Search

Randomised Controlled Trials (RCTs) are regarded as a ‘gold standard’ technique to evaluate and compare clinical interventions. Strict ethical criteria dictate the participation of humans in clinical research, based on informed consent, voluntary decision making and putting patients’ interests first. Demand for RCTs in Trauma and Orthopaedics is high, but patient recruitment continues to pose a significant challenge, especially when the treatments being compared are obviously different. Lack of blinding, treatment preference and negative perception of random allocation to interventions are among the obstacles which need to be considered. Based on review and analysis of current knowledge, an attempt is made to develop a new recruitment process that incorporates high ethical standards and provision of the best possible clinical care for an individual patient. By integrating the principle of clinical equipoise, modern technology and statistical concepts, such as subjective probability, the Patient Eligibility Assessment through Clinical Equipoise (PEACE) framework has been introduced. This provides an alternative that could be used in trials where the fixed eligibility criteria approach is likely to fail. It was tested involving 77 real clinical cases from a national multi-centre trauma RCT, which compared contrasting treatments. A new trial recruitment approach aiming to avoid direct contact between a patient and a treating clinician was rolled out in the same trial. The feedback was collected from both the clinicians and the patients involved. Thematic analysis of 23 semi-structured interviews improved understanding of the various factors influencing patients’ decision about trial participation. Further typological analysis provided a valuable insight into the different attitudes that patients adopted when faced with the dilemma. In particular, that many are positive towards research involvement, but not comfortable with randomisation based on fixed eligibility criteria. According to these results, a new model for patient recruitment is suggested, which could be researched and tested in future trials.

The experimental work described in this dissertation is addresses two problems: the design of a novel photocleavable analog of natural lipids and the development of a new photolabile protecting group for alcohols and carboxylic acids. Several designs of a photocleavable lipid have been explored. The most promising design contained a 3’,5’-dialkoxybenzoin chromophore (photolabile linker), substituted with a pentacosan-13-oxy group (hydrophobic tails), and aspartic acid (polar “head”). Photochemical studies of this de novo designed photolabile lipid showed that upon irradiation with 350 nm light it, in fact, undergoes cleavage, forming benzofuran derivatives and releasing aspartic acid. In our search for a new photolabile protecting (caging) group for alcohols, we have explored the photochemical properties of two chromophores. 3-Hydroxy-2-naphthalenemethanol ethers and esters and 4,4’-dimethoxytrityl ethers were synthesized and their ability to release the protected substrate upon irradiation was examined. 3-Hydroxy-2-naphthalenemethanol derivatives were found to be the more suitable for this purpose. Alkoxy and carboxy derivatives of 3-hydroxy-2-naphthalenemethanol release model substrates, i. e., benzoic acid and benzyl alcohol quantitatively with good quantum yields. The photodeprotection reaction is assumed to proceed via concerted excited state proton transfer, thus avoiding C-O bond heterolysis and the formation of ion pairs. The commonly known problem of lowering the photoefficiency of deprotection reaction due to ion pair recombination is therefore circumvented. Surprisingly, in some cases the chemical yield of substrate release was far from quantitative. This is probably caused by a side reaction of the substrate with a quinone methide intermediate. 5-O’-(4,4’-Dimethoxytrityl) derivatives of a number of DNA nucleosides were shown to regenerate the free nucleoside upon irradiation with 254 nm light with good to excellent chemical yields. Since the 4,4’-dimethoxytrityl group is widely employed in oligonucleotide synthesis, this photoreaction provides a useful orthogonal alternative for deprotection of the 5’ position despite the poor quantum yields.