Characterizing Long COVID in Children and Adolescents.

Importance: Most research to understand postacute sequelae of SARS-CoV-2 infection (PASC), or long COVID, has focused on adults, with less known about this complex condition in children. Research is needed to characterize pediatric PASC to enable studies of underlying mechanisms that will guide future treatment. Objective: To identify the most common prolonged symptoms experienced by children (aged 6 to 17 years) after SARS-CoV-2 infection, how these symptoms differ by age (school-age [6-11 years] vs adolescents [12-17 years]), how they cluster into distinct phenotypes, and what symptoms in combination could be used as an empirically derived index to assist researchers to study the likely presence of PASC. Design, Setting, and Participants: Multicenter longitudinal observational cohort study with participants recruited from more than 60 US health care and community settings between March 2022 and December 2023, including school-age children and adolescents with and without SARS-CoV-2 infection history. Exposure: SARS-CoV-2 infection. Main Outcomes and Measures: PASC and 89 prolonged symptoms across 9 symptom domains. Results: A total of 898 school-age children (751 with previous SARS-CoV-2 infection [referred to as infected] and 147 without [referred to as uninfected]; mean age, 8.6 years; 49% female; 11% were Black or African American, 34% were Hispanic, Latino, or Spanish, and 60% were White) and 4469 adolescents (3109 infected and 1360 uninfected; mean age, 14.8 years; 48% female; 13% were Black or African American, 21% were Hispanic, Latino, or Spanish, and 73% were White) were included. Median time between first infection and symptom survey was 506 days for school-age children and 556 days for adolescents. In models adjusted for sex and race and ethnicity, 14 symptoms in both school-age children and adolescents were more common in those with SARS-CoV-2 infection history compared with those without infection history, with 4 additional symptoms in school-age children only and 3 in adolescents only. These symptoms affected almost every organ system. Combinations of symptoms most associated with infection history were identified to form a PASC research index for each age group; these indices correlated with poorer overall health and quality of life. The index emphasizes neurocognitive, pain, and gastrointestinal symptoms in school-age children but change or loss in smell or taste, pain, and fatigue/malaise-related symptoms in adolescents. Clustering analyses identified 4 PASC symptom phenotypes in school-age children and 3 in adolescents. Conclusions and Relevance: This study developed research indices for characterizing PASC in children and adolescents. Symptom patterns were similar but distinguishable between the 2 groups, highlighting the importance of characterizing PASC separately for these age ranges.

Multisystem Inflammatory Syndrome in U.S. Children and Adolescents.

BACKGROUND: Understanding the epidemiology and clinical course of multisystem inflammatory syndrome in children (MIS-C) and its temporal association with coronavirus disease 2019 (Covid-19) is important, given the clinical and public health implications of the syndrome. METHODS: We conducted targeted surveillance for MIS-C from March 15 to May 20, 2020, in pediatric health centers across the United States. The case definition included six criteria: serious illness leading to hospitalization, an age of less than 21 years, fever that lasted for at least 24 hours, laboratory evidence of inflammation, multisystem organ involvement, and evidence of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) based on reverse-transcriptase polymerase chain reaction (RT-PCR), antibody testing, or exposure to persons with Covid-19 in the past month. Clinicians abstracted the data onto standardized forms. RESULTS: We report on 186 patients with MIS-C in 26 states. The median age was 8.3 years, 115 patients (62%) were male, 135 (73%) had previously been healthy, 131 (70%) were positive for SARS-CoV-2 by RT-PCR or antibody testing, and 164 (88%) were hospitalized after April 16, 2020. Organ-system involvement included the gastrointestinal system in 171 patients (92%), cardiovascular in 149 (80%), hematologic in 142 (76%), mucocutaneous in 137 (74%), and respiratory in 131 (70%). The median duration of hospitalization was 7 days (interquartile range, 4 to 10); 148 patients (80%) received intensive care, 37 (20%) received mechanical ventilation, 90 (48%) received vasoactive support, and 4 (2%) died. Coronary-artery aneurysms (z scores ≥2.5) were documented in 15 patients (8%), and Kawasaki's disease-like features were documented in 74 (40%). Most patients (171 [92%]) had elevations in at least four biomarkers indicating inflammation. The use of immunomodulating therapies was common: intravenous immune globulin was used in 144 (77%), glucocorticoids in 91 (49%), and interleukin-6 or 1RA inhibitors in 38 (20%). CONCLUSIONS: Multisystem inflammatory syndrome in children associated with SARS-CoV-2 led to serious and life-threatening illness in previously healthy children and adolescents. (Funded by the Centers for Disease Control and Prevention.).

