Medicine (RMH) - Theses
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ItemNovel Mapping and Therapeutic Techniques for Treatment of Ventricular Arrhythmias( 2023-11)Ventricular arrhythmias (VAs) are a leading cause of cardiovascular morbidity and sudden cardiac death (SCD). It is estimated that SCD and VA account for 15-20% of all deaths worldwide. Despite the decline in cardiovascular deaths over recent decades, the incidence of sudden cardiac death as a proportion of overall cardiovascular mortality has increased. Medical therapy to prevent sudden arrhythmic death has been shown to be ineffective. Institution of implantable cardiac defibrillators has been shown to reduce mortality from malignant VAs, but these devices do nothing to prevent VAs from occurring. Subsequently catheter ablation for VAs, particularly ventricular tachycardia (VT), is now part of standard of care. Advancement in electroanatomical mapping and ablation technology has led to further insights into VT circuits and the functional nature of the substrate that sustains them. The aim of this thesis was to investigate the diagnostic, mechanistic, and therapeutic techniques used for the treatment of VAs occurring in the presence of structural heart disease. There was a particular focus on the functional assessment of the VT substrate, and how this provides insight into where critical sites of VT re-entry are harboured. Initially, novel therapies for treatment of VAs were reviewed, and a systemic review and meta-analysis was conducted on the role of renal denervation. Subsequently, assessment of the VT circuit was investigated using novel modalities such as an automated conduction velocity mapping algorithm and direct graph mapping (DGM). Analysis of the substrate was then performed using a novel retrospective window of interest (WOI) approach. Finally, a direct comparison of different techniques for annotating local activation time (LAT) was performed. Chapter 1 outlines current understanding of VT and ventricular fibrillation (VF) mechanisms and treatment. Contemporary methods for performing a substrate-based VT ablation are explored. The role of imaging in VAs is discussed, with a focus on mechanistic insights and pre-procedural planning. Finally, novel therapies that may be considered where catheter ablation has failed or is contraindicated are reviewed. Chapter 2 assesses the use of renal denervation for the treatment of refractory VAs in a systematic review and meta-analysis. This was a pooled analysis of 121 patients from seven studies meeting the inclusion criteria. Renal denervation was assessed in its ability to reduce the incidence of VAs, anti-tachycardia pacing (ATP) device therapy, and shocks. This study concluded that renal denervation is an effective treatment for refractory VAs and electrical storm, although randomised data are lacking. Chapter 3 evaluates the utility of a novel automated conduction velocity mapping algorithm (ACVM) in the assessment of both VT circuits and VT substrate. This study included 15 patients with paired high-density substrate and VT activation maps. These maps were assessed using both the traditional mapping methods and with the new ACVM module. Conduction velocity was calculated offline in a custom Matlab program for validation. This study concluded that ACVM is a novel complementary tool that can be used to accurate display complex VT circuits but has limited accuracy in identifying slowed conduction during substrate-based mapping. Chapter 4 investigates the ability of an investigational mapping method ‘Direct Graph Mapping (DGM) to identify mechanism and circuit type in patients with VT and structural heart disease. A total of 35 patients were identified and included in the analysis. Cases were analysed using the current gold standard of mapping (activation + entrainment), ACVM, and DGM. The mapping modalities were compared in their ability to identify the VT mechanism, isthmus location, and circuit type. This study concluded that DGM is a rapid automated algorithm that has a strong level of agreement with the current gold standard mapping modality. Chapter 5 examines the ability of a novel retrospective WOI to identify critical late potentials that are otherwise arbitrarily excluded from contemporary mapping systems. Forty-eight patients were included with paired high density substrate maps and identified critical sites for VT re-entry. These cases were reannotated manually point-by-point and assessed in their ability to display conduction patterns within the VT substrate and predict critical sites from substrate activation features. This study concludes that the standard WOI of contemporary mapping systems is arbitrarily limited and widening the WOI identifies additional very late potentials in 65% of patients. Chapter 6 compares five different methods of annotating local activation time. Fifty cases were included with high density substrate maps and paired identified critical sites of VT re-entry. Each point in each map was manually annotated five different ways, with substrate maps using each annotation method evaluated in their ability to predict the critical site. This study concluded that annotation with LAT-dV/dt (the steepest negative unipolar slope) was not useful in VT mapping due to its inability to identify late potentials. Latest activation annotation was proposed as the gold standard of annotation in VT substrate mapping due to its reliable annotation of late potentials and propensity to be automated.
