Introduction: Pharmacokinetic variability in response to pharmacotherapy contribute to adverse drug reactions, drug-drug interaction and therapeutic failure seen in clinical practice. Poor therapeutic response to medication has been attributed to inter-individual and interethnic variability in cytochrome P450 (CYP450)-dependent metabolism and altered drug absorption via expressed transport channels such as P-glycoprotein (P-gp). An individualised approach in therapeutic management would be beneficial in a South-African population considering the country’s large genetic diversity. A single time point, non-invasive capillary sampling, combined with a low dose probe drug cocktail, to simultaneously quantify in vivo drug and metabolite concentrations, would enhance the feasibility and cost-effectiveness of routine phenotyping in clinical practice and guide personalised prescribing to individual patients. A recent development in dried blood spot sampling is the Mitra™ device, using Volumetric Absorptive Micro Sampling (VAMS™) technology to collect an accurate volume (10-30 µL) of whole blood onto a hydrophilic polymeric tip as an alternative to plasma sampling. Small volume blood sampling however presents bioanalytical challenges in terms of the reproducibility and sensitivity of the quantitative method and the agreement between quantitative measurement from a dried blood spot (DBS) and that from plasma sampling. The physicochemical diversity of the structurally related aromatic probe drugs, used together in a drug cocktail, further require optimised analytical procedures for simultaneous quantification. Phenotyping cocktails are compounded from commercially available dosage forms and introduce challenges with regards to dosage homogeneity, chemical interference or degradation and possible incompatibilities of drugs when used in combination. Aim and objectives: The purpose of this study was to compound the validated “Geneva phenotyping drug cocktail”, from available API sources and develop a validated, targeted, analytical LC-MS/MS method to quantify the seven probe drugs and six respective metabolites in dried blood spots when using the Mitra™ volumetric absorptive micro-sampling device for blood collection. The aim was to assess inter-method agreement of the measured probe drug and metabolite concentrations between the low sample volume, from a dried blood spot, and conventional plasma sampling. Methods: An Agilent binary series LC system coupled to a Sciex 4000 QTRAP triple quadrupole tandem mass spectrometer was used for method optimisation and validation. Targeted LC-MS/MS methods, in both negative and positive ESI mode, were validated according to ICH guidelines for matrix effects, recovery, linearity, limits of quantitation and detection, carry-over, inter and intraday precision and accuracy and analyte stability. The selectivity of the structurally related ionisable analytes was compared between a Kinetex C18 and Kinetex Biphenyl column and the influence of changes in the analytical conditions (involving mobile phase pH and solvent mixture composition as well as the solvent type) studied. An initial assessment of statistical in vitro agreement between plasma and DBS sampling were carried out. USP assays were performed to determine the weight and content uniformity of the compounded phenotyping cocktail containing six of the seven probe drugs. Content uniformity was evaluated with an Acquity UPLC system coupled to a Synapt G2 QTOF mass spectrometer. Results and discussion: A biphenyl stationary phase in combination with methanol as the organic eluent, provided improved resolution and analyte selectivity of the structurally related aromatic compounds. Results from the robustness experiment further confirmed the importance of controlling analytical conditions to ensure reproducibility and reliability of the quantitative method. Separation selectivity and higher throughput were prioritised over optimised ionisation efficiency, although the sensitivity of the analytical method for individual analytes were still within the expected in vivo concentration ranges to infer metabolic and transport phenotypes. This study successfully validated the use of DBS, collected with the volumetrically controlled absorptive microsampling device Mitra™, to measure expected probe drug and metabolite concentrations using the “Geneva phenotyping cocktail”. The validated method met all the required standards accepted in bioanalytical chemistry for specificity, sensitivity, linearity, accuracy, precision, carry-over and stability. From the initial in vitro assessment of agreement, it was concluded that blood cell distribution kinetics are regulated by the blood-to-plasma concentration ratio and time dependent equilibrium between different blood compartments, the physicochemical properties of the analytes, temperature during extraction, analyte concentration and stability. A conclusive confounding factor was the extent to which the extraction procedure liberated bound drug from either plasma proteins or erythrocytes. It was further concluded that the compounded low dose phenotyping cocktail capsules could be used successfully to assess inter-method agreement of drug-based metabolic ratios and drug transport between plasma and DBS collected with the Mitra™ device. Conclusion: To our knowledge, this is the first DBS validation study using the Mitra™ device for the purpose of simultaneous phenotyping of the in vivo P-gp transport and CYP450 metabolic activity of the CYP1A2, -2B6, -2C9, -2C19, -2D6 and -3A4 enzymes and activity. / Thesis (PhD)--University of Pretoria, 2019. / National Research Foundation / Pharmacology / PhD (Pharmacology) / Unrestricted

