Research Theses
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Item Digitalisation in healthcare: the future of surgical training(University College Cork, 2023) Galvin, Daniel; O'Reilly, Barry A.Introduction The impact of digital technology and artificial intelligence (AI) has a daily impact on our lives. Healthcare as an industry is at the forefront of technological innovation. The application of novel technology to aid performance and enhance training in surgery is key. Challenges in surgical training owing to an increase in trainee numbers, a reduction in working hours, increase in complexity and variety of surgeries performed have become major issues in surgical education. The COVID-19 pandemic further compounded these concerns between 2020 and 2022 where there was significant disruption and reduction in elective surgical activity. Methods Five studies examining the challenges in surgical training in gynaecology and their potential solutions were designed. These comprised of a national cross-sectional trainee and trainer survey on the current challenges of surgical training in gynaecology and in training during the COVID-19 pandemic. Potential solutions examined were a trial of the application of artificial intelligence to the grading of surgical performance and two randomised controlled trails of the application of transcranial direct current stimulation (tDCS) to enhance surgical performance in laparoscopic and robotic surgery. Results Our results showed significant challenges in surgical training over the last decade with a significant reduction in trainee confidence and experience in operative gynaecology. The COVID-19 pandemic had a significant impact on operative volumes of both trainees and trainers. Trainees failed to increase their self-reported confidence in performing common gynaecology procedures over the pandemic period. AI grading of operative performance was shown to be a potential means of enhancing trainee feedback and reducing workload for trainers. tDCS was shown to decrease rates of excessive velocity events during novice laparoscopic training setting it out as a potential solution to maximise training opportunities. tDCS was not shown to enhance robotic surgical performance. Conclusion While the current training environment is challenging in operative gynaecology, potential solutions to augment and accelerate training exist. Further study is required to assess the best means of implementing these solutions to ensure continued access to high quality surgical training.Item Defining gut mediated metabolism for health and disease(University College Cork, 2024) Quilter, Karina; Joyce, Susan; Melgar Villeda, Silvia; Science Foundation IrelandWe investigated the overall concept that human produced and microbially modified bile acids could act as an indicator of health. In chapter 3 we verified disruptions to bile acid metabolism in a porcine model of metabolic syndrome towards cardiovascular disease, induced by diet. In chapter 4 we applied dietary means to address mild hypercholesterolemia and followed BA readouts to indicate health parameters, we determined that BAs could be used as indicators of return to health but only when acute fed conditions were initiated and tracked over a 6 hour time period. Furthermore we noted that baseline fold change in BAs could be applied to distinguish responder and non-responder directions in a clinical setting. In chapter 5 we examined the metabolic outputs relating to elite athletes through 3 intervention studies. Our indications were that a key subset of BAs -significant in westernized MetS and CVD induction- were reduced in elite athletes. We further noted that different sports elicited different correlations with both microbes and metabolites in these small cohorts. In chapter 6, the key BAs associated with MetS-CVD and their interchangeable intermediates were examined at the cellular level and shown to have different outcomes in cell organelle functionality and related gene expression systems depending on dietary lipid interventions. In all, certain BAs are convergent indicators of disease, they diversify in health, just like microbiome composition. A number of key BAs were identified that can indicate health and the push towards disease in this study.Item Gut-heart axis in a large animal model of metabolic syndrome and heart failure(University College Cork, 2024) Cluzel, Gaston; Caplice, Noel M.; Stanton, Catherine; SFI ManufacturingBackground The metabolic syndrome (MetS) is a pathological condition diagnosed as the combination of obesity with either hypertension, dyslipidaemia, or hyperglycaemia. MetS constitutes a deadly cocktail of cardiovascular risk factors that greatly increases patient mortality. Among the cardiovascular complications of MetS, heart failure with preserved ejection fraction (HFpEF) represents one of the greatest unmet clinical needs of the 21st century. Indeed, as HFpEF prevalence increases along with soaring MetS cases, current therapeutic strategies fail to prevent disease complications. Therefore, novel approaches are required. MetS and HFpEF are accompanied by a low-grade inflammation (LGI) state. LGI is characterised as a steady but lingering increase in circulating inflammatory factors. Inflammatory signalling is known for promoting structural and functional changes in the myocardium that may contribute to HFpEF. Thus, decreasing LGI may reduce HFpEF progression. While the precise origin of LGI is uncertain, the gut microbiome has recently emerged as a hidden organ with critical immune regulatory