Sex-specific Patterns Research Articles

National trends in pediatric drowning — insights from the Israeli Ministry of Health registry-based cohort

This study analyzes the epidemiology of pediatric drowning in Israel from 2010 to 2022, focusing on differences across age groups, sex, and regions. We conducted a retrospective cohort study using data from the Ministry of Health’s administrative databases, covering all children aged 0–17 years who were seen in the emergency department, discharged after hospitalization, or died at the scene due to drowning, excluding cases of intentional harm or suicide. The primary outcome was the annual drowning rate per 100,000 children, categorized by age, sex, and region, along with hospitalization duration, intensive care unit admissions, and mortality rates. A total of 2101 drowning incidents were identified, with 9% resulting in death. Higher drowning rates were found in younger children (1–4 years) and teenagers (15–17 years), with notable differences by sex. Drowning rates were higher in coastal regions and more frequent during winter and spring. An increase in drowning rates was observed over the last 3 years of the study (2020–2022). Children hospitalized for more than 3 days had significantly higher mortality rates, both in general wards and intensive care units.Conclusions: Pediatric drowning is a persistent public health concern in Israel, with distinct seasonal, regional, age-specific, and sex-specific patterns in incidence and mortality. This study underscores the need for a comprehensive prevention strategy that includes year-round public education, environmental safety measures, and targeted interventions for high-risk groups to reduce drowning incidents and fatalities among children effectively.What is Known:• Pediatric drowning represents a significant public health challenge globally, with varying rates.• In Israel, pediatric drowning is the second leading cause of death from all injury-related deaths. Thus far, the measures and interventions to reduce fatalities were not proven effective enough.What is New:• Pediatric drowning in Israel, with a 9% mortality rate, revealed a biphasic rate varied by sex and is higher in coastal regions and during winter and spring.• There was a notable increase in drowning incidents during the last 3 years of the study period (2020–2022), coinciding with the COVID-19 pandemic.

Sex-specific molecular signature of mouse podocytes in homeostasis and in response to pharmacological challenge with rapamycin

BackgroundSex differences exist in the prevalence and progression of major glomerular diseases. Podocytes are the essential cell-type in the kidney which maintain the physiological blood-urine barrier, and pathological changes in podocyte homeostasis are critical accelerators of impairment of kidney function. However, sex-specific molecular signatures of podocytes under physiological and stress conditions remain unknown. This work aimed at identifying sexual dimorphic molecular signatures of podocytes under physiological condition and pharmacologically challenged homeostasis with mechanistic target of rapamycin (mTOR) inhibition. mTOR is a crucial regulator involved in a variety of physiological and pathological stress responses in the kidney and inhibition of this pathway may therefore serve as a general stress challenger to get fundamental insights into sex differences in podocytes.MethodsThe genomic ROSAmT/mG-NPHS2 Cre mouse model was used which allows obtaining highly pure podocyte fractions for cell-specific molecular analyses, and vehicle or pharmacologic treatment with the mTOR inhibitor rapamycin was performed for 3 weeks. Subsequently, deep RNA sequencing and proteomics were performed of the isolated podocytes to identify intrinsic sex differences. Studies were supplemented with metabolomics from kidney cortex tissues.ResultsAlthough kidney function and morphology remained normal in all experimental groups, RNA sequencing, proteomics and metabolomics revealed strong intrinsic sex differences in the expression levels of mitochondrial, translation and structural transcripts, protein abundances and regulation of metabolic pathways. Interestingly, rapamycin abolished prominent sex-specific clustering of podocyte gene expression and induced major changes only in male transcriptome. Several sex-biased transcription factors could be identified as possible upstream regulators of these sexually dimorphic responses. Concordant to transcriptomics, metabolomic changes were more prominent in males. Remarkably, high number of previously reported kidney disease genes showed intrinsic sexual dimorphism and/or different response patterns towards mTOR inhibition.ConclusionsOur results highlight remarkable intrinsic sex-differences and sex-specific response patterns towards pharmacological challenged podocyte homeostasis which might fundamentally contribute to sex differences in kidney disease susceptibilities and progression. This work provides rationale and an in-depth database for novel targets to be tested in specific kidney disease models to advance with sex-specific treatment strategies.

