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Sex-Based Disparities in Fabry Disease Cause Challenges in Newborn Screening.

INTRODUCTION: Fabry disease (FD) is a multi-systemic, X-linked lysosomal storage disorder caused by decreased &#x3b1;-galactosidase activity. Early diagnosis enables timely treatment, but enzyme-based newborn screening (NBS) may not detect affected females. We hypothesized that enzyme-based NBS limitations contribute to sex-based diagnostic disparities in FD and investigated these differences. METHODS: Retrospective cohort analyses used data from the Fabry Registry (FR: 2001-2023) and Tennessee NBS (2017-2024). Sex differences in diagnosis via NBS, biochemical phenotype, symptom onset, and treatment initiation were analyzed using Wilcoxon and chi-square tests. RESULTS: Among 8,657 FR individuals, 73 (67 males, 6 females) were identified via NBS. FR data show that affected females had significantly higher residual &#x3b1;-galactosidase activity than affected males (leukocyte median: 45.9% vs. 3.9%, plasma median: 32.5% vs. 3.9%; p < 0.0001 for both). FR females had delayed symptom onset (18.1 vs. 11.1 years), later diagnosis (35.5 vs. 30.8 years), and lower treatment rates (51.1% vs. 80.8%) compared to males (all %, p < 0.0001). Tennessee NBS detected 25 males but no females. CONCLUSION: Females with FD have delays in symptom onset, diagnosis, and treatment compared to males. Furthermore, higher residual enzyme activity causes current enzyme-based NBS to miss most females. Incorporating sex-specific cutoffs and/or molecular sequencing into NBS could improve early detection and reduce sex-based disparities.

Humans↗

Disparate effects of insulin reduction with diltiazem on serum dehydroepiandrosterone sulfate levels in obese hypertensive men and women.

Evidence suggests that amelioration of hyperinsulinemic insulin resistance in men with calcium channel blockers of the dihydropyridine class is associated with a fall in serum insulin and a rise in serum dehydroepiandrosterone sulfate (DHEA-S) concentrations. The present study was conducted to determine whether 1) the nondihydropyridine calcium channel blocker diltiazem also reduces circulating insulin levels in humans, and 2) a reduction in circulating insulin with a calcium channel blocker is associated with a rise in serum DHEA-S concentrations in women as well as men. Ten obese hypertensive men and 13 obese hypertensive postmenopausal women were studied. Subjects were assessed at baseline and after the oral administration of diltiazem (60 mg, three times daily) for 18 days. Diltiazem treatment was associated with reductions in fasting serum insulin levels in both the men (from 91 +/- 14 to 56 +/- 12 pmol/L; P < 0.03) and women (from 92 +/- 20 to 48 +/- 9 pmol/L; P = 0.05). Serum glucose levels did not change in either group. In men, concurrent with the fall in serum insulin levels, serum DHEA-S levels rose from 4.05 +/- 1.06 to 6.91 +/- 1.32 mumol/L (P < 0.04), and serum DHEA levels rose from 14.4 +/- 3.0 to 24.3 +/- 4.6 nmol/L (P = 0.05) with diltiazem treatment, whereas serum cortisol did not change. In contrast, diltiazem administration in the women was not associated with any change in serum DHEA-S, DHEA, or cortisol levels. These observations suggest that the action of calcium channel blockers to lower fasting serum insulin levels is not specific for the dihydropyridine class and applies to both men and women. Furthermore, the finding of a sex-based disparity in DHEA-S and DHEA responses to insulin reduction suggests that the metabolism of these steroids may be regulated differently in men than in women.

Adult↗

Sex-based differences in the tensile properties of the human anterior cruciate ligament.

After immense amounts of research, the root cause for the significantly higher rates of anterior cruciate ligament (ACL) failure incidents in females as compared to males still remains unknown and the existing sex-based disparity has not diminished. To date, the possibility that the female ACL is mechanically weaker than the male ACL has not been directly investigated. Although it has been established in the literature that the female ACL is smaller in size, the differences in the structural and material properties of the ACL between sexes have not been studied. The aim of this cadaveric study was to determine if any sex-based differences in the tensile properties of the human ACL exist when considering age as well as ACL and body anthropometric measurements as covariates. Ten male and 10 female unpaired cadaveric knees (mean age 36.75 years) were used for this study. The geometry of the ACL (including length, cross-sectional area, and volume) was analyzed using a 3-D scanning system. The femur-ACL tibia complex was tested to failure along the longitudinal axis of the ligament in a tensile testing machine. The structural properties of the ACL as well as its mechanical properties were determined. Analysis of covariance was performed to assess the effect of sex on tensile properties. The female ACL was found to have a lower mechanical properties (8.3% lower strain at failure; 14.3% lower stress at failure, 9.43% lower strain energy density at failure, and most importantly, 22.49% lower modulus of elasticity) when considering age, ACL, and body anthropometric measurements as covariates.

