Pharmacological Doses of Thiamine Benefit Patients with the Charcot-Marie-Tooth Neuropathy by Changing Thiamine Diphosphate Levels and Affecting Regulation of Thiamine-Dependent Enzymes.

Charcot-Marie-Tooth (CMT) neuropathy is a polygenic disorder of peripheral nerves with no effective cure. Thiamine (vitamin B1) is a neurotropic compound that improves neuropathies. Our pilot study characterizes therapeutic potential of daily oral administration of thiamine (100 mg) in CMT neuropathy and its molecular mechanisms. The patient hand grip strength was determined before and after thiamine administration along with the blood levels of the thiamine coenzyme form (thiamine diphosphate, ThDP), activities of endogenous holo-transketolase (without ThDP in the assay medium) and total transketolase (with ThDP in the assay medium), and transketolase activation by ThDP [1 - (holo-transketolase/total transketolase),%], corresponding to the fraction of ThDP-free apo-transketolase. Single cases of administration of sulbutiamine (200 mg) or benfotiamine (150 mg) reveal their effects on the assayed parameters within those of thiamine. Administration of thiamine or its pharmacological forms increased the hand grip strength in the CMT patients. Comparison of the thiamin status in patients with different forms of CMT disease to that of control subjects without diagnosed pathologies revealed no significant differences in the average levels of ThDP, holo-transketolase, or relative content of holo and apo forms of transketolase. However, the regulation of transketolase by thiamine/ThDP differed in the control and CMT groups: in the assay, ThDP activated transketolase from the control individuals, but not from CMT patients. Thiamine administration paradoxically decreased endogenous holo-transketolase in CMT patients; this effect was not observed in the control group. Correlation analysis revealed sex-specific differences in the relationship between the parameters of thiamine status in both the control subjects and patients with the CMT disease. Thus, our findings link physiological benefits of thiamine administration in CMT patients to changes in their thiamine status, in particular, the blood levels of ThDP and transketolase regulation.

Female sex as a negative predictor of outcomes of ankle arthrodesis: a retrospective comparative monocentric study.

BACKGROUND: End-stage post-traumatic osteoarthritis of the ankle joint may require arthrodesis if conservative treatment fails and a decision against total ankle replacement is made. We aimed to compare the sex-specific differences in outcomes and objectify them using validated specific scores. METHODS: Between 2010 and 2021, 221 patients underwent ankle arthrodesis at our institution, including 143 men (MAA) and 78 women (FAA). In addition to demographic data, the aetiology of osteoarthritis, the Foot Function Index (FFI-D), the Olerud-Molander Score (OMAS), and the Short Form-12 questionnaire (SF-12) were collected in this monocentric study. The mean follow-up time was 5.8 years. End-stage osteoarthritis was mostly due to ankle fractures as a result of sprains, falls, and road traffic accidents. RESULTS: Post-operatively, the mean FFI-D for pain was 17.3 (MAA: 14.7; FAA 22.2) and 43.9 for function (MAA: 41.1; FAA 49.5); the mean OMAS was 58.2; and the mean SF-12 physical component score was 42.5. Women achieved significantly worse results in all scores; only the mental component summary of the SF-12 did not differ between the sexes (p > 0.05). Approximately 34% of women stated that the result in terms of gait pattern was worse than expected (MAA 16.1%; p < 0.05). Again, significantly more men stated that the result was better than expected (MAA: 48.3%; FAA: 31.5%, p < 0.05). CONCLUSIONS: The fact that the clinical results were significantly worse in women after ankle arthrodesis should be considered when determining the indication. However, the expectations of men and women also need to be individually adjusted.

Subregion-specific transcriptomic profiling of rat brain reveals sex-distinct gene expression impacted by adolescent stress.

