Ny forskning om jente- og kvinnehelse

Neoadjuvant chemotherapy (NAC) and adjuvant chemotherapy (AC) provide similar long-term survival in early breast cancer (BC), but their comparative impacts on the trajectory and resolution of symptomatic adverse events (AEs) in routine practice are not well defined. We conducted a prospective observational study of perioperative BC chemotherapy. Symptomatic AEs were graded using a patient reported outcome (PRO)-based questionnaire prepared for this study and aligned with the CTCAE system at the end of chemotherapy and at six months after completion. We compared AE severity distributions between patients treated with NAC and those treated with AC. Ninety-three patient cases were analyzed (NAC: n=48, AC: n=45). The two groups' baseline stage distributions were not significantly different ( p =0.106), but the subtype compositions were ( p =0.002). Multiple AEs at the end of chemotherapy were common in both groups. At chemotherapy completion, significant between-group differences in severity distributions were observed for peripheral sensory neuropathy ( p =0.049) and nail loss ( p =0.011), with higher symptom burdens in the NAC group. At six months post-completion, no statistically significant between-group differences in severity distributions were detected across the assessed AEs. In this real-world prospective cohort, no statistically significant between-group differences in medium-term symptomatic AE severity distributions were detected between patients receiving NAC and those receiving AC.

Multiple Sclerosis (MS) may affect women of childbearing age. Information on safety of disease modifying treatment (DMT) in pregnancy is often limited at time of marketing authorisation. We summarised the EU regulatory experience with the implementation and performance of additional pharmacovigilance activities concerning safety in pregnancy and breastfeeding for medicines to treat MS. We reviewed EU risk management plans (RMPs) for centrally authorised MS DMTs to identify additional pharmacovigilance activities related to pregnancy and breastfeeding. Information was analysed descriptively for type of measure, data collection method and data source. For non-interventional cohort studies and follow-up of reported pregnancy cases, information on current status, planned and actual size and duration was retrieved. We identified 17 DMTs that included 21 additional pharmacovigilance activities related to pregnancy and breastfeeding across 15 RMPs. These comprised nine non-interventional cohort studies and four structured follow-up activities of pregnancy cases that had been started. Of those, three were terminated due to low recruitment with an inclusion rate slower than planned, while inclusion was faster than planned in three finalised activities. Inclusion rate was slowest in primary data collection and faster in secondary analyses and follow-up of reported pregnancy cases. Despite efforts to evaluate safety of MS medicines during pregnancy, recruitment and data collection remain challenging. Planning for use of multiple real-world data sources-including primary data collection, secondary use of electronic health records, and analyses of case reports-may help overcome these challenges and strengthen MS drug safety evaluations in pregnancy. Multiple sclerosis (MS) is a disease of the brain and spinal cord that causes symptoms such as numbness, weakness, difficulty walking and changes in vision. Because MS often affects women who can become pregnant, understanding the safety of these medicines during pregnancy and breastfeeding is essential. When information on safety during pregnancy or breastfeeding is missing at the time of marketing authorisation, the European Medicines Agency (EMA) may require this information to be collected after approval as part of the medicine's Risk Management Plan (RMP). Between 2006 and 2023, EMA authorised 17 medicines for the treatment of MS in the European Union. EMA required the collection of additional safety information during pregnancy for the 15 most recently authorised medicines, mainly through studies and follow‐up of reports from pregnancies in routine medical care. No specific activities focused on breastfeeding. Recruiting pregnant women for studies is difficult, and three studies were stopped early for this reason. This review shows that collecting sufficient safety data in pregnant or breastfeeding women remains challenging and may take years. As seen for more recently authorised MS medicines, improving access to, and combining, different sources of information could help collect safety data during pregnancy and breastfeeding.

The 21-gene recurrence score (RS) assay guides adjuvant chemotherapy decisions in hormone receptor-positive/human epidermal growth factor receptor 2-negative early breast cancer. We evaluated how RS results altered treatment recommendations and were integrated with clinicopathological factors in routine practice. We retrospectively analyzed 41 consecutive patients who underwent RS testing for postoperative treatment planning at a single institution. Pre-test and post-test treatment recommendations were compared. Exploratory analyses examined patients with RS ≤25 who received chemotherapy and treatment patterns in node-positive disease. Median age was 58 years; 20 patients (48.8%) had node-positive disease. RS was 0-10 in nine patients (22.0%), 11-25 in 25 (61.0%), and ≥26 in 7 (17.1%). Treatment recommendations changed in 16 patients (39.0%): chemotherapy was omitted in 13 (31.7%) and added in 3 (7.3%). Among 34 patients with RS ≤25, 29 (85.3%) received endocrine therapy alone and 5 (14.7%) received chemo-endocrine therapy. Patients receiving chemotherapy were younger (median 48 vs . 59 years, p =0.049) and had higher RS values (median 17 vs . 13, p =0.007). Among 20 node-positive patients, 15 (75.0%) received endocrine therapy alone. RS testing altered adjuvant treatment recommendations in 39.0% of patients, predominantly through chemotherapy omission. In patients with RS ≤25, younger age and higher RS were associated with chemotherapy use, suggesting that genomic and clinicopathological information were integrated in routine decision-making.

