Faculty Bibliography

BACKGROUND:Intensive care unit (ICU) staffing models increasingly use advanced practice providers (APPs), with unclear implications for clinical practice patterns. Sedation strategy is a modifiable determinant of clinical outcomes that might differ by staffing model. METHODS:This retrospective cohort study evaluated adults admitted to two medical ICUs in a quaternary teaching hospital, whose staffing differed only by APPs or residents. Patients requiring invasive ventilation for at least 48 h were included. The primary outcome was association of staffing model with sedative exposure during the first week of mechanical ventilation. Time to extubation and vital status at discharge were also assessed. RESULTS:Of 337 included patients, 96 % received continuous sedation on the day of intubation. Admission to the APP ICU was associated with significantly lower benzodiazepine exposure (adjusted OR 0.63; 95 % CI 0.40-0.99; p = 0.04) and higher propofol exposure (adjusted OR 1.73; 95 % CI 1.07-2.79; p = 0.03) on day of intubation. Cumulative benzodiazepine and opioid exposures over the first week after intubation were significantly less, and cumulative propofol exposure significantly more in the APP ICU despite similar sedation depth achieved between ICUs. Receipt of propofol on the first day was associated with shorter time to extubation (adjusted HR 1.45, 95 % CI 1.07-1.98; p = 0.02) and lower in-hospital mortality (adjusted OR 0.55, 95 % CI 0.33-0.93; p = 0.02). CONCLUSION/CONCLUSIONS:Patients admitted to an APP-staffed ICU were more likely to have sedation management reflective of best practice, and this practice was associated with shorter time to extubation and lower mortality.

OBJECTIVE:We aimed to better understand patients' treatment preferences and quantify the level of cancer risk at which treatment preferences change (risk threshold) to inform better counseling of patients with intraductal papillary mucinous neoplasms (IPMNs). SUMMARY BACKGROUND DATA/BACKGROUND:The complexity of IPMN management provides an opportunity to align treatment with individual preference. METHODS:We surveyed a sample of healthy volunteers simulating a common scenario: undergoing an imaging study that incidentally identifies an IPMN. In the scenario, the estimated risk of cancer in the IPMN was 5%. Patients were asked their treatment preference (surgery or surveillance), to quantify the level of cancer risk in the IPMN at which their treatment preference would change (i.e. risk threshold), and their level of cancer anxiety as measured on a 5-point Likert scale. We examined associations between participant characteristics, treatment preferences, and risk threshold using multivariable linear regression. RESULTS:The median risk threshold among the 520 participants was 25% (IQR 2.3-50%). The risk threshold had a bimodal distribution: 40% of participants had a risk threshold between 0-10% and 47% had a risk threshold above 30%. When informed that the risk of cancer was 5%, 62% of participants (n=323) preferred surveillance, and the remaining 38% (n=197) preferred surgery. After adjusting for potential confounders, participants who expressed "worry" or "extreme worry" about the malignancy risk of IPMN had significantly lower risk thresholds than participants who were "not at all worried" (Coefficient -12, 95%CI -21 to -2, P=0.015 and Coefficient -18, 95%CI -29 to -8, P<0.001, respectively). CONCLUSIONS:Participants varied in treatment preference and risk threshold of incidentally identified IPMNs. Given the uncertainty in estimating the true malignant potential of IPMNs, a better understanding of a patient's risk threshold, as influenced by patient concern about malignancy, will help inform the shared decision-making process.

