Faculty Bibliography

PURPOSE:We examined the demographic and clinicopathological parameters associated with the time to convert from active surveillance to treatment among men with prostate cancer. MATERIALS AND METHODS:A multi-institutional cohort of 7,279 patients managed with active surveillance had data and biospecimens collected for germline genetic analyses. RESULTS:Of 6,775 men included in the analysis, 2,260 (33.4%) converted to treatment at a median followup of 6.7 years. Earlier conversion was associated with higher Gleason grade groups (GG2 vs GG1 adjusted hazard ratio [aHR] 1.57, 95% CI 1.36-1.82; ≥GG3 vs GG1 aHR 1.77, 95% CI 1.29-2.43), serum prostate specific antigen concentrations (aHR per 5 ng/ml increment 1.18, 95% CI 1.11-1.25), tumor stages (cT2 vs cT1 aHR 1.58, 95% CI 1.41-1.77; ≥cT3 vs cT1 aHR 4.36, 95% CI 3.19-5.96) and number of cancerous biopsy cores (3 vs 1-2 cores aHR 1.59, 95% CI 1.37-1.84; ≥4 vs 1-2 cores aHR 3.29, 95% CI 2.94-3.69), and younger age (age continuous per 5-year increase aHR 0.96, 95% CI 0.93-0.99). Patients with high-volume GG1 tumors had a shorter interval to conversion than those with low-volume GG1 tumors and behaved like the higher-risk patients. We found no significant association between the time to conversion and self-reported race or genetic ancestry. CONCLUSIONS:A shorter time to conversion from active surveillance to treatment was associated with higher-risk clinicopathological tumor features. Furthermore, patients with high-volume GG1 tumors behaved similarly to those with intermediate and high-risk tumors. An exploratory analysis of self-reported race and genetic ancestry revealed no association with the time to conversion.

OBJECTIVES/OBJECTIVE:We contrasted the relative risks (RR) of short [<7 h] and long [>8 h] sleep experienced by middle-aged (45-64 years) and older (≥65 years) adults, compared with young adults (20-44 years). METHODS:We utilized NHANES data (2005-2016), capturing sociodemographic, socioeconomic, and health-related data among US adults. RESULTS:The Relative Risk (RR) of short sleep between young and middle-aged adults did not differ [RR = 1.02, NS]. However, the RR of short sleep was significantly reduced among older participants [RR = 0.81, p < 0.01]. Middle-aged adults had significantly lower RR of long sleep [RR = 0.80, p < 0.01], whereas older adults had significantly greater RR of long sleep [RR = 1.41, p < 0.01]. Compared with young adults, older adults with or without increased disease burden had significantly lower RR of short sleep [RR = 0.81, p < 0.01 and RR = 0.80, p < 0.01], respectively. However, for middle-aged adults, the RR of short sleep did not differ whether they reported a greater disease burden. Relative to young adults, older adults with or without disease burden had higher RRs of long sleep [RR = 1.39, p < 0.01] and [RR = 1.45, p < 0.01], respectively. For middle-aged adults without disease burden, the RR of long sleep was lower than among young adults [RR = 0.72, p < 0.01]. CONCLUSIONS:Compared with young adults, older adults were not at increased risk for short sleep. Rather, they reported longer sleep time regardless of the presence of disease burden. Future studies should investigate longitudinal effects of aging on objective sleep time, with or without common diseases.

BACKGROUND:Prenatal exposure to mixtures of nonpersistent chemicals is universal. Most studies examining these chemicals in association with fetal growth have been restricted to single exposure models, ignoring their potentially cumulative impact. OBJECTIVE:We aimed to assess the association between prenatal exposure to a mixture of phthalates, bisphenols, and organophosphate (OP) pesticides and fetal measures of head circumference, femur length, and weight. METHODS: RESULTS: DISCUSSION/CONCLUSIONS:Higher exposure to a mixture of phthalates, bisphenols, and OP pesticides was associated with lower EFW in the midpregnancy period. In late pregnancy, these differences were similar but less pronounced. At birth, the only associations observed appeared when comparing individuals from Q1 and Q4. This finding suggests that even low levels of exposure may be sufficient to influence growth in early pregnancy, whereas higher levels may be necessary to affect birth weight. Joint exposure to nonpersistent chemicals may adversely impact fetal growth, and because these exposures are widespread, this impact could be substantial. https://doi.org/10.1289/EHP9178.

