Long-acting antipsychotic treatments: focus on women with schizophrenia.

Effective management of schizophrenia (SZ) requires long-term treatment with antipsychotics (APs) to prevent clinical relapse, attain remission and improve patients' personal and social functioning, and quality of life. Although APs remain the cornerstone treatment for patients with SZ, despite their potential benefits, long-acting injectable APs (LAI-APs) remain underused, most notably in women with SZ. The efficacy and tolerability of APs differ significantly between men and women, and some of these differences are more noticeable depending on the patient's age and the stage of the disorder. Although sex differences may influence treatment outcomes in SZ, their pertinence has been insufficiently addressed, especially regarding the use of LAI-APs. Some biological and social experiences, such as pregnancy, lactation, contraception and menopause, are specific to women, but these remain under-researched issues. Implications of this disorder in parenting are also of special pertinence regarding women; therefore, taking sex differences into account when treating SZ patients is now recommended, and improving personalized approaches has been proposed as a priority in the management of psychosis. In this narrative, critical review, we address some aspects specific to sex and their implications for the clinical management of women with SZ, with a special focus on the potential role of LAI-AP treatments.

• Schizophrenia is a chronic mental illness, and patients often need to take antipsychotic medications in the long-run in order to stay well, avoid re-occurrence of symptoms and improve their everyday functioning and quality of life. • Antipsychotics are available in both pill and injection form. The latter is known as long-acting injectable antipsychotics (LAI-APs) and can be administered from weekly to twice a year. • Despite their effectiveness and practicality due to less frequent administration, LAI-APs remain largely underused, especially in women with schizophrenia. • The efficacy and tolerability of antipsychotics can be very different between men and women, and some of these differences may be more pronounced depending on the patient's age and the phase of the illness. • Notably, physical and social aspects such as pregnancy, lactation, contraception, parenting and menopause and their effects on the treatment with antipsychotics and particularly LAI-APs in women with schizophrenia are under-studied. • Nevertheless, we have now become more aware of the importance of these sex differences, and it is recommended to take them routinely into consideration when treating patients with schizophrenia in clinical practice. • In this article, we discuss how factors specific to sex can influence the treatment of women with schizophrenia and focus on the potential role of LAI-AP medications.

Nut-cracking success and efficiency in two wild capuchin monkey populations.

Capuchins can employ several strategies to deal with environmental challenges, such as using stone tools to access encapsulated resources. Nut-cracking is customary in several capuchin populations and can be affected by ecological and cultural factors; however, data on success and efficiency are only known for two wild populations. In this work, using camera traps, we assessed palm nut-cracking success and efficiency in two newly studied wild bearded capuchin populations (Sapajus libidinosus) and compared them with other sites. We tested the hypothesis that the overall success and efficiency of nut-cracking would be similar between sites when processing similar resources, finding partial support for it. Although using hammerstones of different sizes, capuchins had a similar success frequency. However, efficiency (number of strikes to crack a nut) was different, with one population being more efficient. We also tested whether success and efficiency varied between sexes in adults. We predict adult males would be more successful and efficient when cracking hard nuts. We found no differences between the sexes in one site but found sex differences in the other, although also for the low-resistant nut, which was unexpected. Our data add to the knowledge of capuchin nut-cracking behaviour flexibility, variance and potential cultural traits.

Impact of sex and hypoxia on brain region-specific expression of membrane androgen receptor AR45 in rats.

