Peter A. Margolis

Proactive therapeutic drug monitoring (TDM) for tumor necrosis factor alpha antagonist (anti-TNF) therapy in adult inflammatory bowel disease (IBD) remains controversial, with inconsistent findings from clinical trials and meta-analyses. Pediatric societal guidelines endorse the implementation of proactive TDM. However, the integration of TDM into clinical practice by pediatric gastroenterologists has not been characterized. This study was undertaken to delineate the practice patterns, attitudes, and barriers associated with anti-TNF TDM among pediatric gastroenterologists across the United States. A 28-item questionnaire was developed based on prior adult surveys and current pediatric literature, undergoing 3 rounds of iteration. The survey was comprised of physician demographics, center demographics, TDM practice behavior questions and case-scenarios. The survey was deployed through the ImproveCareNow Learning Health System Network between February and June 2023. Among 380 invitees, 256 (77%) completed the questionnaire. Among respondents, 67% (171) were academic-affiliates, and 55% (140) were female. There was notable variability in the number of patients with IBD seen per practice. All respondents reported using TDM for infliximab, and the majority for adalimumab, and the vast majority utilizing a proactive TDM approach. The principal barriers to TDM implementation were insurance denials, cost, and logistical challenges. More respondents indicated they would initiate TDM during infliximab induction for severe ulcerative colitis than for Crohn's disease. In contrast to the adult literature, most pediatric gastroenterologists report undertaking proactive TDM for anti-TNF agents in IBD management. Precision dosing tools reflective of an individual's pharmacokinetics are desired and need to be further studied.

INTRODUCTION: Human leukocyte antigen (HLA) DQA1*05 has been associated with the development of anti-drug antibodies (ADA) to tumor necrosis factor antagonists (anti-TNFα) and treatment failure among adults with Crohn's disease (CD). However, findings from other studies have been inconsistent with limited pediatric data. METHODS: We analyzed banked serum from patients with CD aged P = 0.08). After stratification by HLA DQA1*05 and by methotrexate vs placebo, patients who were HLA DQA1*05 negative and assigned to methotrexate experienced less treatment failures than HLA DQA1*05-positive patients on placebo (hazard ratio 0.31, 95% CI 0.13–0.70; P = 0.005). A trend toward increased ADA development among HLA DQA1*05-positive participants was not significant (odds ratio 1.96, 95% CI 0.90–4.31, P = 0.09). After further stratification, HLA DQA1*05-negative participants assigned to methotrexate were less likely to develop ADA relative to HLA DQA1*05-positive patients on placebo (odds ratio 0.12, 95% CI 0.03–0.55; P = 0.008). DISCUSSION: In a randomized trial of children with CD initiating anti-TNFα, 40% were HLA DQ-A1*05 positive, which was associated with a trend toward increased risk of both treatment failure and ADA. These risks were mitigated, but not eliminated, by adding oral methotrexate. HLA DQ-A1*05 is an important biomarker for prognosis and risk stratification.

As the COVID-19 pandemic progressed, reliable, accessible, and equitable community-based testing strategies were sought that did not flood already overburdened hospitals and emergency departments. In Hamilton County, Ohio, home to ~800 000 people across urban, suburban, and rural areas, we sought to develop and optimize an accessible, equitable county-wide COVID-19 testing program. Using Coronavirus Aid, Relief, and Economic Security Act funding, multidisciplinary, multiorganization partners created the test and protect program to deliver safe, reliable testing in neighborhoods and organizations needing it most. Our approach involved: (1) use of geospatial analytics to identify testing locations positioned to optimize access; (2) community engagement to ensure sites were in trusted places; and (3) tracking of data over time to facilitate ongoing improvement. Between August 2020 and December 2021, more than 65 000 tests were completed for nearly 46 000 individuals at community-based testing sites. These methods could have application beyond COVID-19 and our region.

