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Circulating micronutrient levels of both serum copper and zinc have been studied to varying degrees in both the general public and patients having undergone bariatric surgery. According to the 2019 ASMBS clinical guidelines, copper supplementation is recommended for patients undergoing metabolic surgery, especially after Roux-en-Y gastric bypass and duodenal switch. Copper excess has not been previously reported to any significant degree in any population. In this study, we investigate an elevated serum copper level in the pre-surgical intervention population of the Bariatric Center of the University Medical Center–New Orleans, a primary safety net hospital for the state of Louisiana. Five hundred five consecutive patients from the bariatric surgery undergoing a workup for surgical intervention were assessed. Patients were included regardless of whether they proceeded to surgery. The study was conducted as a retrospective review of deidentified data that was collected as part of our routine workup for bariatric surgery. The study population of the clinic consisted of a mean BMI of approximately 50 kg/m2, with 91% of the population reporting female and 69% recording an African American race. It was discovered in this population that 26% of the patients had an elevated copper level of > 155 mcg/dl. Additional analysis was performed attempting to elucidate an environmental role in the elevation by qualitative analysis of patient’s location of residence using reported home address. Additional variables were studied as well including serum zinc concentration, age, BMI, and race to address any correlative variables with our findings. This study identifies an elevated serum copper concentration in a pre-intervention underserved bariatric center population positively associated with BMI, female gender, and African American race. Additional studies will be necessary to see if these trends are also apparent in normal weight controls, or if weight loss influences copper levels. Pre-existing serum copper deficiencies may be more prevalent in the bariatric populations than previously believed. Increased serum copper in this population was positively associated with increased BMI, age, and female gender compared to that of the male group. Increased serum copper was also associated more closely with African American ethnicity compared to Caucasian patients.

Background Thromboxane A2 (TXA2) is a platelet- and cyclooxygenase-derived eicosanoid that has been linked to metastasis. We investigated the role of TXA2 in the development of lethal prostate cancer in African American (AA) and European American (EA) men. Methods We measured urinary 11-dehydrothromboxane B2 (TXB2), a stable metabolite of TXA2, with mass spectrometry. Samples were obtained from 977 cases and 1022 controls at time of recruitment. We applied multivariable logistic and Cox regression modeling to examine associations of TXB2 with prostate cancer and patient survival. The median survival follow-up was 8.4 years, with 246 deaths among cases. Aspirin use was assessed with a questionnaire. Race was self-reported. Results Urinary TXB2 was inversely associated with aspirin use. High (>median) TXB2 was associated with prostate cancer in AA (adjusted odds ratio [OR] = 1.50, 95% confidence interval [CI] = 1.13 to 2.00) but not EA men (OR = 1.07, 95% CI = 0.82 to 1.40), suggesting upregulated TXA2 synthesis in AA men with prostate cancer. High TXB2 was positively associated with metastatic prostate cancer (OR = 2.60, 95% CI = 1.08 to 6.28) compared with low (≤median) TXB2. Furthermore, high TXB2 was also associated with all-cause (adjusted hazard ratio = 1.59, 95% CI = 1.06 to 2.40) and prostate cancer-specific mortality (hazard ratio = 4.74, 95% CI = 1.62 to 13.88) in AA men only. Conclusions We report a distinct association of TXB2 with prostate cancer outcomes in AA men. In this high-risk group of men, upregulation of TXA2 synthesis may promote metastasis and lethal disease. Our observation identifies a potential benefit of aspirin in preventing lethal prostate cancer through inhibition of TXA2 synthesis.

In the United States, the incidence of esophageal adenocarcinoma increased markedly since the 1970s with a recent stabilization. Despite evolving screening and surveillance strategies to diagnose, risk triage, and intervene in Barrett's esophagus patients to prevent esophageal adenocarcinoma, most cases present with advanced disease and poor resultant survival. Epidemiologic studies have identified the main risk factors for these conditions, including increasing age, male sex, white race, gastroesophageal reflux disease, abdominal obesity, cigarette smoking, and lack of infection with Helicobacter pylori. This review summarizes the current epidemiologic evidence with implications for screening and surveillance in Barrett's esophagus and esophageal adenocarcinoma.

INTRODUCTION: Gastrointestinal cancers show an unexplained male predominance, but few prospective studies have investigated sex hormones and gastrointestinal cancer risk. This study aimed to determine the impact of circulating sex hormones on risk of esophageal, gastric, and colorectal cancers in men and women.METHODS: We included 219,425 men and 147,180 women from the UK Biobank. Sex hormones were quantified using chemiluminescent immunoassay. Gastrointestinal cancers were identified from cancer registry linkages. Sex hormone concentrations and risk of gastrointestinal cancers were investigated using Cox proportional hazards regression.RESULTS: During the 10 years of follow-up, 376 esophageal adenocarcinoma, 108 esophageal squamous cell carcinoma, and 333 gastric and 2,868 colorectal cancer cases were identified. Increased hazard ratios (HRs) were found for sex hormone–binding globulin (SHBG) and risk of gastric cancer in men (Q4 vs Q1 HR 1.43, 95% confidence interval [CI] 0.95–2.17, Ptrend = 0.01). Free testosterone was inversely associated with esophageal squamous cell carcinoma in women (Q4 vs Q1 HR 0.32, 95% CI 0.11–0.98, Ptrend = 0.05). For colorectal cancer, SHBG was associated with a reduced risk among men (Q4 vs Q1 HR 0.89, 95% CI 0.77–1.03, Ptrend = 0.04) and free testosterone concentrations was associated with a reduction in risk among women (Q4 vs Q1 HR 0.80, 95% CI 0.66–0.97, Ptrend = 0.01). No associations were found for esophageal adenocarcinoma.DISCUSSION: In this large prospective investigation of prediagnostic sex hormones and risk of gastrointestinal cancers, men with higher SHBG concentrations had higher gastric, yet lower colorectal, cancer risks, whereas women with higher free testosterone levels had a lower risk of esophageal squamous cell carcinoma and colorectal cancer.

We explored the Medicare database (1999 to 2014) to provide a comprehensive assessment of testosterone therapy patterns in the older U.S. male population.We estimated annual age-standardized incidence (new users) and prevalence (existing users) of testosterone therapy according to demographic characteristics, comorbidities and potential indications.There were 392,698 incident testosterone therapy users during 88 million person-years. Testosterone therapy users were predominantly younger, white nonHispanic, and located in South and West U.S. Census regions. On average testosterone therapy use increased dramatically during 2007 to 2014 (average annual percent change 15.5%), despite a decrease in 2014. In 2014 the most common recorded potential indications for any testosterone therapy were hypogonadism (48%), fatigue (18%), erectile dysfunction (15%), depression (4%) and psychosexual dysfunction (1%). Laboratory tests to measure circulating testosterone concentrations for testosterone therapy were infrequent with 35% having had at least 1 testosterone test in the 120 days preceding testosterone therapy, 4% the recommended 2 pre-testosterone therapy tests, and 16% at least 1 pre-testosterone therapy test and at least 1 post-testosterone therapy test.Testosterone therapy remains common in the older U.S. male population, despite a recent decrease. Although testosterone therapy prescriptions are predominantly for hypogonadism, a substantial proportion appear to be for less specific conditions. Testosterone tests among men prescribed testosterone therapy appear to be infrequent.

Background Androgen deprivation therapy (ADT), which has a proven role in prostate cancer management, has been associated with various cardiovascular diseases. However few studies have investigated these associations by type of ADT, particularly for newer ADTs such as the gonadotropin-releasing hormone (GnRH) antagonist degarelix. We investigated the risk of cardiovascular disease by type of ADT in a real world setting.MethodsMen newly diagnosed with prostate cancer, from 2009 to 2015, were identified from the Scottish Cancer Registry. ADTs were identified from the nationwide Prescribing Information System. Cardiovascular events were based upon hospitalisation (from hospital records) or death from cardiovascular disease (from death records). Cox regression calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for cardiovascular events with time-varying ADT exposure, comparing ADT users with untreated patients, after adjusting for potential confounders including prior cardiovascular disease.Results The cohort contained 20,216 prostate cancer patients, followed for 73,570 person years, during which there were 3,853 cardiovascular events. ADT was associated with a 25% increase in cardiovascular events (adjusted HR=1.25 95% CI 1.16, 1.35). This reflected increases in cardiovascular events associated with GnRH agonists (adjusted HR=1.26 95% CI 1.16, 1.36), degarelix (adjusted HR=1.49 95% CI 1.16, 1.90), but not bicalutamide monotherapy (adjusted HR=1.01 95% CI 0.82, 1.25). Conclusions There were increased risks of cardiovascular disease with use of GnRH agonists and degarelix, but not with bicalutamide monotherapy. This is the first study to observe increased cardiovascular risks with degarelix, but the cause of this association is unclear and merits further investigation.

