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The increasing number of patients with multimorbidity and the associated increase in medication use has led to a significant increase in the workload of general practice (GP practice) worldwide. Recently, policymakers have recognised the potential to expand clinical roles of GP pharmacists on large scale to meet some of the need of patients with long-term conditions and reduce workload and workforce crisis cross GP practices. However, little is known about the effectiveness of GP pharmacists' roles/interventions in reducing the risk factors of cardiovascular events internationally. In addition, the role and integration of pharmacists into GP practice is still relatively new, unclear and frequently varies between GP practices in England. Therefore, this thesis research aimed to assess the evidence for the effectiveness of GP pharmacist interventions in the control of medical risk factors for the primary prevention of cardiovascular disease (CVD). Furthermore, it aimed to evaluate and explore the role of GP pharmacists, their integration into practice and potential facilitators and barriers to their integration as well as evaluating the patient-facing roles offered by GP pharmacists from patients' perspectives. Four studies were conducted to achieve the aim of this research. Study one investigated the effectiveness of GP pharmacists' interventions in reducing the risk factors of cardiovascular events by conducting a systematic review and meta-analysis. Patients receiving pharmacists-led interventions were associated with a statistically significant reduction in their systolic blood pressure (SBP), diastolic blood pressure (DBP), glycated haemoglobin (HbA1c), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and Triglyceride. In addition, GP-based pharmacists' interventions were also reported to have a positive effect on patient adherence to medications. Study two evaluated the role performed by GP pharmacists and their integration into practice, exploring facilitators and barriers to integration by conducting a cross-sectional study across England. Face-to-face medication review, medicine reconciliation and telephone support for patients were the most reported roles. 82% of GP pharmacists were satisfied with their overall integration into practice. Half of pharmacists were working in a shared office or at a hot desk and 9% had no designated workspace. Pharmacist independent prescribers (PIPs) had more access to a convenient workplace (p=0.016) compared to non-independent prescriber. Study three used a qualitative approach and interviews with GP practice-based PIPs who specialise in medical risk factors of primary prevention of CVD to explore further their roles, integration into GP practice, and possible facilitators and barriers when providing care. A range of patient-facing roles were identified which mainly focused on comprehensive face-to-face medication reviews including medicines reconciliation, adherence, medication management, physical assessment and patient education. Most PIPs reported being well-integrated into their practices and supported by their colleagues. However, PIPs reported some barriers to GP practice integration, which were mainly centred on lack of understanding of pharmacists' roles within multidisciplinary team and, to some extent, resistance from the other healthcare providers in GP practice. Other factors identified in this study that potentially affect PIPs integration in GP practice were clinical competence, previous professional experience and soft skills. Study four assessed patients' perceptions and satisfaction regarding the care provided by PIPs in GP practices. With regards to the interventions deliver in patients' appointment, 95% of patients received medication-related services (alone, or in combination with other services); 48% received lifestyle-related services, and 26% received services related to disease. Patients highlighted extremely positive views and valued the benefits of having a pharmacist appointment at their GP practice. Ninety-seven percent of patients reported confidence in the pharmacist's recommendations. However, 14% felt would still need to consult a GP after their appointment and 11% were undecided. The findings of this thesis research provide evidence for the effectiveness of GP pharmacist interventions on primary prevention of CVD. The findings also outline the potential value of GP pharmacists that still needs to have the role clearly defined in GP practice as well as shed the light on their integration issues. These findings could be significant for the development of the future roles of GP pharmacists in managing patients with the medical risk factors of primary prevention of CVD.

In the lysosomal storage disease (LSD) field there are very few studies examining large cohorts of LSD samples in order to identify suitable new pan-LSD biomarkers and identify pan-LSD disease mechanisms. This thesis investigated the possibility of using a simple fluorimetric test for lysosomal swelling, simple enzyme assays and the associated accumulation of storage material alongside the presence of unique heavy metal accumulation to identify the majority of LSDs. The results showed that lysosomal swelling is a highly sensitive phenotype and that high-throughput analysis can be achieved using the fluorescent marker lysotracker. This probe can be used to screen LSD cells as both a suitable biomarker and potentially for drug screening to develop new treatments for LSDs. This thesis was also identified that secondary alteration of lysosomal enzymes is a common feature of LSDs. Such secondary lysosomal enzyme alteration could be useful for treatment monitoring and some novel biomarkers for some and potentially all of the LSDs have emerged. I have also conducted the first electron microscopy (EM) study that compares all classes of LSDs. This technique was proven to be useful for characterisation of the lipids and other macromolecules stored both primarily and secondarily in the majority of LSDs. EM also confirmed that alteration of secondary lysosomal enzymes could be the reason behind the accumulation of materials in some LSDs. Divalent cation signalling defects have been reported in several LSDs, I therefore studied Ca2+ and trace element (TEs) ion changes across all the LSDs and discovered that lysosomal Ca2+ defects are common and that changes in Zn2+ and a few other TEs were identified in almost all or specifically altered in some of the LSDs respectively. Our results highlight the possibility of using inductively coupled plasma mass spectrometry (ICP-MS) for monitoring changes in blood TE levels during the course of clinical treatment of CLN5 patients. Finally, evidence points to the NPC1 protein function, in terms of Zn2+ efflux from lysosomes, was inhibited by common storage of sphingoid bases and is a common phenotype across the majority of LSDs that explains the occurrence of secondary lipid accumulation across most of the LSDs. Our findings provide new potential biomarkers, new mechanisms of pathogenesis and new therapeutic targets that are common to all of the LSDs validating the power of studying multiple LSDs together.