Sex-specific disparities in disease activity scores among patients with axial spondyloarthritis and their implications for evaluating the response to tumor necrosis factor alpha inhibitor therapy.

BACKGROUND: We aimed to investigate whether there are sex differences in disease activity measures among patients with axial spondyloarthritis (axSpA) and to determine any potential impact on the assessment of treatment responses to tumor necrosis factor alpha inhibitors (TNFi). METHODS: Using the Korean College of Rheumatology Biologics and Targeted Therapy (KOBIO) registry data, we compared sex differences in changes in the Bath Ankylosing Spondylitis Disease Activity Score (BASDAI) and Ankylosing Spondylitis Disease Activity Score (ASDAS) levels at baseline and one year after TNFi initiation in patients with axSpA. RESULTS: This study included 1,753 patients with axSpA who started or changed TNFi, of whom 1,343 (76.6%) were male. At baseline, the mean BASDAI and ASDAS scores of all patients were 5.98 and 3.6, respectively. The BASDAI changes between baseline and the one-year follow-up were independently associated with sex (𝛽 = 0.343, p = 0.011), whereas ASDAS was not (𝛽 = 0.079, p = 0.235). When judging the effect of TNFi at one-year of treatment, male patients were more likely to be assessed as effective by the BASDAI-based criterion (ΔBASDAI ≥ 50% or ≥ 2; OR 1.700, 95% CI 1.200-2.406), while the ASDAS-based criterion (ΔASDAS ≥ 1.1) showed no significant difference between sexes (OR 0.993, 95% CI 0.678-1.455), after adjusting for other baseline characteristics. CONCLUSIONS: The changes in disease activity before and after TNFi use were significantly different between sexes when measured by BASDAI, but not ASDAS. TNFi treatment effects may be interpreted differently between sexes depending on the disease activity measure used.

Sex Differences in Clustering Unhealthy Lifestyles Among Survivors of COVID-19: Latent Class Analysis.

BACKGROUND: The COVID-19 pandemic has underscored the significance of adopting healthy lifestyles to mitigate the risk of severe outcomes and long-term consequences. OBJECTIVE: This study focuses on assessing the prevalence and clustering of 5 unhealthy lifestyle behaviors among Vietnamese adults after recovering from COVID-19, with a specific emphasis on sex differences. METHODS: The cross-sectional data of 5890 survivors of COVID-19 in Vietnam were analyzed from December 2021 to October 2022. To examine the sex differences in 5 unhealthy lifestyle behaviors (smoking, drinking, unhealthy diet, physical inactivity, and sedentary behavior), the percentages were plotted along with their corresponding 95% CI for each behavior. Latent class analysis was used to identify 2 distinct classes of individuals based on the clustering of these behaviors: the "less unhealthy" group and the "more unhealthy" group. We examined the sociodemographic characteristics associated with each identified class and used logistic regression to investigate the factors related to the "more unhealthy" group. RESULTS: The majority of individuals (male participants: 2432/2447, 99.4% and female participants: 3411/3443, 99.1%) exhibited at least 1 unhealthy behavior, with male participants being more susceptible to multiple unhealthy behaviors. The male-to-female ratio for having a single behavior was 1.003, but it escalated to 25 for individuals displaying all 5 behaviors. Male participants demonstrated a higher prevalence of combining alcohol intake with sedentary behavior (949/2447, 38.8%) or an unhealthy diet (861/2447, 35.2%), whereas female participants tended to exhibit physical inactivity combined with sedentary behavior (1305/3443, 37.9%) or an unhealthy diet (1260/3443, 36.6%). Married male participants had increased odds of falling into the "more unhealthy" group compared to their single counterparts (odds ratio [OR] 1.45, 95% CI 1.14-1.85), while female participants exhibited lower odds (OR 0.65, 95% CI 0.51-0.83). Female participants who are underweight showed a higher likelihood of belonging to the "more unhealthy" group (OR 1.11, 95% CI 0.89-1.39), but this was not observed among male participants (OR 0.6, 95% CI 0.41-0.89). In both sexes, older age, dependent employment, high education, and obesity were associated with higher odds of being in the "more unhealthy" group. CONCLUSIONS: The study identified notable sex differences in unhealthy lifestyle behaviors among survivors of COVID-19. Male survivors are more likely to engage in unhealthy behaviors compared to female survivors. These findings emphasize the importance of tailored public health interventions targeting sex-specific unhealthy behaviors. Specifically, addressing unhealthy habits is crucial for promoting post-COVID-19 health and well-being.

