Male Cohort Research Articles

The Thai intrapreneur – A mixed methods study exploring intrapreneurship in Thailand

PurposeThis study explores the concept and antecedents of Intrapreneurship among Thai employees in Bangkok, Thailand. Study design/methodology/approachThe study uses an exploratory sequential mixed methodology. The data were collected from twenty-two in-depth interviews with Thai entrepreneurs and employees, followed by a survey of 648 salaried employees from Bangkok. FindingsThe findings from the interviews suggested that a sense of self-belief and ownership, collaboration in a team, the immediate supervisor, certain characteristics of the job and organization, and a culture of innovation in the organization affected intrapreneurship. The quantitative survey findings confirmed that self-efficacy, entrepreneurial orientation, team cohesion, and organizational support were significantly related to intrapreneurship in Thai companies. Additionally, a split data analysis revealed that the factors affecting intrapreneurship were distinct for the male and female cohorts, whereby self-efficacy was significant in the male data, whereas entrepreneurial orientation and team cohesion were significantly related to intrapreneurship in the female data. Practical implicationsThe study proposes the creation of small teams, introduction of role models and internships, and creation of a platform for exchange of ideas as recommendations to encourage intrapreneurship. The study also notes that these initiatives might affect male and female intrapreneurs distinctly. Originality/valueThis is the first notable mixed methods study on intrapreneurship in Thailand. The findings of this study will, therefore, help managers to encourage employees towards intrapreneurial behavior and pave the way for future research on intrapreneurship in Thailand.

Abstract 1004: Three-dimensional Characterization Of Sex Differences In Abdominal Aortic Aneurysm Progression Via Vascular Deformation Mapping

Introduction: Although Abdominal Aortic Aneurysms (AAA) are more common in men, women are at greater risk for AAA growth and rupture. Vascular deformation mapping (VDM) is a novel technique that utilizes deformable image registration to qualify and quantify three-dimensions (3D) AAA growth using routing clinical computed tomography angiogram (CTA) images. Hypothesis: We hypothesize that females will have higher rates of focal AAA growth when compared to males. Aims: In this study we aimed to leverage VDM to investigate sex differences in AAA growth. Methods: We identified patients with infra-renal AAA and ≥2 CTA from 2010-2021. Patients with non-contrast CT scans or poor image quality were excluded. Propensity score matching was used to identify a cohort of males and females matched on age, hypertension, and smoking history. AAA were segmented and VDM was conducted using a multi-step image registration of aortic CTA studies to generate a deformation field which is then used to quantify 3D AAA growth rate (GR). Patient characteristics, maximum diameter (Dmax), AAA volume (Vmax), and GR were obtained. Statistical shape modeling was utilized to compare average 3D growth patterns between males and females. Results: Seventeen male and females with AAA were matched. There was no differences between sexes in race, diabetes, symptomatic status, or repair. Males had a trend toward larger Dmax (4.9 ± 0.6 vs 4.5 ± 0.6 cm, p = 0.055) and had Vmax at baseline (118.7 ± 69.9 vs 76.6 ± 35.0 cm 3 , p = 0.034). There was no difference between sexes when looking at change in Dmax or Vmax. Male and female AAA had no difference in average GR (0.11 ± 0.08 vs 0.17 ± 0.22 cm/year, p = 0.293). Shape models demonstrated more diffuse AAA growth for males and more eccentric AAA growth for females (Figure 1). Conclusions: Despite comparable changes in Dmax, Vmax, and GR, women demonstrated a more eccentric distribution of AAA growth, a finding which may contribute to higher rupture risk in women.

Genetic Upregulation of Activated Protein C Mitigates Delayed Effects of Acute Radiation Exposure in the Mouse Plasma.

Exposure to ionizing radiation, accidental or intentional, may lead to delayed effects of acute radiation exposure (DEARE) that manifest as injury to organ systems, including the kidney, heart, and brain. This study examines the role of activated protein C (APC), a known mitigator of radiation-induced early toxicity, in long-term plasma metabolite and lipid panels that may be associated with DEARE in APCHi mice. The APCHi mouse model used in the study was developed in a C57BL/6N background, expressing the D168F/N173K mouse analog of the hyper-activatable human D167F/D172K protein C variant. This modification enables increased circulating APC levels throughout the mouse's lifetime. Male and female cohorts of C57BL/6N wild-type and APCHi transgenic mice were exposed to 9.5 Gy γ-rays with their hind legs shielded to allow long-term survival that is necessary to monitor DEARE, and plasma was collected at 6 months for LC-MS-based metabolomics and lipidomics. We observed significant dyslipidemia, indicative of inflammatory phenotype, upon radiation exposure. Additionally, observance of several other metabolic dysregulations was suggestive of gut damage, perturbations in TriCarboxylic Acid (TCA) and urea cycles, and arginine metabolism. We also observed gender- and genotype-modulated metabolic perturbations post radiation exposure. The APCHi mice showed near-normal abundance for several lipids. Moreover, restoration of plasma levels of some metabolites, including amino acids, citric acid, and hypoxanthine, in APCHi mice is indicative of APC-mediated protection from radiation injuries. With the help of these findings, the role of APC in plasma molecular events after acute γ-radiation exposure in a gender-specific manner can be established for the first time.

