Faculty Bibliography

Background: Identifying genetic risk factors for AKI could provide insights into pathophysiology and help identify novel pathways for therapeutic development.
Method(s): We conducted a genome-wide association study in a multi-ethnic population of 1,370 prospectively enrolled subjects in the ASSESS-AKI Study. Genotyping was completed using the Illumina MEGA chip and the Haplotype Reference Consortium was used for genome-wide multiple imputation. Genetic association testing for AKI was conditioned on: age, sex, diabetes, center and first three principal components of ancestry. Threshold for significance included single-nucleotide polymorphisms (SNPs) with a p < 5 X 10^-6.
Result(s): Among 637 AKI and 733 non-AKI participants, 5,645,675 SNPs were tested for the association with AKI. Among AKI participants, 72% had Stage 1 AKI and 7% required new dialysis during hospitalization. We found that 56 SNPs in six novel loci were associated with the development of AKI (Figure 1). The SNP with the strongest association with AKI was rs17538288>A. The minor allele of rs17538288 was associated with an increased risk for AKI (adjusted odds ratio 1.53, 95% confidence interval 1.30-1.79, p=2.08 x 10^-7). Utilizing integrated functional epigenomic analyses, we found that top-performing SNPs localized to regulatory DNA elements in primary human glomerular and cortex cell culture. We also investigated 22 SNPs identified in two prior AKI GWAS studies and found that none of the SNPs replicated in ASSESS-AKI (p<0.05).
Conclusion(s): We identified six novel genetic loci that were associated with prevalent AKI. Functional annotation in kidney cells/tissue provides insights into the mechanism of kidney injury. Future work will require replication in well-phenotyped AKI cohorts and mechanistic studies to understand the relationship of genetic variation and AKI development. (Figure Presented)

Increased investment in primary care is associated with lower healthcare costs and improved population health. The allocation of scarce resources should be driven by robust models that adequately describe primary care activities and spending within a health system, and allow comparisons within and across health systems. However, disparate definitions result in wide variations in estimates of spending on primary care. We propose a new model that allows for a dynamic assessment of primary care spending (PC Spend) within the context of a system's total healthcare budget. The model articulates varied definitions of primary care through a tiered structure which includes overall spending on primary care services, spending on services delivered by primary care professionals and spending delivered by providers that can be characterised by the '4Cs' (first contact, continuous, comprehensive and coordinated care). This unifying framework allows a more refined description of services to be included in any estimate of primary care spend and also supports measurement of primary care spending across nations of varying economic development, accommodating data limitations and international health system differences. It provides a goal for best accounting while also offering guidance, comparability and assessments of how primary care expenditures are associated with outcomes. Such a framework facilitates comparison through the creation of standard definitions and terms, and it also has the potential to foster new areas of research that facilitate robust policy analysis at the national and international levels.

Background: The growing opioid overdose epidemic has grappled the nation with the CDC now reporting that drug overdose deaths have become the most common cause of death for young people. Medical education has historically ignored substance use disorders, and though they generally require all medical students to learn basic life support, they have not taught how to respond to opioid overdoses. Further, medical education is moving towards modalities which utilize adult learning theory. One such modality are online modules. However, there are few studies comparing their outcomes with traditional lectures. Previously, the authors compared in-person and online training of medical students to respond to opioid overdoses using naloxone in a non-randomized controlled setting, which showed no meaningful differences in knowledge, attitudes, and preparedness outcomes for students. In this paper, the authors attempt to use a randomized controlled trial to compare the two educational modalities at a second urban medical school.
Objective(s): The author's primary objective was to demonstrate non-inferiority of online compared to in-person training for knowledge. Our secondary objective were to show non-inferiority of online compared to in-person training attitudes, and preparedness.
Method(s): Our study received IRB exemption as an education intervention. As a part of a transition to clinical clerkships curriculum used for second year medical students, second year medical students in an urban medical school were randomized into training sessions by the office of medical education without foreknowledge of the planned study. Students taking the online training were provided with a link to online modules with pre- and post-tests and video based lectures. Students randomized to the in-person training group took a pre-test just prior to receiving an oral lecture, and then immediately completed a post-test. Paired student's t-tests were used to compare measurements for each group in knowledge, attitudes, and preparedness, and Cohen's D was used to measure the effect size of the change. We calculated 99% confidence intervals for each measure and utilized a margin of non-inferiority of 5%.
Result(s): The in-person group demonstrated a statistically significant increase in knowledge, a non-statistically significant decrease in self-reported preparedness, and a small non-statistically significant increase in attitudes, see Table 1. The online group demonstrated a statistically significant increase in knowledge and self-reported preparedness, without a statistically significant change in attitudes, see Table 1. 99% CIs were [-0.20, 1.09] for knowledge, [6.51, 10.93] for preparedness, and [-2.32, 1.59] for attitudes, see Figure 1.
Conclusion(s): Online training for opioid overdose prevention training provided non-inferior outcomes for knowledge, preparedness, and attitudes. This study supports the use of online opioid overdose prevention training as a non-inferior alternative to in-person training

