Investigating the impact of a clinical pharmacist on the health outcomes of a paediatric pharmacists

Background: Recent fiscal scrutiny and changes in health care financing have necessitated that health care providers justify a clinical and economical basis for their involvement in patient care. Although clinical pharmacists have been shown to enhance patient health outcomes and reduce costs among adult patients, the impact of a pharmacist in paediatric patient care has not been extensively documented. Method: A team of pharmacists was established to conduct a systematic review of the literature. A title scan of papers in 5 databases was performed by 14 pharmacists using the MeSH terms Pharmacists, Medical Intervention, Paediatrics and Cost-Benefit Analysis. The underpinning research question was: "How do the professional activities of a clinical pharmacist impact the health outcomes of paediatric in-patients?" The abstracts of suitable titles were scanned and articles were read to assess relevance. Relevant articles were then evaluated independently by at least two members of the team, using critical appraisal tools suitable for quantitative, qualitative or systematic review studies. Results: The initial search identified 327 citations which after full text review and application of the scoring tool, resulted in 12 studies included in the systematic review. The average number of interventions reported varied from study to study. Dosing recommendations, pharmacokinetics and drug allergy alerts were the most commonly recorded interventions by pharmacists for a paediatric population. Evidence from this review will be used to formulate improvements to in-patient paediatric care. Conclusion: Clinical pharmacists have a positive impact on inpatient paediatric care

A Cell Biologist’s Field Guide to Aurora Kinase Inhibitors

Aurora kinases are essential for cell division and are frequently misregulated in human cancers. Based on their potential as cancer therapeutics, a plethora of small molecule Aurora kinase inhibitors have been developed, with a subset having been adopted as tools in cell biology. Here, we fill a gap in the characterization of Aurora kinase inhibitors by using biochemical and cell-based assays to systematically profile a panel of 10 commercially available compounds with reported selectivity for Aurora A (MLN8054, MLN8237, MK-5108, MK-8745, Genentech Aurora Inhibitor 1), Aurora B (Hesperadin, ZM447439, AZD1152-HQPA, GSK1070916) or Aurora A/B (VX-680). We quantify the in vitro effect of each inhibitor on the activity of Aurora A alone, as well as Aurora A and Aurora B bound to fragments of their activators, TPX2 and INCENP, respectively. We also report kinome profiling results for a subset of these compounds to highlight potential off-target effects. In a cellular context, we demonstrate that immunofluorescence-based detection of LATS2 and histone H3 phospho-epitopes provides a facile and reliable means to assess potency and specificity of Aurora A versus Aurora B inhibition, and that G2 duration measured in a live imaging assay is a specific readout of Aurora A activity. Our analysis also highlights variation between HeLa, U2OS and hTERT-RPE1 cells that impacts selective Aurora A inhibition. For Aurora B, all 4 tested compounds exhibit excellent selectivity and do not significantly inhibit Aurora A at effective doses. For Aurora A, MK-5108 and MK-8745 are significantly more selective than the commonly used inhibitors MLN8054 and MLN8237. A crystal structure of an Aurora A/MK-5108 complex that we determined suggests the chemical basis for this higher specificity. Taken together, our quantitative biochemical and cell-based analyses indicate that AZD1152-HQPA and MK-8745 are the best current tools for selectively inhibiting Aurora B and Aurora A, respectively. However, MK-8745 is not nearly as ideal as AZD1152-HQPA in that it requires high concentrations to achieve full inhibition in a cellular context, indicating a need for more potent Aurora A-selective inhibitors. We conclude with a set of good practice guidelines for the use of Aurora inhibitors in cell biology experiments