Background: Sex differences in oxidative stress-associated cognitive decline are influenced by sex hormone levels. Notably, oxidative stress-associated neuronal cell death can be exacerbated through testosterone signaling via membrane androgen receptor AR45, which is complexed with G protein Gαq within plasma membrane-associated lipid rafts. The objective of this study was to elucidate the impact of sex on the expression of AR45 and Gαq in brain regions associated with cognitive function, specifically hippocampus subregions and entorhinal cortex. Additionally, we investigated whether chronic intermittent hypoxia (CIH), an oxidative stressor with sex-specific effects, would modulate AR45 and Gαq expression in these brain regions. Methods: Adult male and female Sprague-Dawley rats were exposed to CIH or normoxia (room air) during their sleep phase for 14 days. We quantified AR45 and Gαq protein expression in various cognition-associated brain regions [dorsal hippocampal CA1, CA3, dentate gyrus (DG), and entorhinal cortex (ETC)] via western blotting. For comparisons, AR45 and Gαq protein expression were also assessed in brain regions outside the hippocampal-ETC circuit [thalamus (TH) and striatum (STR)]. Results: The highest AR45 levels were expressed in the hippocampal CA1 and DG while the lowest expression was observed in the extrahippocampal STR. The highest Gαq levels were expressed in the hippocampal-associated ETC while the lowest expression was observed in the extrahippocampal TH. Females expressed higher levels of AR45 in the hippocampal DG compared to males, while no sex differences in Gαq expression were observed regardless of brain region assessed. Moreover, there was no effect of CIH on AR45 or Gαq expression in any of the brain regions examined. AR45 expression was positively correlated with Gαq expression in the CA1, DG, ETC, TH, and STR in a sex-dependent manner. Conclusion: Our findings reveal enrichment of AR45 and Gαq protein expression within the hippocampal-ETC circuit, which is vulnerable to oxidative stress and neurodegeneration during cognitive decline. Nonetheless, CIH does not modulate the expression of AR45 or Gαq. Importantly, there are sex differences in AR45 expression and its association with Gαq expression in various brain regions, which may underlie sex-specific differences in cognitive and motor function-associated declines with aging.

Prevalence and types of cancer in older Indians: A multicentric observational study across 17 institutions in India.

The global demographic and epidemiological transition have led to a rapidly increasing burden of cancer, particularly among older adults. There are scant data on the prevalence and demographic pattern of cancer in older Indian persons. This was a multicentric observational study conducted between January 2019 and December 2020. Data were retrieved from existing electronic databases to gather information on two key variables: the total number of patients registered with oncologists and the number of patients aged 60 years and above. The primary objective was to determine the percentage of older adults among patients with cancer served by these hospitals. Secondary objectives included understanding the prevalence of different types of cancer in the older population, and the sex- and geographic distribution of cancer in older Indian patients. We included 272,488 patients with cancer from 17 institutes across India. Among them, 97,962 individuals (36 %) were aged 60 years and above. The proportion of older adults varied between 20.6 % and 53.6 % across the participating institutes. The median age of the older patients with cancer was 67 (interquartile range, 63-72) years. Of the 54,281 patients for whom the details regarding sex were available, 32,243 (59.4 %) were male. Of the 56,903 older patients, head and neck malignancies were the most prevalent, accounting for 11,158 cases (19.6 %), followed by breast cancer (6260 cases, 11 %), genitourinary cancers (6242 cases, 10.9 %), lung cancers (6082 cases, 10.7 %), hepatopancreaticobiliary (6074, 10.7 %), and hematological malignancies (5226 cases, 9.2 %). Over one-third of Indian patients with cancer are aged 60 years and above, with a male predominance. Head and neck, breast, and genitourinary cancers are the most prevalent in this age group. Characterizing the burden of cancer in older adults is crucial to enable tailored interventions and additional research to improve the care and support for this vulnerable population.

Transactional sex and risky sexual practices in Jamaica.

BACKGROUND: Transactional sex relationships (TSRs) create financial and emotional support for men and women, as well as an increased sexual risk. Studies have reported high HIV and STI transmission rates among young women in transactional sex relationships. However, little is known about TSR prevalence in Jamaica and risky sexual practices among participants. This study investigates the sexual behaviour of Jamaicans in TSR. METHODS: Secondary data analysis of a national survey revealed that 586 participants (38%) self-reported being in at least one TSR in the last 12 months. We also identified a third category called "Benefluids", who play both roles of benefactor and beneficiary in transactional sex relationships. RESULTS: 59 percent of male Benefluids had two to five transactional sex relationship partners in the last 12 months, compared to 40% of female Benefluids. Twenty-eight percent of female Benefluids reported sexually transmitted infection symptoms in the last 12 months compared to 13.5% of male Benefluids. While females reported more sexually transmitted infection symptoms, young men had the highest sexual risk precursors. CONCLUSIONS: People in transactional sex relationships often play the role of beneficiaries and benefactors to meet material and sexual needs but this increases the risk of STI symptoms.

