Faculty Bibliography

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by a progressive loss of motor function linked to degenerating extratelencephalic neurons/Betz cells (ETNs). The reasons why these neurons are selectively affected remain unclear. Here, to understand the unique molecular properties that may sensitize ETNs to ALS, we performed RNA sequencing of 79,169 single nuclei from cortices of patients and controls. In both patients and unaffected individuals, we found significantly higher expression of ALS risk genes in THY1⁺ ETNs, regardless of diagnosis. In patients, this was accompanied by the induction of genes involved in protein homeostasis and stress responses that were significantly induced in a wide collection of ETNs. Examination of oligodendroglial and microglial nuclei revealed patient-specific downregulation of myelinating genes in oligodendrocytes and upregulation of an endolysosomal reactive state in microglia. Our findings suggest that selective vulnerability of extratelencephalic neurons is partly connected to their intrinsic molecular properties sensitizing them to genetics and mechanisms of degeneration.

BACKGROUND:Most patients starting chronic in-center hemodialysis (HD) receive conventional hemodialysis (CHD) with three sessions per week targeting specific biochemical clearance. Observational studies suggest that patients with residual kidney function can safely be treated with incremental prescriptions of HD, starting with less frequent sessions and later adjusting to thrice-weekly HD. This trial aims to show objectively that clinically matched incremental HD (CMIHD) is non-inferior to CHD in eligible patients. METHODS:and urine output ≥500 mL/24 h. The 1:1 randomization, stratified by site and dialysis vascular access type, assigns patients to either CMIHD (intervention group) or CHD (control group). The CMIHD group will be treated with twice-weekly HD and adjuvant pharmacologic therapy (i.e., oral loop diuretics, sodium bicarbonate, and potassium binders). The CHD group will receive thrice-weekly HD according to usual care. Throughout the study, patients undergo timed urine collection and fill out questionnaires. CMIHD will progress to thrice-weekly HD based on clinical manifestations or changes in residual kidney function. Caregivers of enrolled patients are invited to complete semi-annual questionnaires. The primary outcome is a composite of patients' all-cause death, hospitalizations, or emergency department visits at 2 years. Secondary outcomes include patient- and caregiver-reported outcomes. We aim to enroll 350 patients, which provides ≥85% power to detect an incidence rate ratio (IRR) of 0.9 between CMIHD and CHD with an IRR non-inferiority of 1.20 (α = 0.025, one-tailed test, 20% dropout rate, average of 2.06 years of HD per patient participant), and 150 caregiver participants (of enrolled patients). DISCUSSION/CONCLUSIONS:Our proposal challenges the status quo of HD care delivery. Our overarching hypothesis posits that CMIHD is non-inferior to CHD. If successful, the results will positively impact one of the highest-burdened patient populations and their caregivers. TRIAL REGISTRATION/BACKGROUND:Clinicaltrials.gov NCT05828823. Registered on 25 April 2023.

Environmental exposure-associated disease is an active area of study, especially in the context of increasing global air pollution and use of inhalants. Our group is dedicated to the study of exposure-related inflammation and downstream health effects. While many studies have focused on the impact of inhalants on respiratory sequelae, there is growing evidence of the involvement of other systems including autoimmune, endocrine, and gastrointestinal. This systematic review aims to provide a recent update that will underscore the associations between inhalation exposures and upper gastrointestinal disease in the contexts of our evolving environmental exposures. Keywords focused on inhalational exposures and gastrointestinal disease. Primary search identified n = 764 studies, of which n = 64 met eligibility criteria. In particular, there was support for existing evidence that PM increases the risk of upper gastrointestinal diseases. Smoking was also confirmed to be major risk factor. Interestingly, studies in this review have also identified waterpipe use as a significant risk factor for gastroesophageal reflux and gastric cancer. Our systematic review identified inhalational exposures as risk factors for aerodigestive disease, further supporting the association between environmental exposure and digestive disease. However, due to limitations on our review’s scope, further studies must be done to better understand this interaction.