functions. Crucially, the gut microbiome is tightly connected to the intestinal barrier. In MetS and HFpEF, patients show alteration of the gut microbiome and of the intestinal barrier, a phenomenon called gut permeability. Gut permeability results in the translocation of bacterial antigens from the gut lumen to circulation. Circulating bacterial antigens are pro-inflammatory, that contributes to LGI and, indirectly, to cardiac structural changes and HFpEF. Therefore, therapeutic strategies aimed at the gut microbiome may effectively prevent HFpEF via reducing gut permeability and LGI. This concept is described as the “gut-heart” axis. The gut-heart axis constitutes a novel field of investigation in cardiometabolic disorders and may answer the urgent need for novel therapeutic strategies directed against HFpEF. However, more research is needed to characterise the mechanisms involved in gut-heart signalling. Aims of the project This thesis aimed at characterising the cardiac pathological mechanisms involved in gut-heart signalling, and determining whether they can be modulated by a microbiota-targeted treatment. Methodology In this project, gut-heart axis pathological signalling was characterised using a porcine model of MetS and HFpEF induced by Western diet (WD) and hypertensive corticosteroid salts (desoxycorticosterone acetate, DOCA). Then, to investigate the effects of a gut microbiome-targeted intervention on MetS and HFpEF, this model was supplemented with a synbiotic product combining soluble corn fibre and Lactobacillus mucosae. Inflammatory signalling associated with HFpEF structural changes was investigated in the four cardiac chambers. In particular, the project focused on the roles of tumour necrosis factor (TNF)-α, lipopolysaccharide (LPS) and NOD-like receptor family, pyrin domain containing 3 (NLRP3). These central inflammatory pathways may be key in transducing gut-originating LGI into cardiac pathological signalling in HFpEF. Results Upon WD and DOCA challenge, the porcine model constituted a clinically-relevant reproduction of MetS and HFpEF. MetS was characterised by increased body weight, severe hypertension, hypercholesterolemia, and hypertriglyceridemia. HFpEF was characterised by left atrium enlargement (LAE) and left ventricle hypertrophy (LVH). LAE was associated with tissue apoptosis, and LVH was accompanied by cardiomyocyte hypertrophy. Left atrium (LA) and left ventricle (LV) also had increased inflammatory activity with cardiac macrophage (Mφ) expansion, and activation of TNF receptor 1 (TNFR1), toll-like receptor 4 (TLR4), and NLRP3 pathways. Moreover, the increase in TNFR1, TLR4, and NLRP3 activity was colocalised with cardiac Mφ, microvascular endothelial cells, and cardiomyocytes. While no structural or pressure-induced changes were observed in right heart chambers, the right atrium and the right ventricle also exhibited prominent inflammatory signalling. Data not reported in this thesis indicated that the model exhibited LGI and features of gut permeability. Overall, the porcine model of MetS and HFpEF was characterised by inflammatory cardiac changes along with systemic and intestinal alterations. Synbiotic treatment of MetS pigs reduced LAE, LA cardiomyocyte apoptosis, and LVH, but did not affect MetS core parameters. These improvements in cardiac structural changes were associated with a reduction in cardiac Mφ expansion and in TNFR1, TLR4, and NLRP3 activity in all four cardiac chambers. Reductions in TNFR1, TLR4, and NLRP3 activity were colocalised within the cardiac Mφ, microvascular endothelial cells, and cardiomyocytes populations. Data not reported in this thesis also indicated that synbiotic treatment reduced LGI and gut permeability. Therefore, synbiotic treatment targeted at the gut microbiome reduced pathological signalling along the gut-heart axis, and effectively reduced cardiac structural changes associated with HFpEF. Discussion The porcine model of MetS and HFpEF stood out as a robust model for investigating gut-heart axis inflammatory signalling. The study also highlighted the central role of TNFR1, TLR4, and NLRP3 in driving structural changes in HFpEF through pro-apoptotic and pro-hypertrophic signalling. Crucially, synbiotic treatment targeted at the gut microbiota effectively reduced HFpEF-associated structural changes via reducing cardiac inflammatory signalling. Finally, while exempt of structural changes, the right heart reflected accurately and dynamically the systemic changes in gut-heart axis pathology and treatment. Conclusions Synbiotic targeting of the gut microbiome resulted in cardiac structural improvements in a clinically-relevant porcine model of MetS and HFpEF. This study demonstrates the critical role of gut-heart inflammatory signalling cardiometabolic disease progression.Item Working relationships in family business: a psychological contract theory perspective(University College Cork, 2024) O'Leary, Olivia; Murphy, Linda; Sherman, Ultan; Duggan, JamesFamily businesses have long been recognised as pillars of economies worldwide, with Ireland boasting a rich history of such enterprises dating back centuries. Despite their prevalence, the distinct characteristics of family businesses present challenges, with their unique dynamics and working relationships often shaping their success or failure. Drawing upon psychological contract theory, this study investigates the formation and content dimensions of psychological contracts among family and non-family employees in family businesses. By comparing and contrasting these perspectives, this study