Trends in Disease Severity Among Critically Ill Children With Severe Acute Respiratory Syndrome Coronavirus 2: A Retrospective Multicenter Cohort Study in the United States.

OBJECTIVES: To describe trends in critical illness from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children over the course of the COVID-19 pandemic. We hypothesized that PICU admission rates were higher in the Omicron period compared with the original outbreak but that fewer patients needed endotracheal intubation. DESIGN: Retrospective cohort study. SETTING: This study took place in nine U.S. PICUs over 3 weeks in January 2022 (Omicron period) compared with 3 weeks in March 2020 (original period). PATIENTS: Patients less than or equal to 21 years old who screened positive for SARS-CoV-2 infection by polymerase chain reaction or hospital-based rapid antigen test and were admitted to a PICU or intermediate care unit were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 267 patients (239 Omicron and 28 original) were reviewed. Forty-five patients in the Omicron cohort had incidental SARS-CoV-2 and were excluded from analysis. The Omicron cohort patients were younger compared with the original cohort patients (median [interquartile range], 6 yr [1.3-13.3 yr] vs 14 yr [8.3-17.3 yr]; p = 0.001). The Omicron period, compared with the original period, was associated with an average increase in COVID-19-related PICU admissions of 13 patients per institution (95% CI, 6-36; p = 0.008), which represents a seven-fold increase in the absolute number admissions. We failed to identify an association between cohort period (Omicron vs original) and odds of intubation (odds ratio, 0.7; 95% CI, 0.3-1.7). However, we cannot exclude the possibility of up to 70% reduction in intubation. CONCLUSIONS: COVID-19-related PICU admissions were seven times higher in the Omicron wave compared with the original outbreak. We could not exclude the possibility of up to 70% reduction in use of intubation in the Omicron versus original epoch, which may represent differences in PICU/hospital admission policy in the later period, or pattern of disease, or possibly the impact of vaccination.

Examining child flourishing, family resilience, and adversity in the 2016 National Survey of Children's Health.

PURPOSE: Explore factors associated with flourishing and family resilience among children aged 6 months to 5 years old in the 2016 National Survey of Children's Health (NSCH). DESIGN AND METHODS: Cross-sectional analysis of the 2016 NSCH was conducted using Kleinman and Norton's Regression Risk Analysis method to derive adjusted risk measures for logistic regression models to assess factors contributing to (1) child flourishing and (2) child flourishing stratified between resilient and non-resilient families. RESULTS: In multivariable models, resilient families less often reported a child with two or more lifetime ACE exposures (ARD -0.11, 95% CI -0.15, -0.08), more likely to live in a supportive neighborhood (ARD 0.08, 95% CI 0.05,0.11), and more likely to report emotional support in raising children (ARD 0.07, 95% CI 0.12, 0.40). Accounting for ACE exposures, within resilient families, child flourishing was more likely when the child lived in a supportive neighborhood (ARD 0.09, 95% CI 0.03, 0.15), received care in a patient centered medical home (ARD 0.09, 95% CI 0.02,0.15), and when parents reported having emotional support in raising children (ARD 0.10, 95% CI 0.05, 0.17) Within non-resilient families, child flourishing was more likely when parents had emotional support in raising children (ARD 0.15, 95% CI 0.04,0.27). CONCLUSION: Promoting emotional support for parents may bolster family resilience and help young children to flourish despite adversity. PRACTICE IMPLICATIONS: Further research and innovative models of care are needed to optimize the role of pediatric primary care in promoting safe, stable, nurturing relationships and environments for children and families.

Using ICD-10 codes to identify elective epilepsy monitoring unit admissions from administrative billing data: A validation study.

