"Going over the parapet": The development of a framework for understanding the translation of evidence from economic evaluations

The thesis contextualises the translation of evidence from economic evaluations into a broader implementation framework, while discussing the features of economic evaluation that make it unique as an innovation. Multiple research methods were used, including a review-based adaptation of the Consolidated Framework for Implementation Research, a discrete choice experiment measuring the preferences of healthcare decision makers for aspects of economic evidence, and interviews with health economists about the evidence translation process. A new framework is proposed - the CFIR-EE (Consolidated Framework for Implementation Research for Economic Evidence)

Intradural spinal metastasis of renal cell cancer. Report of a case and review of 26 published cases

Metastatic disease in the intradural compartment of the spine is a rare manifestation of cancer. We report the case of an 82-year-old patient with an intradural, extramedullary metastasis of renal cell carcinoma in the cervical spine. A literature search for intradural spinal metastases of renal cell carcinoma yielded a total of 26 further cases. 18 patients had sporadic renal cell carcinoma, and 9 patients had von Hippel-Lindau disease (VHL) in which the metastases of the renal cell carcinoma were embedded within spinal haemangioblastomas. Patients presented with paresis, back pain, altered sensation or, less frequently, bladder dysfunction. Intradural spinal metastases were diagnosed at an earlier age in VHL patients than in sporadic cases (mean 43 ± 5years vs. 60 ± 14.5years). The metastasis was surgically removed in 81% of patients. Pain improved in all patients, paresis in 90%, hypaesthesia in 38% and bladder dysfunction in 50%. Death occured as a result of systemic cancer progression. 93% of patients in the sporadic renal cell cancer group died within 1.5years, whereas two thirds of the VHL patients were alive after 2year

Where to from here? Identifying and prioritising future directions for addressing drug-resistant infection in Australia

Background: The Australian National Antimicrobial Resistance Strategy calls for a collaborative effort to change practices that have contributed to the development of drug-resistance and for implementation of new initiatives to reduce antibiotic use. Methods: A facilitated workshop was undertaken at the 2019 National Australian Antimicrobial Resistance Forum to explore the complexity of antimicrobial stewardship (AMS) implementation in Australia and prioritise future action. Participants engaged in rotating rounds of discussion using a world café format addressing six topics relating to AMS implementation. Once all tables had discussed all themes the discussion concluded and notes were summarised. The documents were independently openly coded by two researchers to identify elements relating to the implementation of antimicrobial stewardship. Results: There were 39 participants in the facilitated discussions, including pharmacists, infectious disease physicians, infection prevention nurses, and others. Participants discussed strategies they had found successful, including having a regular presence in clinical areas, adapting messaging and implementation strategies for different disciplines, maintaining positivity, and being patient-focused. Many of the recommendations for the next step involved being patient focussed and outcomesdriven. This involves linking data to practice, using patient stories, using data to celebrate wins and creating incentives. Discussion: Recommendations from the workshop should be included in priority setting for the implementation of AMS initiatives across Australia

Economic evaluation of fecal microbiota transplantation for the treatment of recurrent Clostridium difficile infection in Australia

Clostridium difficile is the most common cause of hospital-acquired diarrhea in Australia. In 2013, a randomized controlled trial demonstrated the effectiveness of fecal microbiota transplantation (FMT) for the treatment of recurrent Clostridium difficile infection (CDI). The aim of this study is to evaluate the cost-effectiveness of fecal microbiota transplantation-via either nasoduodenal or colorectal delivery-compared with vancomycin for the treatment of recurrent CDI in Australia.A Markov model was developed to compare the cost-effectiveness of fecal microbiota transplantation compared with standard antibiotic therapy. A literature review of clinical evidence informed the structure of the model and the choice of parameter values. Clinical effectiveness was measured in terms of quality-adjusted life years. Uncertainty in the model was explored using probabilistic sensitivity analysis.Both nasoduodenal and colorectal FMT resulted in improved quality of life and reduced cost compared with vancomycin. The incremental effectiveness of either FMT delivery compared with vancomycin was 1.2 (95% CI: 0.1, 2.3) quality-adjusted life years, or 1.4 (95% CI: 0.4, 2.4) life years saved. Treatment with vancomycin resulted in an increased cost of AU$4094 (95$26, AU$8161) compared with nasoduodenal delivery of FMT and AU$4045 (95% CI: -AU$33, AU$8124) compared with colorectal delivery. The mean difference in cost between colorectal and nasoduodenal FMT was not significant.If FMT, rather than vancomycin, became standard care for recurrent CDI in Australia, the estimated national healthcare savings would be over AU$4000 per treated person, with a substantial increase in quality of life

