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The hypocretin (Hcrt) system modulates arousal and anxiety-related behaviors and has been considered as a novel treatment target for stress-related affective disorders. We examined the effects of Hcrt acting in the nucleus accumbens shell (NAcSh) and anterodorsal bed nucleus of the stria terminalis (adBNST) on social behavior in male and female California mice (Peromyscus californicus). In female but not male California mice, infusion of Hcrt1 into NAcSh decreased social approach. Weak effects of Hcrt1 on social vigilance were observed in both females and males. No behavioral effects of Hcrt1 infused into the adBNST were observed. Analyses of sequencing data from California mice and Mus musculus NAc showed that Hcrtr2 was more abundant than Hcrtr1, so we infused the selective Hcrt receptor 2 antagonist into the NAcSh, which increased social approach in females previously exposed to social defeat. A calcium imaging study in the NAcSh of females before and after stress exposure showed that neural activity increased immediately following the expression of social avoidance but not during freezing behavior. This observation is consistent with previous studies that identified populations of neurons in the NAc that drive avoidance. Intriguingly, calcium transients were not affected by stress. These data suggest that hypocretin acting in the NAcSh plays a key role in modulating stress-induced social avoidance.

Previous studies have reported alterations in cortical thickness in autism. However, few have included enough autistic females to determine if there are sex specific differences in cortical structure in autism. This longitudinal study aimed to investigate autistic sex differences in cortical thickness and trajectory of cortical thinning across childhood. Participants included 290 autistic (88 females) and 139 nonautistic (60 females) individuals assessed at up to 4 timepoints spanning ~2-13 years of age (918 total MRI timepoints). Estimates of cortical thickness in early and late childhood as well as the trajectory of cortical thinning were modeled using spatiotemporal linear mixed effects models of age-by-sex-by-diagnosis. Additionally, the spatial correspondence between cortical maps of sex-by-diagnosis differences and neurotypical sex differences were evaluated. Relative to their nonautistic peers, autistic females had more extensive cortical differences than autistic males. These differences involved multiple functional networks, and were mainly characterized by thicker cortex at ~3 years of age and faster cortical thinning in autistic females. Cortical regions in which autistic alterations were different between the sexes significantly overlapped with regions that differed by sex in neurotypical development. Autistic females and males demonstrated some shared differences in cortical thickness and rate of cortical thinning across childhood relative to their nonautistic peers, however these areas were relatively small compared to the widespread differences observed across the sexes. These results support evidence of sex-specific neurobiology in autism and suggest that processes that regulate sex differentiation in the neurotypical brain contribute to sex differences in the etiology of autism.

The Four Core Genotypes (FCG) mouse model has become a valuable model to study the mechanistic basis for biological sex differences. This model allows discrimination between influences of gonadal sex (ovaries or testes) from those associated with genetic sex (presence of XX or XY chromosome complement). FCG mice have illuminated distinct effects of gonadal and chromosomal sex on traits ranging from brain structure and behavior to vulnerability to obesity, atherosclerosis, multiple sclerosis, Alzheimers and other diseases. A recent study determined that the YSry- chromosome used in a specific line of C57BL/6J FCG mice harbors nine genes that have been duplicated from the X chromosome. This report raised concern that scores of publications that previously used the FCG model may therefore be flawed, but did not provide details regarding how studies can be evaluated for potential impact (or lack of impact) of the translocation. Here we (1) provide a practical description of the genetic translocation for researchers using the FCG model, (2) document that a majority of the studies cited in the recent report are unlikely to be affected by the translocation, (3) provide a scheme for interpreting data from studies with FCG mice harboring the YSry- translocation, and (4) delineate expression levels of the nine translocated genes across tissue/cell types as a filter for evaluating their potential involvement in specific phenotypes.

Drosophila prolongata is a member of the melanogaster species group and rhopaloa subgroup native to the subtropical highlands of Southeast Asia. This species exhibits an array of recently evolved male-specific morphological, physiological, and behavioral traits that distinguish it from its closest relatives, making it an attractive model for studying the evolution of sexual dimorphism and testing theories of sexual selection. The lack of genomic resources has impeded the dissection of the molecular basis of sex-specific development and behavior in this species. To address this, we assembled the genome of D. prolongata using long-read sequencing and Hi-C scaffolding, resulting in a highly complete and contiguous (scaffold N50 2.2 Mb) genome assembly of 220 Mb. The repetitive content of the genome is 24.6%, the plurality of which are long terminal repeats retrotransposons (33.2%). Annotations based on RNA-seq data and homology to related species revealed a total of 19,330 genes, of which 16,170 are protein-coding. The assembly includes 98.5% of Diptera BUSCO genes, including 93.8% present as a single copy. Despite some likely regional duplications, the completeness of this genome suggests that it can be readily used for gene expression, genome-wide association studies (GWAS), and other genomic analyses.

Sex and gender-biological and social constructs-significantly impact the prevalence of protective and risk factors, influencing the burden of Alzheimer's disease (AD; amyloid beta and tau) and other pathologies (e.g., cerebrovascular disease) which ultimately shape cognitive trajectories. Understanding the interplay of these factors is central to understanding resilience and resistance mechanisms explaining maintained cognitive function and reduced pathology accumulation in aging and AD. In this narrative review, the ADDRESS! Special Interest Group (Alzheimer's Association) adopted a multidisciplinary approach to provide the foundations and recommendations for future research into sex- and gender-specific drivers of resilience, including a sex/gender-oriented review of risk factors, genetics, AD and non-AD pathologies, brain structure and function, and animal research. We urge the field to adopt a sex/gender-aware approach to resilience to advance our understanding of the intricate interplay of biological and social determinants and consider sex/gender-specific resilience throughout disease stages. HIGHLIGHTS: Sex differences in resilience to cognitive decline vary by age and cognitive status. Initial evidence supports sex-specific distinctions in brain pathology. Findings suggest sex differences in the impact of pathology on cognition. There is a sex-specific change in resilience in the transition to clinical stages. Gender and sex factors warrant study: modifiable, immune, inflammatory, and vascular.

Patients with degenerative cervical myelopathy (DCM) experience structural and functional brain reorganization. However, few studies have investigated the influence of sex on cerebral alterations. The present study investigates the role of sex on brain functional connectivity (FC) and global network topology in DCM and healthy controls (HCs). The resting-state functional MRI data was acquired for 100 patients (58 males vs. 42 females). ROI-to-ROI FC and network topological features were characterized for each patient and HC. Group differences in FC and network topological features were examined. Compared to healthy counterparts, DCM males exhibited higher FC between vision-related brain regions, and cerebellum, brainstem, and thalamus, but lower FC between the intracalcarine cortex and frontal and somatosensory cortices, while DCM females demonstrated higher FC between the thalamus and cerebellar and sensorimotor regions, but lower FC between sensorimotor and visual regions. DCM males displayed higher FC within the cerebellum and between the posterior cingulate cortex (PCC) and vision-related regions, while DCM females displayed higher FC between frontal regions and the PCC, cerebellum, and visual regions. Additionally, DCM males displayed significantly greater intra-network connectivity and efficiency compared to healthy counterparts. Results from the present study imply sex-specific supraspinal functional alterations occur in patients with DCM.

The prevalence and progression of cancer differ in males and females, and thus, sexual dimorphism in tumor development directly impacts clinical research and medicine. Long non-coding RNAs (lncRNAs) are increasingly recognized as important players in gene expression and various cellular processes, including cancer development and progression. In recent years, lncRNAs have been implicated in the differences observed in cancer incidence, progression, and treatment responses between men and women. Here, we present a brief overview of the current knowledge regarding the role of lncRNAs in cancer sex dimorphism, focusing on how they affect epigenetic processes in male and female mammalian cells. We discuss the potential mechanisms by which lncRNAs may contribute to sex differences in cancer, including transcriptional control of sex chromosomes, hormonal signaling pathways, and immune responses. We also propose strategies for studying lncRNA functions in cancer sex dimorphism. Furthermore, we emphasize the importance of considering sex as a biological variable in cancer research and the need to investigate the role lncRNAs play in mediating these sex differences. In summary, we highlight the emerging link between lncRNAs and cancer sex dimorphism and their potential as therapeutic targets.

