Faculty Bibliography

Child obesity is widely prevalent, and general pediatricians play an important role in identifying and caring for patients with obesity. Appropriate evaluation and treatment require an understanding of the complex etiology of child obesity, its intergenerational transmission, and its epidemiologic trends, including racial/ethnic and socioeconomic disparities. The American Academy of Pediatrics has published screening, evaluation, and treatment guidelines based on the best available evidence. However, gaps in evidence remain, and implementation of evidence-based recommendations can be challenging. It is important to review optimal care in both the primary care and multidisciplinary weight management settings. This allows for timely evaluation and appropriate referrals, with the pediatrician playing a key role in advocating for patients at higher risk. There is also a role for larger-scale prevention and policy measures that would not only aid pediatricians in managing obesity but greatly benefit child health on a population scale.

OBJECTIVES/OBJECTIVE:To examine racial and ethnic differences in maternal social support in infancy and the relationship between social support and mother-infant health behaviors. METHODS:Secondary analysis of baseline data from a multisite obesity prevention trial that enrolled mothers and their two-month-old infants. Behavioral and social support data were collected via questionnaire. We used modified Poisson regression to determine association between health behaviors and financial and emotional social support, adjusted for sociodemographic characteristics. RESULTS:826 mother-infant dyads (27.3% Non-Hispanic Black, 18.0% Non-Hispanic White, 50.1% Hispanic and 4.6% Non-Hispanic Other). Half of mothers were born in the U.S.; 87% were Medicaid-insured. There were no racial/ethnic differences in social support controlling for maternal nativity. U.S.-born mothers were more likely to have emotional and financial support (rate ratio [RR] 1.14 95% confidence interval [CI]: 1.07, 1.21 and RR 1.23 95% CI: 1.11, 1.37, respectively) versus mothers born outside the U.S. Mothers with financial support were less likely to exclusively feed with breast milk (RR 0.62; 95% CI: 0.45, 0.87) yet more likely to have tummy time ≥12min (RR 1.28; 95% CI: 1.02, 1.59) versus mothers without financial support. Mothers with emotional support were less likely to report feeding with breast milk (RR 0.82; 95% CI: 0.69, 0.97) versus mothers without emotional support. CONCLUSIONS:Nativity, not race or ethnicity, is a significant determinant of maternal social support. Greater social support was not universally associated with healthy behaviors. Interventions may wish to consider the complex nature of social support and population-specific social support needs.

BACKGROUND:Feeding problems are common in early childhood, and some evidence suggests that feeding problems may be associated with psychopathology. Few prospective studies have explored whether toddler feeding problems predict later psychopathology. METHODS:Mothers of 1,136 children from the Upstate KIDS cohort study provided data when children were 2.5 and 8 years of age. Food refusal (picky eating) and mechanical/distress feeding problems and developmental delays were assessed at 2.5 years. Child eating behaviors (enjoyment of food, food fussiness, and emotional under and overeating) and child psychopathology (attention-deficit/hyperactivity (ADHD), oppositional-defiant (OD), conduct disorder (CD), and anxiety/depression) symptoms were assessed at 8 years. RESULTS:Mechanical/distress feeding problems at age 2.5, but not food refusal problems, were associated with ADHD, problematic behavior (OD/CD), and anxiety/depression symptoms at 8 years in models adjusting for eating behaviors at 8 years and child and family covariates. Associations with mechanical/distress feeding problems were larger for ADHD and problematic behavior than anxiety/depression symptoms, though all were modest. Model estimates were similar for boys and girls. CONCLUSIONS:Much of the research on feeding problems focuses on picky eating. This study suggests that early mechanical and mealtime distress problems may serve as better predictors of later psychopathology than food refusal. Parents and pediatricians could monitor children with mechanical/distress feeding problems for signs of developing psychopathology.

