Development of an intervention to support medication management in patients with multimorbidity in primary care

The overarching aim of this thesis was to develop an intervention to support patient-centred prescribing in the context of multimorbidity in primary care. Methods A range of research methods were used to address different components of the Medical Research Council, UK (MRC) guidance on the development and evaluation of complex interventions in health care. The existing evidence on GPs’ perceptions of the management of multimorbidity was systematically reviewed. In qualitative interviews, chart-stimulated recall was used to explore the challenges experienced by GPs when prescribing for multimorbid patients. In a cross-sectional study, the psychosocial issues that complicate the management of multimorbidity were examined. To develop the complex intervention, the Behaviour Change Wheel (BCW) was used to integrate behavioural theory with the findings of these three studies. A feasibility study of the new intervention was then conducted with GPs. Results The systematic review revealed four domains of clinical practice where GPs experienced difficulties in multimorbidity. The qualitative interview study showed that GPs responded to these difficulties by ‘satisficing’. In multimorbid patients perceived as stable, GPs preferred to ‘maintain the status quo’ rather than actively change medications. In the cross-sectional study, the significant association between multimorbidity and negative psychosocial factors was shown. These findings informed the development of the ‘Multimorbidity Collaborative Medication Review and Decision-making’ (MY COMRADE) intervention. The intervention involves peer support: two GPs review the medications prescribed to a complex multimorbid patient together. In the feasibility study, GPs reported that the intervention was appropriate for the context of general practice; was widely applicable to their patients with multimorbidity; and recommendations for optimising medications arose from all collaborative reviews. Conclusion Applying theory to empirical data has led to an intervention that is implementable in clinical practice, and has the potential to positively change GPs’ behaviour in the management of medications for patients with multimorbidity.

Immunotherapy for the treatment of poor prognosis cancers

Cancer is amongst the leading causes of death worldwide and the number one cause in the developed world. Every year there are close to 10 million cancer related deaths and this corresponds to hundreds of millions of euro in health care costs and lost productivity, placing a substantial drain on the economy. The efficacy of traditional treatment modalities for cancer therapy, such as surgery, radiotherapy and chemotherapy has plateaued, and while they are undoubtedly effective at prolonging patient lifespan, there is a high rate of adverse side effects and fatal reoccurrence. Currently, there is a huge amount of interest in the areas of cancer immunosurveillance and cancer immuno-editing, which explain some of the complex interactions between the host immune system and cancer. If left unchecked, cancerous malignancies have the ability to generate an immunosuppressive microenvironment, effectively shielding themselves from elimination and promoting tumour growth and progression. To overcome this, the potential of the immune system must be harnessed and the work undertaken in this thesis sought to contribute to this goal. Focus was placed on using novel therapies, combining tumour ablation with immune-modulating antibodies to maximise tumour elimination in an immune dependent manner, to overcome immunosuppression and promote immune activation. Chapter 2 focuses on the use of ECT as a method of tumour ablation and its effects on the immune system. ECT proved to be effective at inhibiting the tumour growth both in vitro and in vivo, and conferred significant survival advantages in both small and large animal models. More importantly, ECT proved to cause tumour death in an immune dependent manner, displaying the hallmarks of Immunogenic Cell Death, increases in immune cell infiltration and generating tumour-specific immune responses. Chapter 3 focuses on combining ECT with immune checkpoint blockade inhibitors; anti- CTLA-4 and anti-PD-1. Both combinations proved to be effective at inhibiting both primary and distal tumour growth, indicating the generation of tumour specific immune responses and prolonged animal survival. In addition, the treatments caused increases in the levels of certain intra-tumoural immune cell subsets and modulated the cytokine profile of treated animals in a way that was favourable overall. Chapter 4 focuses on the combining ECT with an anti-iCOS agonist antibody, capable of causing immune co-stimulation. This novel combinational therapy proved to be the most effective by far, with a high cure rate achieved across a number of different in vivo tumour models. Total regression was seen in both primary and distal tumours, as well as spontaneous metastases, with the tumour specific immune response generated conferring total protection to animals on tumour rechallenge. Overall the data presented here adds further insight into the area of cancer immunotherapy with some of the novel combinational therapies demonstrating substantial clinic potential.