Anisogamy, different-sized male and female gametes, sits at the heart of sexual selection and conflict between the sexes. Sperm producers (males) and egg producers (females) of the same species generally share most, if not all, of the same genome, but selection frequently favours different trait values in each sex for traits common to both. The extent to which this conflict might be resolved, and the potential mechanisms by which this can occur, have been widely debated. Here, we summarize recent findings and emphasize that once the sexes evolve, sexual selection is ongoing, and therefore new conflict is always possible. In addition, sexual conflict is largely a multivariate problem, involving trait combinations underpinned by networks of interconnected genes. Although these complexities can hinder conflict resolution, they also provide multiple possible routes to decouple male and female phenotypes and permit sex-specific evolution. Finally, we highlight difficulty in the study of sexual conflict over shared traits and promising directions for future research.

IntroductionEmerging evidence links changes in the gut microbiome to late-onset Alzheimer's disease (LOAD), necessitating examination of AD mouse models with consideration of the microbiome.MethodsWe used shotgun metagenomics and untargeted metabolomics to study the human amyloid beta knock-in (hAβ-KI) murine model for LOAD compared to both wild-type (WT) mice and a model for early-onset AD (3xTg-AD).ResultsEighteen-month female (but not male) hAβ-KI microbiomes were distinct from WT microbiomes, with AD genotype accounting for 18% of the variance by permutational multivariate analysis of variance (PERMANOVA). Metabolomic diversity differences were observed in females, however no individual metabolites were differentially abundant. hAβ-KI mice microbiomes were distinguishable from 3xTg-AD animals (81% accuracy by random forest modeling), with separation primarily driven by Romboutsia ilealis and Turicibacter species. Microbiomes were highly cage specific, with cage assignment accounting for more than 40% of the PERMANOVA variance between the groups.DiscussionThese findings highlight a sex-dependent variation in the microbiomes of hAβ-KI mice and underscore the importance of considering the microbiome when designing studies that use murine models for AD.HighlightsMicrobial diversity and the abundance of several species differed in human amyloid beta knock-in (hAβ-KI) females but not males. Correlations to Alzheimer's disease (AD) genotype were stronger for the microbiome than the metabolome. Microbiomes from hAβ-KI mice were distinct from 3xTg-AD mice. Cage effects accounted for most of the variance in the microbiome and metabolome.

Gastrointestinal (GI) disruptions and inflammatory bowel disease (IBD) are commonly associated with Parkinsons disease (PD), but how they may impact risk for PD remains poorly understood. Herein, we provide evidence that prodromal intestinal inflammation expedites and exacerbates PD endophenotypes in rodent carriers of the human PD risk allele LRRK2 G2019S in a sex-dependent manner. Chronic intestinal damage in genetically predisposed male mice promotes α-synuclein aggregation in the substantia nigra, loss of dopaminergic neurons and motor impairment. This male bias is preserved in gonadectomized males, and similarly conferred by sex chromosomal complement in gonadal females expressing human LRRK2 G2019S. The early onset and heightened severity of neuropathological and behavioral outcomes in male LRRK2 G2019S mice is preceded by increases in α-synuclein in the colon, α-synuclein-positive macrophages in the colonic lamina propria, and loads of phosphorylated α-synuclein within microglia in the substantia nigra. Taken together, these data reveal that prodromal intestinal inflammation promotes the pathogenesis of PD endophenotypes in male carriers of LRRK2 G2019S, through mechanisms that depend on genotypic sex and involve early accumulation of α-synuclein in myeloid cells within the gut.

BACKGROUND: Autism spectrum disorder (ASD) is currently diagnosed in approximately 1 in 44 children in the United States, based on a wide array of symptoms, including sensory dysfunction and abnormal language development. Boys are diagnosed ~ 3.8 times more frequently than girls. Auditory temporal processing is crucial for speech recognition and language development. Abnormal development of temporal processing may account for ASD language impairments. Sex differences in the development of temporal processing may underlie the differences in language outcomes in male and female children with ASD. To understand mechanisms of potential sex differences in temporal processing requires a preclinical model. However, there are no studies that have addressed sex differences in temporal processing across development in any animal model of ASD. METHODS: To fill this major gap, we compared the development of auditory temporal processing in male and female wildtype (WT) and Fmr1 knock-out (KO) mice, a model of Fragile X Syndrome (FXS), a leading genetic cause of ASD-associated behaviors. Using epidural screw electrodes, we recorded auditory event related potentials (ERP) and auditory temporal processing with a gap-in-noise auditory steady state response (ASSR) paradigm at young (postnatal (p)21 and p30) and adult (p60) ages from both auditory and frontal cortices of awake, freely moving mice. RESULTS: The results show that ERP amplitudes were enhanced in both sexes of Fmr1 KO mice across development compared to WT counterparts, with greater enhancement in adult female than adult male KO mice. Gap-ASSR deficits were seen in the frontal, but not auditory, cortex in early development (p21) in female KO mice. Unlike male KO mice, female KO mice show WT-like temporal processing at p30. There were no temporal processing deficits in the adult mice of both sexes. CONCLUSIONS: These results show a sex difference in the developmental trajectories of temporal processing and hypersensitive responses in Fmr1 KO mice. Male KO mice show slower maturation of temporal processing than females. Female KO mice show stronger hypersensitive responses than males later in development. The differences in maturation rates of temporal processing and hypersensitive responses during various critical periods of development may lead to sex differences in language function, arousal and anxiety in FXS.

Subcutaneous white adipose tissue (scWAT) is a dynamic storage and secretory organ that regulates systemic homeostasis, yet the impact of endurance exercise training (ExT) and sex on its molecular landscape is not fully established. Utilizing an integrative multi-omics approach, and leveraging data generated by the Molecular Transducers of Physical Activity Consortium (MoTrPAC), we show profound sexual dimorphism in the scWAT of sedentary rats and in the dynamic response of this tissue to ExT. Specifically, the scWAT of sedentary females displays -omic signatures related to insulin signaling and adipogenesis, whereas the scWAT of sedentary males is enriched in terms related to aerobic metabolism. These sex-specific -omic signatures are preserved or amplified with ExT. Integration of multi-omic analyses with phenotypic measures identifies molecular hubs predicted to drive sexually distinct responses to training. Overall, this study underscores the powerful impact of sex on adipose tissue biology and provides a rich resource to investigate the scWAT response to ExT.

Early life stress (ELS) is defined as an acute or chronic stressor that negatively impacts a child's development. ELS is associated with substance use and mental health problems. This narrative literature review focuses on sex and gender differences in the effects of ELS on 1) adolescent neuroendocrine development; 2) pubertal brain maturation; and 3) development of internalizing symptoms and subsequent substance use. We posit that ELS may generate larger hormonal dysregulation in females than males during puberty, increasing internalizing symptoms and substance use. Future research should consider sex and gender differences in neuroendocrine developmental processes when studying the link between ELS and negative health outcomes.

Technical innovation in neuroscience introduced powerful tools for measuring and manipulating neuronal activity via optical, chemogenetic, and calcium-imaging tools. These tools were initially tested primarily in male animals but are now increasingly being used in females as well. In this review, we consider how these tools may work differently in males and females. For example, we review sex differences in the metabolism of chemogenetic ligands and their downstream signaling effects. Optical tools more directly alter depolarization or hyperpolarization of neurons, but biological sex and gonadal hormones modulate synaptic inputs and intrinsic excitability. We review studies demonstrating that optogenetic manipulations are sometimes consistent across the rodent estrous cycle but within certain circuits; manipulations can vary across the ovarian cycle. Finally, calcium-imaging methods utilize genetically encoded calcium indicators to measure neuronal activity. Testosterone and estradiol can directly modulate calcium influx, and we consider these implications for interpreting the results of calcium-imaging studies. Together, our findings suggest that these neuroscientific tools may sometimes work differently in males and females and that users should be aware of these differences when applying these methods.