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ItemSarcopenia as a Comorbid Disease: findings from the RESORT cohort in Australia( 2023-04)Background: Sarcopenia is defined as age-related low muscle mass and muscle strength. The associations between sarcopenia and poor health outcomes have been studied, however sarcopenia should also be studied as a comorbid disease. 1) This thesis aims to find the association between sarcopenia as a comorbid disease and incidence of institutionalisation and mortality. 2) It also aims to find the changes in sarcopenia’s diagnostic parameters (muscle mass, muscle strength, and physical performance) from admission to discharge from geriatric rehabilitation, and the principal diagnoses and geriatric conditions which were determinants of thesis changes. Methods: All patients were recruited from the REStORing health of acutely unwell adulTs (RESORT) cohort. 1) Sarcopenia was defined via three definitions; the European Working Group on Sarcopenia in Older People (EWGSOP), EWGSOP2 (2018), and the Asian Working Group for Sarcopenia 2019 (AWGS 2019). Morbidity was defined via multimorbidity, disease severity, and specific diseases. Incidence of institutionalisation and mortality were recorded from a 3-month follow-up survey and the Australian Births, Deaths and Marriages and medical records, respectively. Logistic regressions were used to find the association between sarcopenia as a comorbid disease and poor health outcomes. 2) Principal diagnoses and geriatric conditions were collected at admission. Patients’ muscle mass (skeletal muscle mass (SMM), SMI index, appendicular lean mass (ALM), ALM index), hand grip strength, and physical performance (Short Physical Performance Battery, gait speed, chair stand test) were measured at admission and discharge. Linear mixed models were used to find the changes in muscle mass, muscle strength, and physical performance from admission to discharge, as well as which principal diagnoses and geriatric conditions were associated with these changes. Results: Sarcopenia when comorbid of high multimorbidity, dementia, diabetes mellitus, and renal impairment had increased odds of institutionalisation 3-months post-discharge and sarcopenia when comorbid of high multimorbidity, high disease severity, chronic obstructive pulmonary disorder, osteoporosis, and renal impairment had increased odds of mortality 3 months post-discharge. Muscle mass, muscle strength, and physical performance all increased from admission to discharge in geriatric rehabilitation. Lowly multimorbid patients had increases in muscle mass and physical performance, whereas highly multimorbid patients had no changes in muscle mass and lesser increases in physical performance. Patients with cognitive impairments had significant increases in muscle strength and physical performance, but those without cognitive impairments had greater increase. Conclusions: Higher odds of incidence of institutionalisation and mortality was associated with sarcopenia as a comorbid disease. Whilst highly multimorbid patients and cognitively impaired patients increased in the sarcopenia parameters, their lowly multimorbid and cognitively intact counterparts improved more. This thesis highlights the needs for sarcopenia diagnostics and interventions in geriatric rehabilitation and that current exercise and nutritional interventions could be adapted to better intervene with lowly multimorbid patients and cognitively impaired patients.
