Breaking Barriers to Rapid Whole Genome Sequencing in Pediatrics: Michigan's Project Baby Deer.

The integration of precision medicine in the care of hospitalized children is ever evolving. However, access to new genomic diagnostics such as rapid whole genome sequencing (rWGS) is hindered by barriers in implementation. Michigan's Project Baby Deer (PBD) is a multi-center collaborative effort that sought to break down barriers to access by offering rWGS to critically ill neonatal and pediatric inpatients in Michigan. The clinical champion team used a standardized approach with inclusion and exclusion criteria, shared learning, and quality improvement evaluation of the project's impact on the clinical outcomes and economics of inpatient rWGS. Hospitals, including those without on-site geneticists or genetic counselors, noted positive clinical impacts, accelerating time to definitive treatment for project patients. Between 95-214 hospital days were avoided, net savings of $4155 per patient, and family experience of care was improved. The project spurred policy advancement when Michigan became the first state in the United States to have a Medicaid policy with carve-out payment to hospitals for rWGS testing. This state project demonstrates how front-line clinician champions can directly improve access to new technology for pediatric patients and serves as a roadmap for expanding clinical implementation of evidence-based precision medicine technologies.

Caspase activation in fetal rat brain following experimental intrauterine inflammation.

Intrauterine inflammation has been implicated in developmental brain injuries, including the development of periventricular leukomalacia (PVL) and cerebral palsy (CP). Previous studies in our rat model of intrauterine inflammation demonstrated apoptotic cell death in fetal brains within the first 5 days after lipopolysaccharide (LPS) administration to mothers and eventual dysmyelination. Cysteine-containing, aspartate-specific proteases, or caspases, are proteins involved with apoptosis through both intracellular (intrinsic pathway) and extracellular (extrinsic pathway) mechanisms. We hypothesized that cell death in our model would occur mainly via activation of the extrinsic pathway. We further hypothesized that Fas, a member of the tumor necrosis factor receptor (TNFR) superfamily, would be increased and the death inducing signaling complex (DISC) would be detectable. Pregnant rats were injected intracervically with LPS at E15 and immunoblotting, immunohistochemical and immunoprecipitation analyses were performed. The presence of the activated form of the effector caspase (caspase-3) was observed 24 h after LPS administration. Caspase activity assays demonstrated rapid increases in (i) caspases-9 and -10 within 1 h, (ii) caspase-8 at 2 h and (iii) caspase-3 at 4 h. At 24 h after LPS, activated caspase-3(+)/Fas(+) cells were observed within the developing white matter. Lastly, the DISC complex (caspase-8, Fas and Fas-associated death domain (FADD)) was observed within 30 min by immunoprecipitation. Apoptosis in our model occurs via both extrinsic and intrinsic pathways, and activation of Fas may play a role. Understanding the mechanisms of cell death in models of intrauterine inflammation may affect development of future strategies to mitigate these injuries in children.

Blood transfusions in children: a multi-institutional analysis of practices and complications.

BACKGROUND: Blood product transfusions are a valuable health-care resource. Guidelines for transfusion exist, but variability in their application, particularly in children, remains. The risk factors that threaten transfusion safety are well established, but because their occurrence in children is rare, single-institution studies have limited utility in determining the rates of occurrence. An epidemiologic approach that investigates blood transfusions in hospitalized children may help improve our understanding of transfused blood products in this vulnerable population. STUDY DESIGN AND METHODS: This was a nonconcurrent cohort study of pediatric patients not more than 18 years of age hospitalized from 2001 to 2003 at 35 academic children's hospitals that are members of the Pediatric Health Information System (PHIS). RESULTS: A total of 51,720 (4.8%) pediatric patients received blood product transfusions during the study period. Red blood cells (n = 44,632) and platelets (n = 14,274) were the two most frequently transfused products. The rate of transfusions was highest among children with neutropenia, agranulocytosis, and sickle cell crisis. Asian and American Indian patients had important differences in the rate of blood transfusions and their complications. Resource use in terms of length of stay and costs were higher in patients who received transfusion. Of those patients who received transfusions, 492 (0.95%) experienced a complication from the administered blood product. This accounted for a rate of complications of 10.7 per 1,000 units transfused. CONCLUSIONS: The administration of blood products to children is a common practice in academic children's hospitals. Complications associated with these transfused products are rare.