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Achromatopsia (ACHM) is an inherited cone photoreceptor dysfunction disorder. Disease-causing sequence variants in the CNGB3 gene account for approximately 40-50% of cases worldwide. There is currently no established cure, although gene-based interventions hold promise for the future. Herein, I investigate retinal structure and function in individuals with molecularly confirmed CNGB3-ACHM. I undertook the largest longitudinal study of retinal structure in ACHM to date, evaluating changes in spectral-domain optical coherence tomography (SD-OCT) parameters over time. The results supported the largely non-progressive nature of the condition, suggesting there may be a wide window for therapeutic intervention. Colour vision deficiency is a key feature of ACHM, and I demonstrated how the computerised low-vision version of the Cambridge Colour Test (lvvCCT) can assess colour vision in affected individuals. Furthermore, I have shown how this test may identify changes in colour discrimination post-intervention. I undertook the largest study characterizing nystagmus in ACHM to date, and subsequently demonstrated that the use of nystagmus as an endpoint in therapeutic trials may be of limited clinical significance. Subjects with ACHM have profound photoaversion which may impair mobility in bright environments. Herein, I have described my work to develop a navigational task to evaluate this, and report the results of the assessments I devised. ACHM impacts upon quality of life (QoL). I evaluated QoL in affected individuals using validated instruments and explored the correlation between QoL and objective tests of visual function. The results suggested that visual function and QoL should be looked at in conjunction when assessing patients, and raised the need for further development of potentially bespoke tools. Finally, I explored the use of magnetic resonance imaging (MRI) for evaluating changes in visual processing beyond the level of the retina, in affected individuals. Some of the data presented herein is from individuals participating in a natural history study of ACHM. These subjects provide a wealth of structural and functional information accumulated over time. I additionally present some baseline test results from individuals enrolled in a gene therapy trial for CNGB3-ACHM. Together, the findings from both cohorts provide important new insights into CNGB3-ACHM, which are directly relevant to interventional clinical trials for ACHM, and potentially other inherited retinal conditions.

The thesis poses the question ‘can we learn the sacred’ and argues that the sacred lies at the heart of learning. We look at the implications of this question and find that it translates into ‘what does it mean to be human?’ We use a phenomenological approach and find that we can experience the sacred and give it meaning and interpretation derived from latent learning. There is always more beyond what the eye can see and the thesis highlights the need to use the inner eye to understand human processes and the ordering of these processes. Experience of the unknown leads us to the phenomenon of giving meaning through experiential and transformative learning and tacit interpretation, and points us to the idea of the sacred. However, we use a methodological agnosticism perspective to see if a secular explanation is possible. Writing as a member of a faith community, my argument is that the experience that we call the sacred, or spiritual, appears to be universal. The contexts of ‘place’ and symbol contribute to the extraordinariness of my experiences. How do others experience the profound and the ineffable? Mystery becomes acculturated and embedded within that context in the initial phase of experiencing but then it transcends culture as it does language. Analysis of my experience and those of others reveals significant findings that impact on learning and transformation of the inner and outer worlds of the human being. We find that the architect designing a religious place functions within the sense of the faith community and will use the symbols of that faith community. In the survey of a number of believers, we tested this interpretation and by interviewing the architect who designed the building, we sought to understand how the architect tries to re-create these experiences. We find that methodological agnosticism cannot provide a secular explanation and that religious discourse is part of our ongoing vocabulary and interaction with our lifeworlds. The thesis offers the conclusion that we can learn the sacred, but the caveat is that it can only be articulated through the symbol. In the final analysis, all human beings are members of One Community, diverse cultures, religions and traditions notwithstanding, and this understanding of the sacred residing at the heart of learning can be universal, if self-erected and social boundaries, if not entirely eliminated, are at least made more porous and accessible.

This thesis is concerned with the use of gauges in the testing of hypotheses. The first chapter includes a brief review of the use of gauges. The gauging generates trinomials and two statistics are considered; G, a general linear function of the trinomial frequencies and R a particularly simple form of G.The second chapter is concerned with the choice of parameters of G. A computationally simple procedure is suggested and it is shown that the procedure is nearly optimal in the sense of maximising power. Chapter 3 is concerned with general properties of R, including an investigation of the use of a normal approximation for R. The use of R for testing hypotheses about the mean of a normal variate is considered in some detail. The case of known variance is covered in Chapter 4 and Chapter 5 is concerned with the case of unknown variance. Chapter 6 is devoted to the use of R in sequential tests about the mean; one- and two-sided alternate hypotheses are considered. Use of gauges to test hypotheses about the means of two related variables is considered in Chapter 7. The case of bivariate normal variable with a known variance-covariance matrix is discussed in some detail. For the case of unknown variance-covariance matrix, an - approximation to the distribution of the test statistic, under the null-hypothesis, is suggested. Finally, some suggestions for further work are made in Chapter 8.