Friedreich's ataxia (FA) is an autosomal recessive disorder caused by reduced frataxin (FXN) expression in mitochondria, where the lethal component is cardiomyopathy. Using the conditional Fxnflox/null::MCK-Cre knock-out (Fxn-cKO) mouse model, we discovered significant sex differences in the progression towards heart failure, with Fxn-cKO males exhibiting a worse cardiac phenotype, low survival rate, kidney and reproductive organ deficiencies. These differences are likely due to a decline in testosterone in Fxn-cKO males. The decrease in testosterone was related to decreased expression of proteins involved in cholesterol transfer into the mitochondria: StAR and TSPO on the outer mitochondrial membrane, and the cholesterol side-chain cleavage enzyme P450scc and ferredoxin on the inner mitochondrial membrane. Expression of excitation-contraction coupling proteins (L-type calcium channel, RyR2, SERCA2, phospholamban and CaMKIIδ) was decreased significantly more in Fxn-cKO males. This is the first study that extensively investigates the sexual dimorphism in FA mouse model with cardiac calcium signaling impairment.

Sexual dimorphism is common throughout the animal kingdom, leading to sex-specific phenotypic differences. The common whitetail skimmer dragonfly, Plathemis lydia (Drury, 1773), is sexually dichromatic, where males of this species display a conspicuous white abdomen and females display a dark brown abdomen. Differences in abdomen conspicuousness between male and female P. lydia are likely attributed to differences in selective pressure where males use their white conspicuous abdomen during male-male territorial chases. We hypothesized that male P. lydia would exhibit wing morphology adaptations to better offset the costs of predation and territoriality and that these adaptations would differ from females. We used field-collected images to quantify differences in body length, wing length, wing area, wing shape, and wing loading between male and female P. lydia. Our results show that male P. lydia have significantly shorter fore and hind wings relative to body size with a higher wing loading when compared to females. We also found that male P. lydia have narrower and pointier fore and hind wings compared to females. These results are consistent with the idea that males are adapted for faster flight, specifically higher acceleration capacity, and higher agility whereas females are adapted for higher maneuverability.

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

Sperm whales exhibit sexual dimorphism and sex-specific latitudinal segregation. Females and their young form social groups and are usually found in temperate and tropical latitudes, while males forage at higher latitudes. Historical whaling data and rare sightings of social groups in high latitude regions of the North Pacific, such as the Gulf of Alaska (GOA) and Bering Sea/Aleutian Islands (BSAI), suggest a more complex distribution than previously understood. Sperm whales are the most sighted and recorded cetacean in marine mammal surveys in these regions but capturing their demographic composition and habitat use has proven challenging. This study detects sperm whale presence using passive acoustic data from seven sites in the GOA and BSAI from 2010 to 2019. Differences in click characteristics between males and females (i.e., inter-click and inter-pulse interval) was used as a proxy for animal size/sex to derive time series of animal detections. Generalized additive models with generalized estimation equations demonstrate how spatiotemporal patterns differ between the sexes. Social groups were present at all recording sites with the largest relative proportion at two seamount sites in the GOA and an island site in the BSAI. We found that the seasonal patterns of presence varied for the sexes and between the sites. Male presence was highest in the summer and lowest in the winter, conversely, social group peak presence was in the winter for the BSAI and in the spring for the GOA region, with the lowest presence in the summer months. This study demonstrates that social groups are not restricted to lower latitudes and capture their present-day habitat use in the North Pacific. It highlights that sperm whale distribution is more complex than accounted for in management protocol and underscores the need for improved understanding of sperm whale demographic composition to better understand the impacts of increasing anthropogenic threats, particularly climate change.

Placerias hesternus, a Late Triassic dicynodont, is one of the last megafaunal synapsids of the Mesozoic. The species has a tusk-like projection on its maxillary bone, known as the caniniform process. This process has been hypothesized to be sexually dimorphic since the 1950s, however this claim has not been thoroughly investigated quantitatively. Here, we examined maxillae, premaxillae, quadrates, and fibulae from a single population from the Placerias Quarry in the Blue Mesa Member of the Chinle Formation, near St. Johns, Arizona, USA to determine if the caniniform process is dimorphic. We made a total of 25 measurements from the four bones and used a maximum likelihood framework to compare the fit of unimodal versus bimodal distributions for each set of measurements. Our results from complete maxillae reveal that the caniniform process has two distinct morphs, with a shorter and longer form. This interpretation is substantiated both by strong statistical support for bimodal distribution of caniniform lengths, and by clustering analysis that clearly distinguishes two morphs for the maxillae. Clustering analysis also shows support for potential dimorphism in the shape of the quadrate. However, no measurements from elements other than the maxilla have a strong likelihood of bimodal distribution. These results support the long-standing hypothesis that the caniniform in Placerias was dimorphic. Alternative explanations to sexual dimorphism that could account for the dimorphism among these fossils include the presence of juveniles in the sample or time-averaged sampling of a chronospecies, but both have been previously rejected for the Placerias Quarry population. The lack of strong dimorphism in non-maxilla elements and increased variation in caniniform length of the large-caniniform morph suggest that the caniniform is a secondary sexual trait, possibly used in intraspecific competition.

Maternal inflammation during gestation is associated with a later diagnosis of neurodevelopmental disorders including autism spectrum disorder (ASD). However, the specific impact of maternal immune activation (MIA) on placental and fetal brain development remains insufficiently understood. This study aimed to investigate the effects of MIA by analyzing placental and brain tissues obtained from the offspring of pregnant C57BL/6 dams exposed to polyinosinic: polycytidylic acid (poly I: C) on embryonic day 12.5. Cytokine and mRNA content in the placenta and brain tissues were assessed using multiplex cytokine assays and bulk-RNA sequencing on embryonic day 17.5. In the placenta, male MIA offspring exhibited higher levels of GM-CSF, IL-6, TNFα, and LT-α, but there were no differences in female MIA offspring. Furthermore, differentially expressed genes (DEG) in the placental tissues of MIA offspring were found to be enriched in processes related to synaptic vesicles and neuronal development. Placental mRNA from male and female MIA offspring were both enriched in synaptic and neuronal development terms, whereas females were also enriched for terms related to excitatory and inhibitory signaling. In the fetal brain of MIA offspring, increased levels of IL-28B and IL-25 were observed with male MIA offspring and increased levels of LT-α were observed in the female offspring. Notably, we identified few stable MIA fetal brain DEG, with no male specific difference whereas females had DEG related to immune cytokine signaling. Overall, these findings support the hypothesis that MIA contributes to the sex- specific abnormalities observed in ASD, possibly through altered neuron developed from exposure to inflammatory cytokines. Future research should aim to investigate how interactions between the placenta and fetal brain contribute to altered neuronal development in the context of MIA.

BackgroundLewy body dementia (LBD) phenotype is associated with the presence and degree of Lewy body, Alzheimer's pathologies, and substantia nigra neuron loss. Nigral neuron loss is associated with parkinsonism in LBD, and females with LBD are less likely than males to have parkinsonism. As sex differences were reported for clinical correlates of Lewy body and Alzheimer's pathologies, we aimed to investigate whether there are also sex differences for correlates of nigral neuron loss.MethodsData were obtained from the National Alzheimer's Coordinating Center for females (n = 159) and males (n = 263) with brainstem, limbic, and neocortical Lewy body pathology. Sex differences for the nigral neuron loss' association with Lewy body pathology staging and core clinical LBD features (cognitive fluctuations, visual hallucinations, rapid eye movement sleep behavior disorder, parkinsonism) during follow-up were analyzed with generalized linear models adjusting for age and Alzheimer's pathology staging. Whether any of the core clinical features at the time of dementia onset can predict underlying nigral neuron loss for females and males were also analyzed with generalized linear models.ResultsCompared to males, females died older and had higher levels of Braak tau staging, but had similar levels of Lewy body pathology staging and nigral neuron loss. Females were less likely than males to have a clinical Lewy body disease diagnosis during follow-up. More advanced Lewy body pathology staging was associated with more nigral neuron loss, more so for males than females. More nigral neuron loss was associated with parkinsonism and clinical LBD diagnosis during follow-up, more so for males than females. Across the subgroup with dementia (40 females, 58 males), core LBD features at first visit with dementia were not associated with nigral neuron loss.ConclusionsNigral neuron loss' association with Lewy body pathology staging and core LBD features can differ by sex. Compared to males, females with Lewy body pathology have a higher risk of underdiagnosis. There is a need to elucidate the mechanisms underlying sex differences for pathology and clinicopathological correlations to advance diagnostic and therapeutic efforts in LBD.

