Bridging conservation across the ex situ-in situ spectrum: Insights into the reproductive ecology of the threatened narrow-headed gartersnake (Thamnophis rufipunctatus).

Zoo-based (ex situ) conservation breeding programs provide invaluable opportunities to uncover enigmatic behaviors and traits of focal species under managed care, which can support research and conservation management efforts. A suite of factors and a limited range have yielded population declines in the threatened narrow-headed gartersnake (Thamnophis rufipunctatus). Better understanding its cryptic ecology and life history (e.g., reproductive ecology) offers conservation benefits. We analyzed data on courtship behavior, parity and litter size, offspring size, and neonatal growth from an ex situ T. rufipunctatus population at the Phoenix Zoo from 2009 to 2018. Courtship behavior and parturition phenology are likely linked with the North American monsoon season, yet the courtship window may be wider than realized. We document the first instances of interannual iteroparity and multigenerational rearing of successful breeders at the ex situ level. Litter sizes varied but were relative to maternal body mass, suggesting that fecundity may be driven by intrinsic condition (e.g., age and size) of breeding females. Mean offspring body masses were equivalent between sexes, and neonate growth trends were quadratic during their first 9 months. Sexual dimorphism became apparent around 4-5 months age. Much of these data are novel for T. rufipunctatus and provide insight into their reproductive ecology. Phenology of reproductive ecology and body size metrics can guide field surveillance, age estimations, and population ecology monitoring, as well as inform ex situ adaptive management practices. Strategies spanning the ex situ-in situ spectrum are applicable to other imperiled taxa to better inform conservation management decisions.

Adaptive management in a conservation breeding program: Mimicking habitat complexities facilitates reproductive success in narrow-headed gartersnakes (Thamnophis rufipunctatus).

Mimicking natural parameters and complexities in zoo conservation breeding programs can facilitate natural physiological and behavioral traits, which in turn can inform more effective species reintroduction efforts. To curtail population declines of threatened narrow-headed gartersnakes (Thamnophis rufipunctatus), the Arizona Center for Nature Conservation/Phoenix Zoo partnered with a multiagency conservation working group to develop an ex situ propagation-for-release program. Initially, Zoo staff followed common snake husbandry protocols of manually inducing brumation (i.e., winter dormancy). Copulation was observed during the first few years, but no births resulted. Also, some older individuals developed post-brumation health abnormalities, prompting a strategic reassessment. To facilitate propagation and improve health, Zoo staff applied ecological knowledge of T. rufipunctatus and an adaptive management strategy to implement key parameters for success: sociality, refugia, breeding and foraging behaviors, and natural brumation. Zoo staff developed a large multisnake enclosure that mimicked natural ecological and habitat complexities including a hibernaculum to stimulate natural brumation. Gartersnakes were left mostly unimpeded to conduct natural behaviors across seasons in the enriched environment. We referenced change in body mass after ten brumation periods as a proxy for health. Under natural brumation, gartersnakes did not lose body mass, and this shift resulted in fully ex situ parturition events-the first for this imperiled species. We highlight the efficacy of adaptive management and incorporation of natural parameters and environmental complexities into conservation breeding programs. These actions can improve the health and success of animals under managed care-processes applicable to a range of taxa targeted for conservation translocations.

Transforming community services through the use of a multidimensional model of clinical leadership.

AIMS AND OBJECTIVES: To evaluate the application of a Multidimensional Model of Clinical Leadership on the community healthcare leader and on transforming community services. BACKGROUND: Healthcare policy advocates clinical leadership as the vehicle to transform community and healthcare services. Few studies have identified the key components of an effective clinical leadership development model. DESIGN: The first two stages of Kirkpatrick's (Personnel Administrator 28, 1983, 62) Four/Five Levels of Evaluation were used to evaluate the application of the multidimensional model of clinical leadership. METHODS: Eighty community healthcare leaders were exposed to this multidimensional clinical leadership development model through attendance of a community clinical leadership development programme. Twenty five leaders participated in focus group interviews. Data from the interviews were analysed utilising thematic content analysis. RESULTS: Three key themes emerged that influenced the development of best practice principles for clinical leadership development: 1. Personal leadership development 2. Organisational leadership 3. The importance of multiprofessional action learning/reflective groups CONCLUSIONS: Emergent best practice principles for clinical leadership development include adopting a multidimensional development approach. This approach encompasses: preparing the individual leader in the role and seeking organisational leadership development that promotes the vision and corporate values of the organisation and delivers on service improvement and innovation. Moreover, application of the Multidimensional Model of Clinical Leadership could offer the best platform for embedding the Six C's of Nursing (Compassion in Practice - Our Culture of Compassionate Care, Department of Health, Crown Copyright, 2012) within the culture of the healthcare organisation: care, compassion, courage, commitment, communication, and competency. This is achieved in part through the application of emotional intelligence to understand self and to develop the personal integrity of the healthcare leader and through supporting a culture of lifelong leadership learning. RELEVANCE TO CLINICAL PRACTICE: Embedding the best practice principles of clinical leadership development within a multidimensional model of clinical leadership provides a promising approach to: equipping the healthcare leader with those transferable leadership skills required to help them embark on a journey of lifelong leadership learning; and producing the healthcare leader who is caring, compassionate and can confidently and effectively transform community services.

