Medicine (RMH) - Theses

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    Electrophysiologic remodelling and arrhythmias in endurance athletes: prevalence and mechanisms
    Flannery, Michael Darragh ( 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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    Pharmacological Treatment of delirium in hospitalised older adults; changing the natural history
    Lange, Peter Warwick ( 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.
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    Investigating the relationship between glycaemia and infections in the hospital setting.
    Barmanray, Rahul ( 2023-09)
    Diabetes mellitus affects up to one third of individuals admitted to hospital. Diabetes and its consequence of hyperglycaemia impede the normal functioning of the immune system and impair vascular function. They are thus associated with increased rates of adverse clinical outcomes in the inpatient setting including healthcare-associated infection. Intervention in the hospital setting to reduce hyperglycaemia may thus prevent the development of infections and other adverse consequences. This thesis describes a broad program of research that sought to reduce hyperglycaemia occurring in hospital with the goal of reducing healthcare-associated infection. In order to carry out this randomised controlled trial it was necessary to perform multiple research studies utilising various methods, to inform the design and enable the conduct of the trial. While there are multiple studies considering the impact of diabetes and hyperglycaemia on outcomes in certain disease states, heterogeneity of definitions and populations precludes ready appreciation of associations and their magnitude. A systematic review and meta-analysis of the literature was thus performed regarding the impact of diabetes and hyperglycaemia on outcomes in hospitalised patients with community-acquired pneumonia, finding that while hyperglycaemia was most strongly associated with adverse outcomes during the inpatient stay, diabetes had the greater association with post-discharge adverse outcomes (chapter 4). To enable the measurement and remote review of glucose across the hospital, a networked blood glucose monitoring system was implemented on all inpatient wards of the hospital. During implementation nurses were surveyed on their perceptions regarding in-hospital glucose monitoring, yielding unexpected results of a perception of greater importance amongst less experienced and non-educator nurses (chapter 5). Following program implementation the accurate use of glucose meters was tracked and found to deteriorate following training and with COVID-19 pandemic preparations (chapter 6). Additionally, glucometric benchmarking was performed and compared to earlier benchmarking, showing the positive effect of quality improvement projects in the intervening period (chapter 7). COVID-19 had significant impacts upon health services and people with diabetes. Performing a multi-centre study across Melbourne in 2020 revealed that unlike international experiences, neither diabetes nor hyperglycaemia was independently associated with increased adverse outcomes (chapter 8). A prospective cohort study was performed of all patients who received glucose testing at our institution (chapter 9). This study showed that hyperglycaemia was independently associated with healthcare-associated infection, acute kidney injury, and stroke occurring in the inpatient setting. Furthermore, the use of propensity weighting suggested a causative role for hyperglycaemia in the relationships. Finally, a randomised controlled trial of early intervention with an electronic specialist-led model of diabetes care was performed (chapter 10). This trial showed that such early intervention can both reduce glucose and healthcare-associated infection in patients with and without diabetes admitted to hospital. The studies in this research program describe a research journey of capacity building and problem defining towards designing and trialling a model of inpatient care that enabled glycaemic reduction with the prevention of healthcare-associated infection. Implementation of a similar model of care in other settings may improve the care of people with diabetes and hyperglycaemia admitted to hospital.
