US Men Research Articles

Abstract LB162: Human herpesvirus 8 infection is associated with prostate cancer among IFNL4-ΔG carriers

Abstract Background: Chronic inflammation as seen with chronic infections, has been proposed as a risk factor for prostate cancer. Numerous studies failed to identify a specific microbial agent associated with prostate cancer risk. We have previously reported that human herpesvirus 8 (HHV-8) is associated with increased prostate cancer risk in Tobago; a population that is 97% of African ancestry. This association was not found in several studies of US men, who were predominately of European American ancestry. It is unclear if the discrepancies between US and Tobago men are due to differences in HHV-8 seroprevalence rates or ancestry-related genetics. Previous studies have reported that the dinucleotide germline variant, rs368234815-ΔG, in the IFNL4 gene encoding interferon λ4 is more prevalent among individuals of African ancestry and impairs viral clearance. In this study, we investigated whether the association of HHV-8 with prostate cancer is IFNL4-ΔG-dependent. Methods: We investigated the association of HHV-8 seropositivity with prostate cancer in 728 IFNL4-ΔG-genotyped cases and 813 genotyped population-based control men from the NCI-Maryland Prostate Cancer Case-Control study. Associations between HHV-8 and prostate cancer were assessed in multivariable unconditional logistic regression models. We calculated adjusted odds ratios (OR) and stratified the analysis into men harboring the IFNL4-ΔG-variant and non-carriers (ΔG/ΔG or ΔG/TT vs. TT/TT). Results: HHV-8 seropositivity was higher in cases than controls (OR 1.76; 95%CI: 1.20 - 2.59). The association of HHV-8 seropositivity with prostate cancer was restricted to carriers of the ΔG allele (OR 2.19: 95%CI: 1.38 - 3.48). HHV-8 seropositivity did not associate with prostate cancer among TT/TT genotype carriers (OR 1.03: 95%CI: 0.51 - 2.11). Further stratification by race/ethnicity showed that HHV-8 is associated with prostate cancer exclusively among carriers of the ΔG allele in both European American (OR 2.59; 95%CI: 1.20 - 5.56) and African American men (OR 1.96; 95%CI: 1.08 - 3.56). Conclusions: HHV-8 seropositivity is associated with increased odds of prostate cancer in men harboring the IFNL4 rs368234815-ΔG variant. Impact: The study establishes IFNL4-ΔG as a candidate prostate cancer risk factor in men with an HHV-8 infection. This gene-environment association of IFNL4-ΔG with prostate cancer should be further evaluated using prospective study designs. Citation Format: Frank J. Jenkins, Tsion Z. Minas, Wei Tang, Tiffany H. Dorsey, Stefan Ambs. Human herpesvirus 8 infection is associated with prostate cancer among IFNL4-ΔG carriers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB162.

Abstract 5934: Weight loss and subsequent cancer diagnosis: A prospective cohort study

Abstract Background: Weight loss is a common symptom in patients with cancer. However, little is known about how much weight loss and over what time period weight loss precedes cancer diagnosis. Herein, we evaluate the association between weight loss and subsequent 2-year cancer diagnosis using repeatedly measured weight data in two large prospective cohorts. Methods: The analysis included 111,891 US women from the Nurses’ Health Study and 45,498 US men from the Health Professional Follow-up Study, who were enrolled in 1978 and 1988, respectively, and followed through 2012, and who were cancer-free and ≥40 years old at study entry. Current weight and lifestyle information were assessed every 2 years by questionnaire, and weight change in the previous 2 years was calculated by comparing two consecutive questionnaires. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for subsequent risk of cancer diagnosis according to weight change percentage. We also examined 20-year trajectories of body mass index (BMI) before cancer diagnosis. Results: During 4.1 million person-years of follow-up, we documented 30,441 incident cancers. Participants with recent weight loss were at increased risk for cancer diagnosis in the subsequent 2 years (Ptrend <0.0001). Compared with participants without weight loss, those who had a weight loss of 5-10% or >10% had a multivariable-adjusted HR for total cancer of 1.09 (95% CI, 1.04-1.13) and 1.17 (95% CI, 1.10-1.24), respectively. For individual cancer types, increased weight loss was associated with a subsequent cancer diagnosis of esophagus, liver, pancreas, leukemia, stomach, myeloma, lung, colorectal, and non-Hodgkin lymphoma (all Ptrend <0.005). Comparing participants with weight loss of >10% to those without weight loss, multivariable-adjusted HRs were 4.22 (95% CI, 2.50-7.13) for esophageal cancer, 3.30 (95% CI, 1.65-6.61) for liver cancer, 2.46 (95% CI, 1.84-3.30) for pancreatic cancer, 2.40 (95% CI, 1.59-3.61) for leukemia, 2.26 (95% CI, 1.32-3.87) for stomach cancer, 1.80 (95% CI, 1.14-2.83) for myeloma, 1.45 (95% CI, 1.22-1.73) for lung cancer, 1.38 (95% CI, 1.14-1.66) for colorectal cancer, and 1.35 (95% CI, 1.06-1.72) for non-Hodgkin lymphoma. The 20-year trajectory of BMI indicated that most weight loss occurred in the 2 years before cancer diagnosis, with the magnitude of weight loss increasing closer to the time of subsequent cancer diagnosis. Conclusion: Recent weight loss of >10% predicts elevated risk of cancer diagnosis in the forthcoming 2 years, particularly for cancers of the upper gastrointestinal tract, hematological system, colorectum, and lung. Citation Format: Qiao-Li Wang, Ana Babic, Michael H. Rosenthal, Alice A. Lee, Yin Zhang, Xuehong Zhang, Mingyang Song, Leandro F. Rezende, Dong Hoon Lee, Leah Biller, Kimmie Ng, Andrew T. Chan, Meir J. Stampfer, Edward L. Giovannucci, Peter Kraft, Chen Yuan, Brian M. Wolpin. Weight loss and subsequent cancer diagnosis: A prospective cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5934.