Differentially co-expressed myofibre transcripts associated with abnormal myofibre proportion in chronic obstructive pulmonary disease.

Skeletal muscle dysfunction is a common extrapulmonary manifestation of chronic obstructive pulmonary disease (COPD). Alterations in skeletal muscle myosin heavy chain expression, with reduced type I and increased type II myosin heavy chain expression, are associated with COPD severity when studied in largely male cohorts. The objectives of this study were (1) to define an abnormal myofibre proportion phenotype in both males and females with COPD and (2) to identify transcripts and transcriptional networks associated with abnormal myofibre proportion in COPD. Forty-six participants with COPD were assessed for body composition, strength, endurance and pulmonary function. Skeletal muscle biopsies from the vastus lateralis were assayed for fibre-type distribution and cross-sectional area via immunofluorescence microscopy and RNA-sequenced to generate transcriptome-wide gene expression data. Sex-stratified k-means clustering of type I and IIx/IIax fibre proportions was used to define abnormal myofibre proportion in participants with COPD and contrasted with previously defined criteria. Single transcripts and weighted co-expression network analysis modules were tested for correlation with the abnormal myofibre proportion phenotype. Abnormal myofibre proportion was defined in males with COPD (n=29) as <18% type I and/or >22% type IIx/IIax fibres and in females with COPD (n=17) as <36% type I and/or >12% type IIx/IIax fibres. Half of the participants with COPD were classified as having an abnormal myofibre proportion. Participants with COPD and an abnormal myofibre proportion had lower median handgrip strength (26.1 vs. 34.0kg, P=0.022), 6-min walk distance (300 vs. 353m, P=0.039) and forced expiratory volume in 1s-to-forced vital capacity ratio (0.42 vs. 0.48, P=0.041) compared with participants with COPD and normal myofibre proportions. Twenty-nine transcripts were associated with abnormal myofibre proportions in participants with COPD, with the upregulated NEB, TPM1 and TPM2 genes having the largest fold differences. Co-expression network analysis revealed that two transcript modules were significantly positively associated with the presence of abnormal myofibre proportions. One of these co-expression modules contained genes classically associated with muscle atrophy, as well as transcripts associated with both type I and type II myofibres, and was enriched for genetic loci associated with bone mineral density. Our findings indicate that there are significant transcriptional alterations associated with abnormal myofibre proportions in participants with COPD. Transcripts canonically associated with both type I and type IIa fibres were enriched in a co-expression network associated with abnormal myofibre proportion, suggesting altered transcriptional regulation across multiple fibre types.

Prognostic Significance of NLR and PLR in COVID-19: A Multi-Cohort Validation Study.

Recent studies have highlighted the prognostic value of easily accessible inflammatory markers, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) for predicting severe outcomes in patients affected by Coronavirus disease 2019 (COVID-19). Our study validates NLR and PLR cut-off values from a prior cohort at IRCCS Policlinico San Matteo (OSM) of Pavia, Italy, across two new cohorts from different hospitals. This aims to enhance the generalizability of these prognostic indicators. In this retrospective cohort study, conducted at Milan's Ospedale Luigi Sacco (OLS) and IRCCS Ospedale Maggiore Policlinico (OMP) hospitals, we assess the predictive capacity of NLR and PLR for three main outcomes-non-invasive ventilation (NIV) or continuous positive airway pressure (CPAP) usage, invasive ventilation (IV), and death-in patients with COVID-19 at admission. For each outcome, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were computed separately for male and female cohorts. Distinct NLR and PLR cut-off values were used for men (7.00, 7.29, 7.00 for NLR; 239.22, 248.00, 250.39 for PLR) and women (6.36, 7.00, 6.28 for NLR; 233.00, 246.45, 241.54 for PLR), retrieved from the first cohort at OSM. A total of 3599 patients were included in our study, 1842 from OLS and 1757 from OMP. OLS and OMP sensitivity values for both NLR and PLR (NLR: 24-67%, PLR: 40-64%) were inferior to specificity values (NLR: 64-76%, PLR: 55-72%). Additionally, PPVs generally remained lower (< 63%), while NPVs consistently surpassed 68% for PLR and 72% for NLR. Finally, both PLR and NLR exhibited consistently higher NPVs for more severe outcomes (> 82%) compared to NPVs for CPAP/NIV. Consistent findings across diverse patient populations validate the reliability and applicability of NLR and PLR cut-off values. High NPVs emphasize their role in identifying individuals less likely to experience severe outcomes. These markers not only aid in risk stratification but also guide resource allocation in emergencies or limited-resource situations.