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ItemThe use of neuroimaging to facilitate detection and management of atrial fibrillation( 2024-02)Ischaemic stroke is a common cause of morbidity in Australia, with over 50,000 new cases per year. Atrial Fibrillation (AF) is the underlying aetiology in at least 25% of cases but may be asymptomatic in one third of patients and hence may go undetected. This has major implications for management, given the proven benefit of anticoagulation. Current diagnostic tests for AF are limited by various factors, including cost, detection rate and availability. There is currently an unmet need for a test which is cost effective, has a high detection rate and is readily available. There is evidence to suggest AF may be associated with specific topographic patterns of cerebral infarction on magnetic resonance imaging (MRI) and larger infarct volumes. Improved detection of AF via association with infarct patterns and volume, may help reduce costly investigations and better target these patients for further workup. However, human analysis of these patterns is often unreliable and performs poorly, particularly in the absence of clinical context. Machine learning, the process of training computers to recognise patterns and make predictions from data, is an important, growing facet of clinical diagnostics. Progress in the field of machine learning has reached a stage where many processes may be automated and interpreted with physician level accuracy. This opens the possibility that machine learning can be used for occult AF detection. This thesis presents work which seeks to add to our current understanding of infarcts on MRI in patients with AF, and how these can be utilised to aid in the diagnosis and management of AF. To this end, three specific works are presented in this thesis which address these aims, two of which have been published and one under review. Chapter 3 is the first paper, titled “Patterns of infarction on MRI in patients with acute ischaemic stroke and cardio-embolism: a systematic review and meta-analysis” and has been published in Frontiers of Neurology. The meta-analysis analysed data from >4000 patients and found patients with AF are more likely to have simultaneous bilateral acute infarcts, as well as larger infarct volumes. This was the largest study to date, in terms of number of patients analysed, and added to our understanding of this important topic. Chapter 4 is the 2nd paper, entitled “Diagnosis of atrial fibrillation by artificial intelligence enabled neuroimaging examination”. This paper details a novel machine learning algorithm which classified MRIs into those belonging to patients with AF, and those without, without any clinical context or information. With 235 patients, this classifier was able to obtain an AUC >0.8, which indicates good discriminative performance between the two groups. Finally, the burden of silent infarcts in patients with AF is high and has significant clinical implications. These include a higher risk of future stroke and cognitive impairment. Compounding the issue is that the optimal time to commence anticoagulation is unclear in patients with AF, and hence patients may be exposed to a higher risk of new infarcts if commenced too late. Chapter 5, entitled “Early anticoagulation in patients with stroke and atrial fibrillation is associated with fewer ischaemic lesions at 1 month: the ATTUNE study” is the 3rd paper and has been published in Stroke and Vascular Neurology. This paper seeks to determine the ideal time to commence anticoagulation in patients with AF, after an ischaemic stroke or TIA. Patients commenced within 4 days of their index event were less likely to suffer new silent infarcts, with no increase in the risk of new haemorrhage. This study demonstrated that early anticoagulation after ischaemic stroke in patients with AF may be safe. Together, these studies further add to our understanding of ischaemic stroke in patients with AF and open exciting new possibilities in the field of AF diagnostics and management. In particular, the machine learning algorithm may point to a future possibility of machine learning assisted diagnosis of occult AF at the point of care.
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ItemInvestigating the Clinical and Imaging Factors Associated with Outcome and Treatment Response to Acute Stroke Therapies( 2023-11)Patients having an acute ischemic stroke are routinely offered treatment in the hope of rapidly restoring blood flow and, in the process, limiting damage to the brain. Thrombolytic medications, such as alteplase, are a mainstay of acute treatment and function by enhancing the activation of plasmin, the major enzyme involved in the breakdown of fbrin within a clot. However, the effectiveness of alteplase is limited in patients with severe strokes due to large clot burden (referred to as a large vessel occlusion). As a result, patients with a large vessel occlusion routinely require endovascular therapy, a procedure to mechanically remove the clot. A novel treatment, tenecteplase, shows promise as a potential replacement to conventional treatments. Using data from randomized controlled trials and a large multicenter prospective observational registry, this thesis examines tenecteplase in further detail - evaluating its effectiveness in relation to time, highlighting its relative strengths and weaknesses, and assessing its safety and efficacy in historically under-studied patient subgroups.
