Background: Precise delineation of the rectum is crucial in treatment planning for cancers in the pelvic region, such as prostate and cervical cancers. Manual segmentation is also still time-consuming and suffers from inter-observer variability. Since there are meaningful differences in rectal anatomy between males and females, incorporating sex-specific anatomical patterns can be used to enhance the performance of segmentations. Furthermore, recent deep learning advancements have provided promising solutions for automatically classifying patient sex from CT scans and leveraging this information for enhancing the accuracy of rectal segmentation. However, their clinical utility requires comprehensive validation against real-world standards. Methods: In this study, a two-stage deep learning pipeline was developed using CT scans from 186 patients with either prostate or cervical cancer. First, a CNN model automatically classified the patient’s biological sex from CT images in order to capture anatomical variations dependent on sex. Second, a sex-aware U-Net model performed automated rectal segmentation, allowing the network to adjust its feature representation based on the anatomical differences identified in stage one. The internal validation had an 80/20 train–test split, and 15% of the training portion was held out for validation to ensure balanced distribution regarding sex and diagnosis. Model performance was evaluated using spatial similarity metrics, including the Dice Similarity Coefficient (DSC), Hausdorff Distance, and Average Surface Distance. Additionally, a radiation oncologist conducted a retrospective clinical evaluation using a 3-point Likert scale. Statistical significance was examined using Wilcoxon signed-rank tests, Welch’s t-tests, and Mann–Whitney U test. Results: The sex-classification model attained an accuracy of 94.6% (AUC = 0.98, 95% CI: 0.96–0.99). Incorporation of predicted sex into the segmentation pipeline improved anatomical consistency of U-Net outputs. Mean DSC values were 0.91 (95% CI: 0.89–0.92) for prostate cases and 0.89 (95% CI: 0.87–0.91) for cervical cases, with no significant difference between groups (p = 0.12). Surface distance metrics calculated on resampled isotropic voxels showed mean HD values of 3.4 ± 0.8 mm and ASD of 1.2 ± 0.3 mm, consistent with clinically acceptable accuracy. On clinical evaluation, 89.2% of contours were rated as excellent, while 9.1% required only minor adjustments. Automated segmentation reduced the average contouring time from 12.7 ± 2.3 min manually to 4.3 ± 0.9 min. Conclusions: The proposed sex-aware deep learning framework offers accurate, robust segmentation of the rectum in pelvic CT imaging by explicitly modeling sex-specific differences in anatomical characteristics. This physiologically informed approach enhances segmentation performance and supports reliable integration of AI-based delineation into radiotherapy workflows to improve both contouring efficiency and clinical consistency.

BackgroundReported estimates of frailty prevalence vary considerably. At least partially attributable to differences in the conceptualization of frailty used, a better understanding of the inter-relationships among frailty domains could clarify contributors to the noted heterogeneity.MethodsA global frailty index (FI) created from baseline data on 30,097 Canadian Longitudinal Study on Aging comprehensive cohort participants was used to define physical, psychological, cognitive, and social domain-specific FIs. These were divided into quintiles with the highest 20% (Q5) representing the frailest participants. Logistic regression was used to estimate the associations between age group and biological sex with domain-specific FIs in unadjusted and adjusted (income, smoking status, nutritional risk, physical activity, social participation, interaction between sex and age group) models. The association between Q5 membership among the frailty domains was estimated using polychoric correlation coefficients.ResultsThe prevalence of physical and cognitive frailty increased with age, but psychological frailty decreased, especially in males. Social frailty showed gradual increases with age in females that were only evident in the oldest age group (75–85) among men. The age-groups*sex interaction p value was p<.001 for social. Polychoric correlations were highest between the psychological/physical and psychological/social domains, and decreased with increasing age for all combinations.ConclusionWe found that domain-specific frailty prevalences differed by age group and sex with low associations among frailty domains, particularly at older ages. Understanding the evolution of these findings could be instrumental in developing tailored interventions to prevent frailty or modify its trajectory.

