Faculty Bibliography

BACKGROUND:Lung cancer screening (LCS) using low-dose computed tomography (LDCT) reduces lung cancer mortality but can lead to downstream procedures, complications, and other potential harms. Estimates of these events outside NLST (National Lung Screening Trial) have been variable and lacked evaluation by screening result, which allows more direct comparison with trials. OBJECTIVE:To identify rates of downstream procedures and complications associated with LCS. DESIGN:Retrospective cohort study. SETTING:5 U.S. health care systems. PATIENTS:Individuals who completed a baseline LDCT scan for LCS between 2014 and 2018. MEASUREMENTS:Outcomes included downstream imaging, invasive diagnostic procedures, and procedural complications. For each, absolute rates were calculated overall and stratified by screening result and by lung cancer detection, and positive and negative predictive values were calculated. RESULTS:Among the 9266 screened patients, 1472 (15.9%) had a baseline LDCT scan showing abnormalities, of whom 140 (9.5%) were diagnosed with lung cancer within 12 months (positive predictive value, 9.5% [95% CI, 8.0% to 11.0%]; negative predictive value, 99.8% [CI, 99.7% to 99.9%]; sensitivity, 92.7% [CI, 88.6% to 96.9%]; specificity, 84.4% [CI, 83.7% to 85.2%]). Absolute rates of downstream imaging and invasive procedures in screened patients were 31.9% and 2.8%, respectively. In patients undergoing invasive procedures after abnormal findings, complication rates were substantially higher than those in NLST (30.6% vs. 17.7% for any complication; 20.6% vs. 9.4% for major complications). LIMITATION:Assessment of outcomes was retrospective and was based on procedural coding. CONCLUSION:The results indicate substantially higher rates of downstream procedures and complications associated with LCS in practice than observed in NLST. Diagnostic management likely needs to be assessed and improved to ensure that screening benefits outweigh potential harms. PRIMARY FUNDING SOURCE:National Cancer Institute and Gordon and Betty Moore Foundation.

AIMS/OBJECTIVE:The study aims to investigate exercise-limiting factors in hypertrophic cardiomyopathy (HCM) using combined stress echocardiography and cardiopulmonary exercise test. METHODS AND RESULTS/RESULTS:A symptom-limited ramp bicycle exercise test was performed in the semi-supine position on a tilting dedicated ergometer. Echocardiographic images were obtained concurrently with gas exchange measurements along predefined stages of exercise. Oxygen extraction was calculated using the Fick equation at each activity level. Thirty-six HCM patients (mean age 67 ± 6 years, 72% men, 18 obstructive HCM) were compared with age and sex-matched 29 controls. At rest, compared with controls, E/E' ratio (6.26 ± 2.3 vs. 14 ± 2.5, P < 0.001) and systolic pulmonary artery pressures (SPAP) (22.6 ± 3.4 vs. 34 ± 6.2 mmHg, P = 0.023) were increased. Along with the stages of exercise (unloaded; anaerobic threshold; peak), diastolic function worsened (E/e' 8.9 ± 2.6 vs. 13.8 ± 3.6 P = 0.011; 9.4 ± 2.3 vs. 18.6 ± 3.3 P = 0.001; 8.7 ± 1.9 vs. 21.5 ± 4, P < 0.001), SPAP increased (23 ± 2.7 vs. 33 ± 4.4, P = 0.013; 26 ± 3.2 vs. 40 ± 2.9, P < 0.001; 26 ± 3.5 vs. 45 ± 7 mmHg, P < 0.001), and oxygen consumption (6.6 ± 1.7 vs. 6.8 ± 1.6, P = 0.86; 18.1 ± 2.2 vs. 14.6 ± 1.5, P = 0.008; 20.3 ± 3 vs. 15.1 ± 2.1 mL/kg/min, P = 0.01) was reduced. Oxygen pulse was blunted (6.3 ± 1.8 vs. 6.2 ± 1.9, P = 0.79; 10 ± 2.1 vs. 8.8 ± 1.6, P = 0.063; 12.2 ± 2 vs. 8.2 ± 2.3 mL/beat, P = 0.002) due to an insufficient increase in both stroke volume (92.3 ± 17 vs. 77.3 ± 14.5 P = 0.021; 101 ± 19.1 vs. 87.3 ± 15.7 P = 0.06; 96.5 ± 12.2 vs. 83.6 ± 16.1 mL, P = 0.034) and oxygen extraction (0.07 ± 0.03 vs. 0.07 ± 0.02, P = 0.47; 0.13 ± 0.02 vs. 0.10 ± 0.03, P = 0.013; 0.13 ± 0.03 vs. 0.11 ± 0.03, P = 0.03). Diastolic dysfunction, elevated SPAP, and the presence of atrial fibrillation were associated with reduced exercise capacity. CONCLUSIONS:Both central and peripheral cardiovascular limitations are involved in exercise intolerance in HCM. Diastolic dysfunction seems to be the main driver for this limitation.

