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Background and Aim: The global burden of gallbladder and biliary tract cancer (GBTC) has been on the rise, making it a major public health concern. We aim to comprehensively analyze sex disparities in the temporal trends of GBTC incidence, mortality, and disability‐adjusted life years (DALYs) regionally and globally from 2010 to 2019. Methods: Age‐standardized rates of GBTC incidence, death, and DALYs were analyzed utilizing the Global Burden of Disease study 2019. Results: From 2010 to 2019, the estimated annual percent change (APC) of the age‐standardized incidence rates (ASIRs) and age‐standardized disability‐adjusted life years (ASDALYs) due to GBTC globally decreased in both sexes (males, APC: −0.80%; APC: −1.00%) and (females, APC: −0.89%; APC: −0.96%). At the same time, age‐standardized death rates (ASDRs) decreased only in males (APC: −0.82%) and remained stable in females. By regions, ASIRs and ASDR increased in both sexes only in Southeast Asia (SEA) but decreased in the other regions. All regions had decreased ASDALYs except for an increase in ASDALYs for females only in the SEA region (APC: 0.41%), and males have a stable trend. Conclusions: Our study reveals substantial geographic variance in the burden of GBTC, specifically in the SEA region. Therefore, localized interventional methodologies must be undertaken to effectively address this global burden from GBTC. [ABSTRACT FROM AUTHOR]

Introduction: Thyroid cancer is more commonly diagnosed in females, however recent research has challenged whether this finding is due to a true difference in biology or rates of diagnosis, with concerns that over‐diagnosis may be a factor in differences. The rates of symptomatic versus incidental diagnosis by males and females is not well known. This study used the Australian and New Zealand Thyroid Cancer Registry (ANZTCR) to explore whether symptomatic presentation varies between sexes. Materials and Methods: Retrospective analysis on ANZTCR data between 2017 and 2022 was performed. Symptomatic cases were those with thyroid compressing symptoms, toxic goiter, Graves' disease, or abnormal laryngoscopy. Cases with asymptomatic goiter or surgeries for a thyroid nodule were classified as incidental. Results: Among 1082 patients with differentiated thyroid cancer, 32% of males and 38% of females presented with symptomatic thyroid disease (p = 0.06). A similar rate of presentation of advanced thyroid cancer (T3/4) was seen with male and female patients (n = 70, 47% vs. n = 79, 53%). Females exhibited a higher prevalence of low‐risk relapse cancers according to American Thyroid Association stratification (66.3% vs. 50.4%), whereas males exhibited a higher prevalence of high‐risk relapse cancers compared to females (27.3% vs. 15.3%, p < 0.001). Regression showed symptoms were associated with more advanced T stage (OR = 1.62, p = 0.02). Discussion: Symptomatic presentation was similar between males and females, but symptomatic presentation was associated with larger cancers. Conclusion: This study highlights comparable rates of symptomatic detection between males and females with DTCs and symptomatic presentations were responsible for less than 40% of presentations. [ABSTRACT FROM AUTHOR]

Aim: To evaluate sex differences in gastric emptying and the glycaemic response to a glucose drink and a high carbohydrate meal in type 2 diabetes (T2D). Methods: In cohort 1, 70 newly diagnosed, treatment‐naïve Chinese patients with T2D (44 men) recruited from a diabetes outpatient clinic ingested a 75‐g glucose drink containing 150 mg 13C‐acetate. In cohort 2, 101 Australian patients with T2D (67 male) recruited from the community, managed by diet and/or metformin monotherapy, ingested a semi‐solid mashed potato meal, labelled with 100 μl 13C‐octanoic acid. Breath samples were collected over 3 and 4 h, respectively, for assessment of gastric emptying, and venous blood was sampled for evaluation of glycaemia (with and without adjustment for each participant's estimated total blood volume). Results: Gastric emptying was slower in female than male subjects in both cohorts (both p <.01). Multiple linear regression analyses revealed that gastric emptying was independently associated with sex (both p <.05). Without adjustment for blood volume, the glycaemic responses to oral glucose and the mixed meal were greater in female subjects (both p <.001). However, after adjustment for blood volume, the glycaemic responses were greater in men (both p <.05). Conclusions: Gastric emptying is slower in women than men with T2D, associated with a reduced blood volume‐adjusted glycaemic response to oral glucose and a mixed meal in women. These observations highlight the sex difference in postprandial glucose handling, which is relevant to the personalized management of postprandial glycaemia in T2D. [ABSTRACT FROM AUTHOR]

