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Glioblastoma (GBM), the most common adult primary brain tumor, has an average survival of only 15–18 months. Recently, the combination of immune checkpoint blockers paired with radiotherapy has shown promise in preclinical murine GBM models. Human clinical trials have largely failed. One reason for this may be the discrepancy between radiation protocols utilized in preclinical models versus clinical practice. For translational relevance, defining correct and comparable radiation dosages and schedules to achieve optimal synergy with immunotherapeutic drugs, is essential. We used the GL261-based syngeneic mouse GBM model to compare the effects of two radiation regimens on tumor cell growth and survival. We assessed the in vivo effects of a single dose of 10 Gy (10Gyx1) or five consecutive doses of 2 Gy (2Gyx5) on the tumor immune microenvironment over time and compared their efficacy when combined with anti-PD-1 in vivo . Our data show that the 10Gyx1 regimen is more effective than 2Gyx5 at inhibiting tumor cell proliferation and growth in vitro and in vivo . Both regimens preserved the antigen-presenting ability of both dendritic cells and local microglia, but 10Gyx1 led to the highest lymphocyte infiltration. The combination of radiation with the checkpoint blocker anti-PD-1 was advantageous for both radiation regimens with animals treated with the 10Gyx1 regimen surviving the longest. Our study highlights how radiation regimen choices may impact the translation of preclinical findings, and in particular, the effects of radiation and immunotherapy in GBM. This work and literature data on the effects of positive hypofractionation in human GBM patients suggest that applying fewer, higher-dose radiation fractions may benefit GBM patients and lead to tumoricidal effects without sacrificing favorable anti-tumor immune responders.

Alzheimer's disease (AD) is a progressive brain disorder that results in the gradual irreversible loss of memory, personality changes and a decline in thinking abilities. These mental losses are directly attributable to the death of neurons and the breakdown of the connections between them caused by two abnormal structures found in the AD brain: amyloid plaques and neurofibrilary tangles. Amyloid plaques are formed from the inappropriate accumulation of pathogenic β-amyloid (Aβ) peptides, the end products of a series of proteolytic cleavages of the β-amyloid precursor protein (βAPP). The doctoral research summarized in this dissertation examines the connection between the intracellular trafficking of βAPP, and βAPP's proteolysis to Aβ. The first chapter describes a series of experiments which directly address the great degree of heterogeneity in βAPP metabolism and Aβ generation. The results presented define the precise intracellular compartments within which varied Aβ peptides are generated, and the compartments from which they are secreted. In addition, we delineate several novel populations of Aβ peptides based upon biochemical parameters such as the optimal pH at which they are generated and their solubility. The following chapter links the generation of Aβ with the intracellular trafficking of βAPP using one principal assay, the cell-free reconstitution of βAPP trafficking. This assay allowed us to demonstrate how diverse molecules and drugs can influence the intracellular generation of Aβ, simply by regulating the rate of βAPP secretion from specific organelles within the secretory pathway. The final chapter extends the results of the previous two chapters, in which the experiments were performed in mammalian cells, to a novel system, the eukaryotic, but unicellular organism, Saccharomyces cerevisiae. The demonstration that budding yeast expressing βAPP can generated authentic Aβ peptides, suggests that these simple genetically manipulatable cells can provide a system within which the elusive proteolytic enzymes which generate Aβ can be discovered. Taken together, the results presented in this thesis indicate that βAPP trafficking and Aβ generation are inextricably intertwined. The hope is that by understanding the regulation of βAPP trafficking, we will one day soon be able to suggest therapeutically relevant targets for intervention in Aβ generation, which might delay or prevent the onset of this tragic disease.

Abstract BACKGROUND: Survival duration and prognostic factors in adult high-grade glioma have been comprehensively analyzed, but less is known about factors contributing to overall survival (OS) and progression-free survival (PFS) in pediatric patients. OBJECTIVE: To identify these factors in the pediatric population. METHODS: We retrospectively reviewed institutional databases evaluating all patients ⩽21 years with high-grade glioma treated between 1988 and 2010. Kaplan-Meier curves and log-rank statistics were used to compare groups univariately. Multivariate analyses were completed using Cox proportional hazards regression models. RESULTS: Ninety-seven patients were identified with a median age of 11 years. Median OS was 1.7 years, and median PFS was 272 days. Location was significant for OS (P > .001). Patients with gross total resection (GTR) had a median OS of 3.4 years vs 1.6 years for subtotal resection and 1.3 years for biopsy patients (P > .001). Female patients had improved OS (P = .01). Female patients with GTR had a mean OS of 8.1 years vs 2.4 years for male patients with GTR and 1.4 years for all other female patients and male patients (P = .001). PFS favored patients ⩽3 and ≥13 years and females (P = .003 and .001). CONCLUSION: OS was significantly correlated with the location of the tumor and the extent of resection. GTR significantly improved overall survival for both glioblastoma multiforme and anaplastic astrocytoma patients, and female patients showed a much larger survival benefit from GTR than male patients.