Stress during adolescence clearly impacts brain development and function. Sex differences in adolescent stress-induced or exacerbated emotional and metabolic vulnerabilities could be due to sex-distinct gene expression in hypothalamic, limbic, and prefrontal brain regions. However, adolescent stress-induced whole-genome expression changes in key subregions of these brain regions were unclear. In this study, female and male adolescent Sprague Dawley rats received one-hour restraint stress daily from postnatal day (PD) 32 to PD44. Corticosterone levels, body weights, food intake, body composition, and circulating adiposity and sex hormones were measured. On PD44, brain and blood samples were collected. Using RNA-sequencing, sex-specific differences in stress-induced differentially expressed (DE) genes were identified in subregions of the hypothalamus, limbic system, and prefrontal cortex. Canonical pathways reflected well-known sex-distinct maladies and diseases, substantiating the therapeutic potential of the DE genes found in the current study. Thus, we proposed specific sex distinct, adolescent stress-induced transcriptional changes found in the current study as examples of the molecular bases for sex differences witnessed in stress induced or exacerbated emotional and metabolic disorders. Future behavioral studies and single-cell studies are warranted to test the implications of the DE genes identified in this study in sex-distinct stress-induced susceptibilities.

Sex-steroid hormones relate to cerebellar structure and functional connectivity across adulthood.

Aging involves complex biological changes that affect disease susceptibility and aging trajectories. Although females typically live longer than males, they have a higher susceptibility to diseases like Alzheimer's, speculated to be influenced by menopause, and reduced ovarian hormone production. Understanding sex-specific differences is crucial for personalized medical interventions and gender equality in health. Our study aims to elucidate sex differences in regional cerebellar structure and connectivity during normal aging by investigating both structural and functional connectivity variations, with a focus on investigating these differences in the context of sex-steroid hormones. The study included 138 participants (mean age = 57(13.3) years, age range = 35-86 years, 54% women). The cohort was divided into three groups: 38 early middle-aged individuals (EMA) (mean age = 41(4.7) years), 48 late middle-aged individuals (LMA) (mean age = 58(4) years), and 42 older adults (OA) (mean age = 72(6.3) years). All participants underwent MRI scans, and saliva samples were collected for sex-steroid hormone quantification (17ß-estradiol (E), progesterone (P), and testosterone (T)). We found less connectivity in females between Lobule I-IV and the cuneus, and greater connectivity in females between Crus I, Crus II, and the precuneus with increased age. Higher 17ß-estradiol levels were linked to greater connectivity in Crus I and Crus II cerebellar subregions. Analyzing all participants together, testosterone was associated with both higher and lower connectivity in Lobule I-IV and Crus I, respectively, while higher progesterone levels were linked to lower connectivity in females. Structural differences were observed, with EMA males having larger volumes compared to LMA and OA groups, particularly in the right I-IV, right Crus I, right V, and right VI. EMA females showed higher volumes in the right lobules V and VI. These results highlight the significant role of sex hormones in modulating cerebellar connectivity and structure across adulthood, emphasizing the need to consider sex and hormonal status in neuroimaging studies to better understand age-related cognitive decline and neurological disorders.

Sex-specific effects of gut microbiome on shaping bile acid metabolism.

Gut microbiome is a group of microorganisms that plays important roles in contributing to health and diseases. These bacterial compositions have been demonstrated to impact bile acids (BAs) profiles, either by directly metabolizing primary BAs to secondary BAs or indirect ways through host metabolism by influencing BAs synthesis, transportation and conjugation in liver. It has been observed sexually dimorphic gut microbiome and bile acids composition, with variations in expression levels of bile acid metabolizing genes in the liver. However, associations between sex-specific differences in gut microbiome and BAs profiles are not well understood. This study aimed to investigate whether gut microbiome could influence BAs profiles in host in a sexspecific manner. We transplanted cecum feces of male and female C57BL/6 mice to male mice and measured BAs concentrations in feces, serum and liver samples 7 days after fecal transplantation. We found different BAs profiles between mice with male and female gut microbiome, including altering levels and proportions of secondary BAs. We also observed varied expression levels of genes related to bile acid metabolism in the liver and distal ileum. Our results highlight sex-specific effects of gut microbiome on shaping bile acid metabolism through gut bacteria and regulation of host genes.

Sex-specific differences in SLE - Significance in the experimental setting of inflammation and kidney damage in MRL-Faslpr mice.

