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This study investigates different modalities for achieving elective single embryo transfer in assisted reproductive technologies (ART) and developing protocols and policies that both permit maximum access to care as well as improving safety of ART by limiting the number of embryos that are transferred. The study includes 16 peer-reviewed journal articles and 1 book chapter published since 2001 and covering my career to date while working in two university affiliated IVF centres: McGill University and the University of Montreal, Canada. It includes research on: • Improving the clinical application of modified natural cycle IVF. A total of 134 MNCIVF cycles were compared with 370 IVF cycles using COS; in patients under the age of 35 years old the clinical pregnancy rate was 27% versus 47% however in patients older than 35 years old the benefits of MNCIVF did not support the poorer prognostic with a clinical pregnancy rate of only 8%. The addition of a NSAID, Indomethacin, further optimized the MNCIVF protocol by decreasing the premature ovulation rate from 16% to 6%, this in turn increased the potential of obtaining the oocyte at retrieval from 64% to 76%. The combination of MNCIVF and surgical sperm retrieval was demonstrated as a viable option in a case report describing a couple who did not want any risk of multiple pregnancy and the least invasive treatment possible to obtain their pregnancies. This treatment was confirmed with a study comparing 81 MNCIVF using ejaculated spermatozoa with 44 MNCIVF using surgically retrieved spermatozoa. There were no differences in the clinical pregnancy rate (31.0% versus 35.1%), however the chance of having an embryo transfer increased in the surgical group (65.9% versus 45.7%). The age of the male partner in the surgical group was older (41.5 versus 36.5) perhaps associated with second relationships; a group for whom MNCIVF can be an interesting treatment option. The use of MNCIVF in young poor responders is suggested as well as an option for egg donation where the donor wants to avoid gonadotrophins. An analysis of over 1500 MNCIVF was carried out demonstrating a clinical pregnancy rate per embryo transfer of 32.5%. Patient cycles were stratified according to ovarian reserve and in younger patients this had little influence on outcome, however in the patients over 35 years of age, the clinical pregnancy rate dropped significantly with a poor ovarian reserve (26.3% versus 6.3%). • Investigating the application of the protocol for in vitro maturation of oocytes. One hundred and seven IVM cycles in patients with polycystic ovarian syndrome were case matched with 107 IVF and COS cycles. There was no significant difference in the clinical pregnancy rate (28% versus 41%) although it came close to significance, however there were less oocytes (10.3 versus 14.9), less mature oocytes (7.8 versus 12.0) and less embryos available (5.8 versus 8.6). Importantly there were no cases of OHSS in the IVM group compared to 11% in the IVF with COS group. A case study describes the use of IVM in combination with PESA and the possibility to successfully obtain and mature oocytes in a PCOS patient and then fertilize those oocytes using spermatozoa retrieved using a simple procedure in an azoospermic partner. Additional more specialized uses of IVM are described including a case report of a young patient with FSH receptor mutation and falling ovarian reserve for whom IVM was used to obtain and mature ten oocytes for fertility preservation following a failed attempt to stimulate her ovaries. • Studying the implementation of legislation and funding related to ART and the impact on treatment in Quebec, Canada. An initial study after the introduction of funding demonstrated a reduction from 25.6% to 3.7% in the multiple pregnancy rate following IVF, with an increase in the use of eSET from 1.6% to 50% of performed embryo transfers. This was followed by studies showing that although the pregnancy rate in IVF dropped under funding, the cumulative pregnancy rate would correct for this drop using a predictive calculation (29.7% versus 31.9%). This was confirmed with data analysis after the first complete year of funding in one clinic, indicating that the transfer of one fresh embryo followed by one frozen-thawed embryo gave equivalent pregnancy rates to DET (47.1% versus 47.1%). A financial analysis furthermore supported the fiscal benefits of funding showing that although funding in absolute terms costs the government more, the cost per baby is lower under funding than with a tax rebate system (49,517$ versus 43,362$) considering the costs of high order multiple pregnancies that are significantly reduced under funding with an eSET policy in place. A final complete analysis of the totality of the funding program after it was shut down, comparing with the year prior to and the year post funding, clearly indicates that the design of funding can influence not only the fiscal burden but also clinical decision making and that this reflects in the results. The cancellation rate increased dramatically (17.0% versus 34.4%) and the live birth rate dropped in all treatment modalities (33.9% versus 23.7%). However, the multiple pregnancy rate dropped from over 25% to under 5% throughout the course of funding and remained under 5% even once funding was withdrawn. These publications form a tiny part of the enormous journey that ART has taken over the course of the last 40 years and continues to take on a daily basis. Additional research is required in all these and other areas related to IVF and embryology in order to further improve all aspects of ovarian stimulation, embryo culture and selection and implantation knowledge and application.