Laboratory polysomnography provides gold-standard measures of sleep physiology, but multi-night investigations are resource intensive. We assessed the night-to-night stability via reproducibility metrics for sleep macrostructure and electroencephalography oscillations in a group of cognitively normal adults attending two consecutive polysomnographies. Electroencephalographies were analysed using an automatic algorithm for detection of slow-wave activity, spindle and K-complex densities. Average differences between nights for sleep macrostructure, electroencephalography oscillations and sleep apnea severity were assessed, and test-retest reliability was determined using two-way intraclass correlations. Agreement was calculated using the smallest real differences between nights for all measures. Night 2 polysomnographies showed significantly greater time in bed, total sleep time (6.3 hr versus 6.8 hr, p < 0.001) and percentage of rapid eye movement sleep (17.5 versus 19.7, p < 0.001). Intraclass correlations were low for total sleep time, percentage of rapid eye movement sleep and sleep efficiency, moderate for percentage of slow-wave sleep and percentage of non-rapid eye movement 2 sleep, good for slow-wave activity and K-complex densities, and excellent for spindles and apnea-hypopnea index with hypopneas defined according to 4% oxygen desaturation criteria only. The smallest real difference values were proportionally high for most sleep macrostructure measures, indicating moderate agreement, and proportionally lower for most electroencephalography microstructure variables. Slow waves, K-complexes, spindles and apnea severity indices are highly reproducible across two consecutive nights of polysomnography. In contrast, sleep macrostructure measures all demonstrated poor reproducibility as indicated by low intraclass correlation values and moderate agreement. Although there were average differences in percentage of rapid eye movement sleep and total sleep time, these were numerically small and perhaps functionally or clinically less significant. One night of in-laboratory polysomnography is enough to provide stable, reproducible estimates of an individual's sleep concerning measures of slow-wave activity, spindles, K-complex densities and apnea severity.

BACKGROUND:There is a need to understand the relationship between COVID-19 Convalescent Plasma (CCP) anti-SARS-CoV-2 IgG levels and clinical outcomes to optimize CCP use. This study aims to evaluate the relationship between recipient baseline clinical status, clinical outcomes, and CCP antibody levels. METHODS:The study analyzed data from the COMPILE study, a meta-analysis of pooled individual patient data from 8 randomized clinical trials (RCTs) assessing the efficacy of CCP vs. control, in adults hospitalized for COVID-19 who were not receiving mechanical ventilation at randomization. SARS-CoV-2 IgG levels, referred to as 'dose' of CCP treatment, were retrospectively measured in donor sera or the administered CCP, semi-quantitatively using the VITROS Anti-SARS-CoV-2 IgG chemiluminescent immunoassay (Ortho-Clinical Diagnostics) with a signal-to-cutoff ratio (S/Co). The association between CCP dose and outcomes was investigated, treating dose as either continuous or categorized (higher vs. lower vs. control), stratified by recipient oxygen supplementation status at presentation. RESULTS:A total of 1714 participants were included in the study, 1138 control- and 576 CCP-treated patients for whom donor CCP anti-SARS-CoV2 antibody levels were available from the COMPILE study. For participants not receiving oxygen supplementation at baseline, higher-dose CCP (/control) was associated with a reduced risk of ventilation or death at day 14 (OR = 0.19, 95% CrI: [0.02, 1.70], posterior probability Pr(OR < 1) = 0.93) and day 28 mortality (OR = 0.27 [0.02, 2.53], Pr(OR < 1) = 0.87), compared to lower-dose CCP (/control) (ventilation or death at day 14 OR = 0.79 [0.07, 6.87], Pr(OR < 1) = 0.58; and day 28 mortality OR = 1.11 [0.10, 10.49], Pr(OR < 1) = 0.46), exhibiting a consistently positive CCP dose effect on clinical outcomes. For participants receiving oxygen at baseline, the dose-outcome relationship was less clear, although a potential benefit for day 28 mortality was observed with higher-dose CCP (/control) (OR = 0.66 [0.36, 1.13], Pr(OR < 1) = 0.93) compared to lower-dose CCP (/control) (OR = 1.14 [0.73, 1.78], Pr(OR < 1) = 0.28). CONCLUSION/CONCLUSIONS:Higher-dose CCP is associated with its effectiveness in patients not initially receiving oxygen supplementation, however, further research is needed to understand the interplay between CCP anti-SARS-CoV-2 IgG levels and clinical outcome in COVID-19 patients initially receiving oxygen supplementation.