TrkB-mediated neuroprotection in female hippocampal neurons is autonomous, estrogen receptor alpha-dependent, and eliminated by testosterone: a proposed model for sex differences in neonatal hippocampal neuronal injury.

BACKGROUND: Neonatal hypoxia ischemia (HI) related brain injury is one of the major causes of learning disabilities and memory deficits in children. In both human and animal studies, female neonate brains are less susceptible to HI than male brains. Phosphorylation of the nerve growth factor receptor TrkB has been shown to provide sex-specific neuroprotection following in vivo HI in female mice in an estrogen receptor alpha (ERα)-dependent manner. However, the molecular and cellular mechanisms conferring sex-specific neonatal neuroprotection remain incompletely understood. Here, we test whether female neonatal hippocampal neurons express autonomous neuroprotective properties and assess the ability of testosterone (T) to alter this phenotype. METHODS: We cultured sexed hippocampal neurons from ERα+/+ and ERα-/- mice and subjected them to 4 h oxygen glucose deprivation and 24 h reoxygenation (4-OGD/24-REOX). Sexed hippocampal neurons were treated either with vehicle control (VC) or the TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) following in vitro ischemia. End points at 24 h REOX were TrkB phosphorylation (p-TrkB) and neuronal survival assessed by immunohistochemistry. In addition, in vitro ischemia-mediated ERα gene expression in hippocampal neurons were investigated following testosterone (T) pre-treatment and TrkB antagonist therapy via q-RTPCR. Multifactorial analysis of variance was conducted to test for significant differences between experimental conditions. RESULTS: Under normoxic conditions, administration of 3 µM 7,8-DHF resulted an ERα-dependent increase in p-TrkB immunoexpression that was higher in female, as compared to male neurons. Following 4-OGD/24-REOX, p-TrkB expression increased 20% in both male and female ERα+/+ neurons. However, with 3 µM 7,8-DHF treatment p-TrkB expression increased further in female neurons by 2.81 ± 0.79-fold and was ERα dependent. 4-OGD/24-REOX resulted in a 56% increase in cell death, but only female cells were rescued with 3 µM 7,8-DHF, again in an ERα dependent manner. Following 4-OGD/3-REOX, ERα mRNA increased ~ 3 fold in female neurons. This increase was blocked with either the TrkB antagonist ANA-12 or pre-treatment with T. Pre-treatment with T also blocked the 7,8-DHF- dependent sex-specific neuronal survival in female neurons following 4-OGD/24-REOX. CONCLUSIONS: OGD/REOX results in sex-dependent TrkB phosphorylation in female neurons that increases further with 7,8-DHF treatment. TrkB phosphorylation by 7,8-DHF increased ERα mRNA expression and promoted cell survival preferentially in female hippocampal neurons. The sex-dependent neuroprotective actions of 7,8-DHF were blocked by either ANA-12 or by T pre-treatment. These results are consistent with a model for a female-specific neuroprotective pathway in hippocampal neurons in response to hypoxia. The pathway is activated by 7,8-DHF, mediated by TrkB phosphorylation, dependent on ERα and blocked by pre-exposure to T.

Sex differences in cachexia and branched-chain amino acid metabolism following chemotherapy in mice.

Chemotherapy is a major contributor to cachexia, but studies often investigate male animals. Here, we investigated whether sex modifies the effects of chemotherapy on cachexia and BCAA metabolism. Ten-week-old CD2F1 male and female mice were treated with the chemotherapy drug cocktail folfiri (50 mg/kg 5-fluorouracil, 90 mg/kg leucovorin, and 24 mg/kg CPT11) (drug) or vehicle twice a week for 6 weeks. Insulin tolerance tests were conducted and BCAA levels and metabolism were measured in plasma and tissues. Drug treatment reduced body and skeletal muscle weights and anabolic signaling in both sexes, with females showing worsened outcomes (p < 0.05 for all). Drug treatment increased plasma BCAA only in males, but BCAA concentrations in the skeletal muscle of both sexes were decreased; this decrease was more profound in males (p = 0.0097). In addition, muscle expression of the BCAA transporter LAT1 was reduced; this reduction was more severe in females (p = 0.0264). In both sexes, the (inhibitory) phosphorylation of BCKD-E1αser293 was increased along with decreased BCKD activity. In the liver, drug treatment increased BCAA concentrations and LAT1 expression, but BCKD activity was suppressed in both sexes (p < 0.05 for all). Our results demonstrate that altered BCAA metabolism may contribute to chemotherapy-induced cachexia in a sex-dependent manner.

