Faculty Bibliography

BACKGROUND:Tumor mutation burden (TMB) has been associated with melanoma immunotherapy (IT) outcomes, including survival. We explored whether combining TMB with immunogenomic signatures recently identified by The Cancer Genome Atlas (TCGA) can refine melanoma prognostic models of overall survival (OS) in patients not treated by IT. METHODS:Cox proportional-hazards (Cox PH) analysis was performed on 278 metastatic melanomas from TCGA not treated by IT. In a discovery and two validation cohorts Cox PH models assessed the interaction between TMB and 53 melanoma immunogenomic features to refine prediction of melanoma OS. RESULTS:Interferon-γ response (IFNγRes) and macrophage regulation gene signatures (MacReg) combined with TMB significantly associated with OS (p = 8.80E-14). We observed that patients with high TMB, high IFNγRes and high MacReg had significantly better OS compared to high TMB, low IFNγRes and low MacReg (HR = 2.8, p = 3.55E-08). This association was not observed in low TMB patients. CONCLUSIONS:We report a model combining TMB and tumor immune features that significantly improves prediction of melanoma OS, independent of IT. Our analysis revealed that patients with high TMB, high levels of IFNγRes and MacReg had significantly more favorable OS compared to high TMB patients with low IFNγRes and low MacReg. These findings may substantially improve current melanoma prognostic models.

OBJECTIVE:We sought to review the literature on cerebrospinal fluid (CSF) testing in patients with COVID-19 for evidence of viral neuroinvasion by SARS-CoV-2. METHODS:We performed a systematic review of Medline and Embase between December 1, 2019 and November 18, 2020 to identify case reports or series of patients who had COVID-19 diagnosed based on positive SARS-CoV-2 polymerase chain reaction (PCR) or serologic testing and had CSF testing due to a neurologic symptom. RESULTS:We identified 242 relevant documents which included 430 patients with COVID-19 who had acute neurological symptoms prompting CSF testing. Of those, 321 (75%) patients had symptoms that localized to the central nervous system (CNS). Of 304 patients whose CSF was tested for SARS-CoV-2 PCR, there were 17 (6%) whose test was positive, all of whom had symptoms that localized to the central nervous system (CNS). The majority (13/17, 76%) of these patients were admitted to the hospital because of neurological symptoms. Of 58 patients whose CSF was tested for SARS-CoV-2 antibody, 7 (12%) had positive antibodies with evidence of intrathecal synthesis, all of whom had symptoms that localized to the CNS. Of 132 patients who had oligoclonal bands evaluated, 3 (2%) had evidence of intrathecal antibody synthesis. Of 77 patients tested for autoimmune antibodies in the CSF, 4 (5%) had positive findings. CONCLUSION:Detection of SARS-CoV-2 in CSF via PCR or evaluation for intrathecal antibody synthesis appears to be rare. Most neurological complications associated with SARS- CoV-2 are unlikely to be related to direct viral neuroinvasion.

BACKGROUND:People with HIV (PWH) experience increased cardiovascular disease (CVD) risk. Many PWH in the USA receive their primary medical care from infectious disease specialists in HIV clinics. HIV care teams may not be fully prepared to provide evidence-based CVD care. We sought to describe local context for HIV clinics participating in an NIH-funded implementation trial and to identify facilitators and barriers to integrated CVD preventive care for PWH. METHODS:Data were collected in semi-structured interviews and focus groups with PWH and multidisciplinary healthcare providers at three academic medical centers. We used template analysis to identify barriers and facilitators of CVD preventive care in three HIV specialty clinics using the Theoretical Domains Framework (TDF). RESULTS:Six focus groups were conducted with 37 PWH. Individual interviews were conducted with 34 healthcare providers and 14 PWH. Major themes were captured in seven TDF domains. Within those themes, we identified nine facilitators and 11 barriers to CVD preventive care. Knowledge gaps contributed to inaccurate CVD risk perceptions and ineffective self-management practices in PWH. Exclusive prioritization of HIV over CVD-related conditions was common in PWH and their providers. HIV care providers assumed inconsistent roles in CVD prevention, including for PWH with primary care providers. HIV providers were knowledgeable of HIV-related CVD risks and co-located health resources were consistently available to support PWH with limited resources in health behavior change. However, infrequent medical visits, perceptions of CVD prevention as a primary care service, and multiple co-location of support programs introduced local challenges to engaging in CVD preventive care. CONCLUSIONS:Barriers to screening and treatment of cardiovascular conditions are common in HIV care settings and highlight a need for greater primary care integration. Improving long-term cardiovascular outcomes of PWH will likely require multi-level interventions supporting HIV providers to expand their scope of practice, addressing patient preferences for co-located CVD preventive care, changing clinic cultures that focus only on HIV to the exclusion of non-AIDS multimorbidity, and managing constraints associated with multiple services co-location. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov , NCT03643705.

