Magnetic resonance angiography (MRA) is clinically used for both arterial and venous assessment. It is an attractive alternative to CTA in younger patients, where risks of ionising radiation are greatest. Beyond neurovascular imaging, contrast enhanced MRA (CE-MRA) is most commonly performed, following injection of a gadolinium chelate. Non-contrast MRA (NC-MRA) refers to a range of techniques performed without exogenous contrast. NC-MRA removes risks of injected contrast and need for renal function testing and intravenous cannulation. Time of flight MRA (TOF) is a well-established technique that remains the mainstay of cerebrovascular MRA. More NC-MRA techniques have been developed recently in reaction to the association of gadolinium chelates with Nephrogenic Systemic Fibrosis (NSF), and gadolinium retention in previously injected subjects. This dissertation explores the clinical applicability of non-contrast magnetic resonance angiography (MRA) techniques. Vascular pathology and currently available angiographic imaging modalities are reviewed. Subsequently, NC-MRA is reviewed in detail, including potential benefits, challenges, mechanisms used to obtain vascular signal and applications. Data from five prior prospective trials by the investigator are then presented. The first study reports on a breath hold flow-independent NC-MRA balanced steady state free precession (bSSFP) technique, describing its performance in 30 patients presenting for assessment of the thoracic aorta, with comparison to contrast-enhanced MRA. Diagnostic image quality was found for all aortic segments, and comparable aortic dimensions to CE-MRA, with a statistically significant but clinically insignificant (<1mm) difference in measured dimension for the ascending aortic segment. The second study evaluates the performance of a Non-contrast Hybrid Arterial Spin Labelling NC-MRA technique (NoHASL) for imaging the circle of Willis in 30 patients presenting with known or suspected cerebrovascular ischaemia. Whilst shown to be feasible, with diagnostic quality imaging obtained, the NoHASL technique was found to have inferior image quality compared to both TOF and CE-MRA. Low prevalence of haemodynamically significant disease limited assessment of technique accuracy. The third study reports the accuracy of three electrocardiographically (ECG)-gated subtractive non-contrast MRA techniques, flow-sensitising dephasing gradient prepared MRA (FSD-MRA), variable flip angle fast spin echo MRA (VFA-MRA) and constant flip angle fast spin echo MRA (CFA-MRA), in the below knee arteries in 21 patients, compared to CE-MRA. FSD-MRA demonstrated highest sensitivity and specificity of 80.3% and 81.7% for haemodynamically significant stenosis respectively, with no significant difference in accuracy identified between the techniques. The fourth study reports feasibility of VFA-MRA for imaging the hand arteries in 9 healthy volunteers and 4 scleroderma patients. The technique showed clear separation of arteries from veins and depiction of stenoses. Vascular reactivity following subject warming was also assessed, highlighting an advantage of NC-MRA, repeatability. The final study applies the CFA-MRA technique to assessment of calibre of the upper extremity veins of healthy volunteers, as preliminary work to evaluate potential feasibility of subsequently applying the technique to patients being considered for haemodialysis. Similar venous calibre was obtained in comparison to CE MRA, however, MRA overestimated calibre in comparison to ultrasound. Finally, a summary of the current state of NC-MRA is presented and potential future advances discussed.

