Faculty Bibliography

Almost five years after COVID-19 emerged, multiple scientific uncertainties remain about why some people experience ongoing symptoms long after being infected with SARS-CoV-2 (Long COVID). The pathophysiology underlying Long COVID and its potential to represent several endotypes are still under investigation. These scientific uncertainties around Long COVID have been cited as a reason to delay treatment trials until the disease is better understood. In this paper, a group of bioethicists, clinician-scientists and people with lived experience with Long COVID argue that it is ethically imperative to conduct trials of disease-modifying treatments for Long COVID now. Furthermore, we argue that although conducting such trials can pose ethical challenges, these challenges can be overcome through careful research priority-setting, rigorous trial design, fair participant selection, and ensuring that the risk-benefit profile is favorable.

Executive function (EF), which includes inhibitory control, working memory, and cognitive flexibility, supports adaptive behavior and predicts long-term academic, social, and mental health outcomes. While EF-related neural networks mature throughout childhood, their earliest developmental origins remain unclear. Large-scale brain systems begin organizing in utero, but whether fetal connectivity prospectively relates to EF has not been tested. We collected resting-state fMRI from 113 fetuses (26-39 weeks gestation). Executive function at age 5 was assessed using the Behavior Rating Inventory of Executive Function-Preschool Version (BRIEF-P), resulting in 52 cases with both usable imaging and outcome data after applying motion and birth-outcome criteria. Whole-brain functional connectivity matrices (197 ROIs) were parcellated into 15 networks, and enrichment analysis identified network pairs with a higher-than-expected density of brain-behavior associations. Six enriched network pairs were associated with global EF, including Frontal, Default Mode Network (DMN), Cerebellar, Salience, and Visual networks. Stronger positive connectivity in Frontal-Salience, DMN-Visual, and Cerebellar-DMN predicted poorer EF, whereas greater negative connectivity in Cerebellar-Visual and Salience-Salience predicted better EF. Subscale analyses revealed both shared and distinct associations across EF domains, with Cerebellar and Salience networks consistently implicated. These findings provide the first evidence linking fetal functional architecture to later EF, highlighting distributed, beyond-frontal systems as early scaffolds of executive control.

IMPORTANCE/UNASSIGNED:Screening by low-dose computed tomography can reduce lung cancer mortality among high-risk individuals, but many lung cancers occur among individuals with a smoking history who are not eligible for screening. OBJECTIVE/UNASSIGNED:To develop and validate the protein-based Integrative Analysis of Lung Cancer Risk and Etiology (INTEGRAL)-Risk model in individuals with a smoking history from the general population. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:Cohorts in the Lung Cancer Cohort Consortium recruited research participants in the US, Europe, Asia, and Australia between 1985 and 2009, who were followed up for lung cancer and other health outcomes until 2021. Fourteen case cohorts of 3695 participants with a smoking history within the Lung Cancer Cohort Consortium, including 2305 randomly sampled participants and 1390 patients diagnosed with lung cancer within 3 years after blood sample collection, were designed. Plasma or serum samples from each participant were assayed using the INTEGRAL protein panel in 2022. The INTEGRAL-Risk model was trained using 7 predefined case cohorts (training set; n = 1951) to estimate absolute risk of being diagnosed with lung cancer based on age, smoking history, and 13 proteins. The validity of the INTEGRAL-Risk model was assessed in 7 independent case cohorts (testing set; n = 1744) at 1, 2, and 3 years after blood collection. EXPOSURE/UNASSIGNED:Absolute risk estimates from the protein-based INTEGRAL-Risk model. MAIN OUTCOMES AND MEASURES/UNASSIGNED:The primary outcome was the validity of the INTEGRAL-Risk model in the testing set with respect to discrimination (area under the curve [AUC]) and calibration (ratio of expected-to-observed cases [E/O]). RESULTS/UNASSIGNED:A total of 3695 participants were included, with 1951 participants (including 807 with lung cancer) in the training set and 1744 participants (including 583 with lung cancer) in the testing set. In the combined 14 training and testing sets, after application of statistical weights, 323 570 participants were represented (185 016 [57%] female; median [IQR] age, 60 [51-67] years). In the independent testing set, discrimination of the INTEGRAL-Risk model was highest at 1 year of follow-up and exceeded that of the questionnaire-based PLCOm2012 (Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial) model (INTEGRAL-Risk AUC of 0.88 [95% CI, 0.85-0.91] vs PLCOm2012 AUC of 0.79 [95% CI, 0.75-0.83]; P value for difference <.001). Using a risk threshold to achieve the same specificity as US Preventive Services Task Force (USPSTF) 2021 criteria, the INTEGRAL-Risk model captured 85% of lung cancer cases compared with 63% by USPSTF 2021 and 70% by PLCOm2012. Discrimination of the INTEGRAL-Risk model decreased with longer prediction horizons, with a 2-year AUC of 0.84 (95% CI, 0.81-0.86) and 3-year AUC of 0.81 (95% CI, 0.79-0.83). The model was well calibrated (E/O over 3 years, 0.87 [95% CI, 0.69-1.14]). CONCLUSIONS AND RELEVANCE/UNASSIGNED:Compared with questionnaire-based approaches, the protein-based INTEGRAL-Risk model improved short-term prediction of lung cancer in people with a smoking history. This model has potential to improve selection of high-risk individuals who are most likely to benefit from lung cancer screening.

