Evolution of the Antigenic Landscape in Children and Young Adults with COVID-19 and MIS-C.

There is minimal knowledge regarding the durability of neutralization capacity and level of binding antibody generated against the highly transmissible circulating Omicron subvariants following SARS-CoV-2 infection in children with acute COVID-19 and those diagnosed with multisystem inflammatory syndrome in children (MIS-C) in the absence of vaccination. In this study, SARS-CoV-2 neutralization titers against the ancestral strain (WA1) and Omicron sublineages were evaluated in unvaccinated children admitted for COVID-19 (n = 32) and MIS-C (n = 32) at the time of hospitalization (baseline) and at six to eight weeks post-discharge (follow-up) between 1 April 2020, and 1 September 2022. In addition, antibody binding to the spike receptor binding domain (RBD) from WA1, BA.1, BA.2.75, and BA.4/BA.5 was determined using surface plasmon resonance (SPR). At baseline, the children with MIS-C demonstrated two-fold to three-fold higher binding and neutralizing antibodies against ancestral WA1 compared to those with COVID-19. Importantly, in children with COVID-19, the virus neutralization titers against the Omicron subvariants at six to eight weeks post-discharge reached the same level as those with MIS-C had at baseline but were higher than titers at 6-8 weeks post-discharge for MIS-C cases. Cross-neutralization capacity against recently emerged Omicron BQ.1, BQ.1.1, and XBB.1 variants was very low in children with either COVID-19 or MIS-C at all time points. These findings about post-infection immunity in children with either COVID-19 or MIS-C suggest the need for vaccinations in children with prior COVID-19 or MIS-C to provide effective protection from emerging and circulating SARS-CoV-2 variants.

Inflammatory and Autoimmune Aspects of Multisystem Inflammatory Syndrome in Children (MIS-C): A Prospective Cohort Study.

Multisystem Inflammatory Syndrome in Children (MIS-C) is a potentially life-threatening complication of COVID-19. The pathophysiological mechanisms leading to severe disease are poorly understood. This study leveraged clinical samples from a well-characterized cohort of children hospitalized with COVID-19 or MIS-C to compare immune-mediated biomarkers. Our objective was to identify selected immune molecules that could explain, in part, why certain SARS-CoV-2-infected children developed MIS-C. We hypothesized that type-2 helper T cell-mediated inflammation can elicit autoantibodies, which may account for some of the differences observed between the moderate-severe COVID-19 (COVID+) and MIS-C cohort. We enumerated blood leukocytes and measured levels of selected serum cytokines, chemokines, antibodies to COVID-19 antigens, and autoantibodies in children presenting to an academic medical center in Connecticut, United States. The neutrophil/lymphocyte and eosinophil/lymphocyte ratios were significantly higher in those in the MIS-C versus COVID+ cohort. IgM and IgA, but not IgG antibodies to SARS-CoV-2 receptor binding domain were significantly higher in the MIS-C cohort than the COVID+ cohort. The serum levels of certain type-2 cytokines (interleukin (IL)-4, IL-5, IL-6, IL-8, IL-10, IL-13, and IL-33) were significantly higher in children with MIS-C compared to the COVID+ and SARS-CoV-2-negative cohorts. IgG autoantibodies to brain antigens and pentraxin were higher in children with MIS-C compared to SARS-CoV-19-negative controls, and children with MIS-C had higher levels of IgG anti-contactin-associated protein-like 2 (caspr2) compared to the COVID+ and SARS-CoV-19-negative controls. We speculate that autoimmune responses in certain COVID-19 patients may induce pathophysiological changes that lead to MIS-C. The triggers of autoimmunity and factors accounting for type-2 inflammation require further investigation.

Going Viral: Assessing the Impact of Social Media on Enrollment in a Coronavirus Disease 2019 (COVID-19) Cohort Study.

