Penciclovir pharmacokinetics after oral and rectal administration of famciclovir in African elephants (Loxodonta africana) shows that effective concentrations can be achieved from rectal administration, despite lower absorption.

OBJECTIVE: To evaluate the pharmacokinetics of famciclovir and its metabolite penciclovir following a single dose administered orally and rectally in African elephants (Loxodonta africana). ANIMALS: 15 African elephants (6 males and 9 females) of various ages. METHODS: Famciclovir (15 mg/kg) was administered orally or per rectum once, with at least a three-week washout period between administrations. Blood was collected at 13 different timepoints per administration for 6 elephants, occurring between February and March 2020. An additional 9 elephants were sampled at variable timepoints per administration utilizing a sparse sampling design between July 2020 and January 2021. Plasma famciclovir and penciclovir levels were measured via HPLC and fluorescence detection. Pharmacokinetic analysis was completed in the summer of 2021 using noncompartmental analysis and nonlinear mixed-effects modeling. RESULTS: Famciclovir was not detected in any sample, suggesting complete metabolism. Key pharmacokinetic parameters for penciclovir following oral administration were time to maximum concentration (tmax; 2.12 hours), area under the concentration-versus-time curve (AUC; 33.93 µg·h/mL), maximum observed concentration (Cmax; 3.73 µg/mL), and absorption half-life (t1/2; 0.65 hours). Following rectal administration, the values were: tmax, 0.65 hours; AUC, 15.62 µg·h/mL; Cmax, 2.52 µg/mL; and absorption t1/2, 0.13 hours. CONCLUSIONS: Famciclovir was rapidly metabolized to penciclovir. Oral administration resulted in slower absorption but higher maximum plasma concentration and higher AUC compared to rectal administration. CLINICAL RELEVANCE: African elephants administered famciclovir via oral and rectal routes resulted in measurable serum penciclovir, and these findings may be utilized by clinicians treating viral infections in this species.

BIOLOGICAL VARIATION OF HEMATOLOGY PARAMETERS AND CLINICAL APPLICATION IN AFRICAN ELEPHANTS (LOXODONTA AFRICANA).

Detailed knowledge of biological variation can facilitate accurate interpretation of clinical pathology parameters. A recent biological variation study in Asian elephants (Elephas maximus) found that hematology parameters had high individuality, which suggests that population-derived reference intervals may be an insensitive diagnostic tool. In elephant medicine, sensitive hematology-related diagnostics are crucial for clinical decision-making, particularly in elephants at risk for elephant endotheliotropic herpesvirus hemorrhagic disease (EEHV-HD). The objective of this study was to assess biological variation of hematology parameters in African elephants to determine whether population-derived reference intervals are a sensitive diagnostic tool for interpreting results and to provide a useful alternative. Eight healthy African elephants had blood collected under behavioral training every other week for 8 wk. Complete blood cell count (CBC) analysis was performed in duplicate to assess analytical variation. Previous methods were used to determine between-individual variation, within-individual variation, index of individuality, and reference change values (RCV). This study found that most hematology parameters displayed intermediate-to-high individuality, which suggests that alternatives to population-derived reference intervals are necessary to detect pathologic changes. To test the results of our biological variation data, a case of EEHV-HD was retrospectively evaluated. Individual normal values and calculated RCV detected a clinically significant monocytopenia, leukopenia, and thrombocytopenia associated with EEHV2 viremia. However, none of these parameters fell outside a population-derived reference interval. This study highlights the utility of biological variation in clinical decision-making and demonstrates that individual normal values and RCV may be important diagnostic tools for CBC interpretation in African elephants.

Updated 5-year results for short course abiraterone acetate and LHRH agonist for unfavorable intermediate and favorable high-risk prostate cancer.

Combined androgen deprivation therapy (ADT) and radiotherapy (RT) improves outcomes for intermediate and high-risk prostate cancer. Treatment intensification with abiraterone acetate/prednisone (AAP) provides additional benefit for high-risk disease. We previously reported 3-year outcomes of a single-arm prospective multicenter trial (AbiRT trial) of 33 patients with unfavorable intermediate risk (UIR) and favorable high risk (FHR) prostate cancer undergoing short course, combination therapy with ADT, AAP, and RT. Here we report the final analysis demonstrating a high rate of testosterone recovery (97%) and excellent biochemical progression-free survival (97%) at 5 years. These data support comparative prospective studies of shorter, more potent ADT courses in favorable high-risk prostate cancer.