Published Article / Personalised funerals are defined as modernised, innovative, customised and specialised types of funerals. Personalised funerals are performed to reflect the individual's life and what he or she has accomplished (Broadbent 2002; Wolcott 1999). The aim of this study was to establish if there is a niche in South Africa for graphic material for personalised funerals. The importance of a personalised funeral is to comfort the attendees and avoid the funeral being too traumatic. One of the main questions that arose during this study is how well South Africans react to the idea of personalised funerals? Traditional funerals are gradually being improved by means of creating a more modernised and customised funeral. Funerals now include pictures, photographs and even slide shows of the deceased person (Jenga 2001). Informal receptions with bright colours and even a party after the services are becoming the preferred method (Edwards 2002). Orchids instead of roses, favourite songs instead of Bach, touching poems instead of traditional prayers (Wolcott 1999), slay coffins instead of a plain wooden coffin (Eybers 2007) all emphasise the need for personalised funerals. The aim of the first questionnaire was to establish if there is a niche in South Africa for graphic design material for personalised funerals and to assist with the various design implications that can be used in a funeral pamphlet. A second questionnaire was developed in order to include the opinion of a professional in the funeral industry, which could be beneficial in the design process. Through analysing these questionnaires, various design concepts were developed and applied to funeral pamphlets. The funeral industry already provides various services, for example catering, hiring of tents and vehicles. Why not graphic designers? The author of this study postulates that this could possibly develop a trend or need in South Africa, and expose more and more South Africans to personalised funerals.

Yes / Objective: To develop a model of the psychological factors which predict people’s intention to adopt personalised nutrition. Potential determinants of adoption included perceived risk and benefit, perceived self-efficacy, internal locus of control and health commitment. Methods: A questionnaire, developed from exploratory study data and the existing theoretical literature, and including validated psychological scales was administered to N = 9381 participants from 9 European countries (Germany, Greece, Ireland, Poland, Portugal, Spain, the Netherlands, the UK, and Norway). Results: Structural equation modelling indicated that the greater participants’ perceived benefits to be associated with personalised nutrition, the more positive their attitudes were towards personalised nutrition, and the greater their intention to adopt it. Higher levels of nutrition self-efficacy were related to more positive attitudes towards, and a greater expressed intention to adopt, personalised nutrition. Other constructs positively impacting attitudes towards personalised nutrition included more positive perceptions of the efficacy of regulatory control to protect consumers (e.g. in relation to personal data protection), higher self-reported internal health locus of control, and health commitment. Although higher perceived risk had a negative relationship with attitude and an inverse relationship with perceived benefit, its effects on attitude and intention to adopt personalised nutrition was less influential than perceived benefit. The model was stable across the different European countries, suggesting that psychological factors determining adoption of personalised nutrition have generic applicability across different European countries. Conclusion: The results suggest that transparent provision of information about potential benefits, and protection of consumers’ personal data is important for adoption, delivery of public health benefits, and commercialisation of personalised nutrition. / This project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement n u 265494 (http://cordis.europa.eu/fp7/home_en.html). Food4Me is the acronym of the project ‘‘Personalised nutrition: an integrated analysis of opportunities and challenges’’ (http://www.food4me.org/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Motivated by the need to provide users with more control and influence over their elearning activities composition yet maintain educational integrity, the pedagogical dependency-based approach for the workflow-enabled elearning system is the core of this dissertation. A solution for keeping workflow as a backbone system for delivery and managing elearning activities and still be able to provide flexible personalized composition has been proposed. The solution is based on separating the personalized composition aspect from the workflow-enabled elearning system. In other words, the AFlex-eL is proposed as a hybrid system where a separate generic component handling the personalized composition is integrated to Flex-eL, a workflow-enabled elearning system. The approach is based on the pedagogical dependencies, which are the constraints that govern how the learning activities should be logical sequenced, and how these activities should be selected and logically sequenced to compose elearning activities. A key feature and strength of the approach is to use the power of pedagogical dependencies to ensure educational integrity is preserved, while still being able to provide flexible learning for each individual. Also addressed are a number of related aspects of the framework including pedagogical dependencies modelling, specification, validation, flexible elearning activities composition, and deployment strategies.