Sex-specific chrono-nutritional patterns and association with body weight in a general population in Spain (GCAT study)

BackgroundAltered meal timing patterns can disrupt the circadian system and affect metabolism. Our aim was to describe sex-specific chrono-nutritional patterns, assess their association with body mass index (BMI) and investigate the role of sleep in this relationship.MethodsWe used the 2018 questionnaire data from the population-based Genomes for Life (GCAT) (n = 7074) cohort of adults aged 40–65 in Catalonia, Spain, for cross-sectional analysis and its follow-up questionnaire data in 2023 (n = 3128) for longitudinal analysis. We conducted multivariate linear regressions to explore the association between mutually adjusted meal-timing variables (time of first meal, number of eating occasions, nighttime fasting duration) and BMI, accounting for sleep duration and quality, and additional relevant confounders including adherence to a Mediterranean diet. Finally, cluster analysis was performed to identify chrono-nutritional patterns, separately for men and women, and sociodemographic and lifestyle characteristics were compared across clusters and analyzed for associations with BMI.ResultsIn the cross-sectional analysis, a later time of first meal (β 1 h increase = 0.32, 95% CI 0.18, 0.47) and more eating occasions (only in women, β 1 more eating occasion = 0.25, 95% CI 0.00, 0.51) were associated with a higher BMI, while longer nighttime fasting duration with a lower BMI (β 1 h increase=-0.27, 95% CI -0.41, -0.13). These associations were particularly evident in premenopausal women. Longitudinal analyses corroborated the associations with time of first meal and nighttime fasting duration, particularly in men. Finally, we obtained 3 sex-specific clusters, that mostly differed in number of eating occasions and time of first meal. Clusters defined by a late first meal displayed lower education and higher unemployment in men, as well as higher BMI for both sexes. A clear “breakfast skipping” pattern was identified only in the smallest cluster in men.ConclusionsIn a population-based cohort of adults in Catalonia, we found that a later time of first meal was associated with higher BMI, while longer nighttime fasting duration associated with a lower BMI, both in cross-sectional and longitudinal analyses.

Sex-specific dietary patterns and their association with metabolic syndrome: Insights from a cross-sectional analysis

AimsThis study aims to identify a posteriori dietary patterns with a sex approach and to evaluate their association with metabolic syndrome criteria. MethodsCross-sectional study conducted in 6821 men and women between 55 and 75 years of age. Forty-two food groups were analyzed from dietary information collected with food frequency questionnaires, using principal component analysis and cluster analysis and then information from both statistical methods was compared. Prevalences were calculated foreach cluster group, based on the number and types of metabolic syndrome criteria they met. ResultsFollowing principal component analysis, two dietary patterns labeled “healthy” and “unhealthy” were identified in both men and women, due to the presence of foods that are considered more or less healthy. These same dietary patterns were found in cluster analysis plus an “intermediate” cluster consisting of both healthy and unhealthy foods. The presence of metabolic syndrome is related to the “healthy” dietary pattern in women and to the “unhealthy” dietary pattern in men. Comparison of the two statistical approaches showed a high level of correlation between them (weighted Kappa = 0.703 in women and weighted Kappa = 0.691 in men). ConclusionsAdherence to both healthy and unhealthy dietary pattern appears to be related to the development of MS. The differences found by sex make it necessary to develop interventions with a sex-specific approach.

A humanized ACE2 mouse model recapitulating age- and sex-dependent immunopathogenesis of COVID-19.

In the ongoing battle against coronavirus disease 2019 (COVID-19), understanding its pathogenesis and developing effective treatments remain critical challenges. The creation of animal models that closely replicate human infection stands as a critical step forward in this research. Here, we present a genetically engineered mouse model with specifically-humanized knock-in ACE2 (hiACE2) receptors. This model, featuring nine specific amino acid substitutions for enhanced interaction with the viral spike protein, enables efficient severe acute respiratory syndrome coronavirus 2 replication in respiratory organs without detectable infection in the central nervous system. Moreover, it mirrors the age- and sex-specific patterns of morbidity and mortality, as well as the immunopathological features observed in human COVID-19 cases. Our findings further demonstrate that the depletion of eosinophils significantly reduces morbidity and mortality, depending on the infecting viral dose and the sex of the host. This reduction is potentially achieved by decreasing the pathogenic contribution of eosinophil-mediated inflammation, which is strongly correlated with neutrophil activity in human patients. This underscores the model's utility in studying the immunopathological aspects of COVID-19 and represents a significant advancement in COVID-19 modeling. It offers a valuable tool for testing vaccines and therapeutics, enhancing our understanding of the disease mechanisms and potentially guiding more targeted and effective treatments.