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ItemInvestigating TGF-ß-activated signaling pathways in monocytes/macrophages in the context of glioblastoma( 2023-12)Glioblastoma is considered the most common primary brain tumour in adults with very few treatment options currently available. Despite intensive research in the field of oncology, the efficiency of glioblastoma treatment has not improved since 2005, stagnating at a median survival rate of 12-15 months after diagnosis. This fact highlights the need for further investigations into glioblastoma tumorigenesis. One of the key mechanisms involved in the progression of glioblastoma is the ability of cancer cells to suppress antitumor immunity by secreting certain bioactive molecules into the tumour microenvironment (TME) that recruit and instruct glioblastoma associated monocytes/macrophages to promote tumour growth, therapy resistance, and recurrence. Multiple studies investigated the protumourigenic functions of highly expressed signalling protein TGF-b in glioblastoma; however, TGF-b modulation of monocytes/macrophages has not been fully understood. The aim of this PhD project was to investigate how monocyte/macrophage functions are modulated by TGF-b in the glioblastoma TME. This project investigated macrophage plasticity by generating and characterising six macrophage phenotypes using immunostaining, flow cytometry, and functional assays, where a novel method was developed to investigate label-free macrophage phenotypes based on machine learning classification techniques. Furthermore, the in vitro work elucidated the molecular mechanism behind TGF-b mediated suppression of the IL-12A gene, which is required for the synthesis of antitumourigenic IL-12 cytokine by monocytes. Applying global proteomics and biochemical techniques, this work also elucidated the molecular mechanism behind TGF-b mediated monocyte chemoattraction. This research provides valuable insights into the role of TGF-b in modulating monocyte/macrophage functions within the glioblastoma TME, shedding light on potential therapeutic avenues for improving glioblastoma treatment outcomes.
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ItemThe impact of prenatal and postnatal factors on infant stunting and growth in East New Britain, Papua New Guinea( 2023-12)Background Stunting, defined as low-height-for-age, affects 165 million children with a global prevalence of 22% for children under 5. Stunting during the first 1000 days of life is associated with childhood mortality and cognitive and physical impairments that are often permanent and irreversible. The causes of stunting and poor growth are poorly understood in most settings. Papua New Guinea has some of the world’s poorest maternal and child health indicators. The national stunting rate is one of the highest globally affecting nearly half of all children under 5. East New Britain (ENB) is a province in the islands region where poor growth is an understudied problem. There are no recent stunting estimates for ENB and no studies on the causes of stunting. This thesis aims to address knowledge gaps on the prevalence and predictors of stunting in ENB, PNG. Methods This PhD study was part of the Healthy Mothers, Healthy Babies (HMHB) research program. This program, established in 2015, included a longitudinal cohort study of mothers and infants, recruited during pregnancy, and followed up to 12 months post-partum. Recruitment of mothers occurred at antenatal clinics at 5 health facilities. Women >16 years of age living in the facilities’ catchment areas, attending the clinic for the first time in the current pregnancy, regardless of gestational age, were eligible to participate. At each site, women were randomly selected. Data from this longitudinal study was used for all chapters of this thesis. Data on infant stunting was analysed cross-sectionally to identify risk factors for stunting at birth, 6 and 12 months. A simultaneous latent growth curve model was developed to describe infant growth and identify factors associated with growth velocity for weight and length. A mediation analysis was conducted to identify mediators on the pathway between maternal education and infant stunting. To further investigate causes of stunting, an exploratory analysis aimed to identify associations of maternal metabolomic profiles, or specific maternal metabolic with low birth weight and stunting at birth using maternal serum samples collected during pregnancy. Results High rates of stunting were observed among infants increasing from 15% at birth to 29% at 12 months. Among both mothers and infants there was a high prevalence of known risk factors for stunting, including maternal nutritional deficiencies and infections. Preterm birth was the strongest predictor of stunting at birth and birth weight was the strongest predictor of infant stunting at 6 months. Maternal anthropometric characteristics, height and MUAC, and maternal education were associated with stunting at 6 or 12 months. Differences in growth velocity between boys and girls were identified and some similar risk factors for growth velocity, as for stunting, were identified, including maternal height and MUAC. Despite the breath of data collected, no post-natal risk factors, including infant illness, breastfeeding and complementary feeding, were associated with infant stunting or growth. Different maternal metabolites and metabolomic pathways were associated with either low birth weight or stunting suggesting that different metabolic profiles or pathways contribute to different aspects of fetal growth. Individual metabolites, including cysteine, glycine and ornithine, were associated with infant birth weight or stunting at birth with substantial effect sizes. Conclusions This study showed a high prevalence of infant stunting and the prevalence of indicators of poor health were high among mothers and infants. Improving the health of mothers in ENB must be a priority if the high rates of infant stunting are to decline. Novel epidemiological and analysis methods identified risk factors for growth velocity distinct from stunting and elucidated casual pathways. These methods can be used to identify targets for interventions and the evaluate the effect of interventions on infant growth and stunting.
