut microbiota, such as cancer, chronic inflammation, and cardiovascular diseases, research is now exploring the potential role of gut microbial dysbiosis in the onset and development of brain-related diseases. When the function of the intestinal barrier is altered by dysbiosis, the aberrant immune system response interacts with the nervous system, leading to a state of “neuroinflammation”. The gut microbiota–brain axis is mediated by inflammatory and immunological mechanisms, neurotransmitters, and neuroendocrine pathways. This narrative review aims to illustrate the molecular basis of neuroinflammation and elaborate on the concept of the gut–brain axis by virtue of analyzing the various metabolites produced by the gut microbiome and how they might impact the nervous system. Additionally, the current review will highlight how sex influences these molecular mechanisms. In fact, sex hormones impact the brain–gut microbiota axis at different levels, such as the central nervous system, the enteric nervous one, and enteroendocrine cells. A deeper understanding of the gut–brain axis in human health and disease is crucial to guide diagnoses, treatments, and preventive interventions.

Failure of senolytic treatment to prevent cognitive decline in a female rodent model of aging

There are sex differences in vulnerability and resilience to the stressors of aging and subsequent age-related cognitive decline. Cellular senescence occurs as a response to damaging or stress-inducing stimuli. The response includes a state of irreversible growth arrest, the development of a senescence-associated secretory phenotype, and the release of pro-inflammatory cytokines associated with aging and age-related diseases. Senolytics are compounds designed to eliminate senescent cells. Our recent work indicates that senolytic treatment preserves cognitive function in aging male F344 rats. The current study examined the effect of senolytic treatment on cognitive function in aging female rats. Female F344 rats (12 months) were treated with dasatinib (1.2 mg/kg) + quercetin (12 mg/kg) or ABT-263 (12 mg/kg) or vehicle for 7 months. Examination of the estrus cycle indicated that females had undergone estropause during treatment. Senolytic treatment may have increased sex differences in behavioral stress responsivity, particularly for the initial training on the cued version of the watermaze. However, pre-training on the cue task reduced stress responsivity for subsequent spatial training and all groups learned the spatial discrimination. In contrast to preserved memory observed in senolytic-treated males, all older females exhibited impaired episodic memory relative to young (6-month) females. We suggest that the senolytic treatment may not have been able to compensate for the loss of estradiol, which can act on aging mechanisms for anxiety and memory independent of cellular senescence.

Tissue-specific sex differences in pediatric and adult immune cell composition and function

Sex-based differences in immune cell composition and function can contribute to distinct adaptive immune responses. Prior work has quantified these differences in peripheral blood, but little is known about sex differences within human lymphoid tissues. Here, we characterized the composition and phenotypes of adaptive immune cells from male and female ex vivo tonsils and evaluated their responses to influenza antigens using an immune organoid approach. In a pediatric cohort, female tonsils had more memory B cells compared to male tonsils direct ex vivo and after stimulation with live-attenuated but not inactivated vaccine, produced higher influenza-specific antibody responses. Sex biases were also observed in adult tonsils but were different from those measured in children. Analysis of peripheral blood immune cells from in vivo vaccinated adults also showed higher frequencies of tissue homing CD4 T cells in female participants. Together, our data demonstrate that distinct memory B and T cell profiles are present in male vs. female lymphoid tissues and peripheral blood respectively and suggest that these differences may in part explain sex biases in response to vaccines and viruses.

Sepsis compromises post-ischemic stroke neurological recovery and is associated with sex differences

AimsInfection is a complication after stroke and outcomes vary by sex. Thus, we investigated if sepsis affects brain from ischemic stroke and sex involvement. Main methodsMale and female Wistar rats, were submitted to middle cerebral artery occlusion (MCAO) and after 7 days sepsis to cecal ligation and perforation (CLP). Infarct size, neuroinflammation, oxidative stress, and mitochondrial activity were quantified 24 h after CLP in the prefrontal cortex and hippocampus. Survival and neurological score were assessed up to 15 days after MCAO or 8 days after CLP (starting at 2 h after MCAO) and memory at the end. Key findingsCLP decreased survival, increased neurological impairments in MCAO females. Early, in male sepsis following MCAO led to increased glial activation in the brain structures, and increased TNF-α and IL-1β in the hippocampus. All groups had higher IL-6 in both tissues, but the hippocampus had lower IL-10. CLP potentiated myeloperoxidase (MPO) in the prefrontal cortex of MCAO male and female. In MCAO+CLP, only male increased MPO and nitrite/nitrate in hippocampus. Males in all groups had protein oxidation in the prefrontal cortex, but only MCAO+CLP in the hippocampus. Catalase decreased in the prefrontal cortex and hippocampus of all males and females, and MCAO+CLP only increased this activity in males. Female MCAO+CLP had higher prefrontal cortex complex activity than males. In MCAO+CLP-induced long-term memory impairment only in females. SignificanceThe parameters evaluated for early sepsis after ischemic stroke show a worse outcome for males, while females are affected during long-term follow-up.