Video-electroencephalogram (EEG) monitoring in the epilepsy monitoring unit (EMU) is essential for managing epilepsy and seizure mimics. Evaluation of care in the EMU would benefit from a validated code set capable of identifying EMU admissions from administrative databases comprised of large, diverse cohorts. We assessed the ability of code-based queries to parse EMU admissions from administrative billing records in a large academic medical center over a four-year period, 2016-2019. We applied prespecified queries for admissions coded as follows: 1) elective, 2) receiving video-EEG monitoring, and 3) including diagnoses typically required by major US healthcare payers for EMU admission. Sensitivity (Sn), specificity (Sp), and predictive value positive/negative (PVP, PVN) were determined. Two approaches were highly effective. Incorporating epilepsy, seizure, or seizure mimic codes as the admitting diagnosis (assigned at admission; Sn 96.3%, Sp 100.0%, PVP 98.3%, and PVN 100.0%) or the principal diagnosis (assigned after discharge; Sn 94.9%, Sp 100.0%, PVP 98.8%, and PVN 100.0%) identified elective adult EMU admissions with comparable reliability (p = 0.096). The addition of surgical procedure codes further separated EMU admissions for intracranial EEG monitoring. When applied to larger, more comprehensive datasets, these code-based queries should enhance our understanding of EMU utilization and access to care on a scalable basis.

Variation of the prevalence of pediatric polypharmacy: A scoping review.

PURPOSE: To examine the range of prevalence of pediatric polypharmacy in literature through a scoping review, focusing on factors that contribute to its heterogeneity in order to improve the design and reporting of quality improvement, pharmacovigilance, and research studies. METHODS: We searched Ovid Medline, PubMed, EMBASE, CINAHL, Ovid PsycINFO, Cochrane CENTRAL, and Web of Science Core Collection databases for studies with concepts of children and polypharmacy, along with a hand search of the bibliographies of six reviews and 30 included studies. We extracted information regarding study design, disease conditions, and prevalence of polypharmacy. RESULTS: Two hundred eighty-four studies reported prevalence of polypharmacy. They were more likely to be conducted in North America (37.7%), published after 2010 (44.4%), cross-sectional (67.3%), in outpatient settings (59.5%). Prevalence ranged from 0.9% to 98.4%, median 39.7% (interquartile range [IQR] 22.0%-54.0%). Studies from Asia reported the highest median prevalence of 45.4% (IQR 27.3%-61.0%) while studies from North America reported the lowest median prevalence of 30.4% (IQR 14.7%-50.2%). Prevalence decreased over time: median 45.6% before 2001, 38.1% during 2001 to 2010, and 34% during 2011 to 2017. Studies involving children under 12 years had a higher median prevalence (46.9%) than adolescent studies (33.7%). Inpatient setting studies had a higher median prevalence (50.3%) than studies in outpatient settings (38.8%). Community level samples, higher number and duration of medications defining polypharmacy, and psychotropic medications were associated with lower prevalence. CONCLUSIONS: The prevalence of pediatric polypharmacy is high and variable. Studies reporting pediatric polypharmacy should account for context, design, polypharmacy definition, and medications evaluated.

Outcome measures in pediatric polypharmacy research: a scoping review.

INTRODUCTION: Various methods have been used to interpret the reports of pediatric polypharmacy across the literature. This is the first scoping review that explores outcome measures in pediatric polypharmacy research. OBJECTIVES: The aim of our study was to describe outcome measures assessed in pediatric polypharmacy research. METHODS: A search of electronic databases was conducted in July 2017, including Ovid Medline, PubMed, Elsevier Embase, Wiley Cochrane Central Register of Controlled Trials (CENTRAL), EBSCO CINAHL, Ovid PsyclNFO, Web of Science Core Collection, ProQuest Dissertations and Thesis A&I. Data were extracted about study characteristics and outcome measures, and also synthesized by harms or benefits mentioned. RESULTS: The search strategy initially identified 8169 titles and screened 4398 using the inclusion criteria after de-duplicating. After the primary screening, a total of 363 studies were extracted for the data analysis. Polypharmacy (prevalence) was identified as an outcome in 31.4% of the studies, prognosis-related outcomes in 25.6%, and adverse drug reactions in 16.5%. A total of 265 articles (73.0%) mentioned harms, including adverse drug reactions (26.4%), side effects (24.2%), and drug-drug interactions (20.9%). A total of 83 studies (22.9%) mentioned any benefit, 48.2% of which identified combination for efficacy, 24.1% combination for treatment of complex diseases, and 19.3% combination for treatment augmentation. Thirty-eight studies reported adverse drug reaction as an outcome, where polypharmacy was a predictor, with various designs. CONCLUSIONS: Most studies of pediatric polypharmacy evaluate prevalence, prognosis, or adverse drug reaction-related out-comes, and underscore harms related to polypharmacy. Clinicians should carefully weigh benefits and harms when introducing medications to treatment regimens.