Teaching the complexities of biological sex determination with the goal of creating a more inclusive classroom and perhaps challenging key components of the oversimplified rhetoric of the gender binary.

The complex impacts of early sexual intercourse, biological sex, and sexual orientation on the risk of depression.

Investigating stroke-related vision impairments and time to incident dementia diagnosis.

Associations between sleep, obesity, and mental health in adolescents: Understanding sex-specific vulnerabilities.

Despite the prominence of individuals presenting for therapy with suicidal thoughts and behaviors (STBs), there is little research available that examines how one or both members of a couple experience STBs when presenting for couple therapy. Thus, there is a prominent gap in the literature in understanding the types of STBs for both adult partners in a committed romantic relationship presenting for couple therapy, reducing clinicians' preparedness to address suicidality in this unique therapy modality. We applied the Three-Step Theory as a guiding framework to investigate the types of couples with suicidal risk that present to couple therapy. We used clinical data from the Marriage and Family Therapy Practice Research Network (n = 337 couples) to identify Dyadic Latent Profiles. We determined a three-profile model: Profile 1: Minimal Risk; Profile 2: Active and Passive Risk; and Profile 3: Both Passive Risk. However, nearly all predictors and covariates (e.g., biological sex, race, relationship duration, mental health treatment, pressure to attend therapy, and intimate partner violence) were not associated with profile membership. These results indicate that while most couples who attend couple therapy are unlikely to display elevated suicide risk, 7% of the sample (Profile 2) displayed active risk based on the Three-Step Theory of suicide. These findings aid clinicians in understanding that a small number of couples present an active risk. Results further encourage clinicians to assess STBs with continuous and not binary assessment questions.

Gender and Sex Conscious Medicine and the future direction of health care: An invited scientific review by the European Board and College of Obstetrics and Gynaecology (EBCOG).

The analysis of fingerprint features for inferring biological sex is a growing area of research in forensic science. This study presents a lightweight and well-validated convolutional neural network (CNN) as an alternative approach for this task. A dedicated dataset of 1,000 fingerprint images was collected from 200 volunteers (100 males and 100 females). To ensure rigorous evaluation of generalisation ability, an independent test set of 100 images from an additional 20 volunteers (10 males and 10 females) was held out for final assessment. The proposed CNN, featuring a dual-convolutional-layer architecture, was optimised using a cross-entropy loss function and the Adam optimiser. It achieved a validation accuracy of 91.00% and a test accuracy of 95.00%, with AUC values of 0.974 and 0.983, respectively. Supplementary fivefold cross-validation on the development cohort yielded a mean accuracy of 90.60% (SD: 2.04%), confirming stable performance. Class activation mapping (CAM) was employed to visualise the model’s focus regions, enhancing interpretability and providing insights into biometric relevance. These results demonstrate that the model compares favourably with traditional methods, suggesting its potential as an efficient and reliable complementary tool for forensic identification.

Sex- and depot-dependent differences in adipocyte morphology and gene expression in diet-induced obesity.