Diagnostic Yield of head Computed Tomography in Patients with Syncope: Sex Differences.

BACKGROUND: Syncope is responsible for approximately 1-3% of all emergency department (ED) visits and up to 6% of all hospital admissions in the United States. Although often of no long-term consequence, syncope can be the first presentation of a range of serious conditions such as strokes, tumors, or subarachnoid hemorrhages. Head computed tomography (CT) scanning is therefore commonly ordered in the ED for patients presenting with syncope to rule out any of these conditions, which may present without other associated physical or neurological findings on initial examination. However, the diagnostic yield of head CTs in patients presenting with syncope is unclear. OBJECTIVES: To determine the diagnostic yield of head CT in the ED in patients with syncope. METHODS: We conducted an observational analytical retrospective cross-sectional study on 360 patients diagnosed with syncope who underwent a head CT to determine the diagnostic yield of syncope to determine whether head CT is necessary for every patient presenting with syncope to the ED. RESULTS: The total of new CT findings was 11.4%. Percentages varied between men (12.8%) and women (9.7%), P = 0.353. There were no significant differences between sexes regarding the findings in head CT, yet the incidence increased, especially among elderly males. CONCLUSIONS: Age had a more significant impact on diagnostic yield of syncope than head CT. The use of a head CT scan as a routine diagnosis tool in patients with syncope is unjustifiable unless there is an indication based on medical history or physical examination.

Sex differences in patients with and without high-risk factors associated with aneurysmal subarachnoid hemorrhage.

BACKGROUND: Controversy remains regarding the appropriate screening for intracranial aneurysms or for the treatment of aneurysmal subarachnoid hemorrhage (aSAH) for patients without known high-risk factors for rupture. This study aimed to assess how sex affects both aSAH presentation and outcomes for aSAH treatment. METHOD: A retrospective cohort study was conducted of all patients treated at a single institution for an aSAH during a 12-year period (August 1, 2007-July 31, 2019). An analysis of women with and without high-risk factors was performed, including a propensity adjustment for a poor neurologic outcome (modified Rankin Scale [mRS] score > 2) at follow-up. RESULTS: Data from 1014 patients were analyzed (69% [n = 703] women). Women were significantly older than men (mean ± SD, 56.6 ± 14.1 years vs 53.4 ± 14.2 years, p < 0.001). A significantly lower percentage of women than men had a history of tobacco use (36.6% [n = 257] vs 46% [n = 143], p = 0.005). A significantly higher percentage of women than men had no high-risk factors for aSAH (10% [n = 70] vs 5% [n = 16], p = 0.01). The percentage of women with an mRS score > 2 at the last follow-up was significantly lower among those without high-risk factors (34%, 24/70) versus those with high-risk factors (53%, 334/633) (p = 0.004). Subsequent propensity-adjusted analysis (adjusted for age, Hunt and Hess grade, and Fisher grade) found no statistically significant difference in the odds of a poor outcome for women with or without high-risk factors for aSAH (OR = 0.7, 95% CI = 0.4-1.2, p = 0.18). CONCLUSIONS: A higher percentage of women versus men with aSAH had no known high-risk factors for rupture, supporting more aggressive screening and management of women with unruptured aneurysms.

Role of estrogen in sex differences in memory, emotion and neuropsychiatric disorders.

Estrogen regulates a wide range of neuronal functions in the brain, such as dendritic spine formation, remodeling of synaptic plasticity, cognition, neurotransmission, and neurodevelopment. Estrogen interacts with intracellular estrogen receptors (ERs) and membrane-bound ERs to produce its effect via genomic and non-genomic pathways. Any alterations in these pathways affect the number, size, and shape of dendritic spines in neurons associated with psychiatric diseases. Increasing evidence suggests that estrogen fluctuation causes changes in dendritic spine density, morphology, and synapse numbers of excitatory and inhibitory neurons differently in males and females. In this review, we discuss the role of estrogen hormone in rodents and humans based on sex differences. First, we explain estrogen role in learning and memory and show that a high estrogen level alleviates the deficits in learning and memory. Secondly, we point out that estrogen produces a striking difference in emotional memories in men and women, which leads them to display sex-specific differences in underlying neuronal signaling. Lastly, we discuss that fluctuations in estrogen levels in men and women are related to neuropsychiatric disorders, including schizophrenia, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), bipolar disorder (BPD), major depressive disorder (MDD), substance use disorder (SUD), and anxiety disorders.

