Sex-specific Differences Research Articles

Sex-dependent effects of acute stress and alcohol exposure during adolescence on mRNA expression of brain signaling systems involved in reward and stress responses in young adult rats

BackgroundAdolescent stress and alcohol exposure increase the risk of maladaptive behaviors and mental disorders in adulthood, with distinct sex-specific differences. Understanding the mechanisms underlying these early events is crucial for developing targeted prevention and treatment strategies.MethodsMale and female Wistar rats were exposed to acute restraint stress and intermittent alcohol during adolescence. We assessed lasting effects on plasma corticosterone (CORT) and adrenocorticotropic hormone (ACTH) levels, and mRNA expression of genes related to corticotropin releasing hormone (CRH), neuropeptide Y (NPY), corticoid, opioid, and arginine vasopressin systems in the amygdala and hypothalamus.ResultsThe main findings are as follows: (1) blood alcohol concentrations (BAC) increased after the final alcohol administration, but stressed males had lower BAC than non-stressed males; (2) Males gained significantly more weight than females; (3) Stressed females showed higher ACTH levels than non-stressed females, with no changes in males; (4) Stress increased CORT levels in males, while stressed, alcohol-treated females had lower CORT levels than non-stressed females; (5) CRH: Females had lower Crhr1 levels in the amygdala, while alcohol reduced Crhr2 levels in males but not females. Significant interactions among sex, stress, and alcohol were found in the hypothalamus, with distinct patterns between sexes; (6) NPY: In the amygdala, stress reduced Npy and Npy1r levels in males but increased them in females. Alcohol decreased Npy2r levels in males, with varied effects in females. Similar sex-specific patterns were observed in the hypothalamus; (7) Corticoid system: Stress and alcohol had complex, sex-dependent effects on Pomc, Nr3c1, and Nr3c2 in both brain regions; (8) Opioid receptors: Stress and alcohol blunted the elevated expression of Oprm1, Oprd1, and Oprk1 in the amygdala of males and the hypothalamus of females; (8) Vasopressin: Stress and alcohol interacted significantly to affect Avp and Avpr1a expression in the amygdala, with stronger effects in females. In the hypothalamus, alcohol increased Avp levels in females.ConclusionsThis study demonstrates that adolescent acute stress and alcohol exposure induce lasting, sex-specific alterations in systems involved in reward and stress responses. These findings emphasize the importance of considering sex differences in the prevention and management of HPA dysfunction and psychiatric disorders.

Sex differences in survival outcomes of early-onset colorectal cancer

Colorectal cancer (CRC) is one of the most fatal cancers in the United States. Although the overall incidence and mortality rates are declining, an alarming rise in early-onset colorectal cancer (EOCRC), defined as CRC diagnosis in patients aged < 50 years, was previously reported. Our study focuses on analyzing sex-specific differences in survival among EOCRC patients and comparing sex-specific predictors of survival in both males and females in the United States. We retrieved and utilized data from the Surveillance, Epidemiology, and End Results (SEER) program. EOCRC patients, between the ages of 20 and 49, were exclusively included. We conducted thorough survival analyses using Kaplan–Meier curves, log-rank tests, Cox regression models, and propensity score matching to control for potential biases. Our study included 58,667 EOCRC patients (27,662 females, 31,005 males) diagnosed between 2000 and 2017. The baseline characteristics at the time of diagnosis were significantly heterogeneous between males and females. Males exhibited significantly worse overall survival (OS), cancer-specific survival (CSS), and noncancer-specific survival (NCSS) in comparison to females in both the general cohort, and the matched cohort. Predictors of survival outcomes generally followed a similar pattern in both sexes except for minor differences. In conclusion, we identified sex as an independent prognostic factor of EOCRC, suggesting disparities in survival between sexes. Further understanding of the epidemiological and genetic bases of these differences could facilitate targeted, personalized therapeutic approaches for EOCRC.