BackgroundDifferential uptake of prostate-specific antigen testing in the US and UK has been linked to between-country differences for prostate cancer incidence. We examined stage-specificfatalprostate cancer incidence trends in the US and England, by treatment and race/ethnicity.MethodsUsing data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results program and Public Health England’s National Cancer Registration and Analysis Service, we identified prostate cancer patients diagnosed between 1995 and 2005, aged 45–84 years. Fatal prostate cancer was defined as death attributed to the disease within 10 years of diagnosis. We used age–period–cohort models to assess trends in fatal prostate cancer incidence.ResultsFatal prostate cancer incidence declined in the US by −7.5% each year and increased in England by 7.7% annually. These trends were primarily driven by locoregional disease in the US and distant disease in England. Black men in both countries had twofold to threefold higher fatal prostate cancer incidence rates, when compared with their white counterparts; however, receipt of radical prostatectomy lessened this disparity.ConclusionsWe report a significant increasing rate of fatal prostate cancer incidence among English men. The black–white racial disparity appears pervasive but is attenuated among those who received radical prostatectomy in the US.

Aim Traditional approaches to ventral hernia repair involve implantation of synthetic mesh (SM), primary suture (PS) repair, and the use of biologic prostheses (BP). A body mass index (BMI) > 30 increases recurrence rates and complications for such repairs. We have begun to use Autologous Fenestrated Cutis Grafts (CG) as an alternative hernia repair. We investigated the impact of obesity on the recurrence and complication rates of CG compared to traditional repairs. Material and Methods A five-surgeon, retrospective study included all ventral/incisional, epigastric and umbilical hernia repairs (SM, PS, and BP from 2015-2020; CG repairs from 2018-2020). Patients with a BMI ≥ 30 were stratified according to surgical approach. Outcomes included recurrence and complication rates. Descriptive statistics for demographics and outcomes were compared and logistic regression performed with p Results A total of 301 hernia repairs were performed (173 CGs, 54 SM, 59 PS, 15 BS). The groups had similar recurrence rates. A significant difference in complications rates did exist (37% CGs, 48.1% SMs, 15.3% PS, 66.7% BP, p Conclusions CG for abdominal wall hernia repair in patients with BMI ≥ 30 is an acceptable hernia repair in obese patients with similar recurrence rates and an acceptable complication profile compared to traditional repairs.

Urinary PGE-M is a stable metabolite of prostaglandin E2 (PGE2). PGE2 is a product of the inflammatory COX signaling pathway and has been associated with cancer incidence and metastasis. Its synthesis can be inhibited by aspirin. We investigated the association of PGE-M with lethal prostate cancer in a case–control study of African American (AA) and European American men. We measured urinary PGE-M using mass-spectrometry. Samples were obtained from 977 cases and 1022 controls at the time of recruitment. We applied multivariable logistic and Cox regression modeling to examine associations of PGE-M with prostate cancer and participant survival. Median survival follow-up was 8.4 years, with 246 deaths among cases. Self-reported aspirin use over the past 5 years was assessed with a questionnaire. Race/ethnicity was self-reported. Urinary PGE-M levels did not differ between men with prostate cancer and population-based controls. We observed no association between PGE-M and aggressive disease nor prostate-cancer-specific survival. However, we observed a statistically significant association between higher (&gt, median) PGE-M and all-cause mortality in AA cases who did not regularly use aspirin (HR = 2.04, 95% CI 1.23–3.37). Among cases who reported using aspirin, there was no association. Our study does not support a meaningful association between urinary PGE-M and prostate cancer. Moreover, PGE-M levels were not associated with aggressive prostate cancer. However, the observed association between elevated PGE-M and all-cause mortality in AA non-aspirin users reinforces the potential benefit of aspirin to reduce mortality among AA men with prostate cancer.

Background: Loss of domain, fascial separation, and wound contamination are all recognized challenges of complex abdominal wall reconstruction. Often, traditional therapies, such as fascial advancement, mesh reinforcement, and the use of bio-prostheses for infection are insufficient. Recently, we have investigated using cutis as an alternative therapy. We present the case of a 61-year old male treated in such a manner. Methods: Our patient presented to our facility with a fascial defect of 30 by 40 cm, and an infected skin graft after undergoing an exploratory laparotomy for a gunshot wound at an outside hospital. During his course, he failed multiple traditional therapies, leaving him with a large open wound, four paired enterocutaneous fistulae, and a cholecystocutaneous fistula. We repaired his fistulae, performed a staged fascial closure, and reinforced it by placing an autograft of de-epithelialized dermis over it, bridging some areas of fascia. Results: The patient had rapid incorporation of his cutis graft, with granulation over the graft within 72 hours. Within three months, all wounds had healed, and the patient had fully recovered. Conclusions: Cutis autograft as a means for reinforcing abdominal wall closure is a versatile tool in the armamentarium of the surgeon to treat complex abdominal wall reconstruction. In the setting of failure of traditional therapies for fascial closure, it can potentially help with simultaneous bridging and reinforcement, demonstrating the strength of this type of repair

Background: We conducted a study to assess whether testosterone therapy (TT) alters prostate cancer risk using a large U.S. commercial insurance research database. Methods: From the HealthCore Integrated Research Database (HIRD), we selected men ages 30 years or greater who were new users of TT during 2007 to 2015. We selected two comparison groups: (i) unexposed (matched 10:1) and (ii) new users of phosphodiesterase type 5 inhibitor (PDE5i). Incident prostate cancer was defined as diagnosis of prostate cancer within 4 weeks following prostate biopsy. Propensity scores and inverse probability of treatment weights were used in Poisson regression models to estimate adjusted incidence rates, incidence rate ratios (IRR), and 95% confidence intervals (CI). Subgroup analyses included stratification by prostate cancer screening, hypogonadism, and follow-up time. Results: The adjusted prostate cancer IRR was 0.77 (95% CI, 0.68–0.86) when comparing TT with the unexposed group and 0.85 (95% CI, 0.79–0.91) in comparison with the PDE5i group. Inverse associations between TT and prostate cancer were observed in a majority of subgroup analyses, although in both comparisons estimates generally attenuated with increasing time following initial exposure. Among TT users, duration of exposure was not associated with prostate cancer. Conclusions: Men who received TT did not have a higher rate of prostate cancer compared with the unexposed or PDE5i comparison groups. The inverse association between TT and prostate cancer could be the result of residual confounding, contraindication bias, or undefined biological effect. Impact: This study suggests that limited TT exposure does not increase risk of prostate cancer in the short term.

Background: Advanced prostate cancer etiology is poorly understood. Few studies have examined associations of anthropometric factors (e.g. early adulthood obesity) with advanced prostate cancer risk.Patients and methods: We carried out pooled analyses to examine associations between body fatness, height, and prostate cancer risk. Among 830 772 men, 51 734 incident prostate cancer cases were identified, including 4762 advanced (T4/N1/M1 or prostate cancer deaths) cases, 2915 advanced restricted (same as advanced, but excluding localized cancers that resulted in death) cases, 9489 high-grade cases, and 3027 prostate cancer deaths. Cox proportional hazards models were used to calculate study-specific hazard ratios (HR) and 95% confidence intervals (CI); results were pooled using random effects models.Results: No statistically significant associations were observed for body mass index (BMI) in early adulthood for advanced, advanced restricted, and high-grade prostate cancer, and prostate cancer mortality. Positive associations were shown for BMI at baseline with advanced prostate cancer (HR = 1.30, 95% CI = 0.95-1.78) and prostate cancer mortality (HR = 1.52, 95% CI = 1.12-2.07) comparing BMI >= 35.0 kg/m(2) with 21-22.9 kg/m(2). When considering early adulthood and baseline BMI together, a 27% higher prostate cancer mortality risk (95% CI = 9% to 49%) was observed for men with BMI = 30.0 kg/m(2) at baseline compared with BMI = 110 cm with = 1.00 with = 1.90 m withConclusion: Our findings suggest that height and total and central adiposity in mid-to-later adulthood, but not early adulthood adiposity, are associated with risk of advanced forms of prostate cancer. Thus, maintenance of healthy weight may help prevent advanced prostate cancer.

