Reforming the legal framework for clinical trials with neonates in Ireland: a children’s rights approach

This thesis assesses the current regulatory framework regarding clinical trials with neonates in Ireland from a children’s rights perspective, as derived from the UN Convention on the Rights of the Child 1989 (UN CRC) and its supporting instruments. The focus on neonates in the thesis is due to the particular need for clinical research with this group of children, their dependency on others for their protection and the lack of attention which has been given to them in the regulatory framework. The importance of children’s rights in this area is linked to the role of human rights in the regulation of clinical research in general. A rights-based approach is of great practical relevance in reforming law, policy and practice. For example, the CRC contains a set of commonly agreed legal benchmarks which can be used to assess the current framework and shape recommendations for reform. In this way, it provides a set of binding norms under international law, which must be complied with by states and state actors in all law, policy and practice affecting children. However, the contribution which a children’s rights approach could make to the regulation of research with children has not, to date, been explored in detail. This thesis aims to address this gap by developing a set of children’s rights-based benchmarks, which are used to assess the Irish regulatory framework for clinical trials with neonates and to develop recommendations for reform. The purpose of the analysis and recommendations is to assess Ireland’s compliance with international children’s rights law in the area and to analyse the potential of children’s rights to effectively address inadequacies in the Irish framework. The recommendations ultimately aim to develop a framework which will enhance the protection of neonates’ rights in this important area of children’s lives.

Vascular calcification and mineral bone disorder in chronic kidney disease

Chronic Kidney Disease (CKD), osteoporosis and mild hyponatremia are all prevalent chronic conditions that may coexist and are often under-recognized. Mineral-Bone Disorder begins early in the natural history of CKD and results in complex abnormalities of bone which ultimately confers a well-established increased risk of fragility fractures in End Stage Kidney Disease. Hyponatremia is a novel, usually renal mediated metabolic perturbation, that most commonly occurs independently of the stage of renal dysfunction but which may also predispose to increased fracture risk. The extent -if any- to which either early stages of renal dysfunction or the presence of hyponatremia contribute to fracture occurrence in the general population, independently of osteoporosis, is unclear. Renal transplantation is the treatment of choice for ESKD and although it restores endogenous renal function it typically fails to normalize either the long term cardiovascular or fracture risk. One potential mechanism contributing to these elevated long-term risks and to diminished Health Related Quality of Life is persistent, post-transplant hyperparathyroidism. In this study we retrospectively examine the association of renal function and serum sodium with Bone Mineral Density and fracture occurrence in a retrospective cohort of 1930 female members of the general population who underwent routine DXA scan. We then prospectively recruited a cohort of 90 renal transplant recipients in order to examine the association of post transplant parathyroid hormone (PTH) level with measures of CKD Mineral Bone Disorder, including, DXA Bone Mineral Density, Vascular Calcification (assessed using both abdominal radiography and CT techniques, as well as indirectly by carotid-femoral Pulse Wave Velocity) and Quality of Life (using the Short Form-12 and a PTH specific symptom score). In the retrospective DXA cohort, moderate CKD (eGFR 30-59ml/min/1.73m2) and hyponatremia (<135mmol/L) were associated with fracture occurrence, independently of BMD, with an adjusted Odds Ratio (95% Confidence Interval), of 1.37 (1.0, 1.89) and 2.25 (1.24, 4.09) respectively. In the renal transplant study, PTH was independently associated with the presence of osteoporosis, adjusted Odds Ratio (95% Confidence Interval), 1.15 (per 10ng/ml increment), (1.04, 1.26). The presence of osteoporosis but not PTH was independently associated with measures of vascular calcification, adjusted ß (95% Confidence Interval), 12.45, (1.16, 23.75). Of the eight quality-of-life domains examined, post-transplant PTH (per 10ng/ml increment), was only significantly and independently associated with reduced Physical Functioning, (95% Confidence Interval), 1.12 (1.01, 1.23). CKD and hyponatremia are both common health problems that may contribute to fracture occurrence in the general population, a major on-going public health concern. PTH and decreased Bone Mineral Density may signal sub-optimal long-term outcomes post renal transplantation, influencing bone and vascular health and to a limited extent long term Health Related Quality of Life