uncovers the underlying processes and implications for the working relationship within family businesses. Conducted through an exploratory qualitative study with four independent family-owned retailers in Ireland, the study revealed distinct patterns in the formation of the psychological contract and illustrated that both family and non-family employees’ psychological contract formation is influenced by critical factors such as pre-entry and post-entry episodes, information sources, and agency relationships. However, family members have a protracted psychological contract formation process rooted in early organic experiences through their family membership. Non-family employees experience psychological formation through recruitment and standardised organisational entry processes. The research uncovers distinctive terms in the psychological contract with family employees, often emphasising familial obligations and legacy preservation, while non-family employees prioritise career development and stable employment. Both family and non-family employees feel obligated to the community in which the business operates. These findings shed light on the unique dynamics at play within family businesses, highlighting the importance of understanding and addressing the diverse needs and expectations of employees. This study contributes to both psychological contract theory and the unique context of family businesses. Furthermore, this thesis deepens our understanding of psychological contract theory by introducing novel concepts such as dormant psychological contracts and the influence of family relationships on employment arrangements. It advances psychological contract theory by demonstrating how early experiences shape working relationships in family businesses. It contributes to the family business domain by illuminating the role of HRM processes and co-workers in constructing psychological contracts in working relationships. Practically, this research offers valuable insights for organisational leaders and HR practitioners in managing working relationships within family businesses. By recognising and addressing the distinct dimensions of psychological contracts, family businesses can build positive employee-organisation relationships, enhance employee engagement, and ultimately improve organisational outcomes. Overall, this thesis comprehensively explores the formation of psychological contracts in family businesses, offering theoretical contributions and practical implications for organisational practice.Item A model of SPRY3 - VGCC interactions relating to autism(University College Cork, 2023) Bharatham Vijayaraghavan, Sashank; Moore, Thomas F.; Burk, KatjaAutism Spectrum Disorder (ASD) is a neurobehavioral condition characterized by impaired social interaction and communication resulting from irregular brain development during infancy and adolescence. Globally, over 168 million cases of ASD have been diagnosed, with Ireland ranking sixth in prevalence (583.69 cases per 100,000 people). Heritability, estimated between 40% and 80% in twin and family studies, underscores the importance of identifying susceptibility genes in ASD research. The ASD susceptibility candidate gene SPRY3 encodes a receptor tyrosine kinase inhibitor and plays a regulatory role in branching morphogenesis. SPRY3 is highly expressed in cerebellar Purkinje cells. Spry3 and p75NTR have opposite expression patterns in the cerebellar vermis of the mouse and it has been hypothesized that reactivation of the epigenetically silenced Y-linked SPRY3 copy in the human might interact with the TrkB and p75NTR signaling pathways to cause Purkinje cell pathology. The current work evaluates the potential that SPRY3-GFP colocalizes with neurotropic receptors in HEK293 cell line model and found that SPRY3-GFP colocalizes with TrkB-RFP and p75NTR-RFP. Significant colocalization of SPRY3 with EGFR-GFP and TrkA-RFP was also observed. This investigation detected no colocalization between SPRY3-RFP and CasR-GFP, which is a G-protein-coupled extracellular calcium-sensing receptor. The involvement of voltage-gated calcium channels (Cav) have been implicated in ASD and their role in the regulation of branching morphogenesis in the brain and lung, and the fact that calcium acts as a secondary messenger to modulate various signaling pathways involved in branching morphogenesis, we hypothesized a functional relationship between SPRY3 and calcium signaling mediated through Cav receptors. SPRY3 plays an important role in regulating axon branching of motor neurons. Similarly, growth cones rely on calcium signaling to respond to guidance cues and adjust their behavior accordingly and it is critical for proper axon extension and guidance. Using calcium imaging in SH-SY5Y cells, we found that adding KCl to SH-SY5Y cells expressing SPRY3-GFP significantly altered the function of Cav 1.2, Cav 1.3, and Cav 2.2. SPRY3-GFP did not alter the levels of calcium when the L-type inhibitor nifedipine was added to SH-SY5Y cells, shows that SPRY3 interacts with Cav 1.2 and Cav 1.3. Cav2.2 is a prominent VGCC in IMR-32 cells, where calcium levels are not altered. Also, we found that adding BDNF to SH-SY5Y cells transfected with SPRY3-GFP shown no changes in intracellular calcium levels. Overall, this study suggests an interaction between SPRY3 and L-type VGCCs, which may be relevant to ASD pathogenesis. In a pilot study, there was no significant difference in the mRNA expression of FMR1-, a known ASD gene in SPRY3-GFP transfected SH-SY5Y cells compared to GFP transfected SH-SY5Y cells.