The present study investigated associations between prenatal mother-father cortisol linkage and infant executive functions. Data come from an international sample (N = 358) of predominantly white and middle- to upper-class first-time parents. During late pregnancy, parents collected diurnal salivary cortisol samples and reported on levels of psychological stress. At 24 months, children completed a battery of executive function tasks. Parent cortisol linkage was operationalized as the time-dependent, within-dyad association between maternal and paternal diurnal cortisol. Results indicated that prenatal linkage was positively related to infant executive functions, suggesting that stronger mother-father cortisol linkage was associated with higher executive function scores. Additionally, this relation was moderated by paternal average cortisol levels such that executive function scores were lower when fathers had higher average cortisol levels and linkage was weak. This association suggests that elevated paternal cortisol amplifies the negative relation between lower cortisol linkage and lower infant executive function scores. Importantly, these findings were observed while controlling for observational measures of caregiving and self-report measures of psychosocial functioning and infant social-emotional behavior. These results suggest that prenatal linkage of mother's and father's stress physiology plays a potentially important part in programming and regulating infant neurocognitive development.

BACKGROUND:Drugs like ecstasy, cocaine, and counterfeit prescription pills can contain fentanyl. We examined knowledge about potential adulteration/contamination of such drugs among people attending electronic dance music (EDM) parties. METHODS:Adults in New York City were surveyed entering randomly selected EDM parties during the summers of 2018 (n=1,029) and 2019 (n=559). Surveys assessed perceptions that: 1) ecstasy/Molly can contain adulterants more dangerous than MDMA, 2) cocaine can contain fentanyl, and 3) prescription pills from non-pharmacy sources can contain fentanyl. We compared prevalence of perceptions between 2018 and 2019. RESULTS:Prevalence of agreeing that cocaine can contain fentanyl increased from 42.1% to 58.6%, a 39.2% increase (p=.003). Increases in agreement were not significant regarding ecstasy potentially containing adulterants (55.0% vs. 59.0%) and non-pharmacy prescription drugs potentially containing fentanyl (46.8% vs. 52.9%). Those reporting past-year ecstasy use in particular reported increased agreement that ecstasy can be adulterated (from 52.9% to 80.0%, a 51.2% increase; p<.001) and those reporting past-year cocaine use reported increased agreement that cocaine can be adulterated (from 48.2% to 70.7%, a 46.7% increase; p=.016). CONCLUSIONS:Knowledge of potential adulteration or contamination of commonly used drugs in this high-risk scene is increasing. Continued education about possible drug contents is needed.