Yes / Personalised diets based on people’s existing food choices, and/or phenotypic, and/or genetic information hold potential to improve public dietary-related health. The aim of this analysis, therefore, has been to examine the degree to which factors which determine uptake of personalised nutrition vary between EU countries to better target policies to encourage uptake, and optimise the health benefits of personalised nutrition technology. A questionnaire developed from previous qualitative research was used to survey nationally representative samples from 9 EU countries (N = 9381). Perceived barriers to the uptake of personalised nutrition comprised three factors (data protection; the eating context; and, societal acceptance). Trust in sources of information comprised four factors (commerce and media; practitioners; government; family and, friends). Benefits comprised a single factor. Analysis of Variance (ANOVA) was employed to compare differences in responses between the United Kingdom; Ireland; Portugal; Poland; Norway; the Netherlands; Germany; and, Spain. The results indicated that respondents in Greece, Poland, Ireland, Portugal and Spain, rated the benefits of personalised nutrition highest, suggesting a particular readiness in these countries to adopt personalised nutrition interventions. Greek participants were more likely to perceive the social context of eating as a barrier to adoption of personalised nutrition, implying a need for support in negotiating social situations while on a prescribed diet. Those in Spain, Germany, Portugal and Poland scored highest on perceived barriers related to data protection. Government was more trusted than commerce to deliver and provide information on personalised nutrition overall. This was particularly the case in Ireland, Portugal and Greece, indicating an imperative to build trust, particularly in the ability of commercial service providers to deliver personalised dietary regimes effectively in these countries. These findings, obtained from a nationally representative sample of EU citizens, imply that a parallel, integrated, public-private delivery system would capture the needs of most potential consumers. / Food4me is the acronym of the EU FP7 Project ‘‘Personalised nutrition: an integrated analysis of opportunities and challenges” (Contract No. KBBE.2010.2.3-02, ProjectNo.265494), http:// www.food4me.org/.

Yes / Personalized nutrition has the potential to improve health, prevent disease and reduce healthcare expenditure. Whilst research hints at positive consumer attitudes towards personalized nutrition that draws upon lifestyle, phenotypic and genotypic data, little is known about the degree to which registered dietitians (RD) are engaged in the delivery of such services. This review sought to determine possible factors associated with the integration of the emerging science of Nutritional Genomics (NGx) into the clinical practice setting by practicing registered dietitians. Scope Search of online databases (Pubmed; National Library of Medicine; Cochrane Library; Ovid Medline) was conducted on material published from January 2000 to December 2014. Studies that sampled practicing dietitians and investigated integration or application of NGx and genetics knowledge into practice were eligible. Articles were assessed according to the American Dietetic Association Quality Criteria Checklist. Key findings Application of nutritional genomics in practice has been limited. Reluctance to integrate NGx into practice is associated with low awareness of NGx, a lack of confidence in the science surrounding NGx and skepticism toward Direct to consumer (DTC) products. Successful application to practice was associated with knowledge about NGx, having confidence in the science, a positive attitude toward NGx, access to DTC products, a supportive working environment, working in the clinical setting rather than the public health domain and being in private rather than public practice. Conclusions There is a need to provide RGs with a supportive working environment that provides ongoing training in NGx and which is integrated with clinical practice.