Sex-Specific Differences in Cardiovascular Adaptations and Risks in Elite Athletes: Bridging the Gap in Sports Cardiology.

The growing participation of women in competitive sports necessitates a comprehensive understanding of sex-specific cardiovascular adaptations and risks. Historically, research has predominantly focused on male athletes, leaving a gap in knowledge about the unique cardiovascular dynamics of female peers. we hypothesized that female athletes exhibit distinct cardiovascular adaptations and face different risks, influenced by physiological, hormonal, and structural differences. A systematic review of the literature was conducted, analyzing studies on cardiovascular responses and adaptations in athletes. Data were extracted on hemodynamic changes, autonomic and neural reflex regulation, cardiac remodeling, and arrhythmias. Comparative analyses were performed to identify sex-specific patterns and discrepancies in cardiovascular health outcomes. We revealed considerable sex differences in cardiovascular adaptations to athletic training. Female athletes generally have longer QT intervals, greater sinoatrial node automaticity, and enhanced atrioventricular node function compared to males. They also exhibit lower sympathetic activity, lower maximal stroke volumes, and a tendency toward eccentric cardiac remodeling. Conversely, male athletes are more prone to concentric hypertrophy and higher incidences of bradyarrhythmia and accessory pathway arrhythmias. Female athletes are more likely to experience symptomatic atrial fibrillation and face higher procedural complications during catheter ablation. Our findings underscore the necessity for sex-specific approaches in sports cardiology. Recognizing and addressing these differences could enhance performance and reduce adverse cardiac events in athletes. Future research should focus on developing tailored screening, prevention, and treatment strategies to bridge the knowledge gap and promote cardiovascular health in both male and female athletes.

A surveillance study of cancer incidence and mortality among young adults in Costa Rica

There has been an increase in certain cancers among young adults (YA) aged 20-39, particularly in LatinAmerica. This is the first study to examine cancer incidence and mortality in YA in Costa Rica, focusing on sex-specific patterns. Invasive cancer cases (excluding non-melanoma skin cancer) in YA from 2006 to 2015 were obtained from the Costa Rican National Registry of Tumors. Utilising SEER∗Stat software, age-standardized incidence rates (IRs) and incidence rate ratios (IRRs) were calculated. Trends and annual percent changes (APCs) in IRs were estimated using the Joinpoint regression analysis program. Cancer deaths from 2000 to 2021 were obtained from the Costa Rican National Institute of Statistics and Census. Age-standardised mortality rates were calculated using STATA®17. YA comprised 10.7% of all invasive cancer cases diagnosed from 2006 to 2015. The age-standardized incidence rate (ASIR) of invasive cancer in YA was 50.9/100,000 person-years. The ASIR was twofold higher for females compared to males (IRR=2.03, 95% CI:1.94, 2.13). This difference increased with age, peaking in the 35-39-year age group (IRR=2.84, 95% CI:2.62, 3.10). Thyroid, breast, and cervical cancer were the most common in females. Testicular cancer was the most common in males. Leading causes of cancer-related deaths included cervical and breast cancer in females and stomach and brain/nervous system cancer in males. The study highlights sex-specific patterns in cancer incidence and mortality among YA in Costa Rica to increase understanding and improve cancer outcomes in this age group. This study was funded by the Intramural Research Program of the National Cancer Institute.

A New Overview of Sex Bias in Fungal Infections.

Fungal infections often disproportionately affect males over females. Since the NIH mandated in 2016 that researchers test their hypotheses in both biological sexes, numerous other fungal infections/colonizations have been found to exhibit sex-specific patterns. These patterns have been observed in various species, including mice, drosophila, cats, and bats, suggesting significant implications for understanding these diseases and developing treatments. Despite the recognition of this sex bias, primary research explaining its underlying causes or mechanisms remains limited. Current evidence suggests that potential causes might be linked to sex hormones, genetic expression, and evolutionary behaviors. This review consolidates recent data on sex bias in fungal infections or colonizations among different species and proposes future research directions to address existing gaps. Thus, this review advances the comprehension of the intricate relationships between biological sex, fungal infections, and broader health implications.

Evaluation of the Effectiveness of Sex Determination in the Great Cormorant (Phalacrocorax carbo) Based on External Measurements.

