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.

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.

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.

Capacity and consent: Knowledge and practice of legal and healthcare standards.

INTRODUCTION:: Healthcare practitioners have a legal, ethical and professional obligation to obtain patient consent for all healthcare treatments. There is increasing evidence which suggests dissonance and variation in practice in assessment of decision-making capacity and consent processes. AIMS:: This study explores healthcare practitioners' knowledge and practices of assessing decision-making capacity and obtaining patient consent to treatment in the acute generalist setting. METHODS:: An exploratory descriptive cross-sectional survey design, using an online questionnaire, method was employed with all professional groups invited via email to participate. Data were collected over 3 months from July to September 2015. Survey content and format was reviewed by the liaison psychiatry team and subsequently contained five sections (demographics, general knowledge and practice, delirium context, legal aspects and education/training). Descriptive, univariate and bivariate analysis of quantitative data and qualitative content analysis of qualitative data were undertaken. ETHICAL CONSIDERATIONS:: The study was approved by the institutional Human Research and Ethics Committee and informed consent was taken to be provided by participants upon completion and submission of the de-identified survey. RESULTS:: In total, 86 participants engaged the survey with n = 24, exiting at the first consent question. Almost two-thirds of respondents indicated that all treatments required patient consent. Knowledge of consent and decision-making capacity as legal constructs was deficient. Decision-making capacity was primarily assessed using professional judgement and perceived predominantly as the responsibility of medical and psychology staff. A range of patient psychological and behavioural symptoms were identified as indicators requiring assessment of decision-making capacity. Despite this, many patients with delirium have their decision-making capacity assessed and documented only sometimes. Uncertain knowledge and inconsistent application of legislative frameworks are evident. Many participants were unsure of the legal mechanisms for obtaining substitute consent in patients with impaired decision-making capacity and refusing treatment. CONCLUSION:: The legal context of decision-making capacity and consent to treatment appears complex for healthcare practitioners. Professional, ethical and legal standards of care in this context can benefit from structured education programmes and supportive governance processes. An understanding of why 'duty of care' is being used as a framework within the context of impaired decision-making capacity is warranted, alongside a review of the context of Duty of Care within health policy, guidance and faculty teaching.

High acuity rural transport: findings from a qualitative investigation.

INTRODUCTION: The High Acuity Response Team (HART) was introduced in British Columbia (BC), Canada, to fill a gap in transport for rural patients that was previously being met by nurses and physicians leaving their communities to escort patients in need of critical care. The HART team consists of a critical care registered nurse (CCRN) and registered respiratory therapist (RRT) and attends acute care patients in rural sites by either stabilizing them in their community or transporting them. HART services are deployed in partnership with provincial ambulance services, which provide vehicles and coordination of all requests in the province for patient transport. This article presents the qualitative findings from a research evaluation of the efficacy of the HART model, including staffing and inter-organizational functioning. METHOD: Open-ended qualitative research interviewing was done with key stakeholders from 21 sites. Research participants included HART CCRNs, RRTs, administrative leads, as well as local emergency department (ED) physicians and nurses. Thematic analysis was done of the transcripts. RESULTS: A total of 107 interviews in 21 study sites were completed. Participants described characteristics of the model, perceptions of efficacy and areas for improvement. Rural sites reported a decrease in physician- and nurse-accompanied transports for high-acuity patients due to the HART team, but also noted challenges in delayed deployment, sometimes leading to adverse patient outcomes. CONCLUSIONS: The salient issues for the HART model were grounded in a somewhat artificial distinction between pre-hospital and interfacility transport for rural patients, which leads to a lack of service coordination and potentially avoidable delays. A beneficial systems change would be to move towards dedicated integration of high-acuity transport services into hospital organizational structures and community health services in rural areas.

'Mental health day' sickness absence amongst nurses and midwives: workplace, workforce, psychosocial and health characteristics.

AIM: To examine the workforce, workplace, psychosocial and health characteristics of nurses and midwives in relation to their reported use of sickness absence described as 'mental health days'. BACKGROUND: The occupational stress associated with the nursing profession is increasingly recognized and nurse/midwifery absenteeism is a significant global problem. Taking a 'mental health day' as sickness absence is a common phenomenon in Australian health care. No previous studies have empirically explored the characteristics of nurses and midwives using such sickness absence. DESIGN: Online cross-sectional survey. METHODS: Survey comprising validated tools and questions on workplace and health characteristics was distributed to nurses and midwives in New South Wales, Australia, between May 2014 - February 2015. Sample characteristics were reported using descriptive statistics. Factors independently predictive of 'mental health day' reportage were determined using logistic regression. RESULTS: Fifty-four percentage of the n = 5041 nurse and midwife respondents took 'mental health days'. Those affected were significantly more likely to be at younger ages, working shifts with less time sitting at work; to report workplace abuse and plans to leave; having been admitted to hospital in previous 12 months; to be current smokers; to report mental health problems, accomplishing less due to emotional problems and current psychotropic medication use. CONCLUSION: Specific characteristics of nurses and midwives who report taking 'mental health day' sickness absence offer healthcare administrators and managers opportunities for early identification and intervention with workplace measures and support frameworks to promote well-being, health promotion and safety.