Trends in Sex Differences of Functional Outcome after Intravenous Thrombolysis in Patients with Acute Ischemic Stroke.

BACKGROUND: Intravenous thrombolysis (IVT) is an approved treatment for patients with acute ischemic stroke irrespective of sex. However, the current literature on sex differences in functional outcomes following IVT is inconsistent. So far, a number of studies - including a previous analysis based on data from the Austrian Stroke Unit Registry (ASUR) - detected significant sex-related differences in functional outcome, while others did not report any differences between women and men. In addition, currently there is a lack of data on how sex-related differences evolve over time. AIMS: To assess time trends of sex-related differences in functional outcome of ischemic stroke in a large nationwide cohort and to investigate associations of patient characteristics with functional outcome post thrombolysis in women and men. These data will offer crucial insights into whether sex differences in functional outcome persist despite the large advances in acute stroke treatment. METHODS: We analyzed retrospective data of consecutive patients with acute ischemic stroke treated with IVT in 39 stroke centers contributing to the ASUR between 2006 and 2021. We included patients over 18 years of age diagnosed with an acute ischemic stroke who received IVT and with available data on functional outcome at 3 months after treatment. The primary outcome parameter was favorable functional outcome (modified Rankin Scale (mRS) of 0-2) at 3 months. Multivariable logistic regression analysis was performed in the overall population and stratified by sex to assess associations of baseline characteristics with functional outcome. RESULTS: Among 11840 patients receiving IVT, 2489/5503 (45.4%) women achieved favorable functional outcome compared to 3787/6337 (59.8%) men. Overall, female sex was a statistically significant predictor of functional outcome after thrombolysis, but additional predictors of outcome differed between women and men. Female sex was independently associated with decreased chances of achieving functional independency (adjOR 0.87, 95%CI 0.79-0.96, p=0.005) and we detected a statistically significant improvement in functional outcome over time only in men (year of treatment, adjOR (per year) 1.04, 95%CI 1.02-1.06, p<0.001) but not in women (adjOR (per year) 1.01, 95%CI 0.99-1.03, p=0.280). Hypertension, smoking, and longer or unknown onset-to-door times were statistically significant predictors of outcome only in male patients, whereas atrial fibrillation, prior myocardial infarction and longer door-to-needle times were significantly associated with outcome only in women. CONCLUSIONS: Sex differences in functional outcome after IVT for acute ischemic stroke are persisting over the past years. Results of our analysis can increase awareness and a resulting focus on sex differences in predictors of outcome could be helpful in mitigating these differences in the future by supporting a more individualized patient care in clinical routine. Follow-up analyses are needed to assess this potential impact and its effect in the future.Data access statement: Data from the Austrian Stroke Unit Registry can only be accessed by the employed statistician (DM), access inquiries have to be addressed to the registry's academic review board.

Reduced spatial frequency differentiation and sex-related specificities in fearful face detection in autism: Insights from EEG and the predictive brain model.

Face processing relies on predictive processes driven by low spatial frequencies (LSF) that convey coarse information prior to fine information conveyed by high spatial frequencies. However, autistic individuals might have atypical predictive processes, contributing to facial processing difficulties. This may be more normalized in autistic females, who often exhibit better socio-communicational abilities than males. We hypothesized that autistic females would display a more typical coarse-to-fine processing for socio-emotional stimuli compared to autistic males. To test this hypothesis, we asked adult participants (44 autistic, 51 non-autistic) to detect fearful faces among neutral faces, filtered in two orders: from coarse-to-fine (CtF) and from fine-to-coarse (FtC). Results show lower d' values and longer reaction times for fearful detection in autism compared to non-autistic (NA) individuals, regardless of the filtering order. Both groups presented shorter P100 latency after CtF compared to FtC, and larger amplitude for N170 after FtC compared to CtF. However, autistic participants presented a reduced difference in source activity between CtF and FtC in the fusiform. There was also a more spatially spread activation pattern in autistic females compared to NA females. Finally, females had faster P100 and N170 latencies, as well as larger occipital activation for FtC sequences than males, irrespective of the group. Overall, the results do not suggest impaired predictive processes from LSF in autism despite behavioral differences in fear detection. However, they do indicate reduced brain modulation by spatial frequency in autism. In addition, the findings highlight sex differences that warrant consideration in understanding autistic females.

