High hydroxyurea usage in sickle cell anemia regardless of patient demographics.

Hydroxyurea is highly effective in sickle cell disease, but it is still underutilized. Reports of hydroxyurea utilization largely use Medicaid data, and socioeconomics is often cited as a barrier. To address whether patient demographics influenced the high hydroxyurea usage rate recently reported for the pediatric sickle cell program of Northern Virginia, analysis of data from 2011 to 2021 revealed no statistical difference in hydroxyurea usage rate between Medicaid and non-Medicaid, African American and African, or age less than 13 and age greater than or equal to 13 years cohorts, demonstrating that hydroxyurea can be successfully implemented across demographic groups.

Effect of voxelotor on cardiopulmonary testing in youths with sickle cell anemia in a pilot study.

BACKGROUND: Individuals with sickle cell anemia (SCA) exhibit decreased exercise capacity. Anemia limits oxygen-carrying capacity and affects cardiopulmonary fitness. The drug voxelotor raises hemoglobin in SCA. We hypothesized that voxelotor improves exercise capacity in youths with SCA. METHODS: In a single-center, open-label, single-arm, longitudinal interventional pilot study (NCT04581356), SCA patients aged 12 and older, stably maintained on hydroxyurea, were treated with 1500 mg voxelotor daily, and performed cardiopulmonary exercise testing before (CPET#1) and after voxelotor (CPET#2). A modified Bruce Protocol was performed on a motorized treadmill, and breath-by-breath gas exchange data were collected. Peak oxygen consumption (peak VO2 ), anaerobic threshold, O2 pulse, VE/VCO2 slope, and time exercised were compared for each participant. The primary endpoint was change in peak VO2 . Hematologic parameters were measured before each CPET. Patient Global Impression of Change (PGIC) and Clinician Global Impression of Change (CGIC) surveys were collected. RESULTS: Ten hemoglobin SS patients aged 12-24 completed the study. All demonstrated expected hemoglobin rise, with average +1.6 g/dL (p = .003) and P50 left shift of average -11 mmHg (p < .0001) with decreased oxygen off-loading at low pO2 . The change in % predicted peak VO2 from CPET#1 to CPET#2 ranged from -12.8% to +11.3%, with significant improvement of more than 5% in one subject, more than 5% decrease in five subjects, and insignificant change of less than 5% in four subjects. All 10 CGIC and seven of 10 PGIC responses were positive. CONCLUSION: In a plot study of 10 youths with SCA, voxelotor treatment did not improve peak VO2 in 9 out of 10 patients.

Ten-year longitudinal analysis of hydroxyurea implementation in a pediatric sickle cell program.

Hydroxyurea (HU) has proven benefit in sickle cell anemia (SCA), but HU is still underutilized. The Pediatric Sickle Cell Program of Northern Virginia prescribes HU regardless of symptoms to all SCA patients age ≥ 9 months and prospectively tracks outcomes. HU is dosed to maximum tolerated dosing (MTD), targeting 30% Hgb F. Longitudinal data from 2009 to 2019 encompassing 1222 HU-eligible and 950 HU-exposure patient-years were analyzed in 2-year intervals for hemoglobin (Hgb), fetal hemoglobin (Hgb F), hospitalizations, transfusions, and treat-and-release ED visits. Comparing HU-eligible patients in the interval prior to HU implementation (2009-2011) to the last interval analyzed after HU implementation (2017-2019), HU usage increased from 33% to 93%, average Hgb increased from 8.3 ± 0.98 to 9.8 ± 1.3 g/dl (p < .0001), average Hgb F rose from 13 ± 8.7% to 26 ± 9.9% (p < .0001), hospitalizations decreased from 0.71 (95% CI 0.54-0.91) to 0.2 (95% CI 0.13-0.28) admissions/person-year, sporadic transfusions decreased from 0.4 (95% CI 0.27-0.55) to 0.05 (95% CI 0.02-0.12) transfusions/person-year. Treat-and-release ED visit rates remained unchanged, varying between 0.49 (95% CI 0.36-0.64) and 0.64 (95% CI 0.48-0.83) visits/person-year. By the last interval, 72% of patients had Hgb ≥ 9 g/dl, 42% had Hgb F ≥ 30%, 79% experienced no hospitalizations, and 94% received no transfusions. Uniform HU prescription for SCA patients with close monitoring to achieve high Hgb F resulted in significant improvements in laboratory and clinical outcomes within 2 years, which continued to improve over the next 6 years. Rigorous HU implementation in a pediatric sickle cell population is feasible, effective, and sustainable.