Sex- specific differences in suspected myocarditis presentations and outcomes

BackgroundSigns and symptoms of myocarditis may vary among men and women. ObjectivesThis study aimed to analyze sex-specific differences in the presentation and outcomes of patients with suspected myocarditis. MethodsPatients meeting clinical ESC criteria for suspected myocarditis were included from two tertiary centers between 2002 and 2021. Baseline characteristics, cardiac magnetic resonance (CMR), and outcomes (i.e. major adverse cardiovascular events (MACE), including all-cause death, ventricular tachycardia, hospitalization for heart failure, and recurrent myocarditis) in women and men were compared. Results776 consecutive patients (mean age 48 ± 16 years, 286 [36.9 %] women) were followed for a median of 3.7 years. Compared to men, women presented more often with severe dyspnea (NYHA III-IV: 25.9 % versus 19.2 % of men; p = 0.029), while chest pain was more frequent in men (39.8 % versus 32.2 % in women; p = 0.037). There was no difference in left ventricular ejection fraction at the time of presentation (women: 48.5 ± 15.4 % versus men: 48.6 ± 15.1 %;p = 0.954). Further, no sex-specific difference in the occurrence of MACE was noted; however, women were more often hospitalized for heart failure than men (women: 9.8 % versus men: 5.3 %, p = 0.018). Accordingly, female sex was independently associated with heart failure hospitalization in an adjusted model (HR: 2.31, 95 % CI:1.25–4.26; p = 0.007). The prognostic value of CMR markers was similar in both sex. ConclusionSignificant sex-specific differences in presentations and imaging findings are found in patients with suspected myocarditis. Female sex is associated with a twofold increase in the risk of heart failure hospitalization, which should be considered in risk stratification.

Mitochondrial dynamics and sex-specific responses in the developing rat hippocampus: Effect of perinatal asphyxia and mesenchymal stem cell Secretome treatment

AimsPerinatal asphyxia is one of the major causes of neonatal death at birth. Survivors can progress but often suffer from long-term sequelae. We aim to determine the effects of perinatal asphyxia on mitochondrial dynamics and whether mesenchymal stem cell secretome (MSC-S) treatment can alleviate the deleterious effects. Materials and methodsAnimals were subjected to 21 min of asphyxia at the time of delivery. MSC-S or vehicle was intranasally administered 2 h post-delivery. Mitochondrial mass (D-loop, qPCR), mitochondrial dynamics proteins (Drp1, Fis1 and OPA1, Western blot), mitochondrial dynamics (TOMM20, Immunofluorescence), as well as mitochondrial membrane potential (ΔΨm) (Safranin O) were evaluated at P1 and P7 in the hippocampus. Key findingsPerinatal asphyxia increased levels of mitochondrial dynamics proteins Drp1 and S-OPA1 at P1 and Fis1 at P7. Mitochondrial density and mass were decreased at P1. Perinatal asphyxia induced sex-specific differences, with increased L-OPA1 in females at P7 and increased mitochondria circularity. In males, asphyxia-exposed animals exhibited a reduced ΔΨm at P7. MSC-S treatment normalised levels of mitochondrial dynamics proteins involved in fission. SignificanceThis study provides novel insights into the effects of perinatal asphyxia on mitochondrial dynamics in the developing brain and on the therapeutic opportunities provided by mesenchymal stem cell secretome treatment. It also highlights on the relevance of considering sex as a biological variable in perinatal brain injury and therapy development. These findings contribute to the development of targeted, personalised therapies for infants affected by perinatal asphyxia.

Sex-specific differences in alive hospital discharge following infrarenal abdominal aortic aneurysm repair.

A longer time to alive hospital discharge following infrarenal abdominal aortic aneurysm (AAA) repair is associated with reduced patient-satisfaction and increased length of stay, hospital-acquired deconditioning, infection and costs. This study investigated sex-specific differences in, and drivers of, the rate of alive hospital discharge. Examination of UK National Vascular Registry (UK NVR), 2014-2019 and Swedish National Patient Registry (SE NPR) elective AAA patients, 2010-2018, for endovascular (EVAR) or open (OAR) aneurysm repair. Cox models assessed sex-specific difference in rate of alive hospital discharge, adjusting for co-morbidity, anatomy, standard-of-care, post-operative complications, and year, with in-hospital death as the competing risk. 29,751 AAA repairs (UK NVR -EVAR 12518:1532; OAR 6803:837; SE NPR - EVAR 4234:792; OAR 2638:497, men:women) were assessed. For EVAR, the unadjusted rate of alive hospital discharge was ∼25% lower for women (UK NVR HR 0.75 [0.71-0.80], p<.001; SE NPR HR 0.75 [0.69-0.81], p<.001). Following adjustment the sex-specific hazard ratio narrowed but remained significant (UK NVR: HR 0.83 [0.79-0.88], p<.001; SE NPR HR 0.83 [0.76-0.89], p<.001). For OAR, the rate of alive hospital discharge was 23-27% lower for women (UK NVR HR 0.73 [0.67-0.78], p<.001; SE NPR HR 0.77 [0.70-0.85], p<.001). Following adjustment the sex-specific hazard ratio narrowed (UK NVR HR 0.82 [0.76-0.88], p<.001; SE NPR HR 0.79 [0.72-0.88], p<.001) but remained significant. Women have a 25% lower rate of alive discharge after aortic surgery, despite adjustment for pre/peri- and postoperative parameters. Efforts to increase rate of alive hospital discharge for women should be sought.