Breast cancer (BC) is the second most common cause of death in women. Current therapies like hormonal therapy, surgery, radiotherapy, and chemotherapy become ineffective due to severe side effects and multidrug resistance. Therefore, there is an urgent need for the development of more effective and safer anti-BC agents. Among different classes of heterocyclic molecules, indazole-based derivatives have emerged as potent anti-BC agents due to their versatile structural features and wide range of biological targets. Indazole is a benzene-pyrazole fused system with potential biological therapeutic significance. This review provides a detailed overview of recent progress in strategies that have expanded the accessible structural diversity of this scaffold. Moreover, mechanistic insights reveal that indazole derivatives mediate their antitumor effects through multi-target modulation, including the inhibition of key kinases such as EGFR, VEGFR, and CDKs, perturbation of microtubule function, activation of apoptotic pathways, and modulation of hormone receptor-dependent signalling, along with SAR. Collectively, this article is a BC-focused integration of different synthetic approaches, the key molecular targets for therapy, and studies showing which groups are responsible for their anti-BC potential, focusing on the latest research published.

The diagnosis of Guillain-Barré syndrome (GBS) relies on evolving clinical features, supported by cerebrospinal fluid (CSF), laboratory investigations, and electrodiagnostic studies. Early investigations may be nondiagnostic and should not delay treatment when progressive neurological deterioration raises clinical suspicion of GBS. Timely treatment is crucial in optimizing maternal and fetal outcomes.

Breast cancer (BC) has become the most prevalent cancer worldwide, and BC patients have the highest rate of depression of all cancer patients. However, previous studies, especially studies based on clinical sample data, have failed to reveal exactly how depression affects BC. Two-sample Mendelian randomization (TSMR) was used to determine the causal relationship between depression and BC. Transcriptomics and metabolomics were used to analyze BC samples from nondepressed and depressed patients and to validate differentially expressed genes and key metabolites in vitro. Molecular docking techniques were used to identify compounds that regulate key targets and validate the functions of the compounds in in vitro and in vivo animal models. Depression was identified as a risk factor for BC by the TSMR analysis. On the basis of clinical samples, for the first time, we identified PPARγ and norepinephrine (NE) as key genes and metabolites that mediate the pro-BC effects of depression. In addition, we demonstrated that quercetin can target PPARγ and reverse the procancer effects of PPARγ inhibition mediated by chronic stress in BC cells. Moreover, we found that PPARγ may be associated with the inhibition of CD8 + T cells in the tumor immune microenvironment. In conclusion, depression can increase the infiltration level of NE in tumors and inhibit the expression of PPARγ in tumor cells, thus promoting the proliferation of BC cells and inhibiting the infiltration of CD8 + T cells in the immune microenvironment, ultimately leading to accelerated tumor growth. Quercetin can target PPARγ and reverse this cancer-promoting process.

To evaluate the independent impact of age and gender on the prevalence of clinically significant chromosomal abnormalities in couples with recurrent pregnancy loss (RPL) and to provide Taiwanese clinicians with local genetic data for genetic counseling. A 5-year retrospective study of 451 individuals (239 females and 212 males) was conducted at a tertiary referral center in Taiwan from 2021 to 2025. Karyotyping was performed by means of G-banding with resolution >550 band level. Common polymorphic variants, such as inv (9) (p12q13) and inv(Y) (p11.2q11.2), were excluded to assess refined cytogenetic risks. Multivariable logistic regression was utilized to calculate adjusted odds ratios (aOR). The prevalence of clinically significant chromosomal abnormalities was 4.43% (20/451). Female gender was identified as a significant independent predictor of abnormality (aOR = 3.70, 95%CI: 1.206-11.346, p = 0.022) after adjusting for age. The distribution of chromosomal abnormalities in 4 different age groups (≦30, 31-35, 36-40, ≧40) did not show significance difference (4.69%, 5.33%, 3.87%, 3.66%. p = 0.909) Both numerical chromosomal aberrations (e.g., sex chromosome mosaicism) and structural rearrangements (e.g., reciprocal and Robertsonian translocations) were more prevalent among females. Notably, females exhibited a predominant higher risk of sex chromosome mosaicism compared with males (aOR = 11.518, 95%CI: 1.454-91.253, p = 0.021) even after adjusting for age. Female gender is a predominant factor for chromosomal abnormalities in RPL, largely attributed to sex chromosome mosaicism and chromosomal translocations. These genetic risks are independent of reproductive age, highlighting the necessity of universal parental karyotyping for all RPL couples, regardless of age, to optimize clinical management.