Vesicular stomatitis virus in two species of rhinoceros at a California zoological park.

OBJECTIVE: To describe an outbreak of vesicular stomatitis virus (VSV) in southern white rhinoceros (SWR; Ceratotherium simum simum) and greater one-horned rhinoceros (GOHR; Rhinoceros unicornis) at a safari park in San Diego, CA, from May to September 2023. ANIMALS: 21 SWR and 5 GOHR in professionally managed care. METHODS: Rhinoceros of both species presented with a range of clinical signs and severities. Lesion locations were categorized as cutaneous (coronary bands, heels and soles, limbs, ventrum, neck folds, and ears) and mucocutaneous (lips, nostrils, mucous membranes of the oral cavity, and vulva). Clinical signs included lethargy, lameness, difficulty with prehension, hyporexia to anorexia, and hypersalivation. Severely affected rhinoceros had clinical pathology findings consistent with systemic inflammation. RESULTS: Vesicular stomatitis New Jersey virus was confirmed via PCR from swabs of lesions in 10/26 (38%) rhinoceros. Of these 10 confirmed cases, 9 (90%) were SWR and 1 (10%) was a GOHR. A further 6/26 (24%) were considered probable cases, and 10/26 (38%) were considered suspect cases based on clinical signs, but the inability to appropriately sample due to the housing environment precluded confirmation. Histopathology samples from 3 rhinoceros were consistent with VSV, and viral RNA was localized in histologic lesions via RNA in situ hybridization for 1 case. All rhinoceros survived infection despite severe systemic illness in 2 animals. CLINICAL RELEVANCE: This case series describes the clinical appearance and progression of VSV in 2 rhinoceros species. To the authors' knowledge, this is the first report of VSV in a rhinoceros.

Pain and Its Association with Survival for Black and White Individuals with Advanced Prostate Cancer in the United States.

Bone pain is a well-known quality-of-life detriment for individuals with prostate cancer and is associated with survival. This study expands previous work into racial differences in multiple patient-reported dimensions of pain and the association between baseline and longitudinal pain and mortality. This is a prospective cohort study of individuals with newly diagnosed advanced prostate cancer enrolled in the International Registry for Men with Advanced Prostate Cancer (IRONMAN) from 2017 to 2023 at U.S. sites. Differences in four pain scores at study enrollment by race were investigated. Cox proportional hazards models and joint longitudinal survival models were fit for each of the scale scores to estimate HRs and 95% confidence intervals (CI) for the association with all-cause mortality. The cohort included 879 individuals (20% self-identifying as Black) enrolled at 38 U.S. sites. Black participants had worse pain at baseline compared with White participants, most notably a higher average pain rating (mean 3.1 vs. 2.2 on a 10-point scale). For each pain scale, higher pain was associated with higher mortality after adjusting for measures of disease burden, particularly for severe bone pain compared with no pain (HR, 2.47; 95% CI: 1.44-4.22). The association between pain and all-cause mortality was stronger for participants with castration-resistant prostate cancer compared with those with metastatic hormone-sensitive prostate cancer and was similar among Black and White participants. Overall, Black participants reported worse pain than White participants, and more severe pain was associated with higher mortality independent of clinical covariates for all pain scales. SIGNIFICANCE: Black participants with advanced prostate cancer reported worse pain than White participants, and more pain was associated with worse survival. More holistic clinical assessments of pain in this population are needed to determine the factors upon which to intervene to improve quality of life and survivorship, particularly for Black individuals.

Parturition and Neonatal Parameters of Three Species of Rhinoceros under Managed Care in the United States.