Aim: Interleukin (IL)‐10 and IL‐12 contribute to immune responses against hepatitis B virus (HBV) infection. Polymorphisms in the IL‐10 and IL‐12A genes might affect the clinical outcome of HBV infection. We evaluated the association of IL‐10 rs1800896 and rs3024490, and IL‐12A rs568408 and rs2243115 with the progression of HBV infection and development of severe liver disease stages in a white European population. Method: A total of 636 white European patients with chronic HBV infection, 239 individuals with spontaneous HBV surface antigen seroclearance, and 254 healthy controls were enrolled. The chronic HBV infection group included patients with hepatitis B envelope antigen (HBeAg) negative chronic hepatitis B (n = 255), with HBeAg positive chronic hepatitis B (n = 99) and with HBeAg negative HBV infection (n = 228). A total of 104 chronically infected patients were diagnosed with liver cirrhosis. Serum levels of cytokines were measured in patients with HBV infection (n = 195) and in healthy controls (n = 160). Results: In adjusted multivariate analysis, the IL‐10 rs1800896 AG/GG genotypes were significantly associated with an increased probability of HBV surface antigen seroclearance (OR = 1.75, 95% CI 1.04–2.94, p = 0.034), with an increased likelihood of HBeAg negative chronic infection (OR = 1.93, 95% CI 1.05–3.54, p = 0.034) and with increased serum cytokines levels in female patients. In contrast, the IL‐12A rs568408 AG/AA genotypes were independently associated with an increased risk to develop liver cirrhosis, with an OR of 1.90 (95% CI 1.07–3.39, p = 0.029) in male patients. Conclusion: The current study shows a sex‐related association of the IL‐10 single‐nucleotide polymorphism rs1800896 and IL‐12A single‐nucleotide polymorphism rs568408 with different stages of HBV infection and with HBV‐related liver cirrhosis in white European patients. [ABSTRACT FROM AUTHOR]

Background: Acute myocardial infarction (AMI) and colon cancer share similar risk factors. Studies have suggested an association between AMI and colon cancer; however, evidence is conflicting. Whether sex disparities exist in this association in the real world remains unknown. Methods: In this population‐based retrospective cohort study, 94,780 and 97,987 male patients and 38,697 and 72,007 female patients with and without new‐onset AMI, respectively, from January 1, 2001, to December 31, 2012, were enrolled from Taiwan's National Health Insurance Research Database. Inverse probability of treatment weighting (IPTW) was used to balance covariates across study groups. The primary outcome was a new diagnosis of colon cancer. Results: The incidence rate of colon cancer was 1.54 (95% confidence interval [CI] = 1.46–1.62) and 1.40 (95% CI = 1.32–1.48) per 1000 person‐years in the male patients and 1.62 (95% CI = 1.50–1.74) and 1.22 (95% CI = 1.13–1.32) in the female patients, in the AMI and non‐AMI groups, respectively. AMI was associated with a significantly higher risk of colon cancer in the female patients (hazard ratio [HR] = 1.31, 95% CI = 1.06–1.61) but not in the male patients (HR = 1.09, 95% CI = 0.95–1.26). In the subgroup analysis, the association between AMI and colon cancer in the female patients was stronger in those aged ≥65 years (HR = 1.28, 95% CI = 1.13–1.44). Conclusions: An increased risk of colon cancer was observed only in the female patients with AMI. The association between AMI and colon cancer in the female patients was the most evident in those aged ≥65 years. [ABSTRACT FROM AUTHOR]

Sex differences play a relevant role in cancer susceptibility, incidence and survival. Exploring such differences is difficult because of the close interplay of genetic, epigenetic and hormonal factors. However, a better understanding of the role of such disparities in cancer mechanisms could improve its prevention and therapy. Our study explores how sex differences in pediatric outcomes vary after undergoing first and advanced‐line therapy for hematological malignancies. The primary goal was to evaluate if sex differences in pediatric outcomes after first‐line therapy persist after allogeneic hematopoietic stem cell transplantation (HSCT). The secondary goal was to analyze sex differences in disease risk at onset and pediatric outcomes after first‐line therapy to compare our results with the literature's reported results. Among a total of 485 patients (280 males, 205 females) admitted for hematological malignancies, disease risk at the onset was significantly higher in males (P <.05). One hundred and seventy‐four patients (111 males and 63 females) had a high‐risk disease requiring HSCT. Before HSCT, all patients underwent myeloablative conditioning, which substantially impaired gonadal function. Although the number of boys undergoing HSCT was almost double that of girls, there were no sex‐related differences in overall survival, cancer relapse and complications after HSCT exposure (P >.05). These findings suggest that the existing sex differences in cancer risk ab initio can be somehow flattened by a conditioning regimen, shedding new light on the role of hormonal factors in cancer mechanism and management. [ABSTRACT FROM AUTHOR]

