Medicine and Radiology - Theses
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Clinical application of non-contrast MRA techniques in the era of nephrogenic systemic fibrosis and gadolinium deposition
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.
Optimising the role of auxiliary midwives to improve maternal and newborn health care in Myanmar: the potential for task shifting
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.
The effect of midlife cardiovascular risk factors on late life brain structure and cognitive function in normal ageing women
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.