BACKGROUND:Black men are disproportionately affected by prostate cancer, the most common non-cutaneous malignancy among men in the USA. The United States Preventive Services Task Force (USPSTF) encourages prostate-specific antigen (PSA) testing decisions to be based on shared decision-making (SDM) clinician professional judgment, and patient preferences. However, evidence suggests that SDM is underutilized in clinical practice, especially among the most vulnerable patients. The purpose of this study is to evaluate the efficacy of a community health worker (CHW)-led decision-coaching program to facilitate SDM for prostate cancer screening among Black men in the primary care setting, with the ultimate aim of improving/optimizing decision quality. METHODS:We proposed a CHW-led decision-coaching program to facilitate SDM for prostate cancer screening discussions in Black men at a primary care FQHC. This study enrolled Black men who were patients at the participating clinical site and up to 15 providers who cared for them. We estimated to recruit 228 participants, ages 40-69 to be randomized to either (1) a decision aid along with decision coaching on PSA screening from a CHW or (2) receiving a decision aid along with CHW-led interaction on modifying dietary and lifestyle to serve as an attention control. The independent randomization process was implemented within each provider and we controlled for age by dividing patients into two strata: 40-54 years and 55-69 years. This sample size sufficiently powered the detection differences in the primary study outcomes: knowledge, indicative of decision quality, and differences in PSA screening rates. Primary outcome measures for patients will be decision quality and decision regarding whether to undergo PSA screening. Primary outcome measures for providers will be acceptability and feasibility of the intervention. We will examine how decision coaching about prostate cancer screening impact patient-provider communication. These outcomes will be analyzed quantitatively through objective, validated scales and qualitatively through semi-structured, in-depth interviews, and thematic analysis of clinical encounters. Through a conceptual model combining elements of the Preventative Health Care Model (PHM) and Informed Decision-Making Model, we hypothesize that the prostate cancer screening decision coaching intervention will result in a preference-congruent decision and decisional satisfaction. We also hypothesize that this intervention will improve physician satisfaction with counseling patients about prostate cancer screening. DISCUSSION/CONCLUSIONS:Decision coaching is an evidence-based approach to improve decision quality in many clinical contexts, but its efficacy is incompletely explored for PSA screening among Black men in primary care. Our proposal to evaluate a CHW-led decision-coaching program for PSA screening has high potential for scalability and public health impact. Our results will determine the efficacy, cost-effectiveness, and sustainability of a CHW intervention in a community clinic setting in order to inform subsequent widespread dissemination, a critical research area highlighted by USPSTF. TRIAL REGISTRATION/BACKGROUND:The trial was registered prospectively with the National Institute of Health registry ( www.clinicaltrials.gov ), registration number NCT03726320 , on October 31, 2018.