Adolescent↗

Comprehensive assessment of genomic heterogeneity, coalterations, and outcomes of patients with colorectal cancer: An AACR GENIE project analysis.

INTRODUCTION: Colorectal cancer remains a leading cause of cancer mortality in the United States and can be characterized by racial and sex-based disparities. The objective of the current study was to characterize the genomic heterogeneity of colorectal cancer among diverse demographic groups, assess coalteration patterns and their impact on long-term outcomes among patients with colorectal cancer. METHODS: Data from the American Association for Cancer Research GENIE registry were analyzed to assess genomic alterations in colorectal cancer. The cohort included 20,542 samples from 19,542 patients, stratified by race or ethnicity, sex, and age of onset (<50 years for early-onset colorectal cancer). Genomic alterations and coalterations among the 48 most prevalent loci were evaluated for any association with overall survival in an external Memorial Sloan Kettering Cancer Center cohort. RESULTS: Among 19,542 patients, KRAS mutations were more prevalent among Black patients (57.1%) compared with White (41.8%) and Asian (43.4%) patients (P < .001), whereas TP53 alterations were more frequent among Asian (75.6%) than White (69.9%) or Black (71.9%) patients (P < .001). Coalterations with KRAS were associated with improved survival over KRAS alteration alone, a pattern less-frequently observed among Black patients. Sex-based differences were also observed, with BRAF mutations more prevalent among females (14.6% vs 9.7%; P < .001) and TP53 mutations more common among males (73% vs 70.5%;P = .009). Although KRAS alterations tended to co-occur with alterations in ATM, ARID1A, CREBBP, FAT1, KMT2B, and KMT2D genes among patients with "early onset" colorectal cancer (all p & q < 0.05), alterations of these gene pairs were mutually exclusive among individuals with late onset colorectal cancer. CONCLUSION: Genomic alterations and coalteration patterns varied relative to race/ethnicity, sex, and age at disease onset. Differences in genomic alteration patterns of colorectal cancer somatic tumor cells are an important consideration to help address disparities among different demographic groups.

Humans↗

Cardiac pathologic findings reveal a high rate of sudden cardiac death of undetermined etiology in younger women.

BACKGROUND: Between 1989 and 1998 there was a 21% increase in estimated sudden cardiac death among US women aged 35 to 44 years. In contrast, the sudden cardiac death rate in age-matched men showed a decreasing trend (-2.8%). Due to under-representation of younger adults in published autopsy series, etiologies of sudden cardiac death merit further investigation. METHODS: We reviewed autopsy and detailed cardiac pathologic findings in younger women (age 35-44 years) from a 270-patient, 13-year (1984-1996) autopsy series of sudden cardiac death, and performed comparisons with findings in age-matched men. RESULTS: Women aged 35 to 44 years constituted 32% of all women in the series compared to men, who constituted 24% of total men (P =.004 vs women). A presumptive cause of sudden cardiac death could not be determined in 13 women (50%). Among women, 6 cases (22%) had significant coronary artery disease. Findings in others included coronary artery anomalies (n = 3), myocarditis (n = 2), hypertrophic cardiomyopathy (n = 1), coronary artery dissection (n = 1) and accessory pathway (n = 1). In younger men, a presumptive cause of sudden cardiac death remained undetermined in only 24% (P =.025 vs younger women), and coronary artery disease accounted for 40% of cases. CONCLUSIONS: In younger women, despite autopsy and detailed cardiac pathologic examination, an attributable cause of sudden cardiac death was not determined in 50% of cases; a 2-fold increase compared to men of the same age. Given the dynamic and multifactorial nature of sudden cardiac death, comprehensive population-based investigations are likely to be necessary to further investigate this unexpected sex-based disparity.