Females are more susceptible to alcohol-related liver disease (ALD) owing to increased risk of alcohol dependence; decreased gastric first-pass effect and increased risk of producing hepatotoxic metabolites, higher alcohol bioavailability, and hormonal fluctuations affecting ethanol metabolism. Male sex is independently associated with hepatitis B virus (HBV) infection and hypertransaminasemia in HBV chronic infection. Compared to women, men have higher risks of being hepatitis B surface antigen (HBsAg) carriers, exhibit higher non-response and lower long-term immunity after prophylactic vaccination, have a higher risk of chronic hepatitis, and fibrotic and hepatocellular carcinoma (HCC). Females have higher spontaneous hepatitis C virus (HCV) clearance and reduced risk of fibrosis, cirrhosis, and HCC than men. However, post-menopausal women experience more rapid progression of hepatic fibrosis and HCC development and lower response rates to antiviral regimens compared to younger women. Hormonal and immunological mechanisms explain these sex differences observed in chronic viral hepatitis B and C. Sex and reproductive status affect the risk of metabolic dysfunction-associated steatotic liver disease (MASLD) development and progression. Genetic sex and sex hormones are involved in the pathogenesis of sex differences in MASLD by differential effects on body fat distribution, insulin sensitivity, and oxidative stress. HCC may arise as a complication of ALD, HBV, HCV, and MASLD and has a definite prevalence in the male sex because of the most robust inflammatory response of the male sex and the anti-inflammatory activity of estrogens. We conclude that those major sex differences which are identifiable in the epidemiology and clinical course of ALD, viral hepatitis owing to HBV and HCV, MASLD, and HCC. These sex disparities are explained by biological sex and sex hormones affecting metabolism, immunity, fibrogenesis, and cancer, and are the foundations for precision medicine approaches in these common hepatological conditions.

Background. This real-life investigation, conducted across multiple centres in Italy, aims to assess the 2-year effectiveness and safety of upadacitinib, a selective JAK1 inhibitor approved for the treatment of axial spondyloarthritis (axSpA). The study includes patients with both radiographic and non-radiographic axSpA and evaluates: (a) clinical outcomes at 6, 12, and 24 months; (b) drug retention rate (DRR); and (c) the influence of treatment line (LoBT), axSpA subtype, and sex on achieving low disease activity (LDA) and very low disease activity (VLDA). By analysing real-life clinical practice data, our analysis provides insight into the long-term therapeutic role of upadacitinib in managing axSpA, particularly in previously-treated patients or those with limited therapeutic options. Methods. Consecutive patients with axSpA, who received upadacitinib between December 2022 and January 2025, were prospectively evaluated across multiple Italian centres. Data collected included baseline disease characteristics, comorbidities, prior and ongoing treatments, and follow-up duration. The primary endpoints were treatment effectiveness and safety, as well as drug retention rate (DRR), assessed at 6, 12, and 24 months from treatment initiation (T0). Effectiveness was evaluated using clinimetric indices, while safety outcomes included infections and adverse events (AEs). Secondary endpoints included the impact of biologic treatment history (bDMARDs), axSpA subtype (radiographic vs. non-radiographic), and sex on the achievement of low disease activity (LDA), defined as BASDAI &lt;4 and/or ASDAS &lt;2.1, and very low disease activity (VLDA), defined as BASDAI &lt;2 and/or ASDAS &lt;1.3, at each time point. Results. A total of 203 patients were included in the analysis [48% male; median age at diagnosis: 44 years; 22.7% HLA-B27 positive -36.6% observed in Northern Italy); 71% with non-radiographic axSpA]. The median number of prior treatment lines was 3 (range: 1–12). At follow up, 170 patients were evaluable at 6 months (T6), 130 at T12 and 62 at T24. Overall, upadacitinib demonstrated a statistically significant improvement in effectiveness outcomes at 6 months, which was sustained over time at 12 and 24 months (Figure 1), regardless of LoBT, axSpA subtype, or sex. Of note, LDA at 24 months was more frequently achieved in the nr-axSpA subset (91.3% vs. 56.3%), while VLDA at 12 months was more commonly associated with female patients (41.5% vs. 21.4%). Remarkably, the DRR was consistently high throughout the observation period, with rates of 92%, 80%, and 55% recorded at 6, 12, and 24 months, respectively. Treatment was discontinued in 40 patients, with 22 cases attributed to primary or secondary loss of effectiveness and 2 cases due to adverse events. Conclusions. Upadacitinib demonstrated a favourable safety and effectiveness profile across the axSpA population, regardless of prior treatment lines, axSpA subtype, or sex. Among evaluable patients sustained remission and consistent drug retention were observed over the two-year follow-up period.