Background/Purpose: We aimed to verify a recent theory that female donors reduced the risk of hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT). Methods: A total of 1118 recipients registered in the Japanese Liver Transplantation Society database were evaluated for HCC, of whom 446 received a graft from female donors (F‐D group) and 672 from male donors (M‐D group). Results: Between the groups, donor age, recipient age and sex, positivity of hepatitis viruses, and graft type were different, whereas tumor‐related factors were all comparable. The 5‐year overall recurrence rates were 14% and 16% in the F‐D and M‐D groups, respectively (P = 0.59). The 5‐year graft recurrence rate was also comparable between the groups (4% and 6%, respectively, P = 0.17). Neither univariate nor multivariate analysis identified donor sex as a significant risk factor for recurrence. Propensity score matching showed similar 5‐year overall recurrence rates (15% in the F‐D group and 14% in the M‐D group, P = 0.63) and graft recurrence rates (5% and 5%, respectively, P = 0.94) between the groups. Conclusion: Donor sex did not affect post‐LT recurrence of HCC in the Japanese cohort and should not be considered in the process of donor selection or organ allocation. [ABSTRACT FROM AUTHOR]

Summary: Sex disparities in the incidence‐arrest statistics for juvenile thieves may stem from preconceived stereotypes impacting bystanders' social‐cognitive processing of a bicycle theft. After reading vignettes describing a bicycle theft, bystanders' reliance on male‐as‐juvenile‐thief stereotypes enhanced their recall of crime and appearance features for the male thief and in their interpretation of his intimidation of a child victim. Bystander sex also affected the results by enhancing appearance recall for the same sex thief. Women interpreted the intentions of the adolescent thieves as stealing, whereas men interpreted the intentions as borrowing. Bystanders endorsed the decision for the father to bring the stolen bicycle to the attention of the police, especially when the victim was a girl, and agreed the police should be involved. The bystanders would be credible witnesses as they could provide the actus reus and mens rea to support a case of larceny‐theft and describe the thief. [ABSTRACT FROM AUTHOR]

Incidence, molecular presentation and outcome of acute myeloid leukaemia (AML) are influenced by sex, but little attention has been directed at untangling sex‐related molecular and phenotypic differences between female and male patients. While increased incidence and poor risk are generally associated with a male phenotype, the poor prognostic FLT3 internal tandem duplication (FLT3‐ITD) mutation and co‐mutations with NPM1 and DNMT3A are overrepresented in female AML. Here, we have investigated the relationship between sex and FLT3‐ITD mutation status by comparing clinical data, mutational profiles, gene expression and ex vivo drug sensitivity in four cohorts: Beat AML, LAML‐TCGA and two independent HOVON/SAKK cohorts, comprising 1755 AML patients in total. We found prevalent sex‐associated molecular differences. Co‐occurrence of FLT3‐ITD, NPM1 and DNMT3A mutations was overrepresented in females, while males with FLT3‐ITDs were characterized by additional mutations in RNA splicing and epigenetic modifier genes. We observed diverging expression of multiple leukaemia‐associated genes as well as discrepant ex vivo drug responses, suggestive of discrete functional properties. Importantly, significant prognostication was observed only in female FLT3‐ITD‐mutated AML. Thus, we suggest optimization of FLT3‐ITD mutation status as a clinical tool in a sex‐adjusted manner and hypothesize that prognostication, prediction and development of therapeutic strategies in AML could be improved by including sex‐specific considerations. [ABSTRACT FROM AUTHOR]