A point prevalence study of the use of psychotropic medication in an acute general hospital.

BACKGROUND: There are high rates of cognitive problems and organic and functional psychiatric disorders in patients admitted to general hospital wards, which may necessitate the use of psychotropic medications. There is evidence of over-prescription of medications such as antipsychotics and antidepressants in community settings such as residential care. However, the prevalence of psychotropic use in general hospitals is unknown. METHODS: A point prevalence study of the use of psychotropic medications in an acute general hospital was conducted by auditing medication charts for type, dose, indication, and other clinical processes associated with their use. RESULTS: The files of 197 patients were audited, 139 (70%) were aged 65 years and over. Eighty-nine (45%) of patients were prescribed a psychotropic, with 35 (17.7%) antidepressants; 21 (11%) antipsychotics; 19 (10%) benzodiazepines; six (3%) mood stabilizer; five (2%) cholinesterase inhibitors; one (0.5%) anti-parkinsonian medication, and one (1%) patient on zolpidem and another patient melatonin (1%). Most prescriptions (72%) were in people 65 years and over and 27 (20%) of indications were found to be off label prescribing. There were deficits in the documentation of indications for the use of psychotropic medications and follow up arrangements. CONCLUSIONS: Rates of benzodiazepines use were less than that reported incomparable settings. Concerns regarding off label prescribing, under-dosing, and lack of adequate documentation of indications and follow-up instructions were raised. Given the potential adverse effects of psychotropic medication, improved governance, and education regarding their use is required.

Decision-Making Capacity and its Relationship to a Legally Valid Consent: Ethical, Legal and Professional Context.

Decision-making capacity has been researched from within the disciplines of bioethics, medicine and law. The field of capacity assessment is dominated by tension between the principles of autonomy (self-determination) and beneficence (protection). Further, decision-making capacity is argued to be the central component of a legally valid consent. This article discusses the relevant ethical, legal and professional responsibilities relating to decision-making capacity and consent to treatment within health care. It begins with an overview of the ethical principles underpinning decision-making capacity and consent, and follows with a legal analysis of these concepts, focusing on the common law of trespass and negligence. The article then explores the concepts of best interests and necessity, which underpin the treatment of incapacitated persons, before concluding with an examination of treatment refusal and legislation relating to decision-making capacity and consent to treatment.

Application and implications of Mental Health Act 2007 (NSW) certificate use in acute generalist settings.

Objective This retrospective study aimed to explore the appropriate application and implications of Mental Health Act 2007 (NSW) (MHA) certificate use in a metropolitan generalist hospital in New South Wales. Methods A de-identified MHA certificate review was undertaken within acute generalist medical and surgical specialties between June 2012 and May 2013. To assess differences, data were separated into two categories according to whether certificates were completed by psychiatry trainees or generalist medical officers. Analysis of indications for detention was also undertaken and qualitatively matched against legislative criteria. Results A total of 43 MHA certificates were included in the review, which highlighted missing elements in most certificates. Differences were found when professional consensus by the researchers was used to match documentation to legislative criteria. The researchers disagreed with nine of the 16 indications (mental illness/mental disorder) by the generalist medical officers and only one indication by a psychiatry trainee. Six of the certificates appeared to be related to lack of capacity and need for treatment of medical conditions, thus more related to Guardianship Act 1987 (NSW) applications. Conclusion This study highlights inconsistencies in legislative knowledge and requirements between professional groups. Education and training opportunities have been identified to ensure greater consistency in application of the MHA, preservation of patient rights and avoidance of stigma. MHA use in this setting should be exercised with caution and by appropriately trained individuals. What is known about the topic? The MHA and its state and territory counterparts provide for the treatment, care and support of people who have a mental illness and the protection of a person's rights therein. Despite not being intended for application in generalist facilities, mental health legislation is widely used in generalist facilities and certificates are completed by generalist health professionals with limited training in this area of practice. What does this paper add? This study adds to the limited body of knowledge in relation to MHA detention in acute generalist facilities. Disparate preparation of medical officers in the use of this legislation has been identified, which has potential wider implications for patients beyond immediate care. What are the implications for practitioners? Inadequate attention to correct completion of MHA certificates and associated documentation could potentially invalidate detention, leaving healthcare professionals and institutions open to litigious claims that restrictive or coercive practices subsequent to the certificate's completion were technically unlawful. Further, detention under the MHA, albeit temporarily, has potential human rights issues attached and wrongful detention could lead to longstanding issues relating to stigma.