Yes / Background: Commercial technology-enabled personalised nutrition is undergoing 19 rapid growth, yet uptake in dietetics practice remains low. This survey sought the opinions 20 of dietetics practitioners on personalised nutrition and related technologies to understand 21 facilitators and barriers to its application in practice. 22 Method: A cross-section of Registered Dietitians were recruited in the US, UK, 23 Australia, Canada, Israel, Mexico, Portugal, Spain and South Africa. The questionnaire 24 sought views on risk of genetic technology, ethics of genetic testing, usefulness of new 25 personalised nutrition technologies, entrepreneurism and the perceived importance of 26 new technologies to dietetics. Validated scales were included to assess personality (Big 27 5) and self-efficacy (NGSEI). The survey was available in English, Spanish and 28 Portuguese. Regression analyses were performed to identify factors associated with 29 integration of nutrigenetic testing into practice, and to identify factors associated with the 30 perceived importance of bio, information and mobile technologies to dietetic practice. 31 Results: A total of 323 responses (response rate 19.7%) were analysed. Dietetic 32 practitioners who had integrated personalised nutrition technology into practice perceived 33 technologies to be less risky (P=0.02), biotechnology to be more important (P<0.01), and 34 professional skills to be less important (P=0.04) than those who had not. They were also 35 more likely to see themselves as entrepreneurs (P<0.01) and to perceive lower risks to be 36 associated with technology (P<0.01). Practitioners of nutrigenetics were lower on 37 neuroticism (P<0.01) and higher on self-efficacy (P<0.01), extraversion (P<0.01) and 38 agreeableness (P<0.01). Higher perceived importance of biotechnology to dietetic 39 practice was associated with higher perceived usefulness of omics tests (P<0.01). 40 Perceived importance of information technology was associated with perceived 41 importance of biotechnology (P<0.01). Mobile technologies were perceived as important 42 by dietitians with the highest level of education (P=0.02). 43 Conclusions: For dietitians to practice technology-enabled personalised nutrition, 44 training will be required to enhance self-efficacy, address risk perceived to be associated 45 with new technologies and to instil an entrepreneurial mindset.

Yes / Purpose - This research explores the perceptions and experiences of early adopters of the technology. Design/Method/Approach - Registered Dietitians (RD´s) (N=14) were recruited from the UK, Canada, South-Africa, Australia, Mexico and Israel. Six qualitative interviews and two focus groups were conducted online using a conference calling platform. Data were recorded, transcribed and thematically analysed. Findings - Early adopters of Nutrigenomics (NGx) were experienced, self-efficacious RD’s who actively sought knowledge of NGx through communication with one another and the broader scientific community. They considered NGx an extension of current practice and believed RD’s had the skills to deliver it. Perceived barriers to widening the application of NGx were linked to skepticism among the wider dietetics community. Proliferation of unregulated websites offering tests and diets was considered ‘pseudoscience’ and detrimental to dietetics fully embracing NGx. The lack of a sustainable public health model for the delivery of NGx was also perceived to hinder progress. Results are discussed with reference to ‘diffusion of innovation theory’. Originality/Value - The views of RD’s who practice NGx have not been previously studied. These data highlight requirements for future dietetic training provision and more inclusive service delivery models. Regulation of NGx services and formal recognition by professional bodies is needed to address the research/practice translation gap.

