Faculty Bibliography

Although policies to remove lead from gasoline have resulted in a substantial reduction in airborne lead, multiple industries are known to generate lead that is released in the air. The present study examines the extent to which residential proximity to a documented source of airborne lead is associated with intellectual and executive function in children. Data were available for n = 849 children from the Family Life Project. Geolocation for children's residences between birth and 36 months were referenced against the Environmental Protection Agency's Risk Screening Environmental Indicators (RSEI) database, which estimates exposure for each ½ mile grid in the contiguous United States. Instrumental variable models were employed to estimate causal associations between exposure and cognitive outcomes measured at 36, 48, and 60 months, using census-documented density of manufacturing employment as the instrument. Models of continuous lead dosage indicated small negative effects for both child IQ and executive function (EF). These results indicate that RSEI estimates of airborne lead exposure are meaningfully associated with decrements in cognitive development.

BACKGROUND:Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4.1% of the phenotypic variance. METHODS:We complemented a new conventional PC GWAS (1D) with genome spatial autocorrelation analysis (2D) permitting to prioritize low frequency variants not detected by GWAS. These were further expanded via Hi-C map (3D) interactions to gain additional insight into the inherited basis of PC. In silico functional analysis of public genomic information allowed prioritization of potentially relevant candidate variants. RESULTS:We identified several new variants located in genes for which there is experimental evidence of their implication in the biology and function of pancreatic acinar cells. Among them is a novel independent variant in NR5A2 (rs3790840) with a meta-analysis p value = 5.91E-06 in 1D approach and a Local Moran's Index (LMI) = 7.76 in 2D approach. We also identified a multi-hit region in CASC8-a lncRNA associated with pancreatic carcinogenesis-with a lowest p value = 6.91E-05. Importantly, two new PC loci were identified both by 2D and 3D approaches: SIAH3 (LMI = 18.24), CTRB2/BCAR1 (LMI = 6.03), in addition to a chromatin interacting region in XBP1-a major regulator of the ER stress and unfolded protein responses in acinar cells-identified by 3D; all of them with a strong in silico functional support. CONCLUSIONS:This multi-step strategy, combined with an in-depth in silico functional analysis, offers a comprehensive approach to advance the study of PC genetic susceptibility and could be applied to other diseases.

BACKGROUND:Altered postinjury platelet behavior is recognized in the pathophysiology of trauma-induced coagulopathy (TIC), but the mechanisms remain largely undefined. Studies suggest that soluble factors released by injury may inhibit signaling pathways and induce structural changes in circulating platelets. Given this, we sought to examine the impact of treating healthy platelets with plasma from injured patients. We hypothesized that healthy platelets treated ex-vivo with plasma from injured patients with shock would impair platelet aggregation, while treatment with plasma from injured patients with significant injury burden, but without shock, would enhance platelet aggregation. METHODS:Plasma samples were isolated from injured patients (pretransfusion) and healthy donors at a Level I trauma center and stored at -80°C. Plasma samples from four separate patients in each of the following stratified clinical groups were used: mild injury/no shock (injury severity score [ISS] 2-15, base excess [BE]>-6), mild injury/with shock (ISS 2-15, BE≤-6), severe injury/no shock (ISS>25, BE>-6), severe injury/with shock (ISS>25, BE≤-6), minimal injury (ISS 0/1, BE>-6), and healthy. Platelets were isolated from three healthy adult males and were treated with plasma for 30 min. Aggregation was stimulated with a thrombin receptor agonist and measured via multiple-electrode platelet aggregometry. Data were normalized to HEPES Tyrode's (HT) buffer-only treated platelets. Associations of plasma treatment groups with platelet aggregation measures were tested with Mann-Whitney U tests. RESULTS:Platelets treated with plasma from patients with shock (regardless of degree of injury) had significantly impaired thrombin-stimulated aggregation compared with platelets treated with plasma from patients without shock (P = 0.002). Conversely, platelets treated with plasma from patients with severe injury, but without shock, had amplified thrombin-stimulated aggregation (P = 0.030). CONCLUSION:Shock-mediated soluble factors impair platelet aggregation, and tissue injury-mediated soluble factors amplify platelet aggregation. Future characterization of these soluble factors will support development of novel treatments of TIC.

BACKGROUND:Telemedicine use rapidly increased during the COVID-19 pandemic. This study assessed quality aspects of rapid expansion of a virtual urgent care (VUC) telehealth system and the effects of a secondary telephonic screening initiative during the pandemic. METHODS:A retrospective cohort analysis was performed in a single health care network of VUC patients from March 1, 2020, through April 20, 2020. Researchers abstracted demographic data, comorbidities, VUC return visits, emergency department (ED) referrals and ED visits, dispositions, intubations, and deaths. The team also reviewed incomplete visits. For comparison, the study evaluated outcomes of non-admission dispositions from the ED: return visits with and without admission and deaths. We separately analyzed the effects of enhanced callback system targeting higher-risk patients with COVID-like illness during the last two weeks of the study period. RESULTS:A total of 18,278 unique adult patients completed 22,413 VUC visits. Separately, 718 patient-scheduled visits were incomplete; the majority were no-shows. The study found that 50.9% of all patients and 74.1% of patients aged 60 years or older had comorbidities. Of VUC visits, 6.8% had a subsequent VUC encounter within 72 hours; 1.8% had a subsequent ED visit. Of patients with enhanced follow-up, 4.3% were referred for ED evaluation. Mortality was 0.20% overall; 0.21% initially and 0.16% with enhanced follow-up (p = 0.59). Males and black patients were significantly overrepresented in decedents. CONCLUSION/CONCLUSIONS:Appropriately deployed VUC services can provide a pragmatic strategy to care for large numbers of patients. Ongoing surveillance of operational, technical, and clinical factors is critical for patient quality and safety with this modality.