A transdisciplinary team approach to scoping reviews: the case of pediatric polypharmacy.

BACKGROUND: Polypharmacy can be either beneficial or harmful to children. We conducted a scoping review to examine the concept of pediatric polypharmacy: its definition, prevalence, extent and gaps in research. In this manuscript, we report our transdisciplinary scoping review methodology. METHODS: After establishing a transdisciplinary team, we iteratively developed standard operating procedures for the study's search strategy, inclusion/exclusion criteria, screening, and data extraction. We searched eight bibliographic databases, screened abstracts and full text articles, and extracted data from included studies using standardized forms. We held regular team meetings and performed ongoing internal validity measurements to maintain consistent and quality outputs. RESULTS: With the aid of EPPI Reviewer collaborative software, our transdisciplinary team of nine members performed dual reviews of 363 included studies after dual screening of 4398 abstracts and 1082 full text articles. We achieved overall agreement of 85% and a kappa coefficient of 0.71 (95% CI 0.68-0.74) while screening full text articles. The screening and review processes required about seven hours per extracted study. The two pharmacists, an epidemiologist, a neurologist, and a librarian on the review team provided internal consultation in these key disciplines. A stakeholder group of 10 members with expertise in evidence synthesis, research implementation, pediatrics, mental health, epilepsy, pharmacoepidemiology, and pharmaceutical outcomes were periodically consulted to further characterize pediatric polypharmacy. CONCLUSIONS: A transdisciplinary approach to scoping reviews, including internal and external consultation, should be considered when addressing complex cross-disciplinary questions.

Are Parental Perceptions of Child Activity Levels and Overall Health More Important than Perceptions of Weight?

Objectives To examine relationships between parental perceptions of child weight and overall health, reported lifestyle behaviors and measured body mass index (BMI). Methods Using community-partnered methods, we surveyed families residing in a two census tract area identified for targeted interventions to decrease diabetes related disparities. The survey included demographics, child dietary and physical activity behaviors, and parental perception of child's health and weight. We measured child BMI using a standardized protocol. Results We surveyed parents of 116 children with a mean age of 7 years (range 3-15) with 51 % boys, 74 % Hispanic, and 26 % Black. Over half of the children (55 %) were overweight or obese. Half (50 %) of the parents underestimated their children's weight. Reported daily hours of walking and/or running trended higher (3.6 vs. 2.6 h, p = 0.08) for children perceived to be of normal weight. Parents who correctly estimated their child's weight status reported more hours of daily walking/running than parents who underestimated child weight status, 4.5 versus 2.4 h, p = 0.0002. Parents of healthy weight children were more likely to report that children were in excellent or very good health compared to parents of overweight/obese children, 75 versus 56 % respectively (p = 0.04). We found significant racial/ethnic differences in reported diet and physical activity behaviors and perception of overall health. Conclusions for Practice Parental perceptions of child health and physical activity level may be related to perceptions of their child's weight status. Study findings informed community-based initiatives for reducing diabetes risk among children.

Voices of multi-ethnic providers in NYC: health care for viral hepatitis to prevent hepatocellular carcinoma.

Worldwide, hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths and the ninth in the US. Hepatitis B and C make up almost 80% of HCC cases. Based on our Hepatitis Outreach Network screening program data, approximately 40% of at-risk foreign-born community members who tested positive for viral hepatitis B and/or C did not follow up for additional care. Our aim was to use theory-driven qualitative research to identify barriers and facilitators to follow-up after viral hepatitis diagnosis among these community members from the viewpoint of primary care providers (PCPs). As viral hepatitis is a precursor of liver cancer, timely treatment of the virus has the potential to reduce the incidence and burden of liver cancer. We performed semi-structured key informant interviews with 20 primary care physicians who predominantly serve Korean, Chinese, Egyptian, and Russian communities. Barriers detected included cultural factors commonly seen amongst immigrant populations such as busy work schedules and non-English language. Common facilitators include increased primary care physician involvement and linkages to care within communities in which patients reside. Providers perceived that they are gatekeepers to specialty care for their patients and therefore key persons to engage in viral hepatitis evaluation and management by specialists. This initial study suggests that re-focusing energy into primary care physicians might offer promise for improved care for individuals from immigrant communities who have viral hepatitis to help them engage in care and thereby reduce the burden of liver cancer.