Unravelling the novel sex determination genotype with 'ZY' and a distinctive 2.15-2.95 Mb inversion among poplar species through haplotype-resolved genome assembly and comparative genomics analysis.

Populus tomentosa, an indigenous tree species, is widely distributed and cultivated over 1,000,000 km2 in China, contributing significantly to forest production, ecological conservation and urban-rural greening. Although a reference genome is available for P. tomentosa, the intricate interspecific hybrid origins, chromosome structural variations (SVs) and sex determination mechanisms remain confusion and unclear due to its broad and even overlapping geographical distribution, extensive morphological variations and cross infiltration among white poplar species. We conducted a haplotype-resolved de novo assembly of P. tomentosa elite individual GM107, which comprises subgenomes a and b with a total genome size of 714.9 Mb. We then analysed the formation of hybrid species and the phylogenetic evolution and sex differentiation across the entire genus. Phylogenomic analyses suggested that GM107 likely originated from a hybridisation event between P. alba (♀) and P. davidiana (♂) approximately 3.8 Mya. A total of 1551 chromosome SVs were identified between the two subgenomes. More noteworthily, a distinctive inversion structure spanning 2.15-2.95 Mb was unveiled among Populus, Tacamahaca, Turaga, Aigeiros poplar species and Salix, highlighting a unique evolutionary feature. Intriguingly, a novel sex genotype of the ZY type, which represents a crossover between XY and ZW systems, was identified and confirmed through both natural and artificial hybrids populations. These novel insights offer significant theoretical value for the study of the species' evolutionary origins and serve as a valuable resource for ecological genetics and forest biotechnology.

Modulation of circulating free testosterone fraction by testosterone, dihydrotestosterone, and estradiol during testosterone replacement therapy.

BACKGROUND: Testosterone, estradiol, and dihydrotestosterone share common ligand binding sites on sex hormone binding globulin and albumin. It is unknown whether and how changes in testosterone, dihydrotestosterone, and estradiol concentrations during testosterone replacement therapy affect free testosterone fraction. OBJECTIVE: To determine the effect of changes in testosterone, dihydrotestosterone, and estradiol concentrations on free testosterone fraction during testosterone replacement therapy of men with hypogonadism. METHODS: Using data from the Testosterone Trials, we assessed the association of changes in total testosterone, estradiol, and dihydrotestosterone concentrations over 12 months of testosterone replacement therapy with changes in free testosterone fraction, measured using equilibrium dialysis. We used random forests to evaluate the associations of predicted mean changes in free testosterone fraction with changes in circulating concentrations of each hormone at low, mean, or high change in the other two hormones. RESULTS: Testosterone replacement therapy not only increased total testosterone, dihydrotestosterone, estradiol, and free testosterone concentrations, but also the percent free testosterone, even though sex hormone binding globulin levels did not change. The predicted changes in free testosterone fraction during testosterone replacement therapy exhibited a non-linear relationship with changes in each of total testosterone, dihydrotestosterone, and estradiol concentrations. Greater increases in testosterone, dihydrotestosterone, and estradiol levels during testosterone replacement therapy were each associated with higher model-predicted percent free testosterone. Substantially smaller changes in molar concentrations of estradiol and dihydrotestosterone had a greater effect on percent free testosterone than those in testosterone. CONCLUSION: During testosterone replacement therapy of men with hypogonadism, changes in testosterone, dihydrotestosterone, and estradiol concentrations each altered percent free testosterone non-linearly. Small changes in estradiol concentrations exerted much larger effect on the free testosterone fraction than testosterone and dihydrotestosterone, suggesting complex interactions of the three hormones with the binding proteins. Assessment of changes in free testosterone during testosterone replacement therapy should include consideration of changes in all three hormones.

Autistic Characteristics, Cognitive Impairment, and Sex as Predictors of Anxiety and Depression among Autistic Youth.