(1) Background: Recent studies have reported elevated risks of multiple cancers in the World Trade Center (WTC) affected community members (also called WTC "Survivors"). The large variety of WTC-cancers created a need to develop a comprehensive cancer database. This paper describes the development of a pan-cancer database at the WTC Environmental Health Center (EHC) Data Center. (2) Methods: A new REDCap-based pan-cancer database was created using the pathology reports and available biomarker data of confirmed cancer cases after review by a cancer epidemiologist, a pathologist, physicians and biostatisticians. (3) Results: The WTC EHC pan-cancer database contains cancer characteristics and emerging biomarker information for cancers of individuals enrolled in the WTC EHC and diagnosed after 11 September 2001 and up to 31 December 2019 obtained from WTC EHC clinical records, pathological reports and state cancer registries. As of 31 December 2019, the database included 3440 cancer cases with cancer characteristics and biomarker information. (4) Conclusions: This evolving database represents an important resource for the scientific community facilitating future research about the etiology, heterogeneity, characteristics and outcomes of cancers and comorbid mental health conditions, cancer economics and gene-environment interaction in the unique population of WTC survivors.

OBJECTIVE:We performed a cross-sectional analysis to determine whether nonsustained ventricular tachycardia (NSVT) and premature ventricular contractions (PVCs) were associated with dementia in a population-based study. METHODS:We included 2,517 (mean age 79 years, 26% Black) participants who wore a 2-week ambulatory continuous ECG recording device in 2016 to 2017. NSVT was defined as a wide-complex tachycardia ≥4 beats with a rate >100 bpm. We calculated NSVT and PVC burden as the number of episodes per day. Dementia was adjudicated by experts. We used logistic regression to assess the associations of NSVT and PVCs with dementia. RESULTS:< 0.001). In Black participants, NSVT was associated with a 3.67 times higher adjusted odds of dementia (95% confidence interval [CI] 1.92-7.02) compared to those without NSVT, whereas in White participants NSVT was not associated with dementia (odds ratio [95% CI] 0.64 [0.37-1.10]). In Black participants only, a higher burden of PVCs was associated with dementia. CONCLUSIONS:Presence of NSVT and a higher burden of NSVT and PVCs are associated with dementia in elderly Black people. Further research to confirm this novel finding and to elucidate the underlying mechanisms is warranted.

BACKGROUND:Digital diabetes prevention programs (dDPPs) are effective behavior change tools to prevent disease progression in patients at risk for diabetes. At present, these programs are poorly integrated into existing health information technology infrastructure and clinical workflows, resulting in barriers to provider-level knowledge of, interaction with, and support of patients who use dDPPs. Tools that can facilitate patient-provider interaction around dDPPs may contribute to improved patient engagement and adherence to these programs and improved health outcomes. OBJECTIVE:This study aims to use a rigorous, user-centered design (UCD) methodology to develop a theory-driven system that supports patient engagement with dDPPs and their primary care providers with their care. METHODS:at 6 and 12 months. Secondary outcomes will be patient engagement (use and activity) in the dDPP. The mediator variables (self-efficacy, digital health literacy, and patient-provider relationship) will be measured. RESULTS:The project was initiated in 2018 and funded in September 2019. Enrollment and data collection for phase 1 began in September 2019 under an Institutional Review Board quality improvement waiver granted in July 2019. As of December 2020, 27 patients have been enrolled and first results are expected to be submitted for publication in early 2021. The study received Institutional Review Board approval for phases 2 and 3 in December 2020, and phase 2 enrollment is expected to begin in early 2021. CONCLUSIONS:Our findings will provide guidance for the design and development of technology to integrate dDPP platforms into existing clinical workflows. This will facilitate patient engagement in digital behavior change interventions and provider engagement in patients' use of dDPPs. Integrated clinical tools that can facilitate patient-provider interaction around dDPPs may contribute to improved patient adherence to these programs and improved health outcomes by addressing barriers faced by both patients and providers. Further evaluation with pilot testing and a clinical trial will assess the effectiveness and implementation of these tools. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov NCT04049500; https://clinicaltrials.gov/ct2/show/NCT04049500. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID)/UNASSIGNED:DERR1-10.2196/26750.