BACKGROUND:Tenofovir alafenamide (TAF) has shown non-inferior efficacy to tenofovir disoproxil fumarate (TDF), with superior bone and renal safety. AIM/OBJECTIVE:To characterise 5-year TAF efficacy and safety in patients of East Asian ethnicity from pivotal Phase 3 studies. METHODS:Patients were randomised (2:1) to receive TAF or TDF for up to 3 years of double-blind treatment, followed by open-label TAF. Patients either continued TAF or switched from TDF to TAF at Week 96 (TDF → TAF 3 years) or Week 144 (TDF → TAF 2 years) of treatment. Efficacy endpoints (virologic, biochemical and serologic) and safety were assessed. RESULTS:Among 591 patients of East Asian ethnicity (TAF, n = 401; TDF → TAF 3 years, n = 84; TDF → TAF 2 years, n = 106), high rates of virologic control were achieved (89%, 94% and 92%, respectively) at Year 5 (missing = failure analysis). At Year 5, rates of alanine aminotransferase normalisation (85%, 90% and 78%) and hepatitis B e antigen loss (36%, 43% and 44%) were similar. Following the switch from TDF to TAF, changes in fasting lipid parameters were consistent with removal of the known lipid-lowering effect of TDF. However, changes in the total cholesterol to high-density lipoprotein ratio (marker of cardiovascular risk) were minimal and comparable in all groups by Year 5. Renal and bone parameters improved after switching. CONCLUSIONS:Through 5 years, rates of virologic suppression were high in East Asian patients treated with TAF or switched from TDF to TAF. TAF and TDF were well tolerated, with improved renal and bone safety observed in patients switching from TDF to TAF.

The degree to which alcohol use is associated with the risk of all-cause mortality and hepatic decompensation after hepatitis C (HCV) diagnosis, treatment, and cure remains unknown. We sought to address this question among patients achieving sustained virologic response (SVR) after direct-acting antiviral treatment in the largest HCV health system in the United States. We extracted data on alcohol use, HCV treatment, SVR, HIV co-infection, demographics, risk behaviours, hepatic decompensation, and mortality from all patients in the 1945 to 1965 VA Birth Cohort. Alcohol use categories were generated using responses to the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) questionnaire and diagnostic codes for alcohol use disorder (AUD): abstinent without a history of AUD, abstinent with a history of AUD, current lower-risk consumption, current moderate-risk consumption, and current high-risk consumption with or without AUD. Cox proportional hazard models were used to examine associations between alcohol category and the risk of hepatic decompensation and all-cause mortality. Among 50,581 patients in the analytic cohort, compared to current drinkers exhibiting lower risk alcohol consumption (referent), current high-risk consumption with or without AUD was associated with increased risk of all-cause mortality (aHR: 1.40, 95% CI: 1.21-1.63) and hepatic decompensation (HR: 2.15, 95% CI: 1.60-2.89) as was abstinence with a history of AUD diagnosis (mortality aHR: 1.63, 95% CI: 1.41-1.89; hepatic decompensation aHR: 1.85, 95% CI: 1.36-2.51). AUD and high-risk alcohol consumption are associated with the risk of hepatic decompensation and all-cause mortality among Veterans who have achieved SVR, including those categorised as being currently abstinent. Interventions for alcohol consumption and use disorder among individuals treated for HCV infection may reduce morbidity and mortality in this population.

BACKGROUND:The COVID-19 pandemic had a significant impact on healthcare delivery. Older adults with multimorbidities were at risk of healthcare disruptions for the management of their chronic conditions. OBJECTIVE:To characterize healthcare disruptions during the COVID-19 healthcare shutdown and recovery period (March 7, 2020-October 6, 2020) and their effects on disease management among older adults with multimorbidities who were patients of NYC Health + Hospitals (H + H), the largest municipal safety-net system in the United States. DESIGN/METHODS:Observational. PATIENTS/METHODS:Patients aged 50 + with hypertension or diabetes and at least one other comorbidity, at least one H + H ambulatory visit in the six months before COVID-19 pandemic onset (March 6, 2020), and at least one visit in the post-acute shutdown period (October 7, 2020 to December 31, 2023). MAIN MEASURES/METHODS:We characterized disruption in care (defined as no ambulatory or telehealth visits during the acute shutdown) and estimated the effect of disruption on blood pressure control, hemoglobin A1c (HbA1c), and low-density lipoprotein (LDL) cholesterol using difference-in-differences models. KEY RESULTS/RESULTS:Out of 73,889 individuals in the study population, 12.5% (n = 9,202) received no ambulatory or telehealth care at H + H during the acute shutdown. Low pre-pandemic healthcare utilization, Medicaid insurance, and self-pay were independent predictors of care disruption. In adjusted analyses, the disruption group had a 3.0-percentage point (95% CI: 1.2-4.8) greater decrease in blood pressure control compared to those who received care. Disruption did not have a significant impact on mean HbA1c or LDL. CONCLUSIONS:Care disruption was associated with declines in blood pressure control, which while clinically modest, could impact risk of cardiovascular outcomes if sustained. Disruption did not affect HbA1c or LDL. Telehealth mitigated impacts of the pandemic on care disruption and subsequent disease management. Targeted outreach to those at risk of care disruption is needed during future crises.