The current trends in demographic processes in Russia - absence of natality increase, population aging, diminution of the number of citizens of reproductive age - bring to the forefront problems of increasing natality and preserving reproductive potential of population. The infertility is one of the most sensitive issues both in the Russian Federation and around the world. Currently, assisted reproductive technologies are one of the most effective methods to overcome infertility.The purpose of the study is to investigate prevalence of methods of assisted reproductive technologies and their efficiency in overcoming infertility in the Russian Federation in 2019-2024.The forms of the Federal statistical observation № 12, 14, 30, 32 were studied. The dynamic series indicators (visual indicators, growth rates, rates of increase/decrease) were calculated. The method of direct ranking and descriptive statistics was applied.The study established decreasing of the number of women and men with registered infertility. The trend of increasing the number of IVF programs by the end of 2024 was noted. The effectiveness of IVF programs is also increasing. The heterogeneity of indicators of prevalence of IVF programs in the Subjects of the Russian Federation is noted.The identified positive dynamics in the number of IVF programs and their efficiency can become additional reserve for natality increasing. However, heterogeneity of indicators of prevalence of ART methods in the Subjects of the Russian Federation may testify necessity of adoption of organizational decisions with purpose to increase accessibility and quality of medical care for patients with infertility. Учитывая современные тенденции демографических процессов в России — отсутствие роста рождаемости и старение населения, уменьшение числа граждан репродуктивного возраста,— на первый план выходят проблемы повышения рождаемости, сохранения репродуктивного потенциала населения. Бесплодие является одной из наиболее сенситивных проблем как в Российской Федерации, так и во всем мире. В настоящее время вспомогательные репродуктивные технологии являются одним из наиболее эффективных методов преодоления инфертильности.Цель исследования — изучить распространенность методов вспомогательных репродуктивных технологий и их эффективность в преодолении инфертильности в Российской Федерации за 2019—2024 гг.Изучены формы федерального статистического наблюдения № 12, 14, 30, 32. Рассчитаны показатели динамического ряда (показатель наглядности, темпы роста, темпы прироста/убыли), использован метод прямого ранжирования, дескриптивной статистики.Выявлено снижение числа женщин и мужчин с зарегистрированным бесплодием. Наблюдается тенденция увеличения числа программ экстракорпорального оплодотворения по итогам 2024 г. Эффективность программ экстракорпорального оплодотворения также имеет тенденцию к росту. Прослеживается неоднородность показателей распространенности программ экстракорпорального оплодотворения в субъектах Российской Федерации.Выявленная положительная динамика числа программ экстракорпорального оплодотворения и их эффективности может стать дополнительным резервом роста рождаемости. Однако неоднородность показателей распространенности методов вспомогательных репродуктивных технологий в субъектах Российской Федерации может свидетельствовать о необходимости принятия организационных решений с целью повышения доступности и качества медицинской помощи пациентам с бесплодием.

Pathological evaluation of endometrial biopsies has been a clinically relevant tool in the management of patients with unexplained infertility and recurrent pregnancy loss. In this article, we provide a practical, morphology-based framework for the interpretation of endometrial biopsies in this population. Chronic endometritis (CE) has attracted the most clinical and investigative attention in recent years. The evolving clinical picture and histological criteria for CE and the significant unresolved questions surrounding diagnostic thresholds are discussed.

Breast cancer endocrine therapies may induce endometrial alterations, but the endometrial effects of antiprogestins remain incompletely defined. This study evaluated the effects of tamoxifen, mifepristone, and ulipristal acetate on endometrial morphology and galectin-3 expression, with the aim of exploring galectin-3 as a candidate marker of endocrine-modulator-associated endometrial remodeling. Endometrial effects were examined in a rat mammary carcinogenesis model treated with tamoxifen, mifepristone, ulipristal acetate, or vehicle control. Uterine tissues were assessed by histology and galectin-3 immunohistochemistry. Complementary in vitro experiments in Ishikawa endometrial adenocarcinoma cells evaluated agent- and dose-associated galectin-3 protein-expression patterns by western blotting. Histological outcomes and in vitro fold-change values were summarized descriptively. In the analyzed cohort, tamoxifen-treated animals showed the highest descriptive proportion of complex endometrial hyperplasia, whereas mifepristone and ulipristal acetate were associated predominantly with simple hyperplastic changes. Normal endometrial morphology was retained in selected mifepristone- and ulipristal acetate-treated animals and in all control animals. Galectin-3 immunoreactivity was low but detectable in morphologically normal endometrium, whereas hyperplastic lesions showed no detectable galectin-3 immunoreactivity under the staining conditions used. In Ishikawa cells, galectin-3 expression showed agent-specific fold-change patterns: tamoxifen and mifepristone were associated with reduced expression at higher concentrations, while ulipristal acetate showed a non-monotonic pattern with increased expression at low and intermediate concentrations and return toward baseline at the highest concentration. In this exploratory model, endocrine-modulator-associated hyperplastic endometrial remodeling was accompanied by reduced or undetectable galectin-3 immunoreactivity, while low-level expression was retained in morphologically normal endometrium. These findings support further investigation of galectin-3 as a candidate marker of endocrine-associated endometrial remodeling, but validation in larger animal cohorts and human endometrial samples from treated patients is required.

