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Dementia refers to an umbrella phenotype of many different underlying pathologies with Alzheimer's disease (AD) being the most common type. Neuropathological examination remains the gold standard for accurate AD diagnosis, however, most that we know about AD genetics is based on Genome-Wide Association Studies (GWAS) of clinically defined AD. Such studies have identified multiple AD susceptibility variants with a significant portion of the heritability unexplained and highlighting the phenotypic and genetic heterogeneity of the clinically defined entity. Furthermore, despite women's increased susceptibility to dementia, there is a lack of sex-specific genetic studies and understanding of sex-specific background for the disorder. Here, we aim to tackle the heterogeneity of AD by specifically concentrating on neuropathological features and pursuing sex-specific analysis. We bring together 14 different genomic and neuropathology datasets (6960 individuals) and we integrate our GWAS findings with transcriptomic and phenotypic data aiming to also identify biomarkers for AD progression. We uncover novel genetic associations to AD neuropathology, including BIN1 and OPCML. Our sex-specific analysis points to a role for BIN1 specifically in women as well as novel AD loci including QRFPR and SGCZ. Post-GWAS analyses illuminate the functional and biological mechanisms underlying AD and reveal sex-specific differences. Finally, through PheWAS and Mendelian Randomization analysis, we identify causal links with AD neuropathology pointing to disrupted lipid metabolism, as well as impaired peripheral immune response and liver dysfunction as part of a vicious cycle that fuels neurodegeneration. [ABSTRACT FROM AUTHOR]

Prolactin (PRL) is secreted throughout life in men and women. At elevated levels, its physiological role in pregnancy and lactation, and pathological effects, are well known. However clinical implications of low circulating PRL are not well established. We conducted a meta-analysis to examine the relationship between low PRL levels and type 2 diabetes. Five papers included cross-sectional studies comprising 8,720 men (mean age range 51.4–60 years) and 3,429 women (49.5–61.6 years), and four papers included cohort studies comprising 2,948 men (52.1–60.0 years) and 3,203 women (49.2–60.1 years). Individuals with pregnancy, lactation and hyperprolactinemia, drugs known to alter circulating PRL levels, or pituitary diseases had been excluded. Although most studies used quartiles to categorize PRL groups for analysis, PRL cut-off values (all measured by chemiluminescence immunoassay) were variably defined between studies: the lowest PRL quartiles ranged from 3.6 ng/ml to 7.2 ng/ml in men and between 4.5 ng/ml to 8 ng/ml in women; and the highest PRL quartiles ranged from 6.9 ng/ml to 13 ng/ml in men and 9.6 ng/ml to 15.8 ng/ml in women. Type 2 diabetes was defined variably using self-reported physician's diagnosis, fasting blood glucose, oral glucose tolerance test or glycated hemoglobin (HbA1C). In cross-sectional studies, compared to individuals in the highest PRL groups (reference), those in the lowest PRL groups had greater risk of type 2 diabetes both in men: odds ratio (OR) and 95% confidence interval = 1.86 (1.56–2.22) and in women: OR = 2.15 (1.63–2.85). In cohort studies, women showed a significant association between low PRL and type 2 diabetes: OR = 1.52 (1.02–2.28) but not men: OR = 1.44 (0.46–4.57). Relatively low heterogeneity was observed (I2 = 25–38.4%) for cross-sectional studies, but higher for cohort studies (I2 = 52.8–79.7%). In conclusion, low PRL is associated with type 2 diabetes, but discrepancy between men and women in the relationship within cohort studies requires further research. [ABSTRACT FROM AUTHOR]

The aging population has significantly increased in South Korea because of the factors such as longer life expectancy and lower birth rate. Healthy aging requires to preserve the cognitive function. Cognitive decline can hinder daily independent living. It is imperative to understand determinants of cognitive function in older adults for formulating effective interventions and policies. This study analyzed the data of Korean Longitudinal Study of Aging (KLoSA) from 2006 to 2020. A total of 4001 participants (1695 men and 2306 women) aged 65 and older were included in the final analysis. The sex-specific differences in cognitive function were assessed using statistical analyses including panel regression and panel quantile regression. Cognitive function had significant difference between men and women. Men showed higher cognitive function scores than women. Both men and women depicted significant influence on cognitive function based on age, employment status and depression. These factors had varying effects depending on the cognitive function level. Men’s age, working status, and depression were associated with dementia regardless of cognitive function, whereas women’s factors were more pronounced with low cognitive function. This study emphasizes the tailored sex-specific interventions and policies to improve cognitive function in older adults by considering sex-specific differences and varying cognitive function levels.

The female menstrual cycle is one of the most overlooked sex-specific factors in drug distribution and response. Unlocking the potential of nanomedicine demands a fundamental understanding of the impact biological sex has on drug distribution, efficacy and adverse effects. [ABSTRACT FROM AUTHOR]

Purpose: Artificial intelligence (AI) has high diagnostic accuracy for coronary artery disease (CAD) from myocardial perfusion imaging (MPI). However, when trained using high-risk populations (such as patients with correlating invasive testing), the disease probability can be overestimated due to selection bias. We evaluated different strategies for training AI models to improve the calibration (accurate estimate of disease probability), using external testing. Methods: Deep learning was trained using 828 patients from 3 sites, with MPI and invasive angiography within 6 months. Perfusion was assessed using upright (U-TPD) and supine total perfusion deficit (S-TPD). AI training without data augmentation (model 1) was compared to training with augmentation (increased sampling) of patients without obstructive CAD (model 2), and patients without CAD and TPD < 2% (model 3). All models were tested in an external population of patients with invasive angiography within 6 months (n = 332) or low likelihood of CAD (n = 179). Results: Model 3 achieved the best calibration (Brier score 0.104 vs 0.121, p < 0.01). Improvement in calibration was particularly evident in women (Brier score 0.084 vs 0.124, p < 0.01). In external testing (n = 511), the area under the receiver operating characteristic curve (AUC) was higher for model 3 (0.930), compared to U-TPD (AUC 0.897) and S-TPD (AUC 0.900, p < 0.01 for both). Conclusion: Training AI models with augmentation of low-risk patients can improve calibration of AI models developed to identify patients with CAD, allowing more accurate assignment of disease probability. This is particularly important in lower-risk populations and in women, where overestimation of disease probability could significantly influence down-stream patient management. [ABSTRACT FROM AUTHOR]

