HRB Clinical Research Facility at UCC - Doctoral Theses

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    Malnutrition & altered body composition in oncology: prevalence, aetiology, consequences & potential therapies
    (University College Cork, 2020-08-10) Sullivan, Erin S.; Ryan, Aoife; Power, Derek
    Malnutrition is common across all cancer sites and stages and its aetiology is multifactorial and complex. It is associated with poorer quality of life, increased morbidity and mortality and is often considered an inevitable consequence of cancer and its treatments. However, we lack efficacious treatments for cancer-related malnutrition. The aim of this thesis was to describe the epidemiology of malnutrition in cancer, examine the causes and consequences of the condition and explore potential treatment strategies. This thesis begins by estimating that across Ireland and the UK, 34% of cancer patients (128,892) are affected by clinically significant weight loss annually and there are 133,707 annual cases of cancer-related sarcopenia (35% patients affected). This thesis shows using computed tomography scans (the gold standard in body composition analysis) that abnormalities of body composition, including loss of fat without loss of muscle, are predictive of poor survival in advanced cancer. Furthermore, cachexia (a syndrome of disease-related appetite loss and wasting) was shown to be more prevalent in those with inflammation and poor performance status and the obesity paradox in colorectal cancer was confirmed (obesity is a risk factor for the disease, but is associated with improved survival). The nutritional experience of patients with cancer is described, namely that nutrition is a high priority for patients, who experience many dietary issues throughout their journey, but that information available to patients is lacking and referral to dietitians is very inconsistent. Finally, a placebo controlled trial of 2 novel dairy-derived, ghrelinergic peptides showed that one of the peptides investigated increased protein intake in healthy males by 23 g per day. Prompt identification of patients with cancer-related malnutrition must be optimised and development of an effective, evidence-based treatment strategy is of the utmost importance as it stands to improve longevity and quality of life for cancer survivors.
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    Deprescribing long-term medications in frail older people approaching end-of-life
    (University College Cork, 2019-10-01) Curtin, Denis; O'Mahony, Denis; Gallagher, Paul; Horizon 2020
    One of the great successes of modern medicine is that it has transformed relatively acute causes of death (i.e. cardiovascular disease, organ failure and some cancers) into chronic diseases. In the developed world, most people will now grow old and, over decades, accumulate various chronic diseases before eventually succumbing to a final illness. Older people in their final years are commonly prescribed multiple medications to manage their chronic diseases. These medications may ameliorate symptoms, prevent future adverse health events and extend life. However, the use of multiple medications is also associated with higher risks of side-effects, adverse drug-interactions, and adherence problems. Furthermore, as older people become increasingly frail, the use of multiple medications may be considered burdensome for them or even futile. For frail older patients taking multiple medications, when does the scale shift from net benefit to net harm? If declining health and death are unavoidable, it follows logically that there must come a point when patients no longer benefit from certain chronic disease therapies. This thesis primarily attempts to address two important questions. Firstly, how can we recognize when older people are approaching end-of-life? For such people, a personalized approach that prioritizes comfort and symptom relief is likely to be more appropriate than the pursuit of strict chronic disease targets. Secondly, when attempting to address a frailer older person’s complex and burdensome medication regimen, how do we separate essential medications from those that are dispensable?
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    Dietary phosphorus in chronic kidney disease
    (University College Cork, 2020) Byrne, Fiona Nora; Eustace, Joe; Kiely, Mairead; Shiely, Frances; Kearney, Patricia M.