Emerging evidence associates CXCR5 expression with immunotherapy outcomes; however, the intrinsic role of tumor-derived CXCR5 in modulating chemo-immunotherapy sensitivity in triple-negative breast cancer (TNBC) remains uncharacterized. This study was conducted using murine 4T1 and human MDA-MB-231 TNBC models. Tumor cell CXCR5 expression was manipulated through overexpression or shRNA-mediated silencing. Therapeutic efficacy of paclitaxel (PTX, 10 mg/kg)±Tislelizumab (TIS, 10 mg/kg) was evaluated using in vivo tumor models and T cell cytotoxicity assays. We demonstrated that combination therapy effectively suppressed 4T1 tumor growth, extended survival, and enhanced intratumoral CD8 + /GZMB + T cell infiltration coupled with increased cleaved-caspase-3 activation in murine studies. In vitro analyses revealed that CXCR5-high MDA-MB-231 cells exhibited heightened sensitivity to T-cell-mediated cytotoxicity in combination with PTX+TIS, corresponding with decreased BCL2 expression and elevated BAX levels. Our findings establish tumor-intrinsic CXCR5 as a pivotal determinant of chemo-immunotherapy efficacy in TNBC, mechanistically linked to enhanced CD8 + T cell infiltration and apoptotic signaling.

Melanoma in young adults causes substantial years of life lost because deaths occur early. Detection pathways, reasons for consultation, and sex differences may influence tumor thickness and prognosis, but evidence in this age group remains limited. We conducted a retrospective cohort study of patients aged 18-44 years with primary cutaneous melanoma diagnosed between 1993 and 2022, with a median follow-up of 142 months. Detection source was classified as self, relatives/friends, or healthcare professionals, and reasons for consultation were recorded for self-detected cases. Outcomes included Breslow thickness (> 2 mm), metastasis, melanoma-related death, survival, and years of life lost. Multivariable logistic regression, Kaplan-Meier analyses, and exploratory Cox regression were performed. Among 316 patients, self-detection was the most common pathway (58.9%). Thick melanoma was more frequent in self-detected cases than in those detected by relatives or healthcare professionals (p = 0.003). Male sex and self-detection were independently associated with thick melanoma. Among self-detected cases, nodularity and bleeding were the strongest predictors. Men had higher metastatic progression (33.1% vs. 18.1%, p = 0.002) and melanoma-related mortality (18.7% vs. 11.3%, p = 0.049). Median years of life lost among melanoma deaths was 29.15 years. In young adults, melanoma prognosis is strongly linked to detection pathway, consultation triggers, and sex. Earlier professional evaluation, especially in young men and in lesions with high-risk features, may reduce advanced disease and years of life lost. Melanoma in young adults can have serious long‐term consequences because deaths occur early in life. In this study, melanomas found by patients themselves were usually thicker and more advanced than those detected by doctors. Men were more likely than women to have thicker tumors, develop metastases, and die from melanoma. Among self‐detected cases, warning signs such as a lump or bleeding were linked to more aggressive disease. Encouraging earlier medical evaluation, especially for young men and for concerning skin changes, could help detect melanoma at a more treatable stage and reduce years of life lost.

Intraocular pressure (IOP) monitoring is a critical aspect of diagnosis, and management of ocular diseases. Therefore, a tractable vertebrate model capable of reliable IOP characterization is highly desirable. The present study aims to perform a preliminary investigation of a handheld rebound tonometer to stably measure IOP and further characterize baseline IOP values in the zebrafish model. The IOP in both eyes (oculus dexter, OD, and oculus sinister, OS) of wild-type zebrafish was measured using the iCare PRO rebound tonometer at the same time points on testing days for 18 months. The long-term IOP values of male zebrafish (3-21 months) were range from 21.96 ± 0.99 to 23.39 ± 0.32 mm Hg (OD) and 22.10 ± 0.93 to 23.38 ± 0.26 mm Hg (OS), while insignificant difference was noted among testing days ( p > 0.05). Similarly, insignificant difference was observed in female zebrafish with IOP values range from 22.10 ± 1.12 to 23.19 ± 0.72 mm Hg (OD) and 22.30 ± 1.00 to 23.15 ± 0.36 mm Hg (OS) ( p > 0.05). A comprehensive evaluation of IOP profiles confirmed no significant differences based on gender, time point, and between eyes. These findings indicated that our iCare tonometer-based experimental methods provide high measurement and time-point consistency, confirming their long-term reproducibility and reliability in measuring IOP in the zebrafish.

