PRC2 disruption in cerebellar progenitors produces cerebellar hypoplasia and aberrant myoid differentiation without blocking medulloblastoma growth.

We show that Polycomb Repressive Complex-2 (PRC2) components EED and EZH2 maintain neural identity in cerebellar granule neuron progenitors (CGNPs) and SHH-driven medulloblastoma, a cancer of CGNPs. Proliferating CGNPs and medulloblastoma cells inherit neural fate commitment through epigenetic mechanisms. The PRC2 is an epigenetic regulator that has been proposed as a therapeutic target in medulloblastoma. To define PRC2 function in cerebellar development and medulloblastoma, we conditionally deleted PRC2 components Eed or Ezh2 in CGNPs and analyzed medulloblastomas induced in Eed-deleted and Ezh2-deleted CGNPs by expressing SmoM2, an oncogenic allele of Smo. Eed deletion destabilized the PRC2, depleting EED and EZH2 proteins, while Ezh2 deletion did not deplete EED. Eed-deleted cerebella were hypoplastic, with reduced proliferation, increased apoptosis, and inappropriate muscle-like differentiation. Ezh2-deleted cerebella showed similar, milder phenotypes, with fewer muscle-like cells and without reduced growth. Eed-deleted and Ezh2-deleted medulloblastomas both demonstrated myoid differentiation and progressed more rapidly than PRC2-intact controls. The PRC2 thus maintains neural commitment in CGNPs and medulloblastoma, but is not required for SHH medulloblastoma progression. Our data define a role for the PRC2 in preventing inappropriate, non-neural fates during postnatal neurogenesis, and caution that targeting the PRC2 in SHH medulloblastoma may not produce durable therapeutic effects.

Modest and variable efficacy of pre-exposure hydroxocobalamin and dicobalt edetate in a porcine model of acute cyanide salt poisoning.

Background: Dicobalt edetate and hydroxocobalamin are widely used to treat hydrogen cyanide poisoning. However, comparative and quantitative efficacy data are lacking. Although post-exposure treatment is typical, it may be possible to administer these antidotes before exposure to first attenders entering a known site of cyanide release, as supplementary protection to their personal protective equipment.Methods: We established an anaesthetised Gottingen minipig model of lethal bolus potassium cyanide (KCN) injection to simulate high dose hydrogen cyanide inhalation. Doses were similar to human lethal doses of KCN. Dicobalt edetate and hydroxocobalamin were administered shortly before KCN and their effect on metabolic and cardiovascular variables and survival time were measured.Results: Increases in arterial lactate were similar after 0.08 and 0.12 mmol/kg KCN. KCN 0.08 mmol/kg was survived by 4/4 animals with moderate cardiovascular effects, while the 0.12 mmol/kg dose was lethal in 4/4 animals, with a mean time to euthanasia of 28.3 (SEM: 13.9) min. Administration of dicobalt edetate (0.021 mmol/kg, 8.6 mg/kg) or hydroxocobalamin (0.054 mmol/kg, 75 mg/kg) at clinically licenced doses had modest effect on lactate concentrations but increased survival after administration of KCN 0.12 mmol/kg (survival: dicobalt edetate 4/4, hydroxocobalamin 2/4) but not 0.15 mmol/kg (0/4 and 0/4, respectively). In a subsequent larger study, doubling the dose of hydroxocobalamin (0.108 mmol/kg, 150 mg/kg) was associated with a modest but inconsistent increased survival after 0.15 mmol/kg KCN (survival: control 0/8, 75 mg/kg 1/10, 150 mg/kg 3/10) likely due to variable pharmacokinetics.Conclusions: In this porcine study of cyanide exposure, with pre-exposure antidote administration, licenced doses of dicobalt edetate and hydroxocobalamin were effective at just lethal doses but ineffective at less than twice the estimated LD50. The efficacy of a rapidly-administered double-dose of hydroxocobalamin was limited by variable pharmacokinetics. In clinical poisoning scenarios, with delayed administration, the antidotes are likely to be even less effective. New antidotes are required for treatment of cyanide exposures appreciably above the minimum lethal dose.

Advocating for end-of-life choice at home: a survey of rural Australian nurses.