Background: Group 2 innate lymphoid cells (ILC2) are stimulated by IL‐33 to increase IL‐5 and IL‐13 production and airway inflammation. While sex hormones regulate airway inflammation, it remained unclear whether estrogen signaling through estrogen receptor‐α (ER‐α, Esr1) or ER‐β (Esr2) increased ILC2‐mediated airway inflammation. We hypothesize that estrogen signaling increases allergen‐induced IL‐33 release, ILC2 cytokine production, and airway inflammation. Methods: Female Esr1‐/‐, Esr2‐/‐, wild‐type (WT), and IL33fl/fleGFP mice were challenged with Alternaria extract (Alt Ext) or vehicle for 4 days. In select experiments, mice were administered tamoxifen or vehicle pellets for 21 days prior to challenge. Lung ILC2, IL‐5 and IL‐13 production, and BAL inflammatory cells were measured on day 5 of Alt Ext challenge model. Bone marrow from WT and Esr1‐/‐ female mice was transferred (1:1 ratio) into WT female recipients for 6 weeks followed by Alt Ext challenge. hBE33 cells and normal human bronchial epithelial cells (NHBE) were pretreated with 17β‐estradiol (E2), propyl‐pyrazole‐triol (PPT, ER‐α agonist), or diarylpropionitrile (DPN, ER‐β agonist) before allergen challenge to determine IL‐33 gene expression and release, extracellular ATP release, DUOX‐1 production, and necrosis. Results: Alt Ext challenged Esr1‐/‐, but not Esr2‐/‐, mice had decreased IL‐5 and IL‐13 production, BAL eosinophils, and IL‐33 release compared to WT mice. Tamoxifen decreased IL‐5 and IL‐13 production and BAL eosinophils. IL‐33eGFP + epithelial cells were decreased in Alt Ext challenged Esr1‐/‐ mice compared to WT mice. 17β‐E2 or PPT, but not DPN, increased IL‐33 gene expression, release, and DUOX‐1 production in hBE33 or NHBE cells. Conclusion: Estrogen receptor ‐α signaling increased IL‐33 release and ILC2‐mediated airway inflammation. [ABSTRACT FROM AUTHOR]

Background and purpose: Unexpected stressful life events may alter immune function and affect susceptibility to autoimmune diseases including multiple sclerosis (MS). Current results from epidemiological investigations examining the role of stress in MS remain inconsistent. The aim was to conduct the hitherto largest population‐based case–control study on this topic. Methods: Extensive questionnaire information collected on lifestyle environmental factors available for 2930 incident MS cases and 6170 controls were used to assess the association of 10 major life events that had occurred before disease onset with the risk of MS by unconditional logistic regressions, adjusting for potential confounders. Stratified analyses were also performed by sex and time. Results: Compelling evidence was found for a link between major life events and risk of MS – most events significantly increased disease risk by 17%–30%. It was further observed that women were affected to a greater extent than men under certain stressful scenarios, and that most events that happened recently (≤5 years prior to MS onset) had significant effects on MS, indicating a critical window in disease development. Conclusion: Stressful life events may have an adverse effect on the risk of MS. Research into the mechanisms of this observation may give important clues to triggering pathogenetic events in MS. [ABSTRACT FROM AUTHOR]

Background Knowledge gaps remain in how gender-related socioeconomic inequality affects sex disparities in cardiovascular diseases (CVD) prevention and outcome. Methods and Results Based on a nationwide population cohort, we enrolled 3 737 036 residents aged 35 to 75 years (2014-2021). Age-standardized sex differences and the effect of gender-related socioeconomic inequality (Gender Inequality Index) on sex disparities were explored in 9 CVD prevention indicators. Compared with men, women had seemingly better primary prevention (aspirin usage: relative risk [RR], 1.24 [95% CI, 1.18-1.31] and statin usage: RR, 1.48 [95% CI, 1.39-1.57]); however, women's status became insignificant or even worse when adjusted for metabolic factors. In secondary prevention, the sex disparities in usage of aspirin (RR, 0.65 [95% CI, 0.63-0.68]) and statin (RR, 0.63 [95% CI, 0.61-0.66]) were explicitly larger than disparities in usage of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (RR, 0.88 [95% CI, 0.84-0.91]) or β blockers (RR, 0.67 [95% CI, 0.63-0.71]). Nevertheless, women had better hypertension awareness (RR, 1.09 [95% CI, 1.09-1.10]), similar hypertension control (RR, 1.01 [95% CI, 1.00-1.02]), and lower CVD mortality (hazard ratio, 0.46 [95% CI, 0.45-0.47]). Heterogeneities of sex disparities existed across all subgroups. Significant correlations existed between regional Gender Inequality Index values and sex disparities in usage of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (Spearman correlation coefficient, r =-0.57, P =0.0013), hypertension control ( r =-0.62, P =0.0007), and CVD mortality ( r =0.45, P =0.014), which remained significant after adjusting for economic factors. Conclusions Notable sex disparities remain in CVD prevention and outcomes, with large subgroup heterogeneities. Gendered socioeconomic factors could reinforce such disparities. A sex-specific perspective factoring in socioeconomic disadvantages could facilitate more targeted prevention policy making.

