Histidyl-tRNA synthetase (HARS) is a highly conserved translation factor that plays an essential role in protein synthesis. HARS has been implicated in the human syndromes Charcot-Marie-Tooth (CMT) Type 2W and Type IIIB Usher (USH3B). The USH3B mutation, which encodes a Y454S substitution in HARS, is inherited in an autosomal recessive fashion and associated with childhood deafness, blindness, and episodic hallucinations during acute illness. The biochemical basis of the pathophysiologies linked to USH3B is currently unknown. Here, we present a detailed functional comparison of wild-type (WT) and Y454S HARS enzymes. Kinetic parameters for enzymes and canonical substrates were determined using both steady state and rapid kinetics. Enzyme stability was examined using differential scanning fluorimetry. Finally, enzyme functionality in a primary cell culture was assessed. Our results demonstrate that the Y454S substitution leaves HARS amino acid activation, aminoacylation, and tRNA binding functions largely intact compared with those of WT HARS, and the mutant enzyme dimerizes like the wild type does. Interestingly, during our investigation, it was revealed that the kinetics of amino acid activation differs from that of the previously characterized bacterial HisRS. Despite the similar kinetics, differential scanning fluorimetry revealed that Y454S is less thermally stable than WT HARS, and cells from Y454S patients grown at elevated temperatures demonstrate diminished levels of protein synthesis compared to those of WT cells. The thermal sensitivity associated with the Y454S mutation represents a biochemical basis for understanding USH3B.

We strive to understand care coordination structures of multidisciplinary teams and to evaluate their effect on post-surgical length of stay (PSLOS) in the Neonatal Intensive Care Unit (NICU). Electronic health record (EHR) data were extracted for 18 neonates, who underwent gastrostomy tube placement surgery at the Vanderbilt University Medical Center NICU. Based on providers' interactions with the EHR (e.g. viewing, documenting, ordering), provider-provider relations were learned and used to build patient-specific provider networks representing the care coordination structure. We quantified the networks using standard network analysis metrics (e.g., in-degree, out-degree, betweenness centrality, and closeness centrality). Coordination structure effectiveness was measured as the association between the network metrics and PSLOS, as modeled by a proportional-odds, logistical regression model. The 18 provider networks exhibited various team compositions and various levels of structural complexity. Providers, whose patients had lower PSLOS, tended to disperse patient-related information to more colleagues within their network than those, who treated higher PSLOS patients (P = 0.0294). In the NICU, improved dissemination of information may be linked to reduced PSLOS. EHR data provides an efficient, accessible, and resource-friendly way to study care coordination using network analysis tools. This novel methodology offers an objective way to identify key performance and safety indicators of care coordination and to study dissemination of patient-related information within care provider networks and its effect on care. Findings should guide improvements in the EHR system design to facilitate effective clinical communications among providers.

Children who are GT dependent can be weaned off GT feedings during a 3-week admission using a multidisciplinary feeding model. The therapeutic gains were maintained at 1 year postdischarge.

The purpose of this longitudinal observational study was to evaluate the effectiveness of a multidisciplinary inpatient treatment model for feeding disorders by analyzing long-term nutritional and health outcomes 12 months following discharge. Fifty patients completed the study. Average caloric intake by mouth as a percentage of goal for gastrostomy tube (GT)-dependent patients (n = 31) increased from pre-admit, week 1, and week 2 of the inpatient program (30%, 70%, and 84%, respectively), and was sustained from week 3 to 12-month follow-up (85% and 86%, respectively). Eighty-one percentage were discharged without GT support and 65% remained off GT support at 12 months. Oral supplement dependence for non-GT patients (n = 19) decreased from pre-admit, discharge, and 12-month follow-up (51%, 31%, and 19% of caloric intake, respectively). BMI z-scores improved during and after treatment. The present study demonstrated an effective approach for treatment of pediatric feeding disorders, including decreased reliance on oral supplementation and GT dependence.