Sex-Based Differences in Lung Cancer Incidence: A Retrospective Analysis of Two Large US-Based Cancer Databases

Background/Objectives: Non-small cell lung cancer (NSCLC) has seen a relative rise in incidence among females versus males in recent years, although males still have a higher overall incidence. However, it is unclear whether this trend is consistent across all populations. Therefore, we retrospectively examined this relationship in two large high-risk clinical cohorts. Methods: First, we analyzed lung cancer incidence among individuals with a smoking history of over 40 pack-years in the National Lung Screening Trial (NLST). Then, we investigated the incidence of second primary NSCLC in patients who underwent lobectomy for previous stage I lung cancer using the Surveillance, Epidemiology, and End Results (SEER) database. We performed both univariate and multivariable time-to-event analyses to investigate the relationship between sex and lung cancer incidence. Results: In the NLST cohort (n = 37,627), females had a higher risk of developing primary NSCLC than males (HR = 1.11 [1.007–1.222], p = 0.035) after adjusting for age and pack-year history. In the SEER cohort (n = 19,327), females again exhibited an increased risk of developing a second primary lung cancer (HR = 1.138 [1.02–1.269], p = 0.021), after adjusting for age, race, grade, and histology. Conclusions: Our analysis reveals that females have a modestly higher lung cancer incidence than males in high-risk populations. These findings underscore the importance of further researching the underlying cellular processes that may cause sex-specific differences in lung cancer incidence.

Sex Differences in Home-Cage Ethanol Drinking and Operant Self-Administration in C57BL/6J Mice but Equivalent Regulation by Glutamate AMPAR Activity.

Considering sex as a biological variable (SABV) in preclinical research can enhance understanding of the neurobiology of alcohol use disorder (AUD). However, the behavioral and neural mechanisms underlying sex-specific differences remain unclear. This study aims to elucidate SABV in ethanol (EtOH) consumption by evaluating its reinforcing effects and regulation by glutamate AMPA receptor activity in male and female mice. C57BL/6J mice (male and female) were assessed for EtOH intake under continuous and limited access conditions in the home cage. Acute sensitivity to EtOH sedation and blood clearance were evaluated as potential modifying factors. Motivation to consume EtOH was measured using operant self-administration procedures. Sex-specific differences in neural regulation of EtOH reinforcement were examined by testing the effects of a glutamate AMPA receptor antagonist on operant EtOH self-administration. Female C57BL/6J mice exhibited a time-dependent escalation in EtOH intake under both continuous and limited access conditions. They were less sensitive to EtOH sedation and had lower blood levels post-EtOH administration (4 g/kg) despite similar clearance rates. Females also showed increased operant EtOH self-administration and progressive ratio performance over a 30-day baseline period compared to males. The AMPAR antagonist GYKI 52466 (0 - 10 mg/kg, IP) dose-dependently reduced EtOH-reinforced lever pressing in both sexes, with no differences in potency or efficacy. These findings confirm that female C57BL/6J mice consume more EtOH than males in home-cage conditions and exhibit reduced acute sedation, potentially contributing to higher EtOH intake. Females demonstrated increased operant EtOH self-administration and motivation, indicating higher reinforcing efficacy. The lack of sex differences in the relative effects of GYKI 52466 suggests that AMPAR activity is equally required for EtOH reinforcement in both sexes.

The effect of intrauterine growth restriction on the developing pancreatic immune system.