The possibility of sex identification of birds has substantial importance for studies on different aspects of bird ecology and behaviour. Using discriminant functions is becoming increasingly popular in studies of bird species that are monomorphic in plumage characteristics because they are cheap, hardly invasive and may be applied to data collected in the past. In this paper, we provide a discriminant function to sex great cormorants using external measurements. Males were larger than females in all linear body measurements, but there were no significant differences between adults and juveniles. Thus, data on juveniles and adults within a sex was combined. Discriminant equations with the most commonly used linear measurements, wing length and bill length, were provided. If identifying birds with discriminant function values D2 < -1.256 as females and those with D2 > 0.916 as males, 99% of birds will be correctly sexed. The method presented here makes it possible to account for sex-specific patterns in ecological studies of the great cormorant and may be applied to data collected in the past. The cross-application of discriminant functions developed for other populations of the great cormorant produces a 5.4% and 7.5% misclassification rate for birds from northern Poland using discriminant equations developed for populations in Greece and the Netherlands, respectively.

Sex-specific clinical and neurobiological correlates of fatigue in older adults.

Fatigue is a common and distressful symptom in older people and has been associated with adverse health outcomes. Nevertheless, its sex-specific pathophysiological underpinnings and clinical correlates have been scarcely investigated. We aimed to comprehensively explore the clinical and neurobiological determinants of fatigue in cognitively unimpaired older adults. A sex-stratified analysis was conducted to look for differences in the clinical expression of fatigue among women and men. Data on cognitively normal individuals were gathered from the Alzheimer's Disease Neuroimaging Initiative (ADNI) 2 study. Fatigue was defined based on self-report at baseline. For each participant, information on sociodemographics, comorbidities, mood, cognitive performance, frailty, and biomarkers of brain pathology was collected. Logistic regression models, stratified by sex, were conducted to explore the factors associated with fatigue. Among the 291 participants selected, 44 subjects (15.1% of the total sample) self-reported fatigue at baseline. Subjects reporting fatigue were more likely women, had higher frailty degrees, and more severe depressive symptoms than those without fatigue. Moreover, they tended to have lower MRI hippocampus volumes. Among women, those reporting fatigue exhibited higher frailty levels, worse depression, and lower MRI hippocampus volumes relative to those without fatigue. Higher frailty degrees were also observed in men reporting vs. non-reporting fatigue. In the adjusted logistic regression model, more severe depression (OR 1.64, 95% CI 1.18-2.28; p < 0.01) and lower MRI hippocampus volumes (OR 0.41, 95% CI 0.19-0.90; p = 0.03) resulted independently associated with fatigue in women, while higher frailty degrees (OR 3.10, 95% CI 1.27-7.54 per 0.1 increase in a 39-item Frailty index; p = 0.01) in men. Fatigue is a complex symptom with a sex-specific pattern of clinical and neurobiological correlates. A better understanding of the underlying mechanisms of these associations is warranted to develop sex-informed approaches for personalized treatments.

Maternal choline supplementation modulates cognition and induces anti-inflammatory signaling in the prefrontal cortices of adolescent rats exposed to maternal immune activation

Maternal infection has long been described as a risk factor for neurodevelopmental disorders, especially autism spectrum disorders (ASD) and schizophrenia. Although many pathogens do not cross the placenta and infect the developing fetus directly, the maternal immune response to them is sufficient to alter fetal neurodevelopment, a phenomenon termed maternal immune activation (MIA). Low maternal choline is also a risk factor for neurodevelopmental disorders, and most pregnant people do not receive enough of it. In addition to its role in neurodevelopment, choline is capable of inducing anti-inflammatory signaling through a nicotinic pathway. Therefore, it was hypothesized that maternal choline supplementation would blunt the neurodevelopmental impact of MIA in offspring through long-term instigation of cholinergic anti-inflammatory signaling.To model MIA in rats, the viral mimetic polyinosinic:polycytidylic acid (poly(I:C)) was used to elicit a maternal antiviral innate immune response in dams both with and without choline supplementation. Offspring were reared to both early and late adolescent stages (postnatal days 28 and 50, respectively), where anxiety-related behaviors and cognition were examined. After behavioral testing, animals were euthanized, and their prefrontal cortices (PFCs) were collected for analysis. MIA offspring demonstrated sex-specific patterns of altered cognition and repetitive behaviors, which were modulated by maternal choline supplementation. Choline supplementation also bolstered anti-inflammatory signaling in the PFCs of MIA animals at both early and late adolescent stages. These findings suggest that maternal choline supplementation may be sufficient to blunt some of the behavioral and neurobiological impacts of inflammatory exposures in utero, indicating that it may be a cheap, safe, and effective intervention for neurodevelopmental disorders.