Background: Over 800 women die from preventable causes related to pregnancy and childbirth every day, almost all of them in low and middle-income countries. Human resource constraints, both in terms of numbers and quality, are at the core of the problem. Task shifting is an approach designed to address the crisis in human resources for health. In 2015, Myanmar reported a maternal mortality ratio of 282 per 100,000 live births with only 14 health care providers per 10,000 people, well below WHO recommendations of 23 health care providers. Currently in Myanmar, most babies are born without the assistance of a skilled birth attendant (e.g. a midwife), a situation believed to be a major contributor to high maternal and newborn mortality. The Ministry of Health and Sports trains and deploys a cadre of volunteers, called auxiliary midwives (AMWs) to provide maternal and newborn care in areas without skilled birth attendants. This thesis examines the role of AMWs and the feasibility and acceptability of task shifting selected interventions to AMWs to improve maternal and newborn health care in Myanmar. Methods: This research involved two studies. The first was a mixed methods study conducted in Magwe Region, Myanmar between July, 2015 and June, 2016 involving a survey of 262 AMWs, complemented by 15 focus group discussions (FGDs) with midwives, AMWs, mothers and community members and 10 key informant interviews with health care providers at different levels within the health care system. This study aimed to understand the skills, knowledge and role of AMWs and the feasibility and acceptability of task shifting essential maternal interventions to AMWs. A second qualitative study, conducted in Magwe and Yangon Regions between June, 2015 and February, 2016, involved 11 FGDs with midwives, AMWs and mothers and 16 key informant interviews to explore the feasibility and acceptability of a new inhaled formulation of oxytocin currently under development for the prevention of postpartum haemorrhage (PPH), and potentially ideal for task shifting to AMWs in future. Results: AMWs are trusted members of the community and provide preventive, promotive and childbirth care in hard-to-reach rural areas. However, in emergency situations involving curative care, AMWs are often required to exceed their assigned role. This pressure to provide curative care in hard-to-reach rural villages where there is no skilled provider or support infrastructure, concerned and frustrated AMWs. Simultaneously, their knowledge of danger signs and skills in conducting safe delivery and newborn practices were found to be poor. AMWs often work alone in many hard-to-reach villages, and both the community and health care providers believe they should be better equipped with the skills needed to undertake basic emergency care. The research also found that AMWs were capable of being utilised – with proper training and supervision – to deliver a package of maternal interventions through task shifting. The main interventions identified as feasible and acceptable for task shifting were oral vitamin supplementation during the antenatal care period, provision of misoprostol to prevent postpartum haemorrhage after childbirth, and the use of oral antibiotics for puerperal sepsis during the postpartum period. The study also endorsed the feasibility of introduction of an inhalable formulation of oxytocin (currently under development) for use by community-based birth care providers in areas lacking electricity and cold storage facilities. Conclusion: AMWs are a large body of health volunteers who have been embedded within the community and health system in Myanmar for nearly four decades, and enjoy widespread community acceptance and trust. The role of this valuable health workforce can be optimised through task shifting of essential maternal interventions to provide effective care to mothers in rural and remote areas. This will require extensive skills-based training, ongoing supportive supervision and strong policy commitment, but if done well, AMWs could play an important role towards reducing maternal and neonatal mortality.  