Alzheimer disease blood-based biomarkers are a cost-effective method for early detection. Few studies provide long-term follow-up of cognition in Black participants. We assessed biomarker association with cognitive decline and dementia risk in Black and White participants. Plasma biomarkers (neurofilament light chain, glial fibrillary acidic protein [GFAP], amyloid-β 42/40 ratio, phosphorylated tau at threonine 217 [pTau217]) were measured in participants from a community-based Chicago cohort without dementia at the time of blood draw. They were evaluated annually for up to 15 years for cognition and dementia. Data included medical history, blood tests (e.g., kidney function), Mini-Mental State Examination (MMSE) score, and APOEε4. Associations of biomarkers with comorbidities, cognitive decline, and risk of dementia were examined within racial groups. To examine racial differences, we repeated the analysis using a Mahalanobis-balanced 1:1 match on biological sex, age, education, Latino/non-Latino status, longitudinal data availability, and clinical status (hypertension, diabetes, glomerular filtration rate, body mass index [BMI], and heart disease). Biomarkers were measured in 431 Black and 583 White participants (mean age of 77 and 80 years and 17% and 21% of men, respectively), generating a balanced sample of 366:366. Biomarker levels were similar across races. Within racial groups, the associations of biomarkers with multiple comorbidities (especially kidney dysfunction and BMI) remained after controlling for demographics, APOEε4 status, and dementia or death within 5 years. Men had lower GFAP than women (all p < 0.001). Within racial groups, pTau217 was associated with a decline in global cognition and domains (all p < 0.001), and between races, pTau217 was associated with a faster decline in global cognition (β = -0.03, SE = 0.012, p = 0.018) and semantic memory (β = -0.068, SE = 0.016, p < 0.001) in Black individuals. The discrimination of dementia by pTau217 (area under the curve [AUC]3-year, Black 0.81, 95% CI 0.74-0.89; AUC3-year, White 0.77, 95% CI 0.71-0.83) was good relative to age (AUC3-year, Black 0.69, 95% CI 0.58-0.79; AUC3-year, White 0.68, 95% CI 0.62-0.75) and MMSE score (AUC3-year, Black 0.81, 95% CI 0.74-0.89; AUC3-year, White 0.72, 95% CI 0.65-0.80). The discrimination by pTau217 did not improve when adding other biomarkers or MMSE score. pTau217 was highly associated with dementia risk and cognitive decline. The association of biomarkers with cognitive decline in Black and White participants was similar. Higher pTau217 was, however, associated with global and semantic memory decline in Black adults. Generalizability is a limitation.

Aging from young to middle-aged and older adulthood modulates sweating differently across body regions, yet how biological aging from young adulthood to the 80s and beyond affects cholinergic sweating remains unclear. A total of 248 participants (143 males and 105 females) were grouped as young (≥18+20s), middle-aged (30s+40s+50s), older (60s+70s) adults, and elderly (80s+90s). Acetylcholine-induced sweat rate, activated sweat gland density, and sweat gland output were assessed via transdermal iontophoresis. Forearm sweat rate declined in the 30s+40s+50s and older in males and the 60s+70s and older in females, compared to the ≥18+20s group (all P≤0.006). Thigh sweat rate also declined with aging and was further reduced in the 60s+70s and 80s+90s compared to the 30s+40s+50s group in males (both P≤0.035). Sweat rate did not differ between the 60s+70s and 80s+90s groups in either region or sex (all P≥0.677). Sex differences in forearm sweat rate persisted across all age groups (all P≤0.012), but diminished on the thigh in the 60s+70s and 80s+90s groups (both P≥0.183). These changes were attributed to reductions in sweat gland output in males and combined reductions in sweat gland density and output in females. Collectively, forearm cholinergic sweating declines from the 30s+40s+50s to the 60s+70s relative to young adults but shows minimal further attenuation beyond the 70s in both sexes. Thigh cholinergic sweating function is more affected by biological aging in males. We also highlight the characteristics of sweating in two participants in their 90s, providing insights into sweating function at the end of the lifespan.