Identifying sex from pharyngeal images using deep learning algorithm

The pharynx is one of the few areas in the body where blood vessels and immune tissues can readily be observed from outside the body non-invasively. Although prior studies have found that sex could be identified from retinal images using artificial intelligence, it remains unknown as to whether individuals’ sex could also be identified using pharyngeal images. Demographic information and pharyngeal images were collected from patients who visited 64 primary care clinics in Japan for influenza-like symptoms. We trained a deep learning-based classification model to predict reported sex, which incorporated a multiple instance convolutional neural network, on 20,319 images from 51 clinics. Validation was performed using 4869 images from the remaining 13 clinics not used for the training. The performance of the classification model was assessed using the area under the receiver operating characteristic curve. To interpret the model, we proposed a framework that combines a saliency map and organ segmentation map to quantitatively evaluate salient regions. The model achieved the area under the receiver operating characteristic curve of 0.883 (95% CI 0.866–0.900). In subgroup analyses, a substantial improvement in classification performance was observed for individuals aged 20 and older, indicating that sex-specific patterns between women and men may manifest as humans age (e.g., may manifest after puberty). The saliency map suggested the model primarily focused on the posterior pharyngeal wall and the uvula. Our study revealed the potential utility of pharyngeal images by accurately identifying individuals’ reported sex using deep learning algorithm.

An Empirical Dietary Pattern Associated With the Gut Microbial Features in Relation to Colorectal Cancer Risk

Background & AimsEpidemiologic evidence for dietary influence on colorectal cancer (CRC) risk through the gut microbiome remains limited. MethodsLeveraging 307 men and 212 women with stool metagenomes and dietary data, we characterized and validated a sex-specific dietary pattern associated with the CRC-related gut microbial signature (CRC Microbial Dietary Score [CMDS]). We evaluated the associations of CMDS with CRC risk according to Fusobacterium nucleatum, pks+Escherichia coli, and enterotoxigenic Bacteroides fragilis (ETBF) status in tumor tissue using Cox proportional hazards regression in the Health Professionals Follow-up Study (1986-2018), Nurses’ Health Study (NHS) (1984-2020), and NHS II (1991-2019). ResultsThe CMDS was characterized by high industrially processed foods and low unprocessed fiber-rich foods intakes. In 259,200 participants, we documented 3,854 incident CRC cases over 6,467,378 person-years of follow-up. CMDS was associated with a higher risk of CRC (Ptrend<0.001), with a multivariable hazard ratio (HRQ5vs.Q1) of 1.25 (95%CI, 1.13-1.39). The association remained after adjusting for previously established dietary patterns, e.g., the Western and prudent diets. Notably, the association was stronger for tumoral F. nucleatum-positive (HRQ5vs.Q1, 2.51; 95%CI, 1.68-3.75; Ptrend<0.001) (Pheterogeneity=0.03, positivity vs. negativity), pks+E. coli-positive (HRQ5vs.Q1, 1.68; 95%CI, 0.84-3.38; Ptrend=0.005) (Pheterogeneity=0.01, positivity vs. negativity), and ETBF-positive CRC (HRQ5vs.Q1, 2.06; 95%CI, 1.10-3.88; Ptrend=0.016) (Pheterogeneity=0.06, positivity vs. negativity), compared with their negative counterparts. ConclusionsCMDS was associated with increased CRC risk, especially for tumors with detectable F. nucleatum, pks+E. coli, and ETBF in tissue. Our findings support a potential role of the gut microbiome underlying the dietary effects on CRC.

The Uncoupling Effect of 17β-Estradiol Underlies the Resilience of Female-Derived Mitochondria to Damage after Experimental TBI.