BackgroundQuality and safety improvement programmes advance the standard of care delivered by health organisations but have been shown to be less effective than anticipated. Implementing improvement programmes require a greater understanding of the impact of the social context and strategies that engage staff.ObjectiveTo investigate factors that shaped the development of interprofessional improvement initiatives in a health organisation.MethodsData are drawn from a large-scale longitudinal action research study examining interprofessional learning and practice. The setting is an autonomous bounded health jurisdiction in Australia. Within the study, health professionals have conceptualised more than 111 interprofessional improvement projects, of which 76 have evolved into ongoing activities. Textual data were analysed using emergent coding and descriptive statistics.ResultsInitiatives were shaped by six determinants: site receptivity; team issues; leadership; impact on healthcare relations; impact on quality and safety issues; and extent to which the projects became institutionally embedded. Initiatives that engaged participants and progressed were characterised by and displayed flexible leadership, and ongoing refinement and maturity over time. The local organisational context and initiatives coevolved.ConclusionsImprovement initiatives are necessary for improved quality of care and patient safety but are difficult to implement and sustain. The factors identified to develop them are constantly under challenge in health services. Improving healthcare quality will, in part, depend upon the ability to provide more flexible and supportive social contexts.

Background The safety-and-quality movement is now two decades old. Errors persist despite best efforts, indicating that there are entrenched overt and perhaps less explicit barriers limiting the success of improvement efforts. Objectives and hypotheses To examine the perspectives of five groups of healthcare workers (administrative staff, nurses, medical practitioners, allied health and managers) and to compare and contrast their descriptions of quality-and-safety activities within their organisation. Differences in perspectives can be an indicator of divergence in the conceptualisation of, and impetus for, quality-improvement strategies which are intended to engage healthcare professions and staff. Design, setting and participants Study data were collected in a defined geographical healthcare jurisdiction in Australia, via individual and group interviews held across four service streams (aged care and rehabilitation; mental health; community health; and cancer services). Data were collected in 2008 and analysed, using data-mining software, in 2009. Results Clear differences in the perspectives of professional groups were evident, suggesting variations in the perceptions of, and priorities for, quality and safety. Conclusions The visual representation of quality and safety perspectives provides insights into the conceptual maps currently utilised by healthcare workers. Understanding the similarity and differences in these maps may enable more effective targeting of interprofessional improvement strategies.

Background A four-year action research study was conducted across the Australian Capital Territory health system to strengthen interprofessional collaboration (IPC) though multiple intervention activities. Methods We developed 272 substantial IPC intervention activities involving 2,407 face-to-face encounters with health system personnel. Staff attitudes toward IPC were surveyed yearly using Heinemann et al's Attitudes toward Health Care Teams and Parsell and Bligh's Readiness for Interprofessional Learning scales (RIPLS). At study's end staff assessed whether project goals were achieved. Results Of the improvement projects, 76 exhibited progress, and 57 made considerable gains in IPC. Educational workshops and feedback sessions were well received and stimulated interprofessional activities. Over time staff scores on Heinemann's Quality of Interprofessional Care subscale did not change significantly and scores on the Doctor Centrality subscale increased, contrary to predictions. Scores on the RIPLS subscales of Teamwork & Collaboration and Professional Identity did not alter. On average for the assessment items 33% of staff agreed that goals had been achieved, 10% disagreed, and 57% checked neutral. There was most agreement that the study had resulted in increased sharing of knowledge between professions and improved quality of patient care, and least agreement that between-professional rivalries had lessened and communication and trust between professions improved. Conclusions Our longitudinal interventional study of IPC involving multiple activities supporting increased IPC achieved many project-specific goals. However, improvements in attitudes over time were not demonstrated and neutral assessments predominated, highlighting the difficulties faced by studies targeting change at the systems level and over extended periods.

Objective. To compare four health professions' attitudes towards interprofessional collaboration (IPC) and their evaluations of a programme aimed at enhancing IPC across a health system. Design. Questionnaire survey. Setting. Australian Capital Territory health services. Participants. Sample of medical (38), nursing (198), allied health (152) and administrative (30) staff. Intervention(s). A 4-year action research project to improve IPC. Main Outcome Measure(s). Questionnaire evaluating the project and responses to the 'Attitudes toward Health Care Teams' and 'Readiness for Interprofessional Learning' scales. Results. Significant professional differences occurred in 90% of the evaluation items. Doctors were the least and administrative staff most likely to agree project aims had been met. Nurses made more favourable assessments than did allied health staff. Doctors made the most negative assessments and allied health staff the most neutral ratings. Improved interprofessional sharing of knowledge, teamwork and patient care were among the goals held to have been most achieved. Reduction in interprofessional rivalry and improved trust and communication were least achieved. Average assessment of individual goals being met was agree (31.9%), neutral (56.9%) and disagree (11.2%). On the two attitude scales, allied health professionals were most supportive of IPC, followed by nurses, administrators and doctors. Conclusions. Although overall attitudes towards IPC were favourable, only a third of participants reported that project goals had been achieved indicating the difficulties of implementing systems change. The response profiles of the professions differed. As in the previous research, doctors were least likely to hold favourable attitudes towards or endorse benefits from social or structural interventions in health care.