Angiopoietin-2, vascular endothelial growth factor family, and heparin binding endothelial growth factor are associated with subclinical atherosclerosis in rheumatoid arthritis

IntroductionPatients with RA are at a higher risk of developing CV diseases than the general population. The precise mechanisms are still unknown. We evaluated the associations between 8 plasma growth factors (GFs) (angiopoietin-2, EGF, HB-EGF, PLGF, TGF-α, VEGFa, VEGFc, and VEGFd) and subclinical arteriosclerosis in RA patients. Materials and methodsA total of 199 patients with RA treated at the Hospital Universitari Sant Joan de Reus (Spain) between 2011 and 2015 were included in this cross-sectional study. Carotid intima media thickness (cIMT), carotid plaque presence (cPP) and pulse wave velocity (PWV) were measured. GFs were measured with Bio-Plex Pro Human Cancer Biomarker Panel 2 (Bio-Rad). Multivariate models and partial least square discriminant analysis (PLS-DA) were used for analysis (RStudio, version 4.0.1). ResultsMultivariate models showed that angiopoietin-2 was associated with cPP and PWV in the overall cohort (OR = 1.53 and β = 0.20, respectively). VEGFc (β = 0.29), VEGFa (β = 0.26) and HB-EGF (β = 0.22) were also associated with PWV. VEGFa (OR = 2.36), VEGFd (OR = 2.29), EGF (OR = 2.62), PLGF (OR = 2.54), and HB-EGF (OR = 2.24) were associated with cPP in men. According to PLS-DA, GFs were able to distinguish between patients with and without cPP in the overall cohort, male cohort, and female cohort. In women, angiopoietin-2 was associated with PWV (β = 0.18). ConclusionsThe selected GFs were closely related to atherosclerosis in patients with RA and are potential predictors of CV disease in patients with RA.

Toward clinical exomes in diagnostics and management of male infertility

Infertility, affecting ∼10% of men, is predominantly caused by primary spermatogenic failure (SPGF). We screened likely pathogenic and pathogenic (LP/P) variants in 638 candidate genes for male infertility in 521 individuals presenting idiopathic SPGF and 323 normozoospermic men in the ESTAND cohort. Molecular diagnosis was reached for 64 men with SPGF (12%), with findings in 39 genes (6%). The yield did not differ significantly between the subgroups with azoospermia (20/185, 11%), oligozoospermia (18/181, 10%), and primary cryptorchidism with SPGF (26/155, 17%). Notably, 19 of 64 LP/P variants (30%) identified in 28 subjects represented recurrent findings in this study and/or with other male infertility cohorts. NR5A1 was the most frequently affected gene, with seven LP/P variants in six SPGF-affected men and two normozoospermic men. The link to SPGF was validated for recently proposed candidate genes ACTRT1, ASZ1, GLUD2, GREB1L, LEO1, RBM5, ROS1, and TGIF2LY. Heterozygous truncating variants in BNC1, reported in female infertility, emerged as plausible causes of severe oligozoospermia. Data suggested that several infertile men may present congenital conditions with less pronounced or pleiotropic phenotypes affecting the development and function of the reproductive system. Genes regulating the hypothalamic-pituitary-gonadal axis were affected in >30% of subjects with LP/P variants. Six individuals had more than one LP/P variant, including five with two findings from the gene panel. A 4-fold increased prevalence of cancer was observed in men with genetic infertility compared to the general male population (8% vs. 2%; p= 4.4×10-3). Expanding genetic testing in andrology will contribute to the multidisciplinary management of SPGF.

Differences in help-seeking behaviour between males and females with multiple pelvic floor symptoms: A qualitative study

BackgroundPelvic floor symptoms (PFS) are common and frequently co-occur, but few patients seek help despite negative effects on their quality of life. Moreover, most studies assessing help-seeking behaviour have only focused on a single PFS. AimWe aimed to explore the barriers to and facilitators of help-seeking behaviour in males and females with at least two PFS. Design and SettingThis interview-based study included participants by age and symptoms (number and type) from a larger group taking part in a survey on PFS in the general population. MethodTwo researchers independently encoded and analyzed the semi-structured interviews, which continued to saturation for both the male and female cohorts. ResultsOf the 25 participants (13 male and 12 female), 9 sought help for all PFS, 10 did not seek help for any PFS, and 6 sought help for some PFS. We identified themes in domains related to the patient, healthcare professional, environment, and symptoms. Although most themes applied to both sexes, some had greater sex specificity. ConclusionMales and females have more similarities than differences in help-seeking behaviour. Healthcare providers should know that patients who seek help for one symptom probably have multiple PFS that the patient has not reported.

In silico analysis of overall survival with YBX1 in male and female solid tumours

The Y-box binding protein-1 (YBX1) gene codes for a multifunctional oncoprotein that is increasingly being linked to the regulations of many aspects of cancer cell biology. Disparities in treatment outcomes between male and female cancer patients are increasingly reported. This study aimed to examine the relationship between YBX1 expression and overall survival in male and female patients with solid tumours. Overall survival and YBX1 expression data for cohorts of male and female cancer patients obtained from freely available databases were analysed with a cox proportional hazard model with covariates of biological sex and YBX1 expression. Kaplan–Meier curves and Violin plots were constructed for segregated male and female cohorts. High YBX1 expression was significantly associated with poor survival in 2 female-only and 4 mixed-sex cancer sites. In female lung cancer patients, better survival and lower YBX1 expression were identified. The clinical importance of YBX1 expression in cancer ought to be evaluated in a sex-specific manner, especially in lung cancer.