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ItemContribution of CCL17 as an inflammatory mediator in rheumatoid arthritis( 2023-10)Rheumatoid arthritis (RA) is an inflammatory, progressive, and destructive autoimmune disease. During RA, intra-articular as well as extra-articular manifestations result in morbidity and extreme cases can lead to mortality. Currently available RA therapies, such as glucocorticoids, methotrexate and TNF-inhibitors are costly and accompanied by significant adverse side effects, as well as limited effectiveness in some patients, highlighting the need for new therapies. Pro-inflammatory cytokines, such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumour necrosis factor (TNF), are among the important causative mediators in the development and progression of RA. Preclinical studies identified that CCL17 is a downstream mediator of GM-CSF. GM-CSF-induced CCL17 expression in monocytes and macrophages is via the epigenetic demethylase, Jumonji domain-containing 3 protein (JMJD3), and the transcription factor, interferon regulatory factor 4 (IRF4). While GM-CSF is one of the most essential cytokines for inducing CCL17 expression, TNF has also been implicated in CCL17 expression and pain development in preclinical models of arthritis in conjunction with GM-CSF. Furthermore, GM-CSF and TNF are produced by numerous cell types in response to various stimuli. Data suggested the possibility that TNF can engage in a cytokine loop, thus potentially linking TNF biology to the GM-CSF-CCL17 pathway. However, there is little evidence about the key cells involved in this linkage. CCL17 is a potential target for treating RA, as it accumulates in the serum and synovial fluid of patients. It is speculated that CCL17 regulates T cell migration to joints via the CCR4 receptor. This receptor is common for both CCL17 and CCL22 cytokines. In contrast to CCL17, CCL22 is decreased in the RA. At the commencement of this PhD project, no specific CCL17-suppressing drugs were available in the clinics. In addition, the cells that might be responsible for CCL17-driven pathology were unknown. In this PhD thesis, FDA-approved drugs were screened in the presence of GM-CSF to identify drugs with the potential to specifically suppress CCL17 expression, but not that of CCL22. Among the 1,500 screened drugs, 5 drugs suppressed GM-CSF-induced CCL17 expression and maintained/increased GM-CSF-upregulated CCL22 in both human monocytes and mouse macrophages, with no toxicity to the cells. The identified drugs were tested in the Zymosan-induced arthritis model (ZIA) to explore their potential to ameliorate arthritic pain and disease. Among them, four drugs significantly inhibited CCL17-dependent pain with a trend towards decreasing the disease in the ZIA model. Analysis of the mechanistic pathways of these drugs in the presence of GM-CSF demonstrated that inhibition of GM-CSF-induced CCL17 expression was due to suppression of both STAT5 activity and IRF4 protein expression. Dendritic cells are thought to be a key cell type that expresses CCL17 in RA patients. There is an imbalance in Tregs/Th17 cells in RA synovial samples which suggests the possibility of a chemotactic function of the increased CCL17 on Th17 cells. However, the potential relationship(s) between CCL17 and immune cells within the RA synovium has not been explored. In this PhD, it was found that macrophage marker (CD68) was the most prevalent marker that co-expressed with CCL17 and its receptor CCR4 in synovial membranes. Significantly, elevated expression of CCL17 was observed in RA synovium compared to that from healthy controls. The thesis showed that the effect of TNF on the expression of CCL17 induced by GM-CSF is different between human and mouse macrophages. Interestingly, TNF alone had no positive effect on CCL17 expression in human monocytes/macrophages as well as in mouse macrophages. In contrast to CCL17 expression, CCL22 was significantly upregulated by TNF in monocytes and macrophages. In conclusion, this thesis indicated the promising effects of repurposed FDA-approved drugs to ameliorate arthritic pain which could be due to inhibition of the GM-CSF/CCL17 pathway. These drugs might be able to be used in future clinical trials. Furthermore, it was shown that the type of immune cells that express CCL17 in response to other cytokines, such as TNF, would be different between humans and mice. This finding once more emphasises the complex role of TNF in inflammation. Furthermore, it was demonstrated that, in addition to T cells, macrophages are among the cells that are important in the pathogenesis of RA, supported by the co-expression of both CCL17 and CCR4 in synovium tissue samples from RA patients.