BACKGROUND:Timely transport of critically injured patients by Emergency Medical Services to verified trauma centers significantly reduces morbidity and mortality. Prior studies demonstrate that undertriage in the prehospital setting impacts outcomes, with rural communities facing additional geographic and systemic barriers to timely trauma care. The area deprivation index, a validated measure of neighborhood-level socioeconomic disadvantage, is associated with poorer health outcomes and may further influence access to trauma centers. Yet, the association between socioeconomic deprivation, rurality, and trauma center transport remains poorly defined. This study aimed to evaluate the extent of urban-rural inequities in Emergency Medical Services transport of critically injured patients to verified trauma centers across all regions of the United States and to assess the association between area deprivation index and likelihood of transport to a trauma center. METHODS:We identified all Emergency Medical Services transported critically injured patients meeting Centers for Disease Control and Prevention field triage criteria for trauma center transport in the National Emergency Medical Services Information System from 2018 to 2022 and mapped Zone Improvement Plan (ZIP) Codes containing verified trauma centers (Levels I-V) using data from the American College of Surgeons, the Trauma Center Association of America, and the American Trauma Society. The cohort was stratified by regions in the United States: Northeast, Midwest, South, and West. The incident scene area deprivation index was obtained from the Neighborhood Atlas at the census block group level. The total number and percentage of patients located in urban and rural Zone Improvement Plan (ZIP) codes transported either to a confirmed trauma center (via the National Emergency Medical Services Information System data) or to a Zone Improvement Plan (ZIP) code that contains a trauma center and the area deprivation index distribution in tertiles (low area deprivation index, moderate area deprivation index, and high area deprivation index) within regions in the United States were calculated with their statistical significance derived from t tests and analyses of variance with post hoc Tukey tests. RESULTS:A total of 36,897,269 critically injured patients met the inclusion criteria, of which 19,874,008 (53.86%) were brought to a trauma center. When stratified by rurality, 7,608,704 (54.01%) and 12,265,304 (53.77%) of critically injured patients within rural and urban areas, respectively, were transported to a trauma center. When comparing across regions, the Northeast region of the United States had the lowest percentage of critically injured patients being transported to a trauma center, whereas the Midwest region had the highest percentage (44.04% vs 67.40%; P < .001). When stratified by rurality, 35.33% vs 46.92% of critically injured patients within rural versus urban areas of the Northeast were transported to a trauma center, whereas 65.47% vs 68.57% of critically injured patients within rural versus urban areas of the Midwest were transported to a trauma center (P < .001). When evaluating area deprivation index, critically injured patients who were injured in more disadvantaged versus advantaged Zone Improvement Plan (ZIP) codes had a higher percentage of patients being transported to a trauma center even when controlling for rurality (56% vs 47%; P < .001). CONCLUSION/CONCLUSIONS:Substantial geographic inequities in the Emergency Medical Services transport of critically injured adult patients to verified trauma centers, varied by geographic region, rurality, and neighborhood-level socioeconomic disadvantage that exist. These findings highlight the complex and regionally variable landscape of trauma access in the United States and underscore the need for targeted, equity-focused strategies to optimize prehospital triage and ensure timely, trauma-informed care across diverse communities.