Sex- and species-specific contribution of CD99 to T cell costimulation during multiple sclerosis

BackgroundDifferences in immune responses between women and men are leading to a strong sex bias in the incidence of autoimmune diseases that predominantly affect women, such as multiple sclerosis (MS). MS manifests in more than twice as many women, making sex one of the most important risk factor. However, it is incompletely understood which genes contribute to sex differences in autoimmune incidence. To address that, we conducted a gene expression analysis in female and male human spleen and identified the transmembrane protein CD99 as one of the most significantly differentially expressed genes with marked increase in men. CD99 has been reported to participate in immune cell transmigration and T cell regulation, but sex-specific implications have not been comprehensively investigated.MethodsIn this study, we conducted a gene expression analysis in female and male human spleen using the Genotype-Tissue Expression (GTEx) project dataset to identify differentially expressed genes between women and men. After successful validation on protein level of human immune cell subsets, we assessed hormonal regulation of CD99 as well as its implication on T cell regulation in primary human T cells and Jurkat T cells. In addition, we performed in vivo assays in wildtype mice and in Cd99-deficient mice to further analyze functional consequences of differential CD99 expression.ResultsHere, we found higher CD99 gene expression in male human spleens compared to females and confirmed this expression difference on protein level on the surface of T cells and pDCs. Androgens are likely dispensable as the cause shown by in vitro assays and ex vivo analysis of trans men samples. In cerebrospinal fluid, CD99 was higher on T cells compared to blood. Of note, male MS patients had lower CD99 levels on CD4+ T cells in the CSF, unlike controls. By contrast, both sexes had similar CD99 expression in mice and Cd99-deficient mice showed equal susceptibility to experimental autoimmune encephalomyelitis compared to wildtypes. Functionally, CD99 increased upon human T cell activation and inhibited T cell proliferation after blockade. Accordingly, CD99-deficient Jurkat T cells showed decreased cell proliferation and cluster formation, rescued by CD99 reintroduction.ConclusionsOur results demonstrate that CD99 is sex-specifically regulated in healthy individuals and MS patients and that it is involved in T cell costimulation in humans but not in mice. CD99 could potentially contribute to MS incidence and susceptibility in a sex-specific manner.

Sex and APOE Genotype Influence Respiratory Function Under Hypoxic and Hypoxic-Hypercapnic Conditions.

The apolipoprotein (APOE) gene has been studied due to its influence on Alzheimer's disease (AD) development and work in an APOE mouse model recently demonstrated impaired respiratory motor plasticity following spinal cord injury (SCI). Individuals with AD often co-present with obstructive sleep apnea (OSA) characterized by cessations in breathing during sleep. Despite the prominence of APOE genotype and sex as factors in AD progression, little is known about the impact of these variables on respiratory control. Ventilation is tightly regulated across many systems, with respiratory rhythm formation occurring in the brainstem but modulated in response to chemoreception. Alterations within these modulatory systems may result in disruptions of appropriate respiratory control and ultimately, disease. Using mice expressing two different humanized APOE alleles, we characterized how sex and the presence of APOE3 or APOE4 influences ventilation during baseline breathing (normoxia) and during respiratory challenge. We show that sex and APOE genotype influence breathing during hypoxic challenge, which may have clinical implications in the context of AD and OSA. Additionally, female mice, while responding robustly to hypoxia, were unable to recover to baseline respiratory levels, emphasizing sex differences in disordered breathing.

Sex differences in hippocampal β-adrenergic receptor subtypes drive retrieval, retention, and learning of cocaine-associated memories

BackgroundDrug seeking behavior occurs in response to environmental contexts and drug-associated cues. The presence of these pervasive stimuli impedes abstinence success. β-adrenergic receptors (β-ARs) have a long-standing historical implication in driving processes associated with contextual memories, including drug-associated memories in substance use disorders. However, sex differences in the role of β-adrenergic receptors in drug memories remain unknown.HypothesisPrior reports indicate a selective role for β2-ARs in retrieval and retention of contextual drug memories in males, and substantial sex differences exist in the expression of β-ARs of male and female rats. Therefore, we hypothesized that there are sex differences in selective recruitment of β-ARs during different stages of memory encoding and retrieval.MethodsThe role of β-ARs in driving retrieval and learning of contextual cocaine memories was investigated using cocaine conditioned place preference (CPP) in adult male and female Sprague–Dawley rats. Rats were infused directly to the dorsal hippocampus with Propranolol (β1 and β2) or ICI-118,551 (β1) and/or Betaxolol (β2), immediately prior to testing (retrieval), or paired to each cocaine (10 mg/kp, IP) conditioning session (learning).ResultsIn males, administration of either β1, β2, or combined β1 and β2-ARs before the initial CPP testing reduced the expression of a CPP compared to vehicle administration. In females, β2-ARs transiently decreased CPP memories, whereas β1 had long lasting but not immediate effects to decrease CPP memories. Additionally, β1 and combined β1 and β2-ARs had immediate and persistent effects to decrease CPP memory expression. DG Fos + neurons predicted cocaine CPP expression in males, whereas CA1 and CA3 Fos + neurons predicted cocaine CPP expression in females.ConclusionThere are significant sex differences in the role of dorsal hippocampus β-ARs in the encoding and expression of cocaine conditioned place preference. Furthermore, sub regions of the dorsal hippocampus appear to activate differently between male and female rats during CPP. Therefore DG, CA3, and CA1 may have separate region- and sex-specific impacts on driving drug- associated, or context-associated cues.