Background Prior studies have shown that women have worse 3-month survival after receiving a left ventricular assist device compared with men. Currently used prognostic scores, including the Heartmate II Risk Score, do not account for the increased residual risk in women. We used the IMACS (International Society for Heart and Lung Transplantation Mechanically Assisted Circulatory Support) registry to create and validate a sex-specific risk score for early mortality in left ventricular assist device recipients. Methods and Results Adult patients with a continuous-flow LVAD from the IMACS registry were randomly divided into a derivation cohort (DC; n=9113; 21% female) and a validation cohort (VC; n=6074; 21% female). The IMACS Risk Score was developed in the DC to predict 3-month mortality, from preoperative candidate predictors selected using the Akaike information criterion, or significant sex × variable interaction. In the DC, age, cardiogenic shock at implantation, body mass index, blood urea nitrogen, bilirubin, hemoglobin, albumin, platelet count, left ventricular end-diastolic diameter, tricuspid regurgitation, dialysis, and major infection before implantation were retained as significant predictors of 3-month mortality. There was significant ischemic heart failure × sex and platelet count × sex interaction. For each quartile increase in IMACS risk score, men (odds ratio [OR], 1.86; 95% CI, 1.74-2.00; P <0.0001), and women (OR, 1.93; 95% CI, 1.47-2.59; P <0.0001) had higher odds of 3-month mortality. The IMACS risk score represented a significant improvement over Heartmate II Risk Score (IMACS risk score area under the receiver operating characteristic curve: men: DC, 0.71; 95% CI, 0.69-0.73; VC, 0.69; 95% CI, 0.66-0.72; women: DC, 0.73; 95% CI, 0.70-0.77; VC, 0.71 [95% CI, 0.66-0.76; P <0.01 for improvement in receiver operating characteristic) and provided excellent risk calibration in both sexes. Removal of sex-specific interaction terms resulted in significant loss of model fit. Conclusions A sex-specific risk score provides excellent risk prediction in LVAD recipients.

Background: We examined the influence of sex, ethnicity, and time on competing cardiovascular and noncardiovascular causes of death following acute myocardial infarction in a multiethnic Asian cohort., Methods and Results: For 12 years, we followed a prospective nationwide cohort of 15 151 patients (aged 22-101 years, median age 63 years; 72.3% male; 66.7% Chinese, 19.8% Malay, 13.5% Indian) who were hospitalized for acute myocardial infarction between 2000 and 2005. There were 6463 deaths (4534 cardiovascular, 1929 noncardiovascular). Compared with men, women had a higher risk of cardiovascular death (age-adjusted hazard ratio [HR] 1.3, 95% CI 1.2-1.4) but a similar risk of noncardiovascular death (HR 0.9, 95% CI 0.8-1.0). Sex differences in cardiovascular death varied by ethnicity, age, and time. Compared with Chinese women, Malay women had the greatest increased hazard of cardiovascular death (HR 1.4, 95% CI 1.2-1.6) and a marked imbalance in death due to heart failure or cardiomyopathy (HR 3.4 [95% CI 1.9-6.0] versus HR 1.5 [95% CI 0.6-3.6] for Indian women). Compared with same-age Malay men, Malay women aged 22 to 49 years had a 2.5-fold (95% CI 1.6-3.8) increased hazard of cardiovascular death. Sex disparities in cardiovascular death tapered over time, least among Chinese patients and most among Indian patients; the HR comparing cardiovascular death of Indian women and men decreased from 1.9 (95% CI 1.5-2.4) at 30 days to 0.9 (95% CI 0.5-1.6) at 10 years., Conclusion: Age, ethnicity, and time strongly influence the association between sex and specific cardiovascular causes of mortality, suggesting that health care policy to reduce sex disparities in acute myocardial infarction outcomes must consider the complex interplay of these 3 major modifying factors., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)