Background:Diabetes is positively associated with various cancers, but its relationship with tumors of the esophagus/esophagogastric junction remains unclear.Methods:Data were harmonized across 13 studies in the International Barrett's and Esophageal Adenocarcinoma Consortium, comprising 2309 esophageal adenocarcinoma (EA) cases, 1938 esophagogastric junction adenocarcinoma (EGJA) cases, 1728 Barrett's esophagus (BE) cases, and 16,354 controls. Logistic regression was used to estimate study‐specific odds ratios (ORs) and 95% CIs for self‐reported diabetes in association with EA, EGJA, and BE. Adjusted ORs were then combined using random‐effects meta‐analysis.Results:Diabetes was associated with a 34% increased risk of EA (OR, 1.34; 95% CI, 1.00‐1.80; I2 = 48.8% [where 0% indicates no heterogeneity, and larger values indicate increasing heterogeneity between studies]), 27% for EGJA (OR, 1.27; 95% CI, 1.05‐1.55; I2 = 0.0%), and 30% for EA/EGJA combined (OR, 1.30; 95% CI, 1.06‐1.58; I2 = 34.9%). Regurgitation symptoms modified the diabetes‐EA/EGJA association (P for interaction = .04) with a 63% increased risk among participants with regurgitation (OR, 1.63; 95% CI, 1.19‐2.22), but not among those without regurgitation (OR, 1.03; 95% CI, 0.74‐1.43). No consistent association was found between diabetes and BE.Conclusions:Diabetes was associated with increased EA and EGJA risk, which was confined to individuals with regurgitation symptoms. Lack of an association between diabetes and BE suggests that diabetes may influence progression of BE to cancer.

PURPOSE To determine whether recommended amounts of leisure-time physical activity (ie, 7.5-15 metabolic equivalent task [MET] hours/week) are associated with lower cancer risk, describe the shape of the dose-response relationship, and explore associations with moderate- and vigorous-intensity physical activity. METHODS Data from 9 prospective cohorts with self-reported leisure-time physical activity and follow-up for cancer incidence were pooled. Multivariable Cox regression was used to estimate adjusted hazard ratios (HRs) and 95% CIs of the relationships between physical activity with incidence of 15 types of cancer. Dose-response relationships were modeled with restricted cubic spline functions that compared 7.5, 15.0, 22.5, and 30.0 MET hours/week to no leisure-time physical activity, and statistically significant associations were determined using tests for trend ( P < .05) and 95% CIs (< 1.0). RESULTS A total of 755,459 participants (median age, 62 years [range, 32-91 years]; 53% female) were followed for 10.1 years, and 50,620 incident cancers accrued. Engagement in recommended amounts of activity (7.5-15 MET hours/week) was associated with a statistically significant lower risk of 7 of the 15 cancer types studied, including colon (8%-14% lower risk in men), breast (6%-10% lower risk), endometrial (10%-18% lower risk), kidney (11%-17% lower risk), myeloma (14%-19% lower risk), liver (18%-27% lower risk), and non-Hodgkin lymphoma (11%-18% lower risk in women). The dose response was linear in shape for half of the associations and nonlinear for the others. Results for moderate- and vigorous-intensity leisure-time physical activity were mixed. Adjustment for body mass index eliminated the association with endometrial cancer but had limited effect on other cancer types. CONCLUSION Health care providers, fitness professionals, and public health practitioners should encourage adults to adopt and maintain physical activity at recommended levels to lower risks of multiple cancers.

OBJECTIVE: To determine the association between osteoarthritis (OA), rheumatoid arthritis (RA), and frailty and to determine whether comorbidities interact with OA and RA to further increase the likelihood of frailty.METHODS: Participants of the UK Biobank age 40-69 years at baseline were included. Demographic, lifestyle, and clinical data were collected at baseline and follow-up in a subset. Frailty was assessed using a frailty index (FI) (continuous) and a modified frailty phenotype (robust, pre-frail, frail). The association between RA and OA and frailty at baseline and follow-up was assessed using multiple regression models. We looked at whether comorbidities, including cardiovascular disease, diabetes mellitus, chronic obstructive pulmonary disease, and depression interacted additively with OA and RA to increase the likelihood of frailty.RESULTS: In total, 457,561 participants contributed data. Those with (versus without) RA (n = 4,894) and OA (n = 35,884), respectively, were more likely to be frail (adjusted relative risk ratio 10.7 [95% confidence interval (95% CI) 9.7, 11.7] and 3.4 [95% CI 3.3, 3.6]) and were more likely to have a higher FI at baseline. There was evidence of additive interaction between RA, OA, and common comorbidities increasing the occurrence of prevalent frailty. Among 25,163 participants included in longitudinal analysis, patients with RA (n = 202) and OA (n = 1,811) at baseline had an increased adjusted frailty incidence rate ratio (2.8 [95% CI 1.7, 4.6] and 1.7 [95% CI 1.3, 2.1], respectively) and also a higher FI during follow-up.CONCLUSION: Individuals with RA and OA are more likely to have, or develop, frailty. Common comorbidities interact with OA and RA to further increase the likelihood of frailty.

Background Physical activity is associated with lower risk for endometrial cancer, but the extent to which the association is mediated by body mass index (BMI) in midlife is unclear. This study describes the physical activity–endometrial cancer association and whether BMI mediates this relationship. Methods Participants were 67 705 women in the National Institutes of Health-AARP Diet and Health Study (50-71 years) who recalled their physical activity patterns starting at age 15-18 years. We identified 5 long-term physical activity patterns between adolescence and cohort entry (ie, inactive, maintained low, maintained high, increasers, decreasers). We used Cox regression to assess the relationship between these patterns and midlife BMI and endometrial cancer, adjusting for covariates. Mediation analysis was used to estimate the proportion of the physical activity–endometrial cancer association that was mediated by midlife BMI. Results During an average 12.4 years of follow-up 1468 endometrial cancers occurred. Compared with long-term inactive women, women who maintained high or increased activity levels had a 19% to 26% lower risk for endometrial cancer (maintained high activity: hazard ratio = 0.81, 95% confidence interval [CI] = 0.67 to 0.98; increasers: hazard ratio = 0.74, 95% CI = 0.61 to 0.91). They also had a 50% to 77% lower risk for obesity in midlife (eg, maintained high activity: odds ratio for a BMI of 30-39.9 kg/m2 = 0.50, 95% CI = 0.46 to 0.55; and maintained high activity, odds ratio for a BMI of ≥40 kg/m2 = 0.32, 95% CI = 0.26 to 0.39). BMI was a statistically significant mediator accounting for 55.5% to 62.7% of the physical activity–endometrial cancer associations observed. Conclusions Both maintaining physical activity throughout adulthood and adopting activity later in adulthood can play a role in preventing obesity and lowering the risk for endometrial cancer.

Objectives To characterize the incidence of clinically diagnosed Paget’s disease of bone in the UK during 1999–2015 and to determine variations in the incidence of disease by age, sex, geography and level of deprivation. Methods Incident cases of Paget’s disease occurring between 1999 and 2015 were identified from primary care records. Overall crude incidence and incidence stratified by age and sex was calculated each year from 1999 to 2015. Direct age- and sex-standardized incidence was also calculated. We used Poisson regression to look at variations in incidence by deprivation and UK region. Results A total of 3592 incident cases of Paget’s disease were identified between 1999 and 2015. Incidence increased with age and at all ages was greater in men than women. In women and men, respectively, crude incidence increased from 0.037 and 0.074/10 000 population per year among those 45–49 years of age to 3.7 and 6.3/10 000 population per year among those ≥85 years. The overall standardized incidence decreased from 0.75/10 000 person-years in 1999 to 0.20/10 000 person-years in 2015. After adjustment for age and sex, incidence was >30% higher in the most- compared with least-deprived quintile of deprivation. There was evidence of geographic variation, with the highest incidence in the North West of England, which persisted after adjustment for age, sex and level of deprivation. Conclusion The incidence of clinically diagnosed Paget’s disease has continued to decrease since 1999. The reason for the decline in incidence remains unknown, although the rapidity of change points to an alteration in one or more environmental determinants.