BACKGROUND:Building a learning health system (LHS) at a federally qualified health center (FQHC) can generate research with diverse communities. However, FQHCs face challenges in integrating research with their mission to deliver high-quality primary care to vulnerable populations. OBJECTIVE:Our FQHC serves over 110,000 patients annually and partners with an academic medical center. We have implemented LHS strategies to align research with health care service priorities, enable clinician involvement in research, support data analysis, disseminate findings, and seek research funding. Drawing on the Consolidated Framework for Implementation Research, we identify contextual factors that impeded or facilitated our LHS implementation. Lessons can inform LHS practice in safety-net primary care. DESIGN/METHODS:Case study of LHS development at an FQHC. STAKEHOLDERS/UNASSIGNED:FQHC leaders, clinicians, staff, and academic partners.  APPROACH: Descriptive analysis of 168 research proposals and 13 grant-funded studies. Review of procedures to approve, implement, and disseminate research. RESULTS:Supportive leadership, preexisting culture of continuous QI, academic partners who understand the FQHC mission, and investment in research infrastructure (e.g., structured research review and access to data) facilitated the implementation of our strategies to integrate research with health care delivery as part of building an LHS. Inherent characteristics of research can pose challenges for research-practice integration, e.g., research often runs on longer timelines than quality improvement initiatives. Importantly, our approach is modular and iterative: we selectively and progressively launched strategies for LHS development, beginning with essential processes to review research, administer grants, provide data, and share findings. Alongside continually enhancing these processes, our work ahead includes building clinician and staff competencies for research, extending data analyst capacity, and establishing an organizational policy on equitable patient and community engagement in research. CONCLUSIONS:Taking a modular approach and iterating LHS activities can enable FQHCs to integrate research with health care service delivery in safety-net primary care.

BACKGROUND AND AIMS/OBJECTIVE:Liver transplant is a specialized treatment for a spectrum of indications that use a scarce resource. Transplant is guided by principles of justice, equity and benefit with a constant conflict between competing interests. Organs are a national resource with a goal of equitable distribution across sites. An AASLD guideline for the evaluation and selection of appropriate transplant candidates has been available since 2005. METHODS:A multidisciplinary writing group of liver transplant experts and a librarian convened over 24 months. The writing group reviewed the literature, generated guideline recommendations and rated the level of evidence for each recommendation based on the Oxford Center for Evidence-Based Medicine. The group categorized the strength of recommendations based on the level of evidence, risk-benefit ratio, and patient preferences. CONCLUSIONS:Liver transplant is a lifesaving procedure that should be offered to selected patients with clear indications and a reasonable prospect of benefit. The evaluation is designed to identify those in need, to outline hurdles to a successful outcome, and to develop an effective transplant plan. The goal of this document is to provide a template for this process.

