Indirect effects of cytomegalovirus in kidney transplantation

Cytomegalovirus (CMV) infection is the most frequent and significant opportunistic infection in kidney transplant recipients. It is associated with direct (CMV disease) and indirect (rejection, poor graft survival) effects with resultant increases in morbidity and mortality. The mechanisms responsible for the indirect effects of CMV infection remain unclear. In this thesis, the indirect effects of cytomegalovirus infection in kidney transplantation are studied. Firstly, the mechanism of CMV infection is investigated. Secondly, the mechanism of CMV associated kidney transplant damage is explored. Thirdly, an assessment for the role of CMV in causing immunosenescence within the kidney transplantation cohort is undertaken. This thesis provides previously undescribed and direct evidence of immune hypo- responsiveness to latent CMV. I have shown CD4$^+$CD27$^-$CD28$^{null}$ cells are pathognomonic of prior CMV exposure and have a role in glomerular endothelial cell damage, an effect which may be mediated by NKG2D. Higher CD4$^+$CD27$^-$CD28$^{null}$ cell counts at 12 months post-transplantation predict a steeper decline in kidney allograft function thereafter. I provide novel insight into the ‘indirect’ effect of CMV in the pathogenesis of CD8$^+$CD28$^{null}$ cells. My study is the first to demonstrate a temporal association between elevated CD8$^+$CD28$^{null}$ cell frequencies and subsequent development of clinically relevant episodes of infection. The findings from this thesis set the scene for future interventional research and therapeutic strategies

Metronomic chemotherapy and drug repurposing: A paradigm shift in oncology

Cancer represents a significant global health and economic burden due to its high mortality rates. While effective in some instances, traditional chemotherapy often falls short of entirely eradicating various types of cancer. It can cause severe side effects due to harm to healthy cells. Two therapeutic approaches have risen to the forefront to address these limitations: metronomic chemotherapy (MCT) and drug repurposing. Metronomic chemotherapy is an innovative approach that breaks from traditional models. It involves the administration of chemotherapeutic regimens at lower doses, without long drug-free intervals that have previously been a hallmark of such treatments. This method offers a significant reduction in side effects and improved disease management. Simultaneously, drug repurposing has gained considerable attraction in cancer treatment. This approach involves utilizing existing drugs, initially developed for other therapeutic purposes, as potential cancer treatments. The application of known drugs in a new context accelerates the timeline from laboratory to patient due to pre-existing safety and dosage data. The intersection of these two strategies gives rise to a novel therapeutic approach named ‘Metronomics.’ This approach encapsulates the benefits of both MCT and drug repurposing, leading to reduced toxicity, potential for oral administration, improved patient quality of life, accelerated clinical implementation, and enhanced affordability. Numerous clinical studies have endorsed the efficacy of metronomic chemotherapy with tolerable side effects, underlining the potential of Metronomics in better cancer management, particularly in low- and middle-income countries. This review underscores the benefits and applications of metronomic chemotherapy and drug repurposing, specifically in the context of breast cancer, showcasing the promising results of pre-clinical and clinical studies. However, we acknowledge the necessity of additional clinical investigations to definitively establish the role of metronomic chemotherapy in conjunction with other treatments in comprehensive cancer management

Formulation, characterization, and applications of organic Pickering emulsions: A comprehensive review

Pickering emulsions are suspensions of droplets of one liquid in another immiscible liquid which are stabilized by solid particles adsorbed at the droplet-liquid interface. The stabilization of emulsion is done by the solid particles that physically prevent droplets from coalescing. It is possible to alter the emulsifying capabilities of starch by expanding its surface area or changing its charge. Pickering emulsions are stabilized by components such as starch, cellulose, or chitosan. Starch based Pickering emulsions are highly biodegradable and have low toxicity. The inclusion of starch assists in the development of more stable and long-lasting emulsions, extending the shelf life of the developed products. Starch stabilized Pickering emulsions can be utilized to encapsulate pharmaceuticals or nutrients for systemic or targeted administration. The potential for controlled release of Pickering emulsions is highlighted in this review when behavior varies in response to environmental factors like temperature, pH, or light. The investigation emphasized Pickering emulsions with biocompatible and biodegradable particles and focused on numerous environmentally friendly and sustainable techniques for making Pickering emulsions, such as using waste or renewable resource-derived particles. The review focuses on the development, characterization, and applications of Pickering emulsions based on biological macromolecules of starch

Mortality prediction after kidney transplantation: comparative clinical use of 7 comorbidity indices.

Objectives: Despite comorbidity associated with chronic kidney disease, little data exist applying comorbidity scoring systems to renal transplant recipients. This study compared the performance of 7 established comorbidity scores in predicting mortality after kidney transplantation.Materials and Methods: We retrospectively analyzed prospectively collected data from 2033 incident renal transplant recipients. Comorbidity was assessed at baseline, and the following scores were derived: Recipient Risk Score, Charlson Comorbidity Index, Age-adjusted Charlson Comorbidity Index, Modified End-Stage Renal Disease Charlson Comorbidity Index, Foley Score, Wright-Khan Index, and Davies Index. Cox models investigated the association of each comorbidity score with mortality; performance characteristics were tested using receiver operating characteristic curve analysis.Results: Age-stratified Cox analyses showed the Recipient Risk Score-based model displayed the best fit, and receiver operating characteristic curve analysis showed the Recipient Risk Score demonstrated greatest predictive use (5-year mortality c-statistic: 0.787). The independent effect of age on mortality was demonstrated after analysis of scores not containing age as a component (the Charlson Comorbidity Index, the Modified End-Stage Renal Disease Charlson Comorbidity Index, the Davies Index); addition of age to these scores improved fit.Conclusions: Of the currently available comorbidity scores, the Recipient Risk Score demonstrated greatest use. This has implications for deceased-donor allocation algorithms, assessment of confounders in clinical research, and potentially, individual patient management