Background/Aims People with osteoarthritis (OA) and rheumatoid arthritis (RA) are at increased risk of frailty, though the role of co-morbidities in contributing to frailty risk in these arthritides is uncertain. The aim of this study was i) to determine the association between common co-morbidities and frailty in OA and RA; and ii) to determine whether co-morbidities interact synergistically with OA and RA to increase the likelihood of frailty. Methods A cross-sectional analysis of the UK Biobank data was carried out. In this national cohort of participants aged 40-69 years, self-reported physician-diagnosed diseases including OA, RA, and common co-morbidities (including hypertension, coronary heart disease, diabetes, stroke/TIA, chronic obstructive pulmonary disease (COPD), and depression) were recorded. Frailty was assessed using a modification of the frailty phenotype (FP), comprising five components: self-reported weight loss, exhaustion, low physical activity (international activity questionnaire), slow walking speed, and low hand-grip strength. Pre-frailty and frailty, was identified based on the presence of 1-2 and ≥3 of these components, respectively. Among participants with OA and RA at baseline, the likelihood of being pre-frail or frail (vs not frail) at baseline among people with (vs without) each of the co-morbidities was assessed using multinomial logistic regression. To determine whether co-morbidities interact synergistically with OA and RA to increase the likelihood of frailty, deviation from additivity of risk was estimated by calculating the attributable proportion (AP) of risk due to biological interaction. An AP > 0 indicates positive (synergistic) biological interaction. Analyses were adjusted for age, sex, smoking status, BMI, and deprivation. Results In total, 457,561 people were included in the analysis; 35,884 (7.8%) had OA and 4,894 (1.1%) had RA. Overall, the mean (SD) age was 56.5 (8.1) years and 54% were female. The overall prevalence of frailty was 3.4%. The prevalence of frailty was higher among those with OA (10.0%) and RA (18.6%). Each of the co-morbidities considered was associated with increased relative risk of pre-frailty and frailty particularly COPD in OA, relative risk ratio (95%CI): pre-frailty, 2.09 (1.80, 2.42) and frailty, 4.45 (3.71, 5.33) and stroke/TIA in RA: pre-frailty, 1.97 (1.18, 3.29) and frailty, 3.64 (2.11, 6.29). Most of the co-morbidities considered interacted synergistically with OA and RA to increase the risk of pre-frailty and frailty, particularly diabetes in OA, AP (95% CI): pre-frailty, 0.13 (0.04, 0.23) and frailty, 0.49 (0.42, 0.55) and stroke/TIA in RA: pre-frailty, 0.34 (0.003, 0.68) and frailty 0.60 (0.38, 0.82). Conclusion Co-morbidity is associated with an increased occurrence of pre-frailty and frailty among people with OA and RA and interacts synergistically with OA and RA to increase the likelihood of pre-frailty and frailty. Disclosure M.J. Cook: None. M. Lunt: None. S.M.M. Verstappen: None. T.W. O'Neill: None.

Background/Aims Previous studies have suggested an association between sleep disturbance and frailty. The mechanism is unknown, though it has been suggested that hormonal factors may play a role. The aim of this analysis was to determine the association between sleep duration, sleep quality and frailty in middle age and older European men and the influence of testosterone on these associations. Methods Men aged 40-79 years were recruited from population samples in eight European centres for participation in the European Male Age Study. Participants were interviewed and asked also to complete a questionnaire about sleep which included a question about average number of hours sleep per night and questions about sleep quality. Sleep quality was scored 0-20 with higher score indicating poor quality. A frailty index (FI) was constructed. Participants also had a single fasting morning venous blood sample taken and total testosterone measured using gas chromatography mass spectrometry. Using negative binomial regression we looked at the association between sleep duration, sleep quality and frailty (outcome; range 0-100) with the results adjusted for putative confounders and also testosterone level. Results 2,369 participants contributed data to the analysis. Mean sleep duration was 7.01 hours. 256 (10.7%) participants had sleep quality scores between 10 -14 and 101 (4.2%) participants’ scores were between 15 and 20. Mean (standard deviation) testosterone level was 16.4 (6.2) pmol/l and 14.7% of subjects had a low testosterone level ( Conclusion Frailty is associated with impaired sleep quality and also sleep duration. The mechanism is unknown though cannot be explained by testosterone level. Disclosure S.D. Sharma: None. M.J. Cook: None. D. Vanderschueren: None. L. Antoniou: None. E. Gielen: None. F.C. Wu: None. T.W. O’Neill: None.

Background/Aims Evidence from the UK suggest that the incidence of Paget's disease of bone declined during the latter half of the last century with a decline also in the incidence of clinically apparent disease. We aimed to characterise the recent incidence of clinically diagnosed Paget’s disease of bone in the UK by age and sex among those aged >18 years and, to determine whether the incidence has changed from 1999-2015. Methods Incident cases of Paget’s disease during 1999-2015 were identified from the first recorded diagnostic code for Paget’s disease in the UK Clinical Practice Research Datalink (CPRD) database. Crude incidence was calculated for each year from 1999 to 2015 and, to account for changes in the distribution of age and sex over time within the CPRD, direct age- and sex-standardised incidence rates were calculated for each year. This was done by multiplying the crude incidence in each age-sex stratum by the age-sex stratum weight of the 1999 population of those at risk of developing Paget’s disease. We looked also at the incidence of disease by quintile of index of multiple deprivation and geographic region. Using Poisson regression, we looked at the influence of deprivation and geography on occurrence of the disease after adjustment for age and sex. Results In total 3,592 incident cases of Paget’s disease were identified between 1999 and 2015. Overall the incidence increased with age and at all ages was greater in men than women. In men, and women, respectively, incidence increased from 0.074 and 0.037 per 10,000 per year at the age of 45-49 years to 6.3 and 3.7 per 10,000 per year at age of 85 years and older. When stratified by year, the age- and sex-standardised incidence fell from 0.75/10,000 person years in 1999 to 0.20/10,000 person years in 2015. Crude incidence (1999-2015) was slightly higher in those living in the most deprived areas (0.53/10,000 person years) compared to those in least deprived areas (0.43/10,000 person years). After adjustment for age and sex, compared to those in the highest quintile of index of multiple deprivation, those in the lowest quintile of index of multiple deprivation had over a 30% increased risk of disease. There was evidence also of geographic variation in the occurrence of disease with the highest incidence in the North West of England. Conclusion The incidence of clinically diagnosed Paget’s disease has continued to decrease since 1999. The reason for the decline remains unknown, though the rapidity of change points to an alteration in one or more environmental determinants. Disclosure M.J. Cook: None. S.R. Pye: None. W.G. Dixon: None. T.W. O'Neill: None.

BACKGROUND AND AIMS: Tissue miRNA can discriminate between esophageal adenocarcinoma (EA) and normal epithelium. However, no studies have examined a comprehensive panel of circulating miRNAs in relation to EA diagnosis and survival. METHODS: We used all 62 EA cases from the U.S. Multi-Center case-control study with available serum matched 1:1 to controls. Cases were followed for vital status. miRNAs (n=2,064) were assessed using the HTG EdgeSeq miRNA Whole Transcriptome Assay. Differential expression analysis of miRNAs in relation to case-control status was conducted. In cases, Cox regression models were fit to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause mortality. P-values were adjusted using the Benjamini-Hochberg (BH) procedure for false discovery rate control. Predictive performance was assessed using cross validation. RESULTS: 68 distinct miRNAs were significantly upregulated between cases and controls (e.g., miR-1255b-2–3p fold change=1.74, BH-adjusted P=0.01). Assessing the predictive performance of these significantly upregulated miRNAs yielded 60% sensitivity, 65% specificity, and 0.62 AUC. miR-4253 and miR-1238–5p were associated with risk of mortality after EA diagnosis (HR=4.85,95%CI:2.30–10.23, BH-adjusted P=0.04 and HR=3.81,95%CI:2.02–7.19, BH-adjusted P=0.04, respectively). CONCLUSIONS: While they require replication, these findings suggest that circulating miRNAs may be associated with EA diagnosis and survival.

International audience; Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.

Osteoarthritis is a painful, disabling condition which is increasing in prevalence as a result of an ageing population. With no recognized disease-limiting therapeutics, arthroplasty of the hip and knee is the most common and effective treatment for lower limb osteoarthritis, however lower limb arthroplasty has a finite life-span and a proportion of patients will require revision arthroplasty. With increasing life expectancy and an increasing proportion of younger ( Statins are cholesterol-modulating drugs widely used for cardiovascular risk reduction which have been noted to have pleiotropic effects including potentially influencing arthroplasty survival. In vitro studies have demonstrated pleiotropic effects in human bone cells, including enhancement of osteoblastogenesis following simvastatin exposure, and in vivo studies have demonstrated that intraperitoneal simvastatin can increase peri-implant bone growth in rats following titanium tibial implant insertion. There is evidence that statins may also influence osseointegration, enhancing bone growth at the bone–implant interface, subsequently improving the functional survival of implants. Data from the Danish Hip Arthroplasty Registry and the Clinical Practice Research Datalink in the UK suggest a reduction in the risk of lower limb revision arthroplasty in statin ever-users versus never-users, and a time-dependent effect of statins in reducing the risk of revision. In this article we review the clinical and experimental evidence linking statins and risk of revision arthroplasty.