Characterization of sexual dimorphism in ANGPTL4 levels and function.

ANGPTL4 is an attractive pharmacological target for lowering plasma triglycerides and cardiovascular risk. Since most preclinical studies on ANGPTL4 were performed in male mice, little is known about sexual dimorphism in ANGPTL4 regulation and function. Here, we aimed to study potential sexual dimorphism in ANGPTL4 mRNA and protein levels and ANGPTL4 function. Additionally, we performed exploratory studies on the function of ANGPTL4 in the liver during fasting using Angptl4-transgenic and Angptl4-/- mice. Compared to female mice, male mice showed higher hepatic and adipose ANGPTL4 mRNA and protein levels, as well as a more pronounced effect of genetic ANGPTL4 modulation on plasma lipids. By contrast, very limited sexual dimorphism in ANGPTL4 levels was observed in human liver and adipose tissue. In human and mouse adipose tissue, ANGPTL8 mRNA and/or protein levels were significantly higher in females than males. Adipose LPL protein levels were higher in female than male Angptl4-/- mice, which was abolished by ANGPTL4 (over) expression. At the human genetic level, the ANGPTL4 E40K loss-of-function variant was associated with similar plasma triglyceride reductions in women and men. Finally, ANGPTL4 ablation in fasted mice was associated with changes in hepatic gene expression consistent with PPARα activation. In conclusion, the levels of ANGPTL4 and the magnitude of the effect of ANGPTL4 on plasma lipids exhibit sexual dimorphism. Nonetheless, inactivation of ANGPTL4 should confer a similar metabolic benefit in women and men. Expression levels of ANGPTL8 in human and mouse adipose tissue are highly sexually dimorphic, showing higher levels in females than males.

Female mice display sex-specific differences in cerebrovascular function and subarachnoid haemorrhage-induced injury.

BACKGROUND: In male mice, a circadian rhythm in myogenic reactivity influences the extent of brain injury following subarachnoid haemorrhage (SAH). We hypothesized that female mice have a different cerebrovascular phenotype and consequently, a distinct SAH-induced injury phenotype. METHODS: SAH was modelled by pre-chiasmatic blood injection. Olfactory cerebral resistance arteries were functionally assessed by pressure myography; these functional assessments were related to brain histology and neurobehavioral assessments. Cystic fibrosis transmembrane conductance regulator (CFTR) expression was assessed by PCR and Western blot. We compared non-ovariectomized and ovariectomized mice. FINDINGS: Cerebrovascular myogenic reactivity is not rhythmic in females and no diurnal differences in SAH-induced injury are observed; ovariectomy does not unmask a rhythmic phenotype for any endpoint. CFTR expression is rhythmic, with similar expression levels compared to male mice. CFTR inhibition studies, however, indicate that CFTR activity is lower in female arteries. Pharmacologically increasing CFTR expression in vivo (3 mg/kg lumacaftor for 2 days) reduces myogenic tone at Zeitgeber time 11, but not Zeitgeber time 23. Myogenic tone is not markedly augmented following SAH in female mice and lumacaftor loses its ability to reduce myogenic tone; nevertheless, lumacaftor confers at least some injury benefit in females with SAH. INTERPRETATION: Female mice possess a distinct cerebrovascular phenotype compared to males, putatively due to functional differences in CFTR regulation. This sex difference eliminates the CFTR-dependent cerebrovascular effects of SAH and may alter the therapeutic efficacy of lumacaftor compared to males. FUNDING: Brain Aneurysm Foundation, Heart and Stroke Foundation and Ted Rogers Centre for Heart Research.

Sex Differences in Short- and Long-Term Survival after Acute Type A Aortic Dissection.