Global trends in hepatitis C-related hepatocellular carcinoma mortality: A public database analysis (1999-2019).

Hepatitis C is the leading cause of chronic liver disease worldwide and it significantly contributes to the burden of hepatocellular carcinoma (HCC). However, there are marked variations in the incidence and mortality rates of HCC across different geographical regions. With the advent of new widely available treatment modalities, such as direct-acting antivirals, it is becoming increasingly imperative to understand the temporal and geographical trends in HCC mortality associated with Hepatitis C. Furthermore, gender disparities in HCC mortality related to Hepatitis C are a crucial, yet underexplored aspect that adds to the disease's global impact. While some studies shed light on gender-specific trends, there is a lack of comprehensive data on global and regional mortality rates, particularly those highlighting gender disparities. This gap in knowledge hinders the development of targeted interventions and resource allocation strategies. To understand the global and regional trends in Hepatitis C-related HCC mortality rates from 1990 to 2019, along with gender disparities. We utilized the Global Burden of Disease database, a comprehensive repository for global health metrics to age-standardized mortality rates due to Hepatitis C-related HCC from 1999 to 2019. Rates were evaluated per 100000 population and assessed by World Bank-defined regions. Temporal trends were determined using Joinpoint software and the Average Annual Percent Change (AAPC) method, and results were reported with 95% confidence intervals (CI). From 1990 to 2019, overall, there was a significant decline in HCC-related mortality rates with an AAPC of -0.80% (95%CI: -0.83 to -0.77). Females demonstrated a marked decrease in mortality with an AAPC of -1.06% (95%CI: -1.09 to -1.03), whereas the male cohort had a lower AAPC of -0.52% (95%CI: -0.55 to -0.48). Regionally, East Asia and the Pacific demonstrated a significant decline with an AAPC of -2.05% (95%CI: -2.10 to -2.00), whereas Europe and Central Asia observed an uptrend with an AAPC of 0.72% (95%CI: 0.69 to 0.74). Latin America and the Caribbean also showed an uptrend with an AAPC of 0.06% (95%CI: 0.02 to 0.11). In the Middle East and North Africa, the AAPC was non-significant at 0.02% (95%CI: -0.09 to 0.12). North America, in contrast, displayed a significant upward trend with an AAPC of 2.63% (95%CI: 2.57 to 2.67). South Asia (AAPC -0.22%, 95%CI: -0.26 to -0.16) and Sub-Saharan Africa (AAPC -0.14%, 95%CI: -0.15 to -0.12) trends significantly declined over the study period. Our study reports disparities in Hepatitis C-related HCC mortality between 1999 to 2019, both regionally and between genders. While East Asia and the Pacific regions showed a promising decline in mortality, North America has experienced a concerning rise in mortality. These regional variations highlight the need for healthcare policymakers and practitioners to tailor public health strategies and interventions. The data serves as a call to action, particularly for regions where mortality rates are not improving, emphasizing the necessity for a nuanced, region-specific approach to combat the global challenge of HCC secondary to Hepatitis C.

Gender-specific association between blood cell parameters and hyperuricemia in high-altitude areas.

Hyperuricemia is a common metabolic disorder linked to various health conditions. Its prevalence varies among populations and genders, and high-altitude environments may contribute to its development. Understanding the connection between blood cell parameters and hyperuricemia in high-altitude areas can shed light on the underlying mechanisms. This study aimed to investigate the relationship between blood cell parameters and hyperuricemia in high-altitude areas, with a particular focus on gender differences. We consecutively enrolled all eligible Tibetan participants aged 18-60 who were undergoing routine medical examinations at the People's Hospital of Chaya County between January and December 2022. During this period, demographic and laboratory data were collected to investigate the risk factors associated with hyperuricemia. Among the participants, 46.09% were diagnosed with hyperuricemia. In the male cohort, significant correlations were found between serum uric acid (SUA) levels and red blood cell (RBC) count, creatinine (Cr). Urea, alanine transaminase (ALT), and albumin (ALB). Notably, RBC exhibited the strongest association. Conversely, in the female cohort, elevated SUA levels were associated with factors such as white blood cell (WBC) count. Urea, ALT, and ALB, with WBC demonstrating the most significant association. Further analysis within the female group revealed a compelling relationship between SUA levels and specific white blood cell subtypes, particularly neutrophils (Neu). This study revealed gender-specific associations between SUA levels and blood cell parameters in high-altitude areas. In males, RBC count may play a role in hyperuricemia, while in females, WBC count appears to be a significant factor. These findings contribute to our understanding of metabolic dynamics in high-altitude regions but require further research for comprehensive mechanistic insights.