The mental health of nurses in acute teaching hospital settings: a cross-sectional survey.

BACKGROUND: Nursing is an emotionally demanding profession and deficiencies in nurses' mental wellbeing, characterised by low vitality and common mental disorders, have been linked to low productivity, absenteeism and presenteeism. Part of a larger study of nurses' health, the aim of this paper was to describe the mental health status and related characteristics of nurses working in two acute metropolitan teaching hospitals. METHODS: A cross sectional survey design was used. The Registered and Enrolled Nurse workforce, employed on any form of contract, at two teaching hospitals in Sydney Australia were invited to participate. The survey tool was compiled of validated tools and questions. Family and medical history and health risk-related characteristics, current psycho-active medications, smoking status, alcohol intake, eating disorders, self-perceived general health, mental health and vitality, demographic, social and occupational details were collected. RESULTS: A total of 1215 surveys were distributed with a usable response rate of 382 (31.4%). Altogether 53 nurses (14%) reported a history of mental health disorders, of which n = 49 (13%) listed diagnoses of anxiety and/or depression; 22 (6%) were currently taking psychoactive medication. Symptoms that could potentially indicate a mental health issue were more common, with 248 (65.1%) reporting they had experienced symptoms sometimes or often in the last 12 month. Nurses had better mental health if they had better general health, lived with a spouse/ partner rather than alone, had fewer symptoms, sleep problems or disordered eating behaviours, were not an informal carer and did not work nights. Nurses had greater vitality if they were male, had better general health, fewer sleep problems or symptoms generally and lived with a spouse/ partner rather than alone; less vitality if they were an informal carer or had disordered eating. CONCLUSION: Nurses and their managers should strive to create workplaces where working practices promote nurses' health and wellbeing, or at least are configured to minimise deleterious effects; where both nurses and their managers are aware of the potential for negative effects on the mental health of the workforce; where cultures are such that this can be discussed openly without fear of stigma or denigration.

Collaboration amongst clinical nursing leadership teams: a mixed-methods sequential explanatory study.

AIM: To explore intra-professional collaboration amongst nursing leadership teams at a tertiary referral hospital in Sydney. BACKGROUND: Effective working within a wide network of alliances is critical to patient outcomes. An understanding of collaboration amongst nursing leadership teams is essential within this context. METHODS: A sequential explanatory mixed-methods design was used. The Collaborative Behaviour scale was sent to 106 Nurse Unit Managers, Nurse Educators and Clinical Nurse Consultants to measure pairwise collaborative behaviours; two follow-up focus groups with 15 participants were conducted. Data were collected between May 2012 and May 2013. A thematic analysis of focus group data provided a detailed explanation of the questionnaire findings. RESULTS: The findings identified high collaboration between dyad groups. Two themes emerged from the thematic analysis: (1) professional role and expectations; with sub-themes of transparency and clarity of individual roles; and intra/interpersonal aspects of role functioning; and (2) organisational infrastructure and governance. CONCLUSION: These leadership teams can be effective and powerful vehicles for change and are central to optimum patient outcomes. Organisational strategic planning and evaluation can benefit from understanding how to promote collaborative behaviours in these nurse leaders. IMPLICATIONS FOR NURSING MANAGEMENT: To date, little research has explored collaboration amongst nursing leadership teams. Successful collaboration may contribute to the efficient use of nursing resources; improve patient outcomes, and ultimately, nurse satisfaction and retention.

Direct care activities for assistants in nursing in inpatient mental health settings in Australia: A modified Delphi study.

This paper describes a modified Delphi approach to developing a set of direct care activities for assistants in nursing (AIN) working in mental health settings within a metropolitan local health district (LHD). Although AIN have been employed in a range of health care settings in recent years, they have not routinely been placed in the mental health context. A modified Delphi method was utilised as it has a proven history of application in the health sector, particularly in circumstances where new guidelines, policies or practice frameworks were required. A set of direct care activities for working in mental health settings was developed from an initial set of baseline descriptors and then two rounds of consensus conferencing with a panel of experts. This paper will detail that process and discuss the resulting implications for the consensus reached on the set of direct care activities.

