Evidence Synthesis and targeting further research for adherence and stratification in health economic evaluations

Cost-effectiveness analysis (CEA) models, used to make health policy decisions, are usually subject to uncertainty. This thesis aims to develop statistical methods to quantify uncertainty and target where reducing uncertainty is most beneficial in a CEA. This enables policy decisions, based on the models, to be better informed. There is a focus on two areas: adherence to interventions and heterogeneity in treatment effects, which are often not modelled due to a lack of good data. A case study of treatment for patients with sleep apnoea is used to illustrate these methods and techniques. Value of Information measures can help prioritise where to focus further research and estimate the expected benefits from a study of particular design and size. Until recently, it has been difficult to evaluate these quantities due to computational complexity. Various recently developed methods to calculate the expected value of information are summarised. Through an application to the case study, the importance of an adequate number of simulations to gain reliable results is highlighted. Adherence to interventions is often neglected in CEAs due to limited and sparse data. Data on adherence to interventions for sleep apnoea is collected. Through Bayesian model-based meta-analyses, implemented by Markov Chain Monte Carlo simulation, the impact of modelling adherence to interventions on the CEA results is explored. Additionally, the value of collecting further information on adherence to interventions is calculated, indicating value in collecting data even at few time points, and in the early period of follow-up. Another under explored area within CEAs is stratification of the optimal treatment decision. Here, the focus is on stratification based on continuous measures of disease severity, which may be associated with differential cost-effectiveness through variations in treatment effects. Aggregate and individual participant data on the impact of baseline covariates and treatment effects is summarised. Bayesian model-based meta-regression is used to explore stratification on one or two measure of treatment severity. The value of collecting further data on factors relating to stratification has been explored by using and extending recent non-parametric regression methods. By using evidence synthesis methods, to make use of all available data, this thesis has found it is possible to incorporate uncertainty due to adherence to interventions and stratifications of treatment decisions into CEA models, allowing future research priorities to be assessed through value of information methods.Claire Simons was funded by an MRC Unit PhD Studentship for the duration of this work (2014-2018) (Grant Number: MC_U105260556)

An investigation of student teachers' attitudes toward varieties of spoken English

ABSTRACT As the lingua franca of South Africa, English is spoken by first language (L1) and additional language (AL) speakers, resulting in varieties of English being spoken. Internationally, research findings suggest that listeners form attitudes toward people according to their language (Cargile et al 1994 and Labov 1969a, b, 1972). In a country with much diversity in language, South Africans’ attitudes and their subsequent behaviour toward speakers are likely to be affected by a speaker’s language or variety thereof. This research aimed to establish the attitudes that student teachers of English, Mathematics and Science hold toward varieties of spoken English, with a specific focus on learners’ spoken English. Two AL varieties of English (Afrikaans South African English and Black South African English) and two L1 varieties (Indian South African English and White South African English) were investigated. 18 third and fourth year student teachers from the University of the Witwatersrand participated in focus groups interviews. Each focus group followed a two-part format. Firstly, participants responded, by means of a questionnaire, to four voice recordings, each representing one of the varieties of English being researched. Secondly, the student teachers discussed their attitudes toward varieties of English. These attitudes were then analysed within a qualitative framework. This analysis was informed by Labov (1969a, b, 1972) who demonstrated that one’s variety of English is not an indicator of one’s intellect and ability. Kachru’s Three Concentric Circles (1996) provided a model for the interpretation of the data. This model distinguishes between L1 and AL varieties of English and illustrates the equality that exists between varieties of English - both of which are key factors within a study of attitudes toward varieties of English in South Africa. The findings indicated that, despite the equality that both Labov (1969a, b, 1972) and Kachru (1996) outline, student teachers’ attitudes toward a speaker’s variety of English are affected by numerous factors. These factors include the student teachers’ racial background, language, education and teaching subjects. Participants voiced a range of attitudes toward varieties of spoken English with some believing that one variety of English, White South Africa English, holds more linguistic capital while other participants perceive English to be a means of communication and therefore do not stress a specific variety of English. A potential consequence of these attitudes is that the participants’ interaction with and treatment of speakers of other varieties of English might be influenced, either negatively or positively. Within the classroom this could affect the teaching and learning process if teachers’ treatment and assessment of their learners are modified according to a learner’s variety of spoken English

Synthesis, molecular modelling and CYP24A1 inhibitory activity of novel of (E)-N-(2-(1H-imidazol-1-yl)-2-(phenylethyl)-3/4-styrylbenzamides