Current literature finds females have improved outcomes over their male counterparts after severe traumatic brain injury (TBI), while the opposite seems to be true for mild TBI. This begs the question as to what may be driving these sex differences after TBI. Estrogen is thought to be neuroprotective in certain diseases, and its actions have been shown to influence mitochondrial function. Mitochondrial impairment is a major hallmark of TBI, and interestingly, this dysfunction has been shown to be more severe in males than females after brain injury. This suggests estrogen could be playing a role in promoting "mitoprotection" following TBI. Despite the existence of estrogen receptors in mitochondria, few studies have examined the direct role of estrogen on mitochondrial function, and no studies have explored this after TBI. We hypothesized ex vivo treatment of isolated mitochondria with 17β-estradiol (E2) would improve mitochondrial function after experimental TBI in mice. Total mitochondria from the ipsilateral (injured) and contralateral (control) cortices of male and female mice were isolated 24 h post-controlled severe cortical impact (CCI) and treated with vehicle, 2 nM E2, or 20 nM E2 immediately before measuring reactive oxygen species (ROS) production, bioenergetics, electron transport chain complex (ETC) activities, and β-oxidation of palmitoyl carnitine. Protein expression of oxidative phosphorylation (OXPHOS) complexes was also measured in these mitochondrial samples to determine whether this influenced functional outcomes with respect to sex or injury. While mitochondrial ROS production was affected by CCI in both sexes, there were other sex-specific patterns of mitochondrial injury 24 h following severe CCI. For instance, mitochondria from males were more susceptible to CCI-induced injury with respect to bioenergetics and ETC complex activities, whereas mitochondria from females showed only Complex II impairment and reduced β-oxidation after injury. Neither concentration of E2 influenced ETC complex activities themselves, but 20 nM E2 appeared to uncouple mitochondria isolated from the contralateral cortex in both sexes, as well as the injured ipsilateral cortex of females. These studies highlight the significance of measuring mitochondrial dysfunction in both sexes after TBI and also shed light on another potential neuroprotective mechanism in which E2 may attenuate mitochondrial dysfunction after TBI in vivo.

Daily rhythms in metabolic and locomotor behaviour of prematurely ageing PolgA mice.

Ageing is an inherent and intricate biological process that takes place in living organisms as time progresses. It involves the decline of multiple physiological functions, leading to body structure and overall performance modifications. The ageing process differs among individuals and is influenced by various factors, including lifestyle, environment and genetic makeup. Metabolic changes and reduced locomotor activity are common hallmarks of ageing. Our study focuses on exploring these phenomena in prematurely ageing PolgA(D257A/D257A) mice (also known as PolgA) aged 41-42 weeks, as they closely mimic human ageing. We assess parameters such as oxygen consumption (VO2), carbon dioxide production (VCO2), respiratory exchange ratio (RER) and locomotor activity using a metabolic cage for 4 days and comparing them with age-matched wild-type littermates (WT). Our findings revealed that VO2, VCO2, RER, locomotor activities, water intake and feeding behaviour show a daily rhythm, aligning with roughly a 24-h cycle. We observed that the RER was significantly increased in PolgA mice compared to WT mice during the night-time of the light-dark cycle, suggesting a shift towards a higher reliance on carbohydrate metabolism due to more food intake during the active phase. Additionally, female PolgA mice displayed a distinct phenotype with reduced walking speed, walking distance, body weight and grip strength in comparison to male PolgA and WT mice, indicating an early sign of ageing. Taken together, our research highlights the impact of sex-specific patterns on ageing traits in PolgA mice aged 41-42 weeks, which may be attributable to human ageing phenotypes. The unique genetic composition and accelerated ageing characteristics of PolgA mice make them invaluable in ageing studies, facilitating the investigation of underlying biological mechanisms and the identification of potential therapeutic targets for age-related diseases.

Worldwide burden of liver cancer across childhood and adolescence, 2000–2021: a systematic analysis of the Global Burden of Disease Study 2021