Animal models are an important tool in the research of chronic autoimmune diseases, like systemic lupus erythematosus (SLE). MRL-Faslpr mice are one of different lupus models that develop spontaneously an SLE-like disease with autoantibodies and immune complex deposition that leads into damage of different organs. In contrast to human SLE, both sexes of MRL-Faslpr mice develop a similar autoimmune disease. Due to the sex bias in human and the delayed disease progression in male MRL-Faslpr mice, the majority of studies have been performed in female mice. To determine the suitability of male MRL-Faslpr mice for SLE research, especially with regard to the 3 R-principle and animal welfare, analyses of phenotype, inflammation and damage with focus on kidney and spleen were performed in mice of both sexes. Female mice developed lymphadenopathy and skin lesions earlier as males. At an age of 3.5 month, more immune cells infiltrated kidney and spleen in females compared to males. At the age of 5 months, however, substantially less sex-specific differences were detected. Since other studies have shown differences between both sexes on other manifestations like autoimmune pancreatitis and Sjögren syndrome in MRL-Faslpr mice, the use of male mice as part of 3 R-principle and animal welfare must be carefully considered.

Sex Differences in the Expression of Cardiac Remodeling and Inflammatory Cytokines in Patients with Obstructive Sleep Apnea and Atrial Fibrillation.

Although there is a link between obstructive sleep apnea (OSA) and atrial fibrillation (AF) and numerous investigations have examined the mechanism of AF development in OSA patients, which includes cardiac remodeling, inflammation, and gap junction-related conduction disorder, there is limited information regarding the differences between the sexes. This study analyzes the impact of sex differences on the expression of cardiac remodeling, inflammatory cytokines, and gap junctions in patients with OSA and AF. A total of 154 individuals diagnosed with sleep-related breathing disorders (SRBDs) were enrolled in the study and underwent polysomnography and echocardiography. Significant OSA was defined as an apnea-hypopnea index (AHI) of ≥15 per hour. Exosomes were purified from the plasma of all SRBD patients and incubated in HL-1 cells to investigate their effects on inflammatory cytokines and GJA1 expression. The differences in cardiac remodeling and expression of these biomarkers in both sexes were analyzed. Of the 154 enrolled patients, 110 patients were male and 44 patients were female. The LA sizes and E/e' ratios of male OSA patients with concomitant AF were greater than those of control participants and those without AF (all p < 0.05). Meanwhile, female OSA patients with AF had a lower left ventricular ejection fraction than those OSA patients without AF and control subjects (p < 0.05). Regarding the expression of inflammatory cytokines and GJA1, the mRNA expression levels of GJA1 were lower and those of IL-1ß were higher in those male OSA patients with AF than in those male OSA patients without AF and control subjects (p < 0.05). By contrast, mRNA expression levels of HIF-1α were higher in those female OSA patients with and without AF than in control subjects (p < 0.05). In conclusion, our study revealed sex-specific differences in the risk factors and biomarkers associated with AF development in patients with OSA.

Sex-specific differences in the clinical profile among psychiatric patients with pulmonary Embolism: a hospital-based retrospective study.