Governmental perspective on fair and equitable provision of bone-anchored prostheses: Barriers and facilitators

Background Individuals with lower limb amputation fitted with conventional artificial limbs often experience continuous socket-related discomfort leading to a dramatic decrease in quality of life. Most of these functional issues can be overcome by replacing the socket with a surgically implanted bone-anchored prosthesis attached directly to the residual bone using an osseointegrated fixation.[1-31] Government organizations are facing challenges in adjusting procedures to accommodate the emergence of bone-anchored prostheses.[32-35] This study shares the knowledge gained by the Queensland Artificial Limb Service (QALS) an Australian State government organization, while implementing a procedure for fair and equitable provision of bone-anchored prostheses care. Aim The aim of this study was to share some insights drawn from QALS’ experience with strong emphasis on barriers and facilitators encountered when implementing procedure for provision of bone-anchored prostheses care in Queensland, Australia. Method Barriers and facilitators were identified over nearly 3 years following typical phases of action research led by QALS’ management team and researchers who consulted key stakeholders (e.g., 18 Queensland - based consumers, 3 prosthetists, 2 multidisciplinary clinical teams)

A systematic review and critical analysis of cost-effectiveness studies for coronary artery disease treatment [version 2; referees: 2 approved]

Background: Cardiovascular disease remains the primary cause of death among Australians, despite dramatic improvements in overall cardiovascular health since the 1980s. Treating cardiovascular disease continues to place a significant economic strain on the Australian health care system, with direct healthcare costs exceeding those of any other disease. Coronary artery disease accounts for nearly one third of these costs and spending continues to rise. A range of treatments is available for coronary artery disease yet evidence of cost-effectiveness is missing, particularly for the Australian context. Cost-effectiveness evidence can signal waste and inefficiency and so is essential for an efficient allocation of healthcare resources. Methods: We used systematic review methods to search the literature across several electronic databases for economic evaluations of treatments for stable coronary artery disease.  We critically appraised the literature found in searches, both against the CHEERS statement for quality reporting of economic evaluations and in terms of its usefulness for policy and decision-makers. Results: We retrieved a total of 308 references, 229 once duplicates were removed. Of these, 26 were excluded as they were not full papers (letters, editorials etc.), 55 were review papers, 50 were not cost-effectiveness analyses and 93 related to a highly specific patient sub-group or did not consider all treatment options.  This left five papers to be reviewed in full. Conclusions: The current cost-effectiveness evidence does not support the increased use of PCI that has been seen in Australia and internationally. Due to problems with accessibility, clarity and relevance to policy and decision-makers, some otherwise very scientifically rigorous analyses have failed to generate any policy changes

Double dissociation of the requirement for GluN2B- and GluN2A-containing NMDA receptors in the destabilization and restabilization of a reconsolidating memory

Signaling at NMDA receptors (NMDARs) is known to be important for memory reconsolidation, but while most studies show that NMDAR antagonists prevent memory restabilization and produce amnesia, others have shown that GluN2B-selective NMDAR antagonists prevent memory destabilization, protecting the memory. These apparently paradoxical, conflicting data provide an opportunity to define more precisely the requirement for different NMDAR subtypes in the mechanisms underlying memory reconsolidation and to further understand the contribution of glutamatergic signaling to this process. Here, using rats with fully consolidated pavlovian auditory fear memories, we demonstrate a double dissociation in the requirement for GluN2B-containing and GluN2A-containing NMDARs within the basolateral amygdala in the memory destabilization and restabilization processes, respectively. We further show a double dissociation in the mechanisms underlying memory retrieval and memory destabilization, since AMPAR antagonism prevented memory retrieval while still allowing the destabilization process to occur. These data demonstrate that glutamatergic signaling mechanisms within the basolateral amygdala differentially and dissociably mediate the retrieval, destabilization, and restabilization of previously consolidated fear memories.This work was supported by UK Medical Research Council (MRC) Programme Grant 9536855 to B.J.E. and was conducted in the Behavioural and Clinical Neuroscience Institute (BCNI), an initiative jointly funded by the MRC and the Wellcome Trust. A.L.M. was supported by a BCNI lectureship, E.M. was supported by a Royal Society Newton International Fellowship, and B.L.G. by a Prior Scholarship from St. John's College, Cambridge

