Non-invasive techniques for imaging in-vivo human corneal sub basal nerve mapping and migration rate in diabetic neuropathy

Purpose Corneal confocal microscopy (CCM) is a rapid non-invasive ophthalmic technique, which has been shown to diagnose and stratify the severity of diabetic neuropathy. Current morphometric techniques assess individual static images of the subbasal nerve plexus; this work explores the potential for non-invasive assessment of the wide-field morphology and dynamic changes of this plexus in vivo. Methods In this pilot study, laser scanning CCM was used to acquire maps (using a dynamic fixation target and semi-automated tiling software) of the central corneal sub-basal nerve plexus in 4 diabetic patients with and 6 without neuropathy and in 2 control subjects. Nerve migration was measured in an additional 7 diabetic patients with neuropathy, 4 without neuropathy and in 2 control subjects by repeating a modified version of the mapping procedure within 2-8 weeks, thus facilitating re-identification of distinctive nerve landmarks in the 2 montages. The rate of nerve movement was determined from these data and normalised to a weekly rate (µm/week), using customised software. Results Wide-field corneal nerve fibre length correlated significantly with the Neuropathy Disability Score (r = -0.58, p < 0.05), vibration perception (r = -0.66, p < 0.05) and peroneal conduction velocity (r = 0.67, p < 0.05). Central corneal nerve fibre length did not correlate with any of these measures of neuropathy (p > 0.05 for all). The rate of corneal nerve migration was 14.3 ± 1.1 µm/week in diabetic patients with neuropathy, 19.7 ± 13.3µm/week in diabetic patients without neuropathy, and 24.4 ± 9.8µm/week in control subjects; however, these differences were not significantly different (p = 0.543). Conclusions Our data demonstrate that it is possible to capture wide-field images of the corneal nerve plexus, and to quantify the rate of corneal nerve migration by repeating this procedure over a number of weeks. Further studies on larger sample sizes are required to determine the utility of this approach for the diagnosis and monitoring of diabetic neuropathy.

Clinical utility of exhaled nitric oxide

Lower airway inflammation is generally classified as eosinophilic or neutrophilic. In conditions where eosinophilic inflammation predominates such as asthma in children, corticosteroids are usually beneficial. Traditionally, lower airway eosinophilia is measured using cellular count (through bronchoalveolar lavage or induced sputum). Both methods have limited applicability in children. When instruments to measure fractional exhaled nitric oxide (FeNO) became available, it presented an attractive option as it provided a non-invasive method of measuring eosinophilic inflammation suitable for children and adult. Not surprisingly, proposals have been made that FeNO measurement can be clinically used in many scenarios including monitoring the response to anti-inflammatory medications, to verify the adherence to treatment, and to predict upcoming asthma exacerbations. This thesis addresses the utility of FeNO levels in various scenarios, specifically in relation to asthma control and cough, a contentious aspect of the diagnosis of asthma. The thesis consists of a series of systematic reviews (related to the main question) and original studies in children. The over-arching aim of the thesis is to determine if FeNO is a clinically useful tool in the management of asthma and common asthma symptoms. The specific aims of the thesis were, to: 1. Determine if children with asthma have more severe acute respiratory symptoms at presentation with an asthma exacerbation and at days 7, 10 and 14 using validated scales. We also examined if children with asthma were more likely to have a persistent cough on day 14 than children with protracted bronchitis and/or controls. 2. Evaluate the efficacy of tailoring asthma interventions based on sputum analysis in comparison to clinical symptoms (with or without spirometry/peak flow) for asthma related outcomes in children and adults. 3. Evaluate the efficacy of tailoring asthma interventions based on exhaled nitric oxide in comparison to clinical symptoms (with or without spirometry/peak flow) for asthma related outcomes in children and adults. 4. Determine if adjustment of asthma medications based on FeNO levels (compared to management based on clinical symptoms) reduces severe exacerbations in children with asthma. 5. Examine the relationship between FeNO and exercise induced broncho-constriction and cough in children The aims above are addressed in respective chapters and all but one has been published/submitted. A synopsis of the findings are: In study-1 (Aim 1), we found that children with protracted bronchitis had the most severe acute respiratory infection symptoms and higher percentage of respiratory morbidity at day 14 in comparison to children with asthma and healthy controls. The systematic review of study-2 (Aim 2) included 246 randomised adult participants (no children) with 221 completing the trials. In the meta-analysis, a significant reduction in number of participants who had one or more asthma exacerbations occurred when treatment was based on sputum eosinophils in comparison to clinical symptoms. In the systematic review of study-3 (Aim 3), we found no significant difference between the intervention group (treatment adjusted based on FeNO) and control group (treatment adjusted based on clinical symptoms) for the primary outcome of asthma exacerbations or for the other outcomes (clinical symptoms, FeNO level and spirometry). In post-hoc analysis, a significant reduction in mean final daily dose ICS per adult was found in the group where treatment was based on FeNO in comparison to clinical symptoms. In contrast, in the paediatric studies, there was a significant increase in ICS dose in the FeNO strategy arm. Thus, controversy remains of the benefit or otherwise of utilising exhaled nitric oxide (FeNO) in routine clinical practice. FeNO levels are dependent on atopy and none of the 7 published trials have considered atopic status in FeNO levels when medications were adjusted. In study-4 (Aim 4), 64 children with asthma were recruited. Their asthma medications were adjusted according to either FeNO levels or usual clinical care utilising a management hierarchy taking into account atopy. It was concluded that tailoring of asthma medications in accordance to FeNO levels (compared to usual management), taking into account atopy status, reduced the number of children with severe exacerbations. However, a FeNO-based strategy resulted in higher daily ICS doses and had no benefit on asthma control. In study-5 (Aim 5), 33 children with cough and 17 controls were recruited. They were randomised to undertake an exercise challenge on day 1, or dry powder mannitol challenge on day 1 (with alternative challenge being done on day 2). In addition, a 24 hour cough meter, skin prick test, capsaicin cough sensitivity test and cough diary were undertaken. The change in cough frequency post exercise was significantly increased in the children with cough. FeNO decreases post exercise regardless of whether EIB is present or not. Limitations in the studies were addressed in the respective chapters. In summary, the studies from this thesis have provided new information on: • The severity of respiratory symptoms was increased in the early phase of the asthma exacerbation but not in the later recovery phase when compared with controls. • The utility of FeNO in the management of children with asthma. • The relationship of FeNO, cough and EIB in children. • Systematic reviews on the efficacy of tailoring asthma interventions based on eosinophilic inflammatory markers (sputum analysis and FeNO) in comparison to clinical symptoms.