BACKGROUND: Pulmonary embolism (PE) is a severe and life-threatening complication of venous thromboembolism. However, there is a lack of systematic studies on differences between female and male PE patients. This paper aimed to compare the sex-specific differences in clinical characteristics and laboratory indicators in psychotic patients with PE. METHODS: This retrospective study enrolled psychiatric patients with PE from June 2018 to June 2022 at Shenzhen Kangning Hospital (Shenzhen Mental Health Center). Demographic characteristics, factors associated with PE, and laboratory indices were collected to assess sex-specific differences. RESULTS: Of the 168 patients, 87 (51.8%) were female and 81 (48.2%) were male, with a mean age of 58 years for females and 46 years for male patients. The male group had higher ratio of hyperprolactinemia, more patients using antipsychotic medications, higher D-dimer levels at PE onset, greater D-dimer difference, and a higher rate of D-dimer elevation than the female group (p < 0.05). Female patients were significantly older, exhibited a higher prevalence of diabetes, and had a greater number of patients taking antidepressants and hypnotics/sedatives than male patients (p < 0.05). Schizophrenia spectrum disorders were more prevalent in male patients, while female patients had a higher incidence of mood disorders (p < 0.05). Among patients aged < 45 years, the male group had higher D-dimer levels at PE onset and greater D-dimer difference (p < 0.05). Among all 112 patients aged ≥ 45 years, male patients were more likely than female patients to have respiratory tract infections, higher D-dimer levels at PE onset, greater D-dimer difference, and a higher rate of D-dimer elevation (p < 0.05). The multiple linear regression analysis indicated that hyperprolactinemia and the use of first-generation antipsychotics (FGAs) were associated with D-dimer levels at PE onset in male patients, while the time of PE onset and protective restraints were associated with D-dimer levels at PE onset in female patients (p < 0.05). CONCLUSION: PE-associated clinical features differ between male and female patients. These differences may imply that the processes and mechanisms of PE onset are sex specific. Male patients are more likely to have respiratory tract infections and higher D-dimer levels at PE onset than female patients. The use of FGAs may be associated with increased D-dimer in male psychiatric patients, while protective restraints may be associated with increased D-dimer in female psychiatric patients.

Sex-specific outcomes and left atrial remodeling following catheter ablation of persistent atrial fibrillation: results from the DECAAF II trial.

BACKGROUND: Catheter ablation is recognized as an effective treatment for atrial fibrillation (AF). Despite its effectiveness, significant sex-specific differences have been observed, which influence the outcomes of the procedure. This study explores these differences in a cohort of patients with persistent AF. We aim to assess sex differences in baseline characteristics, symptoms, quality of life, imaging findings, and response to catheter ablation in patients with persistent AF. METHODS: This post hoc analysis of the DECAAF II trial evaluated 815 patients (161 females, 646 males). Between July 2016 and January 2020, participants were enrolled and randomly assigned to receive either personalized ablation targeting left atrial (LA) fibrosis using DE-MRI in conjunction with pulmonary vein isolation (PVI) or PVI alone. In this analysis, we aimed to compare female and male patients in the full cohort in terms of demographics, risk factors, medications, and outcomes such as AF recurrence, AF burden, LA volume reduction assessed by LGE-MRI before and 3 months after ablation, quality of life assessed by the SF-36 score, and safety outcomes. Statistical methods included t-tests, chi-square, and multivariable Cox regression. RESULTS: Females were generally older with more comorbidities and experienced higher rates of arrhythmia recurrence post-ablation (53.3% vs. 40.2%, p < 0.01). Females also showed a higher AF burden (21% vs. 16%, p < 0.01) and a smaller reduction in left atrial volume indexed to body surface area post-ablation compared to male patients (8.36 (9.94) vs 11.35 (13.12), p-value 0.019). Quality of life scores were significantly worse in females both pre- and post-ablation (54 vs. 66 pre-ablation; 69 vs. 81 post-ablation, both p < 0.01), despite similar improvements across sexes. Safety outcomes and procedural parameters were similar between male and female patients. CONCLUSION: The study highlights significant differences in the outcomes of catheter ablation of persistent AF between sexes, with female patients showing worse quality of life, higher recurrence of AF and AF burden after ablation, and worse LA remodeling.

Acute Coronary Syndrome in Women: An Update.

PURPOSE OF REVIEW: The goal of this manuscript is to provide a concise summary of recent developments in the approach to and treatment of women with acute coronary syndrome (ACS). RECENT FINDINGS: This review covers terminology updates relating to ACS and myocardial injury and infarction. Updates on disparities in recognition, treatments, and outcomes of women with ACS due to atherosclerotic coronary artery disease are covered. Other causes of ACS, including spontaneous coronary artery dissection and myocardial infarction with non-obstructive coronary artery disease are discussed, given the increased frequency in women compared with men. The review summarizes the latest on the unique circumstance of ACS in women who are pregnant or post-partum, including etiologies, diagnostic approaches, medication safety, and revascularization considerations. Compared with men, women with ACS have unique risk factors, presentations, and pathophysiology. Treatments known to be effective for men with atherosclerosis-related ACS are also effective for women; further work remains on reducing the disparities in diagnosis and treatment. Implementation of multimodality imaging will improve diagnostic accuracy and allow for targeted medical therapy in the setting of myocardial infarction with non-obstructive coronary artery disease.