    Hyperphosphataemia is common in the later stages of chronic kidney disease and is a universal problem in end stage kidney disease, where it is associated with increased morbidity and mortality. Treatment includes a low phosphorus diet, that imposes numerous dietary restrictions, lacks a robust evidence base and in current practice fails to distinguish between phytate and non phytate bound phosphorus. The overall aim of this PhD was to provide the evidence basis for a revised low phosphorus diet, and to assess its effectiveness, safety and tolerability. Specific aims were 1) to define revised dietary recommendations for phosphorus in chronic kidney disease and to translate these recommendations into food based advice, 2) to conduct a proof of concept acute feeding study in prevalent haemodialysis patients using the modified diet and 3) to investigate the effectiveness of the modified diet in a multicentre randomised controlled trial in prevalent haemodialysis patients. To update the traditional low phosphorus diet, as chair of a national working group of Irish renal dietitians, I undertook a narrative review of the available renal nutrition literature. We combined the evidence with clinical experience and expertise to update the traditional low phosphorus diet. The modified diet, agreed by consensus, relaxed the restrictions of phytate bound phosphorus, and introduced previously disallowed foods such as pulses, peas, nuts and more whole grains. To ensure adequate but not excessive protein intake, we introduced guidance on bread and cereal intakes and included some advice based on phosphorus to protein ratios. Finally we increased the focus on avoiding phosphate additives. These changes were incorporated into a modified renal diet. The modified diet was initially evaluated against the standard low phosphorus diet in an in-centre, directly observed, one day, cross-over feeding study in order to examine the immediate postprandial effects of the modified diet. We demonstrated that the modified diet blunted post-prandial hyperphosphataemia, was not associated with increased hyperkalaemia and was well tolerated. Given the results of the acute feeding study, we conducted a national multicentre randomised controlled trial, comparing the modified low phosphorus diet with the standard low phosphorus diet in 74 prevalent patients treated with maintenance haemodialysis. The modified renal diet, with its broader food choice, achieved a significantly higher fibre intake, was well tolerated and provided comparable serum phosphate and potassium control as the standard renal diet. Based on the evidence from this project, a decision was taken by the Irish Renal Interest Group of the Irish and Dietetic Institute in January 2019, to endorse the modified low phosphorus diet and to implement it nationally.
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    Implementation of risk based monitoring into academic led clinical trials in Ireland
    (University College Cork, 2018) Hurley, Caroline; Eustace, Joe; Kearney, Patricia M.; Shiely, Frances; Clark, Mike; Flanagan, Evelyn; University College Cork; Health Research Board
    Introduction: In November 2016, the International Conference on Harmonsation (ICH) published a requirement for sponsors to develop a systematic, prioritised, risk-based approach to monitoring clinical trials. This process is more commonly known as Risk Based Monitoring (RBM). However, evidence suggested that a gold standard validated approach to RBM did not exist and it was unclear how sponsors would introduce RBM into their clinical trials units (CTUs). In 2014, Ireland, unlike countries such as Switzerland and the UK, did not have a national strategy to support the introduction of RBM into its publicly funded, academic-led CTUs. The absence of a national strategy and gold standard RBM approach meant it was not clear how RBM would be implemented in CTUs. Therefore, the overarching aim of this thesis was to develop, implement and evaluate a quality improvement intervention to support the introduction of RBM into academic-led clinical trials in Ireland. Methods: This thesis employed a multi-method research strategy directed by the Knowledge to Action (KTA) framework over four years from October 2014 to October 2018. The KTA framework is a conceptual framework to assist the translation of knowledge into sustainable, evidence-based interventions. This thesis used a range of research methods, implemented in four separate sequential phases, to address different components of the KTA framework which primarily involve knowledge creation and knowledge translations. The four phases first involved systematically reviewing the existing evidence of RBM methods. Then, in a mixed method study, I explored the attitudes, and perceived barriers and facilitators to the implementation of RBM in academic-led clinical trials in Ireland. Next, I did a document analysis study to examine the experience of monitoring in a clinical trial. Finally, I developed the quality improvement study by combining the results of the three earlier phases to identify the most appropriate quality improvement intervention to support RBM use in academic led clinical trials in Ireland. Results: The systematic review showed several tools exist to support the implementation of RBM. The mixed methods study showed a need for training and regulatory endorsed guidelines to support the implementation of RBM in academic-led clinical trials. The document analysis showed that on-site and centralised monitoring can be used simultaneously to fulfil ICH GCP’s seventeen monitoring requirements. The findings of these three studies were combined and a brief, face-to-face, interactive education workshop was identified as an effective way to encourage RBM tool usage among clinical researchers working in academic-led clinical trials in Ireland. Conclusion: Applying the KTA framework to empirical data has led to an intervention that is implementable in clinical practice and has the potential to positively change monitoring practices of clinical researchers. This thesis provides critical evidence on the complexities associated with implementing RBM in academic-led clinical trials. It provides practical recommendations to guide clinical researchers who wish to perform RBM.
