The application of antimicrobial stewardship knowledge to nursing practice: A national survey of United Kingdom pre-registration nursing students.

AIM: To assess student nurses understanding and skills in the application of antimicrobial stewardship knowledge to practice. DESIGN: Quantitative. METHODS: Cross-sectional survey. RESULTS: Five hundred and twenty three student nurses responded across 23 UK universities. Although students felt prepared in competencies in infection prevention and control, patient-centred care and interprofessional collaborative practice, they felt less prepared in competencies in which microbiological knowledge, prescribing and its effect on antimicrobial stewardship is required. Problem-based learning, activities in the clinical setting and face-to-face teaching were identified as the preferred modes of education delivery. Those who had shared antimicrobial stewardship teaching with students from other professions reported the benefits to include a broader understanding of antimicrobial stewardship, an understanding of the roles of others in antimicrobial stewardship and improved interprofessional working. CONCLUSION: There are gaps in student nurses' knowledge of the basic sciences associated with the antimicrobial stewardship activities in which nurses are involved, and a need to strengthen knowledge in pre-registration nurse education programmes pertaining to antimicrobial management, specifically microbiology and antimicrobial regimes and effects on antimicrobial stewardship. Infection prevention and control, patient-centred care and interprofessional collaborative practice are areas of antimicrobial stewardship in which student nurses feel prepared. Interprofessional education would help nurses and other members of the antimicrobial stewardship team clarify the role nurses can play in antimicrobial stewardship and therefore maximize their contribution to antimicrobial stewardship and antimicrobial management. IMPLICATIONS FOR THE PROFESSION: There is a need to strengthen knowledge from the basic sciences, specifically pertaining to antimicrobial management, in pre-registration nurse education programmes. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution. IMPACT: What Problem Did the Study Address? Nurses must protect health through understanding and applying antimicrobial stewardship knowledge and skills (Nursing and Midwifery Council 2018); however, there is no research available that has investigated nurses understanding and skills of the basic sciences associated with the antimicrobial stewardship activities in which they are involved. What Were the Main Findings? There are gaps in student nurses' knowledge of the basic sciences (specifically microbiology and prescribing) associated with the antimicrobial stewardship activities in which nurses are involved. Problem-based learning, and activities in the clinical setting, were reported as useful teaching methods, whereas online learning, was seen as less useful. Where and on Whom Will the Research Have an Impact? Pre-registration nurse education programmes. REPORTING METHOD: The relevant reporting method has been adhered to, that is, STROBE.

Structure-Based Exploration of Selectivity for ATM Inhibitors in Huntington's Disease.

Our group has recently shown that brain-penetrant ataxia telangiectasia-mutated (ATM) kinase inhibitors may have potential as novel therapeutics for the treatment of Huntington's disease (HD). However, the previously described pyranone-thioxanthenes (e.g., 4) failed to afford selectivity over a vacuolar protein sorting 34 (Vps34) kinase, an important kinase involved with autophagy. Given that impaired autophagy has been proposed as a pathogenic mechanism of neurodegenerative diseases such as HD, achieving selectivity over Vps34 became an important objective for our program. Here, we report the successful selectivity optimization of ATM over Vps34 by using X-ray crystal structures of a Vps34-ATM protein chimera where the Vps34 ATP-binding site was mutated to approximate that of an ATM kinase. The morpholino-pyridone and morpholino-pyrimidinone series that resulted as a consequence of this selectivity optimization process have high ATM potency and good oral bioavailability and have lower molecular weight, reduced lipophilicity, higher aqueous solubility, and greater synthetic tractability compared to the pyranone-thioxanthenes.

Optimization of Potent and Selective Ataxia Telangiectasia-Mutated Inhibitors Suitable for a Proof-of-Concept Study in Huntington's Disease Models.

Genetic and pharmacological evidence indicates that the reduction of ataxia telangiectasia-mutated (ATM) kinase activity can ameliorate mutant huntingtin (mHTT) toxicity in cellular and animal models of Huntington's disease (HD), suggesting that selective inhibition of ATM could provide a novel clinical intervention to treat HD. Here, we describe the development and characterization of ATM inhibitor molecules to enable in vivo proof-of-concept studies in HD animal models. Starting from previously reported ATM inhibitors, we aimed with few modifications to increase brain exposure by decreasing P-glycoprotein liability while maintaining potency and selectivity. Here, we report brain-penetrant ATM inhibitors that have robust pharmacodynamic (PD) effects consistent with ATM kinase inhibition in the mouse brain and an understandable pharmacokinetic/PD (PK/PD) relationship. Compound 17 engages ATM kinase and shows robust dose-dependent inhibition of X-ray irradiation-induced KAP1 phosphorylation in the mouse brain. Furthermore, compound 17 protects against mHTT (Q73)-induced cytotoxicity in a cortical-striatal cell model of HD.