INTRODUCTION: Rural healthcare resource limitations can affect the choices people make and their quality of life during its end stages. In rural regions of Australia, district nurses (DNs) working in generalist community roles provide access to care by visiting people in their homes. They may be well positioned to improve the quality of the end-of-life experience by advocating for choice and person-centred end-of-life goals; however, knowledge about care in this context is limited. Initial findings from an exploratory qualitative study describing how rural DNs are able to successfully advocate for the end-of-life choices and goals of people living at home need to be confirmed and further developed to inform clinical practice. This survey aimed to test and complement the findings from a narrative exploration of how DNs advocate successfully for the end-of-life goals of rural Australians. METHOD: A sequential mixed methods study based on a pragmatic design was used to explore how DNs advocate successfully for the end-of-life goals of rural Australians. In the first phase of the study two stages of reflection on experience by rural DNs from the state of Victoria (N=7) provided written and in-depth narrative understandings of how advocacy is enabled and actioned in the practice context. The data were analysed with interpretive description, resulting in findings that could be used to inform a survey for the second phase. The survey, reported here, was designed as an online questionnaire to be distributed by email across inner and outer regional Australia. It was trialled by rural health professionals (N=13) and modified according to the advice received. The participation criteria for the survey specified registered nurses working in generalist community nursing roles with experience in providing successful end-of-life advocacy for people at home. Scales were used to test and complement the phase 1 findings and analysed using Cronbach's alpha and descriptive statistics, with a 95% confidence interval calculated. Open-ended questions added to complement the understanding of how successful advocacy is enabled and actioned in this context were analysed with descriptive interpretation. RESULTS: A self-selecting sample of nurses (N=91) responded to the survey between March and July 2015. The response came from most Australian states and territories, and confirmed the findings that willing nursing involvement in end-of-life experiences, specialised rural relational knowledge, and feeling supported, together enable nurses to advocate successfully for person-centred goals. Actions based on advocacy that were highly rated for success include holistic assessment, effective end-of-life communication and the organisation of empowering and supportive care, confirming the phase 1 findings. High levels of emotional intelligence, understandings of 'going beyond duty', the types of support used and the need for advocacy for resources were reported. CONCLUSION: The results provide both confirmatory and new knowledge that can be used with confidence to inform practice with a model for rural end-of-life nursing advocacy in the home setting.

A practice model for rural district nursing success in end-of-life advocacy care.

AIM: The development of a practice model for rural district nursing successful end-of-life advocacy care. BACKGROUND: Resources to help people live well in the end stages of life in rural areas can be limited and difficult to access. District nurse advocacy may promote end-of-life choice for people living at home in rural Australia. The lack of evidence available internationally to inform practice in this context was addressed by exploratory study. METHOD: A pragmatic mixed method study approved by the University Faculty Ethics Committee and conducted from March 2014 to August 2015 was used to explore the successful end-of-life advocacy of 98 rural Australian district nurses. The findings and results were integrated then compared with theory in this article to develop concepts for a practice model. RESULTS: The model illustrates rural district nurse advocacy success based on respect for the rights and values of people. Advocacy action is motivated by the emotional responses of nurses to the end-of-life vulnerability people experience. The combination of willing investment in relationships, knowing the rural people and resources, and feeling supported, together enables district nurses to develop therapeutic emotional intelligence. This skill promotes moral agency in reflection and advocacy action to overcome emotional and ethical care challenges of access and choice using holistic assessment, communication, organisation of resources and empowering support for the self-determination of person-centred end-of-life goals. Recommendations are proposed from the theoretical concepts in the model. LIMITATIONS: Testing the model in practice is recommended to gain the perceptions of a broader range of rural people both giving and receiving end-of-life-care. CONCLUSION: A model developed by gathering and comparing district nursing experiences and understanding using mixed methods and existing theory offers evidence for practice of a philosophy of successful person-centred advocacy care in a field of nursing that lacks specific guidance.

Rural District Nursing Experiences of Successful Advocacy for Person-Centered End-of-Life Choice.

Choices in care during the end stages of life are limited by the lack of resources and access for rural people. Nursing advocacy based on the holistic understanding of people and their rural communities may increase the opportunity for choice and improve the quality of care for people living and dying at home. Pragmatism and nurse agency theory were used for a practical exploration of how district nurses successfully advocate for rural Australian end-of-life goals to begin the development of a practice model. In two stages of data collection, rural district nurse informants ( N = 7) were given the opportunity to reflect on successful advocacy and to write about their experiences before undertaking further in-depth exploration in interviews. They defined successful advocacy as "caring" that empowers people in the "big and small" personal goals important for quality of life. The concepts described that enable successful advocacy were organized into a network with three main themes of "willing" investment in holistic person-centered care, "knowing" people and resources, and feeling "supported." The thematic network description provides deep insight into the emotional skill and moral agency involved in successful end-of-life nurse advocacy and can be used as a sound basis for modeling and testing in future research.

Mixing methodology, nursing theory and research design for a practice model of district nursing advocacy.

AIM: To highlight philosophical and theoretical considerations for planning a mixed methods research design that can inform a practice model to guide rural district nursing end of life care. BACKGROUND: Conceptual models of nursing in the community are general and lack guidance for rural district nursing care. A combination of pragmatism and nurse agency theory can provide a framework for ethical considerations in mixed methods research in the private world of rural district end of life care. DISCUSSION: Reflection on experience gathered in a two-stage qualitative research phase, involving rural district nurses who use advocacy successfully, can inform a quantitative phase for testing and complementing the data. Ongoing data analysis and integration result in generalisable inferences to achieve the research objective. CONCLUSION: Mixed methods research that creatively combines philosophical and theoretical elements to guide design in the particular ethical situation of community end of life care can be used to explore an emerging field of interest and test the findings for evidence to guide quality nursing practice. IMPLICATIONS FOR PRACTICE: Combining philosophy and nursing theory to guide mixed methods research design increases the opportunity for sound research outcomes that can inform a nursing model of care.