Background In the era of widespread prostate-specific antigen testing, it is important to focus etiologic research on the outcome of aggressive prostate cancer, but studies have defined this outcome differently. We aimed to develop an evidence-based consensus definition of aggressive prostate cancer using clinical features at diagnosis for etiologic epidemiologic research. Methods Among prostate cancer cases diagnosed in 2007 in the National Cancer Institute’s Surveillance, Epidemiology, and End Results-18 database with follow-up through 2017, we compared the performance of categorizations of aggressive prostate cancer in discriminating fatal prostate cancer within 10 years of diagnosis, placing the most emphasis on sensitivity and positive predictive value (PPV). Results In our case population (n = 55 900), 3073 men died of prostate cancer within 10 years. Among 12 definitions that included TNM staging and Gleason score, sensitivities ranged from 0.64 to 0.89 and PPVs ranged from 0.09 to 0.23. We propose defining aggressive prostate cancer as diagnosis of category T4 or N1 or M1 or Gleason score of 8 or greater prostate cancer, because this definition had one of the higher PPVs (0.23, 95% confidence interval = 0.22 to 0.24) and reasonable sensitivity (0.66, 95% confidence interval = 0.64 to 0.67) for prostate cancer death within 10 years. Results were similar across sensitivity analyses. Conclusions We recommend that etiologic epidemiologic studies of prostate cancer report results for this definition of aggressive prostate cancer. We also recommend that studies separately report results for advanced category (T4 or N1 or M1), high-grade (Gleason score ≥8), and fatal prostate cancer. Use of this comprehensive set of endpoints will facilitate comparison of results from different studies and help elucidate prostate cancer etiology.

PURPOSE: Daily aspirin use has been shown to reduce risk of colorectal, and possibly other, cancers, but it is unknown if these benefits are consistent across subgroups of people with differing cancer risk factors. We investigated whether age, body mass index (BMI), smoking status, physical inactivity, and family history of cancer modify the effect of daily aspirin use on colorectal, ovarian, breast, endometrial and aggressive prostate cancer risk. METHODS: We pooled 423,495 individuals from two prospective, U.S.-based studies: the NIH-AARP Diet and Health Study (1995–2011) and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (1993–2009). Using Cox proportional hazards regression, we examined associations between daily aspirin use (≥5 days/week) and risk of colorectal, ovarian, breast, endometrial, and aggressive prostate cancer, overall and across strata of risk factors. RESULTS: Daily aspirin use was associated with a 15% reduction in colorectal cancer risk (hazard ratio [HR]: 0.85, 95% confidence interval [CI]: 0.80–0.89). Risk reductions were generally consistent across strata of risk factors but attenuated with increasing BMI (p-interaction=0.16). For ovarian cancer, there was no significant association overall (HR: 0.93, 95% CI: 0.80–1.08) but reduced risk among obese women (HR: 0.73, 95% CI: 0.52–0.98, p-interaction=0.12). Weak or null associations were observed for breast, endometrial, and aggressive prostate cancer, with no strong effect modification observed. CONCLUSIONS: Daily aspirin use appears to reduce colorectal cancer risk regardless of other risk factors, though the potential modifying effect of BMI warrants further investigation and may need to be considered in risk-benefit calculations for aspirin use.

Background In the USA, it is unknown whether metastatic prostate cancer incidence has continued to increase and whether racial differences have persisted. Objective Combining multiple imputation with age and delay adjustment, we provide an up-to-date, comprehensive assessment of US prostate cancer incidence trends by stage and race. Design, setting, and participants From Surveillance Epidemiology and End Results (SEER)-18, 774 240 prostate cancer cases were diagnosed during 2004–2017. Outcome measurements and statistical analysis Multiple imputation assigned prostate cancer stage to the 4.7% of cases with missing stage, which varied by year and race-ethnicity. SEER delay factors adjusted case counts to anticipated future data corrections. Twenty datasets were imputed, and Rubin’s rules were used for summary estimation. Overall and stage-specific rates were estimated and stratified by race and age group. Joinpoint software identified significant temporal changes and estimated annual percentage changes. We compared these estimates without multiple imputation and delay adjustment. Results and limitations Metastatic prostate cancer incidence increased during 2011–2017, with an annual percentage change of 5.5. This was followed by increases in localized and regional disease since 2014. Non-Hispanic black men continued to have the highest incidence, especially for metastatic disease. The increasing rate of metastatic prostate cancer in non-Hispanic white men aged 50–74 yr accelerated recently, and the incidence was 56% higher in 2017 than in 2004. Rates without multiple imputation and delay adjustment were quantitatively and qualitatively different. This observational study is unable to assign causes to observed changes in prostate cancer incidence. Conclusions Multiple imputation and delay adjustment are essential for portraying accurately stage- and race-specific prostate cancer incidence as clinical practice evolves. Patient summary In the USA, diagnosis of prostate cancer that has spread to distant sites (metastatic disease) continues to increase. Black men continue to have higher risks of being diagnosed with metastatic prostate cancer than other race-ethnicities.

Recent epidemiologic studies have examined the association of fish consumption with upper gastrointestinal cancer risk, but the associations with n-3 and n-6 polyunsaturated fatty acid (PUFA) subtypes remain unclear. Using the National Institutes of Health–AARP Diet and Health Study (United States, 1995–2011), we prospectively investigated the associations of PUFA subtypes, ratios, and fish with the incidence of head and neck cancer (HNC; n = 2,453), esophageal adenocarcinoma (EA; n = 855), esophageal squamous cell carcinoma (n = 267), and gastric cancer (cardia: n = 603; noncardia: n = 631) among 468,952 participants (median follow-up, 15.5 years). A food frequency questionnaire assessed diet. Multivariable-adjusted hazard ratios were estimated using Cox proportional hazards regression. A Benjamini-Hochberg (BH) procedure was used for false-discovery control. Long-chain n-3 PUFAs were associated with a 20% decreased HNC and EA risk (for HNC, quintile5 vs. 1 hazard ratio = 0.81, 95% confidence interval: 0.71, 0.92, and BH-adjusted Ptrend = 0.001; and for EA, quintile5 vs. 1 hazard ratio = 0.79, 95% confidence interval: 0.64, 0.98, and BH-adjusted Ptrend = 0.1). Similar associations were observed for nonfried fish but only for high intake. Further, the ratio of long-chain n-3:n-6 was associated with a decreased HNC and EA risk. No consistent associations were observed for gastric cancer. Our results indicate that dietary long-chain n-3 PUFA and nonfried fish intake are associated with lower HNC and EA risk.

ObjectivesEstablished prostate cancer (PCa) risk factors include age, family history of PCa and African ancestry. Studies, mostly among highly screened, predominantly European ancestral populations, suggest that employment in certain occupations (eg, farming, military) may also have an increased risk for PCa. Here, we evaluated the association between usual adult occupation and PCa risk in Ghanaian men, a population with historically low rates of PCa screening.MethodsThe Ghana Prostate Study is a case-control study of PCa that was conducted from 2004 to 2012 in 749 cases and 964 controls. In-person interviews were conducted to collect information from participants, including longest held job. Industrial hygienists classified job titles into occupational categories. Unconditional logistic regression was used to calculate ORs and 95% CIs for the association between longest held job and PCa risk (overall, aggressive (Gleason≥7)), controlling for potential confounders.ResultsRisk was increased among men in management (overall PCa OR=2.2, 95% CI 1.4 to 3.2; aggressive PCa OR=2.2, 95% CI 1.3 to 3.5) and military occupations (overall PCa OR=3.4, 95% CI 1.7 to 7.0; aggressive PCa OR=3.5, 95% CI 1.5 to 8.3). Risks were also elevated for management and military-specific jobs based on 3-digit level Standard Occupational Classification definitions. Sensitivity analyses accounting for access to medical care did not show significant differences.ConclusionsOur study provides some evidence for increased risk of PCa among men in management and military occupations, which is consistent with the published literature. Additional research is needed to clarify the drivers of the associations between these occupations and PCa.

Purpose Cancer of the prostate (CaP) is the leading cancer among men in sub-Saharan Africa (SSA). A substantial proportion of these men with CaP are diagnosed at late (usually incurable) stages, yet little is known about the etiology of CaP in SSA. Methods We established the Men of African Descent and Carcinoma of the Prostate Network, which includes seven SSA centers partnering with five US centers to study the genetics and epidemiology of CaP in SSA. We developed common data elements and instruments, regulatory infrastructure, and biosample collection, processing, and shipping protocols. We tested this infrastructure by collecting epidemiologic, medical record, and genomic data from a total of 311 patients with CaP and 218 matched controls recruited at the seven SSA centers. We extracted genomic DNA from whole blood, buffy coat, or buccal swabs from 265 participants and shipped it to the Center for Inherited Disease Research (Baltimore, MD) and the Centre for Proteomics and Genomics Research (Cape Town, South Africa), where genotypes were generated using the UK Biobank Axiom Array. Results We used common instruments for data collection and entered data into the shared database. Double-entered data from pilot participants showed a 95% to 98% concordance rate, suggesting that data can be collected, entered, and stored with a high degree of accuracy. Genotypes were obtained from 95% of tested DNA samples (100% from blood-derived DNA samples) with high concordance across laboratories. Conclusion We provide approaches that can produce high-quality epidemiologic and genomic data in multicenter studies of cancer in SSA.