Lipidome characterisation and sex-specific differences in type 1 and type 2 diabetes mellitus.

BACKGROUND: In this study, we evaluated the lipidome alterations caused by type 1 diabetes (T1D) and type 2 diabetes (T2D), by determining lipids significantly associated with diabetes overall and in both sexes, and lipids associated with the glycaemic state. METHODS: An untargeted lipidomic analysis was performed to measure the lipid profiles of 360 subjects (91 T1D, 91 T2D, 74 with prediabetes and 104 controls (CT)) without cardiovascular and/or chronic kidney disease. Ultra-high performance liquid chromatography-electrospray ionization mass spectrometry (UHPLC-ESI-MS) was conducted in two ion modes (positive and negative). We used multiple linear regression models to (1) assess the association between each lipid feature and each condition, (2) determine sex-specific differences related to diabetes, and (3) identify lipids associated with the glycaemic state by considering the prediabetes stage. The models were adjusted by sex, age, hypertension, dyslipidaemia, body mass index, glucose, smoking, systolic blood pressure, triglycerides, HDL cholesterol, LDL cholesterol, alternate Mediterranean diet score (aMED) and estimated glomerular filtration rate (eGFR); diabetes duration and glycated haemoglobin (HbA1c) were also included in the comparison between T1D and T2D. RESULTS: A total of 54 unique lipid subspecies from 15 unique lipid classes were annotated. Lysophosphatidylcholines (LPC) and ceramides (Cer) showed opposite effects in subjects with T1D and subjects with T2D, LPCs being mainly up-regulated in T1D and down-regulated in T2D, and Cer being up-regulated in T2D and down-regulated in T1D. Also, Phosphatidylcholines were clearly down-regulated in subjects with T1D. Regarding sex-specific differences, ceramides and phosphatidylcholines exhibited important diabetes-associated differences due to sex. Concerning the glycaemic state, we found a gradual increase of a panel of 1-deoxyceramides from normoglycemia to prediabetes to T2D. CONCLUSIONS: Our findings revealed an extensive disruption of lipid metabolism in both T1D and T2D. Additionally, we found sex-specific lipidome changes associated with diabetes, and lipids associated with the glycaemic state that can be linked to previously described molecular mechanisms in diabetes.

Obesity management: sex-specific considerations.

Obesity is a global health issue that has grown to epidemic proportions. According to World Health Organisation (WHO), overweight and obesity are responsible for more than 1.2 million deaths in Europe each year, representing > 13% of the region's total mortality. Highly processed, calorie-dense foods and reduced physical activity are considered as primary drivers of obesity, but genetic predisposition also plays a significant role. Notably, obesity is more prevalent in women than in men in most countries, and several obesity-related comorbidities exhibit sex-specific pathways. Treatment indication depends on BMI (body mass index), as well as existing comorbidities and risk factors. To reduce obesity-associated comorbidities, a permanent reduction in body weight of (at least) 5-10% is recommended. Treatment guidelines suggest an escalating stepwise approach including lifestyle intervention, pharmacotherapy, and bariatric-metabolic surgery. As cumulative evidence suggests differences in weight loss outcomes, there is growing interest in sex-specific considerations in obesity management. However, most trials do not report weight loss or changes in body composition separately for women and men. Here, we discuss state-of-the-art obesity management and focus on current data about the impact of sex on weight loss outcomes.

Effects of Soy Protein Isolate on Fragile X Phenotypes in Mice.