Background We hypothesized that neo-epitope-based prediction using an advanced in silico T cell epitope screening system (AncerTM) may better identify patients with improved prognosis than tumor mutation burden. Analysis of genomic data derived from the muscle-invasive bladder cancer (BLCA) cohort of The Cancer Genome Atlas (TCGA) database for CD4, CD8, and Treg neo-epitopes was performed to determine whether AncerTM would improve prognostic stratification compared to tumor mutational burden (TMB). Methods BLCA patient mutanomes (n=412) were retrieved from the TCGA and evaluated with AncerTM, an innovative and automated neo-epitope screening platform that combines proprietary machine learningbased HLA I and HLA II neo-epitope identification tools with removal of inhibitory regulatory T cell epitopes for neo-epitope ranking and personalized cancer vaccine design. BLCA patients were separated based on median TMB or neo-epitope burdens. We investigated the effect of integrating both CD8 and CD4 neo-epitope burdens as most mutanome pipelines exclusively focus on the identification of Class I neo-epitopes. Overall survival was analyzed using the Kaplan-Meier method and differences analyzed by log-rank testing. Results Compared to low TMB, high TMB was significantly associated with improved survival (p = 0.0001, difference of 38.5 months in median survival, Figure 1). Improved differentiation of median survival times was obtained when separating patients based on their Class I neoepitope content, as estimated by AncerTM (p < 0.0001, difference of 59.8 months in median survival). Adding Class II neo-epitope burden further increased separation of OS times, showcased by a 69.6-month increase in median survival for BLCA patients with both high CD8 and high CD4 neo-epitope contents compared to other patients (p = 0.0001). Since we discovered that Class II neo-epitopes can induce inhibitory responses, we further evaluated whether the screening of these detrimental sequences could improve our analysis. Upon identifying Class II neo-epitopes likely to induce T effector (Teff) responses, we found that the median survival of patients with high CD8 and high CD4 Teff contents was extended by nearly 4 months to 73.4 months compared, to the remainder of the cohort (p < 0.0001, Figure 2). Conclusions Our analysis suggests that optimal host-immune recognition of CD8+, CD4+, and Treg epitopes plays a key role in cancer survival. While defining CD8 neo-epitope burden enhanced associations with OS, the inclusion of CD4 Teff neo-epitope burden substantially helped identify long-term survivors. These results suggest that defining the number of true neo-epitopes using AncerTM may represent a novel prognostic or predictive biomarker

Polypharmacy is a well-described problem in the geriatric population. It is a relatively new problem for people living with HIV (PLWH), as this group now has a life expectancy approaching that of the general population. Defining polypharmacy for PLWH is difficult, since the most common traditional definition of at least five medications would encompass a large percentage of PLWH who are on antiretrovirals (ARVs) and medications for other medical comorbidities. Even when excluding ARVs, the prevalence of polypharmacy in PLWH is higher than the general population, and not just in resource-rich countries. Using a more nuanced approach with "appropriate" or "safer" polypharmacy allows for a better framework for discussing how to mitigate the associated risks. Some of the consequences of polypharmacy include adverse effects of medications including the risk of geriatric syndromes, drug-drug interactions, decreased adherence, and over- and undertreatment of medical comorbidities. Interventions to combat polypharmacy include decreasing pill burden-specifically with fixed-dose combination (FDC) tablets- and medication reconciliation/deprescription using established criteria. The goal of these interventions is to decrease drug interactions and improve quality of life and outcomes. Some special populations of interest within the community of PLWH include those with chronic pain, substance abuse, or requiring end of life care. A final look into the future of antiretroviral therapy (ART) shows the promise of possible two-drug regimens, which can help reduce the above risks of polypharmacy.