Abstract SY33-02: The circadian cryptochrome, CRY1, is a pro-tumorigenic factor that rhythmically modulates DNA repair

Abstract The second leading cause of cancer-related death in US men is prostate cancer (PCa), which is an androgen-dependent disease in which the androgen receptor (AR) plays an important role. Recent studies have underscored the importance of AR-mediated DNA repair factor regulation as strongly associated with poor outcome in PCa, yet the mechanistic underpinnings of the molecular and cellular consequence of AR-regulated DNA repair and tumor progression have yet to be fully defined. Mining of comprehensive studies designed to identify AR functions critical for PCa revealed that AR binds to multiple regulatory elements within the CRY1 (cryptochrome 1) locus, as observed in several hormone therapy-sensitive PCa models.Here, the circadian factor CRY1, an evolutionally conserved transcriptional coregulator, is identified as a tumor specific regulator of DNA repair. Intriguingly, the N-terminus of CRY1 is a photolyase homology domain suggesting a potential role for CRY1 in DNA damage response. Circadian factors have been implicated in diverse non-canonical physiological functions such as DNA repair, DNA damage checkpoints, and apoptosis. Given the potential implications of CRY1 and DNA repair interplay, this study sought to delineate the molecular and biological consequences of androgen-responsive CRY1 in cancer through cistromic, transcriptomic, and molecular modeling of CRY1 dysregulation in PCa. Key findings demonstrate that CRY1 expression is androgen-responsive and associates with poor outcome in prostate cancer. Functional studies and first-in-field mapping of the CRY1 cistrome and transcriptome reveal that CRY1 regulates DNA repair and the G2/M transition. DNA damage stabilizes CRY1 in cancer (in vitro, in vivo, and human tumors ex vivo), which proves critical for efficient DNA repair. Further mechanistic investigation shows that stabilized CRY1 temporally regulates expression of genes required for homologous recombination. Collectively, these findings reveal that CRY1 is hormone-induced in tumors, is further stabilized by genomic insult, and promotes DNA repair and cell survival through temporal transcriptional regulation. These studies identify the circadian factor CRY1 as pro-tumorigenic and nominate CRY1 as a new therapeutic target. This work was recently published in Nature Communications (Shafi et al, 2021).Ongoing and future work with elucidate the role of CRY1 in PCa by identifying CRY1-driven pathways impacting DNA damage repair (DDR) regulation and CRY1 function on tumor progression and therapeutic response to discern novel pathways to improve existing therapies. Our ongoing work has the potential for broad implications for understanding and treating lethal PCa. Based on our preliminary data, we hypothesize that CRY1 is key modulator of DDR impacting PCa growth and survival, and that delineating the underlying molecular mechanisms of CRY1 and DDR interplay will allow for improved management of advanced disease. Our data indicate that CRY1 expression is altered in PCa, associated with poor outcome, and elicits pro-tumorigenic phenotypes through direct DDR regulation. Our continued work will define the biology of lethal PCa by delineating the molecular and cellular consequence of tumor-associated CRY1 deregulation, providing insight into the function of CRY1 on DNA repair competency. Also, this study will uncover mechanisms of action and identify novel partners for CRY1 function to transcriptionally regulate DNA repair and cancer progression. Lastly, the translational studies from this research study will elucidate the impact of CRY1 function on tumor progression and therapeutic response. Thus, these findings will reveal potential molecular and clinical biomarkers for patients and will ultimately aid in improving existing therapies and developing effective treatments to reduce death from PCa. The long-term impact of CRY1 as a pro-tumorigenic factor driving PCa progression and lethality, emphasizes the importance of developing treatments targeting this factor to mitigate aggressive disease. This study will be crucial in providing novel insight into CRY1 function in human PCa tumors to identify new avenues for therapeutic intervention. This research represents critical steps to understand how circadian factors, specifically CRY1, mediate DNA repair and promote tumorigenesis. Through our collaboration with circadian and DDR experts, this impactful work will not only provide deep mechanistic insight into CRY1 function in PCa, but also lay the foundation for preclinical studies aimed at developing novel strategies for treating CRY1-deregulated cancers. Thus, this ongoing research has immense translational impact serving as the basis for new investigator-initiated clinical trials and altering regimens to emphasize the importance of chronotherapy enhancing standard-of-care to ultimately improve outcome and reduce lethality of PCa. Citation Format: Ayesha Shafi. The circadian cryptochrome, CRY1, is a pro-tumorigenic factor that rhythmically modulates DNA repair [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY33-02.

Abstract 1442: Discovery of recurrence and prognosis associated genes in prostate cancer