One major hallmark of alcohol use disorder (AUD) is the persistence of drinking despite negative consequences. Among indicators of AUD vulnerability, binge drinking has been identified as one of the strongest risk factors. Although the lifetime prevalence of both binge drinking and AUD has historically been higher in men than women, this gap has dramatically narrowed in the last decade. Additionally, sex differences in AUD and binge drinking have been found in clinical and preclinical studies. At the neurobiological level, the insular cortex plays an important role in AUD, with the anterior (aIC) and posterior (pIC) divisions supporting different functions. However, the contributions of the aIC and pIC sections in sexual dimorphism of alcohol binge drinking and the persistence of alcohol drinking despite aversion remain to be uncovered. Using the drinking in the dark model in mice, we validated that female mice have a higher binge ethanol intake compared to males. To evaluate persistent ethanol consumption despite aversion, we supplemented ethanol with the bitter compound quinine, and found a higher persistent drinking in females compared to males. Using fiber photometry recordings, we revealed that aIC activity was increased during binge and persistent ethanol consumption independently of sex, whereas pIC glutamatergic neuron activity was higher during persistent ethanol drinking, specifically in female mice. Using chemogenetics, we revealed that inhibition of aIC glutamatergic neurons reduced intake of bitter solutions independently of the solvent (ethanol or water) in both sexes. In addition, inhibition of pIC glutamatergic neurons exclusively reduced persistent ethanol drinking in females, while decreasing quinine consumption only in males. These findings suggest a sex-dependent function of the pIC in the persistence of ethanol consumption, providing a starting point in understanding sex-specific functions of the insular cortex in the neurobiology of AUD.

Evidence regarding sex-related differences in metformin-associated gastrointestinal adverse events (GIAEs) remains limited. This systematic review and meta-analysis aimed to determine whether sex influences the risk of metformin-associated GIAEs. We included observational studies (5 cohorts and 1 case-control) and a randomized controlled trial identified through searches of Ovid MEDLINE, Ovid EMBASE, and CENTRAL from inception to June 2026. Eligible studies reported metformin-associated GIAEs separately in females and males, while studies in which GIAEs could not be attributed to metformin were excluded. Risk of bias was assessed using the Newcastle-Ottawa Scale for observational studies and the Cochrane Risk of Bias tool for randomized trials. Odds ratios (ORs) with 95% confidence intervals (CIs) were pooled using a random-effects meta-analysis. Seven studies (five cohort studies, one case-control study, and one randomized controlled trial) involving 7,968 participants (3,106 females and 4,862 males) were included. Females had significantly higher odds of metformin-associated GIAEs than males (OR 1.85, 95% CI 1.58-2.17), with consistent findings in sensitivity analyses. Females may have a higher risk of metformin-associated GIAEs than males, highlighting the importance of considering sex differences when prescribing metformin and monitoring gastrointestinal intolerance.

This population-based retrospective study investigated the impact of sex on annual case counts and incidence rates of concussions before and during COVID-19 pandemic. Using administrative data from ICES, we identified 393,397 individuals with concussion between April 2017 and March 2022 in the Province of Ontario, Canada. A one-year washout period (no concussion/head injury diagnosis in the prior 365 days) was employed to ensure new cases. Data were stratified by sex, age groups, and rurality comparing 2019 as the pre-pandemic period to 2020 a the pandemic period. The pandemic led to a sharp decline in concussion rates for both sexes across all age groups. Annual case counts dropped from over 99,000 cases in pre-pandemic years to 33,693 in 2020 with the most significant reductions in school-aged children and adolescents. Despite the overall decline, the female share of diagnosed concussions increased modestly during the pandemic, with age-stratified analyses showing that sex-specific patterns varied across age groups. Poisson regression analysis revealed that females had a 16.8% higher concussion rate than males after adjusting for age and rurality. The pandemic significantly altered healthcare-recorded concussion patterns, likely reflecting both reduced exposure to injury risk and pandemic-related changes in healthcare-seeking and case capture. Our findings underscore the need to incorporate sex as a key variable in future concussion research and prevention strategies.

We examined radon's association with the complete blood count and leukocyte differential to better understand radon-related risks of stroke and myocardial infarction previously observed in the Women's Health Initiative. We conducted a repeated-measures analysis in this prospective cohort of postmenopausal women enrolled between 1993 and 1998 and examined at 5 visits over 19 years in 40 US clinical centers (n = 154,630). We estimated indoor radon concentrations (pCi/L) at time-varying, geocoded addresses of participants (1993-2013) by linking them to the US Geological Survey Radon Index (1993) zoned by US Environmental Protection Agency Action Levels. We estimated covariate-adjusted, longitudinal associations of radon concentrations with complete blood count components using linear mixed-effects models. In a subset (n = 6,313), we evaluated cross-sectional associations with the complete blood count differential using multivariate compositional data analysis. At 2-4 and >4 pCi/L, adjusted mean (95% confidence interval) leukocytes were 48 (33, 63) and 78 (58, 98) cells/μL lower than at <2 pCi/L, while platelets, hematocrit, and hemoglobin were higher: 315 (-280, 910) and 2,033 (1,248, 2,818) cells/μL; 0.27% (0.24%, 0.30%) and 0.23% (0.19%, 0.27%); and 0.09 (0.08, 0.10) and 0.09 (0.07, 0.10) g/dL. Nonlinear spline models of the Radon Index revealed similar associations. Lymphocyte percentages were lower, and other percentages were higher at higher (>4 pCi/L) versus lower (<2 pCi/L) radon concentrations in nonlinear compositional data analysis. The radon-related cardiovascular implications of these modest, prothrombotic, myeloid shifts in the complete blood count/differential among postmenopausal women in the Women's Health Initiative remain unknown.