Over the course of the 20th and 21st centuries the Freudian intrapsychic and drive-based view of development of the human mind has been replaced by work done in several interdisciplinary fields which prove that the human mind is from its very inception a social mind, which best develops in connection with other minds and bodies, in interpersonal realms. It thrives through attunement, attachment, care and synchrony with numerous other minds and personalities. Moreover, research has also shown that higher order faculties in the human subject develop when there is the constant care and sensitivity of another human based on right-brain functions for a lengthy period of time, regardless of the biological sex of the caregiver. These developments of psychoanalytic theory have a strong impact on all aspects of psychotherapy, particularly with regards to the psychotherapy with survivors of what I have called second and third levels of trauma (Mucci, 2013, 2018, 2022), where an interpersonal focus on testimony and bearing witness thorough mind-brain and body are called for, what I term "embodied witnessing" (Mucci, 2018, 2022, 2023a), which could also be applied to personality disorders of traumatic origin, and facilitate healing in trauma survivors.

Effects of glucagon-like peptide 1 receptor signaling in the dorsolateral septum on ethanol operant self-administration and relapse behaviors.

Polychlorinated biphenyls (PCBs) have been associated with sex-dependent liver disease outcomes. Current mechanisms only partially explain these sex differences and alternative mechanisms including gut-liver toxicity warrant investigation. This study aims to identify PCB-induced changes in the hepatic proteome and gut microbiome and determine their contributions to sex-specific PCB toxicity. Male and female C57BL/6J mice were exposed to Aroclor1260 (20 mg/kg) and PCB126 (20 μg/kg) via oral gavage. After two weeks, hepatic and intestinal tissues were collected for peptide measurements (LC/MS) and 16S sequencing respectively. Proteomic analysis revealed that biological sex largely drove differences seen in the hepatic proteome and dictated PCB liver responses. PCB-exposed females manifested higher abundance of aryl hydrocarbon receptor (AHR) targets including CD36 vs. PCB-exposed males. Computational analysis also demonstrated enhanced AHR and liver-X-receptor (LXR) activation (higher z-scores) in PCB-exposed females vs. males. With regards to gut microbiome, both exposure and sex impacted the composition of microbial communities. Intriguingly, only PCB-exposed males exhibited increased Dehalobacterium abundance, and decreased mRNA levels for genes encoding gut barrier and antimicrobial proteins (Ocln, Reg3g). Overall, PCB-exposed females exhibited an altered proteome relevant to AHR and LXR responses, while PCB-exposed males exhibited more distinct changes in gut microbiota coupled with altered ileal gene expression. The findings suggest that, in addition to biological sex, organ-organ interactions should be considered when predicting toxicity outcomes, particularly for persistent compounds such as PCBs that can impact multiple organs simultaneously yet have tissue-specific toxic effects.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-23603-w.