Obesity is a pediatric epidemic that is more prevalent in children with developmental disabilities. We hypothesize that soy protein-based diets increase weight gain and alter neurobehavioral outcomes. Our objective herein was to test matched casein- and soy protein-based purified ingredient diets in a mouse model of fragile X syndrome, Fmr1KO mice. The experimental methods included assessment of growth; 24-7 activity levels; motor coordination; learning and memory; blood-based amino acid, phytoestrogen and glucose levels; and organ weights. The primary outcome measure was body weight. We find increased body weight in male Fmr1KO from postnatal day 6 (P6) to P224, male wild type (WT) from P32-P39, female Fmr1KO from P6-P18 and P168-P224, and female Fmr1HET from P9-P18 as a function of soy. Activity at the beginning of the light and dark cycles increased in female Fmr1HET and Fmr1KO mice fed soy. We did not find significant differences in rotarod or passive avoidance behavior as a function of genotype or diet. Several blood-based amino acids and phytoestrogens were significantly altered in response to soy. Liver weight was increased in WT and adipose tissue in Fmr1KO mice fed soy. Activity levels at the beginning of the light cycle and testes weight were greater in Fmr1KO versus WT males irrespective of diet. DEXA analysis at 8-months-old indicated increased fat mass and total body area in Fmr1KO females and lean mass and bone mineral density in Fmr1KO males fed soy. Overall, dietary consumption of soy protein isolate by C57BL/6J mice caused increased growth, which could be attributed to increased lean mass in males and fat mass in females. There were sex-specific differences with more pronounced effects in Fmr1KO versus WT and in males versus females.

Sex-specific differences in risk factors, comorbidities, diagnostic challenges, optimal management, and prognostic outcomes of heart failure with preserved ejection fraction: A comprehensive literature review.

Due to hormonal variations, heart failure with preserved ejection fraction (HFpEF) remains prevalent in women and affects almost half of the heart failure (HF) patients. Given the yearly death rate of 10-30% and the unavailability of medications targeting HFpEF, the need arises for a better understanding of the fundamental mechanisms of this syndrome. This comprehensive review explores sex-specific differences in traditional risk factors; female-specific factors that may impact HFpEF development and response to therapy, including variations in hormone levels that may occur pre- and post-menopausal or during pregnancy; and disparities in comorbidities, clinical presentation, and diagnostic challenges. Lastly, the review addresses prognostic outcomes, noting that women with HFpEF have a poor quality of life but a higher survival rate. It also discusses novel biomarkers and precision medicine, emphasizing their potential to improve early detection and personalized treatment.

Sex-Specific Variations in the mRNA Levels of Candidate Genes in Peripheral Blood Mononuclear Cells from Patients with Diabetes: A Multistep Study.

BACKGROUND: Type 2 diabetes (T2D) is one of the most prevalent diseases that also show sexual dimorphism in many different aspects. OBJECTIVES: This study aimed to distinguish the mRNA expression of genes in peripheral blood mononuclear cells (PBMCs) in men or women with T2D using a multistep analysis. METHODS: A total of 95 patients with T2D were compared based on their sex in terms of clinical variables and mRNA expression in their PBMCs. RESULTS: Men with T2D had lower LDLC, HDLC, and HbA1c values in their blood, but greater creatinine levels. In men with T2D, TLR4, CCR2, NOX2, and p67phox mRNA expression was greater, but IL6 and NF-κB mRNA expression was lesser in PBMCs. There was a link between fasting plasma glucose (FPG), triglycerides, and hs-CRP, as well as COX1 mRNA in men with T2D. In women with T2D, FPG was associated with the mRNA expression of THBS1 and p67phox, as well as triglycerides and HDLC levels. We found the exclusive effect of FPG on HDLC, HbA1c, as well as p67phox mRNA in PBMCs of women with T2D. Analysis revealed the exclusive effect of FPG on hs-CRP and PAFR mRNA in PBMCs of men with T2D. FPG was shown to be associated with body mass index, hs-CRP, triglycerides, and COX1 mRNA in men with T2D, and with serum triglycerides, THSB1, and p67phox mRNA in women with T2D, according to network analysis. HbA1c was linked with NF-κB mRNA in women with T2D. CONCLUSIONS: Using a multistep analysis, it was shown that network analysis outperformed traditional analytic techniques in identifying sex-specific alterations in mRNA gene expression in PBMCs of T2D patients. The development of sex-specific therapeutic approaches may result from an understanding of these disparities.