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ItemContribution of CCL17 as an inflammatory mediator in rheumatoid arthritis( 2023-10)Rheumatoid arthritis (RA) is an inflammatory, progressive, and destructive autoimmune disease. During RA, intra-articular as well as extra-articular manifestations result in morbidity and extreme cases can lead to mortality. Currently available RA therapies, such as glucocorticoids, methotrexate and TNF-inhibitors are costly and accompanied by significant adverse side effects, as well as limited effectiveness in some patients, highlighting the need for new therapies. Pro-inflammatory cytokines, such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumour necrosis factor (TNF), are among the important causative mediators in the development and progression of RA. Preclinical studies identified that CCL17 is a downstream mediator of GM-CSF. GM-CSF-induced CCL17 expression in monocytes and macrophages is via the epigenetic demethylase, Jumonji domain-containing 3 protein (JMJD3), and the transcription factor, interferon regulatory factor 4 (IRF4). While GM-CSF is one of the most essential cytokines for inducing CCL17 expression, TNF has also been implicated in CCL17 expression and pain development in preclinical models of arthritis in conjunction with GM-CSF. Furthermore, GM-CSF and TNF are produced by numerous cell types in response to various stimuli. Data suggested the possibility that TNF can engage in a cytokine loop, thus potentially linking TNF biology to the GM-CSF-CCL17 pathway. However, there is little evidence about the key cells involved in this linkage. CCL17 is a potential target for treating RA, as it accumulates in the serum and synovial fluid of patients. It is speculated that CCL17 regulates T cell migration to joints via the CCR4 receptor. This receptor is common for both CCL17 and CCL22 cytokines. In contrast to CCL17, CCL22 is decreased in the RA. At the commencement of this PhD project, no specific CCL17-suppressing drugs were available in the clinics. In addition, the cells that might be responsible for CCL17-driven pathology were unknown. In this PhD thesis, FDA-approved drugs were screened in the presence of GM-CSF to identify drugs with the potential to specifically suppress CCL17 expression, but not that of CCL22. Among the 1,500 screened drugs, 5 drugs suppressed GM-CSF-induced CCL17 expression and maintained/increased GM-CSF-upregulated CCL22 in both human monocytes and mouse macrophages, with no toxicity to the cells. The identified drugs were tested in the Zymosan-induced arthritis model (ZIA) to explore their potential to ameliorate arthritic pain and disease. Among them, four drugs significantly inhibited CCL17-dependent pain with a trend towards decreasing the disease in the ZIA model. Analysis of the mechanistic pathways of these drugs in the presence of GM-CSF demonstrated that inhibition of GM-CSF-induced CCL17 expression was due to suppression of both STAT5 activity and IRF4 protein expression. Dendritic cells are thought to be a key cell type that expresses CCL17 in RA patients. There is an imbalance in Tregs/Th17 cells in RA synovial samples which suggests the possibility of a chemotactic function of the increased CCL17 on Th17 cells. However, the potential relationship(s) between CCL17 and immune cells within the RA synovium has not been explored. In this PhD, it was found that macrophage marker (CD68) was the most prevalent marker that co-expressed with CCL17 and its receptor CCR4 in synovial membranes. Significantly, elevated expression of CCL17 was observed in RA synovium compared to that from healthy controls. The thesis showed that the effect of TNF on the expression of CCL17 induced by GM-CSF is different between human and mouse macrophages. Interestingly, TNF alone had no positive effect on CCL17 expression in human monocytes/macrophages as well as in mouse macrophages. In contrast to CCL17 expression, CCL22 was significantly upregulated by TNF in monocytes and macrophages. In conclusion, this thesis indicated the promising effects of repurposed FDA-approved drugs to ameliorate arthritic pain which could be due to inhibition of the GM-CSF/CCL17 pathway. These drugs might be able to be used in future clinical trials. Furthermore, it was shown that the type of immune cells that express CCL17 in response to other cytokines, such as TNF, would be different between humans and mice. This finding once more emphasises the complex role of TNF in inflammation. Furthermore, it was demonstrated that, in addition to T cells, macrophages are among the cells that are important in the pathogenesis of RA, supported by the co-expression of both CCL17 and CCR4 in synovium tissue samples from RA patients.