Background Solid tumors comprise >90% of cancers. Metastatic colorectal cancer, non-small cell lung cancer, and pancreatic cancer are among the leading causes of cancer-related mortality (5-year overall survival: 14%, 6%, and 3%, respectively). 1Chimeric antigen receptor (CAR) T-cell therapy demonstrated clinical outcomes in hematologic malignancies.2 3 However, translating engineered T-cell therapies to solid tumors proves difficult due to a lack of tumor-specific targets that discriminate cancer cells from normal cells. In previous studies, the use of a carcinoembryonic antigen T-cell receptors and mesothelin CARs both resulted in dose-limiting on-target, off-tumor toxicities.4 5 TmodTM CAR T-cell therapy addresses these challenges by leveraging dual receptors to create a robust AND NOT signal integrator capable of killing tumor cells, while leaving healthy cells intact (figure 1).6 Tmod platform technology is a versatile system that may be applied to T cells and natural killer cells in autologous and allogeneic settings. HLA LOH offers a definitive tumor versus normal discriminator target for CAR T-cell therapy.6 7 The 2 receptors comprise an activator that recognizes an antigen present on the surface of normal and tumor cells and a blocker that recognizes a second surface antigen from an allele lost only in tumor cells. HLA LOH has been observed in ~13% across all solid tumors and up to 33% of pancreatic cancers.8 New technologies have shown higher HLA LOH rates; however, it is unclear whether patients with HLA LOH in their primary tumor tissues are at higher risk for recurrence. BASECAMP-1 is an observational study with key objectives: 1) To determine and identify patients with somatic HLA LOH eligible for Tmod CAR T-cell therapy, and 2) Subsequent leukapheresis and manufacturing feasibility for future Tmod CAR T-cell trials. Methods BASECAMP-1 (NCT04981119) patient eligibility has 2 parts (figure 2): 1) Patients will be initially screened to identify germline HLA-A*02 heterozygosity by central nextgeneration sequencing (NGS). If HLA-A*02 heterozygosity is confirmed, primary archival tumor tissue will be analyzed by xT-Onco NGS testing9 to determine if somatic tumor HLAA* 02 LOH is present; 2) If the tumor demonstrates HLAA* 02 LOH and the patient screens eligible, the patient will undergo leukapheresis. Patients enrolled in the study who undergo leukapheresis will be evaluated for safety 7 days post-leukapheresis and followed for relapsed status. Banked T cells will be available for subsequent autologous Tmod CAR T-cell therapy at the time of relapse

BACKGROUND AND OBJECTIVES:Moderate coffee consumption has been associated with lower risk of CKD; however, the exact biologic mechanisms underlying this association are unknown. Metabolomic profiling may identify metabolic pathways that explain the association between coffee and CKD. The goal of this study was to identify serum metabolites associated with coffee consumption and examine the association between these coffee-associated metabolites and incident CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:=1043). Metabolites with significant associations with coffee in both cohorts were then evaluated for their prospective associations with incident CKD in the ARIC study using Cox proportional hazards regression. RESULTS:In the ARIC study, mean (SD) age was 54 (6) years, 56% were daily coffee drinkers, and 32% drank >2 cups per day. In the Bogalusa Heart Study, mean (SD) age was 48 (5) years, 57% were daily coffee drinkers, and 38% drank >2 cups per day. In a meta-analysis of two subsamples of the ARIC study, 41 metabolites were associated with coffee consumption, of which 20 metabolites replicated in the Bogalusa Heart Study. Three of these 20 coffee-associated metabolites were associated with incident CKD in the ARIC study. CONCLUSIONS:-methylcatechol sulfate and 3-methyl catechol sulfate), both of which are xenobiotics involved in benzoate metabolism, may represent potential harmful aspects of coffee on kidney health.

Non-adherence to COVID-19 guidelines may be attributable to low levels of worry. This study assessed whether endorsing COVID-19-stigmatizing restrictions, COVID-19 knowledge, and preferred news source were associated with being 'very worried' versus 'not at all' or 'somewhat' worried about contracting COVID-19. Survey data were collected in July-August 2020 from N = 547 New York State (NYS) and N = 504 national Amazon MTurk workers. Respondents who endorsed COVID-19 stigmatizing restrictions (NYS OR 1.96; 95% CI 1.31, 2.92; national OR 1.80; 95% CI 1.06, 3.08) and consumed commercial news (NYS OR 1.89; 95% CI 1.21, 2.96; national OR 1.93; 95% CI 1.24, 3.00) were more likely to be very worried. National respondents who consumed The New York Times (OR 1.52; 95% CI 1.00, 2.29) were more likely to be very worried, while those with little knowledge (OR 0.24; 95% CI 0.13, 0.43) were less likely to be very worried. NYS (OR 2.66; 95% CI 1.77, 4.00) and national (OR 3.17; 95% CI 1.95, 5.16) respondents with probable depression were also more likely to be very worried. These characteristics can help identify those requiring intervention to maximize perceived threat to COVID-19 and encourage uptake of protective behaviors while protecting psychological wellbeing.