Discovery of a Series of Orally Bioavailable Androgen Receptor Degraders for the Treatment of Prostate Cancer.

Androgen receptor (AR) signaling plays a key role in the progression of prostate cancer. This study describes the discovery and optimization of a novel series of AR PROTAC degraders that recruit the Cereblon (CRBN) E3 ligase. Having identified a series of AR ligands based on 4-(4-phenyl-1-piperidyl)-2-(trifluoromethyl)benzonitrile, our PROTAC optimization strategy focused on linker connectivity and CRBN ligand SAR to deliver potent degradation of AR in LNCaP cells. This work culminated in compounds 11 and 16 which demonstrated good rodent oral bioavailability. Subsequent SAR around the AR binding region brought in an additional desirable feature, degradation of the important treatment resistance mutation L702H. Compound 22 (AZ'3137) possessed an attractive profile showing degradation of AR and L702H mutant AR with good oral bioavailability across species. The compound also inhibited AR signaling in vitro and tumor growth in vivo in a mouse prostate cancer xenograft model.

Development of a Series of Pyrrolopyridone MAT2A Inhibitors.

The optimization of an allosteric fragment, discovered by differential scanning fluorimetry, to an in vivo MAT2a tool inhibitor is discussed. The structure-based drug discovery approach, aided by relative binding free energy calculations, resulted in AZ'9567 (21), a potent inhibitor in vitro with excellent preclinical pharmacokinetic properties. This tool showed a selective antiproliferative effect on methylthioadenosine phosphorylase (MTAP) KO cells, both in vitro and in vivo, providing further evidence to support the utility of MAT2a inhibitors as potential anticancer therapies for MTAP-deficient tumors.

Discovery of AZD4747, a Potent and Selective Inhibitor of Mutant GTPase KRASG12C with Demonstrable CNS Penetration.

The glycine to cysteine mutation at codon 12 of Kirsten rat sarcoma (KRAS) represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 14, AZD4747, a clinical development candidate for the treatment of KRASG12C-positive tumors, including the treatment of central nervous system (CNS) metastases. Building on our earlier discovery of C5-tethered quinazoline AZD4625, excision of a usually critical pyrimidine ring yielded a weak but brain-penetrant start point which was optimized for potency and DMPK. Key design principles and measured parameters that give high confidence in CNS exposure are discussed. During optimization, divergence between rodent and non-rodent species was observed in CNS exposure, with primate PET studies ultimately giving high confidence in the expected translation to patients. AZD4747 is a highly potent and selective inhibitor of KRASG12C with an anticipated low clearance and high oral bioavailability profile in humans.

Optimization of a series of novel, potent and selective Macrocyclic SYK inhibitors.

Spleen tyrosine kinase (SYK) is a non-receptor cytoplasmic kinase. Due to its pivotal role in B cell receptor and Fc-receptor signalling, inhibition of SYK has been a target of interest in a variety of diseases. Herein, we report the use of structure-based drug design to discover a series of potent macrocyclic inhibitors of SYK, with excellent kinome selectivity and in vitro metabolic stability. We were able to remove hERG inhibition through the optimization of physical properties, and utilized a pro-drug strategy to address permeability challenges.

Mapping quality improvement education initiatives to Standards for QUality Improvement Reporting Excellence (SQUIRE) guidelines.

AIMS AND OBJECTIVES: To explore the rigour of nurse-led quality improvement projects involving education, training or continuing professional development, and examine evaluation frameworks contained within. BACKGROUND: Healthcare organisations invest significantly in quality improvement in the pursuit of cost-effective, safe, evidence-based and person-centred care. Consequently, efforts to examine the success of investment in quality improvement activities are prominent, against a backdrop of rising healthcare expenditure, reforms, consumer expectations and feedback. DESIGN: A qualitative document analysis of quality improvement projects located in a local health district repository was undertaken. METHODS: N = 3004 projects were screened against inclusion criteria, with n = 160 projects remaining for analysis. Projects were mapped to an adapted version of the Standards for QUality Improvement Reporting Excellence (SQUIRE), specifically the education extension (SQUIRE-EDU). Additionally, project evaluation frameworks were positioned within Kirkpatrick's four levels of training evaluation model. The SQUIRE checklist was also applied in line with EQUATOR guidelines. RESULTS: Of n = 60 completed projects assessed against four broad SQUIRE-EDU categories and relevant criteria, n = 36 were assessed not to have met any categories, n = 14 projects met one category, n = 8 projects met two categories, and n = 2 projects met three categories. None of the completed projects met all four SQUIRE-EDU categories. There was insufficient documentation relating to evaluation frameworks in n = 133 projects to position within Kirkpatrick's four levels of training evaluation. CONCLUSIONS: Scientific rigour should underpin all quality improvement efforts. We recommend that SQUIRE international consensus guidelines (full or abridged) should guide both the design and reporting of all local quality improvement efforts. RELEVANCE TO CLINICAL PRACTICE: To be of value to the expansion of evidence-based practice, quality improvement platforms should be designed to reflect the structural logic, rigour and reporting recommendations being advocated in consensus reporting guidelines. This may require investment in training and development programs, and identification of governance and support systems. No Patient or Public Contribution, as the study was retrospective in nature and involved a health service repository of quality improvement projects accessible to health service staff only.