Cardiovascular disease and dementia are amongst the major threats to heath and quality of life for Australian women. Since neurodegenerative pathologies develop before the onset of dementia, a life course prospective study is needed to clarify the risk factors. The link between cardiovascular risk factors and dementia is supported by common neurological findings of brain atrophy and cerebrovascular dysfunction. Despite the growing literature reporting the effect of midlife cardiovascular risk factors on late life brain structure and cognitive functional changes, there are still several unanswered questions regarding underlying mechanisms and the best imaging methods for detecting neurological effects of vascular risk factors. The main aim of this thesis is to determine the effects of mid to late life cardiovascular risk burden over two decades on brain volume changes and cognitive function in elderly women. The findings of this thesis identify brain regions and cognitive domains where structural and cerebrovascular deficits are associated with presence of cardiovascular risk factors in midlife and may influence late life cognitive function. The present thesis utilizes the wealth of structural Magnetic Resonance Imaging (MRI) data collected from the Women’s Healthy Ageing Project (WHAP). This Australian population-based study contains data on cardiovascular risk factors and cognitive function from midlife until two decades later. The Framingham Cardiovascular Risk Profile (FCRP) is a validated tool for estimating the 10-year risk of cardiovascular disease based on a midlife profile incorporating several vascular risk factors. This risk score is used to indicate whether the cardiovascular risk burden has any relationship to structural neuroimaging findings and late life cognitive performance. This thesis focuses on the effects of individual cardiovascular risk factors and measured risk score at midlife on late life brain structural changes, evaluated by MRI, and domain-specific cognitive function. The studies herein used a number of methods for brain structural analysis, providing information on both neurodegenerative and cerebrovascular pathologies in elderly women. The first chapter reviews relevant literature in the context of midlife cardiovascular risk factors, brain structure and cognitive function. This chapter also explains the basic principle of MRI physics and brain structural biomarkers for the normal ageing brain. The second chapter covers the general methodology of the thesis, including cardiovascular risk assessments, cognitive measures, MRI acquisition protocols and image processing tools. This thesis included 4 sub-studies: Chapter 3, Study I investigated the influence of midlife cardiovascular risk score on the burden of White Matter Hyperintensity (WMH) lesions in late life and whether this volume of WMH lesions mediated the association between midlife FCRP and cognitive function two decades later. The results show that an increase in FCRP score at midlife is associated with greater WMH volume two decades later, and this is predominantly driven by the impact of High Density Lipoprotein (HDL) cholesterol level, controlling for age, education and APOE ε4 status. This study also demonstrates that the relationship between midlife FCRP score and late life executive function is mediated by WMH volume. Chapter 4, study II examined the role of midlife cardiovascular risk burden on late life grey matter volumes and domain-specific cognitive function in the WHAP-MRI cohort. We found that higher midlife cardiovascular risk burden, as assessed by the FCRP score, is associated with smaller total cortical grey matter volumes, mainly in frontal and temporal lobes, two decades later. Of the FCRP components, age and midlife systolic blood pressure (SBP) are significantly correlated with cortical grey matter volume loss. After adjusting for age, education and APOE ε4 status, SBP assessed 10-years prior to the MRI scans, remained significantly correlated with grey matter volume loss in temporal lobe. This smaller grey matter volume in temporal lobe and increase in whole brain WMH lesions are largely mediated the relationship between midlife FCRP score and late life executive function performance. In addition, lower performance in verbal episodic memory in elderly women is indirectly associated with increase in cardiovascular risk burden at midlife, as measured by FCRP score, through decrease in total brain volumes, particularly in frontal and temporal lobes and in the hippocampus. Stratifying our study by APOE ε4 status shows that an increase in cardiovascular risk burden at midlife is associated with lower performance in executive function two decades later, whereas a decline in verbal episodic memory performance is linked with a decrease in total brain and hippocampal volumes. Chapter 5, study III explored the longitudinal changes in brain volume and cognition over a 10-year period. This study shows that baseline measurements of frontal and temporal grey matter volumes predict changes in verbal episodic memory performance, whereas hippocampal volume at baseline is associated with changes in executive function performance over a 10-year period of follow-ups. In addition, higher whole brain and hippocampal atrophy rates are correlated with a decline in verbal episodic memory. Chapter 6, Study IV explored the impact of hippocampal segmentation methods on correlations with midlife cardiovascular risk factors and late life verbal episodic function. In this study, a combination of manual and automated segmentation methods was applied to measure total and regional hippocampal volumes and their relationship with midlife clinical data and late life verbal episodic memory performance. We found a high correlation between manual tracing of hippocampal volume and automated Freesurfer output segmentations. Midlife FCRP score is not associated with late life hippocampal volumes, adjusted for intracranial volume, age, education and APOE ε4 status. Anterior hippocampal volume segmented either with manual tracing or automated Freesurfer software is sensitive to changes in midlife HDL cholesterol level, while posterior hippocampal volume is linked with verbal episodic memory performance in elderly women. The last chapter, Chapter 7, concludes this work and discusses potential study limitations and future directions. Together, findings from the studies in this thesis highlight the importance of lifespan research. Being one of the few women-specific ageing studies, the implications of these findings for clinical practice are discussed, with a focus on modifiable midlife cardiovascular risk factors for early therapeutic intervention to maintain late life brain health and delay onset of dementia among women.

PURPOSE: Febrile neutropenia (FNP) is a frequent complication of cancer care and evaluation often fails to identify a cause. [(18) F]FDG PET/CT has the potential to identify inflammatory and infectious foci, but its potential role as an investigation for persistent FNP has not previously been explored. The aim of this study was to prospectively evaluate the clinical utility of FDG PET/CT in patients with cancer and severe neutropenia and five or more days of persistent fever despite antibiotic therapy. METHODS: Adult patients with a diagnosis of an underlying malignancy and persistent FNP (temperature ≥38°C and neutrophil count <500 cells/μl for 5 days) underwent FDG PET/CT as an adjunct to conventional evaluation and management. RESULTS: The study group comprised 20 patients with FNP who fulfilled the eligibility criteria and underwent FDG PET/CT in addition to conventional evaluation. The median neutrophil count on the day of the FDG PET/CT scan was 30 cells/μl (range 0-730 cells/μl). Conventional evaluation identified 14 distinct sites of infection, 13 (93 %) of which were also identified by FDG PET/CT, including all deep tissue infections. FDG PET/CT identified 9 additional likely infection sites, 8 of which were subsequently confirmed as "true positives" by further investigations. FDG PET/CT was deemed to be of 'high' clinical impact in 15 of the 20 patients (75 %). CONCLUSION: This study supports the utility of FDG PET/CT scanning in severely neutropenic patients with five or more days of fever. Further evaluation of the contribution of FDG PET/CT in the management of FNP across a range of underlying malignancies is required.

