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Background: Total knee replacement (TKR) is a common operation usually performed to relieve the symptoms of end-stage knee osteoarthritis. Patients often face a long wait for TKR whilst experiencing severe pain. Even after TKR, ~20% of patients continue to experience long-term pain. Providing pre-operative TKR education and prehabilitation (pre-operative health/wellbeing optimisation) support could improve pre- and post-operative outcomes. However, current pre-operative TKR services are variable, inefficient and often inadequate. A rigorously developed digital intervention could help address these problems. Aim: To develop a pre-operative TKR education and prehabilitation digital intervention, the 'Virtual Knee School' (VKS). Methods and findings: The VKS was developed using an evidence-, theory- and person-based approach and complex mixed methods design. A rapid review (n=52 studies) demonstrated that definitive evidence on the optimal content/delivery of pre-operative TKR interventions is lacking. A modified Delphi study (n=30 patients; n=30 professionals) enabled the development of recommendations on pre-operative TKR interventions, which support digital delivery formats. A qualitative descriptive study (n=14 patients) highlighted the VKS should account for individual differences and be tailored to the pre-operative context. Three theoretical modelling approaches helped guide the design, description and evaluation of the VKS. A VKS prototype was developed based on the preceding studies' findings and iteratively refined through think-aloud interviews (n=9 patients). The interviews evaluated the prototype's usability and explored patients' perspectives of it. The findings suggest the VKS would be a valuable resource for many patients pre- and post-TKR, but the digital delivery format is unlikely to meet all patients' individual needs. Conclusions: This project rigorously developed a novel pre-operative TKR digital intervention, which warrants further evaluation. Key implications include: comprehensive pre-operative TKR education and prehabilitation support should be rapidly accessible in digital and non-digital formats; pre-operative TKR digital interventions should employ computer- and self- tailoring to account for patients' individual needs/preferences.

Glucocorticoid excess as a result of Cushing’s syndrome or pharmacological treatment can result in the development of obesity and type 2 diabetes mellitus (T2DM). The reactivation of cortisone to cortisol is catalysed by 11βHSD1 which is expressed widely but notably in adipose tissue and liver. Studies have shown dysregulation of cortisol in these tissues with obesity potentially promoting the development of T2DM. Inhibition of 11βHSD1 has been attempted as a novel treatment for T2DM with observed improvement in glycaemic control, body weight and blood pressure. The efficacy of such agents has been disappointing with few reaching phase 2 trials. With recent evidence of bidirectional activity of 11βHSD1 in vivo it becomes apparent that dysregulation may occur at an intracellular rather than tissue level. In this thesis I address several key outstanding questions concerning the physiology and regulation of 11βHSD1 including: 1. Whether combined therapy with metformin alters 11βHSD1 activity and obscures the efficacy of 11βHSD1inhibitors; 2. Whether the contribution of 11βHSD1 to local cortisol concentrations has been under-estimated by considering total rather than free cortisol turnover; and 3. Whether recycling between cortisol and cortisone in adipose tissue and skeletal muscle in obesity is a neglected feature of 11βHSD1 biochemistry and function. Eight obese healthy men with and without type 2 diabetes were recruited to a randomised placebo controlled cross over trial. They received 4 weeks treatment with metformin and placebo. Participants with T2DM additionally received gliclazide as a further control. Using the deuterated tracer D4-cortisol 11βHSD1 activity was measured. Metformin treatment increased whole body 11βHSD1 in both groups postulated as a result of improved insulin sensitivity. 11βHSD1 is located within cells and so contributes to free tissue cortisol concentrations but perhaps less so to total (protein-bound) cortisol in plasma. It has been shown that 11βHSD1 contributes almost half of total circulating cortisol concentrations at rest. This measurement relied upon blood sampling during steady state deuterated cortisol (D4-cortisol) infusion with measurements of total (free plus protein bound) cortisol which may have underestimated true 11βHSD1 activity. This was therefore investigated by comparing 11βHSD1 activity as calculated using total compared with free cortisol tracer enrichments. Equilibrium dialysis was performed separating free from bound portions in plasma samples taken from healthy volunteers who received D4-cortisol infusion. Analysis revealed similar measurements of 11βHSD1 activity using free compared with total cortisol implicating rapid turnover of glucocorticoids between the free and bound pools. On first discovery 11βHSD1 was seen to be a dehydrogenase enzyme in vitro. Later work recognised reductase activity in vivo and up until recently 11βHSD1 has been viewed as a predominantly reductase enzyme. As with other enzymes in the same family, the ability to catalyse both reductase and dehydrogenase depends upon the availability of substrate and co substrate. Whether dysregulation of 11βHSD1 in the settings of obesity and T2DM is the result of alteration in directionality at a cellular level is not known. Firstly bidirectional activity of 11βHSD1 was confirmed in vitro using HEK-293 cells stably transfected with 11βHSD1. The influence of obesity and acute perturbation with hyperinsulinaemia was subsequently investigated in vivo in a random order cross over single blinded case control study involving ten normal weight and ten obese healthy male volunteers. D4-cortisol and deuterated cortisone (D2-cortisone) were infused for the measurement of reductase and dehydrogenase activity of 11βHSD1 respectively with measurements taken across forearm muscle and abdominal subcutaneous adipose tissue. Across whole body, lean and obese individuals displayed similar 11β-reductase and 11β-dehydrogenase activity. Across tissue, 11β-reductase and 11β-dehydrogenase activity was different from zero across adipose tissue in obese individuals and across skeletal muscle in lean individuals providing further evidence of tissue specific differences in 11βHSD1 with obesity. With the addition of hyperinsulinaemia, reductase and dehydrogenase activity was somewhat increased in lean individuals although there was no statistically significant difference between lean and obese individuals. Across tissue there was a trend for obese individuals to display increased 11β-reductase activity across adipose tissue with hyperinsulinaemia. Comparing the rates of reductase and dehydrogenase activity revealed predominantly reductase activity across tissue in obese and dehydrogenase activity in lean individuals. The development of direction specific inhibitors targeting reductase activity by 11βHSD1 may prove efficacious for the treatment of obesity. In conclusion, 11βHSD1 acts as a bidirectional enzyme in vitro and in vivo. Overall directionality of enzyme activity is altered in a tissue specific manner in the setting of obesity. We have shown that this intracellular regulation of cortisol is reflected equally in the metabolically active free pool and total plasma pool. The efficacy of 11βHSD1 inhibitors as novel agents for the treatment of T2DM and coexisting obesity is not diminished by co-prescription with metformin but may prove more efficacious through the development of reductase specific inhibitors.