Objective This study aimed to quantify the effect of social media posts on study enrollment among children with mild coronavirus disease 2019 (COVID-19). Methods The primary outcome was weekly study enrollments analyzed using a run chart. A secondary analysis used linear regression to assess study enrollments two days before and after a social media post, adjusted for the statewide pediatric seven-day-average severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) case rate, social media posting day, and the interaction of these two variables. Results In seven months before social media posting, only eight patients were enrolled. One week after social media posting began, the median weekly enrollment increased (0 to 3). In the regression model, neither social media post day nor the pediatric SARS-CoV-2 case rate was significantly associated with enrollment rate. However, the interaction of a post day and the pediatric case rate was significant. Conclusion Social media posts significantly increased enrollment among children with mild COVID-19 in a prospective study. This effect was amplified by the presence of high community case rates during the Omicron wave.

The importance of animal specificity in animal experimentation, part I: Anatomy in relation to pediatric urology.

Why and when is animal experimentation relevant? The answer to this question depends on the research question. In this short educational article we aim to raise awareness of the importance of formulating a very specific research question before choosing an animal species. An awareness of anatomical and physiological differences vis-a-vis similarities between species, will increase the potential for obtaining data that is relevant for translation to human conditions.

The importance of animal specificity in animal experimentation, part II: Physiological challenges and opportunities in relation to pediatric urology.

When performing animal experimentation in Pediatric Urology studies, it is important to be aware of physiological differences between species and to understand when relevant disease models are available. Diseased animal models may be more relevant in many cases, rather than performing studies in healthy and normally developed animals. For example, they may be more appropriate for the study of congenital malformations, to investigate the secondary effects of prenatal urinary obstruction, to study the effect of prenatal exposure to endogenous or exogenous factors which may lead to disease, or in testing bioengineered structures. In this short educational article, we aim to describe some disease models that have been used to simulate human pathologies and how, if properly designed, these studies can lead to important new knowledge for human translation. In addition, we also highlight the importance of formulating a research question(s) before deciding on the animal experimental model and species to choose.

Development of a biomarker signature using grating-coupled fluorescence plasmonic microarray for diagnosis of MIS-C.

Multisystem inflammatory syndrome in children (MIS-C) is a rare but serious condition that can develop 4-6 weeks after a school age child becomes infected by SARS-CoV-2. To date, in the United States more than 8,862 cases of MIS-C have been identified and 72 deaths have occurred. This syndrome typically affects children between the ages of 5-13; 57% are Hispanic/Latino/Black/non-Hispanic, 61% of patients are males and 100% have either tested positive for SARS-CoV-2 or had direct contact with someone with COVID-19. Unfortunately, diagnosis of MIS-C is difficult, and delayed diagnosis can lead to cardiogenic shock, intensive care admission, and prolonged hospitalization. There is no validated biomarker for the rapid diagnosis of MIS-C. In this study, we used Grating-coupled Fluorescence Plasmonic (GCFP) microarray technology to develop biomarker signatures in pediatric salvia and serum samples from patients with MIS-C in the United States and Colombia. GCFP measures antibody-antigen interactions at individual regions of interest (ROIs) on a gold-coated diffraction grating sensor chip in a sandwich immunoassay to generate a fluorescent signal based on analyte presence within a sample. Using a microarray printer, we designed a first-generation biosensor chip with the capability of capturing 33 different analytes from 80  µ L of sample (saliva or serum). Here, we show potential biomarker signatures in both saliva and serum samples in six patient cohorts. In saliva samples, we noted occasional analyte outliers on the chip within individual samples and were able to compare those samples to 16S RNA microbiome data. These comparisons indicate differences in relative abundance of oral pathogens within those patients. Microsphere Immunoassay (MIA) of immunoglobulin isotypes was also performed on serum samples and revealed MIS-C patients had several COVID antigen-specific immunoglobulins that were significantly higher than other cohorts, thus identifying potential new targets for the second-generation biosensor chip. MIA also identified additional biomarkers for our second-generation chip, verified biomarker signatures generated on the first-generation chip, and aided in second-generation chip optimization. Interestingly, MIS-C samples from the United States had a more diverse and robust signature than the Colombian samples, which was also illustrated in the MIA cytokine data. These observations identify new MIS-C biomarkers and biomarker signatures for each of the cohorts. Ultimately, these tools may represent a potential diagnostic tool for use in the rapid identification of MIS-C.