Sex differences in neuronal activation in the cortex and midbrain during quinine-adulterated alcohol intake.

Continued alcohol consumption despite negative consequences is a core symptom of alcohol use disorder. This is modeled in mice by pairing negative stimuli with alcohol, such as adulterating alcohol solution with quinine. Mice consuming alcohol under these conditions are considered to be engaging in aversion-resistant intake. Previously, we have observed sex differences in this behavior, with females more readily expressing aversion-resistant consumption. We also identified three brain regions that exhibited sex differences in neuronal activation during quinine-alcohol drinking: ventromedial prefrontal cortex (vmPFC), posterior insular cortex (PIC), and ventral tegmental area (VTA). Specifically, male mice showed increased activation in vmPFC and PIC, while females exhibited increased activation in VTA. In this study, we aimed to identify what specific type of neurons are activated in these regions during quinine-alcohol drinking. We assessed quinine-adulterated alcohol intake using the two-bottle choice procedure. We also utilized RNAscope in situ hybridization in the three brain regions that previously exhibited a sex difference to examine colocalization of Fos, glutamate, GABA, and dopamine. Females showed increased aversion-resistant alcohol consumption compared to males. We also found that males had higher colocalization of glutamate and Fos in vmPFC and PIC, while females had greater dopamine and Fos colocalization in the VTA. Collectively, these experiments suggest that glutamatergic output from the vmPFC and PIC may have a role in suppressing, and dopaminergic activity in the VTA may promote, aversion-resistant alcohol consumption. Future experiments will examine neuronal circuits that contribute to sex differences in aversion resistant consumption.

Sex differences and risk factors of self-reported suicide attempts in middle-aged Chinese Han patients with first-episode drug-naïve anxious depression: a large-scale cross-sectional study.

This study aims to investigate sex differences and risk factors for self-reported suicide attempts among Chinese Han middle-aged patients with first-episode drug-naïve (FEDN) anxious depression (AD). A total of 1796 patients with FEDN major depressive disorder were enrolled in this study, including 341 middle-aged patients with AD. We compared the prevalence, demographics, and clinical characteristics of suicide attempts between male and female patients with FEDN middle-aged AD. We also explored the risk factors for self-reported suicide attempts in this population using binary logistic regression analysis. The male/female ratio was 91/250 and the age of onset was 51.50 ± 4.13. Our results showed that there were no significant sex differences in the prevalence of self-reported suicide attempts in middle-aged patients with FEDN AD. However, we did find significant differences in several demographic and clinical characteristics between self-reported suicide attempters and non-suicide attempters. Moreover, severe anxiety, measured by the Hamilton Anxiety Rating Scale score, was identified as a risk factor for self-reported suicide attempts in female middle-aged AD patients. Additionally, elevated thyroid peroxidase antibody (TPOAb) levels were linked to self-reported suicide attempts in male AD patients. Our findings suggest that there are no significant sex differences in the prevalence of self-reported suicide attempts in this population, but there may be sex-specific risk factors for self-reported suicide attempts in middle-aged AD. Clinical psychiatrists need to pay attention to thyroid hormone levels in middle-aged anxious depression.

Impact of Apolipoprotein E4 on the Locus Coeruleus Functional Connectivity in Preclinical Alzheimer's Disease.

Recent interest has surged in the locus coeruleus (LC) for its early involvement in Alzheimer's disease (AD), notably concerning the apolipoprotein ɛ4 allele (APOE4). This study aimed to discern LC functional connectivity (FC) variations in preclinical AD subjects, dissecting the roles of APOE4 carrier status and amyloid-β (Aβ) deposition. A cohort of 112 cognitively intact individuals, all Aβ-positive, split into 70 APOE4 noncarriers and 42 carriers, underwent functional MRI scans, neuropsychological assessments, and APOE genotyping. The research utilized seed to voxel analysis for illustrating LC rsFC discrepancies between APOE4 statuses and employed a general linear model to examine the interactive influence of APOE4 carrier status and Aβ deposition on LC FC values. The investigation revealed no significant differences in sex, age, or SUVR between APOE4 carriers and noncarriers. It found diminished LC FC with the occipital cortex in APOE4 carriers and identified a significant interaction between APOE4 carrier status and temporal lobe SUVR in LC FC with the occipital cortex. This interaction suggested a proportional increase in LC FC for APOE4 carriers. Additional notable interactions were observed affecting LC FC with various brain regions, indicating a proportional decrease in LC FC for APOE4 carriers. These findings confirm that APOE4 carrier status significantly influences LC FC in preclinical AD, showcasing an intricate relationship with regional Aβ deposition. This underscores the critical role of genetic and pathological factors in early AD pathophysiology, offering insights into potential biomarkers for early detection and intervention strategies.