Infant milk formula manufacture: process and compositional interactions in high dry matter wet-mixes

Infant milk formula (IMF) is fortified milk with composition based on the nutrient content in human mother's milk, 0 to 6 months postpartum. Extensive medical and clinical research has led to advances in the nutritional quality of infant formula; however, relatively few studies have focused on interactions between nutrients and the manufacturing process. The objective of this research was to investigate the impact of composition and processing parameters on physical behaviour of high dry matter (DM) IMF systems with a view to designing more sustainable manufacturing processes. The study showed that commercial IMF, with similar compositions, manufactured by different processes, had markedly different physical properties in dehydrated or reconstituted state. Commercial products made with hydrolysed protein were more heat stable compared to products made with intact protein, however, emulsion quality was compromised. Heat-induced denaturation of whey proteins resulted in increased viscosity of wet-mixes, an effect that was dependant on both whey concentration and interactions with lactose and caseins. Expanding on fundamental laboratory studies, a novel high velocity steam injection process was developed whereby high DM (60%) wet-mixes with lower denaturation/viscosity compared to conventional processes could be achieved; powders produced using this process were of similar quality to those manufactured conventionally. Hydrolysed proteins were also shown to be an effective way of reducing viscosity in heat-treated high DM wet-mixes. In particular, using a whey protein concentrate whereby β-Lactoglobulin was selectively hydrolysed, i.e., α-Lactalbumin remained intact, reduced viscosity of wet-mixes during processing while still providing good emulsification. The thesis provides new insights into interactions between nutrients and/or processing which influence physical stability of IMF both in concentrated liquid and powdered form. The outcomes of the work have applications in such areas as; increasing the DM content of spray drier feeds in order to save energy, and, controlling final powder quality.

Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials

Objective: To assess the effects of selective cyclo-oxygenase-2 (COX 2) inhibitors and traditional non-steroidal anti-inflammatory drugs (NSAIDs) on the risk of vascular events. Design: Meta-analysis of published and unpublished tabular data from randomised trials, with indirect estimation of the effects of traditional NSAIDs. Data sources: Medline and Embase (January 1966 to April 2005); Food and Drug Administration records; and data on file from Novartis, Pfizer, and Merck. Review methods: Eligible studies were randomised trials that included a comparison of a selective COX 2 inhibitor versus placebo or a selective COX 2 inhibitor versus a traditional NSAID, of at least four weeks' duration, with information on serious vascular events (defined as myocardial infarction, stroke, or vascular death). Individual investigators and manufacturers provided information on the number of patients randomised, numbers of vascular events, and the person time of follow-up for each randomised group. Results: In placebo comparisons, allocation to a selective COX 2 inhibitor was associated with a 42% relative increase in the incidence of serious vascular events (1.2%/year v 0.9%/year; rate ratio 1.42, 95% confidence interval 1.13 to 1.78; P = 0.003), with no significant heterogeneity among the different selective COX 2 inhibitors. This was chiefly attributable to an increased risk of myocardial infarction (0.6%/year v 0.3%/year; 1.86, 1.33 to 2.59; P = 0.0003), with little apparent difference in other vascular outcomes. Among trials of at least one year's duration (mean 2.7 years), the rate ratio for vascular events was 1.45 (1.12 to 1.89; P = 0.005). Overall, the incidence of serious vascular events was similar between a selective COX 2 inhibitor and any traditional NSAID (1.0%/year v 0.9/%year; 1.16, 0.97 to 1.38; P = 0.1). However, statistical heterogeneity (P = 0.001) was found between trials of a selective COX 2 inhibitor versus naproxen (1.57, 1.21 to 2.03) and of a selective COX 2 inhibitor versus non-naproxen NSAIDs (0.88, 0.69 to 1.12). The summary rate ratio for vascular events, compared with placebo, was 0.92 (0.67 to 1.26) for naproxen, 1.51 (0.96 to 2.37) for ibuprofen, and 1.63 (1.12 to 2.37) for diclofenac. Conclusions: Selective COX 2 inhibitors are associated with a moderate increase in the risk of vascular events, as are high dose regimens of ibuprofen and diclofenac, but high dose naproxen is not associated with such an excess.