Background and Objectives: Acute type A aortic dissection (AAD) is a life-threatening disease. No differences between men and women have been made in the treatment of AAD so far and knowledge about sex differences regarding long-term outcomes is limited. Materials and Methods: Between 01/2004 and 12/2021, 874 patients were operated on for AAD, including 313 (35.8%) women and 561 (64.2%) men. Clinical and surgical records, including long-term follow-up information, were obtained and analyzed retrospectively. To account for differences in the outcome determined by different preoperative life expectancies, a subgroup analysis for a set of patients matched according to their remaining life expectancy was performed. Results: At the time of AAD, women were older than men (69.1 ± 13.0 vs. 61.8 ± 13.3 years, p < 0.001) and had a shorter remaining statistical life expectancy (18.6 ± 10.8 vs. 21.4 ± 10.4 years, p < 0.001). Significantly more DeBakey type II AAD was found in women (37.1% vs. 25.7%, p < 0.001). Comorbidities and preoperative status at the time of presentation were similar in women and men. More hemiarch procedures (63.3% vs. 52.0%, p < 0.001) and less arch replacements (8.6% vs. 16.6%, p < 0.001) were performed in women, resulting in shorter cross-clamp times for women (92 ± 39 vs. 102 ± 49 min, p < 0.001). The in-hospital mortality was similar in women and men (11.5% vs. 12.7%, p = 0.618). Long-term survival was significantly shorter in women compared to men (9.8 [8.1-11.5] vs. 15.1 [11.9-18.4] years, p = 0.011). A matched subgroup analysis revealed that when comparing groups with a similar remaining life expectancy, the long-term survival showed no significant differences between women and men (9.8 [7.9-11.6] vs. 12.4 [10.1-14.7] years, p = 0.487). Conclusions: There are sex differences in AAD, with DeBakey type II dissection being more frequent in women. The seemingly worse long-term outcome can mostly be attributed to the shorter remaining statistical life expectancy at the time of presentation.

Sexual Dimorphism in the Physiopathology and Immune Response during Acute Toxocara canis Infection.

BACKGROUND: Toxocara canis (T. canis) is a helminth parasite of zoonotic and veterinary health significance that causes the disease known as Toxocariasis. This disease has been associated with conditions of poverty, especially in tropical climate zones throughout the world. Although it rarely causes important clinical manifestations, T. canis can lead to blindness, meningoencephalitis, or other nervous manifestations in humans. Moreover, some studies show its importance in the development of tumor growth, which have been associated with the parasite's ability to modulate the host's immune response. While different studies have evaluated the immune response during this disease, currently, there are no studies where the infection is analyzed from the perspective of sexual dimorphism. METHODS: To evaluate sex differences in susceptibility, we analyzed lesions and parasite loads in lung and liver at 7 days post-infection. In addition, immune cell subpopulations were analyzed in spleen, mesenteric and peripheral lymph nodes. Finally, the production of cytokines and specific antibodies were determined in the serum. Statical analyses were performed using a Two-way ANOVA and a post-hoc Bonferroni multiple comparison test. RESULTS: Female rats had a higher number of larvae in the liver, while male rats had them in the lungs. The percentages of immune cells were evaluated, and in most cases, no significant differences were observed. Regarding the cytokines production, infection can generate a decrease in Th1 such as IL-1ß in both sexes and IL-6 only in females. In the case of Th2, IL-4 increases only in infected males and IL-5 increases in males while decreasing in females due to the effect of infection. IL-10 also decreases in both sexes as a consequence of the infection, and TGF-ß only in females. Finally, the infection generates the production of antibodies against the parasite, however, their quantity is lower in females. CONCLUSIONS: This study demonstrates that T. canis infection is dimorphic and affects females more than males. This is due to a polarization of the inadequate immune response, which is reflected as a higher parasite load in this sex.

Sex differences in luteinizing hormone aggravates Aß deposition in APP/PS1 and Aß1-42-induced mouse models of Alzheimer's disease.