Prevalence of contraindicated combinations amid behavioral and mental health medications filled in a pediatric population.

BACKGROUND: Behavioral or mental health disorders are common in children, adolescents, and young adults. Medication use is increasingly common, with few data describing drug-drug combinations in ambulatory settings. The objectives of this study were to describe the pharmaco-epidemiology of behavioral and mental health (BMH) medications among children, adolescents, and young adults in New York Medicaid and assess the prevalence of contraindicated drug pairs within this population. METHODS: This observational cross-sectional study evaluated New York State Medicaid managed care and fee-for-service enrollees under 21 years of age dispensed BMH medications in 2014. Main outcomes included number of members with prescriptions filled; number filling > 1 medication prescription concurrently for ≥ 30 days (polypharmacy), and number and nature of potentially contraindicated drug pairs. RESULTS: Of 2,430,434 children, adolescents, and young adults, 422,486 (17.4%) had a visit associated with a BMH diagnosis and 141,363 (5.8%) received one or more BMH medications. With 84 distinct medications evaluated, polypharmacy was common, experienced by 53,388 individuals (37.8% of those with a prescription filled), generating 11,115 distinct drug combinations. 392 individuals filled prescriptions for a contraindicated pair of ≥ 2 BMH medications for 30 days or longer. With ≥ 1 day overlap, 651 were exposed to contraindicated medications. The most common contraindicated pairs increased potential risk for prolonged QT interval and serotonin syndrome (n = 378 and n = 250 patients, respectively). Most combinations involved ziprasidone (3247.1 per 10,000 ziprasidone prescriptions filled). CONCLUSIONS: With nearly 6% of members dispensed a BMH medication, contraindicated drug pairs were uncommon. However, any of those combinations represent a potential risk. Clinicians should attend to the balance of potential risks and benefits before contraindicated pairs are dispensed. The methodology described could serve as a basis for monitoring such rare instances and might reduce harm.

A genetically modulated Toll-like-receptor-tolerant phenotype in peripheral blood cells of children with multisystem inflammatory syndrome.

Dysregulated innate immune responses contribute to multisystem inflammatory syndrome in children (MIS-C), characterized by gastrointestinal, mucocutaneous, and/or cardiovascular injury occurring weeks after SARS-CoV-2 exposure. To investigate innate immune functions in MIS-C, we stimulated ex vivo peripheral blood cells from MIS-C patients with agonists of Toll-like receptors (TLR), key innate immune response initiators. We found severely dampened cytokine responses and elevated gene expression of negative regulators of TLR signaling. Increased plasma levels of zonulin, a gut leakage marker, were also detected. These effects were also observed in children enrolled months after MIS-C recovery. Moreover, cells from MIS-C children carrying rare genetic variants of lysosomal trafficking regulator (LYST) were less refractory to TLR stimulation and exhibited lysosomal and mitochondrial abnormalities with altered energy metabolism. Our results strongly suggest that MIS-C hyperinflammation and/or excessive or prolonged stimulation with gut-originated TLR ligands drive immune cells to a lasting refractory state. TLR hyporesponsiveness is likely beneficial, as suggested by excess lymphopenia among rare LYST variant carriers. Our findings point to cellular mechanisms underlying TLR hyporesponsiveness; identify genetic determinants that may explain the MIS-C clinical spectrum; suggest potential associations between innate refractory states and long COVID; and highlight the need to monitor long-term consequences of MIS-C.

Researching COVID to enhance recovery (RECOVER) pediatric study protocol: Rationale, objectives and design.