Loss of NOTCH2 Positively Predicts Survival in Subgroups of Human Glial Brain Tumors

The structural complexity of chromosome 1p centromeric region has been an obstacle for fine mapping of tumor suppressor genes in this area. Loss of heterozygosity (LOH) on chromosome 1p is associated with the longer survival of oligodendroglioma (OD) patients. To test the clinical relevance of 1p loss in glioblastomas (GBM) patients and identifiy the underlying tumor suppressor locus, we constructed a somatic deletion map on chromosome 1p in 26 OG and 118 GBM. Deletion hotspots at 4 microsatellite markers located at 1p36.3, 1p36.1, 1p22 and 1p11 defined 10 distinct haplotypes that were related to patient survival. We found that loss of 1p centromeric marker D1S2696 within NOTCH2 intron 12 was associated with favorable prognosis in OD (P = 0.0007) as well as in GBM (P = 0.0175), while 19q loss, concomitant with 1p LOH in OD, had no influence on GBM survival (P = 0.918). Assessment of the intra-chromosomal ratio between NOTCH2 and its 1q21 pericentric duplication N2N (N2/N2N-test) allowed delineation of a consistent centromeric breakpoint in OD that also contained a minimally lost area in GBM. OD and GBM showed distinct deletion patterns that converged to the NOTCH2 gene in both glioma subtypes. Moreover, the N2/N2N-test disclosed homozygous deletions of NOTCH2 in primary OD. The N2/N2N test distinguished OD from GBM with a specificity of 100% and a sensitivity of 97%. Combined assessment of NOTCH2 genetic markers D1S2696 and N2/N2N predicted 24-month survival with an accuracy (0.925) that is equivalent to histological classification combined with the D1S2696 status (0.954) and higher than current genetic evaluation by 1p/19q LOH (0.762). Our data propose NOTCH2 as a powerful new molecular test to detect prognostically favorable gliomas

Individual and Contextual Factors Associated with Low Childhood Immunisation Coverage in Sub-Saharan Africa: A Multilevel Analysis

Background: In 2010, more than six million children in sub-Saharan Africa did not receive the full series of three doses of the diphtheria-tetanus-pertussis vaccine by one year of age. An evidence-based approach to addressing this burden of un-immunised children requires accurate knowledge of the underlying factors. We therefore developed and tested a model of childhood immunisation that includes individual, community and country-level characteristics. Method and Findings: We conducted multilevel logistic regression analysis of Demographic and Health Survey data for 27,094 children aged 12–23 months, nested within 8,546 communities from 24 countries in sub-Saharan Africa. According to the intra-country and intra-community correlation coefficient implied by the estimated intercept component variance, 21% and 32% of the variance in unimmunised children were attributable to country- and community-level factors respectively. Children born to mothers (OR 1.35, 95%CI 1.18 to 1.53) and fathers (OR 1.13, 95%CI 1.12 to 1.40) with no formal education were more likely to be unimmunised than those born to parents with secondary or higher education. Children from the poorest households were 36% more likely to be unimmunised than counterparts from the richest households. Maternal access to media significantly reduced the odds of children being unimmunised (OR 0.94, 95%CI 0.94 to 0.99). Mothers with health seeking behaviours were less likely to have unimmunised children (OR 0.56, 95%CI 0.54 to 0.58). However, children from urban areas (OR 1.12, 95% CI 1.01 to 1.23), communities with high illiteracy rates (OR 1.13, 95% CI 1.05 to 1.23), and countries with high fertility rates (OR 4.43, 95% CI 1.04 to 18.92) were more likely to be unimmunised. Conclusion: We found that individual and contextual factors were associated with childhood immunisation, suggesting that public health programmes designed to improve coverage of childhood immunisation should address people, and the communities and societies in which they live