Alzheimer's disease (AD) exhibits a higher incidence rate among older women, and dysregulation of the hypothalamic-pituitary-gonadal (HPG) axis during aging is associated with cognitive impairments and the development of dementia. luteinizing hormone (LH) has an important role in CNS function, such as mediating neuronal pregnenolone production, and modulating neuronal plasticity and cognition. The sex differences in LH and its impact on Aß deposition in AD individuals remain unclear, with no reported specific mechanisms. Here, we show through data mining that LH-related pathways are significantly enriched in female AD patients. Additionally, LH levels are elevated in female AD patients and exhibit a negative correlation with cognitive levels but a positive correlation with AD pathology levels, and females exhibit a greater extent of AD pathology, such as Aß deposition. In vivo, we observed that the exogenous injection of LH exacerbated behavioral impairments induced by Aß1-42 in mice. LH injection resulted in worsened neuronal damage and increased Aß deposition. In SH-SY5Y cells, co-administration of LH with Aß further exacerbated Aß-induced neuronal damage. Furthermore, LH can dose-dependently decrease the levels of NEP and LHR proteins while increasing the expression of GFAP and IBA1 in vivo and in vitro. Taken together, these results indicate that LH can exacerbate cognitive impairment and neuronal damage in mice by increasing Aß deposition. The potential mechanism may involve the reduction of NEP and LHR expression, along with the exacerbation of Aß-induced inflammation.

Sex differences in long-term survival after total arterial coronary artery bypass grafting.

OBJECTIVES: It is uncertain if the evidence on improved long-term survival of total arterial coronary artery bypass grafting applies to female patients. This study aims to compare the long-term survival outcomes of using total arterial revascularization (TAR) versus at least 1 saphenous vein graft separately for men and women. METHODS: This retrospective analysis of the Australian and New Zealand Society of Cardiac-Thoracic Surgical Database had administrative linkage to the National Death Index. We identified all patients undergoing primary isolated coronary bypass from June 2001 to January 2020 inclusive. Following sex stratification, propensity score matching with 36 variables and Cox proportional hazard regression were used to facilitate adjusted comparisons. A Cox interaction-term analysis was performed to investigate the impact of sex on TAR survival benefit. The primary outcome was all-cause mortality. RESULTS: Of the 69 624 eligible patients receiving at least 2 grafts, 13 019 (18.7%) were female patients. Matching generated 14 951 male and 3530 female pairs. Compared to vein-dependent procedures, TAR was associated with significantly reduced incidence of long-term all-cause mortality for both male (hazard ratio, 0.86; 95% confidence interval, 0.81-0.91; P < 0.001) and female (hazard ratio, 0.82; 95% confidence interval, 0.73-0.91; P < 0.001) cohorts. Interaction-term analysis indicated no significant subgroup effect from sex (P = 0.573) on the survival advantage of TAR. The treatment effect provided by TAR remained significant across most sex-stratified disease subgroups. CONCLUSIONS: TAR, when compared to the use of at least 1 saphenous vein graft, provides comparable superior long-term survival outcomes in both females and males.

Sex Differences and Clinical Outcomes of Patients with Coronavirus Disease 2019 Infection and Cerebral Venous Sinus Thrombosis: A Systematic Review.

Cerebral venous sinus thrombosis (CVST) is a rare neurovascular condition that has been observed in individuals with coronavirus disease 2019 (COVID-19). This systematic review aimed to explore the sex differences and characteristics of concurrent COVID-19 and CVST cases. A total of 212 CVST patients were included in the study. Women with CVST had a slightly higher mean age compared to men (47.359 years vs 46.08 years). Women were more likely to report symptoms such as fever (56.1%) and decreased sense of smell or taste (71.4%), while men more frequently experienced nausea or vomiting (55.6%), headache (62.9%), and seizures (72%). Notably, current smokers, who were predominantly men, had a higher occurrence of CVST. On the other hand, women had a higher likelihood of CVST risk factors such as oral contraceptive pill (OCP) use and autoimmune diseases. Treatment approaches also showed sex-based differences. Unfractionated heparin was administered more often to women with CVST (63.2%). The in-hospital mortality rate for CVST patients was 21.3%, with men having a significantly higher mortality rate than women (65.2% vs 34.8%, P = .027). Survival analysis revealed that factors such as smoking history, diabetes mellitus, hypertension, OCP use, COVID-19 symptoms, CVST symptoms, and the need for intubation significantly influenced survival outcomes. Understanding these sex differences in COVID-19-related CVST is crucial for accurate diagnosis and effective management, ultimately leading to improved patient outcomes. Our findings highlight the importance of considering sex as a factor in the evaluation and treatment of individuals with COVID-19 and concurrent CVST.

Sex differences and driving impairment related to psychoactive substances.