Personalized absolute benefit of statin treatment for primary or secondary prevention of vascular disease in individual elderly patients

Objective: To estimate the absolute treatment effect of statin therapy on major adverse cardiovascular events (MACE; myocardial infarction, stroke and vascular death) for the individual patient aged C70 years. Methods: Prediction models for MACE were derived in patients aged C70 years with (n = 2550) and without (n = 3253) vascular disease from the ‘‘PROspective Study of Pravastatin in Elderly at Risk’’ (PROSPER) trial and validated in the ‘‘Secondary Manifestations of ARTerial disease’’ (SMART) cohort study (n = 1442) and the ‘‘Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm’’ (ASCOT-LLA) trial (n = 1893), respectively, using competing risk analysis. Prespecified predictors were various clinical characteristics including statin treatment. Individual absolute risk reductions (ARRs) for MACE in 5 and 10 years were estimated by subtracting ontreatment from off-treatment risk. Results: Individual ARRs were higher in elderly patients with vascular disease [5-year ARRs: median 5.1 %, interquartile range (IQR) 4.0–6.2 %, 10-year ARRs: median 7.8 %, IQR 6.8–8.6 %] than in patients without vascular disease (5-year ARRs: median 1.7 %, IQR 1.3–2.1 %, 10-year ARRs: 2.9 %, IQR 2.3–3.6 %). Ninetyeight percent of patients with vascular disease had a 5-year ARR C2.0 %, compared to 31 % of patients without vascular disease. Conclusions: With a multivariable prediction model the absolute treatment effect of a statin on MACE for individual elderly patients with and without vascular disease can be quantified. Because of high ARRs, treating all patients is more beneficial than prediction-based treatment for secondary prevention of MACE. For primary prevention of MACE, the prediction model can be used to identify those patients who benefit meaningfully from statin therapy.

Hospital clinicians information behaviour and attitudes towards the 'Clinical Informationist': an Irish survey

Background: Hospital clinicians are increasingly expected to practice evidence-based medicine (EBM) in order to minimize medical errors and ensure quality patient care, but experience obstacles to information-seeking. The introduction of a Clinical Informationist (CI) is explored as a possible solution. Aims:  This paper investigates the self-perceived information needs, behaviour and skill levels of clinicians in two Irish public hospitals. It also explores clinicians perceptions and attitudes to the introduction of a CI into their clinical teams. Methods: A questionnaire survey approach was utilised for this study, with 22 clinicians in two hospitals. Data analysis was conducted using descriptive statistics. Results: Analysis showed that clinicians experience diverse information needs for patient care, and that barriers such as time constraints and insufficient access to resources hinder their information-seeking. Findings also showed that clinicians struggle to fit information-seeking into their working day, regularly seeking to answer patient-related queries outside of working hours. Attitudes towards the concept of a CI were predominantly positive. Conclusion: This paper highlights the factors that characterise and limit hospital clinicians information-seeking, and suggests the CI as a potentially useful addition to the clinical team, to help them to resolve their information needs for patient care.

Supporting therapist engagement in evidence based practice: Developing a continuing education programme through participatory action research

Therapists find it challenging to integrate research evidence into their clinical decision-making because it may involve modifying their existing practices. Although continuing education (CE) programmes for evidence-based practice (EBP) have employed various approaches to increase individual practitioner’s knowledge and skills, these have been shown to have little impact in changing customary behaviours. To date, there has been little attempt to actively engage therapists as collaborators in developing educational processes concerning EBP. The researcher collaborated with seven clinical therapists (one occupational therapist, four physiotherapists and two speech and language therapists) enrolled in a new post-qualification Implementing Evidence in Therapy Practice (IETP) MSc module to monitor and adapt the learning programme over ten weeks. The participating therapists actively engaged in participatory action research (PAR) iterative cycles of reflecting→ planning→ acting→ observing→ reflecting with the researcher. Mixed methods were used to evaluate the IETP module and its influence on therapists’ subsequent engagement in EBP activities. Data were gathered immediately on completion of the module and five months later. Immediate post-module findings revealed four components as being important to the therapists: 1) characteristics of the learning environment; 2) acquisition of relevant EBP skills; 3) nature of the learning process; and 4) acquiring confidence. The two themes and sub-themes which emerged from individual interviews conducted five months post-module expanded on the four components already identified. Theme 1: Experiencing the learning (sub-themes: module organisation; learning is relational; improving the module); and theme 2: Enacting the learning through a new way of being (sub-themes: criticality and reflection; self agency; modelling EBP behaviours; positioning self in an EB work culture). The therapists’ perspectives had by then shifted from that of a learner to that of a clinician constructing a new sense of self as an evidence-based practitioner. Findings from this study underline the importance of the process of socially constructed knowledge and of empowering learners through collaboratively designed continuing education programmes. In the student-driven learning environment, therapists chose repetitive skill-building and authentic problem-solving activities which reflected the complexity of the environments to which they were expected to transfer their learning. These findings have implications for educators designing EBP continuing education programmes, during which students develop professional ways of being.

