Faculty Bibliography

The COVID-19 pandemic has been associated with increased neuropsychiatric conditions in children and youths, with evidence suggesting that SARS-CoV-2 infection may contribute additional risks beyond pandemic stressors. This study aims to assess the full spectrum of neuropsychiatric conditions in COVID-19 positive children (ages 5-12) and youths (ages 12-20) compared to a matched COVID-19 negative cohort, accounting for factors influencing infection risk. Using EHR data from 25 institutions in the RECOVER program, we conduct a retrospective analysis of 326,074 COVID-19 positive and 887,314 negative participants matched for risk factors and stratified by age. Neuropsychiatric outcomes are examined 28 to 179 days post-infection or negative test between March 2020 and December 2022. SARS-CoV-2 positivity is confirmed via PCR, serology, or antigen tests, while negativity requires negative test results and no related diagnoses. Risk differences reveal higher frequencies of neuropsychiatric conditions in the COVID-19 positive cohort. Children face increased risks for anxiety, OCD, ADHD, autism, and other conditions, while youths exhibit elevated risks for anxiety, suicidality, depression, and related symptoms. These findings highlight SARS-CoV-2 infection as a potential contributor to neuropsychiatric risks, emphasizing the importance of research into tailored treatments and preventive strategies for affected individuals.

The effectiveness of COVID-19 vaccination in children and adolescents with prior SARS-CoV-2 infection remains unclear, particularly for Omicron subvariants. We evaluated vaccine effectiveness against reinfection with Omicron BA.1/2, BA.4/5, XBB, and later subvariants among 5- to 17-year-olds using data from the RECOVER initiative, a national electronic health record database covering 37 U.S. pediatric institutions. We emulated target trials by age group and variant period, comparing previously infected participants between January 2022 and August 2023. During the BA.1/2 period, vaccination reduced the risk of reinfection, with effectiveness rates of 62% in children and 65% in adolescents. During the BA.4/5 period, protection effectiveness in children was 57%, whereas no statistically significant protection was observed in adolescents. During the XBB or later period, no significant protection was observed in either group. In summary, COVID-19 vaccination provided protection against reinfection during early and mid-Omicron periods in previously infected pediatric populations, but effectiveness declined for later variants.

OBJECTIVE:The objective of this study is to examine real-world dose titration patterns of semaglutide for weight management (Wegovy, Novo Nordisk A/S) in US adults and identify characteristics associated with early discontinuation. METHODS:We identified 15,811 commercially insured adults who started semaglutide for weight management (administrated through single-dose prefilled pens) between June 2021 and December 2023. We depicted dose-titration patterns over 5 months and identified factors associated with discontinuation using multivariable Cox regression. Sensitivity analyses examined patterns after supply shortage resolution (after October 2023). RESULTS:Most semaglutide users deviated from the recommended monthly dose-escalation schedule within the first 5 months. By the fifth month, nearly one-half (46%) had discontinued the treatment, with similar rates (48%) among those initiating after supply stabilization. Discontinuation was strongly associated with copayment amount, with rates increased from 41% in the lowest quintile ($1-$54 per month) to 51% in the highest quintile ($161-$1460 per month). Higher discontinuation rates were also associated with lower household income and education level. CONCLUSIONS:The deviations from the recommended dose-escalation schedule and high discontinuation rate among real-world semaglutide users indicate important challenges in the delivery of evidence-based care. Policy interventions that reduce financial barriers to the persistence of semaglutide are needed.

IMPORTANCE/OBJECTIVE:Patients with poor glycaemic control have a high risk for major cardiovascular events. Improving glycaemic monitoring in patients with diabetes can improve morbidity and mortality. OBJECTIVE:To assess the effectiveness of a patient portal message in prompting patients with poorly controlled diabetes without a recent glycated haemoglobin (HbA1c) result to have their HbA1c repeated. DESIGN/METHODS:A pragmatic, randomised clinical trial. SETTING/METHODS:A large academic health system consisting of over 350 ambulatory practices. PARTICIPANTS/METHODS:Patients who had an HbA1c greater than 10% who had not had a repeat HbA1c in the prior 6 months. EXPOSURES/METHODS:A single electronic health record (EHR)-based patient portal message to prompt patients to have a repeat HbA1c test versus usual care. MAIN OUTCOMES/RESULTS:The primary outcome was a follow-up HbA1c test result within 90 days of randomisation. RESULTS:The study included 2573 patients with a mean (SD) HbA1c of 11.2%. Among 1317 patients in the intervention group, 24.2% had follow-up HbA1c tests completed within 90 days, versus 21.1% of 1256 patients in the control group (p=0.07). Patients in the intervention group were more likely to log into the patient portal within 60 days as compared with the control group (61.2% vs 52.3%, p<0.001). CONCLUSIONS:Among patients with poorly controlled diabetes and no recent HbA1c result, a brief patient portal message did not significantly increase follow-up testing but did increase patient engagement with the patient portal. Automated patient messages could be considered as a part of multipronged efforts to involve patients in their diabetes care.