This study explores sex-differences in (a) rates and profiles of autism symptoms as well as in (b) the contribution of intellectual quotient (IQ) to autism symptom presentation in Down syndrome (DS). Participants were 40 males and 38 females with DS, aged 6 to 23 years. Autism symptoms were rated through the Autism Diagnostic Observation Schedule-Second Edition (ADOS-2). Results show no sex differences in the ADOS-2 Calibrated Severity Scores (CSS). However, only females with DS who are classified as DS-Only have higher scores on verbal IQ than those classified as DS + autism. Furthermore, associations between IQ and all CSSs are found for females, but not for males. Findings suggest that verbal cognition may play differential roles for females and males with DS.

Background Aesthetic standards vary and are subjective; artificial intelligence (AI), which is currently seeing a boom in interest, has the potential to provide objective assessment. Objectives The aim of this study was to provide a relatively objective assessment of the aesthetic outcomes of lower blepharoplasty–related surgeries, thereby enhancing the decision-making process and understanding of the surgical results. Methods This study included 150 patients who had undergone lower blepharoplasty–related surgeries. Analysis was performed with FaceAge software, created by the authors' research team, which included 4 publicly available age estimation convolution neural network (CNN) models: Amazon Rekognition (Seattle, WA), Microsoft Azure Face (Redmond, WA), Face++ Detect (Beijing, China), and Inferdo face detection (New York, NY). This application was used to compare the subjects' real age and their age as estimated by the 4 CNNs. In addition, this application was used to estimate patient age based on preoperative and postoperative images of all 150 patients and to evaluate the effect of lower blepharoplasty. Results In terms of accuracy in age prediction, all CNN models exhibited a certain degree of accuracy. For all 150 patients undergoing lower blepharoplasty–related surgeries, these surgeries resulted in about 2 years of rejuvenation with a statistically significant difference; for the sex difference, men had more age reduction than women also with a statistically significant difference; quadrilateral blepharoplasty showed the most significant antiaging effect. Conclusions By using deep-learning models, lower blepharoplasty–related surgeries actually had an effect on perceived age reduction. Deep learning models have the potential to provide quantitative evidence for the rejuvenating effects of blepharoplasty and other cosmetic surgeries. [ABSTRACT FROM AUTHOR]

Background: Impaired knee extensor neuromuscular function has been frequently observed in individuals with patellofemoral pain (PFP); however, few researchers have aimed to understand the influence of sex on knee extensor neuromuscular function in this pathological population. The authors aimed to determine whether there are differences in knee extensor neuromuscular function between sexes in individuals with and without PFP. Hypothesis: Women with PFP would exhibit greater deficits in knee extensor neuromuscular function than men with PFP, compared with sex-matched individuals without PFP. Study Design: Cross-sectional, case-control study. Level of Evidence: Level 4. Methods: A total of 110 individuals were classified into 4 groups: women with PFP (n = 25); men with PFP (n = 30); women without PFP (n = 25); and men without PFP (n = 30). Knee extensor strength (isometric peak torque [PT]), activation (central activation ratio), early, late, and total phase rate of torque development (RTD0-100, RTD100-200, and RTD20-80%), and endurance (isokinetic average PT) were assessed using an isokinetic dynamometer. Group differences were assessed using a 2-way multivariate analysis of variance (sex by PFP). Results: Both women and men with PFP exhibited lower knee extensor strength, activation, early, late, and total phase RTD, and endurance versus sex-matched individuals without PFP (P < 0.05 for all comparisons). Women with PFP exhibited lower early phase (7.91 ± 2.02 versus 9.78 ± 2.43 N·m/s/kg; P < 0.01; Cohen d = 0.83), late phase (5.34 ± 1.02 versus 7.28±2.28 N·m/s/kg; P < 0.01; Cohen d = 1.37), and total phase (7.40 ± 2.57 versus 8.72 ± 2.57 N·m/s/kg; P = 0.03; Cohen d = 0.51) RTD than men with PFP. Conclusion: Compared with sex-matched pain-free individuals, women with PFP displayed lower RTD than men with PFP. Clinicians should note that among individuals with PFP, women are more likely to experience a greater impairment in their knee extensor torque-generating capacity than men. Clinical Relevance: Additional treatment strategies that effectively improve the ability to rapidly generate torque should be developed and implemented, especially when treating women with PFP. [ABSTRACT FROM AUTHOR]

Although abdominal aortic aneurysms (AAA) are more common in men, women are at greater risk for AAA growth/rupture. Vascular deformation mapping (VDM) utilizes deformable image registration to qualify and quantify 3D-AAA growth using computed tomography angiograms (CTA). In this study we leveraged VDM to investigate sex differences in AAA growth patterns. Patients with infra-renal AAA and ≥ 2 CTA were identified. Males and females were matched for age, hypertension, and smoking history. Patient characteristics, maximum diameter (Dmax), and AAA volume were obtained. CTA images were segmented, and VDM was conducted to quantify 3D AAA growth rate per year (GR, cm/year). Statistical shape modeling was utilized to compute mean aneurysm shapes and 3D GR. Average GR was evaluated at specific regions of the aortic surface for males and females. Seventeen males and 17 females were matched. At the individual level, there were no sex differences in changes in Dmax or AAA volume. However, females had larger GR across the anterior and right lateral AAA (1.33 vs 0.89 and 1.56 vs 0.74 cm/year, respectively), despite no difference in posterior or left lateral AAA GR. Despite comparable changes in Dmax, AAA volume, and GR magnitude, women demonstrated a more eccentric, anterior-predominant, AAA growth pattern. [ABSTRACT FROM AUTHOR]

Abstract Although abdominal aortic aneurysms (AAA) are more common in men, women are at greater risk for AAA growth/rupture. Vascular deformation mapping (VDM) utilizes deformable image registration to qualify and quantify 3D-AAA growth using computed tomography angiograms (CTA). In this study we leveraged VDM to investigate sex differences in AAA growth patterns. Patients with infra-renal AAA and ≥ 2 CTA were identified. Males and females were matched for age, hypertension, and smoking history. Patient characteristics, maximum diameter (Dmax), and AAA volume were obtained. CTA images were segmented, and VDM was conducted to quantify 3D AAA growth rate per year (GR, cm/year). Statistical shape modeling was utilized to compute mean aneurysm shapes and 3D GR. Average GR was evaluated at specific regions of the aortic surface for males and females. Seventeen males and 17 females were matched. At the individual level, there were no sex differences in changes in Dmax or AAA volume. However, females had larger GR across the anterior and right lateral AAA (1.33 vs 0.89 and 1.56 vs 0.74 cm/year, respectively), despite no difference in posterior or left lateral AAA GR. Despite comparable changes in Dmax, AAA volume, and GR magnitude, women demonstrated a more eccentric, anterior-predominant, AAA growth pattern.

COVID-19-associated intensive care unit (ICU) admissions were recognized as critical health issues that contributed to morbidity and mortality in SARS-CoV-2-infected patients. Severe symptoms in COVID-19 patients are often accompanied by cytokine release syndrome. Here, we analyzed publicly available data from the Yale IMPACT cohort to address immunological misfiring and sex differences in early COVID-19 patients. In 2020, SARS-CoV-2 was considered far more pathogenic and lethal than other circulating respiratory viruses, and the inclusion of SARS-CoV-2 negative patients in IMPACT cohorts confounds many findings. We ascertained the impact of several important biological variables such as days from symptom onset (DFSO); pre-existing risk factors, including obesity; and early COVID-19 treatments on significantly changed immunological measures in ICU-admitted COVID-19 patients that survived versus those that did not. Deceased patients had 19 unique measures that were not shared with ICU patients including increased granzyme-B-producing GzB+CD8+ T cells and interferon-γ. Male COVID-19 patients in ICU experienced many more changes in immunological and clinical measures than female ICU patients (25% vs. ~16%, respectively). A total of 13/124 measures including CCL5, CCL17, IL-18, IFNα2, Fractalkine, classical monocytes, T cells, and CD4Temra exhibited significant sex differences in female vs. male COVID-19 patients. A total of nine measures including IL-21, CCL5, and CD4Temra differed significantly between female and male healthy controls. Immunosuppressed patients experienced the most decreases in CD4Temra and CD8Tem cell numbers. None of the early COVID-19 treatments were effective in reducing levels of IL-6, a major component of the cytokine storm. Obesity (BMI >30) was the most impactful risk factor for COVID-19-related deaths and worst clinical outcomes. Our analysis highlights the contribution of biological sex, risk factors, and early treatments with respect to COVID-19-related ICU admission and progression to morbidity and mortality.