Rhinoceros species range from near threatened to critically endangered due to habitat loss and poaching. A sustainable ex situ breeding population is critically important to maintain genetic diversity and help ensure the survival of the species; however, not all populations under human care are self-sustaining. While rhinoceros reproductive physiology and pathology have been well studied, there is still a paucity of information describing the normal parameters of parturition and neonatal landmarks. Using video recordings, medical records, and keeper logs, we reviewed and compared data regarding the parturition of three rhinoceros species (black rhinoceros (BR) (Diceros bicornis), n = 4; greater one-horned rhinoceros (GOHR) (Rhinoceros unicornis), n = 21; and southern white rhinoceros (SWR) (Ceratotherium simum simum), n = 22) managed under human care in the United States. Using equine parameters as a model for comparison, we compiled the following data: the signs of impending parturition, durations of the parturition phases, calving presentation, frequency of dystocia or stillbirth, and time from birth to neonatal landmarks. Data from 47 births, including 26 videos, were examined. The durations of parturition phases I, II, and III had median lengths of 153 min (n = 18), 28 min (n = 21), and 205 min (n = 15), respectively. Anterior presentation of the calf was observed in 59% births, whereas posterior presentation occurred in 41% births. Posterior calving presentation was associated with a longer phase II of parturition (p = 0.04), although more data are needed to determine whether the posterior presentation of the calf carries a higher risk for stillbirth. Most (83%) stillbirths occurred in GOHR, indicating that this species might be at a higher risk for stillbirth compared to SWR (17%) (p = 0.07). The median time from birth to the calf standing was longer in the GOHR (64 min) compared to the SWR (30 min) (p = 0.02). Detailed descriptions of the parturition parameters and neonatal landmarks in rhinoceros will aid facilities with rhinoceros breeding programs to recognize abnormalities in the parturient or post-partum periods and guide indications for veterinary intervention.

Are higher follicle-stimulating hormone levels before androgen deprivation therapy for prostate cancer associated with oncological and cardiac outcomes and overall survival?-a population-level analysis.

Background: Androgen deprivation therapy (ADT), commonly delivered via a luteinizing hormone-releasing hormone (LHRH) agonist, is the standard treatment for advanced prostate cancer (PC). While quite effective, it has been associated with an increased risk of major adverse cardiovascular events (MACE). The exact mechanisms are not clear. However, it has been theorized that follicle-stimulating hormone (FSH), a pituitary hormone that is involved in controlling normal testosterone levels, which is decreased with LHRH-agonist therapy, may be the culprit. We performed a retrospective population-level study to test the link of FSH levels on the development of MACE, castrate-resistant PC (CRPC), and death among men starting ADT. Methods: All men (n=1,539) who had an FSH level between 1999 and 2018 within 2 years prior to starting ADT and complete data were identified within the Veterans Affairs (VA) Health System. FSH was dichotomized as low/normal (≤8 IU/mL) and high (>8 IU/mL), using established cut-points. The associations between FSH and time to MACE, death, and CRPC were tested using log-rank tests and multivariable Cox proportional hazards models. Results: Patients with high FSH were older (median 76 vs. 73 years, P<0.001), started ADT earlier (median 2007 vs. 2009, P=0.027), and had lower body mass index (BMI) (median 29.1 vs. 30.1 kg/m2, P=0.004) compared to those with low/normal FSH. On multivariable analysis, there was no association between FSH and time from ADT to MACE, CRPC, or death. Conclusions: In this population-level study of men receiving an FSH test prior to starting ADT, there was no association between FSH levels and time from ADT to MACE, CRPC, or death. Although further studies are needed, these results do not support a link between pre-ADT FSH and long-term oncological or cardiovascular outcomes.

Exposure to Agent Orange and Risk of Bladder Cancer Among US Veterans.

Importance: To date, limited data exist regarding the association between Agent Orange and bladder cancer, and the Institute of Medicine concluded that the association between exposure to Agent Orange and bladder cancer outcomes is an area of needed research. Objective: To examine the association between bladder cancer risk and exposure to Agent Orange among male Vietnam veterans. Design, Setting, and Participants: This nationwide Veterans Affairs (VA) retrospective cohort study assesses the association between exposure to Agent Orange and bladder cancer risk among 2 517 926 male Vietnam veterans treated in the VA Health System nationwide from January 1, 2001, to December 31, 2019. Statistical analysis was performed from December 14, 2021, to May 3, 2023. Exposure: Agent Orange. Main Outcomes and Measures: Veterans exposed to Agent Orange were matched in a 1:3 ratio to unexposed veterans on age, race and ethnicity, military branch, and year of service entry. Risk of bladder cancer was measured by incidence. Aggressiveness of bladder cancer was measured by muscle-invasion status using natural language processing. Results: Among the 2 517 926 male veterans (median age at VA entry, 60.0 years [IQR, 56.0-64.0 years]) who met inclusion criteria, there were 629 907 veterans (25.0%) with Agent Orange exposure and 1 888 019 matched veterans (75.0%) without Agent Orange exposure. Agent Orange exposure was associated with a significantly increased risk of bladder cancer, although the association was very slight (hazard ratio [HR], 1.04; 95% CI, 1.02-1.06). When stratified by median age at VA entry, Agent Orange was not associated with bladder cancer risk among veterans older than the median age but was associated with increased bladder cancer risk among veterans younger than the median age (HR, 1.07; 95% CI, 1.04-1.10). Among veterans with a diagnosis of bladder cancer, Agent Orange was associated with lower odds of muscle-invasive bladder cancer (odds ratio [OR], 0.91; 95% CI, 0.85-0.98). Conclusions and Relevance: In this cohort study among male Vietnam veterans, there was a modestly increased risk of bladder cancer-but not aggressiveness of bladder cancer-among those exposed to Agent Orange. These findings suggest an association between Agent Orange exposure and bladder cancer, although the clinical relevance of this was unclear.