IMPORTANCE/UNASSIGNED:It remains unclear whether children and adolescents with SARS-CoV-2 infection are at heightened risk for long-term kidney complications. OBJECTIVE/UNASSIGNED:To investigate whether SARS-CoV-2 infection is associated with an increased risk of postacute kidney outcomes among pediatric patients, including those with preexisting kidney disease or acute kidney injury (AKI). DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This retrospective cohort study used data from 19 health institutions in the National Institutes of Health Researching COVID to Enhance Recovery (RECOVER) initiative from March 1, 2020, to May 1, 2023 (follow-up ≤2 years completed December 1, 2024; index date cutoff, December 1, 2022). Participants included children and adolescents (aged <21 years) with at least 1 baseline visit (24 months to 7 days before the index date) and at least 1 follow-up visit (28 to 179 days after the index date). EXPOSURES/UNASSIGNED:SARS-CoV-2 infection, determined by positive laboratory test results (polymerase chain reaction, antigen, or serologic) or relevant clinical diagnoses. A comparison group included children with documented negative test results and no history of SARS-CoV-2 infection. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Outcomes included new-onset chronic kidney disease (CKD) stage 2 or higher or CKD stage 3 or higher among those without preexisting CKD; composite kidney events (≥50% decline in estimated glomerular filtration rate [eGFR], eGFR ≤15 mL/min/1.73 m2, dialysis, transplant, or end-stage kidney disease diagnosis), and at least 30%, 40%, or 50% eGFR decline among those with preexisting CKD or acute-phase AKI. Hazard ratios (HRs) were estimated using Cox proportional hazards regression models with propensity score stratification. RESULTS/UNASSIGNED:Among 1 900 146 pediatric patients (487 378 with and 1 412 768 without COVID-19), 969 937 (51.0%) were male, the mean (SD) age was 8.2 (6.2) years, and a range of comorbidities was represented. SARS-CoV-2 infection was associated with higher risk of new-onset CKD stage 2 or higher (HR, 1.17; 95% CI, 1.12-1.22) and CKD stage 3 or higher (HR, 1.35; 95% CI, 1.13-1.62). In those with preexisting CKD, COVID-19 was associated with an increased risk of composite kidney events (HR, 1.15; 95% CI, 1.04-1.27) at 28 to 179 days. Children with acute-phase AKI had elevated HRs (1.29; 95% CI, 1.21-1.38) at 90 to 179 days for composite outcomes. CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this large US cohort study of children and adolescents, SARS-CoV-2 infection was associated with a higher risk of adverse postacute kidney outcomes, particularly among those with preexisting CKD or AKI, suggesting the need for vigilant long-term monitoring.

Pediatric Long COVID has been associated with a wide variety of symptoms, conditions, and organ systems, but distinct clinical presentations, or subphenotypes, are still being elucidated. In this exploratory analysis, we identified a cohort of pediatric (age <21) patients with evidence of Long COVID and no pre-existing complex chronic conditions using electronic health record data from 38 institutions and used an unsupervised machine learning-based approach to identify subphenotypes. Our method, an extension of the Phe2Vec algorithm, uses tens of thousands of clinical concepts from multiple domains to represent patients' clinical histories to then identify groups of patients with similar presentations. The results indicate that cardiorespiratory presentations are most common (present in 54% of patients) followed by subphenotypes marked (in decreasing order of frequency) by musculoskeletal pain, neuropsychiatric conditions, gastrointestinal symptoms, headache, and fatigue.