Discovery of AZD4625, a Covalent Allosteric Inhibitor of the Mutant GTPase KRASG12C.

KRAS is an archetypal high-value intractable oncology drug target. The glycine to cysteine mutation at codon 12 represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 21, AZD4625, a clinical development candidate for the treatment of KRASG12C positive tumors. Highlights include a quinazoline tethering strategy to lock out a bio-relevant binding conformation and an optimization strategy focused on the reduction of extrahepatic clearance mechanisms seen in preclinical species. Crystallographic analysis was also key in helping to rationalize unusual structure-activity relationship in terms of ring size and enantio-preference. AZD4625 is a highly potent and selective inhibitor of KRASG12C with an anticipated low clearance and high oral bioavailability profile in humans.

Empathy education in post-graduate nurses: An integrative review.

AIM: This study reviews the outcomes of programmes teaching empathy to post-graduate nurses. BACKGROUND: Nurses who are able to empathise with their patients, place themselves within a preferred position to deliver better patient outcomes. There have been substantial efforts to improve the empathy skill level of undergraduate nursing students, with success but understanding this skill level at the post graduate level is limited. DESIGN: An integrated literature review of the qualitative and quantitative literature on nurse post graduate education programmes over the last 10 years was conducted. DATA SOURCES: CINAHL, Medline, Psych-Info, Google Scholar and hand searching of reference lists of relevant papers were used. REVIEW METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and the Mixed Methods Appraisal Tool (MMAT) was used for quality appraisal. RESULTS: The review includes nine quantitative non randomised studies and one qualitative study. The findings suggest that empathy skills in post graduate nurses can be improved, but given the variation in the operational definition of empathy used, range in frequency and length of training and speciality specific requirements further work is needed to understand the use of 'empathy' in the post graduate nurse. CONCLUSION: Future non university based or 'in house' empathy education in nursing should focus on the post graduate nurse and the needs of their clinical specialties.

Development and effectiveness of tabletop exercises in preparing health practitioners in violence prevention management: A sequential explanatory mixed methods study.

BACKGROUND: Workplace violence in healthcare remains a significant issue for healthcare professional, in terms of risk to patients and staff. One part of a workplace violence prevention and management programme is to educate staff in their response to critical events. Drawn from the disaster management literature, tabletop exercises were used in this study to simulate workplace violence and educate staff on the appropriate emergency response during a violent event. The use of tabletop exercise in this context is a novel approach to workplace violence prevention management. AIM AND OBJECTIVE: This study describes the development and effectiveness of tabletop exercises in preparing health practitioners in violence prevention and management emergency response systems. METHODS: Using a sequential explanatory mixed method design. The study comprised of two phases 1) quasi-experimental (quantitative) and 2) focus group (qualitative) to evaluate the effectiveness of the violence prevention management tabletop exercises. COREQ guidelines were followed the qualitative arm of the study and the TREND statement for the quantitative part of the study. RESULTS: Statistically significant improvements in healthcare professional confidence levels were found two weeks post the tabletop exercises. A post focus group revealed three categories concerning the participant's experiences of the tabletop exercises, (role clarity, adult learning and organisational support). CONCLUSION: Tabletop exercise may provide a, low cost, context specific novel approach to educating staff in emergency violence response systems at a tertiary referral hospital. Educators and policy makers may consider the use of tabletop exercises in the ongoing work in preparing health care staff for workplace violence. RELEVANCE TO CLINICAL PRACTICE: Successful tabletop exercises should consider a local ward level context, the use of adult learning principles, have high level organisational support and cover role clarity as a key learning area.