Abstract The molecular pathogenesis of Prostate cancer (PCa) is poorly understood, which limits the diagnosis and treatment options. PCa is one of the leading malignant tumors in US men. This research aims to investigate various molecular regulatory pathways triggered by differentially expressed genes (DEGs) to discover Hub genes as diagnostic or therapeutic targets to improve PCa prognosis. We used eight PCa Microarray datasets (GSE46602, GSE38241, GSE69223, GSE3325, GSE32571, GSE55945, GSE104749, and GSE26126) from the NCBI/GEO. We identified DEGs from datasets by comparing PCa (n=247) and control prostate tissues (n=221) using GEO2R with the criteria of |log2FC| (fold change) ≥ 1 and P-value < 0.05. We implemented volcano plot analysis and generated Venn diagrams to identify overlapping genes. We then applied DAVID.6.8, Gene Ontology (GO) and KEGG pathway analysis to potentially associate DEGs' with biological functions and pathways in PCa pathogenesis. The protein-protein interaction (PPI) networks of the recognized DEGs and the significant nodes were constructed by STRING and visualized by Cytoscape and GeneMANIA. Finally, module analysis of the PPI network was performed by MCODE and CytoHubba to identify the Hub genes. The eight GEO datasets include total DEGs = 11595, upregulated = 3795, and downregulated genes = 3548. We identified 472 DEGs overlappings (the Key Genes) among the eight datasets with 357 downregulated and 115 upregulated genes. The GO and KEGG analysis for genes showed that they were principally involved in cell adhesion, focal adhesion, cell proliferation, calcium signaling pathway, extracellular exosome, and cancer pathways. The top significant (P-Value <1.20E-03) transcriptional factors (TFs) connected with downregulated (BACH1, AP1, BACH2, LYF1, SRF, and NF1) and upregulated (MYOD, NFKAPPAB, MSX1, ROAZ, PAX5, and MYCMAX) genes. The PPI networks and the significance analysis were performed (STRING local clustering coefficient of 0.37, average node degree 4.53 and PPI enrichment p-value < 1.0E-16), GeneMANIA maximum resultant genes = 20, and maximum resultant attributes=10. MCODE scores > 7, degree cutoff = 2, node score cutoff = 0.1, Max depth = 100 and k-score = 2). CytoHubba included two topological analysis methods (DNMC and MCC). Results discovered eleven Hub genes (BDNF, CCK, GRIA2, NTRK2, SNAP25, SYN1, SYT1, ACTG2, ANXA2, ANXA6, and MFGE8). The 11 Hub genes among 472 DEGs directly correlate to the recurrence and prognosis of PCa. The discovered Hub genes and pathways may be potentially involved in PCa etiology in different patients. Recognizing these Hub genes may further assist in understanding molecular pathology to develop diagnostic and treatment regimens for a better prognosis of PCa patients. Citation Format: Diaaidden Alwadi, Alok Deoraj, Quentin Felty, Deodutta Roy. Discovery of recurrence and prognosis associated genes in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1442.

Intake of whole grain foods and risk of coronary heart disease in US men and women

BackgroundEpidemiological studies have demonstrated a favorable association of whole grain intake with coronary heart disease (CHD) risk, although whether such an inverse association holds true for individual whole grain foods that have various nutritional profiles has not been examined.MethodsWe followed 74,244 women from Nurses’ Health Study since 1986, 91,430 women from Nurses’ Health Study II since 1991, and 39,455 men from the Health Professionals Follow-Up Study since 1984, who did not have a history of cardiovascular disease or cancer at baseline. Intake of seven individual whole grain foods was repeatedly assessed using a validated semi-quantitative food frequency questionnaire every 2–4 years since baseline. CHD diagnoses were ascertained through review of medical records or death certificates.ResultsWe documented 9461 CHD cases during an average of 25.8 years’ follow-up. In the multivariable-adjusted model, the pooled hazard ratio (HR) (95% CI) of CHD risk corresponding to each one serving/day consumption of total whole grains was 0.93 (0.90–0.95; p trend <0.0001). Higher consumption of most individual whole grain foods was associated with significantly lower risk of CHD. Comparing participants consuming ≥1 serving/day with those consuming < 1 serving/month, the multivariable-adjusted pooled HRs (95% CIs) of CHD were 0.83 (0.78–0.89) for whole grain cold breakfast cereal, 0.92 (0.86–0.99) for dark bread, and 1.08 (0.96–1.22) for popcorn. For other whole grain foods with lower overall intake levels, comparing intake level of ≥2 servings/week with < 1 serving/month, the pooled hazard ratios (95% CIs) were 0.79 (0.74–0.84) for oatmeal, 0.79 (0.71–0.87) for brown rice, 0.84 (0.78–0.90) for added bran, and 0.87 (0.77–0.99) for wheat germ. Cubic spline regression suggested non-linear associations for certain whole grain foods: the risk reduction plateaued approximately over 2 servings/day for total whole grains, 0.5 serving/day for both cold breakfast cereal and dark bread, 0.5 serving/week for oatmeal, 1 serving/week for brown rice, and 2 serving/week for added bran (p for non-linearity <0.01 for all associations).ConclusionsThese data suggest that higher consumption of total whole grains, as well as individual whole grain foods except popcorn, were significantly associated with lower CHD risk. The inverse associations may plateau at various intake levels for total whole grain and individual whole grain foods. This study provides further evidence in support of increasing whole grain intake for the prevention of CHD in US populations.

DynAMo: A dynamic allocation modular sequential trial of approved and promising therapies in men with metastatic CRPC.

5059 Background: Response to androgen signaling inhibitors is highly variable and dictates prognosis in castration resistant prostate cancer (CRPC). The development of effective combinations for CRPC has been hampered by the absence of biomarkers to identify its distinct biological subsets, obligating the homogeneous application of therapies to a heterogeneous disease in clinical trials. We previously defined the aggressive variant prostate cancers as a framework for the study of those with poor responses to androgen signaling inhibitors (dubbed ‘androgen indifferent’) and observed improved outcomes in this subset when carboplatin was added to cabazitaxel (CABCARB). In contrast, results of prospective trials suggested that anti-CTLA-4 therapy may benefit patients with androgen responsive disease. We hypothesized that said combinations applied to subsets defined by early marker declines to androgen ablation would improve overall survival (OS) over historical data in unselected CRPC. Methods: In an open-label, phase II trial (NCT02703623), men with mCRPC received abiraterone and apalutamide (ABIpAPA; Mod 1). At week 8, patients had either a ‘satisfactory’ (S) decline in PSA (≥ 50% from baseline) and CTC (≤5/7.5mL) or ‘unsatisfactory’ (US). S patients ( Mod 2) were randomized to continue ABIpAPA alone ( 2A) or with up to 4 cycles of ipilimumab (IPI, 2B). US patients ( Mod 3) continued ABIpAPA with up to 10 cycles of CABCARB. Thereafter patients continued ABIpAPA until progression. OS was calculated from entry into Mod 2 or 3. Based on historical data, the estimated median OS for men in Mod 2 and Mod 3 were 36 and 16 months respectively. Results: 195 men with CRPC were enrolled between May 2016 and August 2019. 128 (67%) were allocated to S of which 64 each were randomized to receive IPI vs. not. 3 went off study during Mod 1 without clinical decline. Of 64 patients allocated to US, 59 were treated with CABCARB on study . Men in US were more likely to have had de novo metastasis (33% vs 59%, p &lt; 0.001), RECIST measurable disease (23% vs 42%, p = 0.01), and liver metastases (3% vs 13%, p = 0.01). Differences in baseline circulating markers between the groups are shown in Table 1. Serious adverse events were reported for 3 (4.7%), 21 (33%), and 6 (10.2%) patients for M od 2A, 2B, and 3 respectively. One death due to neutropenic sepsis occurred in Mod 3. At a median follow-up of 48 months, the median (95% CI) OS in Mod2A was 44.3 (38.1, 47.7) months, 41.4 (33.3 months, not reached) in Mod 2B, and 18.7 (14.3, 36.3) months in Mod 3. Conclusions: These data substantiate the impact of underlying biology on CRPC patient outcomes and the urgent need for biomarkers that can enable the development of therapies specific to each subset. Correlative studies to identify said biomarkers will be presented. Clinical trial information: NCT02703623.