Immune cells in the pancreas are known to participate in organ development. However, the resident pancreatic immune system has yet to be fully defined. Immune cells also play a role in pathology and are implicated in diseases such as diabetes induced by intrauterine growth restriction (IUGR). We hypothesized that the resident immune system is established during neonatal development and disrupted by IUGR. Using single cell RNAseq and flow cytometry we identified many immune cell populations in the near-term fetus (at embryologic day 22) and neonatal (postnatal day 1, 7, &14) islets, non-endocrine pancreas, and the spleen in the rat. Using flow cytometry, we observed the resident immune system is established during neonatal development in the pancreas and spleen. We identified 9 distinct immune populations in the pancreatic islets and 8 distinct immune populations in the spleen by single cell RNAseq. There were no sex-specific differences in the relative proportion of immune cells in the pancreas or spleen. Finally, we tested if IUGR disrupted the neonatal immune system using bilateral uterine artery ligation. We found significant changes to the percentage of CD11B+ HIS48- and CD8+ T cells in the islets and non-endocrine pancreas and in the spleen. IUGR-induced alterations were influenced by the tissue environment and the sex of the offspring. Future research to define the role of these immune cells in pancreatic development may identify disrupted pathways that contribute to the development of diabetes following IUGR.

Implementation of the Methyl-Seq platform to identify tissue- and sex-specific DNA methylation differences in the rat epigenome

ABSTRACT Epigenomic annotations for the rat lag far behind those of human and mouse, despite the rat’s immense utility in pharmacological and behavioral studies and the need to understand their epigenetic mechanisms. We have designed a targeted-enrichment method followed by next-generation sequencing (Methyl-Seq) to identify DNA methylation (DNAm) signatures across the rat genome. The design reflected an attempt to create a more comprehensive investigation of the rat epigenome, as it included promoters, CpG islands, and island shores of all RefSeq genes. In this study, we implemented the rat Methyl-Seq platform and tested its ability to distinguish differentially methylated regions (DMRs) among three different tissue types, three distinct brain regions, and, in the hippocampus, between males and females. These comparisons yielded DNAm differences of differing magnitudes, many of which were independently validated by bisulfite pyrosequencing, including autosomal regions that were predicted to show the least degree of difference in DNAm between males and females. Quantitative reverse transcription PCR revealed that most genes associated with the DMRs showed tissue-, brain region-, and sex-specific differences in expression. In particular, we found evidence for sex-specific DNAm and expression differences at Tubb6, Lrrn2, Tex26, and Sox5l1, all of which play important roles in neurodevelopment and have been implicated in studies examining sex differences. Our results demonstrate the utility of the rat Methyl-Seq platform and suggest the presence of DNAm differences between the male and female hippocampus. The rat Methyl-Seq has the potential to provide epigenomic insights into pharmacological and behavioral studies performed in the rat.

Antidepressants as new endocrine disruptors? – transcriptomic profiling in gonads of Mytilus trossulus exposed to norfluoxetine

In this study an impact of norfluoxetine (NFLU) on Mytilus trossulus gonads was investigated focusing on sex-related differences in hormonal changes, gene expression, and transcriptomic profiling. Sex-specific differences in gonadal serotonin levels were found. NFLU stimulates serotonin synthesis and/or transport in female gonads, potentially accelerating oocyte maturation and gamete release. In males, NFLU decreases serotonin level what likely leads to impeding sperm maturation and thus spawning delay. Transcriptomic analyses highlighted the presence of NFLU-induced changes in gene expression related to gametogenesis and neurotransmission. In females, NFLU upregulated genes associated with oocyte development and downregulated those involved in sperm maturation. NFLU-treated males exhibited mixed effects in their genes in relation to spermatogenesis. Additionally, sex-related differences in the expression of the CYP450 genes responsible for detoxification were found. Overall, norfluoxetine acts as an endocrine-disrupting chemical and impacts gonadal serotonin levels and gene expression, potentially disrupting reproductive success of M. trossulus.

Mediators of sex-specific differences in rates of stroke mimics among patients treated with intravenous thrombolysis: A nationwide analysis of 174,995 patients