Preliminary evidence suggests that sex steroid hormones, such as Danazol (a synthetic sex steroid hormone) may be involved in enhancing telomerase activity. Elucidating underlying mechanisms of telomerase activity may further therapeutic options for individuals with telomeropathies and potentially avert certain age-related conditions. Therefore, we conducted a cross-sectional study to investigate the relationship between circulating sex steroid hormones and SHBG with leukocyte telomere length among 499 males in NHANES (1999–2002 surveys). Sample-weighted linear regression analyses were conducted to assess age-adjusted and multivariable-adjusted estimates of associations. Estimates were rescaled to represent telomere length change in base pairs per half the value of the interquartile range of the independent variable. Estradiol and free estradiol were significantly inversely associated with leukocyte telomere length (β(continuous per ½ IQR) = −61, p=0.04; free estradiol β(continuous per ½ IQR) = −67, p=0.03). Testosterone, free testosterone, androstanediol glucuronide, and SHBG were not associated with leukocyte telomere length. The inverse association seen in the present study indicates that a Danazol-induced hypoestrogenic state could partly underlie the previously observed association between Danazol therapy and increased leukocyte telomere length.

Incidence of upper gastrointestinal cancers of the oesophagus and stomach show a strong unexplained male predominance. Hormonal and reproductive factors have been associated with upper gastrointestinal cancers in women but there is little available data on men. To investigate this, we included 219,425 men enrolled in the UK Biobank in 2006-2010. Baseline assessments provided information on hormonal and reproductive factors (specifically hair baldness, number of children fathered, relative age at first facial hair and relative age voice broke) and incident oesophageal or gastric cancers were identified through linkage to U.K. cancer registries. Unadjusted and adjusted hazard ratios (HR) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. During 8 years of follow-up, 309 oesophageal 210 gastric cancers occurred. There was some evidence that male pattern baldness, was associated with gastric cancer risk (adjusted HR 1.35, 95% CI 0.97, 1.88), particularly for frontal male pattern baldness (adjusted HR 1.52, 95% CI 1.02, 2.28). There was little evidence of association between other hormonal and reproductive factors and risk of oesophageal or gastric cancer, overall or by histological subtype. In the first study of a range of male hormonal and reproductive factors and gastric cancer, there was a suggestion that male pattern baldness, often used as a proxy of sex hormone levels, may be associated with gastric cancer. Future prospective studies that directly test circulating sex steroid hormone levels in relation to upper gastrointestinal cancer risk are warranted.

Background Metastatic prostate cancer (PCA) remains a highly lethal malignancy in the USA. As prostate-specific antigen testing declines nationally, detailed assessment of current age- and race-specific incidence trends and quantitative forecasts are needed. Objective To evaluate the current trends of metastatic PCA by age and race, and forecast the number of new cases (annual burden) and future trends. Design, setting, and participants We derived incidence data for men aged ≥45 yr who were diagnosed with metastatic PCA from the population-based Surveillance, Epidemiology, and End Results registries. Outcome measurements and statistical analysis We examined the current trends of metastatic PCA from 2004 to 2014, and forecast the annual burden and incidence rates by age and race for 2015–2025, using age–period–cohort models and population projections. We also examined alternative forecasts (2012–2025) using trends prior to the revised screening guidelines issued in 2012. Results and limitations Metastatic PCA, steadily declining from 2004 to 2007 by 1.45%/yr, began to increase by 0.58%/yr after 2008, which accelerated to 2.74%/yr following the 2012 United States Preventive Services Task Force recommendations—a pattern that was magnified among men aged ≤69 yr and white men. Forecasts project the incidence to increase by 1.03%/yr through 2025, with men aged 45–54 yr (2.29%/yr) and 55–69 yr (1.53%/yr) increasing more rapidly. Meanwhile, the annual burden is expected to increase 42% by 2025. Our forecasts estimated an additional 15 891 metastatic cases from 2015 to 2025 compared with alternative forecasts using trends prior to 2012. Conclusions The recent uptick in metastatic PCA rates has resulted in forecasts that project increasing rates through 2025, particularly among men aged ≤69 yr. Moreover, racial disparities are expected to persist and the annual burden will increase considerably. The impact of the prior and current PCA screening recommendations on metastatic PCA rates requires continued examination. Patient summary In this report, we assessed how the incidence of metastatic prostate cancer has changed over recent years, and forecast future incidence trends and the number of new cases expected each year. We found that the incidence of metastatic prostate cancer has been increasing more rapidly since 2012, resulting in a rise in both future incidence and the number of new cases by 2025. Future incidence rates and the number of new cases were reduced in alternative forecasts using data prior to the 2012 United States Preventive Services Task Force (USPSTF) recommendations against prostate-specific antigen (PSA) testing for prostate cancer. There is a need for additional research that examines whether national declines in PSA testing contributed to increases in rates of metastatic disease. The incidence of metastatic disease in black men is still expected to occur at considerably higher rates compared with that in white men.

Background: Sex hormones have been implicated in prostate carcinogenesis, yet epidemiologic studies have not provided substantiating evidence. We tested the hypothesis that circulating concentrations of sex steroid hormones reflect intraprostatic concentrations using serum and adjacent microscopically verified benign prostate tissue from prostate cancer cases. Methods: Incident localized prostate cancer cases scheduled for surgery were invited to participate. Consented participants completed surveys, and provided resected tissues and blood. Histologic assessment of the ends of fresh frozen tissue confirmed adjacent microscopically verified benign pathology. Sex steroid hormones in sera and tissues were extracted, chromatographically separated, and then quantitated by radioimmunoassays. Linear regression was used to account for variations in intraprostatic hormone concentrations by age, body mass index, race, and study site, and subsequently to assess relationships with serum hormone concentrations. Gleason score (from adjacent tumor tissue), race, and age were assessed as potential effect modifiers. Results: Circulating sex steroid hormone concentrations had low-to-moderate correlations with, and explained small proportions of variations in, intraprostatic sex steroid hormone concentrations. Androstane-3α,17β-diol glucuronide (3α-diol G) explained the highest variance of tissue concentrations of 3α-diol G (linear regression r2 = 0.21), followed by serum testosterone and tissue dihydrotestosterone (r2 = 0.10), and then serum estrone and tissue estrone (r2 = 0.09). There was no effect modification by Gleason score, race, or age. Conclusions: Circulating concentrations of sex steroid hormones are poor surrogate measures of the intraprostatic hormonal milieu. Impact: The high exposure misclassification provided by circulating sex steroid hormone concentrations for intraprostatic levels may partly explain the lack of any consistent association of circulating hormones with prostate cancer risk. Cancer Epidemiol Biomarkers Prev; 26(11); 1660–6. ©2017 AACR.

Racial and ethnic disparities in the incidence of esophageal cancer have not been thoroughly characterized with quantitative health-disparity measures. Using data from 1992–2013 from 13 US cancer registries in the Surveillance, Epidemiology, and End Results database, we assessed such disparities according to histological type, based on a variety of disparity metrics. The age-standardized incidence rate of squamous cell carcinoma (SCC) was highest among black persons, while adenocarcinoma mainly affected white men. The rate of SCC decreased over time in all racial/ethnic groups, and this was most pronounced in black persons (by 5.7% per year among men and 5.0% among women). The adenocarcinoma rate rose among non-Hispanic whites and among black men. Racial/ethnic disparities in the incidence of total esophageal cancer decreased over time, which was due mainly to reduced disparities in SCC. The 2 absolute disparity measures—range difference and between-group variance—for adenocarcinoma rose by 3.2% and 6.8% per year, respectively, in men and by 1.8% and 5.3% per year, respectively, in women. This study demonstrates decreased racial/ethnic disparities in the incidence of esophageal SCC over time in the United States, while disparities increased in adenocarcinoma incidence as measured on the absolute scale.

The prevalence of fusions of the transmembrane protease, serine 2, gene (TMPRSS2) with the erythroblast transformation-specific-related gene (ERG), or TMPRSS2:ERG, in prostate cancer varies by race. However, such somatic aberration and its association with prognostic factors have neither been studied in a West African population nor been systematically reviewed in the context of racial differences. We used immunohistochemistry to assess oncoprotein encoded by the ERG gene as the established surrogate of ERG fusion genes among 262 prostate cancer biopsies from the Ghana Prostate Study (2004-2006). Poisson regression with robust variance estimation provided prevalence ratios and 95% confidence intervals of ERG expression in relation to patient characteristics. We found that 47 of 262 (18%) prostate cancers were ERG-positive, and being negative for ERG staining was associated with higher Gleason score. We further conducted a systematic review and meta-analysis of TMPRSS2:ERG fusions in relation to race, Gleason score, and tumor stage, combining results from Ghana with 40 additional studies. Meta-analysis showed the prevalence of TMPRSS2:ERG fusions in prostate cancer to be highest in men of European descent (49%), followed by men of Asian (27%) and then African (25%) descent. The lower prevalence of TMPRSS2:ERG fusions in men of African descent implies that alternative genomic mechanisms might explain the disproportionately high prostate cancer burden in such populations.