Although it is well established that autistic youth are at high risk for anxiety and depression, factors associated with heightened risk within this population are poorly understood. The purpose of this study was to evaluate whether autistic characteristics and cognitive impairment interact to predict anxiety and depression symptoms, and whether the impacts of autistic characteristics and cognitive impairment on anxiety and depression differ for male and female children. Participants comprised 7989 youth (M = 11.23 years) enrolled in SPARK, a national cohort of autistic individuals. Autistic characteristics were assessed via the Social Communication Questionnaire. Anxiety and depression were assessed via the Child Behavior Checklist. Linear regressions were conducted to examine associations between autistic characteristics, cognitive impairment, and symptoms and to test for interactions. The effect of parent-reported autistic characteristics on anxiety was stronger for males than for females, while the effect of cognitive impairment on anxiety was stronger for females than for males. A different pattern was observed for depression. The effect of autistic characteristics on depression was the same for males and females, while cognitive impairment was not associated with depression per parent report. Findings indicate that both male and female children with high levels of autistic characteristics are susceptible to experiencing anxiety and depression, and that autistic female children with intact cognitive abilities are uniquely vulnerable to experiencing anxiety based on parent report. Results have implications for the prevention of internalizing problems in autistic youth, and highlight future directions for longitudinal work examining mechanisms of comorbidity.

Association between oral contraceptives and cervical cancer: A retrospective case-control study based on the National Health and Nutrition Examination Survey.

Background: Cervical cancer is the fourth most common cancer among females globally, with a high incidence and high mortality among females in developing countries. This retrospective case-control study aimed to investigate the association between oral contraceptives and cervical cancer, on which insufficient evidence still exists. Material and Methods: To examine the association between oral contraceptives and cervical cancer based on 7,496 females aged over 20 years from the National Health and Nutrition Examination Survey, multivariable logistic regression conducted from 1999 to 2016 was used. Results: Contraceptive use was positively associated with cervical cancer risk. In model 1 (unadjusted), a 195% increased risk of cervical cancer was observed among those who used oral contraceptives (odds ratio [OR] = 2.27, 95% confidence interval [CI] = 1.39-3.98, p = 0.002) compared to those who did not. In addition, the ORs for the exposed population were 1.74 (95% CI = 1.05-3.08, p = 0.041) and 1.93 (95% CI = 1.16-3.44, p = 0.017) in model 2 (adjusted for age, race, and body mass index [BMI]) and model 3 (adjusted for education level, ratio of family income to poverty, drinking status, smoking status, number of pregnancies, age at first sex, number of sexual partners, and whether to receive the human papillomavirus (HPV) vaccine in addition to model 2), respectively. Furthermore, subgroup analyses stratified by age, smoking status, BMI, age at first sex, number of sexual partners, and whether to receive the HPV vaccine also revealed that oral contraceptives were significantly associated with cervical cancer. Conclusion: This study demonstrated that oral contraceptive use increased the risk of cervical cancer. In addition, the higher risk, including individuals older than 45 years, having a high BMI (≥30 kg/m2), being current smokers, and having more than five sexual partners, may contribute to the development of cervical cancer.

Self-control in criminology: we need a broader conceptualization and links to psychiatric diagnoses.

Background: Poor self-control is a strong correlate of criminal propensity. It is conceptualized and operationalized differently in criminology than in other scientific traditions. Aims: (1) To verify the dimensionality of the criminological Grasmick self-control items, other self-regulation items and morality ones. (2) To re-interpret the dimensions using a clinical perspective, a taxonomic/diagnostic model and references to possible "biological underpinnings." (3) Validate the dimensions by associations with crime. Method: Population: all persons born 1995 in Malmö and living there at age 12. A random sample (N = 525) filled in a comprehensive self-report questionnaire on themes like personality, crime/abuse and social aspects at age 15, 16 and 18. Age 18 data were analysed: 191 men and 220 women. Results: Self-regulation items were 4-dimensional: ADHD problems (Behavior control and Executive skills) and two Aggression factors. Morality items formed a fifth dimension. Negative Affect and Social interaction factors covered the rest of the variance. The validity of these factors was backed up by correlations with similar items/factors. Self-regulation subscales predicted crimes better than the Grasmick scale; an interaction with morality improved prediction still further. Sex differences were over-all small with three exceptions: Aggression, Morality and Negative affect. Conclusion: We identified four dimensions of the 20-item Grasmick instrument: Cognitive action control (impulsiveness/sensation seeking, response inhibition), Executive skills/future orientation, Affective/aggression reactivity and Aggression control. All should be possible to link to brain functional modules. Much can be gained if we are able to formulate an integrated model of self-regulation including distinct brain functional modules, process-and trait-oriented models, relevant diagnoses and clinical experiences of individual cases.