Background: Mountain biking (MTB) is a quickly growing sport, with many athletes sustaining high-impact injuries. Current literature has not analyzed the most recent MTB-related national emergency department (ED) injury data., Hypothesis: It was hypothesized that (1) the total number of injuries presenting to US EDs would significantly increase over the study period, (2) male patients would experience higher rates of shoulder injuries and airborne injury mechanisms than female patients, and (3) youths would present more frequently with injuries of the head and face than adults., Study Design: Descriptive epidemiology study., Methods: All data were extracted from the National Electronic Injury Surveillance System (NEISS), a public database representing approximately 100 US EDs. The NEISS was queried for MTB-related injuries between January 1, 2013, and December 31, 2022., Results: A total of 2543 MTB-related cases presented to US EDs between 2013 and 2022, which extrapolated to a national estimate (NE) of 109,558 injuries using NEISS sample weights. MTB-related injuries increased significantly between 2013 and 2022 ( P = .009), including a 64% increase between 2019 and 2020. The most common injury mechanism was falling off the bike (62.6%; NE = 68,536), and the upper extremity was the most frequently injured body region (22.4%; NE = 24,511). Male patients presented with significantly more shoulder (21.1% vs 7.4%, respectively; P < .001) and trunk (21.4% vs 19.8%, respectively; P < .001) injuries than female patients as well as more airborne injury mechanisms (15.7% vs 10.8%, respectively; P < .001). Female patients sustained significantly more concussions (7.2% vs 3.5%, respectively; P < .001) than male patients. Children presented with higher rates of head/face injuries (34.1%), concussions (6.0%), and airborne mechanisms of injury (19.4%) than any other age group., Conclusion: MTB injuries increased significantly between 2013 and 2022 likely because of the popularity of outdoor sports during COVID-19. The upper extremity was the most frequently injured body region, and falling off the bike was the most common mechanism. Leading injuries and mechanisms varied significantly by sex and age. This study recommends additional MTB safety measures such as shoulder support for male riders, better coaching on front brake control for youth riders, and an increased emphasis on concussion protocols for female riders., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: B.O.P. has received royalties from Arthrex, consulting fees from Arthrex, nonconsulting fees from Arthrex, and education payments from Gotham Surgical. B.R.W. has received nonconsulting fees from Arthrex and Vericel; consulting fees from DePuy Synthes, FH Orthopedics, Medical Device Business Services, and Vericel; honoraria from the Musculoskeletal Transplant Foundation and Vericel; and education payments from Peerless Surgical, Arthrex, and SouthTech Orthopedics. M.J.A. has received consulting fees from Bodycad, DePuy Synthes, and Medical Device Business Services; education payments from Suvon Surgical and Gotham Surgical; and nonconsulting fees from Arthrex. R.M.F. has received nonconsulting fees from Arthrex, Bodycad, and DePuy Synthes; consulting fees from Arthrex; education payments from Gemini Mountain Medical, Arthrex, and Pinnacle; and hospitality payments from JRF Ortho and Smith & Nephew. R.L.P. has received education payments from Gotham Surgical and Arthrex and a grant from Arthrex. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2025.)

• Traumatic fractures due to MTB increased significantly in the past decade, including a sharp 247 % increase in 2020 corresponding with COVID-19. • Trunk fractures had the highest rate of hospitalization and occurred most frequently among airborne mechanisms of injury. • Adult males had the highest rate of fracture occurrence and hospitalization, and would likely benefit from torso protectors for trunk protection. • Pediatric and adolescent riders were most likely to fracture the upper extremity, and should be encouraged to ride with shoulder and elbow pads. Mountain biking (MTB) is a quickly growing sport, with fractures being the most common injury among MTB athletes. Currently, there is a lack of analysis of MTB fractures based on emergency department (ED) data obtained on a national scale. It was hypothesized that the total number of fractures presenting to United States (US) EDs increased significantly over the last decade, and adult male riders experienced higher rates of fracture and fracture-related hospitalization than other demographics. All data was extracted from the National Electronic Injury Surveillance System (NEISS), a public database representing approximately 100 US EDs. NEISS was queried for all MTB-related fractures from January 1st, 2013-December 31, 2022. NEISS returned a national estimate (NE) of 35,260 MTB fractures visiting EDs between 2013 and 2022. Fracture injuries increased significantly over the study period, including a 247 % increase from 2019 to 2020. The mechanism of injury most likely resulting in fracture was being thrown from the bike (39.6 %, NE:5,436). The upper extremity was the most commonly fractured body region (32.8 %, NE:11,574), and trunk fractures had the highest rate of hospitalization (44.2 %, NE:3705). Males accounted for the majority of fractures (87.9 %, NE:30,996), and were more likely to be hospitalized than females (22.2 %>17.4 %). Adults (age≥40) were more likely to sustain a fracture (48.8 %) and be hospitalized because of it (25.8 %) than other age groups. Adults were also most likely to fracture their trunk (33.9 %). MTB fractures increased significantly from 2013 to 2022, possibly due to the gaining popularity of MTB since COVID-19. The upper extremity was the most frequently fractured body region, and being thrown from the bike was the mechanism most likely to result in a fracture. Adult male riders are at a high risk for trunk fractures, demonstrating the importance of protective equipment such as chest and torso protectors for these athletes. III [ABSTRACT FROM AUTHOR]

Abstract Background Beyond their success in cardiovascular disease prevention, statins are increasingly recognized to have sex-specific pleiotropic effects. To gain additional insight, we characterized associations of genetically mimicked statins across the phenotype sex-specifically. We also assessed whether any apparently non-lipid effects identified extended to genetically mimicking other widely used lipid modifiers (proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and ezetimibe) or were a consequence of low-density lipoprotein cholesterol (LDL-c). Methods We performed a sex-specific phenome-wide association study assessing the association of genetic variants in HMGCR, mimicking statins, with 1701 phenotypes. We used Mendelian randomization (MR) to assess if any non-lipid effects found were evident for genetically mimicked PCSK9 inhibitors and ezetimibe or for LDL-c. Results As expected, genetically mimicking statins was inversely associated with LDL-c, apolipoprotein B (ApoB), and total cholesterol (TC) and positively associated with glycated hemoglobin (HbA1c) and was related to body composition. Genetically mimicking statins was also inversely associated with serum calcium, sex hormone-binding globulin (SHBG), and platelet count and positively associated with basal metabolic rate (BMR) and mean platelet volume. Stronger associations with genetically mimicked statins were evident for women than men for lipid traits (LDL-c, ApoB, and TC), calcium, and SHBG, but not for platelet attributes, body composition, or BMR. Genetically mimicking PCSK9 inhibitors or ezetimibe was also associated with lower lipids, but was not related to calcium, SHBG, BMR, or body composition. Genetically higher LDL-c increased lipids and decreased BMR, but did not affect calcium, HbA1c, platelet attributes, or SHBG with minor effects on body composition. Conclusions Similar inverse associations were found for genetically mimicking statins on lipid traits in men and women as for other lipid modifiers. Besides the positive associations with HbA1c, BMI (which may explain the higher BMR), and aspects of body composition in men and women, genetically mimicking statins was additionally associated with platelet attributes in both sexes and was inversely associated with serum calcium and SHBG in women. This genetic evidence suggests potential pathways that contribute to the effects of statins particularly in women. Further investigation is needed to confirm these findings and their implications for clinical practice.