Liver cancer is a significant contributor to the global disease burden, of which hepatoblastomas are the most common liver tumors in children, with 90% of cases occurring within the first 5 years of life. It is important for pediatricians and subspecialists in pediatric gastroenterology and hepatology to have knowledge of the epidemiology and incidence trends of pediatric hepatic cancer, despite its rarity. In the present study, we first provide estimates of the incidence and mortality burden of hepatoblastoma and liver cancer from 2000 to 2021 in the childhood and adolescence. Liver cancer burden and its attributable risk factors were estimated using data from the Global Burden of Disease Study (GBD) 2021. Percentage change was estimated to show the trend of liver cancer estimates from 2000 to 2021. The age-standardized rate (ASR) and estimated annual percentage change (EAPC) were utilized for measuring hepatoblastomas incidence and deaths rate trends. In accordance with the GBD framework, 95% uncertainty intervals (UIs) for all estimates by averaging the data from 1000 draws, with the lower and upper bounds of the 95% UIs. Globally, from 2000 to 2021 in the age 5-19 years group, the incidence cases and deaths cases due to liver cancer decreased from 2449.2 (95% UI: 2235.9-2689.8) to 1692.9 (95% UI: 1482.0-1992.5) and 2248.5 (95% UI: 2053.7-2474.9) to 1516.6 (95% UI: 1322.1-1797.9), respectively. Meanwhile, from 2000 to 2021 in the age 20-24 years group, the incidence cases and deaths cases due to liver cancer decreased from 1453.5 (95% UI: 1327.8-1609.4) to 1285.1 (95% UI: 1159.2-1447.2) and 1432.3 (95% UI: 1307.6-1585.7) to 1195.5 (95% UI: 1066.1-1355.2), respectively. In addition, the prevalence of liver cancer decreased from 41.9% (95% UI: 18.7%-64.7%) to 26.4% (95% UI: 14.2%-39.1%) in the age 5-19 years group, and 46.6% (95% UI: 42.8%-51.5%) to 36.5% (95% UI: 33.1%-40.9%) in the age 20-24 years. From 2000 to 2021, in the age group of 5-19 years, the proportion of liver cancer incidence due to hepatitis B has decreased from 42.2% to 37.9%, while the proportion due to hepatitis C has increased from 1.1% to 1.6%. Additionally, there has been an increase in the proportion of NASH-induced liver cancer incidence from 5.2% to 9.4%, and alcohol use induced liver cancer incidence has also increased from 0.5% to 0.7% over the same period. Globally, from 2000 to 2021, the incidence cases and deaths cases due to hepatoblastoma decreased from 6131.8 (95%UI: 5234.8-6961.9) to 4045.6 (95% UI: 3250-4995.8) and 4059.2 (95% UI: 3494.5-4621.2) to 2416 (95% UI: 1940.2-3022.5), respectively. There was some variation in age-related sex-specific patterns, the highest number of hepatoblastoma incidence cases occurred in children between 2 and 4 years old and females in the age range of 12 months to 9 years had a higher number of new cases. Importantly, the incidence of hepatoblastoma was started to increase sharply after the age of 1 month. The results of the present study are significant for liver health policy and practice in childhood and adolescence. Differentiated intervention and outreach strategies based on age and gender would be necessary to reduce the impact of liver cancer. Early screening and interventions for hepatoblastoma is important especially in the population of under 9 years old. This study was supported by the National Key R&D Program of China (grant numbers 2023YFC2307000), National Natural Science Foundation of China [grant numbers 82170571 and 81974068], China Postdoctoral Science Foundation (grant numbers 2023M741283).

Chemoreflex sensitization occurs in both male and female rats during recovery from acute lung injury.

Sex-specific patterns in respiratory conditions, such as asthma, COPD, cystic fibrosis, obstructive sleep apnea, and idiopathic pulmonary fibrosis, have been previously documented. Animal models of acute lung injury (ALI) have offered insights into sex differences, with male mice exhibiting distinct lung edema and vascular leakage compared to female mice. Our lab has provided evidence that the chemoreflex is sensitized in male rats during the recovery from bleomycin-induced ALI, but whether sex-based chemoreflex changes occur post-ALI is not known. To bridge this gap, the current study employed the bleomycin-induced ALI animal model to investigate sex-based differences in chemoreflex activation during the recovery from ALI. ALI was induced using a single intra-tracheal instillation of bleomycin (bleo, 2.5mg/Kg) (day 1). Resting respiratory frequency (fR) was measured at 1-2 days pre-bleo, day 7 (D7) post-bleo, and 1 month (1 mth) post-bleo. The chemoreflex responses to hypoxia (10% O2, 0% CO2) and normoxic-hypercapnia (21% O2, 5% CO2) were measured before bleo administration (pre-bleo) and 1 mth post-bleo using whole-body plethysmography. The apnea-hypopnea Index (AHI), post-sigh apneas, and sighs were measured at each time point. There were no significant differences in resting fR between male and female rats at the pre-bleo time point or in the increase in resting fR at D7 post-bleo. At 1 mth post-bleo, the resting fR was partially restored in both sexes but the recovery towards normal ranges of resting fR was significantly lower in male rats. The AHI, post-sigh apneas, and sighs were not different between male and female rats pre-bleo and 1 mth post-bleo. However, at D7 post-bleo, the male rats exhibited a higher AHI than female rats. Both male and female rats exhibited a sensitized chemoreflex in response to hypoxia and normoxic-hypercapnia with no significant differences between sexes. A sex difference in resting ventilatory parameters occurs post ALI with a prolonged increase in resting fR and larger AHI in male rats. On the other hand, we did not find any sex differences in the chemoreflex sensitization that occurs at 1 mth post-bleo. This work contributes to a better understanding of sex-based variations in lung disorders.