Adult↗

Sex differences in brain activation elicited by humor.

With recent investigation beginning to reveal the cortical and subcortical neuroanatomical correlates of humor appreciation, the present event-related functional MRI (fMRI) study was designed to elucidate sex-specific recruitment of these humor related networks. Twenty healthy subjects (10 females) underwent fMRI scanning while subjectively rating 70 verbal and nonverbal achromatic cartoons as funny or unfunny. Data were analyzed by comparing blood oxygenation-level-dependent signal activation during funny and unfunny stimuli. Males and females share an extensive humor-response strategy as indicated by recruitment of similar brain regions: both activate the temporal-occipital junction and temporal pole, structures implicated in semantic knowledge and juxtaposition, and the inferior frontal gyrus, likely to be involved in language processing. Females, however, activate the left prefrontal cortex more than males, suggesting a greater degree of executive processing and language-based decoding. Females also exhibit greater activation of mesolimbic regions, including the nucleus accumbens, implying greater reward network response and possibly less reward expectation. These results indicate sex-specific differences in neural response to humor with implications for sex-based disparities in the integration of cognition and emotion.

Adult↗

Age at menopause and subjective cognitive symptoms predict digital cognitive outcomes at the gynecological Well-Woman visit.

INTRODUCTION: Women are at increased risk for Alzheimer's Disease (AD). Growing evidence suggests that the menopausal transition may represent a vulnerable window for development of AD-related pathology. Yet, women are diagnosed with AD later than men. Conducting routine cognitive screenings and integrating information about both cognitive symptoms and age at menopause may help address sex-based disparities in detection and prevention. This study investigated whether subjective cognitive symptoms, in combination with age at menopause, were associated with performance on a digital cognitive task in postmenopausal women. METHODS: 183 postmenopausal women (mean age&#x2009;=&#x2009;63.8, range&#x2009;=&#x2009;45-85) were recruited after their Well-Woman visit. Participants completed the Screener for Cognitive Problems in Everyday Life (SCoPE) to assess subjective cognitive symptoms, followed by a sensitive measure of objective cognition: the Linus Health Digital Clock and Recall (DCR&#x2122;). Information was also collected on age at menopause. We examined associations of subjective cognitive symptoms and age at menopause with digital cognitive performance, adjusting for age, education and depression. Model fit was evaluated using adjusted R2, AIC, and BIC. RESULTS: 48.1% of women reported one or more cognitive symptoms on the SCoPE. On objective testing, 73.2% scored in the normal range, 20.8% in the borderline range, and 6.0% in the impaired range. SCoPE total score was negatively associated with objective cognitive performance in adjusted models (B&#x2009;=&#x2009;-.12, p&#x2009;=&#x2009;.03). Age at menopause showed a significant quadratic association with cognitive performance (B&#x2009;=&#x2009;-0.006, p<.001). SCoPE total was not associated with DCR subtests, while age at menopause predicted both Delayed Recall and Clock Drawing. CONCLUSION: Subjective cognitive symptoms and age at menopause were associated with lower performance on a sensitive, objective cognitive test. Findings support routine cognitive screening and suggest that subjective cognitive symptoms as well as age at menopause are associated with cognitive function.

Humans↗

Changes in ACL T2* Metrics Over the Course of the Female Menstrual Cycle: A New Biomarker for the ACL Injury Risk?

BACKGROUND: Sex-based disparities in the anterior cruciate ligament (ACL) injury risk may be partly explained by cyclic variations in sex hormones that drive systemic shifts in tissue osmoregulation. Ultrashort echo time (UTE) T2* magnetic resonance imaging provides a noninvasive, quantitative means of evaluating the water content and collagen orientation in tissue. HYPOTHESIS: Eumenorrheic female participants will exhibit significant ACL T2* changes across the cycle, while anovulatory control participants will demonstrate no significant changes over time. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: A total of 25 women with no prior knee injuries were enrolled: 10 premenopausal, eumenorrheic participants and 15 anovulatory control participants (6 postmenopausal and 9 premenopausal using oral contraceptives). Bilateral knee magnetic resonance imaging was performed at 4 time points evenly spaced over 1 month, with the first visit within 24 hours of menses onset. Ovulation status was confirmed using commercially available ovulation predictor kits. Three-dimensional UTE sequences (11 echoes; 0.03-25 ms) were acquired to evaluate bicomponent ACL T2* metrics. Linear mixed-effects models assessed temporal differences in long and short T2* values, and the Cohen d quantified effect size. RESULTS: Eumenorrheic participants demonstrated significantly shorter preovulatory long T2* values compared with postovulatory values (mean difference, 1.0 ms [95% CI, 0.2-1.9 ms]; P = .015; Cohen d = 0.51). No significant temporal differences were observed for any T2* metric in anovulatory controls. CONCLUSION: Eumenorrheic female participants exhibited significant preovulatory to postovulatory changes in ACL T2* metrics, while anovulatory controls demonstrated no significant changes over time. These findings suggest that ACL T2* metrics are sensitive to cyclic fluctuations in female sex hormones across the menstrual cycle.