The Clinical Diagnosis-Based Nationwide Epidemiology of Metabolic Dysfunction-Associated Liver Disease in Korea.

BACKGROUND: Although most epidemiological studies have been conducted using a relatively small population or subjects who had medical screenings, the present study aimed to investigate the incidence and prevalence of MASLD (formerly NAFLD) in Korea using nationwide registry data provided by the Health Insurance Review and Assessment Service (HIRA). METHODS: Using nationwide medical records provided by HIRA, we analyzed the entire dataset of patients with MASL (KCD10-K76.0) and MASH (KCD10-K75.8) from 2010 to 2021 and calculated the incidence and prevalence by year, age, and gender. The prevalence and incidence rates were calculated by analyzing the HIRA data covering almost the entire population of Korea for 12 years, from 2010 to 2021, with an average population of 50,856,244 during this period. Statistical analyses included calculating confidence intervals using Ulm's formula and conducting sex- and age-specific analyses with a Cochran-Armitage test for trends. RESULTS: The annual incidence of MASL/MASH increased significantly from 9.71/0.37 in 2010 to 13.95/5.52 per 1000 persons in 2021 (p < 0.01). The annual prevalence of MASL increased from 15.69 in 2010 to 34.23 per 1000 persons in 2021, while the annual prevalence of MASH increased from 0.49 to 9.79 per 1000 persons between 2010 and 2021 (p < 0.01). Regarding the sex-dimorphic feature of MASLD, there was a male predominance in those < 50 years old but a female predominance in those ≥ 50 years old for the incidence and prevalence of MASL and the incidence of MASH. CONCLUSION: The incidence of MASL increased by 3% to 4% every year, while the incidence of MASH increased 14.91-fold from 2010 to 2021. The increasing trend is noteworthy compared with previous reports.

How prenatal cortisol levels may differentially affect the neurodevelopment of boys and girls.

BACKGROUND: Prenatal stress could have serious consequences on maternal and fetal health. In this sense, some studies have stated that maternal HCC during pregnancy could contribute to sex-specific effects on infant neurodevelopment, following the Developmental Origins of Health and Disease Hypothesis. AIM: This study aimed to determine whether maternal hair cortisol concentration (HCC) during each trimester of pregnancy and postpartum could predict the neurodevelopmental outcomes of their 12-month-old offspring, with sex-specific differences considered. STUDY DESIGN: longitudinal. SUBJECTS: The study involved 93 pregnant women and their babies. OUTCOME MEASURE: Hair samples collected during each trimester and postpartum and The Bayley Scales for Infant Development III was used to assess the infants' abilities. RESULTS: The results showed that maternal HCC during the first and second trimesters could predict language and motor abilities. However, when discriminated by sex, only females' cognitive, expressive language, and fine and gross motor skills were predicted by cortisol, not males. CONCLUSIONS: These findings support the idea that non-toxic levels of cortisol can positively influence infants' neurodevelopment.

Holistic pedestrian safety assessment for average males and females.

Objective: An integrated assessment framework that enables holistic safety evaluations addressing vulnerable road users (VRU) is introduced and applied in the current study. The developed method enables consideration of both active and passive safety measures and distributions of real-world crash scenario parameters. Methods: The likelihood of a specific virtual testing scenario occurring in real life has been derived from accident databases scaled to European level. Based on pre-crash simulations, it is determined how likely it is that scenarios could be avoided by a specific Autonomous Emergency Braking (AEB) system. For the unavoidable cases, probabilities for specific collision scenarios are determined, and the injury risk for these is determined, subsequently, from in-crash simulations with the VIVA+ Human Body Models combined with the created metamodel for an average male and female model. The integrated assessment framework was applied for the holistic assessment of car-related pedestrian protection using a generic car model to assess the safety benefits of a generic AEB system combined with current passive safety structures. Results: In total, 61,914 virtual testing scenarios have been derived from the different car-pedestrian cases based on real-world crash scenario parameters. Considering the occurrence probability of the virtual testing scenarios, by implementing an AEB, a total crash risk reduction of 81.70% was achieved based on pre-crash simulations. It was shown that 50 in-crash simulations per load case are sufficient to create a metamodel for injury prediction. For the in-crash simulations with the generic vehicle, it was also shown that the injury risk can be reduced by implementing an AEB, as compared to the baseline scenarios. Moreover, as seen in the unavoidable cases, the injury risk for the average male and female is the same for brain injuries and femoral shaft fractures. The average male has a higher risk of skull fractures and fractures of more than three ribs compared to the average female. The average female has a higher risk of proximal femoral fractures than the average male. Conclusions: A novel methodology was developed which allows for movement away from the exclusive use of standard-load case assessments, thus helping to bridge the gap between active and passive safety evaluations.