INTRODUCTION: Obesity is common among patients with pediatric Crohn's disease (PCD). Some adult studies suggest obese patients respond less well to anti-tumor necrosis factor (TNF) treatment. This study sought compares anti-TNF response and anti-TNF levels between pediatric patients with normal and high body mass index (BMI). METHODS: The COMBINE trial compared anti-TNF monotherapy with combination therapy with methotrexate in patients with PCD. In this secondary analysis, a comparison of time-to-treatment failure among patients with normal BMI vs BMI Z-score >1, adjusting for prescribed anti-TNF (infliximab [IFX] or adalimumab [ADA]), trial treatment assignment (combination vs monotherapy), and relevant covariates. Median anti-TNF levels across BMI category was also examined. RESULTS: Of 224 participants (162 IFX initiators and 62 ADA initiators), 111 (81%) had a normal BMI and 43 (19%) had a high BMI. High BMI was associated with treatment failure among ADA initiators (7/10 [70%] vs 12/52 [23%], hazard ratio 0.29, P = 0.007) but not IFX initiators. In addition, ADA-treated patients with a high BMI had lower ADA levels compared with those with normal BMI (median 5.8 vs 12.8 μg/mL, P = 0.02). IFX trough levels did not differ between BMI groups. DISCUSSION: Overweight and obese patients with PCD are more likely to experience ADA treatment failure than those with normal BMI. Higher BMI was associated with lower drug trough levels. Standard ADA dosing may be insufficient for overweight children with PCD. Among IFX initiators, there was no observed difference in clinical outcomes or drug levels, perhaps due to weight-based dosing and/or greater use of proactive drug monitoring.

Next-generation surveys like the Legacy Survey of Space and Time (LSST) on the Vera C. Rubin Observatory (Rubin) will generate orders of magnitude more discoveries of transients and variable stars than previous surveys. To prepare for this data deluge, we developed the Photometric LSST Astronomical Time-series Classification Challenge (PLAsTiCC), a competition that aimed to catalyze the development of robust classifiers under LSST-like conditions of a nonrepresentative training set for a large photometric test set of imbalanced classes. Over 1000 teams participated in PLAsTiCC, which was hosted in the Kaggle data science competition platform between 2018 September 28 and 2018 December 17, ultimately identifying three winners in 2019 February. Participants produced classifiers employing a diverse set of machine-learning techniques including hybrid combinations and ensemble averages of a range of approaches, among them boosted decision trees, neural networks, and multilayer perceptrons. The strong performance of the top three classifiers on Type Ia supernovae and kilonovae represent a major improvement over the current state of the art within astronomy. This paper summarizes the most promising methods and evaluates their results in detail, highlighting future directions both for classifier development and simulation needs for a next-generation PLAsTiCC data set.

Background Prior studies of early antibiotic use and growth have shown mixed results, primarily on cross-sectional outcomes. This study examined the effect of oral antibiotics before age 24 months on growth trajectory at age 2–5 years. Methods We captured oral antibiotic prescriptions and anthropometrics from electronic health records through PCORnet, for children with ≥1 height and weight at 0–12 months of age, ≥1 at 12–30 months, and ≥2 between 25 and 72 months. Prescriptions were grouped into episodes by time and by antimicrobial spectrum. Longitudinal rate regression was used to assess differences in growth rate from 25 to 72 months of age. Models were adjusted for sex, race/ethnicity, steroid use, diagnosed asthma, complex chronic conditions, and infections. Results 430,376 children from 29 health U.S. systems were included, with 58% receiving antibiotics before 24 months. Exposure to any antibiotic was associated with an average 0.7% (95% CI 0.5, 0.9, p < 0.0001) greater rate of weight gain, corresponding to 0.05 kg additional weight. The estimated effect was slightly greater for narrow-spectrum (0.8% [0.6, 1.1]) than broad-spectrum (0.6% [0.3, 0.8], p < 0.0001) drugs. There was a small dose response relationship between the number of antibiotic episodes and weight gain. Conclusion Oral antibiotic use prior to 24 months of age was associated with very small changes in average growth rate at ages 2–5 years. The small effect size is unlikely to affect individual prescribing decisions, though it may reflect a biologic effect that can combine with others.