IMPORTANCE: The prevalence, pathophysiology, and long-term outcomes of COVID-19 (post-acute sequelae of SARS-CoV-2 [PASC] or "Long COVID") in children and young adults remain unknown. Studies must address the urgent need to define PASC, its mechanisms, and potential treatment targets in children and young adults. OBSERVATIONS: We describe the protocol for the Pediatric Observational Cohort Study of the NIH's REsearching COVID to Enhance Recovery (RECOVER) Initiative. RECOVER-Pediatrics is an observational meta-cohort study of caregiver-child pairs (birth through 17 years) and young adults (18 through 25 years), recruited from more than 100 sites across the US. This report focuses on two of four cohorts that comprise RECOVER-Pediatrics: 1) a de novo RECOVER prospective cohort of children and young adults with and without previous or current infection; and 2) an extant cohort derived from the Adolescent Brain Cognitive Development (ABCD) study (n = 10,000). The de novo cohort incorporates three tiers of data collection: 1) remote baseline assessments (Tier 1, n = 6000); 2) longitudinal follow-up for up to 4 years (Tier 2, n = 6000); and 3) a subset of participants, primarily the most severely affected by PASC, who will undergo deep phenotyping to explore PASC pathophysiology (Tier 3, n = 600). Youth enrolled in the ABCD study participate in Tier 1. The pediatric protocol was developed as a collaborative partnership of investigators, patients, researchers, clinicians, community partners, and federal partners, intentionally promoting inclusivity and diversity. The protocol is adaptive to facilitate responses to emerging science. CONCLUSIONS AND RELEVANCE: RECOVER-Pediatrics seeks to characterize the clinical course, underlying mechanisms, and long-term effects of PASC from birth through 25 years old. RECOVER-Pediatrics is designed to elucidate the epidemiology, four-year clinical course, and sociodemographic correlates of pediatric PASC. The data and biosamples will allow examination of mechanistic hypotheses and biomarkers, thus providing insights into potential therapeutic interventions. CLINICAL TRIALS.GOV IDENTIFIER: Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT05172011.

Child Opportunity Index and Hospital Utilization in Children With Traumatic Brain Injury Admitted to the PICU.

The need to understand how Community-based disparities impact morbidity and mortality in pediatric critical illness, such as traumatic brain injury. Test the hypothesis that ZIP code-based disparities in hospital utilization, including length of stay (LOS) and hospital costs, exist in a cohort of children with traumatic brain injury (TBI) admitted to a PICU using the Child Opportunity Index (COI). DESIGN: Multicenter retrospective cohort study. SETTING: Pediatric Health Information System (PHIS) database. PATIENTS: Children 0-18 years old admitted to a PHIS hospital with a diagnosis of TBI from January 2016 to December 2020 requiring PICU care. To identify the most severely injured children, a study-specific definition of "Complicated TBI" was created based on radiology, pharmacy, and procedure codes. INTERVENTIONS: None. Main Outcomes and Measures: Using nationally normed ZIP code-level COI data, patients were categorized into COI quintiles. A low COI ZIP code has low childhood opportunity based on weighted indicators within educational, health and environmental, and social and economic domains. Population-averaged generalized estimating equation (GEE) models, adjusted for patient and clinical characteristics examined the association between COI and study outcomes, including hospital LOS and accrued hospital costs. The median age of this cohort of 8,055 children was 58 months (interquartile range [IQR], 8-145 mo). There were differences in patient demographics and rates of Complicated TBI between COI levels. The median hospital LOS was 3.0 days (IQR, 2.0-6.0 d) and in population-averaged GEE models, children living in very low COI ZIP codes were expected to have a hospital LOS 10.2% (95% CI, 4.1-16.8%; p = 0.0142) longer than children living in very high COI ZIP codes. For the 11% of children with a Complicated TBI, the relationship between COI and LOS was lost in multivariable models. COI level was not predictive of accrued hospital costs in this study. CONCLUSIONS: Children with TBI requiring PICU care living in low-opportunity ZIP codes have higher injury severity and longer hospital LOS compared with children living in higher-opportunity ZIP codes. Additional studies are needed to understand why these differences exist.

Researching COVID to enhance recovery (RECOVER) pediatric study protocol: Rationale, objectives and design.