Background Ageing is associated with sarcopenia, osteoporosis, and increased fall risk, all of which contribute to increased fracture risk. Mechanically, bone strength adapts in response to forces created by muscle contractions. Adaptations can be through changes in bone size, geometry, and bending strength. Muscle mass is often used as a surrogate for muscle force; however, force can be increased without changes in muscle mass. Increased fall risk with ageing has been associated with a decline in muscle power—which is a measure of mobility. The aims of this study were as follows: (i) to investigate the relationship between muscle parameters in the upper and lower limbs with age in UK men and the influence of ethnicity on these relationships; (ii) to examine the relationships between jump force/grip strength/cross-sectional muscle area (CSMA) with bone outcomes at the radius and tibia. Methods White European, Black Afro-Caribbean, and South Asian men aged 40–79 years were recruited from Manchester, UK. Cortical bone mineral content, cross-sectional area, cortical area, cross-sectional moment of inertia, and CSMA were measured at the diaphysis of the radius and tibia using peripheral quantitative computed tomography. Lower limb jump force and power were measured from a single two-legged jump performed on a ground-reaction force platform. Grip strength was measured using a dynamometer. Associations between muscle and bone outcomes was determined using linear regression with adjustments for age, height, weight, and ethnicity. Results Three hundred and one men were recruited. Jump force was negatively associated with age; for every 10 year increase in age, there was a 4% reduction in jump force (P

Background: Chromosome 8q24 has emerged as an important genetic susceptibility region for several cancers, including prostate cancer; however, little is known about the contribution of DNA methylation in this region to risk. Methods: We prospectively evaluated DNA methylation at 8q24 in relation to prostate cancer using pre-diagnostic blood samples from 694 prostate cancer cases (including 172 aggressive cases) and 703 controls in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. We used logistic regression to estimate odds ratios and 95% confidence intervals. Results: Although none remained significant after adjustment for multiple testing (q>0.05), of the 50 CpG sites meeting quality control, we identified 8 sites that were nominally associated with prostate cancer (Ptrend

Marijuana has been reported to have several effects on the male reproductive system. Marijuana has previously been linked to reduced adult testosterone, however, a study in Denmark reported increased testosterone concentrations among marijuana users. This study was performed to estimate the effect of marijuana use on testosterone in U.S. males. Data on serum testosterone, marijuana use, and covariates for 1577 men from the 2011-2012 U.S. National Health and Nutrition Examination Survey (NHANES) were analyzed. Information on marijuana use was collected by a self-administered computer-assisted questionnaire. Serum testosterone was determined using isotope dilution liquid chromatography tandem mass spectrometry. The effects of marijuana use on serum testosterone concentrations were examined by frequency, duration, and recency of use. Adjusted means and 95% confidence intervals (CI) of serum testosterone across levels of marijuana use were estimated using multiple linear regression weighted by the survey weights. The majority (66.2%) of the weighted study population reported ever using marijuana with 26.6% reporting current marijuana use. There was no difference in serum testosterone between ever users (adjusted mean = 3.69 ng/mL, 95% CI: 3.46, 3.93) and never users (adjusted mean = 3.70 ng/mL, 95% CI: 3.45, 3.98) upon multivariable analysis. However, serum testosterone was inversely associated with time since last regular use of marijuana (p-value for trend = 0.02). When restricted to men aged 18-29 years, this relationship strengthened (p-value for trend0.01), and serum testosterone was also inversely associated with time since last use (p-value for trend0.01), indicating that recency of use, and not duration or frequency, had the strongest relationship with testosterone levels. Serum testosterone concentrations were higher in men with more recent marijuana use. Studies are needed to determine the extent to which circulating testosterone concentrations mediate the relationship of marijuana use with male reproductive outcomes.

Background: Elevated body mass index (BMI, kg m−2) has been consistently associated with oesophageal adenocarcinoma (EA) and gastric cardia adenocarcinoma (GCA) incidence. However, effects of adiposity over the life course in relation to EA/GCA have not been thoroughly explored. Methods: We pooled two prospective cohort studies: NIH-AARP Diet and Health Study and Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, with data on 409 796 individuals (633 EA, 415 GCA). At baseline, participants reported their height and weight at ages 20 and 50 years, and current. Body mass index trajectories were determined using latent class analysis. Hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using proportional hazards regression. Results: Compared with individuals with a BMI

Previous studies have shown an overall decreased risk of second cancers among prostate cancer survivors, but this has not been comprehensively examined by race/ethnicity. We conducted a retrospective cohort study of 716,319 one-year survivors of prostate cancer diagnosed at ages 35–84 during 2000–2015 as reported to 17 US Surveillance, Epidemiology and End Results (SEER) registries. We estimated standardized incidence ratios (SIRs) for second primary non-prostate malignancies by race/ethnicity (non-Latino white, Black, Asian/Pacific Islander [API] and Latino), by Gleason, and by time since prostate cancer diagnosis. Poisson regression models were used to test heterogeneity between groups with the expected number as the offset. 60,707 second primary malignancies were observed. SIRs for all second cancers combined varied significantly by race/ethnicity: SIRwhite: 0.88 (95% confidence interval: 0.87–0.89), SIRLatino: 0.92 (0.89–0.95), SIRBlack: 0.97 (0.95–0.99), and SIRAPI: 1.05 (1.01–1.09) (p-heterogeneity

Contains fulltext : 229320.pdf (Publisher’s version ) (Closed access) BACKGROUND & AIMS: Esophageal adenocarcinoma (EA) and its premalignant lesion, Barrett's esophagus (BE), are characterized by a strong and yet unexplained male predominance (with a male-to-female ratio in EA incidence of up to 6:1). Genome-wide association studies (GWAS) have identified more than 20 susceptibility loci for these conditions. However, potential sex differences in genetic associations with BE/EA remain largely unexplored. METHODS: Given strong genetic overlap, BE and EA cases were combined into a single case group for analysis. These were compared with population-based controls. We performed sex-specific GWAS of BE/EA in 3 separate studies and then used fixed-effects meta-analysis to provide summary estimates for >9 million variants for male and female individuals. A series of downstream analyses were conducted separately in male and female individuals to identify genes associated with BE/EA and the genetic correlations between BE/EA and other traits. RESULTS: We included 6758 male BE/EA cases, 7489 male controls, 1670 female BE/EA cases, and 6174 female controls. After Bonferroni correction, our meta-analysis of sex-specific GWAS identified 1 variant at chromosome 6q11.1 (rs112894788, KHDRBS2-MTRNR2L9, P(BONF) = .039) that was statistically significantly associated with BE/EA risk in male individuals only, and 1 variant at chromosome 8p23.1 (rs13259457, PRSS55-RP1L1, P(BONF) = 0.057) associated, at borderline significance, with BE/EA risk in female individuals only. We also observed strong genetic correlations of BE/EA with gastroesophageal reflux disease in male individuals and obesity in female individuals. CONCLUSIONS: The identified novel sex-specific variants associated with BE/EA could improve the understanding of the genetic architecture of the disease and the reasons for the male predominance.

Highlights • ALE meta-analysis revealed functional activation differences in mTBI. • Reduced activation identified within the right middle frontal gyrus. • Suggests alteration of prefrontal region, associated with executive functioning. • Need for addressing subject- and task-specific variation in future studies., Task-based functional magnetic resonance imaging (fMRI) has been used to examine neuroanatomical and functional changes following mild traumatic brain injury (mTBI). Prior studies have lacked consistency in identifying common regions of altered neural activity during cognitive tasks. This may be partly due to differences in task paradigm, patient heterogeneity, and methods of fMRI analysis. We conducted a meta-analysis using an activation likelihood estimation (ALE) method to identify regions of differential brain activation in patients with mTBI compared to healthy controls. We included experiments that performed scans from acute to subacute time points post-injury. The seven included studies recruited a total sample of 174 patients with mTBIs and 139 control participants. The results of our coordinate based meta-analysis revealed a single cluster of reduced activation within the right middle frontal gyrus (MFG) that differentiated mTBI from healthy controls. We conclude that the cognitive impairments in memory and attention typically reported in mTBI patients may be associated with a deficit in the right MFG, which impacts the recruitment of neural networks important for attentional control.

