A novel class of highly selective inhibitors of p38 MAP kinase was discovered from high throughput screening. The synthesis and optimization of a series of 5-amino-N-phenyl-1H-pyrazol-4-yl-3-phenylmethanones is described. An X-ray crystal structure of this series bound in the ATP binding pocket of unphosphorylated p38alpha established the presence of a unique hydrogen bond between the exocyclic amine of the inhibitor and threonine 106 which likely contributes to the selectivity for p38. The crystallographic information was used to optimize the potency and physicochemical properties of the series. The incorporation of the 2,3-dihydroxypropoxy moiety on the pyrazole scaffold resulted in a compound with excellent drug-like properties including high oral bioavailability. These efforts identified 63 (RO3201195) as an orally bioavailable and highly selective inhibitor of p38 which was selected for advancement into Phase I clinical trials.
A business case plan (BCP) provides a structured framework for evidence-based, transparent business decisions. It is an essential tool that when written well will provide you with the means to translate the cost and benefits of nursing practice proposals, often related in anecdotal terms, into quantifiable, evidence-based terms outlining return on investment and business advantages of investing in nursing initiatives. The BCP should include an analysis of the problem and associated needs, the proposed solutions with options, goals for success, implementation, and evaluation plans, as well as a risk-adjusted cost-benefit analysis. It contains the necessary information to allow decision makers to make well-informed decisions regarding resource allocation. As clinical experts seeking to compete for finite resources in the health care arena, nursing leadership must bridge the language gap between nursing and business finance. This article outlines the required elements of the BCP to provide you with a practical working definition of each element to support your future initiatives in the business of health care improvement.
We evaluated a modified technique for teaching self-control and increasing the duration of waiting for access to a preferred item among 3 children with autism. Participants initially chose an immediate small reinforcer over a delayed large reinforcer and a delayed large reinforcer with a concurrent activity requirement for the duration of the delay. When the delay to the larger reinforcer with the concurrent activity requirement was gradually increased from 0 s to the terminal delay, participants switched to and maintained selection of that option, thereby demonstrating increased self-control. Finally, the duration of the concurrent activity was gradually reduced without changing the duration of the delay to the large reinforcer. All 3 participants continued to select the delayed large reinforcer, showing self-controlled responding in the absence of a concurrent activity.
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