Continuous antibiotic prophylaxis in isolated prenatal hydronephrosis.

BACKGROUND: Prenatal hydronephrosis (PNH) is one of the most common congenital anomalies and can increase the risk of developing a urinary tract infection (UTI) in the first two years of life. Continuous antibiotic prophylaxis (CAP) has been recommended empirically to prevent UTI in children with PNH, but its use has been controversial. OBJECTIVE: We describe the incidence of UTI in children with isolated PNH of the renal pelvis without ureteral dilation. Our objective was to compare patients receiving and not receiving CAP and determine whether CAP is beneficial at preventing UTI in children with isolated PNH. STUDY DESIGN: Children with confirmed PNH were enrolled between 2008 and 2020 into the Society for Fetal Urology Hydronephrosis Registry. Children with isolated dilation of the renal pelvis without ureteral or bladder abnormality were included. The primary outcome was development of a UTI, comparing patients who were prescribed and not prescribed CAP. RESULTS: In this cohort of 801 children, 76% were male, and 35% had high grade hydronephrosis (SFU grades 3-4). CAP was prescribed in 34% of children. The UTI rate among all children with isolated PNH was 4.2%. Independent predictors of UTI were female sex (HR = 13, 95% CI: 3.8-40, p = 0.0001), intact prepuce (HR = 5.1, 95% CI: 1.4-18, p = 0.01) and high grade hydronephrosis (HR = 2.0, 95% CI: 0.99-4.0, p = 0.05; Table) on multivariable analysis. For patients on CAP, the UTI rate was 4.0% compared to 4.3% without CAP (p = 0.76). The risk of UTI during follow-up was not significantly different between patients who received CAP and patients who were not exposed to CAP; adjusting for sex, circumcision status and hydronephrosis grade (HR = 0.72, 95% CI: 0.34-1.5, p = 0.38). In sub-group analysis of patients at higher risk of UTI (uncircumcised males, females and high grade hydronephrosis), CAP use was not associated with a statistically significant reduction in UTI. CONCLUSIONS: The overall UTI rate in children with isolated PNH is very low at 4.2%. In the overall population of patients with isolated PNH, CAP was not associated with reduction in UTI risk, although the limitations in our study make characterizing CAP effectiveness difficult. Clinicians should consider risk factors prior to placing all patients with isolated PNH on CAP.

Kawasaki Disease Hospitalizations in the United States 2016-2020: A Comparison of Before and During the Coronavirus Disease 2019 Era.

BACKGROUND: Kawasaki disease (KD) is an acute vasculitis of young children. A comparison of US hospitalization rates and epidemiologic features of KD in 2020 to those of precoronavirus disease years has yet to be reported. METHODS: Using a large, inpatient database, we conducted a retrospective cohort study and analyzed data for patients with (1) diagnosis coding for KD, (2) IV immunoglobulin treatment administered during hospitalization and (3) discharge date between January 1, 2016, and December 30, 2020. Severe cases were defined as those requiring adjunctive therapy or IV immunoglobulin-resistant therapy. RESULTS: The annual number of KD hospitalizations were stable from 2016 to 2019 (n = 1652, 1796, 1748, 1692, respectively) but decreased in 2020 (n = 1383). KD hospitalizations demonstrated seasonal variation with an annual peak between December and April. A second peak of KD admissions was observed in May 2020. The proportion of KD cases classified as severe increased to 40% in 2020 from 33% during the years 2016-2019 (P < 0.01). Median age in years increased from 2.9 in subjects hospitalized from 2016 to 2019 to 3.2 in 2020 (P = 0.002). CONCLUSIONS: Compared with the previous 4 years, the annual number of pediatric KD admissions decreased, and children discharged with diagnostic codes for KD in 2020 were generally older and more likely to have severe morbidity possibly reflective of misdiagnosed multisystem inflammatory syndrome in children. Clinicians should be wary of a possible rise in KD rates in the postcoronavirus disease 2019 era as social distancing policies are lifted and other viruses associated with KD return.