CYP24A1 (25-hydroxyvitamin D-24-hydroxylase) is a useful enzyme target for a range of medical conditions including cancer, cardiovascular and autoimmune disease, which show elevated CYP24A1 levels and corresponding reduction of calcitriol (the biologically active form of vitamin D). A series of (E)-N-(2-(1H-imidazol-1-yl)-2-(phenylethyl)-3/4-styrylbenzamides have been synthesised using an efficient synthetic route and shown to be potent inhibitors of CYP24A1 (IC50 0.11–0.35 μM) compared with the standard ketoconazole. Molecular modelling using our CYP24A1 homology model showed the inhibitors to fill the hydrophobic binding site, forming key transition metal interaction between the imidazole nitrogen and the haem Fe3+ and multiple interactions with the active site amino acid residues

Pyridine based dual binding site aromatase (CYP19A1) inhibitors

Aromatase (CYP19A1) inhibitors are the mainstay therapeutics for the treatment of hormone dependant breast cancer, which accounts for approximately 70% of all breast cancer cases. However, increased resistance to the clinically used aromatase inhibitors, including letrozole and anastrazole, and off target effects, necessitates the development of aromatase inhibitors with improved drug profiles. The development of extended 4th generation pyridine based aromatase inhibitors with dual binding (haem and access channel) is therefore of interest and here we describe the design, synthesis and computational studies. Cytotoxicity and selectivity studies identified the pyridine derivative (4-bromophenyl)(6-(but-2-yn-1-yloxy)benzofuran-2-yl)(pyridin-3-yl)methanol (10c) as optimal with CYP19A1 IC50 0.83 nM (c.f. letrozole IC50 0.70 nM), and an excellent cytotoxicity and selectivity profile. Interestingly, computational studies for the 6-O-butynyloxy (10) and 6-O-pentynyloxy (11) derivatives identified an alternative access channel lined by Phe221, Trp224, Gln225 and Leu477, providing further insight into the potential binding mode and interactions of the non-steroidal aromatase inhibitors

Liposomal delivery of hydrophobic RAMBAs provides good bioavailability and significant enhancement of retinoic acid signalling in neuroblastoma tumour cells

Retinoid treatment is employed during residual disease treatment in neuroblastoma, where the aim is to induce neural differentiation or death in tumour cells. However, although therapeutically effective, retinoids have only modest benefits and suffer from poor pharmacokinetic properties. In vivo, retinoids induce CYP26 enzyme production in the liver, enhancing their own rapid metabolic clearance, while retinoid resistance in tumour cells themselves is considered to be due in part to increased CYP26 production. Retinoic acid metabolism blocking agents (RAMBAs), which inhibit CYP26 enzymes, can improve retinoic acid pharmacokinetics in pre-clinical neuroblastoma models. Here we demonstrate that in cultured neuroblastoma tumour cells, RAMBAs enhance retinoic acid action as seen by morphological differentiation, AKT signalling and suppression of MYCN protein. Although active as retinoid enhancers, these RAMBAs are highly hydrophobic and their effective delivery in humans will be very challenging. Here we demonstrate that such RAMBAs can be loaded efficiently into cationic liposomal particles, where the RAMBAs achieve good bioavailability and activity in cultured tumour cells. This demonstrates the efficacy of RAMBAs in enhancing retinoid signaling in neuroblastoma cells and shows for the first time that liposomal delivery of hydrophobic RAMBAs is a viable approach, providing novel opportunities for their delivery and application in humans

Multilingual Validation of the First French Version of Munich Dysphagia Test-Parkinson's Disease (MDT-PD) in the Luxembourg Parkinson's Study

The Munich Dysphagia Test for Parkinson's disease (MDT-PD) was initially developed and validated in the German population as a highly sensitive and specific self-reported screening questionnaire to detect early oropharyngeal symptoms and aspiration risk in patients with idiopathic Parkinson's disease (iPD). In order to make this tool accessible for prevention in the French speaking populations worldwide, we performed the first French translation and provide a linguistic and psychometric validation in the unique multilingual environment of the Luxembourg Parkinson's Study

Mycobacterial CYP121 as a target for anti-TB drug discovery

Despite the introduction of the first line treatment regimen forty years ago and the continuous trials since that time to introduce new regimens, tuberculosis (TB) is considered to be the cause of considerable mortality worldwide. Recent research highlighted the Mycobacterium tuberculosis (Mtb)CYP450s as potential drug targets. This article reviews mycobacterial CYP121 as a target for anti-TB drug discovery

Pitfalls and possibilities in literacy research: A review of South African literacy studies, 2004-2018