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    CT dose optimization with model based iterative reconstruction
    (University College Cork, 2019) Moloney, Fiachra; Maher, Michael M.; O'Connor, Owen
    The aim of this thesis is to assess the feasibility of using model-based iterative reconstruction (MBIR) to develop new low-dose CT (computed tomography) protocols in the areas of neck, chest, and abdominal imaging without compromising diagnostic performance. Medical imaging has become the largest source of radiation exposure for humans other than natural background radiation. The availability of and improvements in diagnostic imaging have led to a sevenfold increase in the use of imaging over the past 30 years. This is especially true for CT, with a 7.8% annual increase in the use of CT from 1996 to 2010. The major concern associated with the widespread uptake of CT is the parallel increase in radiation exposure incurred by patients, and while the relationship of diagnostic radiation exposure to a quantifiable risk of cancer induction remains a controversial topic, physicians are beholden to keep radiation doses from diagnostic imaging as low as reasonably possible to limit the risk of radiation-induced cancer. We conducted preliminary phantom and cadaveric studies to examine the performance of MBIR at different radiation dose levels in the thorax and abdomen. Cadavers and phantoms provide a means of safely assessing new technologies and optimizing scan protocols prior to clinical validation. An anthropomorphic torso phantom and 5 human cadavers were scanned at varying radiation dose levels and images reconstructed using three different reconstruction techniques: filtered back projection, hybrid IR and MBIR. MBIR reduced image noise and improved image quality even in CT images acquired with a mean radiation dose reduction of 62%, compared with conventional dose studies reconstructed with hybrid IR, with lower levels of objective image noise, superior diagnostic acceptability and contrast resolution, and comparable subjective image noise and streak artifact scores. We subsequently performed clinical studies with the objectives of assessing MBIR as a tool for image quality improvement and radiation dose reduction in CT, and for the development of new low-dose carotid angiography, chest, and abdominopelvic CT protocols. We developed a low-dose carotid CTA protocol reconstructed with MBIR comparable to a conventional dose CTA protocol in terms of image quality and diagnostic accuracy while enabling a dose reduction of 49.6%. 20 patients were scanned using a split-dose technique with radiation dose divided into a low-dose acquisition reconstructed with MBIR and a conventional dose acquisition reconstructed with hybrid IR. Mean effective dose was significantly lower for the low-dose studies (1.84mSv versus 3.71mSv) and subjective image noise, contrast resolution, and spatial resolution were significantly higher for the low-dose studies. There was excellent agreement for stenosis grading accuracy between low- and conventional dose studies (Cohen κ = 0.806). A modified low-dose CT thorax protocol reconstructed with MBIR was also developed to monitor pulmonary disease progression in patients with cystic fibrosis with our low-dose protocol enabling the acquisition of a full-volume diagnostic quality chest CT at a dose equivalent to that of a chest radiograph (0.09±0.01mSv). Finally, we assessed the feasibility of low-dose abdominopelvic CT performed with MBIR as a radiation dose reduction strategy for imaging patients presenting with acute abdominal pain. A 74.7% mean radiation dose reduction was achieved with scans performed in the peri- and submillisievert range in patients of normal and low BMI, respectively, without compromising diagnostic performance. Dose reduction to the submillisievert range for patients with an elevated BMI was a challenge. The current era is extremely exciting in terms of radiation dose optimization in CT. This thesis is a demonstration of the potential for substantial reductions in radiation exposure, when the benefits of iterative reconstruction are combined with automated tube current modulation and other CT scanner technologies. The combination of all these hardware and software developments is now seeing major benefits for the patient and moving beyond the narrow aim of radiation exposure reduction to a complete change in practice, towards replacement of conventional radiography with low-dose CT, without any penalty for the patient in terms of radiation exposure.