The title of the thesis is The Role of the Prior of St John in Late Medieval England, c. l 300-1540. ' It investigates the unique political role of the Prior of St John in England between 1300 and 1540. It looks at changes in the Prior's public roles over time, with reference to particular moments when individual Priors were senior political figures. It further examines changes in the English Priory and the resulting development of the Prior's role. It also investigates of the effect of events in the eastern Mediterranean and the ensuing consequences for the Hospitallers and Prior of England, analyses the relationship between the Prior's connections with powerful merchants and the appointment of several priors as treasurer of England, and explores of the loss of the order's political control of its estates to local gentry and aristocrats. Chapter 1, the introduction, includes the aims, hypothesis, international background, historiography and methodology. Chapter 2 covers the financial role of the Prior, examining the role played by the three Priors who became treasurers of England, and discusses the Prior as a source of finance for the crown. Chapter 3 looks at the military duties of the Prior in service to the crown. Chapter 4 considers the diplomatic aspect of the Prior's international role. Chapter 5 examines the Prior's political role in national politics, focusing on the development of his role in parliament, great council, and king's council. Chapter 6 treats the Prior and the secularisation of the order in England based on the extant English Hospitaller lease books between 1492 and 1539. Chapter 7, the conclusion, assimilates the information in the preceding chapters, commenting on and analysing the Prior's place in English society. The main conclusion is that the Prior became much more involved in the English political system during the late fourteenth and especially mid-fifteenth centuries than has previously been supposed. This thesis is the only in depth study of the Prior spanning later medieval England. This enables it to chart changes in the Prior's role that shorter studies on individual Priors (Prior Nablous, 1184-1190, Prior Malory, 1432-1440) cannot perceive. In addition, it is the only study to make extensive use of the English National Archives (Public Record Office), whereas other Hospitaller histories draw the bulk of their information from the Hospitaller archives on Malta or from printed primary sources. Furthermore, the study is unique in its concentration the Prior's service to the English crown and in its approach, viewing this service as beneficial, rather than contradictory to the Hospitallers' interests. For the above reasons, this thesis makes a significant contribution to our knowledge of late medieval history, crossing the boundary between `national' and crusading history.

Colorectal cancers that express Micro~atellite Instability (MSI) differ in many clinicopathological and genetic features from 'sporadic' tumours. They also appear to confer an improved prognosis, roughly translating into a 10-20% improvement in S-year patient survival. This advantage is independent of patient age or tumour stage, despite these tumours co~only displaying otherwise advers~- features' such as poor tumour differentiation or mucinous tumour characteristics. One common explanation is that the 'mutator phenotype' limits tumour aggressiveness, but in fact MSI+ colonic adenomata progress faster towards invasive malignancy. Alternatively these tumours may invoke an enhanced immunological response, directed against tumour-derived antigens, which in turn affects the aggressiveness of MSI+ tumours. Although many workers have shown a quantitative increase in tumour lymphocytes compared with MSI- tumours, direct evidence showing that MSI+ tumours elicit enhanced cytotoxicity is limited. Moreover it implies only indirectly that lymphocytes within MSI+ tumours are activated in an antigen-specific manner. In a consecutive series of over 200 prospectively analysed colorectal cancers we assessed populations ofCD8+ and CD4+ T-cells, relative levels 0 f lymphocyte cytotoxicity (Granzyme B), and the degree ofantigen-specific activation in the tumour lymphocyte populations (Interleukin 2 receptor ex-subunit). Complimentary techniques were used. Firstly, gene expression of all markers was determined by real-time fully quantitative RT-PCR (faqman) to assay mRNA levels within fresh-frozen tumour samples. Secondly, protein expression of markers was compared using appropriate monoclonal antibodies and immunohistochemistry (IHC) from formalin-fixed paraffin-embedded specimens. Microsatellite stable (MSI-) and MSH groups were directly compared. In addition, clinico-pathological data was correlated with immunological variables in order to identify Supplied by The British Library - 'The world's knowledge' any independently predictive features for eitllCr survival, or for use as a model to allow identification of MSI+ tumours by incorporating standard c1inico-pathological variables and simple immunohistochemistry. The findings of this work corroborate the commonly reported c1inico-pathological features of MSI+ tumours. In addition we demonstrate significant differences in T-cell mRNA expression and immunohistochemical quantity, bOtll overall (CD3+) and for CD8+ and CD4+ subsets. Moreover, an observed significant difference in Granzyme B levels and IL2-RiX expression suggests tllat the lymphocyte population in MSI+ tumours is botll more highly activated and tllat this activation is likely to be antigen-specific. No firm commentary on survival differences can be made witllin our study group, nor prognostic relationships to any measured variable. Comparisons between the mRNA expression data and immunohistochemistry are made and tlle limitations of each technique are discussed.

Analysis of corrosion in marine and acid environments is a complicated task, involving the interaction of thermodynamic, kinetic and geometrical factors. Two mathematical models which predict corrosion behaviour have been implemented for personal computers. The first program uses an assumption of unidirectional current flow to simplify the prediction of potential distributions for systems of essentially cylindrical geometry containing natural seawater-based electrolytes of differing strength. Using experimentally determined electrochemical and flow rig data, experimental and theoretical results were compared. The correlation between the two was shown to be poor, and this is attributed to the unrepresentative nature of the electrochemical data input to the model. The second model involves the synthesis of polarization curves. Several algorithms to model passivating behaviour have been studied, and one was selected and incorporated into the calculation routine. A number of kinetic and thermodynamic parameters are used in algorithms describing such behaviour, along with activation, concentration and solution polarization effects, for a number of redox reactions, which are then combined to produce an overall potential-log current density curve. Experimentally determined data for pure iron and different stainless steels in marine and acid environments of differing dissolved oxygen content and temperature were obtained. Theoretical models were constructed for each system, and compared to experimental data. Excellent correlation between experimental and theoretical data was obtained for potential ranges in excess of 2 V. Trends in parameter values were discussed, and compared to published data. The transition between stable and unstable passivity of stainless steels was shown to be dependent on the oxygen reduction diffusion limited current density and the iron dissolution reaction free corrosion current density, which in turn was linked to the dissolved oxygen content and temperature of the electrolyte. A new model for the behaviour of stainless steels in the transpassive region was proposed.