Background Solid tumors comprise >90% of cancers. Nonsmall cell lung cancer (NSCLC), metastatic colorectal cancer (CRC), and pancreatic cancer are the leading causes of cancerrelated mortality (5-year overall survival: 26%, 15%, and 11%, respectively).1 Chimeric antigen receptor (CAR) T-cell therapy has demonstrated clinical efficacy in hematologic malignancies.2,3 However, translating engineered T-cell therapies to solid tumors has proven to be challenging due to a lack of tumor-specific targets that can discriminate cancer cells from normal cells. Previous studies using carcinoembryonic antigen (CEA) T-cell receptors and mesothelin (MSLN) CARs resulted in dose-limiting on-target, off-tumor toxicities.4,5 To create a therapeutic safety window, Tmod CAR T-cell therapy utilizes dual-signaling receptors to create a robust logic gate capable of killing tumor cells, while leaving healthy cells intact.6,7 The 2 receptors in Tmod CAR T-cell therapy comprise an activator that recognizes an antigen on the surface of tumor cells that may also be present on normal cells, such as CEA and MSLN, and a blocker that recognizes a second surface antigen from an allele lost only in tumor cells (figure 1).8,9 Human leukocyte antigen (HLA) loss of heterozygosity (LOH) offers a definitive tumor versus normal discriminator target for CAR T-cell therapy.10 The frequency of HLA LOH among advanced NSCLC, CRC, and pancreatic cancers in the Tempus real-world dataset is 16.3% with a range of 15.6%- 23.1%.11 LOH can be reliably detected using the Tempus xTOnco next-generation sequencing (NGS) assay.12,13 Different activator/blocker combinations can be engineered with the Tmod platform technology and may be applied to T cells and natural killer cells in autologous and allogeneic settings. BASECAMP-1 is a currently enrolling observational study with key objectives: 1) To identify patients with somatic HLA LOH eligible for Tmod CAR T-cell therapy, and 2) Subsequent apheresis and manufacturing feasibility for the future EVEREST CEA or MSLN Tmod CAR T-cell studies. Methods BASECAMP-1 (NCT04981119) patient eligibility has 2 parts (figure 2): 1) Patients will be initially screened to identify germline HLA-A*02 heterozygosity by central NGS. If HLA-A*02 heterozygosity is confirmed, primary archival tumor tissue will be analyzed for somatic mutations by xTOnco NGS testing; 2) If the tumor demonstrates HLAA* 02:01 LOH and the patient is eligible after screening, the patient will undergo apheresis. Banked T cells will be available for the autologous EVEREST Tmod CAR T-cell therapy interventional study to reduce waiting time at relapse. (Figure Presented)

BACKGROUND:The diagnosis of multiple sclerosis (MS) requires demyelinating events that are disseminated in time and space. Peripapillary retinal nerve fiber layer (pRNFL) thickness as measured by optical coherence tomography (OCT) distinguishes eyes with a prior history of acute optic neuritis (ON) and may provide evidence to support a demyelinating attack. OBJECTIVE:To investigate whether a deep learning (DL)-based network can distinguish between eyes with prior ON and healthy control (HC) eyes using peripapillary ring scans. METHODS:We included 1033 OCT scans from 415 healthy eyes (213 HC subjects) and 510 peripapillary ring scans from 164 eyes with prior acute ON (140 patients with MS). Data were split into 70% training, 15% validation, and 15% test data. We included 102 OCT scans from 80 healthy eyes (40 HC) and 61 scans from 40 ON eyes (31 MS patients) from an independent second center. Receiver operating characteristic curve analyses with area under the curve (AUC) were used to investigate performance. RESULTS:We used a dilated residual convolutional neural network for the classification. The final network had an accuracy of 0.85 and an AUC of 0.86, whereas pRNFL only had an AUC of 0.77 in recognizing ON eyes. Using data from a second center, the network achieved an accuracy of 0.77 and an AUC of 0.90 compared to pRNFL, which had an AUC of 0.84. INTERPRETATION:DL-based disease classification of prior ON is feasible and has the potential to outperform thickness-based classification of eyes with and without history of prior ON.

Investigations into the causal underpinnings of disease processes can be aided by the incorporation of genetic information. Genetic studies require populations varied in both ancestry and prevalent disease in order to optimize discovery and ensure generalizability of findings to the global population. Here, we report the genetic determinants of the serum proteome in 466 African Americans with chronic kidney disease attributed to hypertension from the richly phenotyped African American Study of Kidney Disease and Hypertension (AASK) study. Using the largest aptamer-based protein profiling platform to date (6,790 proteins or protein complexes), we identified 969 genetic associations with 900 unique proteins; including 52 novel cis (local) associations and 379 novel trans (distant) associations. The genetic effects of previously published cis-protein quantitative trait loci (pQTLs) were found to be highly reproducible, and we found evidence that our novel genetic signals colocalize with gene expression and disease processes. Many trans- pQTLs were found to reflect associations mediated by the circulating cis protein, and the common trans-pQTLs are enriched for processes involving extracellular vesicles, highlighting a plausible mechanism for distal regulation of the levels of secreted proteins. Thus, our study generates a valuable resource of genetic associations linking variants to protein levels and disease in an understudied patient population to inform future studies of drug targets and physiology.