IMPORTANCE:Children with developmental delays are at a heightened risk of experiencing mental health challenges, and this risk is exacerbated among racially minoritized children who face disproportionate adversity. Understanding the impact of parenting interventions on biological markers associated with these risks is crucial for mitigating long-term health disparities. OBJECTIVE:To examine the effect of 20 weeks of an internet-based parent-child interaction training (iPCIT) program on biomarkers associated with aging and chronic inflammation among preschoolers with developmental delay at 12-month follow-up. DESIGN, SETTING, AND PARTICIPANTS:An observational secondary analysis of data from a randomized clinical trial conducted from March 17, 2016, to December 15, 2020, to assess changes in salivary DNA methylation (DNAm)-derived biomarkers following iPCIT intervention. Participants were recruited from 3 Part C early intervention sites in a large southeastern US city. Eligible participants included children recruited within 3 months of their third birthday who had a Child Behavior Checklist Externalizing Problems T score greater than 60 and provided saliva in at least 1 study wave. Data analysis was conducted May 2023 to April 2024. INTERVENTION:Participants received either iPCIT (a telehealth therapeutic intervention focused on enhancing the parent-child relationship and addressing behavioral challenges in young children) or referrals as usual. MAIN OUTCOMES AND MEASURES:DNAm at the 12-month follow-up was assessed using the Infinium HumanMethylationEPIC Bead Chip Assay to derive biomarkers DunedinPACE, C-reactive protein (CRP), and interleukin-6 (IL-6). Analyses were intent-to-treat and used path analysis. RESULTS:A total of 71 children (mean [SD] age, 36.27 [0.61] months 51 male [71.8%] and 20 female [28.2%]) were analyzed, of whom 34 received iPCIT and 37 received referrals as usual. The iPCIT group had a slower pace of aging (β = 0.26; 95% CI, 0.06 to 0.50; P = .03) and less DNAm-derived CRP (β = 0.27; 95% CI, 0.05 to 0.49; P = .01) relative to the control condition at the 12-month follow-up. These associations remained significant after accounting for baseline DNAm score, child demographics, and symptom severity, and were independent of predicted buccal epithelial cell proportion for both DunedinPACE and CRP. There was no association with DNAm-derived IL-6 (β = 0.14; 95% CI, -0.08 to 0.36; P = .21). CONCLUSIONS AND RELEVANCE:In this study of a parenting intervention, iPCIT, the association of intervention with decreased molecular markers of inflammation and biological aging suggests their potential to modify aspects of the biological embedding of stress. Understanding the systemic biological impact of such interventions offers insights into addressing health disparities and promoting resilience among vulnerable populations. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT03260816.

IMPORTANCE:Research on fetal epigenetic programming suggests that the intrauterine environment can have long-term effects on offspring disease susceptibility. OBJECTIVE:To examine the association between prenatal maternal occupation and child epigenetic age acceleration (EAA) among a farmworker community. DESIGN, SETTING, AND PARTICIPANTS:This cohort study included participants in the Center for the Health Assessment of Mothers and Children of Salinas, a prospective, Latino, prebirth cohort. Pregnant women were recruited from October 1, 1999, to October 1, 2000, from 6 community clinics in California's Salinas Valley agricultural region. Participants were 18 years or older, English or Spanish speaking, Medicaid eligible, and at 20 weeks' gestation or earlier at enrollment. Mother-child pairs who had blood DNA methylation measured at the ages of 7, 9, and 14 years were included. Data were analyzed from July 2021 to November 2023. EXPOSURES:Prenatal maternal occupation was ascertained through study interviews conducted during prenatal visits and shortly after delivery. MAIN OUTCOMES AND MEASURES:Child EAA at 7, 9, and 14 years of age was estimated using DNA methylation-based epigenetic age biomarkers. Three EAA measures were calculated: the Horvath EAA, skin and blood EAA, and intrinsic EAA. Linear mixed-effects models were used to estimate longitudinal associations of prenatal maternal occupation and child EAA, adjusting for confounders and prenatal organophosphate pesticide exposure. RESULTS:Analyses included 290 mother-child pairs (mean [SD] maternal age at delivery, 26.5 [5.2] years; 152 [52.4%] female infants); 254 mothers (87.6%) were born in Mexico, 33 (11.4%) in the US, and 3 (1.0%) in other countries; and 179 families (61.7%) were below the federal poverty line during pregnancy. Mothers reported engaging in several types of work during pregnancy, including agricultural fieldwork (90 [31.0%]), other agricultural work (40 [13.8%]), nonagricultural work (53 [18.3%]), or no work (107 [36.9%]). Children whose mothers worked in agricultural fields during pregnancy had a mean of 0.66 (95% CI, 0.17-1.15) years of greater Horvath EAA, 0.62 (95% CI, 0.31-0.94) years of greater skin and blood EAA, and 0.45 (95% CI, 0.07-0.83) years of greater intrinsic EAA compared with children whose mothers did not work during pregnancy. CONCLUSIONS AND RELEVANCE:In this cohort study, prenatal maternal agricultural fieldwork was associated with accelerated childhood epigenetic aging independent of organophosphate pesticide exposure. Future research on which factors related to agricultural fieldwork accelerate aging in the next generation can inform targeted prevention programs and policies that protect children's health.