Satisfaction with clinical placement--The perspective of nursing students from multiple universities.

Projected nursing shortfalls in Australia have identified the need for organisational planning and strategies around recruitment and retention in healthcare facilities. Strategies include but are not limited to alliances with university faculty and the quality of undergraduate clinical placement experience. This cross-sectional study explored undergraduate nursing students' satisfaction with clinical placement experience from the perspective of multiple university faculties, and the relationship this has with future employment intention at a metropolitan hospital in Sydney, New South Wales. Findings from respondents demonstrated satisfaction with the clinical placement on the following criteria: expectations being met; welcoming of unit staff and attitudes of thereafter; clinical and university facilitator support; and participation in patient care. Three quarters of respondents also indicated that they would consider the hospital as a future employer. Satisfaction with clinical placement experience may aid organisational recruitment strategies.

'eSimulation'. Part 2: Evaluation of an interactive multimedia mental health education program for generalist nurses.

This paper reports on an evaluation of an eSimulation mental health education program for generalist nurses; developed using the following five key attributes of simulation: (1) creating a hypothetical opportunity; (2) authentic representation; (3) active participation; (4) integration; (5) repetition, evaluation and reflection. Four themes emerged from a qualitative thematic analysis of semi-structured interview data involving fourteen generalist nurses. The following four themes: (1) authenticity; (2) participation; (3) clinical reasoning; (4) control of learning provide supporting evidence that these attributes are positioned within the learning resource. Participants found the scenarios within the resource realistic, engaging and relevant to their scope of practice. This type of learning resource may help in developing the knowledge, skills and confidence of generalist nurses in delivering safe and competent mental health care in the generalist setting, when access to specialist services and appropriate means of training are unavailable.

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.

Hydantoin based inhibitors of MMP13--discovery of AZD6605.

Piperidine ether and aryl piperazine hydantoins are reported as potent inhibitors of MMP13. A medicinal chemistry campaign focused on replacing the reverse hydroxamate zinc binding group associated with historical inhibitors with a hydantoin zinc binding group then optimising MMP13 potency, solubility and DMPK properties whilst maintaining good selectivity over MMP14. A number of high quality candidates were progressed and following rat and dog safety evaluation, AZD6605 (3m) was identified as a candidate drug.

Discovery of AZD3514, a small-molecule androgen receptor downregulator for treatment of advanced prostate cancer.

Removal of the basic piperazine nitrogen atom, introduction of a solubilising end group and partial reduction of the triazolopyridazine moiety in the previously-described lead androgen receptor downregulator 6-[4-(4-cyanobenzyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (1) addressed hERG and physical property issues, and led to clinical candidate 6-(4-{4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (12), designated AZD3514, that is being evaluated in a Phase I clinical trial in patients with castrate-resistant prostate cancer.

Assessing patient capacity to consent to treatment: an integrative review of instruments and tools.

AIMS AND OBJECTIVES: To provide a narrative synthesis of research findings on instruments or tools designed to aid assessment of patient capacity to consent to treatment. BACKGROUND: Capacity assessment is of significant priority within health care as a finding of incapacity is a vehicle for the removal of many of an individual's fundamental rights. Despite there being many instruments and tools available to aid health professionals in the assessment of patient capacity, there are no standardised guidelines from professional bodies that inform the assessment of mental capacity. DESIGN: Integrative review. METHOD: Primary studies of instruments or tools concerning assessment of patient capacity to consent to treatment, published in English in peer-reviewed journals between January 2005-December 2010, were included in the review. Review papers of capacity assessment instruments were included for years including and prior to 2006. RESULTS: Nineteen instruments were found which assess patient capacity to consent. Key themes were identified in terms of capacity domains assessed, psychometric properties, instrument implementation, patient populations studied and instrument versus clinician judgement. CONCLUSION: Despite a plethora of capacity assessment instruments and tools available, only a small number of instruments were found to have demonstrated both reliability and validity. Further research is required to improve the validity of existing capacity assessment instruments. RELEVANCE TO CLINICAL PRACTICE: Increased attention to patient rights and autonomy arguably places a considerable burden on healthcare professionals to facilitate capacity assessments across a continuum of health care. Despite a plethora of capacity assessment instruments and tools being available to healthcare professionals, a comprehensive assessment requires time and is often difficult in the acute care setting. A strictly formulaic approach to the assessment of capacity is unlikely to capture specific individual nuances; therefore, capacity assessment instruments should support, but not replace, experienced clinical judgement.