BACKGROUND:Medication non-adherence, which is common in chronic diseases such as heart failure, is often estimated using proportion of days covered (PDC). PDC is typically calculated using medication fill information from pharmacy or insurance claims data, which lack information on when medications are prescribed. Many electronic health records (EHRs) have prescription and pharmacy fill data available, enabling enhanced PDC assessment that can be utilized in routine clinical care. OBJECTIVE:To describe our approach to calculating PDC using linked EHR-pharmacy data and to compare to PDC calculated using pharmacy-only data for patients with heart failure. METHODS:We performed a retrospective cohort study of adult patients with heart failure who were prescribed guideline-directed medical therapy (GDMT) and seen in a large health system. Using linked EHR-pharmacy data, we estimated medication adherence by PDC as the percent of days in which a patient possessed GDMT based on medication pharmacy fills over the number of days the prescription order was active. We also calculated PDC using pharmacy-only data, calculated as medications possessed over days with continued medication fills. We compared these two approaches for days observed and PDC using a paired t-test. RESULTS:Among 33,212 patients with heart failure who were prescribed GDMT, 2226 (6.7%) never filled their medications, making them unavailable in the assessment of PDC using pharmacy-only data (n = 30,995). Linked EHR-pharmacy data had slightly longer days observed for PDC assessment (164.7 vs. 163.4 days; p < 0.001) and lower PDC (78.5 vs. 90.6, p < 0.001) as compared to assessment using pharmacy-only data. CONCLUSIONS:Linked EHR-pharmacy data can be used to identify patients who never fill their prescriptions. Estimating adherence using linked EHR-pharmacy data resulted in a lower mean PDC as compared to estimates using pharmacy-only data.

IMPORTANCE/OBJECTIVE:Prior studies have demonstrated the effectiveness of COVID-19 vaccines in children and adolescents. However, the benefits of vaccination in these age groups with prior infection remain underexplored. OBJECTIVE:To evaluate the effectiveness of COVID-19 vaccination in preventing reinfection with various Omicron subvariants (BA.1/2, BA.4/5, XBB, and later) among 5- to 17-year-olds with prior SARS-CoV-2 infection. DESIGN/METHODS:A target trial emulation through nested designs with distinct study periods. SETTING/METHODS:The study utilized data from the Research COVID to Enhance Recovery (RECOVER) initiative, a national electronic health record (EHR) database comprising 37 U.S. children's hospitals and health institutions. PARTICIPANTS/METHODS:Individuals aged 5-17 years with a documented history of SARS-CoV-2 infection prior to the study start date during a specific variant-dominant period (Delta, BA.1/2, or BA.4/5) who received a subsequent dose of COVID-19 vaccine during the study periods were compared with those with a documented history of infection who did not receive SARS-CoV-2 vaccine during the study period. Those infected within the Delta-Omicron composite period (December 1, 2021, to December 31, 2021) were excluded. The study period was from January 1, 2022, to August 30, 2023, and focused on adolescents aged 12 to 17 years and children aged 5 to 11 years. EXPOSURES/METHODS:At least received one COVID-19 vaccination during the study period vs. no receipt of any COVID-19 vaccine during the study period. MAIN OUTCOMES AND MEASURES/METHODS:The primary outcome is documented SARS-CoV-2 reinfection during the study period (both asymptomatic and symptomatic cases). The effectiveness of the COVID-19 vaccine was estimated as (1- hazard ratio) *100%, with confounders adjusted by a combination of propensity score matching and exact matching. RESULTS:The study analyzed 87,573 participants during the BA.1/2 period, 229,326 during the BA.4/5 period, and 282,981 during the XBB or later period. Among vaccinated individuals, significant protection was observed during the BA.1/2 period, with effectiveness rates of 62% (95% CI: 38%-77%) for children and 65% (95% CI: 32%-81%) for adolescents. During the BA.4/5 period, vaccine effectiveness was 57% (95% CI: 25%-76%) for children, but not statistically significant for adolescents (36%, 95% CI: -16%-65%). For the XBB period, no significant protection was observed in either group, with effectiveness rates of 22% (95% CI: -36%-56%) in children and 34% (95% CI: -10%-61%) in adolescents. CONCLUSIONS AND RELEVANCE/CONCLUSIONS:COVID-19 vaccination provides significant protection against reinfection for children and adolescents with prior infections during the early and mid-Omicron periods. This study also highlights the importance of addressing low vaccination rates in pediatric populations to enhance protection against emerging variants.

BACKGROUND:Cardiometabolic comorbidities such as obesity, diabetes, and hypertension are highly prevalent in heart failure (HF). We aimed to examine the association between severity of cardiometabolic comorbidities and hospitalization in patients with HF. METHODS: RESULTS: CONCLUSIONS:Greater cardiometabolic comorbidity burden was associated with increased risk of all-cause hospitalization in HF. This reinforces the role for targeting severely uncontrolled cardiometabolic comorbidities to reduce morbidity in HF.