Dietary Phytoestrogens and Total and Cause-Specific Mortality: Results From Two Prospective Cohort Studies

ObjectivesEvidence regarding dietary phytoestrogens in relation to mortality remains limited and mixed. We aimed to examine associations of dietary intake of total and subclasses of phytoestrogens, specifically: isoflavones, lignans, and coumarins, with total and cause-specific mortality in US men and women.MethodsWe prospectively followed 75,981 women in the Nurses’ Health Study (1984–2018), and 44,001 men in the Health Professionals Follow-up Study (1986–2018), who were free of cardiovascular disease (CVD), diabetes, or cancer at baseline. Diet was repeatedly assessed using validated food frequency questionnaires every 2–4 years. Associations with total and cause-specific mortality (CVD, cancer, and other) were assessed using time-dependent Cox models with adjustments for demographics, dietary and lifestyle factors, and medical history.ResultsDuring 3,427,156 person-years of follow-up, we documented 50,734 deaths, including 12,492 CVD deaths, 13,726 cancer deaths, and 24,516 other deaths. In multivariable-adjusted analyses, higher total phytoestrogen intake was associated with lower total, CVD, and other mortality: comparing extreme quintiles, the pooled HRs (95%CIs) were 0.89 (0.87, 0.92) for total mortality, 0.90 (0.85, 0.96) for CVD mortality, and 0.86 (0.82, 0.90) for other mortality. Furthermore, isoflavones, lignans, and coumarins were all inversely associated with mortality. Specifically, for total mortality, comparing extreme quintiles, the pooled HRs (95%CIs) were 0.90 (0.87, 0.92) for total isoflavones, 0.93 (0.90, 0.96) for total lignans, and 0.93 (0.90, 0.95) for coumarins. These phytoestrogens were also significantly associated with lower CVD mortality or other mortality, although only coumarins were significantly associated with lower cancer mortality. Primary food sources of phytoestrogens, such as tofu, soymilk, whole grains, tea, flaxseed, and flaxseed oil, were inversely associated with total mortality.ConclusionsHigher intake of total phytoestrogens, including isoflavones, lignans, and coumarins as well as foods rich in these compounds were associated with lower total and certain cause-specific mortality in generally healthy U.S. adults. These data suggest that these phytochemicals and their dietary sources may be integrated into an overall healthy diet to achieve a longer life span.Funding SourcesNIH.

Impact of adverse health outcomes (AHOs) on self-reported physical and mental health in U.S. testicular cancer survivors (TCS).

12080 Background: No study has systematically evaluated the impact of AHOs on PROMIS-validated measures of physical and mental health in TCS. Patient-reported outcomes are increasingly recognized as crucial in TCS follow-up, given their young age at diagnosis and high cure rates. Methods: Eligible TCS (age &lt; 60 yr at diagnosis, given first-line cisplatin-based chemotherapy (CHEM)) completed comprehensive health surveys, prescription drug usage, and PROMIS global physical health and global mental health measures. PROMIS scores were compared to US subpopulation norms for similar-age men. 2017-2018 NHANES data were compared with select survey responses. Linear regression examined the relationship between individual AHOs (pain, obesity, cisplatin-induced peripheral neuropathy (CIPN)), cisplatin-related AHOs (CIPN, hearing loss, vertigo, tinnitus, renal disease), cardiovascular (CVD) AHOs (7 AHO), and all AHOs taken together (24 AHOs), with PROMIS global physical and mental health measures. Regression models were adjusted for age, cisplatin dose, time since CHEM, education, income, smoking, and alcohol. Results: Among 213 TCS (median age at evaluation: 46 yr; IQR: 38-52 yr; median time since CHEM completion: 10.6 yr; IQR: 6.8-16.6 yr), the most common AHOs were tinnitus (60%), self-reported hearing loss (60%), CIPN (55%), and Raynaud Phenomenon (43%). The median number of AHOs was 5 (IQR: 3-7), and 12% of TCS had ≥10 AHOs. Only 1.4% of TCS had no AHOs. Compared to NHANES men without cancer, controlling for age, education, and race, fewer TCS currently smoked (3% vs. 22%; P&lt;.001) and fewer were obese (31% vs. 43%, P=.026) but alcohol intake was comparable. However, TCS had significantly lower physical (mean: 48.5 vs. 51.2, P&lt;.001) and mental health (mean: 48.4 vs. 50.8, P&lt;.001) than US men. Increasing numbers of AHOs were significantly associated with decreasing physical ( P&lt;.001) and mental health ( P&lt;.001) after adjustment. The magnitude of effect was strongest for the number of cisplatin-related AHOs with both physical (β: -1.3; 95% CI: -1.9, -0.7; P&lt;.001) and mental health (β: -1.3; 95% CI: -2.1, -0.4; P=.003) after adjustment. In individual AHO adjusted models, CIPN (β: -1.8; 95% CI: -3.3, -0.4), pain (β: -5.0; 95% CI: -6.8, -3.2) and obesity (β: -2.7; 95% CI: -4.3, -1.1) were significantly associated with decreased physical health. Only pain (β: -5.9; 95% CI: -8.4, -3.4) and CIPN (β: -2.0; 95% CI: -4.0, -0.1), but not obesity, were associated with decreased mental health. Conclusions: At a median of 11 years after CHEM completion, 50% of TCS have ≥5 AHOs, and over 1 in 10 have ≥10 AHOs. AHO following cisplatin chemotherapy have major deleterious impacts on patient-reported measures of physical and mental health. Future survivorship research should focus on developing preventive and interventional strategies to care for TCS most vulnerable for impaired physical and mental health after CHEM.