Understanding the contribution of the host's genetic background to cancer immunity may lead to improved stratification for immunotherapy and to the identification of novel therapeutic targets. We investigated the effect of common and rare germline variants on 139 well-defined immune traits in ∼9000 cancer patients enrolled in TCGA. High heritability was observed for estimates of NK cell and T cell subset infiltration and for interferon signaling. Common variants of IFIH1, TMEM173 (STING1), and TMEM108 were associated with differential interferon signaling and variants mapping to RBL1 correlated with T cell subset abundance. Pathogenic or likely pathogenic variants in BRCA1 and in genes involved in telomere stabilization and Wnt-β-catenin also acted as immune modulators. Our findings provide evidence for the impact of germline genetics on the composition and functional orientation of the tumor immune microenvironment. The curated datasets, variants, and genes identified provide a resource toward further understanding of tumor-immune interactions.

Background/UNASSIGNED:Rheumatic heart disease (RHD) in sub-Saharan Africa contributes to significant cardiac morbidity and mortality, yet prevalence estimates of RHD lesions in pregnancy are lacking. Objectives/UNASSIGNED:Our first aim was to evaluate women using echocardiography to estimate the prevalence of RHD and other cardiac lesions in low-risk pregnancies. Our second aim was to assess the feasibility of screening echocardiography and its acceptability to patients. Methods/UNASSIGNED:We prospectively recruited 601 pregnant women from a low-risk antenatal clinic at a tertiary care maternity centre in Western Kenya. Women completed a questionnaire about past medical history and cardiac symptoms. They underwent standardized screening echocardiography to evaluate RHD and non-RHD associated cardiac lesions. Our primary outcome was RHD-associated cardiac lesions and our secondary outcome was a composite of any clinically-relevant cardiac lesion or echocardiography finding. We also recorded duration of screening echocardiography and its acceptability among pregnant women in this sample. Results/UNASSIGNED:The point prevalence of RHD-associated cardiac lesions was 5.0/1,000 (95% confidence interval: 1.0-14.5), and the point prevalence of all clinically significant lesions/findings was 21.6/1,000 (11.6-36.7). Mean screening time was seven minutes (SD 1.7, range: 4-17) for women without cardiac abnormalities and 13 minutes (SD 4.6, range: 6-23) for women with abnormal findings. Echocardiography was acceptable to women with 74.2% agreeing to participate. Conclusions/UNASSIGNED:The prevalence of clinically-relevant cardiac lesions was moderately high in a low-risk population of pregnant women in Western Kenya.

BACKGROUND:A stepped-wedge, cluster randomized controlled trial assessed the effectiveness of practice facilitation (PF) for adoption of guidelines for prevention and treatment of cardiovascular disease risk factors. This study estimated the associated cost of PF for guideline adoption in small, private primary care practices. METHODS:The cost analysis included categories for start-up costs, intervention costs, and practice staff costs for the implemented PF-guided intervention. We estimated the total 1-year costs to operate the program and calculated the mean and range of the cost-per-practice by quarter of the intervention. We estimated the lower and upper bounds for all salary expenses, rounding to the nearest $100. RESULTS:Total 1-year intervention costs for all 261 practices ranged from $7,900,000 to $10,200,000, with program and practice salaries comprising $6,600,000-$8,400,000 of the total. Start-up costs were a small proportion (3%) of the total 1-year costs. Excluding start-up costs, quarter 1 cost-per-practice was the most expensive at $20,400-$26,700, and quarter 4 was the least expensive at about $10,000. Practice staff time (compared with program staff time) was the majority of the staffing costs at 75-84%. CONCLUSIONS:The PF strategy costs approximately $10,000 per practice per quarter for program and practice costs, once implemented and running at highest efficiency. Whether this program is "worth it" to the decision-maker depends on the relative costs and effectiveness of their other options for improving cardiovascular risk reduction. TRIAL REGISTRATION/BACKGROUND:This study is retrospectively registered on January 5, 2016, at www.clinicaltrials.gov as NCT02646488 .