Design and Implementation of an Agitation Code Response Team in the Emergency Department.

STUDY OBJECTIVE: Agitation, defined as excessive psychomotor activity leading to violent and aggressive behavior, is becoming more prevalent in the emergency department (ED) amidst a strained behavioral health system. Team-based interventions have demonstrated promise in promoting de-escalation, with the hope of minimizing the need for invasive techniques, like physical restraints. This study aimed to evaluate an interprofessional code response team intervention to manage agitation in the ED with the goal of decreasing physical restraint use. METHODS: This quality improvement study occurred over 3 phases, representing stepwise rollout of the intervention: (1) preimplementation (phase I) to establish baseline outcome rates; (2) design and administrative support (phase II) to conduct training and protocol design; and (3) implementation (phase III) of the code response team. An interrupted time-series analysis was used to compare trends between phases to evaluate the primary outcome of physical restraint orders occurring during the study period. RESULTS: Within the 634,578 ED visits over a 5-year period, restraint use significantly declined sequentially over the 3 phases (1.1%, 0.9%, and 0.8%, absolute change -0.3% between phases I and III, 95% confidence interval [CI] -0.4% to 0.3%), which corresponded to a 27.3% proportionate decrease in restraint rates between phases I and III. For the interrupted time-series analysis, there was a significantly decreasing slope in biweekly restraints in phase II compared to phase I (slope, -0.05 restraints per 1,000 ED visits per 2-week period, 95% CI -0.07 to -0.03), which was sustained in an incremental fashion in phase III (slope, -0.05, 95% CI -0.07 to -0.02). CONCLUSION: With the implementation of a structured agitation code response team intervention combined with design and administrative support, a decreased rate of physical restraint use occurred over a 5-year period. Results suggest that investment in organizational change, along with interprofessional collaboration during the management of agitated patients in the ED, can lead to sustained reductions in the use of an invasive and potentially harmful measure on patients.

Discovery of the Oxadiazine FRM-024: A Potent CNS-Penetrant Gamma Secretase Modulator.

The recent approval of aducanumab for Alzheimer's disease has heightened the interest in therapies targeting the amyloid hypothesis. Our research has focused on identification of novel compounds to improve amyloid processing by modulating gamma secretase activity, thereby addressing a significant biological deficit known to plague the familial form of the disease. Herein, we describe the design, synthesis, and optimization of new gamma secretase modulators (GSMs) based on previously reported oxadiazine 1. Potency improvements with a focus on predicted and measured properties afforded high-quality compounds further differentiated via robust Aß42 reductions in both rodents and nonhuman primates. Extensive preclinical profiling, efficacy studies, and safety studies resulted in the nomination of FRM-024, (+)-cis-5-(4-chlorophenyl)-6-cyclopropyl-3-(6-methoxy-5-(4-methyl-1H-imidazole-1-yl)pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine, as a GSM preclinical candidate for familial Alzheimer's disease.

SM16, an orally active TGF-beta type I receptor inhibitor prevents myofibroblast induction and vascular fibrosis in the rat carotid injury model.

OBJECTIVE: TGF-beta plays a significant role in vascular injury-induced stenosis. This study evaluates the efficacy of a novel, small molecule inhibitor of ALK5/ALK4 kinase, in the rat carotid injury model of vascular fibrosis. METHODS AND RESULTS: The small molecule, SM16, was shown to bind with high affinity to ALK5 kinase ATP binding site using a competitive binding assay and biacore analysis. SM16 blocked TGF-beta and activin-induced Smad2/3 phosphorylation and TGF-beta-induced plasminogen activator inhibitor (PAI)-luciferase activity in cells. Good overall selectivity was demonstrated in a large panel of kinase assays, but SM16 also showed nanomolar inhibition of ALK4 and weak (micromolar) inhibition of Raf and p38. In the rat carotid injury model, SM16 dosed once daily orally at 15 or 30 mg/kg SM16 for 14 days caused significant inhibition of neointimal thickening and lumenal narrowing. SM16 also prevented induction of adventitial smooth muscle alpha-actin-positive myofibroblasts and the production of intimal collagen, but did not decrease the percentage of proliferative cells. CONCLUSIONS: These results are the first to demonstrate the efficacy of an orally active, small-molecule ALK5/ALK4 inhibitor in a vascular fibrosis model and suggest the potential therapeutic application of these inhibitors in vascular fibrosis.

Design, Synthesis, and Evaluation of a Novel Series of Oxadiazine Gamma Secretase Modulators for Familial Alzheimer's Disease.

Herein we describe the design, synthesis, and evaluation of a novel series of oxadiazine-based gamma secretase modulators obtained via isosteric amide replacement and critical consideration of conformational restriction. Oxadiazine lead 47 possesses good in vitro potency with excellent predicted CNS drug-like properties and desirable ADME/PK profile. This lead compound demonstrated robust Aß42 reductions and subsequent Aß37 increases in both rodent brain and CSF at 30 mg/kg dosed orally.