Pharmacokinetics of intravenous propofol in southern white rhinoceros (Ceratotherium simum simum) after intramuscular etorphine-butorphanol-medetomidine-azaperone.

OBJECTIVE: To determine the pharmacokinetics of a single bolus of intravenous (IV) propofol after intramuscular administration of etorphine, butorphanol, medetomidine, and azaperone in 5 southern white rhinoceros to facilitate reproductive evaluations. A specific consideration was whether propofol would facilitate timely orotracheal intubation. ANIMALS: 5 adult, female, zoo-maintained southern white rhinoceros. PROCEDURES: Rhinoceros were administered etorphine (0.002 mg/kg), butorphanol (0.02 to 0.026 mg/kg), medetomidine (0.023 to 0.025 mg/kg), and azaperone (0.014 to 0.017 mg/kg) intramuscularly (IM) prior to an IV dose of propofol (0.5 mg/kg). Physiologic parameters (heart rate, blood pressure, respiratory rate, and capnography), timed parameters (eg, time to initial effects and intubation), and quality of induction and intubation were recorded following drug administration. Venous blood was collected for analysis of plasma propofol concentrations using liquid chromatography-tandem mass spectrometry at various time points after propofol administration. RESULTS: All animals were approachable following IM drug administration, and orotracheal intubation was achieved at 9.8 ± 2.0 minutes (mean ±SD) following propofol administration. The mean clearance for propofol was 14.2 ± 7.7 ml/min/kg, the mean terminal half-life was 82.4 ± 74.4 minutes, and the maximum concentration occurred at 2.8 ± 2.9 minutes. Two of 5 rhinoceros experienced apnea after propofol administration. Initial hypertension, which improved without intervention, was observed. CLINICAL RELEVANCE: This study provides pharmacokinetic data and insight into the effects of propofol in rhinoceros anesthetized using etorphine, butorphanol, medetomidine, and azaperone. While apnea was observed in 2 rhinoceros, propofol administration allowed for rapid control of the airway and facilitated oxygen administration and ventilatory support.

DETECTION OF ELEPHANT ENDOTHELIOTROPIC HERPESVIRUS 1A IN ARCHIVAL TISSUE USING RNASCOPE® IN SITU HYBRIDIZATION.

Hemorrhagic disease due to elephant endotheliotropic herpesvirus infection (EEHV-HD) is an important cause of calf mortality in managed and free-ranging Asian (Elephas maximus) and African elephant (Loxodonta spp.) populations. Consequently, infection has profound implications for elephant population growth and sustainability. The mechanisms of disease caused by EEHV (i.e., infection, dissemination, shedding, latency) are relatively undefined, in part because of a lack of robust validated assays for detecting viral gene products in relevant samples. To address this issue, we used RNAscope® in situ hybridization (ISH) based on EEHV1A DNA polymerase and terminase genes to detect EEHV1A RNA in archival formalin-fixed, paraffin-embedded Asian elephant heart and tongue from PCR-confirmed cases (n = 4) of EEHV-HD and Asian elephants (n = 2) that died from other causes. EEHV1A-positive cases had positive hybridization signal in endothelial cell nuclei of both tissues for both DNA polymerase and terminase. EEHV-negative cases lacked signal. In positive cases, the number of positive nuclei was manually assessed to provide an estimate of the viral load and compare sensitivity of the two probes. In all cases, heart had greater signal than tongue for both probes (Wilcoxon rank test; P ≤ 0.01). Overall, terminase hybridization signal was greater than DNA polymerase signal (Wilcoxon rank test; P ≤ 0.01). Results indicate RNAscope ISH is a valuable tool for detection of EEHV in archival samples and for confirming infection. Additionally, the terminase gene is the optimal target and heart is preferable to tongue for detection in cases of EEHV-HD. Results will inform future investigations of viral tropism in EEHV-HD cases due to EEHV1A.