Many late-stage chronic Lyme disease clinical findings are neuropsychiatric. A total clinical assessment is critical in diagnosis, especially since controversy surrounds the reliability of laboratory testing. The clinical findings of one hundred Lyme disease patients with chronic neuropsychiatric symptoms were entered into a database. The prevalence of each clinical finding pre-infection and post-infection was compared and calculated within the 95% confidence interval. Patients had minimal symptoms pre-infection, but a high post-infection prevalence of a broad spectrum of acquired multisystem symptoms. These findings included impairments of attention span, memory, processing, executive functioning, emotional functioning, behavior, psychiatric syndromes, vegetative functioning, neurological, musculoskeletal, cardiovascular, upper respiratory, dental, pulmonary, gastrointestinal, genitourinary, and other symptoms. The most prevalent symptoms included sustained attention impairments, brain fog, unfocused concentration, joint symptoms, distraction by frustration, depression, working memory impairments, decreased school/job performance, recent memory impairments, difficulty prioritizing multiple tasks, fatigue, non-restorative sleep, multitasking difficulties, sudden mood swings, hypersomnia, mental apathy, decreased social functioning, insomnia, tingling, word finding difficulties, name retrieval, headaches, sound hypersensitivity, paresis, anhedonia, depersonalization, cold intolerance, body temperature fluctuations, light sensitivity and dysfluent speech. The average patient had five symptoms pre-infection and 82 post-infection. Pattern recognition is critical in making a diagnosis. This study was used to develop three clinical assessment forms.

Obesity has been associated with an increased risk of advanced prostate cancer. However, most studies have been conducted among North American and European populations. Prostate cancer mortality appears elevated in West Africa, yet risk factors for prostate cancer in this region are unknown. We thus examined the relationship between obesity and prostate cancer using a case-control study conducted in Accra, Ghana in 2004–2012. Cases and controls were drawn from a population-based sample of 1,037 men screened for prostate cancer, yielding 73 cases and 964 controls. An additional 493 incident cases were recruited from the Korle-Bu Teaching Hospital. Anthropometric measurements were taken at enrollment. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between body mass index (BMI), waist circumference (WC), waist-hip ratio (WHR) and prostate cancer, adjusting for potential confounders. The mean BMI was 25.1 kg/m(2) for cases and 24.3 kg/m(2) for controls. After adjustment, men with BMI ≥30 kg/m(2) had an increased risk of prostate cancer relative to men with BMI

The Infectious Disease Society of America, American Academy of Neurology, and American Academy of Rheumatology jointly proposed Lyme disease guidelines. Four areas most relevant to psychiatry were reviewed—the disclaimer, laboratory testing, and adult and pediatric psychiatric sections. The disclaimer and the manner in which these guidelines are implemented are insufficient to remove the authors and sponsoring organizations from liability for harm caused by these guidelines. The guidelines and supporting citations place improper credibility upon surveillance case definition rather than clinical diagnosis criteria. The guidelines fail to address the clear causal association between Lyme disease and psychiatric illnesses, suicide, violence, developmental disabilities and substance abuse despite significant supporting evidence. If these guidelines are published without very major revisions, and if the sponsoring medical societies attempt to enforce these guidelines as a standard of care, it will directly contribute to increasing a national and global epidemic of psychiatric illnesses, suicide, violence, substance abuse and developmental disabilities and the associated economic and non-economic societal burdens. The guideline flaws could be improved with a more appropriate disclaimer, an evidence-based rather than an evidence-biased approach, more accurate diagnostic criteria, and recognition of the direct and serious causal association between Lyme disease and psychiatric illnesses.

s Background Patients with chronic viral infections including human immunodeficiency virus (HIV), hepatitis B (HBV) and hepatitis C (HCV) are at increased risk of developing malignancies. The safety and efficacy of ICI therapy in patients with both cancer and chronic viral infections is not well established as most clinical trials of ICIs excluded these patient populations. Methods We performed a retrospective analysis of patients with advanced-stage cancers and HIV, HBV, or HCV infection treated with ICI therapy at 5 MedStar Health hospitals from January 2011 to April 2018. Results We identified 50 patients including 16 HIV, 29 HBV/HCV, and 5 with concurrent HIV and either HBV or HCV. In the HIV cohort (n = 21), any grade immune-related adverse events (irAEs) were 24% with grade ≥ 3 irAEs 14%. Among 5 patients with matched pre/post-treatment results, no significant changes in HIV viral load and CD4+ T-cell counts were observed. RECIST confirmed (n = 18) overall response rate (ORR) was 28% with 2 complete responses (CR) and 3 partial responses (PR). Responders included 2 patients with low baseline CD4+ T-cell counts (40 and 77 cells/ul, respectively). In the HBV/HCV cohort (n = 34), any grade irAEs were 44% with grade ≥ 3 irAEs 29%. RECIST confirmed ORR was 21% (6 PR). Among the 6 patients with known pre/post-treatment viral titers (2 HCV and 4 HBV), there was no evidence of viral reactivation. Conclusions Our retrospective series is one of the largest case series to report clinical outcomes among HIV, HBV and HCV patients treated with ICI therapy. Toxicity and efficacy rates were similar to those observed in patients without chronic viral infections. Viral reactivation was not observed. Tumor responses occurred in HIV patients with low CD4 T-cell counts. While prospective studies are needed to validate above findings, these data support not excluding such patients from ICI–based clinical trials or treatment.

Background Frailty is a clinical syndrome associated with adverse health outcomes. Frailty and disability can co-occur though are distinct entities. There are few prospective data looking at the occurrence and development of frailty, disability, and work disability in people with osteoarthritis (OA) and rheumatoid arthritis (RA). Objectives To determine the odds of prevalent and incident frailty, disability, and work disability in people with OA or RA, compared to people without these diseases. Methods Subjects aged 40-69 were recruited to the UK Biobank cohort. Data, including self-reported physician-diagnosed OA and RA, were collected at baseline (2007-10) and, in a subset, at follow up (2012-16). Frailty was measured using a modified Fried phenotype comprising five components: self-reported weight loss, exhaustion, low physical activity, slow usual walking pace, and low measured grip-strength (1). Participants were classified as robust if none of the components were present, pre-frail if 1-2 components were present and frail if ≥3 components were present. Participants were classified as having a disability if they indicated receiving a disability allowance/benefit. Participants indicating that they were unable to work due to disability or illness were classified as work disabled. Incident frailty was defined as frail at follow up and robust or pre-frail at baseline. Incident disability or work disability, respectively was defined as receiving a disability benefit or indicating work disability at follow up but not at baseline. Results The mean (SD) age of the 465,379 participants at baseline was 56.5 (8.1) years and 54.3% were female. At baseline, 8.0% of the cohort reported that they had OA and 1.1% RA. At baseline, the prevalence of pre-frailty and frailty was 45.9% and 3.1%, respectively. 3.4% of the cohort indicated receiving a disability benefit, and 3.6% being work disabled. In a model adjusted for age, sex, smoking status and deprivation, compared to those without OA, those with OA were more likely to be pre-frail, odds ratio (OR) (95% CI), 1.8 (1.7,1.8), or frail, OR 4.5 (4.3,4.7), than robust. The adjusted OR (95% CI) for pre-frailty and frailty in those with RA (vs no RA) was 2.8 (2.6, 3.0) and 10.6 (9.7, 11.6), respectively. The adjusted OR (95% CI) for disability benefit was 3.9 (3.8, 4.1) in people with OA (vs no OA) and 7.7 (7.2, 8.2) in people with RA (vs no RA). The adjusted OR (95% CI) for work disability at baseline was 3.5 (3.3, 3.6) in people with OA and 4.8 (4.4, 5.2) in people with RA. Data were available for 26,932 participants at follow up. The mean (SD) follow up time was 5.3 (1.5) years. Of those without frailty at baseline, 573 participants developed frailty during follow up. There were 292 incident cases of disability benefit and 137 incident cases of work disability. The adjusted OR (95% CI) for incident frailty in people with OA and RA at baseline was 2.3 (1.8, 2.9) and 3.3 (1.9, 5.7), respectively. The adjusted OR (95% CI) for incident disability benefit in people with OA and RA at baseline, was 2.7 (2.0, 3.6) and 3.2, (1.7, 6.2), respectively. The adjusted OR (95% CI) for incident work disability in people with OA and RA at baseline was 2.3 (1.3, 3.9) and 3.7 (1.3, 10.1), respectively. Conclusion People with OA and RA have an increased risk of being, or becoming, frail, disabled, or work disabled. Further work is needed to determine effective strategies for preventing or delaying the occurrence of frailty, disability, and work disability in people with OA and RA. References [1] Hanlon P, Nicholl BI, Jani BD, Lee D, McQueenie R, Mair FS. Frailty and pre-frailty in middle-aged and older adults and its association with multimorbidity and mortality: A prospective analysis of 493 737 UK biobank participants. The Lancet Public health 2018;3:e323-e32 Disclosure of Interests None declared