Associations between Types of Dietary Sugar and Risk of Coronary Heart Disease in US Men and Women

ObjectivesTo investigate the associations of dietary sugars, including total fructose equivalents (TFE) and total glucose equivalents (TGE), with coronary heart disease (CHD) risk in two prospective cohort studies, the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). We hypothesized that added sugar, TGE, and TFE intakes were positively associated with CHD risk, but that natural sugar was not associated with higher risk. MethodsWe followed 76,815 women (NHS, 1980–2020) and 39,215 men (HPFS, 1986–2016) who were free of diabetes, cardiovascular disease, and cancer and had completed a semiquantitative food frequency questionnaire (SFFQ) at baseline. Dietary sugar intake was updated every 2–4 years by SFFQs. We defined TFE as fructose monosaccharides and fructose from sucrose, and TGE as glucose monosaccharides and glucose from sucrose, maltose, lactose, and starch. CHD outcomes were ascertained through medical record review and death certificates. Cox proportional hazards models were used to quantify associations between sugar intake and CHD risk with adjustment for potential confounding factors in NHS and HPFS separately. We then pooled risk estimates from the two cohorts using fixed-effects meta-analysis. Secondarily, we examined the associations of sucrose, lactose, starch, and total, added and natural sugars with CHD risk. ResultsWe documented 9,683 incident CHD cases during up to 40 years of follow-up. Higher intake of TGE, compared with total fat, was significantly associated with higher CHD risk, whereas TFE intake was not associated with CHD risk. Comparing extreme quintiles of intake, the hazard ratios (HRs, 95% confidence interval [CI]) of CHD were 1.16 (1.06–1.25; ptrend < .001) for TGE and 1.06 (0.97–1.16; ptrend = 0.09) for TFE. Replacing 5% of energy from total fat with equivalent energy from total and added sugars were associated with estimated increases in CHD risk of 4% (HR: 1.04, 95% CI: 1.02–1.07) and 5% (HR 1.05, 95% CI: 1.01–1.09). Intakes of natural sugar, sucrose, or lactose were not significantly associated with CHD risk. Starch intake was positively associated with CHD risk (HR comparing extreme quintiles: 1.21, 95% CI: 1.11–1.31; ptrend < 0.001). ConclusionsOur findings support limiting dietary intake of starch and suggest that intake of TGE but not TFE is associated with a higher risk of CHD. Funding SourcesNIH

0698 Genetic susceptibility to elevated C-reactive protein and risk of obstructive sleep apnea in US men and women

Abstract Introduction Obstructive sleep apnea (OSA) may trigger inflammation. However, growing evidence suggests a role for inflammation in predisposing OSA through increased upper airway size/collapsibility and altered ventilatory control. Inflammation also promotes sleep disturbance and excessive daytime sleepiness (EDS). Genetic analysis may provide further insights into the causal relationship between chronic inflammation and OSA incidence. Methods In 33,171 participants of European ancestry from the Nurses’ Health Study (NHS), NHS2 and the Health Professionals Follow-up Study, we quantified genetic predisposition to inflammation using a weighted polygenic risk score (PRS) based on 51 loci identified for C-reactive protein (CRP) in a recent genome-wide association meta-analysis. OSA was determined using self-reported diagnoses, which were demonstrated to reliably indicate moderate-to-severe OSA in these cohorts. EDS was defined based on self-reports of disrupted daily activities due to sleepiness ≥4 days/week. Multivariable logistic regression was used to estimate the odds ratio (OR) for OSA risk according to the number of risk alleles, adjusted for age, sex, BMI, genotyping platforms and 10 genetic principal components. Mendelian randomization using individual-level participant data was performed to evaluate the association between genetically determined CRP levels and OSA risk. Results A total of 3,163 participants (9.5%) had clinically diagnosed OSA (575 with EDS). While the CRP PRS (explained 5.0% variance in circulating levels) was not associated with OSA risk overall (OR per increment of 5 risk alleles: 1.00; 95% CI: 0.96, 1.04; p=0.96), a significant positive association was observed for OSA with concurrent EDS (Comparable OR: 1.13; 95% CI: 1.04, 1.23; p=0.003). In contrast, among participants without clinically diagnosed OSA, there was no association between the PRS and EDS (Comparable OR for EDS: 1.02; 95% CI: 0.98, 1.06; p=0.28). In Mendelian randomization, each doubling of genetically elevated CRP was associated with 44% higher odds of OSA with EDS (95% CI: 1.13, 1.82). Conclusion Chronic inflammation (characterized by elevated CRP levels) may be casually associated with risk of developing symptomatic OSA with EDS, but not OSA or EDS alone. To confirm our findings, future investigations are needed to evaluate the genetic associations with objective measures of OSA severity across diverse populations and elucidate mechanisms driven by specific inflammatory mediators. Support (If Any) NIH grants UM1CA186107, U01CA176726, U01CA167552, K01HL143034, R35HL135818

Trends and Racial Disparities in the Prevalence of Urinary Incontinence Among Men in the USA, 2001–2020