Validation of the prostate cancer comorbidity index in predicting cause-specific mortality in men undergoing radical prostatectomy.

PURPOSE: Accurate prediction of competing risks of mortality remains a key component of prostate cancer treatment decision-making. We sought to validate the Prostate Cancer Comorbidity Index (PCCI) score for predicting other-cause mortality (OCM) and cancer outcomes in men undergoing radical prostatectomy (RP). MATERIALS AND METHODS: We sampled 4857 men with prostate cancer treated with RP in the VA from 2000-2018. Risks of OCM, 90-day all-cause mortality (ACM), prostate cancer-specific mortality, metastasis, and biochemical recurrence by PCCI score were assessed using Cox proportional hazards and logistic regression. We compared prediction of 90-day ACM between PCCI and the American Society of Anesthesiology (ASA) score, a validated predictor of short-term mortality. RESULTS: Over median follow-up of 6.7 years (IQR 3.7-10.3), there was a stepwise increase in risk of OCM with higher PCCI score, with hazards (95%CI) of 1.53 (1.14-2.04), 2.11 (1.55-2.88), 2.36 (1.68-3.31), 3.61 (2.61-4.98), and 4.99 (3.58-6.96) for PCCI 1-2, 3-4, 5-6, 7-9, and 10 + (vs. 0), respectively. Projected 10-year cumulative incidence of OCM was 8%, 12%, 16%, 19%, 26%, and 32% for scores of 0, 1-2, 3-4, 5-6, 7-9, and 10+ , respectively. Men with PCCI 7+ had greater odds of 90-day ACM (OR 3.48, 95%CI 1.26-9.63) while men with higher ASA did not. Higher PCCI score was associated with worse cancer outcomes, with the highest categories driving the associations. CONCLUSIONS: The PCCI is a robust measure of short- and long-term OCM after RP, validated for use in clinical care and health services research focusing on surgical patient populations.

Metabolic syndrome is associated with aggressive prostate cancer regardless of race.

PURPOSE: Recent meta-analyses suggest the Metabolic Syndrome (MS) increases high-grade prostate cancer (PC), although studies are inconsistent and few black men were included. We investigated MS and PC diagnosis in black and white men undergoing prostate biopsy in an equal access healthcare system. We hypothesized MS would be linked with aggressive PC, regardless of race. METHODS: Among men undergoing prostate biopsy at the Durham Veterans Affairs Hospital, medical record data abstraction of diagnosis or treatment for hypertension (≥ 130/85 mmHg), dyslipidemia (HDL < 40 mg/dL), hypertriglyceridemia (≥ 150 mg/dL), diabetes, hyperglycemia (fasting glucose ≥ 100 ml/dL), and central obesity (waist circumference ≥ 40 inches) were done. Biopsy grade group (GG) was categorized as low (GG1) or high (GG2-5). Multinomial logistic regression was used to examine MS (3-5 components) vs. no MS (0-2 components) and diagnosis of high grade and low grade vs. no PC, adjusting for potential confounders. Interactions between race and MS were also tested. RESULTS: Of 1,051 men (57% black), 532 (51%) had MS. Men with MS were older, more likely to be non-black, and had a larger prostate volume (all p ≤ 0.011). On multivariable analysis, MS was associated with high-grade PC (OR = 1.73, 95% CI 1.21-2.48, p = 0.003), but not overall PC (OR = 1.17, 95% CI 0.88-1.57, p = 0.29) or low grade (OR = 0.87, 95% CI 0.62-1.21, p = 0.39). Results were similar in black and non-black men (all p-interactions > 0.25). CONCLUSION: Our data suggest that metabolic dysregulation advances an aggressive PC diagnosis in both black and non-black men. If confirmed, prevention of MS could reduce the risk of developing aggressive PC, including black men at higher risk of PC mortality.