A Novel NR5A1 Mutation in a Thai Boy with 46, XY DSD.

Disorders of sex development (DSD) can be classified as 46,XX DSD, 46,XY DSD, and sex chromosome DSD. Several underlying causes including associated genes have been reported. Steroidogenic factor-1 is encoded by the NR5A1 gene, a crucial regulator of steroidogenesis in the growth of the adrenal and gonadal tissues. It has been discovered to be responsible for 10 to 20% of 46, XY DSD cases. Here, we described a 2-month-old infant who had ambiguous genitalia and 46, XY. Using whole exome sequencing followed by polymerase chain reaction-Sanger sequencing, a novel heterozygous nonsense c.1249C > T (p.Gln417Ter) variant in the NR5A1 gene was identified. It is present in his mother but absent in his father and maternal aunt and uncle. At the age of 7 months, the patient received a monthly intramuscular injection of low-dose testosterone for 3 months in a row. His penile length and diameter increased from 1.8 to 3 cm and from 0.8 to 1.3 cm, respectively. The patient also had normal adrenal reserve function by adrenocorticotropic hormone stimulation test. This study identified a novel causative p.Q417X (c.1249C > T) variant in NR5A1 causing 46,XY DSD in a Thai boy which is inherited from his unaffected mother.

Hepatoprotective effects of Xiaoyao San formula on hepatic steatosis and inflammation via regulating the sex hormones metabolism.

BACKGROUND: The modified Xiaoyao San (MXS) formula is an adjuvant drug recommended by the National Health Commission of China for the treatment of liver cancer, which has the effect of preventing postoperative recurrence and metastasis of hepatocellular carcinoma and prolonging patient survival. However, the molecular mechanisms underlying that remain unclear. AIM: To investigate the role and mechanisms of MXS in ameliorating hepatic injury, steatosis and inflammation. METHODS: A choline-deficient/high-fat diet-induced rat nonalcoholic steatohepatitis (NASH) model was used to examine the effects of MXS on lipid accumulation in primary hepatocytes. Liver tissues were collected for western blotting and immunohistochemistry (IHC) assays. Lipid accumulation and hepatic fibrosis were detected using oil red staining and Sirius red staining. The serum samples were collected for biochemical assays and NMR-based metabonomics analysis. The inflammation/lipid metabolism-related signaling and regulators in liver tissues were also detected to reveal the molecular mechanisms of MXS against NASH. RESULTS: MXS showed a significant decrease in lipid accumulation and inflammatory response in hepatocytes under metabolic stress. The western blotting and IHC results indicated that MXS activated AMPK pathway but inhibited the expression of key regulators related to lipid accumulation, inflammation and hepatic fibrosis in the pathogenesis of NASH. The metabonomics analysis systemically indicated that the arachidonic acid metabolism and steroid hormone synthesis are the two main target metabolic pathways for MXS to ameliorate liver inflammation and hepatic steatosis. Mechanistically, we found that MXS protected against NASH by attenuating the sex hormone-related metabolism, especially the metabolism of male hormones. CONCLUSION: MXS ameliorates inflammation and hepatic steatosis of NASH by inhibiting the metabolism of male hormones. Targeting male hormone related metabolic pathways may be the potential therapeutic approach for NASH.

Excess cardiovascular mortality in men with non-alcoholic fatty liver disease: A cause for concern!