Biological sex is increasingly recognized as a fundamental variable in cardiovascular and cerebrovascular disease, yet its integration into our understanding of post-cardiac arrest brain injury (PCABI) pathophysiology remains limited. Although mortality following cardiac arrest remains universally high, males have a higher lifetime incidence while females experience disproportionately poor survival and neurological outcomes, particularly after menopause. Rather than a binary difference, evidence indicates three possible functionally distinct risk profiles: males with relatively stable neurological vulnerability across the lifespan, premenopausal females with apparent neuroprotection, and postmenopausal females at increased risk of neurological sequelae. Neurological injury is the primary determinant of survival and long-term function after cardiac arrest, yet mechanisms underlying sex differences in PCABI remain poorly defined. To address this, this review integrates clinical observations with experimental and translational evidence to develop a conceptual framework for hypothesis generation in sex-specific PCABI. We examine differences in arrest etiology, resuscitation, and post-resuscitation care, drawing on pathophysiological insights from myocardial infarction and ischemic stroke to contextualize PCABI-relevant pathways. Across the phases of ischemic depolarization, reperfusion repolarization, dysregulation, and recovery/repair, we synthesize biologically plausible mechanisms through which hormones, autonomic regulation, vascular reactivity, immune responses, and excitotoxic signaling may shape diverging patterns of injury and recovery. We identify key calls to action for research priorities and propose strategies to incorporate sex- and age-informed frameworks into PCABI research. Specifically, our calls to action will address the inclusion of sex and age-disaggregated analyses into research designs, develop generalizable and standardized assessments for hormonal status to assist with phenotyping and consider confounding by disparities in healthcare access or delivery between sexes. Treating sex as a primary biological variable, rather than a covariate or supplementary analysis, will be essential for advancing precision critical care and improving outcomes following cardiac arrest.

Equality in clinical trial enrollment by sex is important for detecting sex-specific differences in treatment safety and efficacy. This study analyzed sex differences in enrollment for Post-traumatic Stress Disorder (PTSD) randomized controlled clinical trials (RCTs) to determine the contexts in which enrollment disparities are most pronounced and inform strategies to improve equitable representation in future PTSD clinical trials. Data were obtained from the PTSD Repository, which encompasses all US-based and international RCTs published across a 36-year period between January 1, 1988 and April 1, 2024. One-sample Wilcoxon signed rank tests compared the median sex composition of RCT enrollment to that of U.S. PTSD cases and tested whether median deviation from sex parity in enrollment (50% each sex) differed from zero. Hierarchical multiple regression models predicted female enrollment proportion and deviation from sex parity based on trial characteristics including location, timing, size, eligibility criteria, and intervention. Across all 527 PTSD RCTs encompassing 47,699 participants (44.9% female), median female enrollment was consistently lower than population-based expectations (53.0% female [95% CI: 44.1%-57.5%] vs. 74.2% expected). Lower female enrollment was predicted by requirement of active military or veteran-only status at all trial sites (B=-60.60, β=-0.810, p < 0.001), inclusion of comorbid substance use disorder (B=-9.42, β=-0.117, p = 0.002), and pharmacotherapy (B=-10.58, β=-0.137, p < 0.001). Only 12.7% of all PTSD RCTs enrolled between 40 and 60% of each sex. Female patients are under-enrolled in PTSD RCTs compared to population-based expectations. Eligibility criteria emphasizing male-dominant subpopulations (e.g., military cohorts, comorbid substance use) appear to contribute to these disparities.

Lead (Pb) is a neurotoxic heavy metal that crosses the placental barrier and may affect fetal development. However, the effects of chronic developmental Pb exposure on oxidative stress, stress-related endocrine responses, and depression-like behavior, particularly regarding sex differences, remain unclear. This study evaluated the effects of chronic Pb exposure from gestation to adulthood on redox balance, corticosterone responses, and depression-like behavior in male and female mice. Pregnant C57BL/6J mice received 250 ppm lead acetate in drinking water from gestational day 0 until offspring reached adulthood. Depression-like behavior was assessed using the forced swimming and tail suspension tests. Reactive oxygen species and lipid peroxidation were measured in the prefrontal cortex and hippocampus, and plasma corticosterone was quantified following behavioral stress. Chronic Pb exposure increased immobility in both behavioral tests and increased oxidative stress markers in the prefrontal cortex and hippocampus, with sex- and region-dependent differences. Pb exposure also altered corticosterone dynamics in both sexes: males showed a delayed corticosterone peak, whereas females exhibited a prolonged response that remained elevated 24 h after stress. Overall, chronic developmental Pb exposure was associated with depression-like behavior, oxidative imbalance, and altered corticosterone responses in a sex-dependent manner. These findings highlight biological sex as an important factor influencing the neurobehavioral, redox, and stress-related endocrine consequences of chronic developmental Pb exposure.