Sample Size, Power, and Risk of Misclassification in Pediatric Urology Hospital Rankings.

PURPOSE: We investigated 2019 and 2020 U.S. News & World Report methodologies of assessing pediatric urology surgical revision rates for distal hypospadias, pyeloplasty, and ureteral reimplantation to evaluate statistical power and misclassification risks. MATERIALS AND METHODS: Median annual volumes of distal hypospadias, pyeloplasty, and ureteral reimplantation procedures by hospital from 2016 to 2018 were calculated using the Pediatric Health Information System® database. U.S. News & World Report 2019 and 2020 methodologies were assessed to calculate power required to detect differences between hospitals and risk of hospital misclassifications. RESULTS: Median (IQR) annual hospital procedure volume was 72 (43-97) for distal hypospadias procedures, 19 (9-34) for pyeloplasties, and 35 (19-50) for ureteral reimplantations. Based on 2019 methodology, in order to achieve 80% power 764 cases/hospital are required to distinguish between a 1% vs 3% surgical revision rate, 1,500 cases/hospital are required to distinguish between a 3% vs 5% revision rate, and 282 cases/hospital are required to distinguish between a 1% vs 5% revision rate. Based on 2020 methodology, 98.0% of hospitals do not have adequate ureteral reimplantation volume to achieve full points even when reporting no revisions; similarly, 66.0% do not have adequate pyeloplasty volume, and 10.9% do not have adequate distal hypospadias volume. Risks of misclassification exceed 50% in several instances among hospitals reporting distal hypospadias and pyeloplasty revisions using both 2019 and 2020 methodology. CONCLUSIONS: Based on median-volume hospitals, current U.S. News & World Report methods for classifying revision rates for distal hypospadias, pyeloplasty, and ureteral reimplantation have insufficient power and are at high risk for misclassification.

How to more effectively determine what is true: The limits of intuition.

The plethora of scientific data and explosion of published materials often leave it challenging to develop a clear and concise overview of many scientific topics. A number of factors may contribute to our misunderstanding. It is the focus of this article to describe primary reasons for failure to establish a clear, factual and functional understanding regarding scientific areas of inquiry.

Parental perception of bladder spasms and hematuria after surgery for vesicoureteral reflux: A prospective multicenter study.

INTRODUCTION: Anti-reflux surgery success has been well-documented in the literature. Little data exists about the characterization of the child's symptoms regarding pain, bladder spasms, and hematuria following these procedures. These symptoms may affect the choice of surgery for families and providers. OBJECTIVE: To characterize parent's perception of recovery from surgery and preparedness for recovery from surgery. We hypothesized that parents of children undergoing open intravesical reimplantation (Open) would report a higher incidence of bladder spasms and hematuria compared to children undergoing robotic extravesical reimplantation (RALR) or endoscopic treatment (DxHA). STUDY DESIGN: A 20-question survey was developed to assess perception of recovery preparedness, pain, and symptoms. Parents completed the survey at a follow-up visit occurring 3-6 weeks post-discharge. Chi-square and t-test or their non-parametric equivalents were used for between-group comparisons. RESULTS: Participating were three institutions and eleven surgeons. Eighty-four parents completed the survey a median of 33 days (IQR 27-40) post-surgery. More parents reported bladder spasms and hematuria in the Open group vs RALR and DxHA. Although there was no difference in maximum bladder spasm pain, duration of pain medication for spasms was longer with Open vs RALR. Most parents (87%) reported they were prepared for their child's symptoms after surgery. Approximately one-quarter of parents whose child underwent Open (33%) or RALR (36%) reported the bladder spasms were more painful than expected, and almost half of parents whose child underwent Open (49%) reported hematuria was worse than expected. DISCUSSION: We found that Open had significantly worse parental reports of bladder spasms, pain medication usage, and severity of hematuria than RALR and DxHA. Although most parents said they were prepared for their child's recovery, many reported the symptoms were worse than expected. These contradictions may reflect a need for improved physician to parent communication when discussing anti-reflux surgery.