BACKGROUND/UNASSIGNED:Annually since 2008; over 38% of fatally injured motorcycle riders and 20% of pedalcyclists involved in traffic crashes were under the influence of alcohol, yet public health surveillance of alcohol involvement in these injuries is underdeveloped. This study determined alcohol involvement among fatally and non-fatally injured pedalcycle and motorcycle riders and compared findings across three national public-use datasets. METHODS/UNASSIGNED:Using the 2019 National Emergency Medical Services Information System (NEMSIS), the Fatality Analysis Reporting System (FARS), and National Electronic Injury Surveillance System (NEISS) datasets, we identified alcohol involvement in fatal and non-fatal injuries to pedalcycle and motorcycle riders (≥21 years). Alcohol involvement was positive based on the clinician's evaluation of alcohol at the scene (NEMSIS) or within the ED record (NEISS); or when Blood Alcohol Content (BAC) values were ≥.01 (FARS). Pedalcycle and motorcycle injuries were identified across datasets using: 1) ICD10 codes for pedalcycle (V10-V19) or motorcycle (V20-V29) within the cause of injury and EMS respondent's impression of the encounter variables (NEMSIS); 2) product codes for bicycles or moped/power-assisted cycle/minibike/two-wheeled, powered, off-road vehicles (NEISS); and 3) American National Standard Institute's classifications for pedalcycle and motorcycle in the person and vehicle type variables (FARS). The descriptive epidemiology was compared across datasets. RESULTS/UNASSIGNED:There were 26,295 pedalcyclist and 50,122 motorcycle rider injuries resulting in an EMS response within NEMSIS data; 10.2% and 8.5% of these injuries respectively involved alcohol. These estimates were greater than the 7.3% of pedalcyclist and 6.1% of moped/power-assisted cycle/minibike/two-wheeled, powered, off-road vehicle injuries involving alcohol among patients who presented to an ED within the NEISS dataset. Based on FARS data, alcohol was involved in 27.0% of pedalcyclist and 42.0% of motorcyclist fatal injuries. Regardless of the data source, pedalcyclist and motorcycle fatal and non-fatal injuries were more likely to involve alcohol among middle-aged adults compared to older and early aged adults, and for men compared to women, with proportions that were generally 3-8% higher for men. CONCLUSIONS/UNASSIGNED:Measures for pedalcycle and motorcycle injuries and alcohol involvement vary substantially across national public-use datasets. Standardized, valid, and feasible methods are needed to accurately inform injury prevention efforts.

BACKGROUND:In recent years the US health-care system has witnessed a substantial increase in telehealth use. Telehealth enhances health-care access and quality and may reduce costs. However, there is a concern that the shift from in-person to telehealth care delivery may differentially improve cancer care access and quality in certain clinical settings and for specific patient populations while potentially exacerbating disparities in care for others. Our National Cancer Institute-funded center, called Telehealth Research and Innovation for Veterans with Cancer (THRIVE), is focused on health equity for telehealth-delivered cancer care. We seek to understand how social determinants of telehealth-particularly race and ethnicity, poverty, and rurality-affect the use of telehealth. METHODS:THRIVE draws from the Health Disparities Research Framework and the Consolidated Framework for Implementation Research. THRIVE consists of multiple cores that work synergistically to assess and understand health equity for telehealth-delivered cancer care. These include the Administrative Core, Research and Methods Core, Clinical Practice Network, and Pragmatic Trial. RESULTS:As of October 2023, we identified and trained 5 THRIVE scholars, who are junior faculty beginning a research career. We have reviewed 20 potential pilot studies, funding 6. Additionally, in communication with our funders and advisory boards, we have adjusted our study design and analytic approach, ensuring feasibility while addressing our operational partners' needs. CONCLUSIONS:THRIVE has several key strengths. First, the Veterans Health Administration's health-care system is large and diverse regarding health-care setting type and patient population. Second, we have access to longitudinal data, predating the COVID-19 pandemic, about telehealth use. Finally, equitable access to high-quality care for all veterans is a major tenet of the Veterans Health Administration health-care mission. As a result of these advantages, THRIVE can focus on isolating and evaluating the impact of social determinants of telehealth on equity in cancer care.

The COVID-19 pandemic placed a spotlight on the potential to dramatically increase the use of telehealth across the cancer care continuum, but whether and how telehealth can be implemented in practice in ways that reduce, rather than exacerbate, inequities are largely unknown. To help fill this critical gap in research and practice, we developed the Framework for Integrating Telehealth Equitably (FITE), a process and evaluation model designed to help guide equitable integration of telehealth into practice. In this manuscript, we present FITE and showcase how investigators across the National Cancer Institute's Telehealth Research Centers of Excellence are applying the framework in different ways to advance digital and health equity. By highlighting multilevel determinants of digital equity that span further than access alone, FITE highlights the complex and differential ways structural determinants restrict or enable digital equity at the individual and community level. As such, achieving digital equity will require strategies designed to not only support individual behavior but also change the broader context to ensure all patients and communities have the choice, opportunity, and resources to use telehealth across the cancer care continuum.

BACKGROUND/OBJECTIVES/OBJECTIVE:Patients often face uncertainty about what they should know after prostate cancer diagnosis. Web-based information is common but is at risk of being of poor quality or readability. SUBJECTS/METHODS/METHODS:We used ChatGPT, a freely available Artificial intelligence (AI) platform, to generate enquiries about prostate cancer that a newly diagnosed patient might ask and compared to Google search trends. Then, we evaluated ChatGPT responses to these questions for clinical appropriateness and quality using standardised tools. RESULTS:ChatGPT generates broad and representative questions, and provides understandable, clinically sound advice. CONCLUSIONS:AI can guide and empower patients after prostate cancer diagnosis through education. However, the limitations of the ChatGPT language-model must not be ignored and require further evaluation and optimisation in the healthcare field.