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ItemElectrophysiologic remodelling and arrhythmias in endurance athletes: prevalence and mechanisms( 2023-03)Introduction Endurance sport participation has many health benefits including improved cardiovascular fitness and longer life expectancy. It is a paradox that endurance sport participation is also associated with cardiac arrhythmias. The true prevalence and incidence of arrhythmias in endurance athletes is difficult to define due to variable definitions of endurance sport participation and identifying athletes with arrhythmias. There are several proposed mechanisms by which endurance sport may predispose athletes to arrhythmias. Aims The aim of this thesis is to characterise what electrophysiologic changes are normal in endurance athletes, define the risk of arrhythmias attributable to endurance sport participation and investigate the mechanistic causes for an increased burden of arrhythmias. Results To characterise normal electrophysiologic changes in endurance athletes we recruited 223 current and former athletes as well as fifty-two nonathletic control participants. We found that bradycardia and notably ventricular pauses are very common in athletes and rare in non-athletes. We found no significant association of ectopic burden with endurance sport. To investigate the mechanisms by which endurance sport leads to bradycardia in athletes we performed an experimental study in thirty volunteers split equally between nonathletes, endurance athletes and endurance athletes with extreme bradycardia. By administering autonomic blockade, we confirmed that bradycardia in athletes is not due to autonomic influence. Furthermore, this is the first study which has shown high vagal tone does not explain extreme resting bradycardia in athletes. To better define the risk of atrial fibrillation attributable to endurance sport, we performed a case control study which strictly defined past endurance sport participation. We recruited 121 former elite rowers who competed at a national, world championship or Olympic level and compared them to an age, gender and ethnicity matched cohort from the UK Biobank at a ratio of 100:1. Despite less traditional risk factors we found the prevalence of atrial fibrillation 6.7 times higher in the athlete cohort and incidence was 2.8 times higher over two years of follow up. Using a polygenic risk score we were able to show that genetic risk plays a role in which athletes develop atrial fibrillation in a similar manner to non-athletes. In our last study we attempted to identify why some athletes develop atrial fibrillation. In our previous study we demonstrated that genetic risk plays a role in which athletes develop atrial fibrillation but does not appear to explain the excess burden of atrial fibrillation in endurance athletes. For this study we performed a case control study with fifty-three current and former endurance athletes with atrial fibrillation age and gender matched to fifty-three athletes without atrial fibrillation. We found that endurance sports athletes with atrial fibrillation have similar risk factor profiles, body composition, training history, physical fitness and electrophysiologic remodelling to endurance athletes without atrial fibrillation. Conclusion Endurance sport training leads to profound electrophysiologic remodelling which is not explained by autonomic tone. The risk of atrial fibrillation in markedly increased in endurance athletes but the mechanisms which lead to the excess burden of atrial fibrillation in endurance athletes remain elusive.
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ItemPharmacological Treatment of delirium in hospitalised older adults; changing the natural history( 2023-08)Delirium is a neuropsychiatric syndrome characterised by the acute onset of fluctuating cognitive disturbances including awareness and attention deficits, hallucinations, delusions, and circadian rhythm changes. Delirium is a common condition in hospitalised older adults that portends a poor prognosis and provokes many malign complications. Under-diagnosis is a problem in Delirium despite its prevalence. Delirium lacks any therapy that improves the natural history of the disorder: while antipsychotics are frequently used for symptoms, clear evidence of benefit is lacking and the superiority of any single agent over another is unknown. Once established then, Delirium’s course cannot be modified. Circadian rhythm disturbances are common in Delirium. Melatonin is a pineal gland hormone that contributes to circadian regulation, and secretion is perturbed in Delirium. Melatonin is available as an oral medication, approved for use in sleep disorders. Melatonin has been used to prevent Delirium onset but has not been evaluated for treatment of established Delirium. This thesis examined the prevalence and prevalence of under-diagnosis of Delirium, finding it large. The thesis examined melatonin for treatment of Delirium severity in hospitalised older patients. An effect on a comprehensive rating scale of Delirium symptoms was not found.