In this review, the International Neonatal Consortium NEC working group addresses key issues that relate to the diagnosis, prevention, and treatment of NEC while suggesting a path forward to evaluate the safety and efficacy of each product. Despite years of clinical investigation, additional key data elements are needed to meet the requirements of regulatory agencies and evidence-based medicine.4 These include reliable diagnostic criteria, biomarkers predictive of risk and prognosis, and criteria for the design and conduct of clinical trials with consistent and clinically meaningful outcome measures for therapeutic trials.
OBJECTIVE: The aim of the study was to determine the rate of progression from acute recurrent pancreatitis (ARP) to chronic pancreatitis (CP) in children and assess risk factors.
CONCLUSIONS: Children with ARP rapidly progress to CP, exocrine pancreatic insufficiency, and diabetes. The progression to CP is faster in children who were 6 years or older at the first episode of AP or with pathogenic PRSS1 variants. The factors that affect the aggressive disease course in childhood warrant further investigation.
Abstract: Autoinflammatory syndromes are characterized by dysregulation of the innate immune response with subsequent episodes of acute spontaneous inflammation. Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory bone disorder that presents with bone pain and localized swelling. Ali18 mice, isolated from a mutagenesis screen, exhibit a spontaneous inflammatory paw phenotype that includes sterile osteomyelitis and systemic reduced bone mineral density. To elucidate the molecular basis of the disease, positional cloning of the causative gene for Ali18 was attempted. Using a candidate gene approach, a missense mutation in the C-terminal region of Fgr, a member of Src family tyrosine kinases (SFKs), was identified. For functional confirmation, additional mutations at the N terminus of Fgr were introduced in Ali18 mice by CRISPR/Cas9-mediated genome editing. N-terminal deleterious mutations of Fgr abolished the inflammatory phenotype in Ali18 mice, but in-frame and missense mutations in the same region continue to exhibit the phenotype. The fact that Fgr null mutant mice are morphologically normal suggests that the inflammation in this model depends on Fgr products. Furthermore, the levels of C-terminal negative regulatory phosphorylation of FgrAli18 are distinctly reduced compared with that of wild-type Fgr. In addition, whole-exome sequencing of 99 CRMO patients including 88 trios (proband and parents) identified 13 patients with heterozygous coding sequence variants in FGR, including two missense mutant proteins that affect kinase activity. Our results strongly indicate that gain-of-function mutations in Fgr are involved in sterile osteomyelitis, and thus targeting SFKs using specific inhibitors may allow for efficient treatment of the disease.
Abstract: The objective of the current study was to develop a population pharmacokinetics (PK) model for erythropoietin (Epo) in premature infants and healthy adults to characterize the variation in PK, and to study the differences in Epo PK in these 2 populations. Thirteen very low-birth-weight premature infants (<1500 g at birth), and 10 healthy adults received up to 4 intravenous doses of Epo that ranged from 10 to 500 U/kg. The final model had a target-mediated saturable, nonlinear, elimination pathway that incorporated the mechanism of Epo binding to its receptors along with a parallel linear, central elimination pathway. Epo clearance was found to be significantly higher in preterm infants compared to adults. Epo clearance via the nonlinear pathway was found to be much higher in infants; they had an Epo receptor capacity of 133 pM vs 86.6 pM in adults, which is most likely due to the higher erythroid progenitor cell mass per kilogram of body weight in infants. The parallel linear elimination was found to be more dominant in adults, reaching 91% of the total clearance with a 500-U/kg dose compared to just 6.1% of the total clearance following the same dose in preterm infants. Thus, this mechanism-based population PK model revealed that receptor-based nonlinear elimination is the dominant Epo elimination pathway in premature infants, and parallel linear elimination is dominant in adults.
Congratulations to Dr. Polly Ferguson, Division Director of the Division of Rheumatology, for being co-author on some recent guidelines published for the American College of Rheumatology/Arthritis Foundation. The guidelines are below:
Abstract: Clinical ethics, with its emphasis on the actions of clinicians, risks overlooking the ways in which broader health-care structures influence the behavior of health-care providers. Analysis of a factual case study demonstrates that status quo reimbursement practices may place behavior analysts in a position where, no matter how they act, they risk acting unethically. By contrast, the reimbursement model set by accountable care organizations (ACOs), part of the Patient Protection and Affordable Care Act (also known as Obamacare), may offer a solution. However, making good on the promise of ACOs will require more resources than any individual behavior analyst possesses. In order to encourage institutional structures that facilitate ethical practice, behavior analysts’ professional organizations should engage in contemporary political discussions about the state of American health care.
Congratulations to Dr. Bell, Dr. Colaizy, and Dr. Rysavy for their most recent article in JAMA Pediatrics!
Brumbaugh JE, Hansen NI, Bell EF, Sridhar A, Carlo WA, Hintz SR, Vohr BR, Colaizy TT, Duncan AF, Wyckoff MH, Baack ML, Rysavy MA, DeMauro SB, Stoll BJ, Das A, Higgins RD, for the National Institute of Child Health and Human Development Neonatal Research Network. Outcomes of Extremely Preterm Infants With Birth Weight Less Than 400 g. JAMA Pediatr. Published online March 25, 2019. doi:10.1001/jamapediatrics.2019.0180.
Conclusions and Relevance Infants born with a birth weight less than 400 g are at high risk of mortality and significant morbidity. Although 21% of infants survived to 18 to 26 months’ corrected age with active treatment, neurodevelopment impairment was common among survivors
Congratulations to Dr. Uc on another publication in the Journal of Pediatric Gastroenterology and Nutrition!
Schwarzenberg SJ, Uc A, Zimmerman B, Wilschanski M, Wilcox CM, Whitcomb DC, Werlin SL, Troendle D, et al. Chronic Pancreatitis: Pediatric and Adult Cohorts Show Similarities in Disease Progress Despite Different Risk Factors. J Pediatr Gastroenterol Nutr. 2019 Apr;68(4):566-573. doi: 10.1097/MPG.0000000000002279.
“Despite disparity in age of onset, children and adults with chonic pancreatitis (CP) exhibit similarity in demographics, CP treatment, and pain. Differences between groups in radiographic findings and diabetes prevalence may be related to differences in risk factors associated with disease and length of time of CP.”