Kayak marathon competitions entail several laps and frequent portages in all boat classes. Race demands related to modern elite kayak marathon competition rules have not been evaluated. This investigation characterized mean race speed, lap and portage speeds, frequency of speed changes, and heart rate (HR) responses in elite paddlers of both sexes. During the 2022 European Marathon Championships, national team marathon paddlers in the K1 and K2 classes (N = 30, 15 women) wore a chest belt with integrated global positioning system and HR sensors. Elite kayak marathon paddlers maintain an exercise intensity of 85% to 91% HRmax irrespective of sex and boat type. Mean and peak paddling speeds were lower for women compared to men (P values ranging: .001-.001). In K1, men had more relative speed shifts of both 5% to 10% (35.6 [16.3] vs 25.5 [10.6]; P = .0283) and above 10% (P values ranging .0283-.0003). In K2, there were no statistical differences in speed shifts. In all boat classes, mean boat speed of the final 100 m was always significantly faster than the mean speed of the first part of the lap (P values ranging: .0105-.00000001). Portage running speed varied by 9.4% between sexes. During marathon races, world-class kayak paddlers sustain a mean of 85% to 91% HRmax for a prolonged period (121-129 min), with men in K1 having more speed shifts of 5% to 10% compared to women. To handle race demands, we therefore suggest that on-water training for both sexes include high-intensity steady-state exercise interspersed by frequent, more intense speed bouts.

Sex differences in outcomes after endovascular treatment (EVT) for dural arteriovenous fistula (dAVF) remain unclear. This study aimed to compare 30-day complications and outcomes between women and men using data from the Japanese Registry of Neuroendovascular Therapy registry in Japan. We analyzed data from a nationwide retrospective registry (2015-2019), comparing outcomes between women and men who underwent EVT for dAVFs. The primary outcome was worsening of modified Rankin Scale (mRS) score ≥ 2 at 30 days after EVT. Secondary outcomes included 30-day morbidity, defined as any procedure-related complication such as intracranial hemorrhage or ischemic stroke, favorable outcome (mRS 0-2), and mortality. Among 3156 patients (1561 women, 1532 men; mean age 68.8 vs. 63.8 years, p < 0.0001), dAVF location and preprocedural symptoms differed significantly by sex. Worsening of mRS ≥ 2 occurred in 7.1% of women and 11.6% of men (adjusted odds ratio [aOR] 0.84; 95% CI 0.64-1.11; p = 0.23). Thirty-day morbidity was similar (5.3% vs. 5.4%; aOR 1.07; 95% CI 0.77-1.48). Hemorrhagic complications were more frequent in women (1.9% vs. 1.3%; aOR 1.93; 95% CI 1.07-3.50). Favorable outcomes were slightly more common in women (90.1% vs. 86.2%), and 30-day mortality was low in both groups (<1%). This large retrospective registry study found significant sex-based differences in dAVF location but no significant differences in worsening of mRS ≥ 2, 30-day morbidity or the rate of patients achieving a favorable mRS score at 30 days after EVT.

The pelvis plays a crucial role in sex estimation when reconstructing an individual's biological profile from skeletal remains. The present study aims to evaluate the sex differences in size and shape of the hip bones and sacrum using geometric morphometrics and to compare the degree of sexual dimorphism captured by size and shape variables within and between these skeletal elements. The study sample included the abdominal computed tomography scans of 255 adult Bulgarians (125 males and 130 females). Surface models of the pelvis were generated and used for landmark digitization. The three-dimensional coordinates of 35 landmarks were collected from the left and right hip bones, and 34 landmarks were recorded from the sacrum. The landmark data of each bone were subjected to Generalized Procrustes Analysis, Principal Component Analysis, Procrustes ANOVA, and classification methods (linear discriminant analysis of centroid size and support vector machine analysis of shape variables). In the present study, classification accuracies were interpreted as indicators of sexual dimorphism within the studied sample rather than as estimates of predictive model performance. The results indicated that the size and shape of all three bones differed significantly between males and females. The ability of centroid size to distinguish between the sexes was low, with classification accuracies of 69% for the right and left hip bones and 66% for the sacrum. In contrast, shape variables exhibited substantially greater sex differentiation, with values of 99% for the right and left hip bones and 91% for the sacrum, indicating pronounced sexual dimorphism in the shape of these bones within the studied sample.

Postoperative delirium is a common complication in older adults. Binary delirium outcomes may obscure clinically meaningful, sex-specific differences in delirium severity and burden. We sought to characterize these patterns in a surgical cohort. We prospectively studied older patients with repeated postoperative delirium assessments, obtaining daily Delirium Rating Scale (DRS) scores to measure severity, calculating area under the curve (AUC) across postoperative assessments as a measure of cumulative delirium burden (total symptom load over time). We used sex-stratified models and pooled models with sex interaction terms, adjusting for age, American Society of Anesthesiology (ASA) physical status, opioid exposure, and other physiologic covariates. Risk factors for delirium severity and burden differed significantly by sex. Among women, higher ASA class was the primary predictor of increased delirium burden (AUC: β = 2.79 per class; peak DRS: β = 1.71). Among men, increasing age (AUC: β = 0.427 per year) and intraoperative opioid exposure were strongly associated with higher burden. The age-by-sex interaction was significant across all outcomes ( p < 0.05), with age being a much stronger predictor of delirium severity in men than in women. At matched baseline risk, predicted delirium severity was consistently higher in men. Delirium risk factors are sex-differentiated. For men, age was the dominant predictor of delirium severity and burden, whereas for women, baseline physiologic status was more strongly associated with these outcomes. These findings highlight the importance of using severity-based outcomes to reveal sex-specific vulnerability patterns that are otherwise obscured by simple binary endpoints.