Non-alcoholic fatty liver disease (NAFLD) has emerged as the commonest cause of chronic liver disease worldwide in recent years. With time, our understanding of NAFLD has evolved from an isolated liver condition to a systemic disease with significant manifestations beyond the liver. Amongst them, cardiovascular diseases (CVDs) are the most important and clinically relevant. Recent research supports a strong independent link between NALFD and CVD beyond the shared risk factors and pathophysiology. Female sex hormones are well known to not only protect against CVD in pre-menopausal females, but also contribute to improved adipose tissue function and preventing its systemic deposition. Recent research highlights the increased risk of major adverse cardiovascular-cerebral events (MACCE) amongst male with NAFLD compared to females. Further, racial variation was observed in MACCE outcomes in NAFLD, with excess mortality in the Native Americans and Asian Pacific Islanders compared to the other races.

The influence of gender on outcomes following transcatheter aortic valve implantation.

Objectives: This study aimed to compare gender-related differences in short- and long-term outcomes after transcatheter aortic valve implantation. Methods: Patients who underwent transcatheter aortic valve implantation (TAVI) for severe aortic stenosis (AS) from September 2017 to December 2022 were enrolled. The primary endpoint was 5-year all-cause mortality. The secondary endpoints were 30-day mortality and the incidence of post-procedural complication. Patients were separated according to gender before statistical analysis. To compare patients with similar baseline characteristics, we performed a propensity matching. Results: A total of 704 patients [females, 361 (51.3%); males, 343 (48.7%)] were enrolled. Compared to women, men had a higher incidence of smoking (40.5% vs. 14.7%, p < 0.001), diabetes (32.9% vs. 25.1%, p < 0.025), peripheral artery disease (35.8% vs. 18.3%, p < 0.001), and previous cardiac surgery (13.7% vs. 7.2%, p = 0.006) and a lower ejection fraction [56.6 (9.3) vs. 59.8 (7.5), p = 0.046]. Female patients were frailer at the time of the procedure [poor mobility rate, 26% vs. 11.7%, p < 0.001; CCI (Charlson comorbidity index) 2.4 (0.67) vs. 2.32 (0.63), p = 0.04]. Despite these different risk profiles, no significant differences were reported in terms of post-procedural outcomes and long-term survival. Propensity score matching resulted in a good match of 204 patients in each group (57.9% of the entire study population). In the matched cohort, men had a significantly higher incidence of new pacemaker implantation compared to women [33 (16.2%) vs. 18 (8.8%)]. The Kaplan-Meier 5-year survival estimate was 82.4% for women and 72.1% for men, p = 0.038. Conclusions: Female gender could be considered as a predictor of better outcomes after TAVI.

Sex differences in the inflammation-depression link: A systematic review and meta-analysis.

Major Depressive Disorder (MDD) is a heterogeneous disorder that affects twice as many women than men. Precluding advances in more tailored and efficacious treatments for depression is the lack of reliable biomarkers. While depression is linked to elevations in inflammatory immune system functioning, this relationship is not evident among all individuals with depression and may vary based on symptom subtypes and/or sex. This systematic review and meta-analysis examined whether inflammatory immune peripheral markers of depression are sex-specific. PRISMA guidelines were followed for the systematic review, and a comprehensive search strategy that identified studies from PubMed and PsycInfo was applied. Studies were included if they reported C-reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor (TNF)-α and/or IL-1ß for males and/or females among depressed and healthy adults. We identified 23 studies that satisfied these inclusion criteria. Random-effects meta-analysis models were fit, and measures of association were summarized between levels of circulating markers of inflammation in depressed and healthy males and females. Sex-based analyses revealed elevated levels of CRP among females with depression (Cohen's d = 0.19) relative to their healthy counterparts (p = 0.02), an effect not apparent among males (Cohen's d = -0.01). Similarly, levels of IL-6 were increased among females with depression compared to healthy controls (Cohen's d = 0.51; p = 0.04), but once again this was not found among males (Cohen's d = 0.16). While TNF-α levels were elevated among individuals with depression compared to controls (p = 0.01), no statistically significant sex differences were found. The meta-analysis for IL-1ß resulted in only three articles, and thus, results are presented in the supplemental section. This meta-analysis advances our understanding of the unique involvement of inflammatory biomarkers in depression among men and women, which may help inform more tailored sex-specific treatment approaches in the future.

Sex hormones differently regulate lipid metabolism genes in primary human hepatocytes.