Humans↗

Sex-based differences in the anthropometric characteristics of the anterior cruciate ligament and its relation to intercondylar notch geometry: a cadaveric study.

BACKGROUND: A significantly higher rate of anterior cruciate ligament injuries occurs in women involved in sports activities compared to the corresponding male population. Reasons for this disparity are not well understood; however, sex-based differences in the geometry of the anterior cruciate ligament, its morphologic characteristics, and the intercondylar notch size have been cited as possible factors. HYPOTHESES: (1) The anterior cruciate ligament in women has a shorter length, and smaller cross-sectional area and volume than that in men. (2) The female anterior cruciate ligament has a lower mass density. (3) Ligament size is proportional to notch width in both male and female populations. STUDY DESIGN: Descriptive laboratory study. METHODS: Using a 3-dimensional imaging system, the authors measured the geometric parameters, including length, area, and volume, of the anterior cruciate ligaments of 10 male and 10 female donors (all Caucasian). A digital image of the frontal plane of the knee flexed at 90 degrees was used to measure notch size. After the ligament's removal from its attachment sites, its mass was measured using a digital balance. Geometric parameters, mass density, and notch size were compared based on sex. Correlation analyses between ligament size and body anthropometric characteristics, and between notch size and ligament size were performed. RESULTS: The anterior cruciate ligament in women was smaller in length, cross-sectional area, volume, and mass when compared to that in men. No significant difference in ligament mass density was found between the sexes. Also, no differences were found in notch geometry between male and female populations. A correlation between notch size and ligament size was found for men but not for women. CONCLUSIONS: Because the densities of female and male anterior cruciate ligaments appear to be similar, the smaller ligament size in women may contribute to their having a higher rate of ligament injuries. Anterior cruciate ligament size increases in proportion to notch width in men but not in women.

Adolescent↗

To be one of the boys: aftershocks of the World War I nursing experience.

The mass deployment of nurses during World War I removed them from their structured professional culture and thrust them into the unfamiliar world of men at war. Analysis of personal accounts indicates that for some nurses, this event increased awareness of conflicts between autonomous professional practice and the "good woman" image. It led them to examine the disparity between healing and participation in war and to experience sex-based inequality in the face of equal danger. The emerging dialectic provoked personal and professional change. The value of confrontation with differentness as an impetus to growth is examined.

Female↗

State of the heart: building science to improve women's cardiovascular health.

Cardiovascular disease is the No. 1 killer of women in the United States, and marked disparities in cardiovascular health exist between women and men and among groups of women. Coronary heart disease is underdiagnosed, undertreated, and under-researched in women. Women with suspected heart disease are less likely than men to receive indicated diagnostic tests and procedures; sex-based biases in treatment of myocardial infarction persist; and women continue to be underrepresented in cardiovascular research. An accumulating body of literature points to 3 major explanations: sex-based physiology, provider bias, and psychosocial influences. Women's acute and prodromal signs and symptoms of myocardial infarction have been described, yet women have difficulty recognizing and acting on these indications. Primary and secondary prevention of heart disease in women is imperative; although the science is lacking in several areas, existing evidence on diet, hormone therapy, aspirin, physical activity and obesity, and diabetes can serve as the basis for interventions. Potentially, large impacts could be made on women's morbidity and mortality if current scientific knowledge were implemented. The state of the science of women and heart disease is reviewed, with a focus on those areas with the greatest potential to address the needs of women's cardiovascular status. Key gaps in the science and remaining questions are presented as a research agenda for the coming decade.

