Towards the enantioselective synthesis of Plakortide P and its application to the development of drugs for the treatment of Chagas disease

The primary focus of this thesis was the asymmetric peroxidation of α,β-unsaturated aldehydes and the development of this methodology to include the synthesis of bioactive chiral 1,2-dioxane and 1,2-dioxalane rings. In Chapter 1 a review detailing the new and improved methods for the acyclic introduction of peroxide functionality to substrates over the last decade was discussed. These include a detailed examination of metal-mediated transformations, chiral peroxidation using organocatalytic means and the improvements in methodology of well-established peroxidation pathways. The second chapter discusses the method by which peroxidation of our various substrates was attempted and the optimisation studies associated with these reactions. The method by which the enantioselectivity of our β-peroxyaldehydes was determined is also reviewed. Chapters 3 and 4 focus on improving the enantioselectivity associated with our asymmetric peroxidation reaction. A comprehensive analysis exploring the effect of solvent, concentration and temperature on enantioselectivity was examined. The effect that different catalytic systems have on enantioselectivity and reactivity was also investigated in depth. Chapter 5 details the various transformations that β-peroxyaldehydes can undergo and the manipulation of these transformations towards the establishment of several routes for the formation of chiral 1,2-dioxane and 1,2-dioxalane rings. Chapter 6 details the full experimental procedures, including spectroscopic and analytical data for the compounds prepared during this research.

Statistical methods for polyhedral shape classification with incomplete data - application to cryo-electron tomographic images

A certain type of bacterial inclusion, known as a bacterial microcompartment, was recently identified and imaged through cryo-electron tomography. A reconstructed 3D object from single-axis limited angle tilt-series cryo-electron tomography contains missing regions and this problem is known as the missing wedge problem. Due to missing regions on the reconstructed images, analyzing their 3D structures is a challenging problem. The existing methods overcome this problem by aligning and averaging several similar shaped objects. These schemes work well if the objects are symmetric and several objects with almost similar shapes and sizes are available. Since the bacterial inclusions studied here are not symmetric, are deformed, and show a wide range of shapes and sizes, the existing approaches are not appropriate. This research develops new statistical methods for analyzing geometric properties, such as volume, symmetry, aspect ratio, polyhedral structures etc., of these bacterial inclusions in presence of missing data. These methods work with deformed and non-symmetric varied shaped objects and do not necessitate multiple objects for handling the missing wedge problem. The developed methods and contributions include: (a) an improved method for manual image segmentation, (b) a new approach to 'complete' the segmented and reconstructed incomplete 3D images, (c) a polyhedral structural distance model to predict the polyhedral shapes of these microstructures, (d) a new shape descriptor for polyhedral shapes, named as polyhedron profile statistic, and (e) the Bayes classifier, linear discriminant analysis and support vector machine based classifiers for supervised incomplete polyhedral shape classification. Finally, the predicted 3D shapes for these bacterial microstructures belong to the Johnson solids family, and these shapes along with their other geometric properties are important for better understanding of their chemical and biological characteristics.

Relevance of anatomy to medical education and clinical practice: perspectives of medical students, clinicians, and educators

Introduction: Against a backdrop of ever-changing diagnostic and treatment modalities, stakeholder perceptions (medical students, clinicians, anatomy educators) are crucial for the design of an anatomy curriculum which fulfils the criteria required for safe medical practice. This study compared perceptions of students, practising clinicians, and anatomy educators with respect to the relevance of anatomy education to medicine. Methods: A quantitative survey was administered to undergraduate entry (n = 352) and graduate entry students (n = 219) at two Irish medical schools, recently graduated Irish clinicians (n = 146), and anatomy educators based in Irish and British medical schools (n = 30). Areas addressed included the association of anatomy with medical education and clinical practice, mode of instruction, and curriculum duration. Results: Graduate-entry students were less likely to associate anatomy with the development of professionalism, teamwork skills, or improved awareness of ethics in medicine. Clinicians highlighted the challenge of tailoring anatomy education to increase student readiness to function effectively in a clinical role. Anatomy educators indicated dissatisfaction with the time available for anatomy within medical curricula, and were equivocal about whether curriculum content should be responsive to societal feedback. Conclusions: The group differences identified in the current study highlight areas and requirements which medical education curriculum developers should be sensitive to when designing anatomy courses.

Valuing maternity care: a comparison of stated preference methods with an application to cost-benefit analysis

This research investigates whether a reconfiguration of maternity services, which collocates consultant- and midwifery-led care, reflects demand and value for money in Ireland. Qualitative and quantitative research is undertaken to investigate demand and an economic evaluation is performed to evaluate the costs and benefits of the different models of care. Qualitative research is undertaken to identify women’s motivations when choosing place of delivery. These data are further used to inform two stated preference techniques: a discrete choice experiment (DCE) and contingent valuation method (CVM). These are employed to identify women’s strengths of preferences for different features of care (DCE) and estimate women’s willingness to pay for maternity care (CVM), which is used to inform a cost-benefit analysis (CBA) on consultant- and midwifery-led care. The qualitative research suggests women do not have a clear preference for consultant or midwifery-led care, but rather a hybrid model of care which closely resembles the Domiciliary Care In and Out of Hospital (DOMINO) scheme. Women’s primary concern during care is safety, meaning women would only utilise midwifery-led care when co-located with consultant-led care. The DCE also finds women’s preferred package of care closely mirrors the DOMINO scheme with 39% of women expected to utilise this service. Consultant- and midwifery-led care would then be utilised by 34% and 27% of women, respectively. The CVM supports this hierarchy of preferences where consultant-led care is consistently valued more than midwifery-led care – women are willing to pay €956.03 for consultant-led care and €808.33 for midwifery-led care. A package of care for a woman availing of consultant- and midwifery-led care is estimated to cost €1,102.72 and €682.49, respectively. The CBA suggests both models of care are cost-beneficial and should be pursued in Ireland. This reconfiguration of maternity services would maximise women’s utility, while fulfilling important objectives of key government policy.