Introduction: Globally, women with dementia have a higher disease burden than men with dementia. In addition, women with diabetes especially are at higher risk for cognitive impairment and dementia compared to men with diabetes. Differences in the influence of diabetes on the cerebral vasculature and brain structure may contribute to these sex-specific differences. We examined sex-specific patterns in the relationship between diabetes and brain structure, as well as diabetes and cognitive function. Methods: In total, 893 patients [age 79 ± 6.6 years, 446 (50%) women] from the Amsterdam Ageing Cohort with available data on brain structures (assessed by an MRI or CT scan) and cognitive function were included. All patients underwent a thorough standardized clinical and neuropsychological assessment (including tests on memory, executive functioning, processing speed, language). Brain structure abnormalities were quantified using visual scales. Results: Cross-sectional multivariable regression analyses showed that diabetes was associated with increased incidence of cerebral lacunes and brain atrophy in women (OR 2.18 (1.00–4.72) but not in men. Furthermore, diabetes was associated with decreased executive function, processing speed and language in women [B −0.07 (0.00–0.13), −0.06 (0.02–0.10) and −0.07 (0.01–0.12) resp.] but not in men. Conclusions: Diabetes is related to increased risk of having lacunes, brain atrophy and impaired cognitive function in women but not in men. Further research is required to understand the time trajectory leading up to these changes and to understand the mechanisms behind them in order to improve preventive health care for both sexes. [ABSTRACT FROM AUTHOR]

Abstract Background ABO blood group is associated with differences in lifespan, cardiovascular disease, and some cancers, for reasons which are incompletely understood. To gain sex-specific additional insight about potential mechanisms driving these common conditions for future interventions, we characterized associations of ABO blood group antigen across the phenotype sex-specifically. Methods We performed a phenome-wide association study (PheWAS) assessing the association of tag single nucleotide polymorphisms (SNPs) for ABO blood group antigens (O, B, A1, and A2) with 3873 phenotypes. Results The tag SNP for the O antigen was inversely associated with diseases of the circulatory system (particularly deep vein thrombosis (DVT)), total cholesterol, low-density lipoprotein cholesterol (LDL-C), and ovarian cancer, and positively associated with erythrocyte traits, leukocyte counts, diastolic blood pressure (DBP), and healthy body composition; the tag SNP for the A1 antigen tended to have associations in reverse to O. Stronger associations were more apparent for men than women for DVT, DBP, leukocyte traits, and some body composition traits, whereas larger effect sizes were found for women than men for some erythrocyte and lipid traits. Conclusion Blood group has a complex association with cardiovascular diseases and its major risk factors, including blood pressure and lipids, as well as with blood cell traits and body composition, with some differences by sex. Lower LDL-C may underlie some of the benefits of blood group O, but the complexity of associations with blood group antigen suggests overlooked drivers of common chronic diseases.

IntroductionGlobally, women with dementia have a higher disease burden than men with dementia. In addition, women with diabetes especially are at higher risk for cognitive impairment and dementia compared to men with diabetes. Differences in the influence of diabetes on the cerebral vasculature and brain structure may contribute to these sex-specific differences. We examined sex-specific patterns in the relationship between diabetes and brain structure, as well as diabetes and cognitive function.MethodsIn total, 893 patients [age 79 ± 6.6 years, 446 (50%) women] from the Amsterdam Ageing Cohort with available data on brain structures (assessed by an MRI or CT scan) and cognitive function were included. All patients underwent a thorough standardized clinical and neuropsychological assessment (including tests on memory, executive functioning, processing speed, language). Brain structure abnormalities were quantified using visual scales.ResultsCross-sectional multivariable regression analyses showed that diabetes was associated with increased incidence of cerebral lacunes and brain atrophy in women (OR 2.18 (1.00–4.72) but not in men. Furthermore, diabetes was associated with decreased executive function, processing speed and language in women [B −0.07 (0.00–0.13), −0.06 (0.02–0.10) and −0.07 (0.01–0.12) resp.] but not in men.ConclusionsDiabetes is related to increased risk of having lacunes, brain atrophy and impaired cognitive function in women but not in men. Further research is required to understand the time trajectory leading up to these changes and to understand the mechanisms behind them in order to improve preventive health care for both sexes.

Objectives: Electric biking (e-biking) is a rapidly growing recreation, sport, and mode of transportation that often presents to emergency departments (EDs) with high-impact head injuries. This study aimed to evaluate the epidemiology of e-bike-related concussions and closed-head injuries (CHI) to inform more effective injury prevention strategies., Methods: The National Electronic Injury Surveillance (NEISS) was queried for e-bike related concussions and CHIs presented to national EDs from 1 January 2013-31 December 2022. Patient demographics, diagnoses, and dispositions were recorded, and injury narratives were reviewed to identify mechanisms of injury and motor vehicle (MV) involvement., Results: A total of 11,052 nationally estimated (NE) e-bike head injuries presented to US EDs from 2013 to 2022. E-bike head injuries increased significantly from 2013 to 2022 ( p  = .006, β = 372.5), with 40.8% of all head injuries occurring in 2022. Nearly one-third of patients (31.0%) required hospital admission, with hospitalization occurring most frequently among ages 51 and older (44.5%). MV involvement accounted for 27.6% of head injuries, and caused a higher proportion of hospitalizations than mechanisms without MVs (35.6% vs. 29.4%, respectively; p  < 0.001). High school age riders had the most MV incidents (53.2%), while the middle school age group had the highest proportion of concussions (26.5%) among all age groups. Relative to females, males were more likely to be involved in an MV incident (28.5% vs. 15.5%; p  < 0.001) and were more likely to be hospitalized (33.0% vs. 25.4%; p  < 0.001)., Conclusion: The incidence of concussions and CHIs due to e-bikes increased significantly from 2013 to 2022, while high proportions of hospitalization indicate serious injury severity and large medical costs associated with these injuries. The prevalence of crashes involving MVs, especially among teenagers, calls for further research on commuter and recreational e-bike use along with new traffic legislation to protect young e-bikers.

Unmarried status has been associated with higher proportions of locally advanced stage and lower treatment dose intensification rates in several urological and non-urological malignancies. However, no previous investigators focused on the association between unmarried status and advanced stage (T 3-4 N 0-2) at presentation and lower nephroureterectomy (RNU) and systemic therapy (ST) rates in non-metastatic upper tract urothelial carcinoma (UTUC) patients. Using the Surveillance, Epidemiology, and End Results (SEER) database 2000-2020, all non-metastatic UTUC patients were identified. Multivariable logistic regression models (LRMs) tested for differences in stage at presentation and treatment (RNU and ST) according to marital status (married vs unmarried), in a sex-specific fashion. Of all 8544 non-metastatic UTUC patients, 4748 (56%) were male vs 3190 (44%) were female. Of all 4748 male UTUC patients, 1191 (25%) were unmarried. Of all 3190 female UTUC patients, 1608 (50%) were unmarried. In multivariable LRMs predicting RNU, unmarried status was an independent predictor of lower RNU rates in male (Odds Ratio [OR]: 0.56; P <.001), but not in female (OR: 0.81; P =.1) non-metastatic UTUC patients. In multivariable LRMs predicting ST exposure, unmarried status was an independent predictor of lower ST rates in both male (OR:0.73; P =.03) and female (OR:0.64; P <.001) UTUC patients. In multivariable LRMs predicting locally advanced stage (T 3-4 N 0-2), unmarried status was not associated with an increased risk of locally advanced stage at presentation in either male (OR: 0.95; P =.5) or female (OR: 0.99; P =.9) UTUC patients. Unmarried male UTUC patients appear at risk of less being able to access RNU, relative to their married counterparts. Moreover, unmarried UTUC patients appear to less benefit from ST, regardless of sex. Conversely, unmarried status was not associated with an increased risk of locally advanced stage at presentation in either male or female UTUC patients. Among 8,544 non-metastatic UTUC patients identified within the SEER database 2000-2020, unmarried status was independently associated with lower nephroureterectomy (RNU) rates in males (Odds Ratio [OR]: 0.56; P <.001) but not females (OR: 0.81; P =.1) and with lower systemic therapy rates in both male (OR:0.73; P <.001) and female (0.64; P <.001). However, unmarried status did not correlate with an increased risk of locally advanced stage at presentation in either gender. Unmarried male UTUC patients may face challenges accessing RNU compared to their married counterparts. Moreover, unmarried UTUC patients appear to less benefit from ST, regardless of sex. [ABSTRACT FROM AUTHOR]