BACKGROUND: Females have been historically excluded from biomedical research due in part to the documented presumption that results with male subjects will generalize effectively to females. This has been justified in part by the assumption that ovarian rhythms will increase the overall variance of pooled random samples. But not all variance in samples is random. Human biometrics are continuously changing in response to stimuli and biological rhythms; single measurements taken sporadically do not easily support exploration of variance across time scales. Recently we reported that in mice, core body temperature measured longitudinally shows higher variance in males than cycling females, both within and across individuals at multiple time scales. METHODS: Here, we explore longitudinal human distal body temperature, measured by a wearable sensor device (Oura Ring), for 6 months in females and males ranging in age from 20 to 79 years. In this study, we did not limit the comparisons to female versus male, but instead we developed a method for categorizing individuals as cyclic or acyclic depending on the presence of a roughly monthly pattern to their nightly temperature. We then compared structure and variance across time scales using multiple standard instruments. RESULTS: Sex differences exist as expected, but across multiple statistical comparisons and timescales, there was no one group that consistently exceeded the others in variance. When variability was assessed across time, females, whether or not their temperature contained monthly cycles, did not significantly differ from males both on daily and monthly time scales. CONCLUSIONS: These findings contradict the viewpoint that human females are too variable across menstrual cycles to include in biomedical research. Longitudinal temperature of females does not accumulate greater measurement error over time than do males and the majority of unexplained variance is within sex category, not between them.

STUDY OBJECTIVES: Disturbances of sleep maintenance and sleep duration are common in older adults and associated with an increased risk for age-related mortality and morbidity. Converging evidence implicates inflammation as an underlying mechanism, especially in females. However, it is unknown what specific aspects of sleep disturbance impact inflammatory mechanisms in older adults. METHODS: Using data from community-dwelling older adults who participated in the Sleep Health and Aging Research (SHARE) field study (n = 262, mean age 71.9 ± 8.0 years), we conducted a secondary analysis to examine whether disturbance of sleep maintenance (i.e. greater amount of wake time after sleep onset [WASO]) and sleep duration (i.e. shorter total sleep time [TST]) assessed by sleep diary and actigraphy are associated with greater activation of nuclear factor (NF)-κB and signal transducer and activator of transcription (STAT) family proteins STAT1, STAT3, and STAT5 in peripheral blood monocytic cells. In addition, moderation effects of sex were explored. RESULTS: Data were available for sleep diary (n = 82), actigraphy (n = 74), and inflammatory signaling and transcriptional measures (n = 132). As assessed by sleep diary, greater amount of WASO (β = 0.39, p < 0.01), but not TST, was associated with higher levels of NF-κB. Whereas diary-assessed sleep measures were not associated with STAT family proteins, a moderation analysis revealed that greater diary-assessed WASO was associated with higher levels of STAT1 (p < 0.05), STAT3 (p < 0.05), and STAT5 (p < 0.01) in females, but not in males. Actigraphy-assessed sleep measures were not associated either with NF-κB or STAT activation. CONCLUSIONS: In older adults, self-reported disturbance of sleep maintenance assessed by sleep diary was uniquely associated with higher levels of NF-κB, along with higher levels of STAT family proteins in females, but not in males. Our data suggest that improvingself-reported sleep maintenance might mitigate age-related increases in inflammatory signaling and transcriptional pathways, possibly more strongly in females, with the potential to reduce mortality risk in older adults.

BACKGROUND: Sex is an integral variable often overlooked in complex disease genetics. Differences between sexes have been reported in natural history, disease complications, and age of onset in inflammatory bowel disease (IBD). While association studies have identified >230 IBD loci, there have been a limited number of studies investigating sex differences underlying these genetic associations. METHODS: We report the first investigation of sex-dimorphic associations via meta-analysis of a sex-stratified association study (34 579 IBD cases, 39 125 controls). In addition, we performed chromosome (chr) X-specific analyses, considering models of X inactivation (XCI) and XCI escape. Demographic and clinical characteristics were also compared between sexes. RESULTS: We identified significant differences between sexes for disease location and perianal complication in Crohns disease and disease extent in ulcerative colitis. We observed genome-wide-significant sex-dimorphic associations (P

Lay abstractThis study examined a widely used autism screening tool, the Modified Checklist for Autism in Toddlers, Revised, with Follow-Up to identify differences in screening for autism between toddler males and females. Examining sex differences in screening for autism in toddlerhood is important as it determines who will be referred for evaluations and receive diagnoses, which is critical for access to autism-specific early intervention. This study found that females were less likely to screen positive and be invited for evaluations compared with males. Females at high likelihood for autism were less likely to be diagnosed with autism, which decreases confidence in the screener's results. Importantly, the Modified Checklist for Autism in Toddlers, Revised, with Follow-Up accurately identified both males and females with autism. Future research should examine ways to improve accuracy in screening results for females.

IntroductionWe examined whether sex modifies the association between APOE ε2 and cognitive decline in two independent samples.MethodsWe used observational data from cognitively unimpaired non-Hispanic White (NHW) and non-Hispanic Black (NHB) adults. Linear mixed models examined interactive associations of APOE genotype (ε2 or ε4 carrier vs. ε3/ε3) and sex on cognitive decline in NHW and NHB participants separately.ResultsIn both Sample 1 (N = 9766) and Sample 2 (N = 915), sex modified the association between APOE ε2 and cognitive decline in NHW participants. Specifically, relative to APOE ε3/ε3, APOE ε2 protected against cognitive decline in men but not women. Among APOE ε2 carriers, men had slower decline than women. Among APOE ε3/ε3 carriers, cognitive trajectories did not differ between sexes. There were no sex-specific associations of APOE ε2 with cognition in NHB participants (N = 2010).DiscussionIn NHW adults, APOE ε2 may protect men but not women against cognitive decline.HighlightsWe studied sex-specific apolipoprotein E (APOE) ε2 effects on cognitive decline. In non-Hispanic White (NHW) adults, APOE ε2 selectively protects men against decline. Among men, APOE ε2 was more protective than APOE ε3/ε3. In women, APOE ε2 was no more protective than APOE ε3/ε3. Among APOE ε2 carriers, men had slower decline than women. There were no sex-specific APOE ε2 effects in non-Hispanic Black (NHB) adults.

BACKGROUND: Studies that examined sex differences in first-episode patients consistently show that males compared to females have poor premorbid adjustment, earlier age of onset, worse clinical characteristics, and poorer outcomes. However, little is known about potential mediators that could explain these sex differences. METHODS: Our sample consisted of 137 individuals with first episode schizophrenia (males, n = 105; 77%) with a mean age of 22.1(s.d. = 4.1) years and mean education of 12.5(s.d. = 1.7) years. At entry, patients were within 2 years of their first psychotic episode onset. Baseline assessments were conducted for premorbid adjustment, symptoms, cognitive functioning, insight, and at 6-months for role and social functioning. RESULTS: Males as compared to females had poorer premorbid adjustment across several key developmental periods (p < 0.01), an earlier age of onset [M = 20.3(3.3) v. 22.8(5.6), p = 0.002], more negative symptoms (p = 0.044), poorer insight (p = 0.031), and poorer baseline and 6-month role (p = 0.002) and social functioning (p = 0.034). Several of these variables in which males showed impairment were significant predictors of 6-month role and social functioning. Premorbid adjustment and insight mediated the relationship between sex and role and social functioning at 6-months, but not negative symptoms. DISCUSSION: Males compared to females were at lower levels across several key premorbid and clinical domains which are strongly associated with functional outcome supporting the hypothesis that males might have a more disabling form of schizophrenia. The relationship between sex with role and social functioning was mediated through premorbid adjustment and insight suggesting pathways for understanding why females might have a less disabling form of schizophrenia.