Covalent inhibitors of oncoprotein KRAS have initial efficacy, but responses lack durability. Covalently modified oncoproteins are presented as MHC-restricted hapten-peptides (p*MHC) on the cancer cell surface, enabling combination of targeted therapy with immunotherapy to overcome drug resistance. Building on indirect evidence of KRAS^G12C-derived p*MHCs, we use immunopeptidomics to identify and directly quantify these synthetic neoantigens. To address challenges by their low copy number, we develop AETX-R114, a T cell engaging bispecific antibody with picomolar affinity for MHC-restricted sotorasib-modified KRAS^G12C peptides presented by three HLA-A3 supertype alleles. AETX-R114 dramatically increases the half-life and thereby the number of presented p*MHCs, enabling selective and potent killing of resistant cancer cells both in vitro and in vivo. To broaden the therapeutic potential of creating and targeting synthetic neoantigens, we further develop AETX-R302, which recognizes divarasib-modified KRAS^G12C peptides presented on alleles from the HLA-A2 and A3 supertypes. Cryo-EM structure determination reveals the molecular basis for breaking HLA supertype restriction. Collectively, our study illustrates how engineered antibodies can transform synthetic neoantigens into actionable cancer immunotherapy targets.

PURPOSE/OBJECTIVE:Patients with stage II and resected stage III melanomas have variable clinical outcomes, evidence of underlying biological differences in tumors and/or the patients themselves, beyond stage. The approval of adjuvant immunotherapy for stage IIB/C and resected stage III/IV disease (and adjuvant targeted therapy for resected stage III disease), has created a pressing need to develop biomarkers to accurately distinguish patients at low- versus high-risk for recurrence and death from melanoma. MicroRNAs (miRNAs) are promising biomarkers because of their stability in tissues/fluids and their demonstrated functional and prognostic roles in melanoma. We hypothesized that miRNA expression could be integrated into prognostic models that would more accurately classify 5-year survival outcomes than clinical factors alone. PATIENTS AND METHODS/METHODS:Using a Nanostring miRNA Expression Assay, we analyzed 715 primary melanomas from patients with stage II or stage III disease within the InterMEL consortium, and examined associations between miRNA expression and melanoma-specific death. RESULTS:When integrated into clinical prognostic models for 5-year melanoma-specific survival, miRNA signatures improved the area under the receiver operating characteristic curve (AUC) for stage II patients from 0.71 for a 'clinical factors-only' model to 0.81 for a 'clinical plus miRNA' model in an independent test set, an improvement of 0.10 with 95% CI (0.03, 0.19). The improvement was more modest for stage III patients that were included in the analysis. CONCLUSIONS:Incorporating miRNA expression in primary melanomas may enhance the accuracy of clinical prognostic models, and potentially aid the selection of melanoma patients for adjuvant treatment and clinical trials.

BACKGROUND:Familial dysautonomia (FD) is a hereditary neurodevelopmental disorder caused by aberrant splicing of the ELP1 gene, leading to a tissue-specific reduction in ELP1 protein expression. Preclinical models indicate that increasing ELP1 levels can mitigate disease manifestations. A blood-based ELP-1 protein assay may provide a reliable way to monitor gene target engagement. DESIGN AND METHODS/METHODS:Using a newly developed radioimmunoassay, we quantified ELP1 protein levels in peripheral blood samples collected from 59 homozygous FD patients carrying the IVS20 + 6T>C mutation and 66 heterozygous carriers. To assess the reproducibility of the measurement, replicate samples were collected in 43 participants. Longitudinal variability was evaluated in 22 participants who underwent repeat sampling 1 year later. RESULTS: = 0.827, p < 0.001). An ELP1 threshold of 492 pg/mL yielded a sensitivity of 80.2% (CI of 70.6 to 87.2%) and a specificity of 98.2% (95% CI of 90%-99%) with a positive likelihood ratio of 46.5, indicating that individuals with FD were over 46 times more likely to have ELP1 levels below this threshold compared to non-affected carriers. CONCLUSION/CONCLUSIONS:Blood ELP1 levels are robust and reproducible, with concentrations below 492 pg/mL strongly indicative of disease. Moreover, given their longitudinal stability, ELP1 can serve as a marker of target engagement to evaluate the efficacy of gene-targeted therapies aimed at correcting ELP1 gene splicing and protein production.