Clinical characteristics of 172 children and adolescents with body dysmorphic disorder.

Body dysmorphic disorder (BDD) often starts in childhood, with most cases developing symptoms before age 18. Yet, BDD research has primarily focused on adults. We report the clinical characteristics of the world's largest cohort of carefully diagnosed youths with BDD and focus on previously unexplored sex and age differences. We systematically collected clinical data from 172 young people with BDD consecutively referred to 2 specialist pediatric obsessive-compulsive and related disorders outpatient clinics in Stockholm, Sweden and in London, England. A series of clinician-, self-, and parent-reported measures were administered. The cohort consisted of 136 girls, 32 boys, and 4 transgender individuals (age range 10-19 years). The mean severity of BDD symptoms was in the moderate to severe range, with more than one third presenting with severe symptoms and more than half showing poor or absent insight/delusional beliefs. We observed high rates of current psychiatric comorbidity (71.5%), past or current self-harm (52.1%), suicide attempts (11.0%), current desire for cosmetic procedures (53.7%), and complete school dropout (32.4%). Compared to boys, girls had significantly more severe self-reported BDD symptoms, depression, suicidal thoughts, and self-harm. Compared to the younger participants (14 or younger), older participants had significantly more severe compulsions and were more likely to report a desire for conducting cosmetic procedures. Adolescent BDD can be a severe and disabling disorder associated with significant risks and substantial functional impairment. The clinical presentation of the disorder is largely similar across sexes and age groups, indicating the importance of early detection and treatment. More research is needed specifically focusing on boys and pre-pubertal individuals with BDD.

Entering Kindergarten After Years of Play: A Cross-Case Analysis of School Readiness Following Play-Based Education.

Cross-case study research was used to explore the school readiness of four 5-year-old children entering kindergarten during the 2020-2021 school year after three or more years of play-based early childhood education at a Reggio Emilia-inspired early childhood education center. Data included a series of three 1-h individual interviews with four mothers and three kindergarten teachers, field visits during remote learning, and artifact collection over the course of the school year. Themes describing the children's school readiness were developed through cross-case analysis. Participants described the children as learners, explorers, communicators, and empathizers. The learner theme centers on the children's responsiveness to instruction; the explorer theme describes how the children approached learning; the communicator theme illustrates the children's prowess with social connection and self-advocacy, and the empathizer theme shows the thoughtfulness and emotional sensitivity these children displayed. Findings suggest that play-based learning prepared these children for successful kindergarten experiences and was a viable early childhood education pedagogy fostering school readiness.

A direct comparison of mouse and human intestinal development using epithelial gene expression patterns.

BACKGROUND: Preterm infants are susceptible to unique pathology due to their immaturity. Mouse models are commonly used to study immature intestinal disease, including necrotizing enterocolitis (NEC). Current NEC models are performed at a variety of ages, but data directly comparing intestinal developmental stage equivalency between mice and humans are lacking. METHODS: Small intestines were harvested from C57BL/6 mice at 3-4 days intervals from birth to P28 (n = 8 at each age). Preterm human small intestine samples representing 17-23 weeks of completed gestation were obtained from the University of Pittsburgh Health Sciences Tissue Bank, and at term gestation during reanastamoses after resection for NEC (n = 4-7 at each age). Quantification of intestinal epithelial cell types and messenger RNA for marker genes were evaluated on both species. RESULTS: Overall, murine and human developmental trends over time are markedly similar. Murine intestine prior to P10 is most similar to human fetal intestine prior to viability. Murine intestine at P14 is most similar to human intestine at 22-23 weeks completed gestation, and P28 murine intestine is most similar to human term intestine. CONCLUSION: Use of C57BL/6J mice to model the human immature intestine is reasonable, but the age of mouse chosen is a critical factor in model development.