Integrated chronic disease management in primary-secondary care : a systematic literature review of the evidence

Introduction: Diabetes has traditionally been managed as a single chronic disease state, but it exists with co-morbidities such as depression and metabolic syndrome. Treatment is multifaceted, requiring both primary and secondary care, however, the delivery of diabetes care is often fragmented. Integrated chronic disease management is a growing model of interest, and is underpinned by the chronic care model (CCM), devised as a guide for primary care management of patients with chronic conditions. The model identifies six key elements for effective care, and has shown promise in improving the management of diabetes. Aim: To find empirical evidence of integrated care interventions targeted at co-morbidities including diabetes, across primary/secondary care. Method: A systematic review of peer reviewed literature from PubMed, CINAHL, Embase, Cochrane Library and Joanna Briggs was performed. Studies were reviewed according to inclusion criteria- studies published in English, between 2004-2014, empirical studies, studies with evidence of primary/secondary implementation, and those dealing with chronic co-morbid disease states. Results: 51 studies met the inclusion criteria. Included studies were mostly from the US (38), with five from Australia, UK (2), Canada (2), Netherlands (1), Norway (1), Ireland (1), and one multi-country study. It was found that all interventions adopted at least one (average 3-4) of the chronic care model, with the majority implementing delivery system redesign activities within the primary care practice/s. We found evidence of interventions which significantly reduced emergency department and hospital admissions, improved processes of care, patient health outcomes such as HbA1c, improved patient satisfaction, and reduced costs. Conclusion/Implications for practice: Diabetes exists as a co-morbid disease, requiring both primary and secondary care. We found that integrated care interventions adopting elements of the chronic care model positively impacted on patient outcomes, service utilisation, as well as costs. This review has highlighted that it may not be necessary to adopt all CCM elements to improve clinical outcomes, patient satisfaction and costs.

Quantifying economic values of coastal and marine ecosystem services and assessing their use in decision-making : applications in New Caledonia and Australia

This thesis deals with the issues of quantifying economic values of coastal and marine ecosystem services and assessing their use in decision-making. The first analytical part of the thesis focuses on estimating non-market use and non-use values, with an application in New-Caledonia using Discrete Choice Experiment. The second part examines how and to what extent the economic valuation of ecosystem services is used in coastal management decision-making with an application in Australia. Using a multi-criteria analysis, the relative importance of ecological, social and economic evaluation criteria is also assessed in the context of coastal development.