Objective: Network analysis was used to explore the complex inter-relationships between social participation activities and depressive symptoms among the Chinese older population, and the differences in network structures among different genders, age groups, and urban-rural residency would be compared. Methods: Based on the 2018 wave of the Chinese Longitudinal Healthy Longevity Survey (CLHLS), 12,043 people aged 65 to 105 were included. The 10-item Center for Epidemiologic Studies Depression (CES-D) Scale was used to assess depressive symptoms and 10 types of social participation activities were collected, including housework, tai-chi, square dancing, visiting and interacting with friends, garden work, reading newspapers or books, raising domestic animals, playing cards or mahjong, watching TV or listening to radio, and organized social activities. R 4.2.1 software was used to estimate the network model and calculate strength and bridge strength. Results: 21.60% (2,601/12,043) of the participants had depressive symptoms. The total social participation score was negatively associated with depressive symptoms after adjusting for sociodemographic factors. The network of social participation and depressive symptoms showed that “D9 (Inability to get going)” and “S9 (Watching TV and/or listening to the radio)” had the highest strength within depressive symptoms and social participation communities, respectively, and “S1 (Housework)”, “S9 (Watching TV and/or listening to the radio)”, and “D5 (Hopelessness)” were the most prominent bridging nodes between the two communities. Most edges linking the two communities were negative. “S5 (Graden work) - D5 (Hopelessness)” and “S6 (Reading newspapers/books) - D4 (Everything was an effort)” were the top 2 strongest negative edges. Older females had significantly denser network structures than older males. Compared to older people aged 65–80, the age group 81–105 showed higher network global strength. Conclusions: This study provides novel insights into the complex relationships between social participation and depressive symptoms. Except for doing housework, other social participation activities were found to be protective for depression levels. Different nursing strategies should be taken to prevent and alleviate depressive symptoms for different genders and older people of different ages.

Baozhong Yang,1,&ast; Wei Wei,1,2,&ast; Jun Fang,1,2 Yating Xue,1,2 Jiacheng Wei1,2 1Department of Anaesthesiology, Taiyuan Central Hospital, Taiyuan, People’s Republic of China; 2School of Anesthesia, Shanxi Medical University, Shanxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Baozhong Yang, Email yangbz2000@163.comAbstract: More than half of people with diabetes experience neuropathic pain. Previous research has shown that diabetes patients’ neuropathic pain exhibits a circadian cycle, which is characterized by increased pain sensitivity at night. Additional clinical research has revealed that the standard opioid drugs are ineffective at relieving pain and do not change the circadian rhythm. This article describes diabetic neuropathic pain and circadian rhythms separately, with a comprehensive focus on circadian rhythms. It is hoped that this characteristic of diabetic neuropathic pain can be utilized in the future to obtain more effective treatments for it.Keywords: diabetic neuropathies, circadian rhythm, pain, chronotherapy, microglia, sex characteristics

Objectives This cross-sectional study examined sex differences in Health-Related Quality of Life (HRQoL) among seniors with Type 2 Diabetes Mellitus (T2DM). Methods Data from the Korea National Health and Nutrition Examination Survey (2008–2020) were analyzed. The EuroQol-5 Dimensions (EQ-5D), a measure of HRQoL, was used. It comprises five dimensions: mobility, self-care, usual activity, pain/discomfort, and anxiety/depression, each with three levels. Results Analysis of 3,826 older adults with T2DM showed a significant increasing trend in the EQ-5D Index from the 4th survey phase onwards (P for trend < 0.001 for both men and women). Men consistently reported higher EQ-5D levels than women across all survey years. Women’s EQ-5D levels remained lower than men’s, maintaining a decade-old disparity (P < 0.05). Men scored significantly higher (P < 0.05) in most EQ-5D domains, except for self-care and anxiety/depression, resulting in a higher total EQ-5D Index (P = 0.001). Increased comorbidities were strongly associated with lower EQ-5D levels in both sexes. Additionally, there was a negative correlation between the EQ-5D Index and refined grain intake for both sexes (P for trend < 0.001), with high-EQ-5D groups consuming fewer refined grains. Women in the high-EQ-5D group consumed more nuts, vegetables, and meat compared to men (P for trend < 0.05). Conclusions Our study highlights the sex disparities in HRQoL among older adults with T2DM. The findings suggest the need for tailored treatment guidelines aimed at improving the HRQoL of elderly T2DM patients, with a focus on their sex-specific characteristics. Implementing these tailored guidelines could enhance the HRQoL of older women with T2DM and promote more equitable healthcare outcomes. This underscores the importance of considering sex differences to comprehensively improve the well-being of this population.

Abstract Background Cranial, facial, nasal, and maxillary widths have been shown to be significantly affected by the individual’s sex. The present study aims to use measurements of dental arch and maxillary skeletal base to determine sex, employing supervised machine learning. Materials and methods Maxillary and mandibular tomographic examinations from 100 patients were analyzed to investigate the inter-premolar width, inter-molar width, maxillary width, inter-pterygoid width, nasal cavity width, nostril width, and maxillary length, obtained through Cone Beam Computed Tomography scans. The following machine learning algorithms were used to build the predictive models: Logistic Regression, Gradient Boosting Classifier, K-Nearest Neighbors (KNN), Support Vector Machine (SVM), Multi-Layer Perceptron Classifier (MLP), Decision Tree, and Random Forest Classifier. A 10-fold cross-validation approach was adopted to validate each model. Metrics such as area under the curve (AUC), accuracy, recall, precision, and F1 Score were calculated for each model, and Receiver Operating Characteristic (ROC) curves were constructed. Results Univariate analysis showed statistical significance (p

Aim: To determine the differences in comorbidities, therapy and echocardiographic measures among patients hospitalized for heart failure relative to gender. Methods: The study included patients hospitalized for heart failure at the Department of Cardiovascular Diseases of the Clinical Hospital Center Osijek in the period from 1 January 2020 to 30 March 2021. Results: There were 200 patients included in the study, of which 100 (50%) were male and 100 (50%) were female. Female patients were older, while male patients more frequently had a history of coronary artery disease. Men had a higher dose of loop diuretic on admission to the hospital. No significant difference was found in the representation of beta blockers and ACE inhibitors in therapy with regard to gender. On the other hand, men more frequently used MRA, sacubitril/valsartan and antiplatelet medication at hospital admission. Male patients had a larger left ventricular end-diastolic diameter, left ventricular end-systolic diameter and a lower left ventricular ejection fraction (EF). Regarding the type of heart failure according to EF, 72% of men had HFrEF, 20% HFmrEF and 8% HFpEF. In women, 47% had HFrEF, 33% HFmrEF and 20% HFpEF. During hospitalization due to heart failure, 22 patients died, an equal number of men and women. Conclusion: This research confirmed the differences in risk factors and pathophysiology of heart failure between males and females. Medicine is progressing towards an individual approach to each patient, so further research will be needed to find the best therapy for both male and female patients. Sažetak Cilj: Odrediti razlike u komorbiditetima, terapiji i ehokardiografskim mjerenjima među pacijentima hospitaliziranima zbog zatajenja srca u odnosu na spol. Metode: Studija je uključila pacijente hospitalizirane zbog zatajenja srca na Odjelu za kardiovaskularne bolesti Kliničkog bolničkog centra Osijek u razdoblju od 1. siječnja 2020. do 30. ožujka 2021. godine. Rezultati: U studiju je bilo uključeno 200 pacijenata, od kojih je 100 (50 %) bilo muškaraca i 100 (50 %) žena. Ženske pacijentice bile su starije, dok su muškarci češće imali povijest koronarne arterijske bolesti. Muškarci su na prijemu u bolnicu primali višu dozu diuretika Henleove petlje. Nije pronađena značajna razlika u zastupljenosti beta blokatora i ACE inhibitora u terapiji s obzirom na spol. S druge strane, muškarci su češće koristili MRA, sakubitril/valsartan i antitrombocitne lijekove pri prijemu u bolnicu. Muški pacijenti imali su veći krajnji dijastolički promjer lijeve klijetke, krajnji sistolički promjer lijeve klijetke i nižu ejekcijsku frakciju (EF) lijeve klijetke. S obzirom na tip zatajenja srca prema EF-u, 72 % muškaraca je imalo HFrEF, 20 % HFmrEF, i 8 % HFpEF. Kod žena, 47 % ih je imalo HFrEF, 33 % HFmrEF i 20 % HFpEF. Tijekom hospitalizacije zbog zatajenja srca, umrla su 22 pacijenta, jednak broj muškaraca i žena. Zaključak: Ovo istraživanje potvrdilo je razlike u rizičnim čimbenicima i patofiziologiji zatajenja srca između muškaraca i žena. Medicina napreduje prema individualnom pristupu svakom pacijentu, stoga će biti potrebna daljnja istraživanja kako bi se pronašla najbolja terapija za muškarce i žene.