INTRODUCTION: Intra-arterial mechanical thrombectomy (IAMT) is an endovascular technique that allows for the acute retrieval of intravascular thrombi and is increasingly being used for the treatment of acute ischaemic stroke (AIS). There are currently two anaesthetic options during IAMT: general anaesthesia (GA) and conscious sedation (CS). The decision to use GA versus CS is the source of controversy, as it requires careful balance between patient pain, movement and airway protection whilst minimising time delay and haemodynamic fluctuations. This review examines and summarises the evidence for the use of GA versus CS in the treatment of AIS by IAMT. METHODS: Studies were identified using systematic bibliographic searches. The five applicable studies were analysed with reference to overall outcomes and the key parameters that govern the decision to use GA or CS. The key parameters included the impact of GA and CS on pain, complication rates, time delays, airway protection and haemodynamic stability. RESULTS: Several retrospective analyses have shown that the use of GA is associated with adverse outcomes. CONCLUSION: Intra-arterial mechanical thrombectomy under general anaesthesia is associated with poor outcomes in observational studies. It is reasonable to offer conscious sedation as the preferred option where adverse patient factors such as agitation are lacking.

BACKGROUND: Supratentorial atypical teratoid rhabdoid tumor (ATRT) in many cases has a distinctive appearance on post-gadolinium MRI. OBJECTIVE: We sought to determine whether this is a unique appearance allowing ATRT to be distinguished accurately from other types of pediatric supratentorial tumors. MATERIALS AND METHODS: Retrospective review of all available preoperative MRI of pediatric supratentorial tumors at two tertiary children's hospitals, and systematic literature review of case series and reports describing the MRI imaging appearances of supratentorial ATRT. RESULTS: We had 61 supratentorial tumors, including 32 gliomas, 6 ATRT, 8 ependymomas, 6 gangliogliomas, 2 pilomyxoid astrocytomas, 3 primitive neuro-ectodermal tumors, 2 choroid plexus papillomas, and 2 meningiomas. ATRT presented in significantly younger patients than astrocytomas (mean age 2.6 years vs. 9.9 years, P < 0.05). The visual pattern of a thick, wavy (irregular) heterogeneously enhancing wall around a cystic center was seen in 5/6 (83%) ATRTs and only 3/55 (5.4%) other tumors (P < 0.0001), for specificity of 95%, sensitivity of 83%, positive predictive value of 63% and a negative predictive value of 95%. CONCLUSION: A supratentorial tumor with a thick, wavy (irregular) heterogeneously enhancing wall surrounding a central cystic region is suggestive of ATRT in the appropriate clinical setting, especially in a child of preschool age.

A single mild traumatic brain injury (mTBI) typically causes only transient symptoms, but repeated mTBI (RmTBI) is associated with cumulative and chronic neurological abnormalities. Clinical management of mTBI is challenging due to the heterogeneous, subjective and transient nature of symptoms, and thus would be aided by objective biomarkers. Promising biomarkers including advanced magnetic resonance imaging (MRI) and plasma levels of select proteins were examined here in a rat model of RmTBI. Rats received either two mild fluid percussion or sham injuries administered five days apart. Rats underwent MRI and behavioral testing 1, 3, 5, 7, and 30 days after the second injury and blood samples were collected on days 1, 7, and 30. Structural and diffusion-weighted MRI revealed that RmTBI rats had abnormalities in the cortex and corpus callosum. Proteomic analysis of plasma found that RmTBI rats had abnormalities in markers indicating axonal and vascular injury, metabolic and mitochondrial dysfunction, and glial reactivity. These changes occurred in the presence of ongoing cognitive and sensorimotor deficits in the RmTBI rats. Our findings demonstrate that RmTBI can result in chronic neurological abnormalities, provide insight into potential contributing pathophysiological mechanisms, and supports the use of MRI and plasma protein measures as RmTBI biomarkers.