Background: Beyond their success in cardiovascular disease prevention, statins are increasingly recognized to have sex-specific pleiotropic effects. To gain additional insight, we characterized associations of genetically mimicked statins across the phenotype sex-specifically. We also assessed whether any apparently non-lipid effects identified extended to genetically mimicking other widely used lipid modifiers (proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and ezetimibe) or were a consequence of low-density lipoprotein cholesterol (LDL-c).Methods: We performed a sex-specific phenome-wide association study assessing the association of genetic variants in HMGCR, mimicking statins, with 1701 phenotypes. We used Mendelian randomization (MR) to assess if any non-lipid effects found were evident for genetically mimicked PCSK9 inhibitors and ezetimibe or for LDL-c.Results: As expected, genetically mimicking statins was inversely associated with LDL-c, apolipoprotein B (ApoB), and total cholesterol (TC) and positively associated with glycated hemoglobin (HbA1c) and was related to body composition. Genetically mimicking statins was also inversely associated with serum calcium, sex hormone-binding globulin (SHBG), and platelet count and positively associated with basal metabolic rate (BMR) and mean platelet volume. Stronger associations with genetically mimicked statins were evident for women than men for lipid traits (LDL-c, ApoB, and TC), calcium, and SHBG, but not for platelet attributes, body composition, or BMR. Genetically mimicking PCSK9 inhibitors or ezetimibe was also associated with lower lipids, but was not related to calcium, SHBG, BMR, or body composition. Genetically higher LDL-c increased lipids and decreased BMR, but did not affect calcium, HbA1c, platelet attributes, or SHBG with minor effects on body composition.Conclusions: Similar inverse associations were found for genetically mimicking statins on lipid traits in men and women as for other lipid modifiers. Besides the positive associations with HbA1c, BMI (which may explain the higher BMR), and aspects of body composition in men and women, genetically mimicking statins was additionally associated with platelet attributes in both sexes and was inversely associated with serum calcium and SHBG in women. This genetic evidence suggests potential pathways that contribute to the effects of statins particularly in women. Further investigation is needed to confirm these findings and their implications for clinical practice. [ABSTRACT FROM AUTHOR]

Hypothesis: Basketball-related shoulder dislocations frequently present to emergency departments in the US. This study aimed to identify the primary mechanisms, distributions, and trends of these injuries., Methods: All data were extracted from the National Electronic Injury Surveillance System, a public database representing approximately 100 US emergency departments. National Electronic Injury Surveillance System was queried for all basketball-related injuries and shoulder dislocations from January 1, 2013 to December 31, 2022. Clinical narratives were used to assign injury mechanisms and the presence of player contact., Results: Between 2013 and 2022, 52,417 basketball-related shoulder dislocations were reported. A total of 30.9% of all basketball-related shoulder injuries were dislocations and 30.5% of all joint dislocations occurred at the shoulder. Basketball-related shoulder dislocations decreased significantly from 2013 to 2022 (P < .001). From 2019 to 2020, a 31.0% decrease was identified. The most common mechanism of shoulder dislocation was falling (36.9%). Males accounted for 92.5% of all shoulder dislocations. However, females were significantly more likely than males to dislocate their shoulders from player contact (15.5% of female dislocations vs. 10.0% of male dislocations, P < .001). Only 0.2% of all dislocations resulted in hospitalization. A total of 10.4% of dislocations resulted from contact with another player. Compared to other age groups, young adults (43.3%) and adolescents (42.7%) presented with the majority of shoulder dislocations. Children were more likely to dislocate their shoulder from sustaining a direct blow (25.5%), while all other age groups were more likely to have fallen. Children were also the most likely to sustain a dislocation involving player contact (23.9%)., Conclusion: Basketball-related shoulder dislocations decreased significantly from 2013 to 2022. Females and children were significantly more likely to present with a dislocation by sustaining player contact. Across all demographics, teaching athletes how to break their falls safely may decrease rates of dislocation by minimizing impacts on a posteriorly outstretched arm., (Copyright © 2024 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Abstract Background Type 2 diabetes is a chronic disease associated with poorer health outcomes and decreased health related quality of life (HRQoL). The aim of this analysis was to explore the impact of a disease management programme (DMP) in type 2 diabetes on HRQoL. A multilevel model was used to explain the variation in EQ-VAS. Methods A cluster-randomized controlled trial—analysis of the secondary endpoint HRQoL. Our study population were general practitioners and patients in the province of Salzburg. The DMP “Therapie-Aktiv” was implemented in the intervention group, and controls received usual care. Outcome measure was a change in EQ-VAS after 12 months. For comparison of rates, we used Fisher’s Exact test; for continuous variables the independent T test or Welch test were used. In the multilevel modeling, we examined various models, continuously adding variables to explain the variation in the dependent variable, starting with an empty model, including only the random intercept. We analysed random effects parameters in order to disentangle variation of the final EQ-VAS. Results The EQ-VAS significantly increased within the intervention group (mean difference 2.19, p = 0.005). There was no significant difference in EQ-VAS between groups (mean difference 1.00, p = 0.339). In the intervention group the improvement was more distinct in women (2.46, p = 0.036) compared to men (1.92, p = 0.063). In multilevel modeling, sex, age, family and work circumstances, any macrovascular diabetic complication, duration of diabetes, baseline body mass index and baseline EQ-VAS significantly influence final EQ-VAS, while DMP does not. The final model explains 28.9% (EQ-VAS) of the total variance. Most of the unexplained variance was found on patient-level (95%) and less on GP-level (5%). Conclusion DMP “Therapie-Aktiv” has no significant impact on final EQ-VAS. The impact of DMPs in type 2 diabetes on HRQoL is still unclear and future programmes should focus on patient specific needs and predictors in order to improve HRQoL. Trial registration Current Controlled trials Ltd., ISRCTN27414162