IntroductionWomen are at higher risk of stroke mimics; however, the underlying reasons are unclear. MethodsIn this retrospective cohort study of the 2016–2020 National Inpatient Sample database, we identified patients treated with intravenous thrombolysis (IVT). Demographic information, vascular risk factors, comorbidities, and presence of known risk factors for stroke mimics (seizures, migraines, demyelinating diseases, psychiatric illnesses, and functional neurological disorders [FND]) were identified using ICD-10 codes. Rates of no cerebral infarction (NCI) were compared between men and women. Mediation analyses were conducted to identify significant drivers of sex-specific differences in the rate of NCI. Results174,995 IVT-treated patients were identified; 41,605 (23.8 %) had NCI. Female patients had significantly higher rates of NCI compared to men (26.2 % vs. 20.9 %, p < 0.001). Women had significantly higher rates of stroke mimic risk factors (seizures, migraines, demyelinating disease, anxiety, depression, FND, and electrolyte derangements; all p < 0.001). Mediation analyses revealed that 39.8 %, 19.1 % of female sex's association with higher rates of NCI were mediated by higher rates of migraines and FND among women, respectively (both p < 0.001). ConclusionsIVT-treated women were more likely to have NCI than men. This relationship was largely mediated by higher rates of migraine and FND among women.

Gonadal rematuration and sex-specific reproductive impairment in Manila clams under ocean acidification

Ocean acidification (OA) can affect marine bivalves at various levels of biological organization. Yet, little effort has been devoted to understanding how OA affects the reproductive events of marine bivalves during multiple cycles of maturation. Here, we tested sex-specific reproductive responses of Manila clams (Ruditapes philippinarum) to OA during gonadal rematuration. Under acidified conditions, both male and female clams exhibited delayed gonadal rematuration following spawning and impairments in gonadal tissues, which can be likely ascribed to lowered concentrations of hormones and vitellogenin. The findings indicate that marine bivalves experience significant declines in reproductive capacity as a result of OA during their reproductive cycles, with clear sex-specific differences. Consequently, it is essential to consider sex-specific reproduction responses of marine bivalves to OA when developing conservation strategies and forecasting population sustainability in a rapidly acidifying marine environment.

Sex-specific gene expression differences in the prefrontal cortex of major depressive disorder individuals

Major depressive disorder (MDD) is a leading global cause of disability, being more prevalent in females, possibly due to molecular and neuronal pathway differences between females and males. However, the connection between transcriptional changes and MDD remains unclear. We identified transcriptionally altered genes (TAGs) in MDD through gene and transcript expression analyses, focusing on sex-specific differences. Analyzing 263 brain samples from both sexes, we conducted differential gene expression, differential transcript expression, and differential transcript usage analyses, revealing 1169 unique TAGs, primarily in the prefrontal areas, with nearly half exhibiting transcript-level alterations. Females showed notable RNA splicing and export process disruptions in the orbitofrontal cortex, alongside altered DDX39B gene expression in five of the six brain regions in both sexes. Our findings suggest that disruptions in RNA processing pathways may play a vital role in MDD.

Differential Impact of Adolescent or Adult Stress on Behavior and Cortical Parvalbumin Interneurons and Perineuronal Nets in Male and Female Mice.

Stress has become a common public health concern, contributing to the rising prevalence of psychiatric disorders. Understanding the impact of stress considering critical variables, such as age, sex, and individual differences, is of the utmost importance for developing effective intervention strategies. Stress effects (daily footshocks for 10 days) during adolescence (postnatal day [PND] 31-40) and adulthood (PND 65-74) were investigated on behavioral outcomes and parvalbumin (PV)-expressing GABAergic interneurons and their associated perineuronal nets (PNNs) in the prefrontal cortex of male and female mice 5 weeks post stress. In adulthood, adolescent stress induced behavioral alterations in male mice, including anxiety-like behaviors, social deficits, cognitive impairments, and altered dopamine system responsivity. Applying integrated behavioral z-score analysis, we identified sex-specific differences in response to adolescent stress, with males displaying greater vulnerability than females. Furthermore, adolescent-stressed male mice showed decreased PV+ and PNN+ cell numbers and PV+/PNN+ colocalization, while in females, adolescent stress reduced prefrontal PV+/PNN+ colocalization in the prefrontal cortex. Further analysis identified distinct behavioral clusters, with certain females demonstrating resilience to adolescent stress-induced deficits in sociability and PV+ cell number. Adult stress in male and female mice did not cause long-lasting changes in behavior and PV+ and PNN+ cell number. Our findings indicate that the timing of stress, sex, and individual variabilities seem to be determinants for the development of behavioral changes associated with psychiatric disorders, particularly in male mice during adolescence.