Cardiovascular Diseases↗

Cardiovascular disease in women.

Almost 62 million Americans have one or more types of cardiovascular disease and, of these, more than 32 million are female. This translates into an average of 1 in 5 women, making cardiovascular disease the leading killer of women in the U.S., responsible for more than half a million deaths a year. While it has been known for some time that differences exist between the sexes regarding coronary heart disease, it has only been in the last 10 years that these disparities in incidence, morbidity, mortality, risk factors, diagnosis, and treatment have been explored. Research has shown a gap in the utilization of medical therapy, diagnostic studies, and revascularization procedures involving women. In addition, women s outcomes after myocardial infarction have been consistently demonstrated to be poorer than those of men. Another important issue that has just started to be addressed is that the predominantly male-focused cardiovascular research has been generalized to women. Only in recent years have women been included in clinical trials or databases in sufficient numbers for sex-based analysis of the data. The topic of cardiovascular disease in women is diverse and complex. In this article, some of the important issues will be introduced and discussed, highlight our current understanding of the problem and to emphasize the areas in which further study and progress is needed. These issues include the epidemiology of coronary heart disease, the diagnosis of coronary heart disease, the medical therapy of acute coronary syndromes, coronary revascularization, and hormone replacement therapy.

Cardiovascular Diseases↗

The mechanical properties of the human patellar tendon are correlated to its mass density and are independent of sex.

BACKGROUND: A diverse range of values for the mechanical properties of the human patellar tendon has been reported in the literature. Donor age has been excluded as a factor that causes this disparity. However, the effects of donor sex and tissue mass density on the mechanical properties of the patellar tendon have not been established. More importantly, predictors of the mechanical properties of the patellar tendon, used as grafts in anterior cruciate ligament reconstruction surgeries, are not available. METHODS: Uniaxial tension tests were performed to determine the effects of donor sex and mass density of the tissue on the mechanical properties of twenty unpaired human patellar tendons (10 male and 10 female; age, 17-50). Mass density of the patellar tendon was determined by measuring its volume and mass. FINDINGS: No evidence of sex-based differences in any of the mechanical properties of the patellar tendon was found. The results revealed a diverse range of mass densities extending from a low of 0.76 g/cm(3) to a high of 2.68 g/cm(3) (250% difference). Furthermore, it was determined that the ultimate tensile strength (mean=58.71 MPa), elastic modulus (mean=507.38 MPa) and strain energy density (mean=4.59 MPa) of the patellar tendon were significantly correlated to its mass density. The tensile strength and elastic modulus were significantly higher for those patellar tendons having a mass density greater than 1.67 g/cm(3). INTERPRETATION: The mass density of the patellar tendon may be considered as an indicator of mechanical properties of the patellar tendon or graft quality.

Adolescent↗

Male sex hormones promote vagally mediated reflex airway responsiveness to cholinergic stimulation.

A sex disparity in airway responsiveness to cholinergic stimulation has been observed in laboratory mice in that males are considerably more responsive than females, but the basis for this difference is unclear. In this report, we demonstrate that male sex hormones promote murine airway responsiveness to cholinergic stimulation via vagus nerve-mediated reflex mechanisms. In tissue bath preparations, no sex-based differences were observed in the contractile responses of isolated tracheal and bronchial ring segments to carbachol, indicating that the mechanism(s) responsible for the in vivo sex difference is (are) absent ex vivo. Bilateral cervical vagotomy was found to abolish in vivo airway responsiveness to methacholine in male mice, whereas it did not alter the responses of females, suggesting a regulatory role for male sex hormones in promoting reflex airway constriction. To test this possibility, we next studied mice with altered circulating male sex hormone levels. Castrated male mice displayed airway responsiveness equivalent to that observed in intact females, whereas administration of exogenous testosterone to castrated males restored responsiveness, albeit not to the level observed in intact males. Administration of exogenous testosterone to intact female mice similarly enhanced responsiveness. Importantly, the promotive effects of exogenous testosterone in castrated male and intact female mice were absent when bilateral vagotomy was performed. Together, these data indicate that male sex hormones promote cholinergic airway responsiveness via a vagally mediated reflex mechanism that may be important in the regulation of airway tone in the normal and diseased lung.

Animals↗