Prospective longitudinal follow-up of children with sickle cell disease treated with hydroxyurea since infancy.

BACKGROUND: Hydroxyurea (HU) increases fetal hemoglobin (HgbF) and ameliorates sickle cell disease (SCD) symptoms. Studies have demonstrated the safety and efficacy of HU in infants and children. Initiation of HU in infancy for children with SCD needs to be implemented in community practice. PROCEDURE: Starting in 2011, the Pediatric Sickle Cell Program of Northern Virginia initiated HU in infants with SCD. A prospective longitudinal database tracked the clinical course and outcomes. RESULTS: Twenty-four children with HgbSS who started HU by age 1 were continuously followed for a total of 95 person-years. Age at the time of analysis ranged from 2 to 7 years. Average hemoglobin at 6-month intervals ranged from 9.5 + 1.9 to 10.7 + 0.8 g/dL, and average HgbF ranged from 27.8 + 5.0% to 34.1 + 6.6%. Twenty-seven hospitalizations occurred (0.28/person-year), all before age 3, including 19 (70%) for fever or infection, five (19%) for splenic sequestration, and one (4%) for pain in an infant prior to starting HU. The treat-and-release emergency department visits totaled 68 (0.72/person-year), including 62 visits (91%) for fever, infection, or viral illness, and two visits (3%) for pain/dactylitis in infants before HU initiation. Splenic sequestration accounted for all five transfusions. No pain episodes requiring medical attention were documented after HU initiation. No complicated acute chest syndrome, no abnormal or conditional transcranial Doppler ultrasound, and no overt strokes occurred. CONCLUSION: Implementation of HU in infancy for patients with SCD in community practice is feasible and is highly effective in preventing disease complications.

Discontinuation of Folic Acid Supplementation in Young Patients With Sickle Cell Anemia.

Folic acid (FA) is commonly prescribed for patients with sickle cell anemia, but evidence for the efficacy of this practice is lacking. We stopped FA supplementation and measured red blood cell folate levels after discontinuation of FA in 72 patients with clinically severe forms of sickle cell disease. We compared hemoglobin and reticulocyte counts before and after FA discontinuation in 51 of those patients, the majority of whom were on hydroxyurea. No patients had red blood cell folate levels below normal and no significant difference in hemoglobin levels (P=0.18) or reticulocyte counts (P=0.37) was found before and after FA discontinuation.

Parental symptoms of posttraumatic stress after pediatric extracorporeal membrane oxygenation*.

OBJECTIVE: To investigate the prevalence of posttraumatic stress symptoms in parents of children who have been supported on extracorporeal membrane oxygenation and to explore associated factors. DESIGN: Descriptive cross-sectional study. SETTING: A specialist pediatric tertiary center in the United Kingdom. SUBJECTS: Parents (n = 52) of children who had been supported with extracorporeal membrane oxygenation at least 6 months previously. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Self-reported questionnaires were completed measuring posttraumatic stress symptom, family functioning, depression, anxiety, and demographic variables. Approximately 20% of parents experienced posttraumatic stress symptoms at levels suggestive of a diagnosis of posttraumatic stress disorder, irrespective of the time that had elapsed since extracorporeal membrane oxygenation. Although having a child who had ongoing illness before extracorporeal membrane oxygenation was associated with avoidance posttraumatic stress symptoms, results suggest that other previously identified risk factors, such as gender and family functioning, may not be risk factors for posttraumatic stress symptom in this population. CONCLUSIONS: A substantial number of parents in this population experience posttraumatic stress symptom. Psychological interventions may be targeted toward those whose child has had ongoing illness before extracorporeal membrane oxygenation.