District nurse advocacy for choice to live and die at home in rural Australia: a scoping study.

BACKGROUND: Choice to live and die at home is supported by palliative care policy; however, health resources and access disparity impact on this choice in rural Australia. Rural end-of-life home care is provided by district nurses, but little is known about their role in advocacy for choice in care. OBJECTIVES: The study was conducted to review the scope of the empirical literature available to answer the research question: What circumstances influence district nurse advocacy for rural client choice to live and die at home?, and identify gaps in the knowledge. METHOD: Interpretive scoping methodology was used to search online databases, identify suitable studies and select, chart, analyse and describe the findings. RESULTS: 34 international studies revealed themes of 'the nursing relationship', 'environment', 'communication', 'support' and 'the holistic client centred district nursing role. DISCUSSION: Under-resourcing, medicalisation and emotional relational burden could affect advocacy in rural areas. CONCLUSION: It is not known how district nurses overcome these circumstances to advocate for choice in end-of-life care. Research designed to increase understanding of how rural district nurses advocate successfully for client goals will enable improvements to be made in the quality of end-of-life care offered.

Use of a laryngeal mask airway in a brachycephalic dog with masticatory myositis and trismus.

An 8-month old, male, neutered bulldog was presented for investigation of a 2-day history of trismus. Endotracheal intubation was impossible as the dog was only able to open his mouth approximately 2 cm. A laryngeal mask airway was blindly inserted after induction of general anesthesia to maintain the patient on inhalational anesthesia and improve respiration for computed tomography and muscle biopsy. The dog recovered from anesthesia uneventfully.

Evaluation of transdermal fentanyl patch attachment in dogs and analysis of residual fentanyl content following removal.

OBJECTIVE: To investigate whether the method used to attach matrix-type fentanyl patches influences the degree of skin attachment and the amount of active drug remaining in patches after use. STUDY DESIGN: Prospective, randomised clinical study. STUDY POPULATION: Fifteen adult dogs of mixed breeds. METHODS: Two equally sized matrix-type fentanyl patches were attached to the dorsal third of the lateral thorax of fifteen dogs for 72 hours. The two patches were attached using different techniques: Method AD used an adhesive dressing in combination with a transparent film. Method TG used tissue adhesive applied to the edges of the patch. After 72 hours the patches were removed and the proportion of the patch attached at this time calculated. The residual content of the patches was analysed using a validated gas chromatography-mass spectrometery (GC-MS) analysis technique. RESULTS: After 72 hours of continuous attachment, the mean proportion of drug uptake for method AD was 17.2 (SD ± 11.1)% and for method TG this was 16.9 (SD ± 7.3)%. The median proportion of attachment for method AD was 100% and for method TG was 95.6%. CONCLUSIONS: The method of attachment did not significantly influence the uptake of fentanyl from matrix-type patches. The method of attachment resulted in a significant difference in the proportion of the patch attached 72 hours after placement, with method AD resulting in a greater median proportion of attachment than TG. CLINICAL RELEVANCE: The method used to attach matrix-type fentanyl patches to dogs should not interfere with drug uptake. The residual fentanyl content remaining in these patches after 72 hours of continuous application is significant and could lead to intoxication if ingested by humans.

The mixed attitudes of nurse's to caring for people with mental illness in a rural general hospital.

Mainstreaming of mental health care and the prevalence of mental illness have increased the requirement for care by nurses in the general hospital setting. In rural Australia, mental health services are limited and nurses have less access to support and education. Little is known about how these factors influence attitudes and the care of people with mental illness in rural hospitals. A qualitative descriptive study was used to investigate nurses' attitudes to caring for people with mental illness, the issues that impact on their ability to provide care, and the effect of education, experience, and support. In 2003, 10 nurses from two wards in a rural hospital were interviewed. Participants from one ward had education and support from mental health nurses. Attitudes were found to be inextricably linked to issues that influence nurses' ability to provide care. Dislike was apparent from nurses who suggested it was not their role. Others identified fear, causing avoidance. Conversely, those receiving support and education described increased comfort, with some nurses expressing enthusiasm for mental health care, seeing it as integral to nursing. The priority of physical care, time constraints, environmental unsuitability, rurality, and the lack of skill, knowledge, and mental health services reduced safety and effective care. A limited ability to help was reported, despite support for Mental Health Strategy goals. Positive experience promoted through education and support was required for nurses to improve care and attitudes. Notably, collaboration with mental health nurses was identified as helping nurses overcome fear and increase competence in caring for people with mental illness.