Genetic bases of sexual size dimorphism (SSD) in Markhoz goat (5268 kids descended from 242 sires and 1499 dams) were unraveled as it was thought that sex-specific genetic mechanism is in the place governing SSD of birth weight (BW), weaning weight at 90 days of age (WW_90d), and post-weaning weights at 6 (W6), 9 (W9), and 12 (W12) months of age. Male kids excelled for BW, WW_90d, W6, W9, and W12 than their female counterparts in the tune of 10, 17, 14, 17, and 23%, respectively. Estimates of sexual dimorphism levels (expressed as M/F) were 1.09, 1.17, 1.14, 1.17, and 1.23 for BW, WW_90d, W6, W9, and W12, respectively, which indicated relatively low levels of sexual size dimorphism in the studied traits. Though the additive genetic, residual and phenotypic variances were higher in males than females, for mostly all studied traits, but the heritability estimates for all traits except birth weight were higher in females. Differences in direct and maternal effects between male and female kids indicated that body weights traits could be treated as separate trait for male and female kids. Cross-sex genetic correlations revealed that almost all ages, genetic correlations between the two sexes, were high, and the lowest estimate (0.88) was for W6, which highlighted this trait as the most dimorphic trait in this breed. High and positive genetic correlations between the sexes indicated that selection for body weight in males would result in a correlated response in females and vice versa and, consequently, would prevent phenotypic divergence. [ABSTRACT FROM AUTHOR]

• Unmarried status was associated with an increased risk of locally advanced stage. • Unmarried female PUC patients more frequently harbored advanced stage at presentation. • Unmarried status was associated with lower rates of bi-/trimodal therapy. • Unmarried male PUC patients less likely to benefit from bi-/trimodal therapy. Unmarried status has been associated with advanced stage at presentation and lower treatment dose intensification rates in several urological and non-urological malignancies. However, no previous investigators focused of the association of unmarried status with locally advanced stage (T 3-4 N 0-2) at presentation and lower bi-/trimodal therapy rates in primary urethral carcinoma (PUC) patients. To address these knowledge gaps, we relied on the Surveillance, Epidemiology, and End Results (SEER) database. Within the SEER database 2000 to 2020, all non-metastatic PUC patients were identified. Logistic regression models (LRMs) tested for differences in stage at presentation and treatment modality in the overall cohort and then in a sex-specific fashion, according to marital status (married vs unmarried). Of all 1,430 non-metastatic PUC patients, 1,004 (70%) were male vs 426 (30%) were female. Of 1,004 male PUC patients, 272 (27%) were unmarried. Of all 426 female PUC patients, 239 (56%) were unmarried. In multivariable LRMs predicting T 3-4 N 0-2 , unmarried status was independently associated with an increased risk of locally advanced stage at presentation in the overall cohort (odds ratio [OR]:1.31; P = 0.03) and in female patients (OR:1.62; P = 0.02), but not in male PUC patients (P = 0.6). In multivariable LRMs predicting bi-/trimodal therapy, unmarried status was an independent predictor of lower bi-/trimodal therapy rates in the overall cohort (OR:0.73; P = 0.02) and in male patients (OR:0.60; P = 0.007), but not in female PUC patients (P = 0.6). Unmarried female PUC patients more likely harbored locally advanced stage at presentation. Conversely, unmarried male PUC patients are less likely to benefit from bi-/trimodal therapy. [ABSTRACT FROM AUTHOR]

Background: The impact of patient sex on the prevalence of foot and ankle injuries has been established. Reporting of differences on treatment outcomes is lacking. The purpose of this study was to identify trends in sex-specific outcomes across high-impact journals over a 5-year time period. Methods: Two independent investigators reviewed journal issues published during 2 calendar years (2011 and 2016) in the 5 highest-impact orthopedic foot and ankle/sports subspecialty journals (Foot & Ankle International [ FAI ], Foot and Ankle Surgery [ FAS ], American Journal of Sports Medicine [ AJSM ], Arthroscopy, and Knee Surgery, Sports Traumatology, Arthroscopy [ KSSTA ]). Studies were stratified into those that involved sex-specific analysis (SSA), where sex was a variable in a multifactorial statistical model, and those that only reported sex as a demographic characteristic or utilized sex-matched cohorts. Results: A total of 473 studies evaluating a total of 273 128 patients met criteria. An average of 43.9% (119 967 patients) of the population were female. Only 16.7% (79/473) of studies included sex as variable in a statistical model. Thirteen percent (25/193) and 19.3% (54/280) of studies reported SSA in 2011 and 2016, respectively. FAI was the only journal demonstrating a significant improvement of reporting SSA from 2011 to 2016 (P <.002). Thirty percent (24/79) of studies that performed SSA demonstrated significant differences between male and female outcomes. Conclusion: Reporting of SSA in the orthopedic literature continued to be lacking. Only 16.7% of all articles evaluated in 2011 and 2016 performed SSA, with 30% of this subset reporting a statistically significant difference in outcomes. Level of Evidence: Level III, comparative study. [ABSTRACT FROM AUTHOR]

• Primary urethral carcinoma is a rare malignancy, accounting for <1% of GU malignancies. • Married status independently predicted lower CSM in the entire cohort of PUC patients. • Married status was associated with lower CSM in female but not in male PUC patients. It is unknown whether married status may be associated with lower cancer-specific mortality (CSM) rates in primary urethral carcinoma (PUC) patients. To test for differences in CSM rates, according to marital status, we relied on the Surveillance, Epidemiology, and End Results (SEER) database 2000–2020. Patient (age, sex, race/ethnicity, marital status), tumor (stage, histology), and treatment (surgery, systemic therapy) characteristics of PUC patients were tabulated. Then, Kaplan–Meier plots, as well as univariable and multivariable Cox regression (MCR) models tested for differences in CSM rates according to marital status in overall cohort and then in sex-specific subgroup analyses. Of all 1,571 PUC patients, 70% were male vs. 30% female. Females were statistically significantly younger (68 vs. 73 years), more frequently unmarried (54 vs. 28%), non-Caucasian (43 vs. 24%), more frequently harbored T 3-4 N 0 M 0 (39 vs. 18%) and less frequently T 1-2 N 0 M 0 (53 vs. 69%) or T any N 1-2 M 0 /T any N any M 1 (8 vs. 13%), relative to males. Moreover, we recorded differences in histotype proportions in females vs. males (urothelial 30 vs. 64%; squamous 24 vs. 22%; adenocarcinoma 36 vs. 7%; others 10 vs. 6%) and surgical treatment (none 22 vs. 17%; excisional biopsy 22 vs. 36%; partial urethrectomy 14 vs. 16%; radical urethrectomy 42 vs. 31%). In MCR models focusing on the entire cohort, married status independently predicted lower CSM (hazard ratio [HR]:0.82; P = 0.02). Similarly, in MCR models focusing on females, married status independently predicted lower CSM (HR:0.73; P = 0.03). Conversely, in MCR models focusing on males, married status failed to independently predict lower CSM (HR:0.89; P = 0.3). Married status was associated with lower CSM in PUC patients. However, this benefit applies to female PUC patients, but not to their male counterparts. [ABSTRACT FROM AUTHOR]