Background: Cranial, facial, nasal, and maxillary widths have been shown to be significantly affected by the individual's sex. The present study aims to use measurements of dental arch and maxillary skeletal base to determine sex, employing supervised machine learning. Materials and methods: Maxillary and mandibular tomographic examinations from 100 patients were analyzed to investigate the inter-premolar width, inter-molar width, maxillary width, inter-pterygoid width, nasal cavity width, nostril width, and maxillary length, obtained through Cone Beam Computed Tomography scans. The following machine learning algorithms were used to build the predictive models: Logistic Regression, Gradient Boosting Classifier, K-Nearest Neighbors (KNN), Support Vector Machine (SVM), Multi-Layer Perceptron Classifier (MLP), Decision Tree, and Random Forest Classifier. A 10-fold cross-validation approach was adopted to validate each model. Metrics such as area under the curve (AUC), accuracy, recall, precision, and F1 Score were calculated for each model, and Receiver Operating Characteristic (ROC) curves were constructed. Results: Univariate analysis showed statistical significance (p < 0.10) for all skeletal and dental variables. Nostril width showed greater importance in two models, while Inter-molar width stood out among dental measurements. The models achieved accuracy values ranging from 0.75 to 0.85 on the test data. Logistic Regression, Random Forest, Decision Tree, and SVM models had the highest AUC values, with SVM showing the smallest disparity between cross-validation and test data for accuracy metrics. Conclusion: Transverse dental arch and maxillary skeletal base measurements exhibited strong predictive capability, achieving high accuracy with machine learning methods. Among the evaluated models, the SVM algorithm exhibited the best performance. This indicates potential usefulness in forensic sex determination. [ABSTRACT FROM AUTHOR]

Background: Subarachnoid hemorrhage (SAH) represents a severe stroke subtype. Our study aims to develop gender‐specific prognostic prediction models derived from distinct prognostic factors observed among different‐gender patients. Methods: Inclusion comprised SAH‐diagnosed patients from January 2014 to March 2016 in our institution. Collected data encompassed patients' demographics, admission severity, treatments, imaging findings, and complications. Three‐month post‐discharge prognoses were obtained via follow‐ups. Analyses assessed gender‐based differences in patient information. Key factors underwent subgroup analysis, followed by univariate and multivariate analyses to identify gender‐specific prognostic factors and establish/validate gender‐specific prognostic models. Results: A total of 929 patients, with a median age of 57 (16) years, were analyzed; 372 (40%) were male, and 557 (60%) were female. Differences in age, smoking history, hypertension, aneurysm presence, and treatment interventions existed between genders (p < 0.01), yet no disparity in prognosis was noted. Subgroup analysis explored hypertension history, aneurysm presence, and treatment impact, revealing gender‐specific variations in these factors' influence on the disease. Screening identified independent prognostic factors: age, SEBES score, admission GCS score, and complications for males; and age, admission GCS score, intraventricular hemorrhage, treatment interventions, symptomatic vasospasm, hydrocephalus, delayed cerebral ischemia, and seizures for females. Evaluation and validation of gender‐specific models yielded an AUC of 0.916 (95% CI: 0.878–0.954) for males and 0.914 (95% CI: 0.885–0.944) for females in the ROC curve. Gender‐specific prognostic models didn't significantly differ from the overall population‐based model (model 3) but exhibited robust discriminative ability and clinical utility. Conclusion: Variations in baseline and treatment‐related factors among genders contribute partly to gender‐based prognosis differences. Independent prognostic factors vary by gender. Gender‐specific prognostic models exhibit favorable prognostic performance. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension affects females more frequently than males, and there are known sex‐related differences in the lungs. However, normal sex‐related differences in pulmonary vascular structure remain incompletely described. We aimed to contrast computed tomography‐derived pulmonary vascular volume and its distribution within the lungs of healthy adult females and males. From the CanCOLD Study, we retrospectively identified healthy never‐smokers. We analyzed full‐inspiration computed tomography images, using vessel and airway segmentation to generate pulmonary vessel volume, vessel counts, and airway counts. Vessels were classified by cross‐sectional area >10, 5–10, and <5 mm2 into bins, with volume summed within each area bin and in total. We included 46 females and 36 males (62 ± 9 years old). Females had lower total lung volume, total airway counts, total vessel counts, and total vessel volume (117 ± 31 vs. 164 ± 28 mL) versus males (all p < 0.001). Females also had lower vessel volume >10 mm2 (14 ± 8 vs. 27 ± 9 mL), vessel volume 5–10 mm2 (35 ± 11 vs. 55 ± 10 mL), and vessel volume <5 mm2 (68 ± 18 vs. 82 ± 19 mL) (all p < 0.001). Normalized to total vessel volume, vessel volume >10 mm2 (11 ± 4 vs. 16 ± 4%, p < 0.001) and 5–10 mm2 (30 ± 6 vs. 34 ± 5%, p = 0.001) remained lower in females but vessel volume <5 mm2 relative to total volume was 18% higher (59 ± 8 vs. 50 ± 7%, p < 0.001). Among healthy older adults, pulmonary vessel volume is distributed into smaller vessels in females versus males. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate the relationship between plasma glucose profiles and periodontal disease (PD) severity in men and women Methods: We conducted a cross-sectional cohort study, enrolling all eligible patients with type 2 diabetes mellitus (T2DM) who regularly visited the outpatient department Results: Patients were divided into severe and non-severe PD groups. The severe PD group showed a male predominance and significantly higher hemoglobin A1c (HbA1c) levels than the non-severe PD group. The optimal HbA1c cutoff value on the receiver operating characteristic curve for predicting severe PD was 7.3% [56 mmol/mol] (sensitivity, 52%; specificity, 73%; P = 0.01). Multivariate logistic regression revealed that male sex (odds ratio [OR], 2.75; 95% confidence interval [CI], 1.19–6.34; P = 0.01) and higher HbA1c levels (OR, 3.09; 95% CI, 1.42–6.70; P < 0.01) were independently and significantly associated with the presence of severe PD. The prevalence rates of severe PD in patients with HbA1c levels < 7.3% [56 mmol/mol] and HbA1c levels ≥ 7.3% [56 mmol/mol] were 17.4% and 53.3% in women, and 50.0% and 66.7% in men, respectively. Conclusions: Men with T2DM had a high risk of severe PD independent of HbA1c levels. Plasma glucose management may be crucial for maintaining periodontal health in T2DM patients, particularly in women. [ABSTRACT FROM AUTHOR]

In 2022 Greece became the fifth country in the world to ban harmful interventions and treatments on intersex infants and children. Previously, Malta, Portugal, Germany and Iceland also legally banned harmful interventions on intersex persons. A crucial difference between Greece and the rest of the aforementioned countries is that it is a Christian Orthodox country located in Southeastern Europe, on the Balkan Peninsula. Drawing from a contextual approach to law, in this comparative analysis the authors will use „contextuality“ to explore the meaning behind legal developments that took place in Greece regarding intersex rights and how they could potentially impact the overall situation of intersex rights in the Balkans. In addition, with this paper the authors seek to relocate the dominant focus of intersex rights from Western and Northern Europe with the aim to boost awareness of intersex issues in the Western Balkan region, especially Serbia. [ABSTRACT FROM AUTHOR]

Background and Objectives: There are typical differences in body composition and distribution of muscle fiber types between women and men. However, research investigating the effects of exercise based on sex differences is limited, and studies examining sex differences in physiological adaptations according to exercise type are scarce. We aimed to compare the effects of exercise types on muscle strength and body composition in men and women through a meta-analysis. Materials and Methods: A systematic literature search was conducted using the PubMed/Medline, Web of Science, CINAHL, and EBSCO databases. Keywords included "endurance training", "resistance training", "concurrent training", "muscle strength", "body composition", "sex characteristics", and "men and women". The standardized mean difference (SMD) was presented separately for men and women based on the pre- and post-intervention values for each exercise type. Results: Concurrent training showed the greatest effect on the increase in leg press muscle strength in men, and resistance training showed the greatest effect in women. Concurrent training showed the greatest effect size in both men and women in increasing bench press muscle strength. Resistance training and concurrent training showed a small effect size on lean mass reduction in both men and women. Endurance training and concurrent training significantly reduced fat mass in men. However, no significant changes in fat mass were observed in any exercise type among women. Conclusions: Concurrent training is the most efficient type of exercise for men, as it is effective in increasing upper- and lower-body muscle strength, increasing lean mass, and reducing fat mass. Resistance training is most effective in increasing muscle strength in females, whereas endurance training is most effective in reducing fat mass. However, it is difficult to corroborate these results because of the lack of study samples included in the analysis and the differences in exercise methods, participant age, and exercise duration. [ABSTRACT FROM AUTHOR]