This work evaluates the advantages in drug stability testing of following the decomposition by analysis of decomposition products. Conventional methods of drug stability testing are criticised and the limitations are shown to be largely a result of analysing for un-decomposed drug. Using simulated analytical results incorporating various levels of precision, the use of product concentration is shown to be capable of producing conventional rate constants in shorter times, by utilising smaller extents of reaction than use of intact drug analysis. The simulation is applied to single, parallel, consecutive and reversible reactions. The findings of the simulated decompositions are supported by practical decomposition studies on several drugs. HPLC with ultraviolet detection is used as a single analytical method for both reactant and product. Aspirin and diiodoaspirin represent single-decomposition product systems; tetracycline is examined as a drug decomposition involving parallel, consecutive and reversible reactions. Nafimidone is studied to establish the advantages and limitations of product and reactant measurements, where all decomposition products have not been identified. The oxidation of 5-hydroxymethylfurfural is also examined to determine the usefulness of product analysis in limit testing and in establishing reaction pathways. In all cases where product identity is known, it is shown that the initial rate method employing product concentrations provides more rapid determination of rate constants. It is suggested that reaction order is overemphasized in shelf-life determination of drugs and that the initial rate method with analysis of product can minimise - and in certain cases, eliminate - the need for temperature stressing to determine shelf-life. HPLC is shown to be very generally applicable in product measurement. New criteria for stability-indicating assays that allow use of the initial rate method are demonstrated for the above drugs, and for succinylsulphathiazole, diphenhydramine and chloramphenicol. The separations obtained are described in terms of current ion pairing ideas.

Abstract: Streptococcus pyogenes, also known as Group A Streptococcus (GAS) is a bacterium that causes diseases such as pharyngitis, acute rheumatic fever and invasive disease. In Alberta, the invasive GAS incidence rate has increased from 4.77/100 000 (2010) to 7.69/100 000 (2016). GAS emm 1 and 59 were the most common emm types associated with invasive disease in 2004-2011. However, a more in-depth insight into recent emm types and epidemiological trends correlated with invasive GAS has not been conducted. In addition, the theoretical coverage of invasive GAS with the 26-valent and 30-valent vaccines, two GAS vaccine candidates, in Alberta has not been assessed. With regards to the 26-valent and 30-valent vaccines, an issue that arises may be their limited coverage. To improve the coverage, GAS phosphoglycerate kinase (PGK) could be added to the candidates or be an alternative to them. GAS PGK is a glycolytic enzyme that is present on the bacterial surface and reacts with human immunoglobulin. Although PGK has been demonstrated on the surface of a few GAS emm types, an extensive assessment of its surface presence has not been conducted. In addition, the mechanisms behind PGK surface expression on GAS have not been explored either. The objectives of this research project are to investigate epidemiological trends associated with invasive GAS in Alberta in 2013- 2016, provide an assessment of the theoretical coverage of the 26-valent and 30-valent vaccines in Alberta for invasive GAS and determine the extent of surface PGK presence in GAS emm types tested using enzyme linked immunosorbent assay. Between 2013- 2016, a total of 1 085 invasive GAS cases were selected for analysis. The top five invasive GAS emm types in Alberta during this period, in order of prevalence, were emm 1 (204 cases), 82 (71 cases), 28 (70 cases), 101 (66 cases) and 41 (62 cases). Other interesting features were that invasive GAS emm 74 was first detected in Alberta (fifteen cases in 2016) and GAS emm 59 invasive cases increased from five cases (2013) to 20 (2016), possibly indicating its reemergence in the province. Invasive GAS in Alberta also shows seasonality, affects males (incidence rate of 9.9/100 000 population in 2016) more than females (6.1/100 000 population) and seems to mainly target 51->80 year olds based on specific laboratory-acquired data. According to the theoretical coverage assessment for the 26-valent and 30-valent vaccines, the 30-valent vaccine had better coverage than the 26-valent vaccine in combating recent invasive GAS in Alberta. However, the non-coverage of both vaccine candidates seems to be gradually worsening in Alberta over the years assessed. Therefore, the GAS PGK antigen may help to increase the coverage for the 30-valent vaccine in Alberta. Twenty-one GAS strains were tested for surface PGK. Out of these 21, 19 demonstrated the surface protein. These 19 strains consisted of 17 different M/emm types, of which 14 had previously not been known to possess surface PGK. In addition, the surface expression of PGK on GAS was not apparently affected by the tissue microenvironment. Rather, surface PGK expression was GAS strain-specific. The comparison of GAS strains with detectable and non-detectable surface PGK may lead to a better understanding as to how this protein is surface expressed, as well as its additional roles in GAS pathogenesis.