Examining the utility of the Violence Prevention Climate scale: In a metropolitan Australian general hospital.

AIM AND OBJECTIVES: To evaluate and examine the utility of the Violence Prevention Climate scale by generalist healthcare professionals. BACKGROUND: Workplace violence in general hospital settings remains a challenge for healthcare organisations. High rates of violence are still being reported towards healthcare workers, despite organisational violence prevention strategies being implemented. There is a major challenge to healthcare organisation in the measurement of the effectiveness of these interventions, traditionally completed via the reporting and monitoring of workplace violent incidents. A novel approach to measuring workplace violence is by studying hospital atmosphere or climate. DESIGN: A cross-sectional survey using the STARD guidelines was used. METHODS: The Violence Prevention Climate scale was completed by 194 healthcare staff working in the emergency department, medical/surgical wards, respiratory/infectious disease, spinal care, renal unit, corrections health, and rehabilitation and community services of a major Australian tertiary referral hospital. The Violence Prevention Climate scale has previously been validated and used in mental health settings, but not general hospital settings. A content analysis of an open-ended question on violence prevention management strategies was also conducted. RESULTS: Comprising of 14 items with two factors (patients and staff), the study revealed a 9-item staff factor scale that can be used in the general hospital setting, the patient factor did not show adequate reliability. The content analysis revealed seven categories of staff identified violence prevention and management strategies. CONCLUSIONS: The use of the 9-item scale across an organisation annually, or added to existing organisational workforce surveys, could prove to be practical way of measuring the social climate of violence in a general hospital setting. RELEVANCE TO CLINICAL PRACTICE: The results of which could guide clinical practice, workplace safety, policy and educational initiatives for the prevention and management of workplace violence.

Mental Capacity Assessments for COVID-19 Patients: Emergency Admissions and the CARD Approach.

The doctrine of consent (or informed consent, as it is called in North America) is built upon presumptions of mental capacity. Those presumptions must be tested according to legal rules that may be difficult to apply to COVID-19 patients during emergency presentations. We examine the principles of mental capacity and make recommendations on how to assess the capacity of COVID-19 patients to consent to emergency medical treatment. We term this the CARD approach (Comprehend, Appreciate, Reason, and Decide).

COVID-19 and Australian Prisons: Human Rights, Risks, and Responses.

Australian prisons are overpopulated with people suffering from numerous health problems. COVID-19 presents a significant threat to prisoner health. This article examines the current regulatory responses from Australian state and territory governments to COVID-19 and a recent case which tested the human rights of prisoners during a pandemic.

The misuse of "duty of care" as justification for non-consensual coercive treatment.

The duty of care concept is a common law legal principle which underpins all healthcare interactions. However, evidence within the Australian context suggests misuse of this common law principle as a justification for non-consensual coercive treatment. Misuse seems to occur particularly where patients have impaired decision-making capacity and/or refuse treatment. In this article, we discuss the emerging evidence of misuse, which arguably reflects healthcare practitioner confusion between the doctrines of 'duty of care' and 'necessity', and posit that cognisance of lawful substitute consent processes are lacking. We then discuss the concept of duty of care as an obligation, as opposed to a power, before presenting the elements of a valid consent and legislation relating to substitute consent, which allow health practitioners to proceed with treatment. We conclude this article with a discussion of the circumstances where treatment may be given without consent.

Understanding Ethical and Legal Obligations in a Pandemic: A Taxonomy of "Duty" for Health Practitioners.

From the ethics perspective, "duty of care" is a difficult and contested term, fraught with misconceptions and apparent misappropriations. However, it is a term that clinicians use frequently as they navigate COVID-19, somehow core to their understanding of themselves and their obligations, but with uncertainty as to how to translate or operationalize this in the context of a pandemic. This paper explores the "duty of care" from a legal perspective, distinguishes it from broader notions of duty on professional and personal levels, and proposes a working taxonomy for practitioners to better understand the concept of "duty" in their response to COVID-19.

Identification of a novel series of azabenzimidazole-derived inhibitors of spleen tyrosine kinase.