Unveiling the female experience through adult mortality and survivorship in Milan over the last 2000 years

This study challenges historical paradigms using a large-scale integrated bioarchaeological approach, focusing on the female experience over the last 2,000 years in Milan, Italy. Specifically, 492 skeletons from the osteological collection of Milan were used to elucidate female survivorship and mortality by integrating bioarchaeological and paleopathological data, paleoepidemiological analyses, and historical contextualization. Findings revealed changes in female longevity, with a notable increase from Roman to contemporary eras, albeit plateauing in the Middle Ages/modern period. Significant sex-specific differences in mortality risk and survivorship were observed: females had higher mortality risk and lower survivorship in the Roman (first-fifth century AD) and Modern (16th-18th century AD) eras, but this trend reversed in the contemporary period (19th-20th century AD). Cultural and social factors negatively impacted female mortality in Roman and modern Milan, while others buffered it during the Middle Ages (sixth-15th century AD). This study underscored the importance of bioarchaeological inquiries in reconstructing the past, providing answers that may challenge historical assumptions and shedding light on how the interplay of cultural, social, and biological factors shaped the female experience across millennia.

Impact of Sex on the Therapeutic Efficacy of Rosiglitazone in Modulating White Adipose Tissue Function and Insulin Sensitivity.

Obesity and type 2 diabetes mellitus are global public health issues. Although males show higher obesity and insulin resistance prevalence, current treatments often neglect sex-specific differences. White adipose tissue (WAT) is crucial in preventing lipotoxicity and inflammation and has become a key therapeutic target. Rosiglitazone (RSG), a potent PPARγ agonist, promotes healthy WAT growth and mitochondrial function through MitoNEET modulation. Recent RSG-based strategies specifically target white adipocytes, avoiding side effects. Our aim was to investigate whether sex-specific differences in the insulin-sensitizing effects of RSG exist on WAT during obesity and inflammation. We used Wistar rats of both sexes fed a high-fat diet (HFD, 22.5% fat content) for 16 weeks. Two weeks before sacrifice, a group of HFD-fed rats received RSG treatment (4 mg/kg of body weight per day) within the diet. HFD male rats showed greater insulin resistance, inflammation, mitochondrial dysfunction, and dyslipidemia than females. RSG had more pronounced effects in males, significantly improving insulin sensitivity, fat storage, mitochondrial function, and lipid handling in WAT while reducing ectopic fat deposition and enhancing adiponectin signaling in the liver. Our study suggests a significant sexual dimorphism in the anti-diabetic effects of RSG on WAT, correlating with the severity of metabolic dysfunction.

Left Atrial Wall Thickness Estimated by Cardiac CT: Implications for Catheter Ablation of Atrial Fibrillation.

Atrial wall thickness (AWT) is a significant factor in understanding the pathological physiological substrate of atrial fibrillation, with a potentially substantial impact on the outcomes of catheter ablation procedures. Precise measurements of the AWT may provide valuable insights for categorising patients with AF and planning targeted interventions. Objectives: The purpose of this study was to evaluate the characteristics of the left atrium (LA) using non-invasive multidetector computed tomography (MDCT) scans and subsequent three-dimensional (3D) image post-processing using novel software designed to calculate atrial thickness dimensions and mass. Methods: We retrospectively analysed 128 consecutive patients (33.6% females; mean age 55.6 ± 11.2 years) referred for AF ablation (37 with persistent AF and 91 with paroxysmal AF) who underwent preprocedural MDCT. The images were post-processed and analysed using the ADAS software (Galgo Medical), automatically calculating the LA volume and regional wall thickness. In addition, the software employed a regional semi-automatic LA parcellation feature that divided the atrial wall into 12 segments, generating atrial wall thickness (AWT) maps per segment for each patient. Results: This study demonstrated considerable variability in the average thickness of LA walls, with the anterior segments being the thickest across the cohort. Distinct sex-specific differences were observed, with males exhibiting greater anterior and septal wall thickness than females. No significant associations were identified between the average AWT and body mass index, LA volume, or sphericity. Survival analysis conducted over 24 months revealed a meaningful relationship between mean anterior wall thickness and recurrence-free survival, with increased thickness associated with a lower likelihood of AF-free survival. No such relationship was observed for the indexed LA volume. Conclusions: The variability in AWT and its association with recurrence-free survival following AF ablation suggest that AWT should be considered when stratifying patients for AF management and ablation strategies. These findings underscore the need for personalised treatment approaches and further research on the interplay of the structural properties of the left atrium as factors that can serve as important prognostic markers in AF treatment.