Adolescent nicotine exposure induces long-term, sex-specific disturbances in mood and anxiety-related behavioral, neuronal and molecular phenotypes in the mesocorticolimbic system.

The majority of lifetime smokers begin using nicotine during adolescence, a critical period of brain development wherein neural circuits critical for mood, affect and cognition are vulnerable to drug-related insults. Specifically, brain regions such as the medial prefrontal cortex (mPFC), the ventral tegmental area (VTA), nucleus accumbens (NAc) and hippocampus, are implicated in both nicotine dependence and pathological phenotypes linked to mood and anxiety disorders. Clinical studies report that females experience higher rates of mood/anxiety disorders and are more resistant to smoking cessation therapies, suggesting potential sex-specific responses to nicotine exposure and later-life neuropsychiatric risk. However, the potential neural and molecular mechanisms underlying such sex differences are not clear. In the present study, we compared the impacts of adolescent nicotine exposure in male vs. female rat cohorts. We performed a combination of behavioral, electrophysiological and targeted protein expression analyses along with matrix assisted laser deionization imaging (MALDI) immediately post-adolescent exposure and later in early adulthood. We report that adolescent nicotine exposure induced long-lasting anxiety/depressive-like behaviors, disrupted neuronal activity patterns in the mPFC-VTA network and molecular alterations in various neural regions linked to affect, anxiety and cognition. Remarkably, these phenotypes were only observed in males and/or were expressed in the opposite direction in females. These findings identify a series of novel, sex-selective biomarkers for adolescent nicotine-induced neuropsychiatric risk, persisting into adulthood.

Abstract 3764: Spatially resolved immune landscape revealed sex-biased T-cell infiltration in glioblastoma

Abstract Glioblastoma (GBM) multiforme is the most aggressive type of brain cancer. These lethal brain tumors are characterized by the inter- and intra-tumor molecular heterogeneity and demonstrated cell plasticity. A male:female distribution of 1.6:1; survival outcome from treatment (debulking, radiation, and temozolomide) benefits females nearly twice that for males. Through spatial transcriptomics, we interrogated the immune landscape of GBM, seeking to tease out whether distinct biological and therapeutic niches in GBM were evident, and to understand how the tumor microenvironments contributed to the heterogeneity of GBM. We designed a set of RNA hybridization probes specifically for portraying the cell identities and cell functional states within GBM tumor. The probe set was used to profile six human GBM samples from male and female cohorts on the Vizgen MERSCOPE platform. An integrated analysis of 505,614 cells from the six samples yielded a rich and varied spatial cell atlas of glioblastoma. Our preliminary findings depict distinct spatial niches of different tumor cell subpopulations that are associated with local environmental factors such as hypoxia. We identified a small cluster of cells that are in neuronal-like state, which could potentially drive invasion. We found spatial proximity of CD4+ cells and cells that express HIF1A, suggesting the dynamic interactions between tumor cells, regulatory T cells and tumor microenvironment. We also observed significant difference in the degree of CD8+ T-cell infiltration in female samples versus male samples. The average CD4+/CD8+ T-cell ratio in males is twice as high as that of females, suggesting intrinsic sex-based differences in immune response to tumor. Expansion of these studies in additional specimens will further illuminate microenvironmental influences on glioma progression and may instruct specific interventions leading to more effective and predictable immune-oncology of this disease. Citation Format: Yue Hao, George Reid, Angela Baker, Karen L. Fink, George J. Snipes, Bruce E. Mickey, Andrew E. Sloan, Jill S. Barnholtz-Sloan, Michael Berens. Spatially resolved immune landscape revealed sex-biased T-cell infiltration in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3764.

Abstract 3372: Clinical genetic testing results in metastatic prostate cancer patients