BACKGROUND: Prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is higher in men than in women. Hormonal and genetic causes may account for the sex differences in MASLD. Current human in vitro liver models do not sufficiently take the influence of biological sex and sex hormones into consideration. METHODS: Primary human hepatocytes (PHHs) were isolated from liver specimen of female and male donors and cultured with sex hormones (17ß-estradiol, testosterone and progesterone) for up to 72 h. mRNA expression levels of 8 hepatic lipid metabolism genes were analyzed by RT-qPCR. Sex hormones and their metabolites were determined in cell culture supernatants by LC-MS analyses. RESULTS: A sex-specific expression was observed for LDLR (low density lipoprotein receptor) with higher mRNA levels in male than female PHHs. All three sex hormones were metabolized by PHHs and the effects of hormones on gene expression levels varied depending on hepatocyte sex. Only in female PHHs, 17ß-estradiol treatment affected expression levels of PPARA (peroxisome proliferator-activated receptor alpha), LIPC (hepatic lipase) and APOL2 (apolipoprotein L2). Further changes in mRNA levels of female PHHs were observed for ABCA1 (ATP-binding cassette, sub-family A, member 1) after testosterone and for ABCA1, APOA5 (apolipoprotein A-V) and PPARA after progesterone treatment. Only the male PHHs showed changing mRNA levels for LDLR after 17ß-estradiol and for APOA5 after testosterone treatment. CONCLUSIONS: Male and female PHHs showed differences in their expression levels of hepatic lipid metabolism genes and their responsiveness towards sex hormones. Thus, cellular sex should be considered, especially when investigating the pathophysiological mechanisms of MASLD.

Sex differences in the diagnostic algorithm of screening for heart failure by symptoms and NT-proBNP in patients with type 2 diabetes.

OBJECTIVES: This study aimed to assess the guideline recommended diagnostic tools NT-proBNP and NYHA classification, with a focus on sex-specific differences. BACKGROUND: Patients with Type 2 Diabetes (T2D) face a heart failure (HF) risk up to four times higher than those without T2D, particularly affecting women more than twice as much as men. Despite distinct pathophysiological differences between men and women, there are currently no sex-specific recommendations for the diagnostic algorithm of HF in diabetic patients. METHODS: A total of 2083 patients with T2D were enrolled, and the primary endpoint was heart failure during hospitalization within a 5-year timeframe. The secondary endpoint was all-cause death. RESULTS: In female patients, frequency of HF diagnosis prior to or during hospitalization and mortality did not differ significantly between NYHA II and III, in contrast to male patients. Additionally, there was no notable difference in mean NT-proBNP levels between NYHA stage II and III only in female patients. The multivariable regression analysis highlighted NYHA classification not to be a predictor of NT-proBNP levels in female but solely in male patients. On multivariable Cox regression NYHA score was also no significant risk factor for occurence of HF in female patients. Furthermore, there was no significant disparity in mortality between men with NT-proBNP levels between 125 and 400 pg/ml and those below 125 pg/ml, whereas in women mortality was significantly higher in the group with NT-proBNP levels between 125 and 400 pg/ml than below 125 pg/ml. CONCLUSION: These findings suggest that NYHA classification may not be the most suitable tool for assessing the diagnosis of HF in female patients with T2D. Moreover, the need for consideration of a more symptom-independent screening for HF in female patients with T2D and re-evaluation of current guidelines especially regarding sex-specific aspects is highlighted.

Sex differences in the association of physical functions with hospitalization and mortality events among community-dwelling older adults with disabilities.

This study aimed to investigate the role of sex in the association between physical function and the occurrence of hospitalization and mortality among community-dwelling older adults with impairments in activities of daily living (ADL). Participants included community-dwelling older adults aged ≥65 years with ADL disabilities. Physical functions (hand grip strength [HGS], knee extension muscle strength, and comfortable walking speed [CWS]) were measured at baseline and analyzed for association with hospitalization and mortality by sex using Cox regression analysis, adjusted for potential confounders. In this Cox regression analysis, HGS was significantly associated with the occurrence of hospitalization and mortality in women, whereas CWS was significantly associated with the occurrence of hospitalization and HGS with mortality in men. These findings reveal that the predictive ability of adverse events in community-dwelling older adults with disabilities differs by sex, requiring outcome- and sex-specific prognostication.