Modulation of intestinal TLR4 expression in infants with neonatal opioid withdrawal syndrome.

OBJECTIVE: Neonatal Opioid Withdrawal Syndrome (NOWS) has been associated with the development of necrotizing enterocolitis (NEC) in term and late-preterm neonates. In this study, we used stool gene expression to determine if an increase in baseline inflammation in the intestine of infants with NOWS is associated with these findings. STUDY DESIGN: Stool samples were prospectively collected between days 1-3 and days 4-9 after delivery for opioid-exposed ( n = 9) or non-exposed neonates (n = 8). Stool gene expression for TLR4 and HMGB1 was determined via real-time PCR. RESULTS: TLR4 expression was higher in the stool of the non-exposed group in both time periods, between days 1-3 (P < 0.0001) and days 4-9 (P < 0.05) after delivery. No significant difference in HMGB1 expression was found at either time point (P > 0.05). CONCLUSION: These findings point to an important interplay between opioid exposure and/or NOWS and the inflammatory milieu of the neonatal intestine.

Microfluidic device facilitates in vitro modeling of human neonatal necrotizing enterocolitis-on-a-chip.

Necrotizing enterocolitis (NEC) is a deadly gastrointestinal disease of premature infants that is associated with an exaggerated inflammatory response, dysbiosis of the gut microbiome, decreased epithelial cell proliferation, and gut barrier disruption. We describe an in vitro model of the human neonatal small intestinal epithelium (Neonatal-Intestine-on-a-Chip) that mimics key features of intestinal physiology. This model utilizes intestinal enteroids grown from surgically harvested intestinal tissue from premature infants and cocultured with human intestinal microvascular endothelial cells within a microfluidic device. We used our Neonatal-Intestine-on-a-Chip to recapitulate NEC pathophysiology by adding infant-derived microbiota. This model, named NEC-on-a-Chip, simulates the predominant features of NEC, including significant upregulation of proinflammatory cytokines, decreased intestinal epithelial cell markers, reduced epithelial proliferation, and disrupted epithelial barrier integrity. NEC-on-a-Chip provides an improved preclinical model of NEC that facilitates comprehensive analysis of the pathophysiology of NEC using precious clinical samples. This model is an advance toward a personalized medicine approach to test new therapeutics for this devastating disease.

Evaluation of the Neonatal Sequential Organ Failure Assessment and Mortality Risk in Preterm Infants with Necrotizing Enterocolitis.

INTRODUCTION: The neonatal sequential organ failure assessment (nSOFA) score is a tool for calculating mortality risk of infants in the neonatal intensive care unit. The utility of the nSOFA in determining the risk of mortality or the association with surgical intervention among infants with necrotizing enterocolitis (NEC) has not been investigated. METHODS: We performed a retrospective, cohort study of preterm (<37 weeks) infants with NEC Bell's stage ≥ IIA at six hospitals from 2008 to 2020. An nSOFA score (range 0-15) was assigned to each patient at nine time points from 48 h before or after clinical illness was suspected. RESULTS: Of the 259 infants, nSOFA scores for infants who died (n = 39) or had the composite outcome of surgery or death (n = 114) were significantly higher (p < 0.05) early in the NEC course compared to nSOFA scores for infants who survived medical NEC. Twelve hours after evaluation, the area under the receiver operating characteristic curve was 0.87 (95% confidence interval [CI], 0.80-0.93) to discriminate for mortality and 0.84 (95% CI, 0.79-0.90) for surgery or death (p < 0.001). A maximum nSOFA score of ≥4 at -6, 0, 6, or 12 h following evaluation was associated with a 20-fold increase in mortality and 19-fold increase in surgery or death compared with a score of <4 (p < 0.001). CONCLUSION: In this multicenter cohort, the nSOFA score was able to discriminate well for death as well as surgery or death among infants with NEC. The nSOFA is a clinical research tool that may be used in infants with NEC to improve classification by objective quantification of organ dysfunction.