Abstract Background: A proportion of prostate cancers (PCa) are hereditary, driven by likely pathogenic/pathogenic germline variants (PGVs) in DNA repair genes. PGVs in BRCA2 contribute to aggressive prostate cancer biology and overall poorer survival. Genetic testing and targeted sequencing panels help identify PGV carriers who are susceptible to aggressive PCa and may be candidates for targeted therapy with PARP inhibitors. Prior research suggested a high rate of 10-20% of metastatic PCa (mPCa) patients have PGVs in DNA repair genes; however, many of these studies reported highly selected research cohorts. The real-world rate of DNA repair PGVs and whether any genotype-phenotype correlations exist in broader, more racially diverse clinical populations are not well understood. Patients and Methods: We studied two prospective cohorts of males with PCa who presented for genetic testing due to meeting NCCN personal history genetic testing criteria for prostate cancer (metastatic or high risk/very high risk localized). We report PGV frequencies of mPCa patients who underwent genetic testing in a point of care model at the Basser Center within Penn Medicine (Penn-POC, n=596), and a cancer genetics practice at the Corporal Michael Crescenz VA Medical Center in Philadelphia (VA-GT, n = 171). PGVs were identified in ATM, BRCA1, BRCA2, CHEK2, EPCAM, HOXB13, MLH1, MSH2, MSH6, NBN, PMS2, TP53. Results: The Penn-POC and VA-GT cohort included 437 (73.3%) and 59 (34.5%) self-identified white patients, respectively, and 121 (20.3%) and 107 (62.6%) self-identified black patients, respectively. In the Penn-POC and VA-GT cohorts, 7.2% and 7.6% patients were found to carry a PGV, respectively, and 11.9% and 18.1% of patients had variants of uncertain significance (VUS), respectively. The most common PGVs in the Penn-POC cohort were in BRCA2 (2.2%), ATM (1.9%), and BRCA1 (1.3%). The most common PGVs in the VA-GT cohort were in BRCA2 (2.9%), ATM (1.1%), and CHEK2 (1.2%). PGV rates were not statistically different between self-identified white and black patients in either cohort (Penn-POC p= 0.4036; VA-GT p=0. 0.4061). Overall PGV frequencies between the Penn-POC and VA-GT cohorts are not statistically different. There is a correlation between carrier status and age at diagnosis with a significant difference between carriers and non-carriers (p=0.0433) as well as with family history of first degree relatives with PCa (p=0.0184). However, there was not a significant correlation between carrier status and clinical stage at diagnosis, Gleason grade group, or other clinical variables. Conclusions: We report a lower rate of DNA repair PGVs in two prospectively ascertained, racially diverse cohorts of mPCa patients, approximately 7%, compared to the previously reported rates of 10-20%. Our results suggest age and family history, but not other pathological variables are clinical predictors for carrying a PGV in mPCa patients. Citation Format: Taylor Crawford, Emanuel Barrett, Tara Al-Saleem, Maliha Tayeb, Heather Symecko, Caitlin Orr, Vivek Narayan, Samuel Takvorian, Ravi B. Parikh, Yu-Ning Wong, Kyle Robinson, Lisa B. Aiello, Catherine Wolfe, Derek Mann, Kelsey Spielman, Susan M. Domchek, Kara N. Maxwell. Clinical genetic testing results in metastatic prostate cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3372.

Abstract 6832: Gender specific role of LMTK3 in neuronal-tumor microenvironment crosstalk in CRC

Abstract Background: Lemur tail kinase 3 (LMTK3) is a serine/threonine protein kinase with roles in multiple cellular pathways, including Wnt signaling, KIT modulation, and the estrogen receptor pathway; identifying it as a potential target in various cancers. LMTK3 is highly expressed within the central nervous system (CNS) and has been demonstrated to influence neuronal signaling. This study aimed to investigate the potential connection between LMTK3 and neuronal signaling pathways in colorectal cancer (CRC). Methods: Using the Cre/loxP system, we generated a C57BL/6 mouse strain that lacks the expression of LMTK3. 1 × 106 MC38 cells were subcutaneously implanted into 8 weeks old male and female wildtype (WT) and knockout (KO) mice. Tumor growth was measured until endpoint was reached. Tumors were then processed for RNA sequencing. Differentially expressed genes (DEGs) for each comparison group: WT Female vs WT Male, WT Female vs KO Female, WT Male vs KO Male, and KO Female vs KO Male were analyzed. Ingenuity pathway analysis (IPA) was done for identification of upstream regulators involved and affected cellular pathways. Expression levels of DEGs for glutamate receptor subunits were validated using qRT-PCR. Results: Both male and female LMTK3 KO mice showed highly significant (p&amp;lt;0.01) reduced tumor size when compared to WT mice of the same sex. Additionally, the KO female tumors were significantly (p&amp;lt;0.05) smaller when compared to the KO males. RNA sequencing revealed 761 DEGs in KO and WT female and 133 DEGs in KO female and male cohort comparisons (q&amp;lt;0.05). IPA results showed significant (p&amp;lt;0.01, Z-score←2) alterations in pathways including glutaminergic receptor signaling, neurovascular coupling, CREB signaling in neurons, and synaptic long-term depression in the WT vs KO female tumor cohort comparison. Within these pathways DEGs: CACNA1E, CACNA2DA, CACNG2, GRIA1, GRIA2, GRIN1, and GRIN2B, were downregulated in KO females. Upstream regulator analysis identified transcription regulators such as OTX2 and NEUROD1 as well as beta-estradiol to be significantly inhibited (p&amp;lt;0.01, Z-score←2) in KO females. qRT-PCR analysis showed significant (p&amp;lt;0.05) decreased expression in GRIA1, GRIN1, and GRIN2B as well as GRIN2A and GRIN2C in KO females when compared to WT females or KO males, validating RNA seq results. Conclusions: These results showed the involvement of LMTK3 in the gut-brain axis and its effect on CRC tumor growth. Downregulation of multiple neuronal pathways and genes suggest that LMTK3 may influence neuron signaling and neurotransmitter release to produce stimulatory or inhibitory effects within the tumor environment. The concurrent inhibition of beta-estradiol in LMTK3 KO tumors allude to possible sex differences the kinase’s effect on the observed tumor growth. Further studies are needed to confirm the mechanism of interaction of LMTK3 within these pathways. Citation Format: Lesly Torres-Gonzalez, Shivani Soni, Yan Yang, Goar Smbatyan, Jae Ho Lo, Pooja Mittal, Francesca Battaglin, Indrakant K. Singh, Priya Jayachandran, Sandra Algaze, Alexandra Wong, Karam Ashouri, Wu Zhang, Georgios Giamas, Joshua Millstein, Heinz-Josef Lenz. Gender specific role of LMTK3 in neuronal-tumor microenvironment crosstalk in CRC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6832.