Abstract Background Quantification of ventricular performance requires a comprehensive metric which is manageable for patient care and clinical trials. Ejection fraction (EF) has been embraced as an attractive candidate. However, being a dimensionless ratio, EF has serious limitations. Methods We aim to identify what information is not recognized when limiting the volume-related analysis by exclusively relying on EF. This investigation applies the volume domain concept, relating end-systolic volume (ESV) to end-diastolic volume (EDV). This approach allows graphical identification of the information not covered by EF. Implications for atria, left ventricle (LV) and right ventricle (RV) are investigated in healthy individuals, and cardiac patient groups using various imaging modalities. Results The Pythagorean theorem indicates that the hypotenuse which relates any {EDV, ESV} combination to EF corresponds with the information not covered by the single metric EF. The impact of the recovered EF companion (EFC) is illustrated in healthy adults (N = 410, LV 2D echocardiography), heart transplant patients (N = 101, LV CT), individuals with heart failure (N = 197, biplane angiocardiography), for the RV with corrected Fallot (N = 124, MRI), diameters for left atrium (N = 49, MRI) and area for right atrium (N = 51, MRI). For any limited EF range we find a spectrum of EFC values, showing that the two metrics contain (partly) independent information, and emphasizing that the sole use of EF only partially conveys the full information available. Conclusions The EFC is a neglected companion, containing information which is additive to EF. Analysis based on ESV and EDV is preferred over the use of EF. Highlights • The metric ejection fraction (EF) refers to a ratio and provides incomplete information. • Limitations inherent to the use of EF have barely been studied or reported. • There is a missing EF companion (EFC), which can readily be visualized. • The EFC is principally associated with end-diastolic volume (EDV). • Analysis of end-systolic volume and EDV is preferred above the use of EF and EFC. [ABSTRACT FROM AUTHOR]

The heart is often regarded as a compression pump. Therefore, determination of pressure and volume is essential for cardiac function analysis. Traditionally, ventricular performance was described in terms of the Starling curve, i.e., output related to input. This view is based on two variables (namely, stroke volume and end-diastolic volume), often studied in the isolated (i.e., denervated) heart, and has dominated the interpretation of cardiac mechanics over the last century. The ratio of the prevailing coordinates within that paradigm is termed ejection fraction (EF), which is the popular metric routinely used in the clinic. Here we present an insightful alternative approach while describing volume regulation by relating end-systolic volume (ESV) to end-diastolic volume. This route obviates the undesired use of metrics derived from differences or ratios, as employed in previous models. We illustrate basic principles concerning ventricular volume regulation by data obtained from intact animal experiments and collected in healthy humans. Special attention is given to sex-specific differences. The method can be applied to the dynamics of a single heart and to an ensemble of individuals. Group analysis allows for stratification regarding sex, age, medication, and additional clinically relevant covariates. A straightforward procedure derives the relationship between EF and ESV and describes myocardial oxygen consumption in terms of ESV. This representation enhances insight and reduces the impact of the metric EF, in favor of the end-systolic elastance concept advanced 4 decades ago. [ABSTRACT FROM AUTHOR]

Background: In older people chronological age may not be the best predictor of residual lifespan and mortality, because with age the heterogeneity in health is increasing. Biomarkers for biological age and residual lifespan are being developed to predict disease and mortality better at an individual level than chronological age. In the current paper we aim to classify a group of older people into those with longevity potential or controls.Methods: In the Leiden Longevity Study participated 1671 offspring of nonagenarian siblings, as the group with longevity potential, and 744 similarly aged controls. Using known risk factors for cardiovascular disease, previously reported markers for human longevity and other physiological measures as predictors, classification models for longevity potential were constructed with multiple logistic regression of the offspring-control status.Results: The Framingham Risk Score is predictive for longevity potential (AUC = 64.7). Physiological parameters involved in immune responses and glucose, lipid and energy metabolism further improve the prediction performance for longevity potential (AUCmale = 71.4, AUCfemale = 68.7).Conclusion: Using the Framingham Risk Score, the classification of older people in groups with longevity potential and controls is moderate, but can be improved to a reasonably good classification in combination with markers of immune response, glucose, lipid and energy metabolism. We show that individual classification of older people for longevity potential may be feasible using biomarkers from a wide variety of different biological processes.

Single variant analysis in genome-wide association studies (GWAS) has been proven to be successful in identifying thousands of genetic variants associated with hundreds of complex diseases. However, these identified variants only explain a small fraction of inheritable variability in many diseases, suggesting that other resources, such as multilevel genetic variations, may contribute to disease susceptibility. In this work, we propose to combine genetic variants that belong to a gene set, such as at gene- and pathway-level to form an integrated signal aimed to identify major players that function in a coordinated manner conferring disease risk. The integrated analysis provides novel insight into disease etiology while individual signals could be easily missed by single variant analysis. We apply our approach to a genome-wide association study of type 2 diabetes (T2D) with male and female data analyzed separately. Novel sex-specific genes and pathways are identified to increase the risk of T2D. We also demonstrate the performance of signal integration through simulation studies.

Single variant analysis in genome-wide association studies (GWAS) has been proven to be successful in identifying thousands of genetic variants associated with hundreds of complex diseases. However, these identified variants only explain a small fraction of inheritable variability in many diseases, suggesting that other resources, such as multilevel genetic variations, may contribute to disease susceptibility. In this work, we proposed to combine genetic variants that belong to a gene set, such as at gene- and pathway-level to form an integrated signal aimed to identify major players that function in a coordinated manner conferring disease risk. The integrated analysis provides novel insight into disease etiology while individual signals could be easily missed by single variant analysis. We applied our approach to a genome-wide association study of type 2 diabetes (T2D) with male and female data analyzed separately. Novel sex-specific genes and pathways were identified to increase the risk of T2D. We also demonstrated the performance of signal integration through simulation studies. [ABSTRACT FROM AUTHOR]

Studies of adolescent body image and screen use are mostly limited to girls, and longitudinal data are scarce. We examined cross-sectional and longitudinal associations between these variables in mid-adolescent boys and girls. Data was collected when participants were at age 15 and 17, by questionnaire and objective measurements ( n = 152 had complete data). Sex-specific linear regression was used to explore cross-sectional and longitudinal associations of self-reported screen use (total use, and time spent in gaming, TV/DVD/internet-based watching and internet use for communication) and body image, adjusting for vigorous physical activity, symptoms of depression, and body composition. Screen time was negatively associated with body image at both time points, although more strongly at age 15, and for girls only. Gaming and TV/DVD/internet watching was more strongly associated with body image than internet use for communication. Girls with above median screen time at both ages had 14% lower body image score at age 17 than girls with below median screen time at both time points. Our results suggest that screen use is likely to play a role in the development of body dissatisfaction among adolescent females. Limiting screen time may, therefore, help to mitigate body dissatisfaction in adolescent girls.