In pediatric low-grade gliomas not amenable to complete resection, various chemotherapy regimens are the mainstream of treatment. An excellent overall survival of these patients makes justification of the intensification of chemotherapy difficult and calls for the development of new strategies. Bevacizumab, a humanized monoclonal antibody directed against Vascular endothelial growth factor (VEGF), has been successfully used in combination with irinotecan in a number of adult and pediatric studies and reports. Fifteen patients at median age of 7 years old (range 3 months to 15 years) were treated with bevacizumab in combination with conventional low-toxicity chemotherapy. The majority had chiasmatic/hypothalamic and midline tumors, seven had confirmed BRAF pathway alterations including neurofibromatosis type 1 (2). Fourteen patients had more than one progression and three had radiotherapy. No deaths were documented, PFS at 11 and 15 months was 71.5% ± 13.9% and 44.7% ± 17.6% respectively. At the end of follow-up 40% of patients has radiologically stable disease, three patients progressed shortly after completion of bevacizumab and two showed mixed response with progression of cystic component. Rapid visual improvement was seen in 6/8 patients, resolution of endocrine symptoms in 2/4 and motor function improvement in 4/6. No relation between histology or BRAF status and treatment response was observed. Treatment-limiting toxicities included grade 4 proteinuria (2) and hypertension (2) managed with cessation (1) and pausing of therapy plus antihypertensives (1). In conclusion, bevacizumab is well tolerated and appears most effective for rapid tumor control to preserve vision and improve morbidity.

Objective: To quantify the impact of the change in definition of severe pneumonia on documented pneumonia burden. Methods: We reviewed existing data acquired during observational hospitalized pneumonia studies, before the introduction of the pneumococcal conjugate vaccine, in infants aged 2-23 months from Fiji, Gambia, Lao People's Democratic Republic, Malawi, Mongolia and Viet Nam. We used clinical data to calculate the percentage of all-cause pneumonia hospitalizations with severe pneumonia, and with primary end-point consolidation, according to both the 2005 or 2013 World Health Organization (WHO) definitions. Where population data were available, we also calculated the incidence of severe pneumonia hospitalizations according to the different definitions. Findings: At six of the seven sites, the percentages of all-cause pneumonia hospitalizations due to severe pneumonia were significantly less (P < 0.001) according to the 2013 WHO definition compared with the 2005 definition. However, the percentage of severe pneumonia hospitalizations, according to the two definitions of severe pneumonia, with primary end-point consolidation varied little within each site. The annual incidences of severe pneumonia hospitalizations per 100 000 infants were significantly less (all P < 0.001) according to the 2013 definition compared with the 2005 definition, ranging from a difference of -301.0 (95% confidence interval, CI: -405.2 to -196.8) in Fiji to -3242.6 (95% CI: -3695.2 to -2789.9) in the Gambia. Conclusion: The revision of WHO's definition of severe pneumonia affects pneumonia epidemiology, and hence the interpretation of any pneumonia intervention impact evaluation.

BACKGROUND: Stereotactic ablative body radiotherapy (SABR) is a non-invasive alternative to surgery to control primary renal cell cancer (RCC) in patients that are medically inoperable or at high-risk of post-surgical dialysis. The objective of the FASTRACK II clinical trial is to investigate the efficacy of SABR for primary RCC. METHODS: FASTRACK II is a single arm, multi-institutional phase II study. Seventy patients will be recruited over 3 years and followed for a total of 5 years. Eligible patients must have a biopsy confirmed diagnosis of primary RCC with a single lesion within a kidney, have ECOG performance ≤2 and be medically inoperable, high risk or decline surgery. Radiotherapy treatment planning is undertaken using four dimensional CT scanning to incorporate the impact of respiratory motion. Treatment must be delivered using a conformal or intensity modulated technique including IMRT, VMAT, Cyberknife or Tomotherapy. The trial includes two alternate fractionation schedules based on tumour size: for tumours ≤4 cm in maximum diameter a single fraction of 26Gy is delivered; and for tumours > 4 cm in maximum diameter 42Gy in three fractions is delivered. The primary outcome of the study is to estimate the efficacy of SABR for primary RCC. Secondary objectives include estimating tolerability, characterising overall survival and cancer specific survival, estimating the distant failure rate, describing toxicity and renal function changes after SABR, and assessment of cost-effectiveness of SABR compared with current therapies. DISCUSSION: The present study design allows for multicentre prospective validation of the efficacy of SABR for primary RCC that has been observed from prior single institutional and retrospective series. The study also allows assessment of treatment related toxicity, overall survival, cancer specific survival, freedom from distant failure and renal function post therapy. TRIAL REGISTRATION: Clinicaltrials.gov NCT02613819 , registered Nov 25th 2015.