Further medical experience will be required to validate these results: How experience -based medicine shapes the validity of medical evidence.

This communication contextualizes the importance of clinical experience or experience-based medicine within the current paradigm of evidence-based medicine, complementing our previously published series of five short educational articles on evidence-based medicine. Previously we focused on optimizing medical decisions using publications of well-conducted research. Previous commentaries included a backgrounder, the hierarchy of evidence, data acquisition, tools for critical appraisal, and clinical use of evidence based medicine.

Survival and Kidney Outcomes of Children with an Early Diagnosis of Posterior Urethral Valves.

BACKGROUND AND OBJECTIVES: Posterior urethral valve is the most common cause of bladder outlet obstruction in infants. We aimed to describe the rate and timing of kidney-related and survival outcomes for children diagnosed with posterior urethral valves in United States children's hospitals using the Pediatric Health Information System database. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This retrospective cohort study included children hospitalized between January 1, 1992 and December 31, 2006, who were in their first year of life, had a diagnosis of congenital urethral stenosis, and underwent endoscopic valve ablation or urinary drainage intervention, or died. Records were searched up to December 31, 2018 for kidney-related mortality, placement of a dialysis catheter, and kidney transplantation. Cox regression analysis was used to identify risk factors, and Kaplan-Meier survival analysis used to determine time-to-event probability. Subgroup survival analysis was performed with outcomes stratified by the strongest identified risk factor. RESULTS: Included were 685 children hospitalized at a median age of 7 (interquartile range, 1-37) days. Thirty four children (5%) died, over half during their initial hospitalization. Pulmonary hypoplasia was the strongest risk factor for death (hazard ratio, 7.5; 95% confidence interval [95% CI], 3.3 to 17.0). Ten-year survival probability was 94%. Fifty-nine children (9%) underwent one or more dialysis catheter placements. Children with kidney dysplasia had over four-fold risk of dialysis catheter placement (hazard ratio, 4.6; 95% CI, 2.6 to 8.1). Thirty-six (7%) children underwent kidney transplant at a median age of 3 (interquartile range, 2-8) years. Kidney dysplasia had a nine-fold higher risk of kidney transplant (hazard ratio, 9.5; 95% CI, 4.1 to 22.2). CONCLUSIONS: Patients in this multicenter cohort with posterior urethral valves had a 5% risk of death, and were most likely to die during their initial hospitalization. Risk of death was higher with a diagnosis of pulmonary hypoplasia. Kidney dysplasia was associated with a higher risk of need for dialysis/transplant. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_10_03_CJN04350419.mp3.

Current treatment of pediatric bladder and prostate rhabdomyosarcoma (bladder preserving vs. radical cystectomy).