Untargeted Metabolomic Analysis of Human Milk from Mothers of Preterm Infants.

The application of metabolomics in neonatology offers an approach to investigate the complex relationship between nutrition and infant health. Characterization of the metabolome of human milk enables an investigation into nutrients that affect the neonatal metabolism and identification of dietary interventions for infants at risk of diseases such as necrotizing enterocolitis (NEC). In this study, we aimed to identify differences in the metabolome of breast milk of 48 mothers with preterm infants with NEC and non-NEC healthy controls. A minimum significant difference was observed in the human milk metabolome between the mothers of infants with NEC and mothers of healthy control infants. However, significant differences in the metabolome related to fatty acid metabolism, oligosaccharides, amino sugars, amino acids, vitamins and oxidative stress-related metabolites were observed when comparing milk from mothers with control infants of ≤1.0 kg birth weight and >1.5 kg birth weight. Understanding the functional biological features of mothers' milk that may modulate infant health is important in the future of tailored nutrition and care of the preterm newborn.

Indole-3-Carbinol-Dependent Aryl Hydrocarbon Receptor Signaling Attenuates the Inflammatory Response in Experimental Necrotizing Enterocolitis.

Necrotizing enterocolitis (NEC) causes significant morbidity and mortality in premature infants; therefore, the identification of therapeutic and preventative strategies against NEC remains a high priority. The ligand-dependent transcription factor aryl hydrocarbon receptor (AhR) is well known to contribute to the regulation of intestinal microbial communities and amelioration of intestinal inflammation. However, the role of AhR signaling in NEC is unclear. Experimental NEC was induced in 4-d-old wild-type mice or mice lacking AhR expression in the intestinal epithelial cells or AhR expression in CD11c+ cells (AhRΔCD11c) by subjecting animals to twice daily hypoxic stress and gavage feeding with formula supplemented with LPS and enteric bacteria. During NEC, compared with wild-type mice treated with vehicle, littermates treated with an AhR proligand, indole-3-carbinol, had reduced expression of Il1b and Marco, a scavenger receptor that mediates dendritic cell activation and the recognition and clearance of bacterial pathogens by macrophages. Furthermore, indole-3-carbinol treatment led to the downregulation of genes involved in cytokine and chemokine, as revealed by pathway enrichment analysis. AhR expression in the intestinal epithelial cells and their cre-negative mouse littermates were similarly susceptible to experimental NEC, whereas AhRΔCD11c mice with NEC exhibited heightened inflammatory responses compared with their cre-negative mouse littermates. In seeking to determine the mechanisms involved in this increased inflammatory response, we identified the Tim-4- monocyte-dependent subset of macrophages as increased in AhRΔCD11c mice compared with their cre-negative littermates. Taken together, these findings demonstrate the potential for AhR ligands as a novel immunotherapeutic approach to the management of this devastating disease.

Evaluation of the Neonatal Sequential Organ Failure Assessment and Mortality Risk in Preterm Infants With Late-Onset Infection.