AIMS: Sex differences in long-term outcomes following hospitalization for heart failure (HF) across ejection fraction (EF) subtypes are not well described. In this study, we evaluated the risk of mortality and rehospitalization among males and females across the spectrum of EF over 5 years of follow-up following an index HF hospitalization event. METHODS AND RESULTS: Patients hospitalized with HF between 1 January 2006 and 31 December 2014 from the American Heart Associations Get With The Guidelines-Heart Failure registry with available 5-year follow-up using Medicare Part A claims data were included. The association between sex and risk of mortality and readmission over a 5-year follow-up period for each HF subtype (HF with reduced EF [HFrEF, EF ≤40%], HF with mildly reduced EF [HFmrEF, EF 41-49%], and HF with preserved EF [HFpEF, EF >50%]) was assessed using adjusted Cox models. The effect modification by the HF subtype for the association between sex and outcomes was assessed by including multiplicative interaction terms in the models. A total of 155 670 patients (median age: 81 years, 53.4% female) were included. Over 5-year follow-up, males and females had comparably poor survival post-discharge; however, females (vs. males) had greater years of survival lost to HF compared with the median age- and sex-matched US population (HFpEF: 17.0 vs. 14.6 years; HFrEF: 17.3 vs. 15.1 years; HFmrEF: 17.7 vs. 14.6 years for age group 65-69 years). In adjusted analysis, females (vs. males) had a lower risk of 5-year mortality (adjusted hazard ratio [aHR] 0.89, 95% confidence interval [CI] 0.87-0.90, p

BackgroundThe higher incidence of non-Hodgkin lymphoma (NHL) in males is not well understood. Although reactive oxygen species (ROS) have been implicated as causes of NHL, they cannot be measured directly in archived blood.MethodsWe performed untargeted adductomics of stable ROS adducts in human serum albumin (HSA) from 67 incident NHL cases and 82 matched controls from the European Prospective Investigation into Cancer and Nutrition-Italy cohort. Regression and classification methods were employed to select features associated with NHL in all subjects and in males and females separately.ResultsSixty seven HSA-adduct features were quantified by liquid chromatography-high-resolution mass spectrometry at Cys34 (n = 55) and Lys525 (n = 12). Three features were selected for association with NHL in all subjects, while seven were selected for males and five for females with minimal overlap. Two selected features were more abundant in cases and seven in controls, suggesting that altered homeostasis of ROS may affect NHL incidence. Heat maps revealed differential clustering of features between sexes, suggesting differences in operative pathways.ConclusionsAdduct clusters dominated by Cys34 oxidation products and disulfides further implicate ROS and redox biology in the etiology of NHL. Sex differences in dietary and alcohol consumption also help to explain the limited overlap of feature selection between sexes. Intriguingly, a disulfide of methanethiol from enteric microbial metabolism was more abundant in male cases, thereby implicating microbial translocation as a potential contributor to NHL in males.ImpactOnly two of the ROS adducts associated with NHL overlapped between sexes and one adduct implicates microbial translocation as a risk factor.

Prior studies suggest that sex differences in emotion regulation (ER) ability contribute to sex disparities in affective disorders. In behavioral studies, females rely more on maladaptive strategies to cope with emotional distress than males. Neuroimaging studies suggest that males more efficiently regulate emotion than females by showing less prefrontal cortex activity (suggesting less effort) for similar amygdala activity (similar regulation outcome). However, physiological studies involving heart rate variability (HRV) indicated that, compared with males, females have higher resting HRV, indicative of parasympathetic dominance and better control of emotion. To help resolve these apparently inconsistent findings, we examined sex differences in how resting HRV relates to brain activity while using cognitive reappraisal, one of the adaptive strategies. Based on 51 males and 49 females, we found that females showed different levels of self-rated emotional intensity and amygdala activity for negative versus positive emotions, while males did not. Females also showed greater overall prefrontal cortex activity but similar levels of amygdala activity compared to males. Sex differences in how resting HRV related to brain activity during ER were evident only during viewing or regulating positive emotion. The results suggest that sex differences in the neural correlates of ER and resting HRV might lie in valence more than arousal modulation.

Sympathetic activation during cold exposure increases adipocyte thermogenesis via the expression of mitochondrial protein uncoupling protein 1 (UCP1)1. The propensity of adipocytes to express UCP1 is under a critical influence of the adipose microenvironment and varies between sexes and among various fat depots2-7. Here we report that mammary gland ductal epithelial cells in the adipose niche regulate cold-induced adipocyte UCP1 expression in female mouse subcutaneous white adipose tissue (scWAT). Single-cell RNA sequencing shows that glandular luminal epithelium subtypes express transcripts that encode secretory factors controlling adipocyte UCP1 expression under cold conditions. We term these luminal epithelium secretory factors 'mammokines'. Using 3D visualization of whole-tissue immunofluorescence, we reveal sympathetic nerve-ductal contact points. We show that mammary ducts activated by sympathetic nerves limit adipocyte UCP1 expression via the mammokine lipocalin 2. In vivo and ex vivo ablation of mammary duct epithelium enhance the cold-induced adipocyte thermogenic gene programme in scWAT. Since the mammary duct network extends throughout most of the scWAT in female mice, females show markedly less scWAT UCP1 expression, fat oxidation, energy expenditure and subcutaneous fat mass loss compared with male mice, implicating sex-specific roles of mammokines in adipose thermogenesis. These results reveal a role of sympathetic nerve-activated glandular epithelium in adipocyte UCP1 expression and suggest that mammary duct luminal epithelium has an important role in controlling glandular adiposity.

Rationale: Central sleep apnea (CSA) is pervasive during sleep at high altitude, disproportionately impacting men and associated with increased peripheral chemosensitivity. Objectives: We aimed to assess whether biological sex affects loop gain (LGn) and CSA severity during sleep over 9-10 days of acclimatization to 3,800 m. We hypothesized that CSA severity would worsen with acclimatization in men but not in women because of greater increases in LGn in men. Methods: Sleep studies were collected from 20 (12 male) healthy participants at low altitude (1,130 m, baseline) and after ascent to (nights 2/3, acute) and residence at high altitude (nights 9/10, prolonged). CSA severity was quantified as the respiratory event index (REI) as a surrogate of the apnea-hypopnea index. LGn, a measure of ventilatory control instability, was quantified using a ventilatory control model fit to nasal flow. Linear mixed models evaluated effects of time at altitude and sex on respiratory event index and LGn. Data are presented as contrast means with 95% confidence intervals. Results: REI was comparable between men and women at acute altitude (4.1 [-9.3, 17.5] events/h; P = 0.54) but significantly greater in men at prolonged altitude (23.7 [10.3, 37.1] events/h; P = 0.0008). Men had greater LGn than did women for acute (0.08 [0.001, 0.15]; P = 0.047) and prolonged (0.17 [0.10, 0.25]; P

INTRODUCTION: Sex differences in dementia risk, and risk factor (RF) associations with dementia, remain uncertain across diverse ethno-regional groups. METHODS: A total of 29,850 participants (58% women) from 21 cohorts across six continents were included in an individual participant data meta-analysis. Sex-specific hazard ratios (HRs), and women-to-men ratio of hazard ratios (RHRs) for associations between RFs and all-cause dementia were derived from mixed-effect Cox models. RESULTS: Incident dementia occurred in 2089 (66% women) participants over 4.6 years (median). Women had higher dementia risk (HR, 1.12 [1.02, 1.23]) than men, particularly in low- and lower-middle-income economies. Associations between longer education and former alcohol use with dementia risk (RHR, 1.01 [1.00, 1.03] per year, and 0.55 [0.38, 0.79], respectively) were stronger for men than women; otherwise, there were no discernible sex differences in other RFs. DISCUSSION: Dementia risk was higher in women than men, with possible variations by country-level income settings, but most RFs appear to work similarly in women and men.