An analysis of 105 female-perpetrated mass murders.

Most research on mass murderers to date has focused on perpetrators of male sex, while research on perpetrators of female sex has been relegated to case reports and series. We aimed to more fully examine the phenomenon of female-perpetrated mass murder. We analyzed 1715 worldwide incidents of personal-cause mass murder from 1900 to 2019, identifying 105 (6%) events perpetrated by females. We defined mass murder as any event involving at least three fatalities, not including the perpetrator, using any method. We identified cases of mass murder from English-language databases of mass murder or murder in print or online. There were no significant differences in age and race between female and male perpetrators. Relative to males, female perpetrators were significantly less likely to employ firearms in their mass murders, using them in less than half of cases, compared to over 70% for males. The prevalence of psychotic signs and symptoms among female mass murderers was more than double that among males (25.7% vs. 12.5%, p < 0.01), while the rate of nonpsychotic psychiatric or neurological conditions was also much greater among female perpetrators (29.5% vs. 17.1%, p < 0.01). Over half of female perpetrators took or attempted to take their own lives. More than three-quarters of mass murders by females involved at least one family member as a victim. This study underscores sex-specific differences in the perpetration of mass murder and the need for further research to understand how insights about such dynamics might lead to the development of more effective and informed intervention policies.

Sex-Specific Imaging Biomarkers for Parkinson's Disease Diagnosis: A Machine Learning Analysis.

This study aimed to identify sex-specific imaging biomarkers for Parkinson's disease (PD) based on multiple MRI morphological features by using machine learning methods. Participants were categorized into female and male subgroups, and various structural morphological features were extracted. An ensemble Lasso (EnLasso) method was employed to identify a stable optimal feature subset for each sex-based subgroup. Eight typical classifiers were adopted to construct classification models for PD and HC, respectively, to validate whether models specific to sex subgroups could bolster the precision of PD identification. Finally, statistical analysis and correlation tests were carried out on significant brain region features to identify potential sex-specific imaging biomarkers. The best model (MLP) based on the female subgroup and male subgroup achieved average classification accuracy of 92.83% and 92.11%, respectively, which were better than that of the model based on the overall samples (86.88%) and the overall model incorporating gender factor (87.52%). In addition, the most discriminative feature of PD among males was the lh 6r (FD), but among females, it was the lh PreS (GI). The findings indicate that the sex-specific PD diagnosis model yields a significantly higher classification performance compared to previous models that included all participants. Additionally, the male subgroup exhibited a greater number of brain region changes than the female subgroup, suggesting sex-specific differences in PD risk markers. This study underscore the importance of stratifying data by sex and offer insights into sex-specific variations in PD phenotypes, which could aid in the development of precise and personalized diagnostic approaches in the early stages of the disease.

Sex-Specific Roles of Hypocretin Receptor Signaling in CRF Neurons on Alcohol Drinking, Anxiety, and BNST Neuronal Excitability.

Alcohol use disorder (AUD) is characterized by compulsive alcohol consumption and negative emotional states during withdrawal, often perpetuating a cycle of addiction through arousal dysfunction. The hypocretin/orexin (Hcrt) neuropeptide system, a key regulator of arousal, has been implicated in these processes, particularly in its interactions with corticotropin-releasing factor (CRF) neurons within the bed nucleus of the stria terminalis (BNST). We investigated the role of Hcrt receptor signaling in CRF neurons in modulating alcohol intake, anxiety behaviors, and BNST excitability, with a focus on sex-specific differences. Using CRF-specific genetic deletion of HcrtR1 and/or HcrtR2 receptors in mice, we found that deletion of HcrtR1 significantly reduced alcohol intake, with sex-specific effects on BNST excitability. CRF-specific HcrtR2 deletion, while not affecting alcohol consumption, decreased baseline anxiety-like behaviors in males relative to females. Moreover, the double deletion of both Hcrt receptors from CRF neurons led to reduced alcohol drinking in males and dampened anxiety behaviors and BNST excitability in both sexes during protracted withdrawal. These findings suggest that Hcrt signaling in CRF neurons plays a critical role in the persistence of excessive alcohol consumption and the development of negative affective states, with distinct contributions from HcrtR1 and HcrtR2. The observed sex-specific differences underscore the need for tailored therapeutic approaches targeting the Hcrt system in the treatment of AUD.