BackgroundMale urinary incontinence (UI) affects quality of life and leads to a significant burden to the health care system. However, the contemporary prevalence and recent trends in UI and its subtypes among US men remain unknown. ObjectiveWe evaluated 20-yr trends in the prevalence of UI and its subtype in US men aged ≥20 yr. Design, setting, and participantsA serial, cross-sectional analysis of the US nationally representative data from the National Health and Nutrition Examination Survey among men from 2001 to 2020. Outcome measurements and statistical analysisPrevalence of any, stress, urgency and overflow UI were derived. The frequency of UI was assessed in four categories: less than one time per month, a few times per month, a few times per week, and every day and/or night. All analyses were conducted using sample weights, stratification, and clustering of the complex sampling design. Sociodemographic and lifestyle correlates of UI over time were identified using multivariable logistic regressions. Results and limitationsData on 22994 US men (mean age, 46.6 yr [standard error, 0.20]; weighted population, 848642150) were analyzed. The prevalence of any UI increased from 2001–2002 (11.5% [95% confidence interval {CI}, 10.0–13.0]) to 2017–2020 (19.3% [95% CI, 17.2–21.3]), driven by urgency (from 9.0% [95% CI, 7.5–10.4]) to 15.2% [95% CI, 13.4–16.9]) and overflow UI (from 3.3% [95% CI, 2.7–4.0] to 5.5% [95% CI, 4.5–6.4]; all p for trend < 0.01). UI affects 38.5% US men ≥60 yr of age, with increasing trends in urgency and overflow UI and a decreasing trend in stress UI (all p for trend < 0.05). Racial/ethnic disparities were noted, with patterns differed by UI subtype. Compared with non-Hispanic White, non-Hispanic Black men were more likely to report urgency UI (odds ratio [OR], 1.94 [95% CI, 1.71–2.20]). Hispanic men were more likely to report urgency UI (OR, 1.33 [95% CI, 1.14–1.56]), but less likely to report stress (OR, 0.74 [95% CI, 0.56–0.98]) and overflow (OR, 0.75 [95% CI, 0.58–0.98]) UI. Men with higher body mass index and current smokers were more likely to report any, stress, and urgency UI than their counterparts. A higher prevalence of any UI was found in men with low family poverty ratios and chronic diseases, and those who were physically inactive. ConclusionsFrom 2001 to 2020, the overall prevalence of UI increased among US men, particularly for urgency and overflow UI. Patient summaryIn this report, we looked at the prevalence of urinary incontinence among US men in a nationally representative sample. We found that urinary incontinence increased in the past 20 yr driving by the urgency and overflow urinary incontinence.

Abstract 195: The Effect Of Phosphodiesterase-5 Inhibitors On Major Adverse Cardiovascular Events And Mortality In A Large Cohort Of Men With Erectile Dysfunction From A Nationwide Insurance Database: A Retrospective Study

Background: Phosphodiesterase type 5 inhibitor (PDE-5i) medications are effective in treating Erectile Dysfunction (ED) for tens of millions of men in the US and worldwide. The objective of this study was to determine the effect of PDE-5is on the incidence of major adverse cardiovascular events (MACE) (composite outcome of cardiovascular (CV) death, hospitalization for myocardial infarction, coronary revascularization, stroke, heart failure, or unstable angina pectoris) and all-cause death. Methods: A retrospective observational cohort study was conducted in a large US commercial and Medicare insurance claims database in men with ≥1 diagnosis of ED without prior MACE hospitalization within 1 year from Jan 2006 to Oct 2020. The exposed group had ≥1 claim for PDE-5i; the unexposed group had no claims for PDE-5i and were matched 2:1 on baseline risk variables. The primary outcome was MACE and secondary outcome was all-cause death, determined by multivariate Cox proportional hazard modeling. Death data were obtained via National Death Index linkage. Results: In this population, MACE was reduced by 13% in men exposed (n=23,816) to PDE-5is (hazard ratio (HR) 0.87; 95% Confidence Interval (CI) 0.79-0.95) vs. non-exposure (n=48,682) over mean follow up of 29 and 37 months, respectively. This was driven by reductions in coronary revascularization (HR 0.85; 0.73-0.98), heart failure (HR 0.83; 0.72-0.97), unstable angina (HR 0.78; 0.64-0.96), and CV death (HR 0.61; 0.41-0.90). PDE-5i-exposed men had a 25% reduction in all-cause death (HR 0.75; 0.65-0.87). Men without coronary artery disease but with CV risk factors at baseline showed a similar pattern. In the main study cohort, men in the highest quartile of PDE-5i exposure had the greatest reductions in MACE (HR 0.45; 0.37-0.54) and all-cause death (HR 0.51; 0.37-0.71) vs. the lowest exposure quartile. In a subgroup with baseline type 2 diabetes (n=6,305), PDE-5i exposure was associated with a lower MACE risk (HR 0.79; 0.64-0.97). All comparisons are significant at p&lt;0.05. Conclusions: In a large population of US men with ED, PDE-5i exposure was associated with reductions in MACE, CV death, and overall death risk compared to non-exposure. Risk reduction was positively correlated with PDE-5i exposure level.

Rethinking a Miracle: The Role of Whiteness in the 1980 Miracle on Ice

Abstract At the 1980 Winter Olympics, the US men's ice hockey team defeated Soviet Russia in the semifinals. This touchstone moment in US Cold War history has been studied as a political victory for an American public exhausted by a series of public political defeats; a lynchpin in the development of a militarized masculinity; and a glorified memory of US power. However, this scholarship makes just passing reference to the whiteness imbued in the rhetoric surrounding the 1980 US-Soviet Olympic hockey match, and as such, does little to explain the racial dynamics present in the performance of remembering the Miracle. This article argues that the way media sources, political figures, and athletes commemorated the Miracle reinforced an understanding of white, working-class families as the normal, better standard for Americans in the larger political and cultural context of the late 1970s and early 1980s. Thus, the Miracle on Ice cannot simply be viewed as an innocuous moment enshrined in Cold War and sports history. Rather, the nostalgia attached to the Miracle reveals a sustained investment in the normalization of whiteness as ideal within the United States. The Miracle, far from simply being an underdog story, is a tale told and retold to demonstrate why the normative American family is white and working class.