OBJECTIVE: The first aim of the study was to identify sex differences in the use of psychoactive substances among subjects with a previous driving under the influence (DUI) episode. The secondary objective was to propose specific strategies for medico-legal improvements. METHODS: This was a retrospective observational study that took place between June 1, 2019, and August 31, 2023. It was conducted on DUI subjects examined for reinstatement of their driver's license using an integrated medico-legal and toxicological approach. Ethyl glucuronide (EtG) and illicit psychoactive substances were determined from hair samples. We performed descriptive statistical analyses for the entire sample as well as separately by sex. Additionally, we conducted binary logistic regression analyses separately for males and females to identify protective/risk factors associated with previous road accidents and judgments of unfitness to drive due to excessive alcohol consumption (EtG ≥ 30 pg/mg). RESULTS: The study included 2,221 subjects, comprising 1,970 men and 251 women. Men exhibited a higher prevalence of tobacco, alcohol, and illicit psychoactive substance use. Women were more frequently co-users of alcohol and psychoactive substances and involved in road accidents at the time of DUI. Among the men, being married or having a partner was found to be a protective factor concerning past traffic accidents. For both sexes, a DUI episode with a blood alcohol concentration (BAC) exceeding 1.5 g/L or the co-ingestion of alcohol and drugs was identified as a risk factor for road accident involvement. For men, smoking more than 20 cigarettes per day and, for women, having a DUI episode with a BAC over 1.5 g/L were the main factors indicating unfitness to drive, as determined through high hair EtG levels (> 30 pg/mg). Women with a previous history of road accidents were less likely to have EtG levels of 30 pg/mg or more. CONCLUSIONS: The study confirmed sex differences in subjects with a previous DUI episode. A BAC exceeding 1.5 g/L or the simultaneous use of alcohol and drugs at the time of DUI necessitate careful assessment of both men and women seeking driver's license reinstatement. In women, a BAC exceeding 1.5 g/L is considered a risk factor for a subsequent judgment of unfitness to drive. The medico-legal assessment should also involve a thorough investigation of smoking habits in men, as these habits could be related to an increased risk of excessive alcohol consumption.

Sex differences in cytokines and adipokines in obese patients with PsA and controls undergoing a weight loss intervention.

OBJECTIVE: In this post hoc analysis of a previously published study, we compared cytokines and adipokine levels in women and men with psoriatic arthritis (PsA) at baseline (BL) and 6 months (M6) following a weight loss intervention. METHODS: Patients with PsA (n=41) between 25 and 75 years of age, with body mass index (BMI)≥33 kg/m2 were included in a weight loss intervention with a very low energy diet (VLED) for 12 or 16 weeks depending on BL BMI<40 or ≥40 kg/m2. As controls (n=39), obese individuals, already planned for VLED treatment were recruited and matched for sex, age and weight to the patients with PsA. Cytokines and adipokines were measured at BL and M6. RESULTS: At BL, serum levels of interleukin (IL)-23, leptin and high molecular weight-adiponectin were higher in women with PsA compared with men, whereas serum levels of interferon (IFN)-γ, IL-12/IL-23 p40 and IL-13 were significantly lower in women. Serum IL-23 was significantly reduced at M6 compared with BL in women but not in men with PsA. In women with PsA, the reduction in IL-23 at M6, ∆IL-23, were positively correlated with ∆Disease Activity Score 28 C reactive protein (CRP) (Spearman's correlation (rS)=0.486, p=0.016), ∆CRP (rS=0.468, p=0.021), ∆leptin (rS=0.683, p<0.001) and negatively correlated with ∆total-adiponectin (rS=-0.433, p=0.035). Also in women, ∆Disease Activity in Psoriatic Arthritis was positively correlated with ∆tumour necrosis factor-α (rS=0.417, p=0.034), ∆IL-1ß (rS=0.550, p=0.034), ∆IFN-γ (rS=0.414, p=0.035) and ∆leptin (rS=0.410, p=0.038). None of these correlations were significant in men with PsA. CONCLUSIONS: Women and men with PsA differed with regard to serum levels of cytokines and adipokines before and after weight loss.

Sex differences in outcomes after revascularization for acute lower limb ischemia: Propensity score adjusted analysis.