The use of atraumatic restorative treatment in elderly patients: a randomised controlled clinical trial

Objectives: to assess elderly patients’ dental status and dental habits and compare the survival rates, impact on patients’ quality of life and cost-effectiveness of Atraumatic Restorative Treatment (ART) and a conventional treatment (CT) to restore carious lesions in an elderly population. Methods: In this randomised clinical trial, 99 independently living adults (65-90 yrs) with carious lesions were randomly allocated to receive either ART or CT. Details of restored, missing and carious teeth were recorded and patients answered some questions about their oral hygiene and dental attendance habits. Direct and indirect costs were measured based on treatment time, materials and labour. Effectiveness was measured using restoration survival percentage after one year. The survival of restorations was assessed 6 months and one year after restoration placement by an independent examiner. Oralhealth related quality of life (OHRQoL) was assessed using the OHIP-14 at baseline and 2 months after treatment together with a global transition statement. Results: The patient sample comprised 46 (46.46%) male and 53 (53.54) female participants at baseline, with a mean age of 73.18 (SD=6.76). The mean DMFT of the entire sample was 27.10. Ninety patients and 268 restorations could be assessed after one year, 127 ART (46 patients) and 141 conventional restorations (44 patients). 93.7% and 97.2% of the restorations placed were considered successful in the ART and CT groups, respectively. The OHIP scores did not change dramatically 2 months after treatment, in either group. The global transition scale showed an improvement in overall oral health after treatment for the majority of patients. The ART were more cost-effective compared to the CT restorations. Conclusions: ART presented survival rates similar to CT after 1 year and was a more cost-effective alternative to treat the elderly.

Pharmacotherapy optimization in older patients by a structured clinical pharmacist assessment and intervention

Introduction: Older individuals are particularly vulnerable to potentially inappropriate prescribing (PIP), drug related problems (DRPs) and adverse drug reactions (ADRs). A number of different interventions have been proposed to address these issues. However to-date there is a paucity of well-designed trials examining the impact of such interventions. Therefore the aims of this work were to: (i) establish a baseline PIP prevalence both nationally and internationally using the STOPP, Beers and PRISCUS criteria, (ii) identify the most comprehensive method of assessing PIP in older individuals, (iii) develop a structured pharmacist intervention supported by a computer decisions support system (CDSS) and (iv) examine the impact of this intervention on prescribing and incidence of ADRs. Results: This work identified high rates of PIP across all three healthcare settings in Ireland, 84.7% in the long term care, 70.7% in secondary care and 43.3% in primary care being reported. This work identified that for a comprehensive assessment of prescribing to be undertaken, an amalgamation of all three criteria should be deployed simultaneously. High prevalences of DRPs and PIP in older hospitalised individuals were identified. With 82.0% and 76.3% of patients reported to have at least one DRP or PIP instance respectively. The structured pharmacist intervention demonstrated a positive impact on prescribing, with a significant reduction MAI scores being reported. It also resulted in the intervention patients’ having a reduced risk of experiencing an ADR when compared to the control patients (absolute risk reduction of 6.8 (95% CI 1.5% - 12.3%)) and the number needed to treat = 15 (95% CI 8 - 68). However the intervention was found to have no significant effect on length of stay or mortality rate. Conclusion: This work shows that PIP is highly prevalent in older individuals across three healthcare settings in Ireland. This work also demonstrates that a structured pharmacist intervention support by a dedicated CDSS can significantly improve the appropriateness of prescribing and reduce the incidence of ADRs in older acutely ill hospitalised individuals.