Is time to castration resistant prostate cancer a potential intermediate end-point for time to metastasis among men initiating androgen deprivation therapy for non-metastatic prostate cancer with rapid PSA doubling time (<9 months)?

PURPOSE: Metastasis-free survival (MFS) is a surrogate for overall survival (OS) in men with non-metastatic castration-resistant prostate cancer (CRPC), but this endpoint may take years to develop in men with non-metastatic castrate-sensitive disease. The study objective was to examine whether progression to CRPC is a potential intermediate endpoint for developing metastatic disease in patients with biochemical recurrence (BCR) after radical prostatectomy (RP). MATERIALS AND METHODS: Men with BCR following RP who had PSA doubling times (PSADT) < 9 months and no metastasis at the time of initiating androgen deprivation therapy (ADT) (n = 210) were included. The primary objective was to assess the correlation between CRPC-free survival (CRPC-FS) and MFS, and the secondary objective was to assess the correlation between time to metastasis and time to CRPC. Kendall's Tau was used to test the correlation for the primary and secondary outcomes. RESULTS: The median MFS was 104 months (95% CI: 83-114) and median CRPC-FS was 100 months (95% CI: 80-114). Based on the Kaplan-Meier curve, the greatest difference in time to MFS and CRPC-FS was around 70% free survival, which was reached at 61.2 months for MFS and 49.6 months for CRPC-FS. Kendall's Tau for the correlation between CRPC-FS and MFS and between time to CRPC and time to metastasis was 0.867 (95% CI: 0.765-0.968) and 0.764 (95% CI: 0.644-0.884), respectively. CONCLUSIONS: Given the high correlation between CRPC-FS and MFS, after validation, CRPC-FS may serve as a potential intermediate endpoint in trials for men with BCR initiating ADT following local therapy.

Identification of Patients With Metastatic Prostate Cancer With Natural Language Processing and Machine Learning.

PURPOSE: Understanding treatment patterns and effectiveness for patients with metastatic prostate cancer (mPCa) is dependent on accurate assessment of metastatic status. The objective was to develop a natural language processing (NLP) model for identifying patients with mPCa and evaluate the model's performance against chart-reviewed data and an International Classification of Diseases (ICD) 9/10 code-based method. METHODS: In total, 139,057 radiology reports on 6,211 unique patients from the Department of Veterans Affairs were used. The gold standard was metastases by detailed chart review of radiology reports. NLP performance was assessed by sensitivity, specificity, positive predictive value, negative predictive value, and date of metastases detection. Receiver operating characteristic curves was used to assess model performance. RESULTS: When compared with chart review, the NLP model had high sensitivity and specificity (85% and 96%, respectively). The NLP model was able to predict patient-level metastasis status with a sensitivity of 91% and specificity of 81%, whereas sensitivity and specificity using ICD9/10 billing codes were 73% and 86%, respectively. For the NLP model, date of metastases detection was exactly concordant and within < 1 week in 55% and 58% of patients, compared with 8% and 17%, respectively, using the ICD9/10 billing codes method. The area under the curve for the NLP model was 0.911. A limitation is the NLP model was developed on the basis of a subset of patients with mPCa and may not be generalizable to all patients with mPCa. CONCLUSION: This population-level NLP model for identifying patients with mPCa was more accurate than using ICD9/10 billing codes when compared with chart-reviewed data. Upon further validation, this model may allow for efficient population-level identification of patients with mPCa.

Are higher pre-diagnosis follicle stimulating hormone levels associated with long-term prostate cancer risk?