Background: Given the comprehensively documented literacy crisis in South Africa and the gaps in what is known about the effective teaching of reading and writing in schools, high-quality literacy research is a priority. Objectives: This article evaluates South African research from two annotated bibliographies on reading in African languages at home language level (2004-2017) and South African research on teaching reading in English as a first additional language (2007-2018). It also aims to provide guidelines for addressing these weaknesses. Methods: Examples of 70 quantitative and qualitative research studies from the annotated bibliographies were critically analysed, identifying key weaknesses in the research as a whole and examples of excellent quality. Results: Weaknesses evident in the research reviewed, suggested greater consideration is needed to lay sound methodological foundations for quality literacy research. Three methodological issues underlying local literacy research that require greater attention are research design, selection and use of literature and research rigour. High-quality research examples are referenced but, for ethical reasons, examples of what we consider to be flawed research are described generally. Guidelines are offered for addressing these pitfalls that, in our view, contribute to research of limited quality. Since many universities require submission of a journal article as a requirement for postgraduate students, preparation for such an article is considered. Conclusion: While this article is not intended to be a comprehensive guide, we hope it is useful to supervisors, postgraduate students and early career researchers currently undertaking, or planning to undertake, literacy research and to writing for publication

Analysis of the binding sites of vitamin D 1α-hydroxylase (CYP27B1) and vitamin D 24-hydroxylase (CYP24A1) for the design of selective CYP24A1 inhibitors: homology modelling, molecular dynamics simulations and identification of key binding requirements

A homology model of human CYP27B1 was built using MOE and was further optimised by molecular dynamics simulations of the hCYP27B1 homology model and a hCYP27B1-SDZ-88357 complex. Docking results from the hCYP27B1-SDZ-88357 complex showed amino acids Arg107, Asn387 and Asp320 have an important role in binding interaction, with Asp320 part of the important acid-alcohol pair situated in the I-helix with the conserved sequence (A/G) GX (E/D) (T/S), which assumes an essential role in the binding of an oxygen molecule for catalysis. Additional docking experiments with selective hCYP27B1 or hCYP24A1 inhibitors using both the hCYP27B1 model and a triple mutant hCYP24A1 model provided further support for the importance of H-bonding interactions with the three identified active site amino acids. To confirm the role of Arg107, Asn387 and Asp320 in the active site of hCYP27B1 compounds were designed that would form H-bonding interactions, as determined from docking experiments with the hCYP27B1 model. Subsequent synthesis and CYP24A1 and CYP27B1 enzyme assays of the designed compounds 1a and 1b showed a ∼5-fold selectivity for CYP27B1 confirming the importance of Asp320 in particular and also Asn387 and Arg107 as important amino acids for CYP27B1 inhibitory activity

The relationship between the insulin-like growth factor-1 axis, weight loss, an inflammation-based score and survival in patients with inoperable non-small cell lung cancer

<b>Background & aims:</b> The involvement of a systemic inflammatory response, as evidenced by the Glasgow Prognostic Score (GPS), is associated with weight loss and poor outcome in patients with non-small cell lung cancer. There is good evidence that nutritional and functional decline in patients with advanced malignant disease is associated with catabolic changes in metabolism. However, defects in anabolism may also contribute towards nutritional decline in patients with cancer. The aim of the present study was to examine the relationship between IGF-1 and IGFBP-3, performance status, mGPS and survival in patients with inoperable NSCLC. <b>Methods:</b> 56 patients with inoperable NSCLC were studied. The plasma concentrations of IGF-1, IGFBP-3 and leptin were measured using ELISA and RIA. <b>Results:</b> The patients were predominantly male (61%), over 60 years old (80%), with advanced (stage III or IV) disease (98%), with a BMI≥20 (84%), an ECOG-ps of 0 or 1 (79%), a haemoglobin (59%) and white cell count (79%) in the reference range. On follow-up 43 patients died of their cancer. On univariate analysis, BMI (p<0.05), Stage (p<0.05), ECOG-ps (p<0.05), haemoglobin (p<0.05), white cell count (p<0.05) and mGPS (p<0.05) were associated with cancer specific survival. There was no association between age, sex, treatment, IGF-1, IGFBP-3, IGF-1:IGFBP-3 ratio, or leptin and cancer specific survival. With an increasing mGPS concentrations of haemoglobin (p<0.005) and IGFBP-3 (p<0.05) decreased. mGPS was not associated with either IGF-1(p>0.20), or leptin (p>0.20). <b>Conclusions:</b> In summary, the results of this study suggest that anabolism (IGF-1 axis) does not play a significant role in the relationship between nutritional and functional decline, systemic inflammation and poor survival in patients with inoperable NSCLC