https://www.um.edu.mt/library/oar/handle/123456789/132183 2026-05-31T10:48:35Z 2026-05-31T10:48:35Z https://www.um.edu.mt/library/oar/handle/123456789/132373 2025-02-25T08:58:35Z 2024-01-01T00:00:00Z

Title: Genetic variants in corneal dystrophy genes : a Maltese cohort study : inhibition of TGFBI as a treatment modality Abstract: The three aims of this study were to a) establish which worldwide populations have a corneal dystrophy (CD) genetic makeup closest to that of the Maltese; b) identify mutations present in a Maltese family that exhibit granular corneal dystrophy 1 (GCD1), a subtype of TGFBI CDs; c) explore TGFBI inhibition as a treatment modality. Genetic prevalence of CD subtypes and fixation index (FST) values for Maltese single nucleotide polymorphisms (SNPs) were calculated and compared to global cohorts. Clinical exome sequencing was performed on mouthwash samples from Maltese GCD1 phenotype individuals. A scoping literature review to identify compounds that decrease corneal TGFBIp (protein) levels was conducted to explore their potential to be used as a cost-effective approach via drug repurposing. Human corneal epithelial cells (HCECs) were cultured and shRNA mediated knockdown (KD) of TGFBI was effectively performed. HCECs were also exposed to lithium (Li) and mitomycin C (MMC). RNA extraction and sequencing revealed gene expression levels in control, TGFBI KD, Li and MMC treated HCECs. Differential expression (DE) and enrichment analysis (ORA) were performed on these samples. FST values showed least differentiation with Puerto Rican, Mexican, and Colombian cohorts. The mutation in the GCD1 phenotype patients was identified as R555W (TGFBI gene). 16 compounds that can theoretically reduce the levels of mutant TGFBIp in corneal cells were identified. ORA of TGFBI KD DE genes showed enrichment of adhesion and signalling proteins. Surprisingly, TGFBI expression was found to be upregulated in the Li and MMC groups at 72hours. Identifying the Hispanic cohorts as those with a CD genome closest to the Maltese implies that when no comparable Maltese data is available, research in these cohorts can be used to guide future treatment strategies for Maltese CD individuals. The clinical exome sequencing study is the first CD genetic study that has ever been carried out on GCD1 Maltese individuals, generating new data about the previously unknown genetic pool. This project is also the first of its kind to explore the DE of genes in KD, Li and MMC treated HCECs, leading to further understanding of TGFBI related molecular pathways in HCECs. Surgical treatment of TGFBI CDs can be associated with serious complications and recurrence is almost universal. The introduction of gene therapy as a treatment option would be a breakthrough. Description: Ph.D.(Melit.)

2024-01-01T00:00:00Z https://www.um.edu.mt/library/oar/handle/123456789/132262 2025-02-25T08:44:58Z 2024-01-01T00:00:00Z

Title: Achilles tendon rupture : epidemiology, outcomes after treatment and an analysis of plantar foot pressures Abstract: The influence of socioeconomic deprivation status (SEDS) on the epidemiology of primary Achilles tendon rupture (ATR) has not been explored, while the general epidemiology of Achilles tendon re-ruptures (ATRR) is poorly understood. The optimal management of ATR remains controversial and recent trends towards functional rehabilitation are not supported by robust evidence. The studies comprising this thesis sought to define the epidemiology of primary ATR, with particular focus on the influence of SEDS; to describe the epidemiology and risk factors for ATRR; to report on comparative outcomes from randomised controlled trials comparing long-term outcomes after traditional operative and non-operative management and short-term outcomes after traditional and functional non-operative rehabilitation; and to report on changes in static plantar loading patterns, physical and patient reported parameters after functional nonoperative treatment of ATR. ATR and ATRR were commoner in males and individuals with lower levels of socioeconomic deprivation. The nature of ATR varied with variations in SEDS. Risk factors for ATRR were identified, including younger age and immobilising treatment of ATR. Patients treated surgically did not report superior long-term outcomes to those treated non-operatively. Functional rehabilitation was found to be a safe alternative to immobilising treatment, giving better early outcomes, albeit with a higher incidence of minor skin complications. There was no difference in outcomes beyond one year after injury. Functional, non-operative rehabilitation was associated with reduced forefoot loading and increased rearfoot loading. These changes reduced with time but persisted nine months after injury and were accompanied by progressive changes in uninjured foot loading. Description: Ph.D.(Melit.)

2024-01-01T00:00:00Z