BACKGROUND:Melamine, melamine derivatives, and aromatic amines are nitrogen-containing compounds with known toxicity and widespread commercial uses. Nevertheless, biomonitoring of these chemicals is lacking, particularly during pregnancy, a period of increased susceptibility to adverse health effects. OBJECTIVES/OBJECTIVE:We aimed to measure melamine, melamine derivatives, and aromatic amine exposure in pregnant women across the United States (U.S.) and evaluate associations with participant and urine sample collection characteristics. METHODS:We measured 43 analytes, representing 45 chemicals (i.e., melamine, three melamine derivatives, and 41 aromatic amines), in urine from pregnant women in nine diverse ECHO cohorts during 2008-2020 (N = 171). To assess relations with participant and urine sample collection characteristics, we used generalized estimating equations to estimate prevalence ratios (PRs) for analytes dichotomized at the detection limit, % differences (%Δ) for continuous analytes, and 95% confidence intervals. Multivariable models included age, race/ethnicity, marital status, urinary cotinine, and year of sample collection. RESULTS:Twelve chemicals were detected in >60% of samples, with near ubiquitous detection of cyanuric acid, melamine, aniline, 4,4'-methylenedianiline, and a composite of o-toluidine and m-toluidine (99-100%). In multivariable adjusted models, most chemicals were associated with higher exposures among Hispanic and non-Hispanic Black participants. For example, concentrations of 3,4-dichloroaniline were higher among Hispanic (%Δ: +149, 95% CI: +17, +431) and non-Hispanic Black (%Δ: +136, 95% CI: +35, +311) women compared with non-Hispanic White women. We observed similar results for ammelide, o-/m-toluidine, 4,4'-methylenedianiline, and 4-chloroaniline. Most chemicals were positively associated with urinary cotinine, with strongest associations observed for o-/m-toluidine (%Δ: +23; 95% CI: +16, +31) and 3,4-dichloroaniline (%Δ: +25; 95% CI: +17, +33). Some chemicals exhibited annual trends (e.g., %Δ in melamine per year: -11; 95% CI: -19, -1) or time of day, seasonal, and geographic variability. DISCUSSION/CONCLUSIONS:Exposure to melamine, cyanuric acid, and some aromatic amines was ubiquitous in this first investigation of these analytes in pregnant women. Future research should expand biomonitoring, identify sources of exposure disparities by race/ethnicity, and evaluate potential adverse health effects.

BACKGROUND:Gender composition among surgical academic leadership, including academic medical journals, disproportionately favors men and may inadvertently introduce a bias. An understanding of the factors associated with gender representation among urologic journals may aid in prioritizing an equitable balance. OBJECTIVE:To evaluate female representation on editorial boards of pre-eminent international urologic journals. DESIGN, SETTING, AND PARTICIPANTS/METHODS:The names and position descriptions of urologic journal leadership appointees were collected in October 2021. Gender was assessed using gender-api.com or through personal title, as available. Journal characteristics were summarized using SCImago, a bibliometric indicator database extracted from Scopus journal data. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS/METHODS:A multivariate logistic regression analysis was performed to describe associations between SCImago Journal Rank (SJR) quartile and geographic region with female gender representation. Quartile 1 (Q1) was considered the top quartile and Q4 the bottom quartile concordant with journal impact factor. RESULTS AND LIMITATIONS/CONCLUSIONS:A total of 105 urology-focused journals were identified with 5989 total editorial board members, including 877 (14.6%) female, 5112 (85.4%) male, and two nonbinary persons. Female representation differed significantly by journal leadership position, SJR quartile, and geographic region. On the multivariate analysis of overall female representation, Q1 journals had higher odds of female representation than Q2 and Q3 journals, and had no significant difference from Q4 journals. Additionally, compared with Western Europe, North American journals had 78% higher odds while Asiatic journals had 50% lower odds of female representation. This study is limited by the inability to account for outside factors that lead to invitation or acceptance of journal leadership positions. CONCLUSIONS:Contemporary female leadership at urology journals is about six times less common than male leadership across all journals, although trends in their proportion were noted when assessed by journal quartile and region. Addressing this gender imbalance represents an important step toward achieving gender equity in the field of urology. PATIENT SUMMARY/RESULTS:In this study, we looked at the gender balance of academic journal leaders who serve as gatekeepers for sharing urologic research with the public. We found that the most prestigious journals and those in western countries tended to have the highest female representation. We hope that these findings help the academic community recognize and improve gender representation.

INTRODUCTION/BACKGROUND:Understanding educational patterns in excess mortality during the coronavirus disease 2019 (COVID-19) pandemic may help to identify strategies to reduce disparities. It is unclear whether educational inequalities in COVID-19 mortality have persisted throughout the pandemic, spanned the full range of educational attainment, or varied by other demographic indicators of COVID-19 risks, such as age or occupation. METHODS:This study analyzed individual-level California Department of Public Health data on deaths occurring between January 2016 and February 2021 among individuals aged ≥25 years (1,502,202 deaths). Authors applied ARIMA (autoregressive integrated moving average) models to subgroups defined by the highest level of education and other demographics (age, sex, race/ethnicity, U.S. nativity, occupational sector, and urbanicity). Authors estimated excess deaths (the number of observed deaths minus the number of deaths expected to occur under the counterfactual of no pandemic) and excess deaths per 100,000 individuals. RESULTS:Educational inequalities in excess mortality emerged early in the pandemic and persisted throughout the first year. The greatest per-capita excess occurred among people without high-school diplomas (533 excess deaths/100,000), followed by those with a high-school diploma but no college (466/100,000), some college (156/100,000), and bachelor's degrees (120/100,000), and smallest among people with graduate/professional degrees (101/100,000). Educational inequalities occurred within every subgroup examined. For example, per-capita excess mortality among Latinos with no college experience was 3.7 times higher than among Latinos with at least some college experience. CONCLUSIONS:Pervasive educational inequalities in excess mortality during the pandemic suggest multiple potential intervention points to reduce disparities.