Reduced Emergency Department Utilization by Patients With Epilepsy Using QI Methodology.

BACKGROUND: Epilepsy or seizure care is the most common neurologic condition that presents to an emergency department (ED) and accounts for a large number of annual cases. Our aim was to decrease seizure-related ED visits from our baseline of 17 ED visits per month per 1000 patients to 13.6 ED visits per month per 1000 patients (20%) by July 2014. METHODS: Our strategy was to develop a quality improvement (QI) project utilizing the Institute for Healthcare Improvement model. Our defined outcome was to decrease ED utilization for children with epilepsy. Rate of ED visits as well as unplanned hospitalizations for epilepsy patients and associated health care costs were determined. A QI team was developed for this project. Plan do study act cycles were used with adjustments made when needed. RESULTS: Nineteen months after implementation of the interventions, ED visits were reduced by 28% (from 17 visits per month per 1000 patients to 12.2 per month per 1000 patients) during the past year. The average number of inpatient hospitalizations per month was reduced by 43% from 7 admissions per month per 1000 patients to 4 admissions per month per 1000 patients. For both outcome measures, a 2-sample Poisson rate exact test yielded a P value < .0001. Health care claims paid were less with $115 200 reduction for ED visits and $1 951 137 reduction for hospitalizations. CONCLUSIONS: Applying QI methodology was highly effective in reducing ED utilization and unplanned hospitalizations for children with epilepsy at a free-standing children's hospital.

Crystal structures and mutagenesis of PPP-family ser/thr protein phosphatases elucidate the selectivity of cantharidin and novel norcantharidin-based inhibitors of PP5C.

Cantharidin is a natural toxin and an active constituent in a traditional Chinese medicine used to treat tumors. Cantharidin acts as a semi-selective inhibitor of PPP-family ser/thr protein phosphatases. Despite sharing a common catalytic mechanism and marked structural similarity with PP1C, PP2AC and PP5C, human PP4C was found to be insensitive to the inhibitory activity of cantharidin. To explore the molecular basis for this selectivity, we synthesized and tested novel C5/C6-derivatives designed from quantum-based modeling of the interactions revealed in the co-crystal structures of PP5C in complex with cantharidin. Structure-activity relationship studies and analysis of high-resolution (1.25Å) PP5C-inhibitor co-crystal structures reveal close contacts between the inhibitor bridgehead oxygen and both a catalytic metal ion and a non-catalytic phenylalanine residue, the latter of which is substituted by tryptophan in PP4C. Quantum chemistry calculations predicted that steric clashes with the bulkier tryptophan side chain in PP4C would force all cantharidin-based inhibitors into an unfavorable binding mode, disrupting the strong coordination of active site metal ions observed in the PP5C co-crystal structures, thereby rendering PP4C insensitive to the inhibitors. This prediction was confirmed by inhibition studies employing native human PP4C. Mutation of PP5C (F446W) and PP1C (F257W), to mimic the PP4C active site, resulted in markedly suppressed sensitivity to cantharidin. These observations provide insight into the structural basis for the natural selectivity of cantharidin and provide an avenue for PP4C deselection. The novel crystal structures also provide insight into interactions that provide increased selectivity of the C5/C6 modifications for PP5C versus other PPP-family phosphatases.