BACKGROUND: Previous reports have suggested higher rates of mortality and amputation for female patients in acute lower limb ischemia (ALI). The aims of the present study were to investigate if there is a difference in mortality, amputation, and fasciotomy between the sexes. METHODS: A retrospective cohort study of consecutive patients undergoing index revascularization for ALI between 2001 and 2018 was conducted. A propensity score was created through a logistic regression with female/male sex as an outcome. Cox regression analyses for 90-day and 1-year mortality, combining major amputation/mortality, and logistic regression for major bleeding and fasciotomy, were performed. All analyses were performed with and without adjusting for propensity score. RESULTS: A total of 709 patients were included in the study of which 45.9% were women. Mean age was 72.1 years. Females were older and had higher rates of atrial fibrillation, embolic disease, and lower estimated glomerular filtration rate, while men more often had anemia and chronic peripheral arterial disease. Mortality at 1 year was 21.2% for women and 14.7% for men. The adjusted hazard ratio for 1-year mortality was 0.99 (95% CI 0.67-1.46). Fasciotomy was performed in 7.1% of female and 12.8% of male patients; the adjusted odds ratio was 0.52 (95% CI 0.29-0.91). CONCLUSION: Sex was not found to be an independent risk factor for mortality or combined major amputation/mortality after revascularization for acute lower limb ischemia, whereas women had lower odds of undergoing fasciotomy. Whether women are underdiagnosed or do not develop acute compartment syndrome in the lower leg as often as men should be evaluated prospectively.

Sex differences in the susceptibility to valproic acid-associated liver injury in epileptic patients.

BACKGROUND: Valproic acid has been widely used as an antiepileptic drug for several decades. Long-term valproic acid treatment is usually accompanied by liver injury. Although both men and women are susceptible to valproic acid-associated liver injury, hepatotoxicity differs between the sexes. However, the mechanisms underlying sex differences in valproic acid-associated liver injury remain unclear. METHODS: To explore potential risk factors for the susceptibility to valproic acid-associated liver injury, 231 pediatric patients with epilepsy (119 males, 112 females) were enrolled for laboratory and genetic analysis. RESULTS: Heterozygous genotype of catalase C-262T (P = 0.045) and the concentrations of glutathione (P = 0.002) and thiobarbituric acid-reactive substances (P = 0.011) were associated with the sex-specific susceptibility to valproic acid-associated liver injury. Meanwhile, logistic regression analysis revealed that carriers of heterozygous genotype of catalase C-262T (P = 0.010, odds ratio: 4.163; 95 percent confidence interval 1.400 - 7.378), glutathione concentration (P = 0.001, odds ratio: 2.421; 95 percent confidence interval 2.262 - 2.591) and male patients (P = 0.005, odds ratio: 1.344; 95% confidence interval 0.782 - 2.309) had a higher risk for valproic acid-associated liver injury. DISCUSSION: The mechanism underlying valproic acid-induced hepatotoxicity remains unclear. Additionally, factors that may contribute to the observed differences in the incidence of hepatotoxicity between males and females have yet to be defined. This study identifies several genetic factors that may predispose patients to valproic acid-associated hepatotoxicity. LIMITATIONS: This relatively small sample size of children with one ethnicity some of whom were taking other antiepileptics that are potentially hepatotoxic. CONCLUSION: Catalase C-262T genotype, glutathione concentration and gender (male) are potential risk factors for the susceptibility to valproic acid-associated liver injury.

Sex differences in colorectal cancer: with a focus on sex hormone-gut microbiome axis.

Sexual dimorphism has been observed in the incidence and prognosis of colorectal cancer (CRC), with men generally exhibiting a slightly higher incidence than women. Research suggests that this difference may be attributed to variations in sex steroid hormone levels and the gut microbiome. The gut microbiome in CRC shows variations in composition and function between the sexes, leading to the concept of 'microgenderome' and 'sex hormone-gut microbiome axis.' Conventional research indicates that estrogens, by promoting a more favorable gut microbiota, may reduce the risk of CRC. Conversely, androgens may have a direct pro-tumorigenic effect by increasing the proportion of opportunistic pathogens. The gut microbiota may also influence sex hormone levels by expressing specific enzymes or directly affecting gonadal function. However, this area remains controversial. This review aims to explore the differences in sex hormone in CRC incidence, the phenomenon of sexual dimorphism within the gut microbiome, and the intricate interplay of the sex hormone-gut microbiome axis in CRC. The objective is to gain a better understanding of these interactions and their potential clinical implications, as well as to introduce innovative approaches to CRC treatment.