Addiction is conceptualized as a maladaptive form of learning in which drug-associated memories progressively strengthen during abstinence and increasing relapse vulnerability. This process may be particularly complex in the context of cocaine and ethanol abuse, a prevalent pattern of polyconsumption linked to greater clinical severity. To model this condition, in our previous work male and female rats were subjected to an incubation of drug-seeking paradigm. While females exhibited robust incubation of cocaine plus ethanol seeking after prolonged withdrawal, males did not (Garrido-Matilla et al., 2025). In the present study, we characterized neurobiological alterations in the same cohort by analysing gene expression of endocannabinoid, glutamatergic, and GABAergic systems, as well as neurotransmission-related amino acids in the hippocampus and PFC. In the hippocampus, females showed increased cannabinoid receptor 1 expression and reduced monoacylglycerol lipase levels, together with upregulation of GABA A receptor subunits, suggesting persistent adaptations in synaptic plasticity. In contrast, males exhibited downregulation of glutamatergic-related genes along with increased taurine and L-glutamine levels. In the PFC, females displayed increased cannabinoid receptor 1 and NMDA receptor subunit 2B expression, reduced GABAergic-related gene expression, and decreased taurine and L-glutamine levels, consistent with an altered excitatory-inhibitory balance. Moreover, prefrontal glutamate levels positively correlated with cocaine plus ethanol intake in females. Overall, these findings reveal sex-dependent neuroadaptations within the hippocampus and PFC following cocaine plus ethanol polyconsumption, with pronounced endocannabinoid and GABAergic alterations in females, and glutamatergic changes in males that may reflect compensatory mechanisms potentially limiting relapse vulnerability.

Biological sex underpins phenotypic differences in many cardiopulmonary conditions. In pulmonary hypertension, most studies have focused on the "sex paradox" in pulmonary arterial hypertension (PAH), where females are more susceptible to PAH but have better right ventricular function, better response to PAH medications, and better survival than males. Sex differences have also been observed in chronic thromboembolic pulmonary hypertension (CTEPH) but are less well characterized. To investigate sex differences in males and females diagnosed with CTEPH in the United States. Using the multicenter United States CTEPH Registry, we explored sex differences in a CTEPH population at baseline and follow-up. We collected data every 6 months for a total of 48 months. Sex was determined from self-reported "male," "female," or "transgender" categories recorded on case report forms. We report descriptive analyses comparing male and female characteristics. We examined prespecified variables of interest using regression modeling, including adjustment for age, body mass index (BMI), and interaction terms (sex vs age, sex vs BMI). Survival analysis was performed with Cox proportional hazards modeling. Females (n = 367, 49.1%) had greater BMI than males (median [IQR] F: 32 kg/m2 [26.6, 38.8] vs M: 28.7 kg/m2 [25.5, 33.8]). Males were more likely to have a recognized history of acute deep vein thrombosis (OR 2.6; CI 1.9-3.5). Males had better baseline PH-specific health-related quality of life (HRQoL) by EmPHasis10 (-3.3; CI -5.0- (-1.7), World Health Organization functional class (FC III/IV OR 0.52, CI 0.37-0.74) and longer 6-minute walk distance (+82.3 m, CI 56.4-108.2). Males were less likely to have distally located disease (OR 0.53, CI 0.35-0.78) and were less likely to have inoperable CTEPH (OR 0.62, CI 0.40-0.96). Post-PTE, females had persistently worse HRQoL and function, with increased need for adjunctive therapies. There was no difference in overall survival between males and females (HR 1.11; CI 0.71-1.75). Males and females may have distinct CTEPH phenotypes, which impact access to and feasibility of PTE. There are sex-associated disparities in the experience of CTEPH as a disease state, and differential impacts on HRQoL that warrant further investigation.

Cardiovascular disease (CVD) accounts for over $300 billion in direct health care costs and is expected to rise over time, worsening the economic burden. To close the gap in CVD outcomes between men and women, sex-specific study designs and druggable targets are essential. Sex differences driven by sex hormones are well established in CVD, particularly the cardioprotective effects of testosterone in men and estradiol in women; however, the role of sex chromosomes, particularly X-linked genes, is not yet fully understood. Sexual dimorphism in CVD shows that women are protected compared to men, which diminishes with age. The low awareness and understanding of CVD risk in women contribute to delays in treatment. Oxidative stress is a key player in CVD. In this review, we briefly introduce reactive oxygen species (ROS) and sex chromosomes. Next, we examine X-linked escapee genes, which provide a unique perspective on sex differences in biology. Thereafter, we discuss the role of oxidative stress in CVD and risk factors, including hypertension and atherosclerosis, and identify knowledge gaps and potential research opportunities to address CVD disparity among women. In closing, we highlight the clinical trial outcomes in CVD and antioxidant treatments.