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.

Balancing hERG affinity and absorption in the discovery of AZD5672, an orally active CCR5 antagonist for the treatment of rheumatoid arthritis.

Modifications to a series of potent and selective substituted 1-(3,3-diphenylpropyl)-piperidine phenylacetamide CCR5 antagonists were explored with the aim of reducing affinity at the hERG cardiac ion channel. Replacement of one aromatic ring in the diphenylpropyl region with less lipophilic, saturated heterocyclic rings and subsequent optimisation of the other phenyl ring led to the identification of clinical compound AZD5672 which retained excellent potency while reducing hERG affinity. Modulating lipophilicity affected the interplay between potency, hERG affinity and absorption. AZD5672 was found to have an acceptable balance of these properties and was progressed to a phase II clinical trial to test the hypothesis that inhibition of CCR5 will bring benefits in the treatment of rheumatoid arthritis.

Dipeptidyl nitrile inhibitors of Cathepsin L.

A series of potent Cathepsin L inhibitors with good selectivity with respect to other cysteine Cathepsins is described and SAR is discussed with reference to the crystal structure of a protein-ligand complex.

Discovery and characterization of MAPK-activated protein kinase-2 prevention of activation inhibitors.

Two structurally distinct series of novel, MAPK-activated kinase-2 prevention of activation inhibitors have been discovered by high throughput screening. Preliminary structure-activity relationship (SAR) studies revealed substructural features that influence the selective inhibition of the activation by p38α of the downstream kinase MK2 in preference to an alternative substrate, MSK1. Enzyme kinetics, surface plasmon resonance (SPR), 2D protein NMR, and X-ray crystallography were used to determine the binding mode and the molecular mechanism of action. The compounds bind competitively to the ATP binding site of p38α but unexpectedly with higher affinity in the p38α-MK2 complex compared with p38α alone. This observation is hypothesized to be the origin of the substrate selectivity. The two lead series identified are suitable for further investigation for their potential to treat chronic inflammatory diseases with improved tolerability over previously studied p38α inhibitors.

Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor.

Epidermal growth factor receptor (EGFR) inhibitors have been used clinically in the treatment of non-small-cell lung cancer (NSCLC) patients harboring sensitizing (or activating) mutations for a number of years. Despite encouraging clinical efficacy with these agents, in many patients resistance develops leading to disease progression. In most cases, this resistance is in the form of the T790M mutation. In addition, EGFR wild type receptor inhibition inherent with these agents can lead to dose limiting toxicities of rash and diarrhea. We describe herein the evolution of an early, mutant selective lead to the clinical candidate AZD9291, an irreversible inhibitor of both EGFR sensitizing (EGFRm+) and T790M resistance mutations with selectivity over the wild type form of the receptor. Following observations of significant tumor inhibition in preclinical models, the clinical candidate was administered clinically to patients with T790M positive EGFR-TKI resistant NSCLC and early efficacy has been observed, accompanied by an encouraging safety profile.

A novel series of p38 MAP kinase inhibitors for the potential treatment of rheumatoid arthritis.

A novel p38 MAP kinase inhibitor structural class was discovered through selectivity screening. The rational analogue design, synthesis and structure-activity relationship of this series of bis-amide inhibitors is reported. The inhibition in vitro of human p38alpha enzyme activity and lipopolysaccharide-induced tumour necrosis factor-alpha release is described for the series. The activity in vivo and pharmacokinetic properties are exemplified for the more potent analogues.