Background and objectives: osteoporosis (OP) is prevalent among older adults, and nutritional factors significantly contribute to its development. Although some studies suggest niacin may influence bone health, the existing evidence remains inconclusive. This study investigates the dose-response relationship between dietary niacin intake and osteoporosis risk in US adults aged 50 years or older, using nationally representative data from the National Health and Nutrition Examination Survey (NHANES, 2007-2018). Methods and design: this cross-sectional study included 2308 adults aged ≥ 50 years from the NHANES. Dietary niacin intake was assessed using two non-consecutive 24-hour dietary recalls. Weighted multivariable logistic regression analyzed associations between niacin and OP, while restricted cubic spline (RCS) models evaluated potential nonlinear dose-response relationships. Results: the baseline analysis revealed significantly lower dietary niacin intake levels among OP patients. Multivariable logistic regression demonstrated that, after adjusting for confounders, participants in the highest percentile of dietary niacin intake exhibited a significantly reduced OP risk compared to those in the lowest percentile (OR: 0.81, 95 % CI: 0.68-0.84, p = 0.03), with a significant dose-response trend (p for trend = 0.04). Using RCS modeling, this study is the first to identify a nonlinear dose-response relationship (inverted U-shaped curve, overall p < 0.05, nonlinear p < 0.05) between niacin intake and OP risk. Subgroup analyses further revealed sex-specific differences in the association (p for interaction = 0.027), suggesting that niacin's skeletal benefits may vary by biological sex. These findings provide novel insights into niacin's role in OP prevention and inform personalized dietary recommendations. Conclusions: this study, based on NHANES data (2007-2018), first reveals a nonlinear inverted U-shaped association between dietary niacin intake and osteoporosis risk in a US population aged ≥ 50 years, filling the research gap in dose-response characteristics among middle-aged and elderly populations. It proposes a bone-protective threshold for niacin intake (18.62-50 mg/d), providing potential evidence for revising current dietary guidelines. Furthermore, the study innovatively employs RCS models to identify gender-specific inflection points, and is the first to demonstrate the significant moderating effect of gender on the niacin-osteoporosis association. These findings establish a scientific foundation for personalized nutritional interventions.

Abstract Glioblastoma (GBM) is 1.6 times more common in males who also have a shorter overall survival than females. The immune system is suppressed in GBM, and studies have found sex differences in the immune response. While preclinical GBM models are used to interrogate GBM pathophysiology, few include resection, despite its role in the standard of care. The aim of this study was to determine sex differences in surgical resection in GBM. We developed a preclinical GBM resection model in which mice were implanted with syngeneic GBM cells and underwent tumor resection. RNA sequencing was used to characterize transcriptional changes, and immune phenotype after surgery was investigated via flow cytometry. In an immunocompetent model, females survived longer than males after resection, but there were no significant transcriptional differences found between the sexes. Interestingly, the sex bias in survival was abrogated in immunocompromised mice. Immunocompetent female mice who underwent resection had higher levels of immune cell infiltration in their resection cavity while males had decreased T regulatory (Treg) cells post-resection. When Tregs were depleted via the utilization of Foxp3DTR mice, the sex bias in survival was abrogated. Analysis of GBM patients in the National Cancer Database found that while female patients survive longer than male patients after resection, there is no sex bias in survival after biopsy alone. These results demonstrate a sex bias in survival after resection that is immune-dependent. Tregs may serve a protective role post-operatively and should be further studied to understand how and when they become important for survival. These data underscore the complexity of sex bias and the immune system in GBM and the need to account for biological sex and resection in preclinical models to investigate next-generation therapies.

The clinical characteristics of type 2 diabetes (T2D) differ between the sexes. For example, the risk of T2D is higher in males than in premenopausal females, whereas the risk of T2D-associated cardiovascular disease is higher in females. The sex-dependent mechanisms of T2D pathogenesis remain incompletely understood. Publicly available human islet datasets, such as HPAP and Humanislets.com, offer a valuable tool for uncovering the impact of biological sex on islet structure, gene expression, and function at a scale that was not previously possible. We performed an integrated analysis of data from publicly available sources to identify sex differences in baseline islet characteristics in donors without diabetes and subsequently examined these features in donors who lived with T2D. Among donors without diabetes, female islets had a greater proportion of alpha-cells compared with male islets and showed enriched expression of ribosomal and mitochondrial pathways in both beta-and alpha-cells. Measurements of mitochondrial function in female islets revealed lower spare respiratory capacity compared to male islets due to higher basal respiration. Male and female islets had distinct changes in gene and protein expression in the context of T2D with female islets having greater preservation of insulin content and fewer defects in islet function. Together, these data show female islets have fewer islet impairments in T2D. This highlights the need for detailed mechanistic studies in both sexes to support effective and sex-informed interventions for T2D.