Mortality Time-Trends of Different Cardiovascular Diseases in a Practically Extinct Cohort of Italian Middle-Aged Men Followed-Up for 61 Years: A Possible Etiological Explanation?

To study a male Italian cohort (initially aged 40-59, n = 1712) during 61 years and the natural history of major CVD mortality categories including coronary heart disease (CHD), stroke and other heart diseases of uncertain etiology (HDUE), including congestive heart failure) along with their risk factor relationships. Cox models were run with 12 covariates as possible predictors measured at entry to the study. About 93% of all CVD deaths were covered by the three major groups selected here (N = 751): 37.4% of them were diagnosed as CHD, 30.6% as stroke and 28.5% as HDUE. CHD declined in the last 20 years of follow-up, while a sharp increase in HDUE mortality was seen. Baseline mean levels of serum cholesterol were 209.6, 204.2 and 198.0 mg/dL, respectively, for CHD, stroke and HDUE deaths: the multivariable coefficients of serum cholesterol were positive and significant for CHD (p < 0.0001), and stroke (p = 0.0203) and not significant for HDUE (p = 0.3467). In Fine-Gray models, the algebraic signs of cholesterol coefficients were opposite for CHD versus the other mortality categories (t = 3.13). The predictive performances of remaining risk factors were varied whereas that of Cox models was not very good, probably due to the attrition phenomenon and possible competing risks. Large differences in natural history and risk factors were found comparing the three CVD conditions, potentially indicating different etiologies and pointing to the need of not mixing them up in a grouped CVD category.

Sex differences in long-term survival after total arterial coronary artery bypass grafting.

It is uncertain if the evidence on improved long-term survival of total arterial coronary artery bypass grafting applies to female patients. This study aims to compare the long-term survival outcomes of using total arterial revascularization (TAR) versus at least 1 saphenous vein graft separately for men and women. This retrospective analysis of the Australian and New Zealand Society of Cardiac-Thoracic Surgical Database had administrative linkage to the National Death Index. We identified all patients undergoing primary isolated coronary bypass from June 2001 to January 2020 inclusive. Following sex stratification, propensity score matching with 36 variables and Cox proportional hazard regression were used to facilitate adjusted comparisons. A Cox interaction-term analysis was performed to investigate the impact of sex on TAR survival benefit. The primary outcome was all-cause mortality. Of the 69 624 eligible patients receiving at least 2 grafts, 13 019 (18.7%) were female patients. Matching generated 14 951 male and 3530 female pairs. Compared to vein-dependent procedures, TAR was associated with significantly reduced incidence of long-term all-cause mortality for both male (hazard ratio, 0.86; 95% confidence interval, 0.81-0.91; P < 0.001) and female (hazard ratio, 0.82; 95% confidence interval, 0.73-0.91; P < 0.001) cohorts. Interaction-term analysis indicated no significant subgroup effect from sex (P = 0.573) on the survival advantage of TAR. The treatment effect provided by TAR remained significant across most sex-stratified disease subgroups. TAR, when compared to the use of at least 1 saphenous vein graft, provides comparable superior long-term survival outcomes in both females and males.

Whole-Exome Sequencing (WES) Reveals Novel Sex-Specific Gene Variants in Non-Alcoholic Steatohepatitis (MASH).

Non-alcoholic steatohepatitis (NASH, also known as MASH) is a severe form of non-alcoholic fatty liver disease (NAFLD, also known as MASLD). Emerging data indicate that the progression of the disease to MASH is higher in postmenopausal women and that genetic susceptibility increases the risk of MASH-related cirrhosis. This study aimed to investigate the association between genetic polymorphisms in MASH and sexual dimorphism. We applied whole-exome sequencing (WES) to identify gene variants in 8 age-adjusted matched pairs of livers from both male and female patients. Sequencing alignment, variant calling, and annotation were performed using standard methods. Polymerase chain reaction (PCR) coupled with Sanger sequencing and immunoblot analysis were used to validate specific gene variants. cBioPortal and Gene Set Enrichment Analysis (GSEA) were used for actionable target analysis. We identified 148,881 gene variants, representing 57,121 and 50,150 variants in the female and male cohorts, respectively, of which 251 were highly significant and MASH sex-specific (p < 0.0286). Polymorphisms in CAPN14, SLC37A3, BAZ1A, SRP54, MYH11, ABCC1, and RNFT1 were highly expressed in male liver samples. In female samples, Polymorphisms in RGSL1, SLC17A2, HFE, NLRC5, ACTN4, SBF1, and ALPK2 were identified. A heterozygous variant 1151G>T located on 18q21.32 for ALPK2 (rs3809983) was validated by Sanger sequencing and expressed only in female samples. Immunoblot analysis confirmed that the protein level of β-catenin in female samples was 2-fold higher than normal, whereas ALPK2 expression was 0.5-fold lower than normal. No changes in the protein levels of either ALPK2 or β-catenin were observed in male samples. Our study suggests that the perturbation of canonical Wnt/β-catenin signaling observed in postmenopausal women with MASH could be the result of polymorphisms in ALPK2.

