Evaluation and Implementation of KIDs List Recommendations in a University Health System.

OBJECTIVE: The study aims to identify the rate of inappropriate prescribing per the Key Potentially Inappropriate Drugs in Pediatrics (KIDs) List versus total prescribing in patients at University of Missouri Health Care hospitals. METHODS: This retrospective study evaluated orders for patients treated at University of Missouri Health Care inpatient units or emergency departments with a KIDs List medication between September 1, 2019, and September 1, 2020, or a reported adverse event to one of these medications between September 1, 2015, and September 1, 2020. Patients were excluded if the patient safety report was related to a medication error rather than an adverse event. Safety measures assessed included age and weight filtering, dose-range checking, clinical decision support, and override availability. RESULTS: There were 39 inappropriate orders and 4 possible adverse events identified. A total of 8 of 33 medications (24%) had age and weight filtering in place for at least 1 order sentence, 1 of 38 (2.6%) had dose-range checking, no medications had an active clinical decision support alert, and 33 of 38 (87%) had availability on automated dispensing cabinet override. CONCLUSIONS: Use of KIDs List medications is appropriately low, but low levels of safety measure implementation leave pediatric patients vulnerable.

A High Affinity hRpn2-Derived Peptide That Displaces Human Rpn13 from Proteasome in 293T Cells.

Rpn13 is a proteasome ubiquitin receptor that has emerged as a therapeutic target for human cancers. Its ubiquitin-binding activity is confined to an N-terminal Pru (pleckstrin-like receptor for ubiquitin) domain that also docks it into the proteasome, while its C-terminal DEUBAD (DEUBiquitinase ADaptor) domain recruits deubiquitinating enzyme Uch37 to the proteasome. Bis-benzylidine piperidone derivatives that were found to bind covalently to Rpn13 C88 caused the accumulation of polyubiquitinated proteins as well as ER stress-related apoptosis in various cancer cell lines, including bortezomib-resistant multiple myeloma lines. We find that a 38-amino acid peptide derived from the C-terminus of proteasome PC repeat protein hRpn2/PSMD1 binds to hRpn13 Pru domain with 12 nM affinity. By using NMR, we identify the hRpn13-interacting amino acids in this hRpn2 fragment, some of which are conserved among eukaryotes. Importantly, we find the hRpn2-derived peptide to immunoprecipitate endogenous Rpn13 from 293T cells, and to displace it from the proteasome. These findings indicate that this region of hRpn2 is the primary binding site for hRpn13 in the proteasome. Moreover, the hRpn2-derived peptide was no longer able to interact with endogenous hRpn13 when a strictly conserved phenylalanine (F948 in humans) was replaced with arginine or a stop codon, or when Y950 and I951 were substituted with aspartic acid. Finally, over-expression of the hRpn2-derived peptide leads to an increased presence of ubiquitinated proteins in 293T cells. We propose that this hRpn2-derived peptide could be used to develop peptide-based strategies that specifically target hRpn13 function in the proteasome.