BACKGROUND: Follicle stimulating hormone (FSH) is a pituitary hormone that helps regulate testosterone homeostasis. Although it is generally accepted that FSH levels increase with LHRH-agonist therapy for prostate cancer (PC), the specific impact of FSH levels on risk of PC diagnosis is largely unknown. The objective of this study was to perform a population-level analysis to assess the association between FSH levels and PC diagnosis. METHODS: All men (n = 386,018) who had a pre-PC diagnosis FSH level and complete data were identified within the Veterans Affairs Health System between 1999 and 2018. The association between FSH level and time from FSH test to PC diagnosis was tested using stratified Cox proportional hazards models. Multivariable models were adjusted for age, year, race, body mass index, and Charlson comorbidity index. Due to nonproportional hazards over time, time to PC was modeled separately: ≤4 years after an FSH test and >4 years following an FSH test. RESULTS: Median age at first FSH level was 64 years (interquartile range [IQR]: 54-72), median year of FSH was 2010 (IQR: 2005-2014), and 70% of the cohort was white. Median follow-up was 76 months (IQR: 38-126) during which 17,519 men (4.5%) were diagnosed with PC. On multivariable analysis, in the first 4 years after FSH test, there was no association between FSH and time to PC diagnosis. Starting from 4 years after FSH test, on multivariable analysis, a higher FSH level was associated with lower risk of PC with continuous modeling, but found no association with log continuous and categorical modeling. CONCLUSIONS: In this population-level study among male veterans receiving an FSH test for an unknown clinical indication, associations between FSH levels and PC risk were inconsistent and likely driven by selection bias and confounding variables. Future studies should consider different study designs.

Racial differences in circulating mitochondria-derived peptides may contribute to prostate cancer health disparities.

INTRODUCTION: The mitochondrial genome has small open reading frames (sORF) which produce measurable mitochondrial-derived peptides (MDPs), including humanin, SHLP2, and MOTS-c. Previously, among men undergoing prostate biopsy, we found higher serum SHLP2 was linked with lower prostate cancer (PC) risk in European American men (EAM), while null associations were found in African American men (AAM). Here, in different patients undergoing prostate biopsy, we tested the link between SHLP2, humanin and MOTS-c and PC risk by race. METHODS: Plasma SHLP2, humanin, and MOTS-c were measured in 198 men (50/49 EAM/AAM cases; 50/49 EAM/AAM controls) undergoing biopsy. Logistic and multinomial regression models tested associations between each MDP and PC diagnosis, low-grade (grade group, GG1) and high-grade (GG2-5). Models were adjusted for age, body mass index, digital rectal examination, and prostate specific antigen (PSA). We tested interactions between MDPs and race. RESULTS: Among controls, humanin was similar by race (p = 0.60), but both SHLP2 (p = 0.007) and MOTS-c (p = 0.026) were lower in AAM controls versus EAM controls. Among EAM, higher MDP values were associated with lower PC risk (all p ≤ 0.001), with null associations in AAM (all p-interactions ≤ 0.01). Similarly, higher MDP expression was associated with decreased risk of low- and high-grade PC in EAM (all p ≤ 0.005) with null associations in AAM. CONCLUSIONS: Higher MDP levels were associated with lower PC risk in EAM but not AAM. Generally, AAM controls had lower MDP levels. These data support MDPs and mitochondrial dysfunction in PC, suggesting greater dysfunction in AAM may contribute to excess PC risk. Future larger studies are needed to confirm these results.

Change in distress about police brutality and substance use among young people, 2017-2020.

BACKGROUND: It is unknown whether increasing attention to police brutality is a source of stress associated with substance use risk among young people. METHODS: A longitudinal racially/ethnically diverse cohort from Los Angeles, California (n = 1797) completed baseline (2017; mean age: 17.9) and follow-up (2020; mean age: 21.2) surveys assessing level of concern, worry, and stress about police brutality (range: 0 'not at all' - 4 'extremely') and past 30-day nicotine, cannabis, alcohol, other drug, and number of substances used (0-19). Regression models, adjusted for demographic characteristics and baseline substance use, evaluated whether changes in distress about police brutality from 2017 to 2020 were associated with substance use in 2020 overall and stratified by race/ethnicity. RESULTS: Distress about police brutality increased between 2017 (mean: 1.59) and 2020 (mean: 2.43) overall. Black/African American and Hispanic/Latino respondents consistently had the highest mean distress levels at both timepoints. In the full sample, each one-unit greater increase in distress about police brutality from 2017 to 2020 was associated with 11% higher odds of cannabis use, 13% higher odds of alcohol use, and 8% higher risk of using an additional substance for the number of substances used outcome. Race/ethnicity-stratified models indicated that greater increases in distress from 2017 to 2020 was associated with substance use among Black/African American, Hispanic, and multiracial respondents in 2020, but not Asian American/Pacific Islander and White respondents. CONCLUSIONS: Distress about police brutality may be associated with substance use, particularly among certain racial/ethnic minority young people. Further investigation of whether police brutality affects health in disparity populations is needed.