Evaluating the management trends for priapism and assessing the risk of priapism after in-office intracavernosal injections: a cross-sectional analysis.

We describe the management trends of patients suffering from any priapism and evaluate the risks of developing priapism after intracavernosal injections (ICI) performed in office. We queried TriNetX for two separate male adult cohorts - those presenting with any priapism based on International Classification of Disease code, N48.3 (priapism) and those who underwent ICI in office based on Current Procedural Terminology code, 54235 (injection of corpora cavernosa with pharmacologic agent[s]). We evaluated treatment options for these patients after any priapism and described demographic risks for developing priapism after ICI performed in office. There were 17,545 priapism encounters and 26,104 usages of ICI in the office. Most common treatment for any priapism was corporal irrigation/injection of medications (11.3%). Patients presenting with priapism after ICI were younger (age > 65 years, OR 0.44 [95% CI 0.38-0.51], p < 0.01) and had a higher prevalence of mood disorders (20% vs 14%), behavioral disorders (7% vs 2%) and sickle cell disease (6% vs <1%). They were less likely to have diabetes (14% vs 22%), hypertension (33% vs 40%), prostate cancer (13% vs 25%) or have taken sildenafil or tadalafil (29-30% vs 35-38%). For patients administering ICI, proper screening and counseling of priapism is important to reduce complications.

(147) Analysis of Sexual Dysfunction Development among Male and Female Living Kidney Donors

Abstract Introduction The need for kidney donations in patients with end-stage kidney disease has continued to exceed the number of deceased donor transplants, signifying the need for the continued growth, sustainability, and success of living kidney donation. Following donation, living kidney donors have excellent survival rates with mixed data regarding long-term outcomes of renal failure, hypertension, and proteinuria. However, no studies to our knowledge have looked at differences in the development of long-term sexual dysfunction following living kidney donation, a potentially serious quality of life issue. Objective To analyze differences in five-year sexual dysfunction outcomes among male and female living kidney donors using the US Collaborative Network within the TriNetX database, a federated network of EMR data from multiple healthcare organizations across the United States. Methods We used the TriNetX database to perform a propensity score-matched cohort study comparing five-year outcomes of sexual dysfunction development among adult (≥18) male living kidney donors (Male) and female living kidney donors (Female) from December 2013 to December 2022. Living kidney donors were defined as the presence of one diagnostic code and one procedural code. Patients were excluded from the study if they had any instance of diagnosed transplant status (by ICD-10) or transplantation procedures (by CPT) prior to the kidney donor status. Patients were matched on age, sex, race, ethnicity, marital status, diabetes mellitus, cardiovascular disease, personal history of genitourinary disease, presence of urogenital implants, mood disorders, BMI, tobacco and alcohol use, and problems related to lifestyle and socioeconomic circumstances. Primary outcomes analysis included 5-year hazard ratio of diagnosed decreased libido, sexual dysfunction (composite of new diagnosed male ED, vaginismus/dyspareunia, infertility, orgasmic disorders, arousal/desire disorders, or unspecified), UTI, and STDs. Secondary outcomes included sex counseling or problems in relationship with spouse or partner. Results There were 2,821 patients in each cohort after matching (Male, Female). Mean age of the cohort was 42.7 ± 12.7, 73.3% were White, and 10.8% were Hispanic/Latino (p &amp;gt;0.05). At 5-years, Kaplan-Meier analysis revealed that the Male donor cohort had a significantly higher hazard ratio (HR) than Female donors for sexual dysfunction (HR: 3.006, 95% Confidence Interval [CI]: 1.761,5.131). Between the cohorts, 39 (1%) Male patients developed ED and ~10 (&amp;lt;1%) Female patients developed vaginismus/dyspareunia within 5 years. No significant difference was found for the development of sexual arousal disorders/desire disorders (0.17% vs 0.06%, p = 0.052), orgasmic disorders (0.03% vs 0.03%, p = 0.99), decreased libido (0.48% vs 0.85%, p =0.94) and STD’s (0.72% vs 0.89%, p = 0.70). For secondary outcomes, no significant difference was found for the 5-year hazard of need for sex counseling or interpersonal relationship issues. Conclusions In our analysis of this large, real-world database, we found that male living kidney donors had higher rates of sexual dysfunction development 5-years post-living kidney donation. While living kidney donation is a safe, viable, and excellent alternative to deceased kidney donation, clinicians and living donors should both be aware about the potential association of developing sexual dysfunction post-donation. Disclosure No.