The number of students entering higher education has grown considerably during the last decade. High student numbers and the attendant large class sizes present significant challenges for teachers. Such challenges include knowing how to ensure students are engaging in appropriate out-of-class activity, how to provide prompt and personalised feedback and how to establish what students know and what they don't. If these challenges are left un-resolved the students' learning will not be well supported. This could ultimately lead to students failing modules. This research presents a response to the growth of the student population and was prompted by a high failure rate in a core first year engineering module. The large numbers of students enrolled on the module presented exactly the kinds of challenges noted above, and the existing assessment regime did little to motivate student learning. The response presented in this thesis is the design, development, testing, implementation and evaluation of a new assessment programme; an approach to assessment that provides students with unique weekly tasks. The tasks were formally assessed and contributed towards the students' marks for the module. To ensure the viability of the assessment programme, bespoke computer tools were developed to create, collect and mark the tasks, and to provide feedback to the students. The implementation has been evaluated through an exploration of the impact of the assessment programme on student support, teaching and student learning. In three of the four years where the students were exposed to the assessment programme, the failure rate on the module decreased. The reduction in failure rate is arguably associated with the alignment of the assessment programme with good pedagogy. During the implementation of the assessment programme, the students were engaging in appropriate out-of-class activity in relation to the current topic area. The students had an opportunity to engage in dialogue with their peers and were receiving prompt and regular feedback. The teachers also benefited, since they were able to prepare lectures according to the students' level of demonstrable understanding. In the case where the failure rate did not improve, the students themselves suggested they were downloading and using worked solutions to the problems from the internet. It is suggested that such activity neither provides meaningful opportunity to practise, nor alerts the students to their genuine levels of understanding of the topic areas. In this case the students were following solution procedures rather than developing their own. Student feedback on the assessment has been positive, with many noting how being led to engage with their studies was useful. Somewhat concerning was the feedback from students who noted &quot;they thought the work would help them with their examinations&quot;, &quot;they wanted the assessment programme used on other modules&quot; and yet many indicated &quot;they would not have engaged with the activity if it did not count towards the module grade&quot;.

Personalised medicine describes the practice of tailoring medical care to the individual characteristics of each patient. Fundamental to this practice is the identification of markers associated with differential treatment response. Such markers can be identified through the assessment of treatment effect modification using statistical methods. Randomised controlled trials provide the optimal setting for evaluating differential response to treatment. Due to restrictions regarding sample size, study length and ethics, observational studies are more appropriate in many circumstances, particularly for the identification of markers associated with adverse side-effects and long term response to treatments. However, the analysis of observational data raises some additional challenges. The overall aim of this thesis was to develop statistical methodology for the analysis of observational data, specifically primary care databases, to identify and evaluate markers associated with differential treatment response. Three aspects of the assessment of treatment effect modification in an observational setting were addressed. The first aspect related to the assessment of treatment effect modification on the additive measurement scale which corresponds to a comparison of absolute treatment effects across patient subgroups. Various ways in which this can be assessed in an observational setting were reviewed and a novel measure, the ratio of absolute effects, which can be calculated from certain multiplicative regression models, was proposed. The second aspect regarded the confounding adjustment and it was investigated how the presence of interactions between the moderator and confounders on both treatment receipt and outcome can bias estimates of treatment effect modification if unaccounted for using Monte Carlo simulations. It was determined that the presence of bias differed across different confounding adjustment methods and, in the majority of settings, the bias was reduced when the interactions between the moderator and confounders were accounted for in the confounding adjustment model. Thirdly, it has been proposed that patient data in observational studies be organised into and analysed as series of nested nonrandomised trials. This thesis extended this study design to evaluate predictive markers of differential treatment response and explored the benefits of this methodology for this purpose. It was suggested how absolute treatment effect estimates can be estimated and compared across patient subgroups in this setting. A dataset comprising primary care medical records of adults with rheumatoid arthritis was used throughout this thesis. Interest lay in the identification of characteristics predictive of the onset of type II diabetes associated with steroid (glucocorticoid) therapy. The analysis in this thesis suggested older age may be associated with a higher risk of steroid-associated type II diabetes, but this warrants further investigation. Overall, this thesis demonstrates how observational studies can be analysed such that accurate and meaningful conclusions are made within personalised medicine research.