Importance: Infection in neonates remains a substantial problem. Advances for this population are hindered by the absence of a consensus definition for sepsis. In adults, the Sequential Organ Failure Assessment (SOFA) operationalizes mortality risk with infection and defines sepsis. The generalizability of the neonatal SOFA (nSOFA) for neonatal late-onset infection-related mortality remains unknown. Objective: To determine the generalizability of the nSOFA for neonatal late-onset infection-related mortality across multiple sites. Design, Setting, and Participants: A multicenter retrospective cohort study was conducted at 7 academic neonatal intensive care units between January 1, 2010, and December 31, 2019. Participants included 653 preterm (<33 weeks) very low-birth-weight infants. Exposures: Late-onset (>72 hours of life) infection including bacteremia, fungemia, or surgical peritonitis. Main Outcomes and Measures: The primary outcome was late-onset infection episode mortality. The nSOFA scores from survivors and nonsurvivors with confirmed late-onset infection were compared at 9 time points (T) preceding and following event onset. Results: In the 653 infants who met inclusion criteria, median gestational age was 25.5 weeks (interquartile range, 24-27 weeks) and median birth weight was 780 g (interquartile range, 638-960 g). A total of 366 infants (56%) were male. Late-onset infection episode mortality occurred in 97 infants (15%). Area under the receiver operating characteristic curves for mortality in the total cohort ranged across study centers from 0.71 to 0.95 (T0 hours), 0.77 to 0.96 (T6 hours), and 0.78 to 0.96 (T12 hours), with utility noted at all centers and in aggregate. Using the maximum nSOFA score at T0 or T6, the area under the receiver operating characteristic curve for mortality was 0.88 (95% CI, 0.84-0.91). Analyses stratified by sex or Gram-stain identification of pathogen class or restricted to infants born at less than 25 weeks' completed gestation did not reduce the association of the nSOFA score with infection-related mortality. Conclusions and Relevance: The nSOFA score was associated with late-onset infection mortality in preterm infants at the time of evaluation both in aggregate and in each center. These findings suggest that the nSOFA may serve as the foundation for a consensus definition of sepsis in this population.

Interleukin-22 signaling attenuates necrotizing enterocolitis by promoting epithelial cell regeneration.

Necrotizing enterocolitis (NEC) is a deadly intestinal inflammatory disorder that primarily affects premature infants and lacks adequate therapeutics. Interleukin (IL)-22 plays a critical role in gut barrier maintenance, promoting epithelial regeneration, and controlling intestinal inflammation in adult animal models. However, the importance of IL-22 signaling in neonates during NEC remains unknown. We investigated the role of IL-22 in the neonatal intestine under homeostatic and inflammatory conditions by using a mouse model of NEC. Our data reveal that Il22 expression in neonatal murine intestine is negligible until weaning, and both human and murine neonates lack IL-22 production during NEC. Mice deficient in IL-22 or lacking the IL-22 receptor in the intestine display a similar susceptibility to NEC, consistent with the lack of endogenous IL-22 during development. Strikingly, treatment with recombinant IL-22 during NEC substantially reduces inflammation and enhances epithelial regeneration. These findings may provide a new therapeutic strategy to attenuate NEC.

Conceptualizing and managing risk in pediatric OCD: Case examples.

It is not uncommon for patients with obsessive-compulsive disorder (OCD) to present with symptoms that suggest possible risk. This can include apparent risk, which reflects the content of obsessional fears, and genuine risk arising as the unintended consequence of compulsive behaviors. In both situations, risk can cause confusion in relation to diagnosis and treatment. The current article adds to the small existing literature on risk in OCD by presenting case examples illustrating different types of risk in the context of pediatric OCD, along with a discussion of their implications for management. The cases highlight that it is crucial that risk in OCD is considered carefully within the context of the phenomenology of the disorder. Guidance is offered to support clinical decision making and treatment planning.

Family accommodation in pediatric body dysmorphic disorder: A qualitative study.

Family accommodation (FA) is significant in a range of disorders, yet it has never been explored in body dysmorphic disorder (BDD). Interviews were conducted with five young people with BDD, five parents, and five clinicians to explore the types, impact, and purpose of FA in BDD. Every participant reported significant FA of BDD, and the types reported were broadly similar to those found in other disorders. Reassurance giving/seeking and engagement in rituals were the two most common forms of FA reported with funding products being the third. Unsurprisingly, the driver for FA was to reduce the young person's distress and risk. Every participant commented on the negative impact FA had, including the financial burden, social implications, emotional well-being of family members, relationships, and conflict within the family, yet all young people also thought there were positive aspects to FA. Findings are discussed in the context of the limitations of this study.