BACKGROUND:Transition-age (TA) adults are less likely than adults aged 26 and older to receive medications for opioid use disorder (MOUD), and among those treated, disproportionately receive naltrexone over more effective agonist MOUD (buprenorphine and methadone). Given that prescribers ultimately determine medication selection, understanding how age influences their clinical decisions is essential to addressing these disparities. This study examines how prescribers incorporate age into MOUD prescribing decisions for this developmentally vulnerable population. METHODS:Using 2022 New York State Medicaid claims, we identified MOUD prescribers with substantial experience (treating n ≥ 5 TA adults) and conducted semi-structured interviews with 18 outpatient prescribers (MD/DOs, NPs, PAs) from diverse geographic and clinical settings. We applied an inductive thematic analysis approach to explore how prescribers incorporated age and age-related factors into their clinical decision-making around MOUD. RESULTS:Most prescribers did not endorse chronological age as a factor influencing their prescribing patterns, but rather described tailoring treatment based on age-related factors more commonly seen in TA adults. These included developmental characteristics (perceived lack of commitment, peer influence), socioeconomic barriers (e.g., unreliable transportation leading to missed appointments), family influence, and concerns about MOUD dependence. In response to these age-related factors, prescribers implemented harm-reduction principles by adjusting MOUD type prescribing to accommodate TA adults' life-stage realities. In contrast, a small subset of prescribers explicitly cited chronological age as directly influencing MOUD prescribing, expressing hesitations about initiating buprenorphine or referring TA adults for methadone due to long-term dependence concerns. CONCLUSION/CONCLUSIONS:These findings suggest two key mechanisms through which age may influence MOUD prescribing disparities among TA adults: (1) prescribers' responses to age-related life-stage challenges (e.g., developmental and social factors, structural barriers) and (2) explicit prescriber age-based hesitancy about initiating long-term agonist maintenance in younger patients. The first mechanism appeared more influential than explicit hesitancy. These mechanisms may help explain documented disparities in MOUD type prescribed. Addressing these disparities may require multi-level interventions: prescriber education affirming agonist MOUD effectiveness for TA adults, efforts to reduce MOUD misconceptions among patients and families, peer-based approaches that leverage social influence positively, and flexible harm-reduction-oriented clinic policies that accommodate structural barriers while supporting access to evidence-based MOUD.

BACKGROUND/UNASSIGNED:Lung cancer remains the leading cause of cancer-related mortality worldwide, with low-dose computed tomography screening demonstrating an approximately 20% reduction in mortality among high-risk individuals. Despite this benefit, screening prevalence remains suboptimal, with often less than 20% of eligible individuals reported to be up to date on screening. Shared decision-making is essential for effective lung cancer screening (LCS) implementation, with decision aids shown to enhance patient knowledge and engagement. OBJECTIVE/UNASSIGNED:The aim of this study is to identify patient preferences, concerns, and design considerations through qualitative evaluation of MyLungHealth, a personalized patient-facing educational tool for LCS integrated with electronic health records, and to describe how these findings informed iterative design modifications. METHODS/UNASSIGNED:We employed qualitative research methods through focus groups (n=34) and individual interviews (n=18) with individuals who met screening eligibility criteria. Participants were recruited from the University of Utah Health and New York University Langone Health between May and December 2023. Feedback was analyzed using Braun and Clarke's thematic analysis principles. RESULTS/UNASSIGNED:Six themes were organized into three overarching domains. Domain A included interpretation and impact of personalized risk information: theme 1, difficulties interpreting risk information, and theme 2, varied impacts of risk information on motivation. Domain B included autonomy, privacy, and user interface preferences: theme 3, desire for autonomy and control over personal health data, and theme 4, preference for straightforward language and multiple information formats. Domain C included integration with clinical workflows and patient portal systems: theme 5, expectations for integration with health care provider workflows, and theme 6, mixed experiences with personal health record systems. These insights led to key design modifications, including simplified risk presentation, multimodal content delivery options (video and text), and implementation of electronic health record alerts for clinicians. CONCLUSIONS/UNASSIGNED:The user-centered design process for MyLungHealth revealed important considerations for developing effective patient education tools for LCS. The findings highlighted the need for simplified risk presentation, personalized information delivery, and integration with clinical workflows. These findings underscore the importance of balancing comprehensive risk communication with user accessibility.