Association of Playing College American Football With Long-term Health Outcomes and Mortality

Exposure to repetitive head impacts from playing American football (including impacts resulting in symptomatic concussions and subconcussive trauma) is associated with increased risk for later-life health problems, including cognitive and neuropsychiatric decline and neurodegenerative disease. Most research on long-term health consequences of playing football has focused on former professional athletes, with limited studies of former college players. To estimate the prevalence of self-reported health conditions among former college football players compared with a sample of men in the general population as well as standardized mortality ratios (SMRs) among former college football players. This cohort study included data from 447 former University of Notre Dame (ND) football players aged 59 to 75 years who were seniors on the rosters from 1964 to 1980. A health outcomes survey was distributed to living players and next of kin of deceased players for whom contact information was available. The survey was completed from December 2018 to May 2019. Participation in football at ND. Prevalence of health outcomes was compared between living former players who completed the survey and propensity score-matched participants in the Health and Retirement Study (HRS). Standardized mortality ratios of all causes and specific causes of death among all former players were compared with those among men in the general US population. A total of 216 living players completed the health survey (median age, 67 years; IQR, 63-70 years) and were compared with 638 participants in the HRS (median age, 66 years; IQR, 63-70 years). Former players reported a higher prevalence of cognitive impairment (10 [5%] vs 8 [1%]; P = .02), headaches (22 [10%] vs 22 [4%]; P = .001), cardiovascular disease (70 [33%] vs 128 [20%]; P = .001), hypercholesterolemia (111 [52%] vs 182 [29%]; P = .001), and alcohol use (185 [86%] vs 489 [77%]; P = .02) and a lower prevalence of diabetes (24 [11%] vs 146 [23%]; P = .001). All-cause mortality (SMR, 0.54; 95% CI, 0.42-0.67) and mortality from heart (SMR, 0.64; 95% CI, 0.39-0.99), circulatory (SMR, 0.23; 95% CI, 0.03-0.83), respiratory (SMR, 0.13; 95% CI, 0.00-0.70), and digestive system (SMR, 0.13; 95% CI, 0.00-0.74) disorders; lung cancer (SMR, 0.26; 95% CI, 0.05-0.77); and violence (SMR, 0.10; 95% CI, 0.00-0.58) were significantly lower in the ND cohort than in the general population. Mortality from brain and other nervous system cancers was significantly higher in the ND cohort (SMR, 3.82; 95% CI, 1.04-9.77). Whereas point estimates were greater for all neurodegenerative causes (SMR, 1.42; 95% CI, 0.29-4.18), amyotrophic lateral sclerosis (SMR, 2.93; 95% CI, 0.36-10.59), and Parkinson disease (SMR, 2.07; 95% CI, 0.05-11.55), the difference did not reach statistical significance. In this cohort study of former college football players, both positive and negative health outcomes were observed. With more than 800 000 former college players living in the US, additional research appears to be needed to provide stakeholders with guidance to maximize factors that improve health outcomes and minimize factors that may increase risk for later-life morbidity and mortality.

Representation of sustainability in US men’s fashion magazines: A content analysis based exploratory study

This exploratory study aims to investigate the representation of sustainability in US men’s fashion magazines. Specifically, employing quantitative and qualitative content analysis, this study identifies and analyses meanings of sustainability, the companies having sustainable practices, the products with sustainable attributes and specific sustainable practices. 41 and seventeen articles related to fashion and sustainability were collected from the two US online men’s fashion magazines, Gentlemen’s Quarterly (GQ) and Esquire, respectively. For both magazines, the environmental dimension is more frequently addressed than the social dimension in the articles. Various terms are used to describe the same subject and the two magazines have different preferences when selecting words to present the same issue. For example, GQ prefers ‘eco-friendly’, but Esquire picks ‘planet’ when discussing the environmental dimension. Moreover, the concept of sustainability is ambiguous in the two magazines due to overlapped terms and lack of explanation. In both magazines, the most frequently mentioned product is footwear. However, GQ tends to introduce sustainable practices concerning solid waste and focus on the luxury sector. Comparably, Esquire focuses more on the environmental impacts of raw material sourcing and the affordable fashion sector. This study contributes to the body knowledge of sustainability communication in the men’s fashion sector. Researchers can employ the results to conduct further analysis, such as examining the difference between sustainability representation in magazines and academic studies. Based on the results, companies should improve their communication with consumers regarding their sustainable practices.

Avocado Consumption and Risk of Cardiovascular Disease in US Adults.

BackgroundEpidemiologic studies on the relationship between avocado intake and long‐term cardiovascular disease (CVD) risk are lacking.Methods and ResultsThis study included 68 786 women from the NHS (Nurses’ Health Study) and 41 701 men from the HPFS (Health Professionals Follow‐up Study; 1986–2016) who were free of cancer, coronary heart disease, and stroke at baseline. Diet was assessed using validated food frequency questionnaires at baseline and then every 4 years. Cox proportional hazards regressions were used to estimate hazard ratios and 95% CIs. A total of 14 274 incident cases of CVD (9185 coronary heart disease events and 5290 strokes) were documented over 30 years of follow‐up. After adjusting for lifestyle and other dietary factors, compared with nonconsumers, those with analysis‐specific higher avocado intake (≥2 servings/week) had a 16% lower risk of CVD (pooled hazard ratio, 0.84; 95% CI, 0.75–0.95) and a 21% lower risk of coronary heart disease (pooled hazard ratio, 0.79; 95% CI, 0.68–0.91). No significant associations were observed for stroke. Per each half serving/day increase in avocado intake, the pooled hazard ratio for CVD was 0.80 (95% CI, 0.71–0.91). Replacing half a serving/day of margarine, butter, egg, yogurt, cheese, or processed meats with the equivalent amount of avocado was associated with a 16% to 22% lower risk of CVD.ConclusionsHigher avocado intake was associated with lower risk of CVD and coronary heart disease in 2 large prospective cohorts of US men and women. The replacement of certain fat‐containing foods with avocado could lead to lower risk of CVD.

Environmental Phenol and Paraben Exposure Risks and Their Potential Influence on the Gene Expression Involved in the Prognosis of Prostate Cancer.