BACKGROUND/UNASSIGNED:With a rise in mass casualty incidents, training in hemorrhage control using tourniquets has been championed as a basic-and lifesaving-procedure for bystanders and medical professionals alike. The current standard for training is in-person (IP) courses, which can be limited based on instructor availability. Virtual reality (VR) has demonstrated the potential to improve the accuracy of certain medical tasks but has not yet been developed for hemorrhage control. The objective of this study was to evaluate the efficacy of a VR hemorrhage trainer in learner retention of tourniquet application when compared to traditional IP instructor teaching among a cohort of emergency medicine residents practicing in a Level I trauma center. METHODS/UNASSIGNED:This was a prospective, observational study of 53 emergency medicine residents at an inner-city program. Participants were randomly assigned to either the control or the VR group. On Day 0, all residents underwent a training session (IP vs. VR) for the proper, stepwise application of a tourniquet, as defined by the American College of Trauma Surgeons. Each participant was then assessed on the application of a tourniquet by a blinded instructor using the National Registry Hemorrhage Control Skills Lab rubric. After 3 months, each resident was reevaluated on the same rubric, with subsequent data analysis on successful tourniquet placement (measured as under 90 s) and time to completion. RESULTS/UNASSIGNED: = 0.62). Stratifying the success of tourniquet placement by level of resident training did not demonstrate any statistically significant differences. CONCLUSIONS/UNASSIGNED:In this pilot study of emergency medicine residents, we found no significant differences in successful hemorrhage control by tourniquet placement between those trained with VR compared to a traditional IP course among emergency medicine residents. While more studies with greater power are needed, the results suggest that VR may be a useful adjunct to traditional IP medical training.

PURPOSE/OBJECTIVE:Investigate associations of maternal social experiences with offspring epigenetic age acceleration (EAA) from birth through mid-childhood among 205 mother-offspring dyads of minoritized racial and ethnic groups. METHODS:We used linear regression to examine associations of maternal experiences of racial bias or discrimination (0 = none, 1-2 = intermediate, or 3+ = high), social support (tertile 1 = low, 2 = intermediate, 3 = high), and socioeconomic status index (tertile 1 = low, 2 = intermediate, 3 = high) during the prenatal period with offspring EAA according to Horvath's Pan-Tissue, Horvath's Skin and Blood, and Intrinsic EAA clocks at birth, 3 years, and 7 years. RESULTS:In comparison to children of women who did not experience any racial bias or discrimination, those whose mothers reported highest levels of racial bias or discrimination had lower Pan-Tissue clock EAA in early (-0.50 years; 90% CI: -0.91, -0.09) and mid-childhood (-0.75 years; -1.41, -0.08). We observed similar associations for the Skin and Blood clock and Intrinsic EAA. Maternal experiences of discrimination were not associated with Pan-Tissue EAA at birth. Neither maternal social support nor socioeconomic status predicted offspring EAA. CONCLUSIONS:Children whose mothers experienced higher racial bias or discrimination exhibited slower EAA. Future studies are warranted to confirm these findings and establish associations of early-life EAA with long-term health outcomes.

Drawing from insights from communication science and behavioral economics, the University of Pennsylvania Telehealth Research Center of Excellence (Penn TRACE) is designing and testing telehealth strategies with the potential to transform access to care, care quality, outcomes, health equity, and health-care efficiency across the cancer care continuum, with an emphasis on understanding mechanisms of action. Penn TRACE uses lung cancer care as an exemplar model for telehealth across the care continuum, from screening to treatment to survivorship. We bring together a diverse and interdisciplinary team of international experts and incorporate rapid-cycle approaches and mixed methods evaluation in all center projects. Our initiatives include a pragmatic sequential multiple assignment randomized trial to compare the effectiveness of telehealth strategies to increase shared decision-making for lung cancer screening and 2 pilot projects to test the effectiveness of telehealth to improve cancer care, identify multilevel mechanisms of action, and lay the foundation for future pragmatic trials. Penn TRACE aims to produce new fundamental knowledge and advance telehealth science in cancer care at Penn and nationally.

In kidney transplantation, day-zero biopsies are used to assess organ quality and discriminate between donor-inherited lesions and those acquired post-transplantation. However, many centers do not perform such biopsies since they are invasive, costly and may delay the transplant procedure. We aim to generate a non-invasive virtual biopsy system using routinely collected donor parameters. Using 14,032 day-zero kidney biopsies from 17 international centers, we develop a virtual biopsy system. 11 basic donor parameters are used to predict four Banff kidney lesions: arteriosclerosis, arteriolar hyalinosis, interstitial fibrosis and tubular atrophy, and the percentage of renal sclerotic glomeruli. Six machine learning models are aggregated into an ensemble model. The virtual biopsy system shows good performance in the internal and external validation sets. We confirm the generalizability of the system in various scenarios. This system could assist physicians in assessing organ quality, optimizing allograft allocation together with discriminating between donor derived and acquired lesions post-transplantation.