PURPOSE OF REVIEW: To discuss alternative strategies for multimodal treatments of nonmetastatic bladder-prostate rhabdomyosarcoma performed with the aim of preserving organ function. RECENT FINDINGS: Bladder-prostate rhabdomyosarcomas are seldom fully resectable at presentation or after induction chemotherapy, and extensive resection might not improve survival. When an organ-sparing approach is pursued, radiotherapy might be unavoidable to achieve reliable local control of the disease. Benefits of preoperative vs. postoperative radiotherapy have yet to be investigated. Multimodal treatments may often result in bladder function impairment and erectile dysfunction. To reduce long-term side effects of radiotherapy, irradiation modalities allowing for more targeted treatment should be favoured. For this purpose, external beam proton therapy or nonradical surgery associated with brachytherapy may be viable options. Nevertheless, experience with these treatments is still limited. Advancements in lower urinary tract reconstruction make preservation of volitional voiding and erectile function possible after cystoprostatectomy. But in the context of multimodal treatment, cystoprostatectomy is reserved to patients who respond poorly to other treatments. SUMMARY: For the vast majority of bladder-prostate rhabdomyosarcoma, we believe that reliable local control of disease can only be achieved with the use of radiotherapy. Efforts should be made to find the best modality for targeted radiotherapy. Further studies are required to compare preoperative vs. postoperative radiotherapy and the best dose to be administered in order to reduce long-term side effects. If creation of an orthotopic continent diversion is deemed appropriate in patients undergoing cystoprostatectomy, it should be performed concurrently with extirpative surgery.

The recent evolution of the breadth of practice for pediatric surgeons in the United States, 2005-2014.

PURPOSE: Our objective was to determine if there was an association between subspecialist supply and a specific sub-set of procedures performed by pediatric surgeons over a 10-year period. METHODS: Data source was the Pediatric Health Information Systems database. Included were patients < 12 years who underwent one of nine outpatient surgical procedures between 1/1/2005 and 12/31/2014. Procedures were grouped into categories: pediatric surgery cases (PS), overlapping otolaryngology cases (OO), and overlapping urology cases (OU). Outcomes were number of cases performed by pediatric surgeons per pediatric surgeon, and proportion of cases performed by pediatric surgeons. Linear regression was used to test for association and temporal trends. RESULTS: Included were 193,695 procedures, 18.9% PS, 4.8% OO, and 76.3% OU. There was a strong association between specialty supply and number of cases performed by pediatric surgeons. Temporally, there was no change in proportion of pediatric surgeons who performed PS cases (R2 = 0.08, p = 0.08), but a downward trend in proportion of OO (R2 = 0.82, p < 0.001) and OU cases. (R2 = 0.79; p < 0.001.) CONCLUSION: We found an association between physician supply and pediatric surgeon case type, and a reduction in OO and OU cases performed by pediatric surgeons. These findings suggest a narrowing of case-mix for pediatric surgeons.

Role of urinary tract infection in bladder cancer: a systematic review and meta-analysis.

PURPOSE: We sought to examine the literature reporting the effect of urinary tract infection (UTI) on non-schistosomiasis-related UBC (UBCNS) through a systematic review and meta-analysis. METHODS: A predefined study protocol was developed according to PRISMA. Medline and Scopus were searched for all studies investigating exposure to UTI with UBCNS as the primary outcome. Potential studies were screened against eligibility criteria. Clinical heterogeneity was assessed and groups with more than two studies were evaluated by random effect meta-analysis. Study-level bias was assessed with the Newcastle-Ottawa Scale (NOS). In cases of substantial between study heterogeneity (I2 > 50%), predefined sensitivity and subgroup analyses were performed. RESULTS: Of 16 eligible studies, eight case-control studies spanning four decades and five countries were suitable for quantitative analysis. Main analysis favored exposure to UTI increasing risk of subsequent UBCNS (RR 1.33 [95% CI 1.14-1.55]). This effect was no longer statistically significant after excluding studies published prior to year 2000 and at high risk of bias. Between study heterogeneity was considerable for nearly all analyses and not reduced by predefined sensitivity or subgroup analyses. CONCLUSION: Exposure to UTI favors increased risk for UBCNS, particularly in men, but these effects were statistically insignificant when pooling data from the most recent and highest quality studies. These data do not support findings of previously published studies, that report on heterogenous populations with poor definitions of UTI and minimal control for important confounders. Results from previous studies should be viewed as hypothesis generating. This review highlights the need for higher quality investigation.