Hearing, Balance, and Mortality: Sex-Specific Patterns in a Longitudinal Study.

Assess the association of hearing on sex-specific overall mortality and death from acute cardiovascular disease and evaluate if these effects are modulated by postural balance. Cohort study. Otolaryngology department at an academic hospital. Patients underwent standard clinical examination, laboratory examination including stabilometry and audiometry. Pure tone average on the best hearing ear was calculated from 0.5, 1, 2, and 3 kHz. Cause of death was retrieved from the Norwegian Cause of Death Registry. A total of 1036 patients (58.8% women) were followed for 26 ± 3 years. In Cox regression analyses for overall mortality adjusted for age, past medical history, and vestibular disease, 10 dB increase in hearing threshold was associated with a 14% increase in mortality among men (hazard ratio 95% confidence interval: 1.02-1.28, P = .02), but no significant association was seen between hearing and mortality in women (0.92-1.15, P = .60). The same analyses for acute cardiovascular death found that a 10 dB increase in hearing threshold was associated with a 57% increase in hazard ratio in men (1.21-2.05, P < .001), but no significant effect of hearing on survival was seen in women (P = .71). Adjusting for postural balance did not change the association between hearing and mortality. This study finds hearing threshold is associated with overall mortality and acute cardiovascular death among men, with no such association observed among women. Our findings indicate important differences between men and women and suggest that such differences should be taken into consideration in audiological research.

Effects of Testosterone on Gene Expression Are Concordant between Sexes but Divergent across Species of Sceloporus Lizards.

AbstractHormones mediate sexual dimorphism by regulating sex-specific patterns of gene expression, but it is unclear how much of this regulation involves sex-specific hormone levels versus sex-specific transcriptomic responses to the same hormonal signal. Moreover, transcriptomic responses to hormones can evolve, but the extent to which hormonal pleiotropy in gene regulation is conserved across closely related species is not well understood. We addressed these issues by elevating testosterone levels in juvenile females and males of three Sceloporus lizard species before sexual divergence in circulating testosterone and then characterizing transcriptomic responses in the liver. In each species, more genes were responsive to testosterone in males than in females, suggesting that early developmental processes prime sex-specific transcriptomic responses to testosterone later in life. However, overall transcriptomic responses to testosterone were concordant between sexes, with no genes exhibiting sex-by-treatment interactions. By contrast, hundreds of genes exhibited species-by-treatment interactions, particularly when comparing distantly related species with different patterns of sexual dimorphism, suggesting evolutionary lability in gene regulation by testosterone. Collectively, our results indicate that early organizational effects may lead to sex-specific differences in the magnitude, but not the direction, of transcriptomic responses to testosterone and that the hormone-genome interface accrues regulatory changes over evolutionary time.

Sex-specific overdominance at the maturation vgll3 gene for reproductive fitness in wild Atlantic salmon.

Linking reproductive fitness with adaptive traits at the genomic level can shed light on the mechanisms that produce and maintain sex-specific selection. Here, we construct a multigenerational pedigree to investigate sex-specific selection on a maturation gene, vgll3, in a wild Atlantic salmon population. The vgll3 locus is responsible for ~40% of the variation in maturation (sea age at first reproduction). Genetic parentage analysis was conducted on 18,265 juveniles (parr) and 685 adults collected at the same spawning ground over eight consecutive years. A high proportion of females (26%) were iteroparous and reproduced two to four times in their lifetime. A smaller proportion of males (9%) spawned at least twice in their lifetime. Sex-specific patterns of reproductive fitness were related to vgll3 genotype. Females showed a pattern of overdominance where vgll3*EL genotypes had three-fold more total offspring than homozygous females. In contrast, males demonstrated that late-maturing vgll3*LL individuals had two-fold more offspring than either vgll3*EE or vgll3*EL males. Taken together, these data suggest that balancing selection in females contributes to the maintenance of variation at this locus via increased fitness of iteroparous vgll3*EL females. This study demonstrates the utility of multigenerational pedigrees for uncovering complex patterns of reproduction, sex-specific selection and the maintenance of genetic variation.