OBJECTIVE:Phthalates are recognized endocrine disruptors and emerging neurotoxicants. Prenatal exposure to di-2-ethylhexyl phthalate (DEHP) has been linked to adverse neurodevelopmental and neuropsychiatric outcomes, and maternal oxidative stress may play a mechanistic role in prenatal DEHP's neurotoxicity. MATERIALS AND METHODS/METHODS:Participants were drawn from the New York University Children's Health and Environment Study. Prenatal DEHP exposure and maternal lipid peroxidation were assessed using repeated creatinine-adjusted maternal urinary measurements across pregnancy, collected from January 2016-April 2020. Neonatal brain-derived neurotrophic factor (BDNF) was measured in cord serum (N = 337), and internalizing and externalizing problems were assessed at an average age of 2 years using the Child Behavior Checklist for Ages 1.5-5 (CBCL 1½-5) (N = 824). DEHP metabolites (mEHHP; mEOHP; mECPP) were averaged across pregnancy, and cumulative lipid peroxidation biomarkers (8-iso-PGF2α; 15-PGF2α; 8,15-PGF2α; MDA) were estimated using area-under-the-curve values from linear mixed-effects spline models. Partial least squares path modeling evaluated direct and indirect associations using latent constructs for DEHP exposure, lipid peroxidation, CBCL 1½-5, and socioeconomic status; other covariates were modeled as single variables. Sex differences were assessed using bootstrapping and sex-stratified models, adjusting for maternal and child age, parity, pre-pregnancy body mass index, cotinine exposure, and socioeconomic status. RESULTS:Prenatal DEHP exposure was positively associated with maternal lipid peroxidation in all models (β's = 0.11-0.27). Sex-stratified analyses showed that prenatal DEHP exposure was positively associated with CBCL 1½-5 in male children only (β = 0.11), but not with BDNF in either sex. Maternal lipid peroxidation was not associated with BDNF or CBCL 1½-5 in either sex. CONCLUSION/CONCLUSIONS:Prenatal DEHP exposure is associated with maternal oxidative stress and total behavioral problems in male children only, but maternal oxidative stress does not mediate these relationships. Alternative upstream mechanisms may underlie both maternal oxidative stress and neurobehavioral outcomes. Future studies should investigate endocrine, metabolic, and epigenetic pathways to clarify DEHP neurotoxicity.

BACKGROUND:Epigenetic modification of the APOL1 gene carrying risk alleles (G1 and G2) may represent a therapeutic strategy for APOL1-related kidney diseases. However, DNA methylation changes associated with APOL1 have not been thoroughly characterized. METHODS:) and with urine albumin-to-creatinine ratio (ACR). Methylation patterns were additionally assessed for differentially methylated regions and associations with kidney function. We further evaluated whether APOL1 risk-associated CpGs can modulate the relationship between APOL1 risk alleles and kidney function measures. RESULTS:and ACR. APOL1 risk-associated CpGs showed significant interactions with APOL1 risk alleles in relation to kidney function. CONCLUSION/CONCLUSIONS:APOL1 risk alleles are associated with complex DNA methylation alterations across the APOL1-APOL4-MYH9 region, potentially regulating multiple genes within this locus. APOL1 risk-associated CpGs may represent therapeutic targets for APOL1-related kidney diseases.

INTRODUCTION/UNASSIGNED:Platelet hyperreactivity is linked to inflammation and cardiovascular risk in nonpregnant populations, but its relationship to placentally mediated pregnancy outcomes is undefined. We prospectively evaluated platelet hyperreactivity in pregnancy and subsequent ischemic placental disease (IPD), and examined aspirin's (ASA) effect on platelet activity by baseline platelet phenotype. METHODS/UNASSIGNED: RESULTS/UNASSIGNED:Of 66 pregnant participants recruited, 61 had first-trimester LTA; 20 (32.8%) had platelet hyperreactivity. Participants with hyperreactivity were more likely to develop IPD than those without (55% versus 24%, adjusted odds ratio [aOR] 3.77 (95% CI [1.05-13.53]), with consistent directionality across individual components despite low event frequencies. Participants with platelet hyperreactivity showed greater platelet aggregation to ADP, collagen, and low-dose AA. Platelet transcriptomic profiling distinguished participants with versus without platelet hyperreactivity and revealed differential expression of pathways related to platelet activity, energy metabolism, and immune regulation. Among 45 high-risk participants recommended ASA, those with hyperreactivity exhibited higher AA-induced aggregation (24% vs 12.5% platelet aggregation, p=0.01) despite similar serum TxB2 levels. CONCLUSION/UNASSIGNED:First-trimester platelet hyperreactivity was present in approximately one-third of participants and was independently associated with increased risk of IPD. Participants with platelet hyperreactivity demonstrated distinct transcriptomic signatures and greater platelet aggregation despite ASA use. Together, these findings support a contributory role for platelets in placental ischemic pathology and highlight the need to elucidate mechanisms and develop platelet-targeted preventive strategies.