Background: ABO blood group is associated with differences in lifespan, cardiovascular disease, and some cancers, for reasons which are incompletely understood. To gain sex-specific additional insight about potential mechanisms driving these common conditions for future interventions, we characterized associations of ABO blood group antigen across the phenotype sex-specifically.Methods: We performed a phenome-wide association study (PheWAS) assessing the association of tag single nucleotide polymorphisms (SNPs) for ABO blood group antigens (O, B, A1, and A2) with 3873 phenotypes.Results: The tag SNP for the O antigen was inversely associated with diseases of the circulatory system (particularly deep vein thrombosis (DVT)), total cholesterol, low-density lipoprotein cholesterol (LDL-C), and ovarian cancer, and positively associated with erythrocyte traits, leukocyte counts, diastolic blood pressure (DBP), and healthy body composition; the tag SNP for the A1 antigen tended to have associations in reverse to O. Stronger associations were more apparent for men than women for DVT, DBP, leukocyte traits, and some body composition traits, whereas larger effect sizes were found for women than men for some erythrocyte and lipid traits.Conclusion: Blood group has a complex association with cardiovascular diseases and its major risk factors, including blood pressure and lipids, as well as with blood cell traits and body composition, with some differences by sex. Lower LDL-C may underlie some of the benefits of blood group O, but the complexity of associations with blood group antigen suggests overlooked drivers of common chronic diseases. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. Background: Palliative care improves quality of life in patients with heart failure. Whether men and women with heart failure derive similar benefit from palliative care interventions remains unknown. Methods: In a secondary analysis of the PAL-HF trial (Palliative Care in Heart Failure), we analyzed differences in quality of life among men and women with heart failure and assessed for differential effects of the palliative care intervention by sex. Differences in clinical characteristics and quality-of-life metrics were compared between men and women at serial time points. The primary outcome was change in Kansas City Cardiomyopathy Questionnaire score between baseline and 24 weeks. Results: Among the 71 women and 79 men, there was a significant difference in baseline Kansas City Cardiomyopathy Questionnaire (24.5 versus 36.2, respectively; P =0.04) but not Functional Assessment of Chronic Illness Therapy-Palliative Care scale (115.7 versus 120.3; P =0.27) scores. Among those who received the palliative care intervention (33 women and 42 men), women's quality-of-life score remained lower than that of men after enrollment. Treated men's scores were significantly higher than those untreated (6-month Kansas City Cardiomyopathy Questionnaire, 68.0 [interquartile range, 52.6–85.7] versus 41.1[interquartile range, 32.0–78.3]; P =0.047), whereas the difference between treated and untreated women was not significantly different (P =0.39). Rates of death and rehospitalization, as well as the composite end point, were similar between treated and untreated women and men. Conclusions: In the PAL-HF trial, women with heart failure experienced a greater symptom burden and poorer quality of life as compared with men. The change in treated men's Kansas City Cardiomyopathy Questionnaire score between baseline and 24 weeks was significantly higher than those untreated; this trend was not observed in women. Thus, there may be a sex disparity in response to palliative care intervention, suggesting that sex-specific approaches to palliative care may be needed to improve outcomes. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT0158960. [ABSTRACT FROM AUTHOR]

Obsessive-compulsive disorder (OCD) is a highly heritable complex phenotype that demonstrates sex differences in age of onset and clinical presentation, suggesting a possible sex difference in underlying genetic architecture. We present the first genome-wide characterization of the sex-specific genetic architecture of OCD, utilizing the largest set of OCD cases and controls available from the Psychiatric Genomics Consortium. We assessed evidence for several mechanisms that may contribute to sex differences including a sex-dependent liability threshold, the presence of individual sex-specific risk variants on the autosomes and the X chromosome, and sex-specific pleiotropic effects. Furthermore, we tested the hypothesis that genetic heterogeneity between the sexes may obscure associations in a sex-combined genome-wide association study. We observed a strong genetic correlation between male and female OCD and no evidence for a sex-dependent liability threshold model, suggesting that sex-combined analysis does not suffer from widespread loss of power because of genetic heterogeneity between the sexes. While we did not detect any significant sex-specific genome-wide single nucleotide polymorphisms (SNP) associations, we did identify two significant gene-based associations in females: GRID2 and GRP135, which showed no association in males. We observed that the SNPs with sexually differentiated effects showed an enrichment of regulatory variants influencing expression of genes in brain and immune tissues. These findings suggest that future studies with larger sample sizes hold great promise for the identification of sex-specific genetic risk factors for OCD., (© 2018 Wiley Periodicals, Inc.)

Background: Type 2 diabetes is a chronic disease associated with poorer health outcomes and decreased health related quality of life (HRQoL). The aim of this analysis was to explore the impact of a disease management programme (DMP) in type 2 diabetes on HRQoL. A multilevel model was used to explain the variation in EQ-VAS. Methods: A cluster-randomized controlled trial—analysis of the secondary endpoint HRQoL. Our study population were general practitioners and patients in the province of Salzburg. The DMP "Therapie-Aktiv" was implemented in the intervention group, and controls received usual care. Outcome measure was a change in EQ-VAS after 12 months. For comparison of rates, we used Fisher's Exact test; for continuous variables the independent T test or Welch test were used. In the multilevel modeling, we examined various models, continuously adding variables to explain the variation in the dependent variable, starting with an empty model, including only the random intercept. We analysed random effects parameters in order to disentangle variation of the final EQ-VAS. Results: The EQ-VAS significantly increased within the intervention group (mean difference 2.19, p = 0.005). There was no significant difference in EQ-VAS between groups (mean difference 1.00, p = 0.339). In the intervention group the improvement was more distinct in women (2.46, p = 0.036) compared to men (1.92, p = 0.063). In multilevel modeling, sex, age, family and work circumstances, any macrovascular diabetic complication, duration of diabetes, baseline body mass index and baseline EQ-VAS significantly influence final EQ-VAS, while DMP does not. The final model explains 28.9% (EQ-VAS) of the total variance. Most of the unexplained variance was found on patient-level (95%) and less on GP-level (5%). Conclusion: DMP "Therapie-Aktiv" has no significant impact on final EQ-VAS. The impact of DMPs in type 2 diabetes on HRQoL is still unclear and future programmes should focus on patient specific needs and predictors in order to improve HRQoL. Trial registration Current Controlled trials Ltd., ISRCTN27414162 [ABSTRACT FROM AUTHOR]

Background: Ejection fraction (EF) is commonly applied as a clinically relevant metric to assess ventricular function. The numerical value of EF depends on the interplay between end-systolic volume (ESV) and end-diastolic volume (EDV). Remarkably, the relative impact of the two constitutive components on EF received little attention., Methods: Three patient groups not using beta-blockers were analyzed for a robust investigation into the relative contribution of ESV and EDV when assessing EF: cardiac patients (N=155) with left ventricular (LV) data obtained by biplane ventriculography, near-normals (N=276) by gated SPECT investigation, and an MRI-based post Fallot repair study including right ventricular (RV) data (N=124), besides LV. We compared various routes to evaluate EF via linear and several types of nonlinear regression with ESV as independent variable. Advanced statistics was applied to evaluate sex-specific differences., Results: In all cases ESV emerges as the dominant component of EF, with less (P<0.0001) impact of EDV. The relationship for EF versus ESV is nonlinear (P<0.0001), and similar for both sexes. A linear approach may be inadequate and generate erroneous statistical outcomes when comparing subgroups of patients., Conclusions: Values for EF primarily depend on ESV, both for LV and RV. This relationship is essentially nonlinear, and similar for both sexes. A logarithmic approximation is convenient and often acceptable. However, application of linear regression for EF vs ESV may lead to incorrect conclusions, particularly when comparing males and females., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Cardiac function is best described by investigating the pressure-volume relationships. This information permits description in terms of the ventricular volume regulation graph (VRG), estimation of systolic elastance, evaluation of lusitropic properties, and assessment of ventriculo-arterial coupling. Current techniques yield noninvasive determination of cardiac compartmental volumes, along with systolic/diastolic arterial pressure, while ventricular end-diastolic pressure can be inferred from an echocardiography-based surrogate measure. Ventricular volume is known to vary with age, as well as to be affected by intrinsic cardiac disease and abnormalities of the vascular system. Moreover, 35 years ago it has been shown in healthy adults that left ventricular volume is significantly smaller in women compared to men. This important observation has serious implications for several metrics which are routinely used in clinical practice, e.g., ejection fraction. The remarkable difference between ventricular size in men and women is also a powerful starting point for the study of aging and the investigation of interventions such as exercise. In this review we evaluate sex-specific characteristics of the VRG and the implications for various cardiac patient populations, during basal conditions and intervention such as exercise.