Single-Cell RNA sequencing investigation of female-male differences under PAD conditions.

Peripheral arterial disease (PAD) is an age-related medical condition affecting mostly muscular arteries of the limb. It is the 3rd leading cause of atherosclerotic morbidity. The mechanical environment of endothelial cells (ECs) in PAD is characterized by disturbed blood flow (d-flow) and stiff extracellular matrices. In PAD, the stiffness of arteries is due to decreased elastin function and increased collagen content. These flow and stiffness parameters are largely missing from current models of PAD. It has been previously proven that ECs exposed to d-flow or stiff substrates lead to proatherogenic pathways, but the effect of both, d-flow and stiffness, on EC phenotype has not been fully investigated. In this study, we sought to explore the effect of sex on proatherogenic pathways that could result from exposing endothelial cells to a d-flow and stiff environment. We utilized the scRNA-seq tool to analyze the gene expression of ECs exposed to the different mechanical conditions both in vitro and in vivo. We found that male ECs exposed to different mechanical stimuli presented higher expression of genes related to fibrosis and d-flow in vitro. We validated our findings in vivo by exposing murine carotid arteries to d-flow via partial carotid artery ligation. Since women have delayed onset of arterial stiffening and subsequent PAD, this work may provide a framework for some of the pathways in which biological sex interacts with sex-based differences in PAD.

Cigarette smoke-induced injury induces distinct sex-specific transcriptional signatures in mice tracheal epithelial cells.

The airway epithelial barrier is crucial for defending against respiratory insults and diseases. Disruption of epithelial integrity contributes to respiratory diseases, and sex-specific differences in susceptibility and severity have been observed. However, sex-specific differences in the context of respiratory diseases are often overlooked, especially in murine models. In this study, we investigated the in vitro transcriptomics of male and female murine tracheal epithelial cells (mTECs) in response to chronic cigarette smoke (CS) exposure using an International Organization for Standardization (ISO) puff regimen. Our findings reveal sex-specific differences in the baseline characteristics of airway epithelial cells. Female mTECs demonstrated stronger barrier function and higher ciliary function compared with males. The barrier function was disrupted in both males and females following chronic CS, but the difference was more significant in females due to their higher baseline. Female mice exhibited transcriptional signatures suggesting dedifferentiation with increased basal cells and markers of cellular senescence. Pathway analysis indicated potential protective roles of planar cell polarity (PCP) in preventing dedifferentiation in male mice exposed to CS. We also observed sex-specific differences in the DNA damage response and antioxidant levels, suggesting distinct mechanisms underlying cellular stress. Understanding these sex-specific mechanisms could facilitate the development of targeted therapeutic strategies for lung diseases associated with environmental insults. Recognizing sex-based differences in disease susceptibility and treatment response can lead to personalized care and improved outcomes. Clinical trials should consider sex as a biological variable to develop effective interventions that address the unique differences between men and women in respiratory diseases.NEW & NOTEWORTHY The study underscores the importance of considering sex-specific differences in the airway epithelium in respiratory diseases such as COPD. Differences in gene expression between males and females at baseline and in response to chronic injury in the airway epithelium could have implications on disease susceptibility, both in COPD and other respiratory diseases. Therefore, understanding these differences is crucial for developing targeted therapies to treat respiratory diseases based on a sex-specific manner.