Importance: The prevalence, pathophysiology, and long-term outcomes of COVID-19 (post-acute sequelae of SARS-CoV-2 [PASC] or "Long COVID") in children and young adults remain unknown. Studies must address the urgent need to define PASC, its mechanisms, and potential treatment targets in children and young adults. Observations: We describe the protocol for the Pediatric Observational Cohort Study of the NIH's RE searching COV ID to E nhance R ecovery (RECOVER) Initiative. RECOVER-Pediatrics is an observational meta-cohort study of caregiver-child pairs (birth through 17 years) and young adults (18 through 25 years), recruited from more than 100 sites across the US. This report focuses on two of five cohorts that comprise RECOVER-Pediatrics: 1) a de novo RECOVER prospective cohort of children and young adults with and without previous or current infection; and 2) an extant cohort derived from the Adolescent Brain Cognitive Development (ABCD) study ( n =10,000). The de novo cohort incorporates three tiers of data collection: 1) remote baseline assessments (Tier 1, n=6000); 2) longitudinal follow-up for up to 4 years (Tier 2, n=6000); and 3) a subset of participants, primarily the most severely affected by PASC, who will undergo deep phenotyping to explore PASC pathophysiology (Tier 3, n=600). Youth enrolled in the ABCD study participate in Tier 1. The pediatric protocol was developed as a collaborative partnership of investigators, patients, researchers, clinicians, community partners, and federal partners, intentionally promoting inclusivity and diversity. The protocol is adaptive to facilitate responses to emerging science. Conclusions and Relevance: RECOVER-Pediatrics seeks to characterize the clinical course, underlying mechanisms, and long-term effects of PASC from birth through 25 years old. RECOVER-Pediatrics is designed to elucidate the epidemiology, four-year clinical course, and sociodemographic correlates of pediatric PASC. The data and biosamples will allow examination of mechanistic hypotheses and biomarkers, thus providing insights into potential therapeutic interventions. Clinical Trialsgov Identifier: Clinical Trial Registration: http://www.clinicaltrials.gov . Unique identifier: NCT05172011.

Predicting risk for death from MRSA bacteremia.

Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is often fatal. To determine predictors of risk for death, we conducted a retrospective cohort study. We examined 699 episodes of MRSA bacteremia involving 603 patients admitted to an academic medical center in New York City during 2002-2007. Data came from chart reviews, hospital databases, and recultured frozen MRSA specimens. Among the 699 episodes, 55 were caused by vancomycin-intermediate resistant S. aureus strains, 55 by heteroresistant vancomycin-intermediate S. aureus strains, and 589 by non-vancomycin-resistant strains; 190 (31.5%) patients died. We used regression risk analysis to quantify the association between clinical correlates and death. We found that older age, residence in a nursing home, severe bacteremia, and organ impairment were independently associated with increased risk for death; consultation with an infectious disease specialist was associated with lower risk for death; and MRSA strain types were not associated with risk for death.

Rank reversal in indirect comparisons.

OBJECTIVE: To describe rank reversal as a source of inconsistent interpretation intrinsic to indirect comparison (Bucher HC, Guyatt GH, Griffith LE, Walter SD. The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials. J Clin Epi 1997;50:683-91) of treatments and to propose best practice. METHODS: We prove our main points with intuition, examples, graphs, and mathematical proofs. We also provide software and discuss implications for research and policy. RESULTS: When comparing treatments by indirect means and sorting them by effect size, three common measures of comparison (risk ratio, risk difference, and odds ratio) may lead to vastly different rankings. CONCLUSIONS: The choice of risk measure matters when making indirect comparisons of treatments. The choice should depend primarily on the study design and the conceptual framework for that study.

Weekend Versus Weekday Asthma-Related Emergency Department Utilization.

OBJECTIVE: To assess variation in asthma-related emergency department (ED) use between weekends and weekdays. METHODS: Cross-sectional administrative claims-based analysis using California 2016 Medicaid data and Vermont 2016 and Massachusetts 2015 all-payer claims databases. We defined ED use as the rate of asthma-related ED visits per 100 child-years. A weekend visit was a visit on Saturday or Sunday, based on date of ED visit claim. We used negative binomial regression and robust standard errors to assess variation between weekend and weekday rates, overall and by age group. RESULTS: We evaluated data from 398,537 patients with asthma. The asthma-related ED visit rate was slightly lower on weekends (weekend: 18.7 [95% confidence interval (CI): 18.3-19.0], weekday: 19.6 [95% CI, 19.3-19.8], P < .001). When stratifying by age group, 3- to 5-year-olds had higher rates of asthma-related ED visits on weekends than weekdays (weekend: 33.7 [95% CI, 32.6-34.7], weekday: 29.8 [95% CI, 29.1-30.5], P < .001) and 12- to 17-year-olds had lower rates of ED visits on weekends than weekdays (weekend: 13.0 [95% CI: 12.5-13.4], weekday: 16.3 [95% CI: 15.9-16.7], P < .001). In the other age groups (6-11, 18-21 years) there were not statistically significant differences between weekend and weekday rates (P > .05). CONCLUSIONS: In this multistate analysis of children with asthma, we found limited overall variation in pediatric asthma-related ED utilization on weekends versus weekdays. These findings suggest that increasing access options during the weekend may not necessarily decrease asthma-related ED use.