Spleen Tyrosine Kinase (SYK) is a well-studied enzyme with therapeutic applications in oncology and autoimmune diseases. We identified an azabenzimidazole (ABI) series of SYK inhibitors by mining activity data of 86,000 compounds from legacy biochemical assays with SYK and other homologous kinases as target enzymes. A structure-based design and hybridization approach was then used to improve the potency and kinase selectivity of the hits. Lead compound 23 from this novel ABI series has a SYK IC50 = 0.21 nM in a biochemical assay and inhibits growth of SUDHL-4 cells at a GI50 = 210 nM.

Optimization of a series of potent, selective and orally bioavailable SYK inhibitors.

Spleen tyrosine kinase (SYK) is a non-receptor cytosolic kinase. Due to its pivotal role in B cell receptor and Fc-receptor signaling, inhibition of SYK has been targeted in a variety of disease areas. Herein, we report the optimization of a series of potent and selective SYK inhibitors, focusing on improving metabolic stability, pharmacokinetics and hERG inhibition. As a result, we identified 30, which exhibited no hERG activity but unfortunately was poorly absorbed in rats and mice. We also identified a SYK chemical probe, 17, which exhibits excellent potency at SYK, and an adequate rodent PK profile to support in vivo efficacy/PD studies.

Structure-Based Design and Pharmacokinetic Optimization of Covalent Allosteric Inhibitors of the Mutant GTPase KRASG12C.

Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRASG12C mutant represents an "Achilles heel" and has recently yielded to covalent targeting with small molecules that bind the mutant cysteine and create an allosteric pocket on GDP-bound RAS, locking it in an inactive state. A weak inhibitor at this site was optimized through conformational locking of a piperazine-quinazoline motif and linker modification. Subsequent introduction of a key methyl group to the piperazine resulted in enhancements in potency, permeability, clearance, and reactivity, leading to identification of a potent KRASG12C inhibitor with high selectivity and excellent cross-species pharmacokinetic parameters and in vivo efficacy.

Mind the gaps: identifying opportunities in mental health assessment and mental health certificate completion in rural and remote NSW, Australia.

OBJECTIVE: This study aimed to examine the quality of mental health certificate (MHC) completion in rural and remote New South Wales, to include the determination of those identified as mentally ill or mentally disordered, and subsequent processes thereafter. METHODS: MHCs were collected from April 2016 to March 2017. A de-identified review was undertaken and audited for completion of mandatory criteria. Data were separated by three groups of completing health practitioners, and descriptive and inferential statistics calculated to assess for differences between groups. RESULTS: A total of 277 MHCs were included. Local medical officers were significantly more likely to: have longer assessment periods, indicate mentally disordered rather than mentally ill, and to have the mental health certificate revoked upon reassessment at a declared mental health facility, than their psychiatry or accredited person peers. They were also significantly less likely to complete documentation relating to behaviour personally assessed or observed by others. CONCLUSION: This study identified inconsistencies in documentation completion between groups, highlighting training opportunities for non-mental health specialists, particularly mental health assessment and lawful detention requirements. Attention to this is warranted within medical training syllabuses, post-graduate training and support programs.

Discovery of a Potent and Selective Oral Inhibitor of ERK1/2 (AZD0364) That Is Efficacious in Both Monotherapy and Combination Therapy in Models of Nonsmall Cell Lung Cancer (NSCLC).

The RAS/MAPK pathway is a major driver of oncogenesis and is dysregulated in approximately 30% of human cancers, primarily by mutations in the BRAF or RAS genes. The extracellular-signal-regulated kinases (ERK1 and ERK2) serve as central nodes within this pathway. The feasibility of targeting the RAS/MAPK pathway has been demonstrated by the clinical responses observed through the use of BRAF and MEK inhibitors in BRAF V600E/K metastatic melanoma; however, resistance frequently develops. Importantly, ERK1/2 inhibition may have clinical utility in overcoming acquired resistance to RAF and MEK inhibitors, where RAS/MAPK pathway reactivation has occurred, such as relapsed BRAF V600E/K melanoma. We describe our structure-based design approach leading to the discovery of AZD0364, a potent and selective inhibitor of ERK1 and ERK2. AZD0364 exhibits high cellular potency (IC50 = 6 nM) as well as excellent physicochemical and absorption, distribution, metabolism, and excretion (ADME) properties and has demonstrated encouraging antitumor activity in preclinical models.