Weight loss via a low-carbohydrate diet improved the intestinal permeability marker, zonulin, in prostate cancer patients.

BACKGROUND: Accumulating evidence suggest that gut microbiota may impact urologic health including prostate cancer (PC), potentially via affecting intestinal permeability (IP). Studies have indicated that disrupted IP may be improved by healthy diets and weight loss. In the Carbohydrate and Prostate Study 2 (CAPS2) clinical trial, which showed that a low-carbohydrate diet (LCD) reduced weight significantly in men with PC and suggestively slowed PC disease progression, we explored the impact of LCD on an IP marker, zonulin and an inflammation marker, high sensitivity C-reactive protein (hsCRP). METHODS: CAPS2 was a 6-month randomized controlled trial testing a LCD intervention vs. control on PC progression using prostate-specific antigen doubling time (PSADT) as the marker. All 45 participants had prior primary PC treatment, PSADT >3 and <36 months, and body mass index (BMI) ≥24 kg/m2. RESULTS: At 6-month, zonulin decreased in the LCD arm (median -8.3%, IQR -16.6, 0.3%) while the control increased slightly (median 1.4%, IQR -3.0, 13.3%; p = .014). No changes were observed in hsCRP. Linear regression models showed that weight change was significantly associated with log(PSADT) such that the greater the weight loss, the longer the PSADT(p = .003). There was a similar inverse trend between change in zonulin and log(PSADT) (p = .050). Nevertheless, the mediation analysis showed that zonulin was not a significant intermediary mechanism of the effect of weight change on PSADT (p = .3). CONCLUSION: Future studies are merited to examine further the potential association of IP with inflammation and to clarify if improvement in IP is associated with decreased PC progression. Trial registration: NCT01763944. KEY MESSAGESGut microbiota may impact urologic health including prostate cancer, potentially via affecting intestinal permeability.Weight loss significantly improved intestinal permeability in prostate cancer patients.Improvement in intestinal permeability was associated with slowed prostate cancer progression as indicated by the PSA doubling time.

Red Blood Cell Distribution Width Is Associated with All-cause Mortality but Not Adverse Cancer-specific Outcomes in Men with Clinically Localized Prostate Cancer Treated with Radical Prostatectomy: Findings Based on a Multicenter Shared Equal Access Regional Cancer Hospital Registry.

BACKGROUND: Recent reports with a small number of patients showed an association of red blood cell distribution width (RDW) with prostate cancer (PCa) progression. OBJECTIVE: To investigate whether preoperative RDW can serve as a prognostic marker in patients with PCa undergoing radical prostatectomy (RP) in a large, equal access, and diverse patient cohort. DESIGN SETTING AND PARTICIPANTS: Data were retrospectively collected on 4756 men treated with RP at eight Veteran Affairs medical centers within the Shared Equal Access Regional Cancer Hospital (SEARCH) database from 1999 through 2017. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Biochemical recurrence (BCR) was the primary outcome, while metastasis, all-cause mortality (ACM), and prostate cancer-specific mortality (PCSM) were secondary outcomes. RESULTS AND LIMITATIONS: The mean (standard deviation) age was 62 yr (6.1), and 1589 (33%) men were black. The median (interquartile range) follow-up was 82 mo (46-127). Preoperative RDW either as a continuous variable or when stratified by quartiles was not associated with BCR. Likewise, preoperative RDW was not associated with metastases or PCSM. However, higher RDW was significantly associated with higher ACM, both as a continuous variable (p < 0.001) and when stratified by quartiles in univariable and multivariable models (p < 0.001). RDW was found to be correlated with D'Amico risk classification of PCa. Study limitations include its retrospective nature and lack of data regarding advanced PCa. CONCLUSIONS: Preoperative RDW was not associated with PCa outcomes in men treated with RP but was associated with ACM. While RDW may be a biomarker of overall health, it is not a biomarker for PCa outcomes. These results emphasize the importance of diverse, larger sized studies in genitourinary cancer research. PATIENT SUMMARY: Prostate cancer includes a wide spectrum of diseases with different genetic, pathological, and oncological behaviors. Red blood cell distribution width is helpful in predicting the overall survival for a localized prostate cancer patient, and hence, it can help inform personalized treatment decisions and operative care.