The heart can be viewed not just as muscle pump but also as an important checkpoint for a complex network of nervous, endocrine, and immune signals. The heart is able to process neurological signals independently from the brain and to crosstalk with the endocrine and immune systems. The heart communicates with the psyche through the neuro-endocrine-immune system in a highly integrated way, in order to maintain the homeostasis of the whole body with peculiarities specific to males and females.

Phenotypic sex differences in coronary artery disease (CAD) and its risk factors have been apparent for many decades in basic and clinical research; however, whether these are also present at the gene level and thus influence genome-wide association and genetic risk prediction studies has often been ignored. From fundamental and medical standpoints, this is critically important to assess in order to fully understand the underlying genetic architecture that predisposes to CAD and better predict disease outcomes based on the interaction between genes, sex effects, and environment. In this chapter we aimed to (1) integrate the history and latest research from genome-wide association studies for CAD and clinical and genetic risk scores for prediction of CAD, (2) highlight sex-specific differences in these areas of research, and (3) discuss reasons why sex differences have often not been considered and, where present, why sex differences exist at genetic and phenotypic levels and how important they are for consideration in future research. While we find interesting examples of sex differences in effects of genetic variants on CAD, genome-wide association and genetic risk studies have typically not tested for sex-specific effects despite mounting evidence from diverse fields that these are likely very important to consider at both the genetic and phenotypic levels. In-depth testing for sex effects in large-scale genome-wide association studies that include autosomal and often excluded sex chromosomes alongside parallel improvements in resolution of sex-specific differences for risk factors and disease outcomes for CAD has the potential to substantially improve clinical and genetic risk prediction studies. Developing sex-tailored genetic risk scores as has been done recently for other disorders might be also warranted for CAD. In the era of precision medicine, this level of accuracy is essential for such a common and costly disease.

Despite several advancements in stroke care, disparities continue to exist with regard to sex differences in cerebrovascular disease. These sex differences are due to a combination of several factors, many of which are unique to the female sex. Some of these unique factors, such as pregnancy and menopause, are related to hormonal changes seen throughout the female life cycle. Hormonal fluctuations, which impact the protective effects of the female sex hormones, can be induced by the use of hormonal contraception. Other risk factors, although present in both sexes, have a higher prevalence in elderly females, such as atrial fibrillation leading to cardioembolic strokes. Similarly, differences in premorbid modified Rankin Scale have an impact on the differences in stroke outcome between the two sexes. Clinical research aimed toward highlighting potential causes of these disparities has shown important differences in the calibers of blood vessels in the cerebral circulation between the two sexes, whereas basic science research has shown differences in circulating endothelial progenitor cell pools between males and females, with higher levels being more protective. With the increasing awareness of these sex differences, future research is being geared toward gender-specific modes of therapy, focusing on the molecular level, as well as the individual patient.

The definition of "abnormal" in clinical sciences is often based on so-called reference values which point to a range that experts by some sort of consensus consider as normal when looking at biological variables. Such a level is commonly calculated by taking (twice) the standard deviation from the mean, or considering certain percentiles. The suspicion or even confirmation of a disease is then established by demonstrating that the value measured exceeds the upper or lower reference value. As is often the case, the measurement accuracy may depend on the conditions and specific method employed to collect and analyze data. This implies that, for example, data assessed by 2D echocardiography possibly differ from those obtained by MRI and therefore require modality-specific reference values. In this review we summarize reference values for the electrocardiogram, cardiac compartmental volumes, and arterial vessel size in males and females for various age groups. These values may further depend on other variables such as body size, physical training status, and ethnicity. Additional variables relevant for cardiology such as those referring to the microcirculation and biomarkers are only mentioned with reference to the pertinent literature. In general, the sex- and age-specific differences observed are often remarkable and warrant consideration in clinical practice and basic biomedical sciences.

Recent advances in cardiac imaging techniques have substantially contributed to a growing interest in the analysis of global cardiac chamber dimensions and regional myocardial deformation. During the cardiac cycle, ventricular luminal volume varies due to the contraction process, which also confers a shape change including substantial alteration of long axis length, as well as rotation of the base compared to the apex. Local deformation can be assessed by strain (rate) analysis. Reviewing the present literature, it must be concluded that there is no single metric available to comprehensively characterize ventricular function. Every candidate advanced thus far has been found to incompletely reflect ventricular performance. This observation is not surprising in view of the complexity of the cardiac pump system. Additionally, sex-specific modifiers may play a role. More than three decades ago, it was shown that on average the ventricular volume is smaller in healthy women compared to matched males. Therefore, the present contribution concerns the interpretation of data derived from the healthy heart in both men and women. Starting from the classical Starling concept, we apply a simple mathematical transformation which permits an insightful representation of ventricular mechanics. Relating end-systolic volume (ESV) to end-diastolic volume creates the ventricular volume regulation graph which features the pertinent working point of an individual heart. This fundamental approach illustrates why certain proposed performance indexes cannot individually reveal the essence of ventricular systolic function. We demonstrate that particular metrics are highly interconnected and just tell us the same story in a different disguise. It is imperative to understand which associations exist and if they expectedly are (nearly) linear or frankly nonlinear. Notably, ejection fraction (EF) is primarily determined by ESV, while in turn EF is not much different from ventriculo-arterial coupling (VAC). Insight into cardiac function is promoted by identification of the paramount/essential components involved. The smaller ESV (p < 0.0001) implies that EF is higher in women and may also have consequences for VAC.

The increase in pulse pressure (PP) that occurs with advancing age is predominantly due to reduced arterial distensibility leading to decreased aortic compliance, particularly in the elderly, in whom high blood pressure mainly manifests as isolated systolic hypertension. Since age-related changes in stroke volume are minimal compared with changes in PP, PP is often considered a surrogate measure of arterial stiffness. However, since PP is determined by both cardiac and arterial function, a more precise and reliable means of assessment of arterial stiffness is arterial pulse wave velocity (PWV), a parameter that is only dependent on arterial properties. Arterial stiffness as measured by PWV has been found to be a powerful pressure-related indicator for cardiovascular morbidity and mortality. We analyzed PP and PWV in men and women of various age groups in healthy volunteers as well as cardiac patients with different types of diseases. The findings identified several striking sex-specific differences which demand consideration in guidelines for diagnostic procedures, for epidemiological analysis, and in evaluation of therapeutic interventions.