Posterior C1-C2 fusion is a highly successful treatment for atlantoaxial instability and other pathologies of the cervical spine, with fusion rates approaching 95%-100%. However, poor visualization of the lateral masses of C1 secondary to the course of the C2 nerve root along with blood loss from the venous plexus and compression of the C2 nerve from lateral mass screws are technical obstacles that can arise during surgery. Thus, sacrifice of the C2 nerve root has long since been debated in fusions involving the C1 and C2 vertebral bodies. Cadaveric dissections on four adult specimens were performed. Both intradural and extradural courses of C2 were studied in detail. The tentative site of C2 nerve root compression during placement of C1 lateral mass screws was studied in detail. Both the indication as well as the ease of C2 neurectomy were studied in relation to postoperative compression and entrapment. Four-six dorsal rootlets of C2 nerve were observed while studying the intradural course. The extradural course was studied with respect to the lateral mass of C1. The greater occipital nerve (GON) course was fairly consistent in all specimens. Transection of C2 around its ganglion would allow for proper C1 lateral mass screw placement as the course of C2 nerve interferes with proper placement of instrumentation. C2 nerve root transection is associated with occipital numbness but this often has no effect on health-related quality of life (HRQOL). The C2 nerve root preservation is often associated with entrapment neuropathy or occipital neuralgia, which greatly affects HRQOL. The C2 nerve root transection helps in better visualization, aids in optimal placement of C1 lateral mass screws, minimizes estimated blood loss and improves surgical outcome with successful fusion.

PurposeHealth service effectiveness continues to be limited by misaligned objectives between policy makers and frontline clinicians. While capturing the discretion workers inevitably exercise, the concept of “street-level bureaucracy” has tended to artificially separate policy makers and workers. The purpose of this paper is to understand the role of social-organizational context in aligning policy with practice.Design/methodology/approachThis mixed-method participatory study focuses on a locally developed tool to implement an Australia-wide strategy to engage and respond to mental health services for parents with mental illness. Researchers: completed 69 client file audits; administered 64 staff surveys; conducted 24 interviews and focus groups (64 participants) with staff and a consumer representative; and observed eight staff meetings, in an acute and sub-acute mental health unit. Data were analyzed using content analysis, thematic analysis and descriptive statistics.FindingsBased on successes and shortcomings of the implementation (assessment completed for only 30 percent of clients), a model of integration is presented, distinguishing “assimilist” from “externalist” positions. These depend on the degree to which, and how, the work environment affords clinicians the setting to coordinate efforts to take account of clients’ personal and social needs. This was particularly so for allied health clinicians and nurses undertaking sub-acute rehabilitative-transitional work.Originality/valueA new conceptualization of street-level bureaucracy is offered. Rather than as disconnected, it is a process of mutual influence among interdependent actors. This positioning can serve as a framework to evaluate how and under what circumstances discretion is appropriate, and to be supported by managers and policy makers to optimize client-defined needs.

Purpose Health service effectiveness continues to be limited by misaligned objectives between policy makers and frontline clinicians. While capturing the discretion workers inevitably exercise, the concept of “street-level bureaucracy” has tended to artificially separate policy makers and workers. The purpose of this paper is to understand the role of social-organizational context in aligning policy with practice. Design/methodology/approach This mixed-method participatory study focuses on a locally developed tool to implement an Australia-wide strategy to engage and respond to mental health services for parents with mental illness. Researchers: completed 69 client file audits; administered 64 staff surveys; conducted 24 interviews and focus groups (64 participants) with staff and a consumer representative; and observed eight staff meetings, in an acute and sub-acute mental health unit. Data were analyzed using content analysis, thematic analysis and descriptive statistics. Findings Based on successes and shortcomings of the implementation (assessment completed for only 30 percent of clients), a model of integration is presented, distinguishing “assimilist” from “externalist” positions. These depend on the degree to which, and how, the work environment affords clinicians the setting to coordinate efforts to take account of clients’ personal and social needs. This was particularly so for allied health clinicians and nurses undertaking sub-acute rehabilitative-transitional work. Originality/value A new conceptualization of street-level bureaucracy is offered. Rather than as disconnected, it is a process of mutual influence among interdependent actors. This positioning can serve as a framework to evaluate how and under what circumstances discretion is appropriate, and to be supported by managers and policy makers to optimize client-defined needs.