Prostate cancer (PCa) is one of the leading malignant tumors in US men. The lack of understanding of the molecular pathology on the risk of food supply chain exposures of environmental phenol (EP) and paraben (PB) chemicals limits the prevention, diagnosis, and treatment options. This research aims to utilize a risk assessment approach to demonstrate the association of EP and PB exposures detected in the urine samples along with PCa in US men (NHANES data 2005–2015). Further, we employ integrated bioinformatics to examine how EP and PB exposure influences the molecular pathways associated with the progression of PCa. The odds ratio, multiple regression model, and Pearson coefficients were used to evaluate goodness-of-fit analyses. The results demonstrated associations of EPs, PBs, and their metabolites, qualitative and quantitative variables, with PCa. The genes responsive to EP and PB exposures were identified using the Comparative Toxicogenomic Database (CTD). DAVID.6.8, GO, and KEGG enrichment analyses were used to delineate their roles in prostate carcinogenesis. The plug-in CytoHubba and MCODE completed identification of the hub genes in Cytoscape software for their roles in the PCa prognosis. It was then validated by using the UALCAN database by evaluating the expression levels and predictive values of the identified hub genes in prostate cancer prognosis using TCGA data. We demonstrate a significant association of higher levels of EPs and PBs in the urine samples, categorical and numerical confounders, with self-reported PCa cases. The higher expression levels of the hub genes (BUB1B, TOP2A, UBE2C, RRM2, and CENPF) in the aggressive stages (Gleason score > 8) of PCa tissues indicate their potential role(s) in the carcinogenic pathways. Our results present an innovative approach to extrapolate and validate hub genes responsive to the EPs and PBs, which may contribute to the severity of the disease prognosis, especially in the older population of US men.

Olympic Games, media coverage and brand image/performance from fan and gender perspectives

PurposeThe purpose of this paper is to explore and test certain assumptions concerning the role of the media in its coverage of the Olympic Games, US men's and women's basketball in particular, and its perceived impact on brand image of the athletes' performance from a fan's motivational and financial perspective.Design/methodology/approachUses and gratifications theory and sport fan motivation scales were used to identify potential impacts of media coverage and branding on athletic performance. Based on a study of 143 working professionals that identified themselves as Olympic sport fans in the Pittsburgh, PA metropolitan area, several hypotheses were tested.FindingsThe most to least important factor-based constructs found from a PCA (Principal Components Analysis)/factor analysis included competitiveness, fan commitment, media connections, media impacts, demographics and financial impacts. When using the construct athletic performance at the Olympic level as the dependent variable, results suggested that competitiveness, media connections and fan commitment were significant for males only, while only media connections for significant for females. Males were found to be more player-centric than females, willing to be more focused on the competitive nature of the Olympic Games and to dedicate more money for such activities.Originality/valueFocusing on Olympic Games and associated athletes' competitive nature opens a unique perspective from fan's gender perspective.

Longitudinal relationships between muscle dysmorphia symptoms and suicidal ideation.

Muscle Dysmorphia (MD) is a severe subtype of body dysmorphic disorder (BDD) that shares symptomatic overlap with eating disorders. Although associations between eating disorders/BDD and suicidality are well documented, research has rarely examined associations between MD symptoms and suicidality, which is concerning given MD is associated with additional suicide risk factors compared with these disorders. Further, existing associations between MD symptoms and suicidality have yet to establish temporal ordering for these relationships. Therefore, the current study investigated longitudinal relationships between MD symptoms and suicidal ideation to establish the direction of the MD-suicidality relationship. Participants were 272 US men displaying sub-clinical MD symptoms who completed self-report measurement at three time points over 6weeks. Longitudinal relationships between MD symptoms and suicidal ideation were examined using a three-wave autoregressive cross-lagged model. Certain MD symptoms were longitudinally predicted by suicidal ideation. Specifically, suicidal ideation longitudinally predicted increased drive for size and appearance intolerance. Results may suggest that individuals engage in MD symptoms potentially to cope with distressing thoughts of suicide. Clinicians should provide clients with comorbid MD and suicidality with appropriate coping tools to manage distress from suicidal thoughts outside of engaging in compulsive exercise characteristic of MD symptoms.

Abstract P173: Sex Differences In Risk Factors For Cardiovascular Disease Mortality Among US Women And Men

Ling Tian, Amanda H. Anderson, Kirsten S. Dorans, Marie A. Krousel-wood, Joshua D. Bundy Introduction: Previous studies suggest cardiovascular disease (CVD) risk factors differ among women compared with men. Quantifying sex differences in the associations of risk factors for CVD mortality in US nationally representative data could aid researchers and clinicians in improving the efficiency of primordial prevention of CVD. Hypothesis: Associations of systolic blood pressure (SBP), total cholesterol, glycated hemoglobin (HbA1c), body mass index (BMI), current smoking, and predicted 10-year risk of atherosclerotic CVD with CVD mortality differ among women compared with men, and these sex differences are modified by age. Methods: Data from non-pregnant and non-breastfeeding participants aged ≥40 years from the National Health and Nutrition Examination Survey (NHANES) 1999-2006, linked to the National Death Index through December 31, 2015, were analyzed. Multivariable-adjusted Cox proportional hazards regression was used to estimate hazard ratios (95% confidence intervals) for CVD mortality. Interaction terms were used to model associations by age (40-49, 50-59, and ≥60 years) and sex (women and men) subgroups. Results: 9,486 participants (mean age, 57.7; 51.9% women) were included in the current analysis. During an average 12.3-year follow-up, we observed 807 (8.5%) CVD deaths (328 in women; 479 in men). Associations of risk factors with CVD mortality were similar among women compared with men, although they were attenuated with increasing age (Figure). Conclusions: Among both US women and men, higher levels of SBP, smoking, and predicted 10-year ASCVD risk are strongly associated with higher risk of CVD mortality. Population-level interventions targeting these risk factors as early as possible in US men and women could reduce the burden of CVD.