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    Advancing Translational Care in Genetic Dilated Cardiomyopathy: Genotype-Phenotype Correlations, Natural History and Risk Prediction
    Peters, Stacey Amanda ( 2023-03)
    Dilated Cardiomyopathy (DCM) is a common heart disorder characterised by reduced left ventricular (LV) systolic function that is not due to coronary artery disease. DCM can be familial, acquired, or idiopathic, though increasingly, all DCM is thought to have some genetic basis. Genetic testing for DCM has expanded in recent years due to improved technologies, reduced cost and increasing awareness. However, translation of clinical results remains challenging, particularly in relation to interpreting test results, enacting gene-based management approaches, and devising best monitoring and surveillance strategies for at-risk individuals. Further research is required to (a) define genotype-phenotype correlations, (b) understand the expected natural history of disease, (c) explore the role of environmental factors in disease manifestations, and (d) evaluate methods of risk prediction in genotype positive, unaffected individuals. In this thesis, these research areas were addressed in a series of studies divided into two research streams. Stream 1 focuses on genotype phenotype correlations with a focus on arrhythmic DCM and SCN5A DCM. First, in Chapter 2 a systematic approach was used to assess the strength of evidence for the putative cardiomyopathy genes and establish phenotypic correlates for each. The data from this work was published in a larger review Fatkin D, .. Peters S., Kovacic J.C. Contemporary and Future Approaches to Precision Medicine in Inherited Cardiomyopathies, 2021, J Am Coll Card. DCM genes that produce an arrhythmic phenotype have specific clinical implications and are emerging as important in personalised therapy of cardiomyopathies. In Chapter 3 the evidence for arrhythmic DCM genes was reviewed in a paper titled Peters S, .. Fatkin D. Arrhythmic Genotypes in Familial Dilated Cardiomyopathy: Implications for Genetic Testing and Clinical Management, 2019, Heart & Lung Circulation. One of the arrhythmic DCM genes of note was SCN5A, which appears to be the only arrhythmic DCM gene with a genotype directed therapy. In Chapter 4 a long-term followup of a family with the recurring SCN5A variant p.R222Q was performed, titled Peters S, .. Fatkin D. Longterm Efficacy and Safety of Sodium Channel Antagonists in p.R222Q SCN5A related Arrhythmic Dilated Cardiomyopathy, 2021, JACC Clin Electrophysiol. In Chapter 5 a systematic analysis of SCN5A variants with an association to DCM was performed, identifying unifying patterns of genotype and phenotype. This work was published in Peters S, .. Fatkin D. Arrhythmic Phenotypes are a Defining Feature of Dilated Cardiomyopathy-Associated SCN5A Variants: A Systematic Review, 2022, Circulation Genomic and Precision Medicine. Stream 2 of this thesis focuses on environmental factors, natural history and subclinical disease in familial DCM, utilizing a deeply characterised cohort of individuals from the Royal Melbourne Hospital (RMH) with confirmed genetic DCM. In Chapter 6 (manuscript in preparation), the role of environmental factors in the natural history of familial DCM is assessed. In Chapter 7, a focus specifically on pregnancy as an important environmental risk factor was performed, and this work was published in a research letter titled Peters S, .. Zentner D. Pregnancy Outcomes in Females with Dilated Cardiomyopathy-Associated Rare Genetic Variants, 2022, Circulation Genomic and Precision Medicine. In Chapter 8 (manuscript in preparation), specialised cardiac imaging techniques were used to evaluate for subclinical disease among genoptype positive, phenotype negative individuals. Genotype positive, phenotype negative individuals had lower average global longitudinal strain, and higher average LV volumes compared to genotype negative controls. Further, a significant interaction between genotype, environmental factors and GLS was found, indicating, again, that genotype positive individuals may be particularly vulnerable to environmental stressors. The studies in this PhD have gone some way to advancing translational care in genetic dilated cardiomyopathy in relation to genotype-phenotype correlations and risk prediction. This research paves the way for prospective longer term evaluations of genetic DCM cohorts to establish personalised treatment pathways.
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    The role of neutrophils in immunity to malaria
    Chishimba, Sandra Mushili ( 2023-07)
    The global malaria burden continues to remain high with most deaths occurring in young children. Understanding the protective immune mechanisms against malaria is imperative for the development of a highly efficacious vaccine since RTS,S and R21 which are recommended malaria vaccines, have modest efficacy and are limited to young children. Recent reports indicate that neutrophils may potentially play a key role in protective immunity against malaria via antibody-mediated interactions with Fc-gamma receptors (FcgR) expressed on their surface. Additionally, complement proteins may promote parasite clearance via interaction with antibodies. This thesis presents new findings on antibody interactions with complement (C1q) and FcgRs on neutrophils in immunity against severe malaria. It further presents new information on neutrophil phenotypes in response to naturally acquired malaria as well as phenotypes and transcription profiles in controlled human malaria infections (CHMI), and in vitro models. First, cytophilic IgG1 and IgG3 antibody subclasses, and antibodies that can fix C1q, or engage FcgRs to induce phagocytic clearance of merozoites were investigated. Additionally, opsonic phagocytosis of merozoites by neutrophils was quantified. These investigations were carried out on samples from young Papua New Guinean (PNG) children (n = 383) presenting with severe malaria versus uncomplicated malaria. In children presenting with severe malaria, cytophilic antibodies, antibodies that can fix C1q, or engage FcgRs against whole merozoites and neutrophil phagocytosis of merozoites opsonized by serum antibodies were lower than children with uncomplicated malaria. There was a strong association between high antibody responses to merozoites that fix complement or bind FcgRs, and reduced odds of severe disease. Second, cryopreserved neutrophils from children and adults in PNG, were phenotyped by examining receptors relevant to functions and malaria immunity. Neutrophils from children infected with P. vivax malaria (n = 37) had increased CD66b expression compared to uninfected children. Increased statistical power by combining uninfected children (n = 29) and uninfected adults (n = 35) into one group and comparing them with P. vivax and P. falciparum (n = 25) infected children further highlighted increased CD64 expression on neutrophils from malaria infected children compared to uninfected group. Neutrophils from uninfected children had distinct phenotypic differences from uninfected adults. There were also some differences identified in neutrophil phenotypes in males compared to females infected with P. falciparum. In addition, neutrophil phenotypes from uninfected adults and uninfected children varied substantially from neutrophils from malaria-naive adult Australian residents (n = 11), revealing increased CD64, CD54, and CD66b, and decreased CD62L, CD16, and CD32a expression, although CD32a expression in malaria-exposed children did not differ from malaria-naive adults. Neutrophil phenotype changes relevant to effector function and immunity to malaria model were assessed at multiple time points in a controlled human experimental P. falciparum infection trial. The study included 8 healthy Australian adult participants who were treated at day 8 of malaria infection. Neutrophil phenotypic changes occurred as early as day 4, prior to substantial blood-stage parasitemia. There were significant and substantial changes in neutrophil phenotypes following treatment to clear parasitemia and some changes persisted weeks post-treatment. To further understand neutrophil responses to malaria, phenotype changes in response to direct interaction with merozoites in an in vitro model were examined. There were no phenotype changes after neutrophils were incubated with unopsonized merozoites or with merozoites opsonized with serum from malaria-naive donors. In contrast, distinct changes in phenotypes were observed after incubation of neutrophils with merozoites opsonized by naturally-acquired antibodies from children. These changes included upregulated CD66b and downregulated CD64, CD32a, CD16, and CD62L expression. Finally, transcriptional analysis of neutrophil gene sets relevant to functions and clearance of malaria parasites were explored among samples from a controlled P. falciparum experimental infection trial in healthy Australian adults (n = 12) and using in vitro models. CHMI data revealed upregulation of gene sets including phagocytosis pathways and cytokine mediated signalling pathways. In vitro transcriptional analysis of neutrophils incubated with merozoites opsonized by purified IgG from malaria-exposed children showed upregulated gene sets including respiratory burst and cytokine activity compared to neutrophils incubated with merozoites opsonized with IgG from malaria-naive individuals. However, gene set enrichment analysis did not reveal any significant change in phagocytosis gene sets. The data generated in this thesis advances our knowledge on antibody mechanisms involved in immunity to malaria and provides new knowledge on the phenotypes and functions of neutrophils in response to malaria. Given that emerging data are increasingly indicating an important role for neutrophils in naturally-acquired and vaccine-induced immunity, this knowledge will be valuable for informing the development of more efficacious malaria vaccines.
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    Dissecting the antibody responses in pregnancy malaria
    Kassa, Meseret Workineh ( 2023-09)
    Abstract Malaria remains a major public health problem in tropical and subtropical areas of the world. It is a leading cause of morbidity and mortality in these areas, especially in young children and pregnant women. Pregnant women, despite lifetime malaria exposure, have increased susceptibility to Plasmodium falciparum malaria. This is due to the ability of parasites to sequester in the placenta by expressing VAR2CSA, a P. falciparum erythrocyte membrane protein 1 (PfEMP1) that is upregulated during pregnancy. With repeated exposure, pregnant women develop antibodies to VAR2CSA that are associated with reduced adhesion of infected erythrocytes (IEs) to the placenta, which may improve pregnancy outcomes. However, the development and function of these antibodies may depend on a combination of factors, including transmission intensity, cross species immunity, and maternal genetics. This PhD thesis aims to dissect diverse aspects of antibody responses to malaria in pregnancy and factors that may affect acquisition and functions of these antibodies. Aim 1 in this thesis examined antibody responses to P. falciparum and P. vivax antigens in pregnant women residing in low malaria transmission areas in the Brazilian Amazon region (chapter 4 and 5). The total and opsonic IgG antibody levels to pregnancy specific whole parasite surface antigens on CS2-IEs (CS2VSA), individual recombinant VAR2CSA domains and to other malaria antigens were assessed in the plasma of 408 Brazilian pregnant women using various assay formats including flow cytometry, enzyme linked immune assay (ELISA), and multiplex assays. Antibodies to CS2VSA were generally low but were higher in currently infected women and women with multiple P. falciparum episodes over pregnancy. Many women (21%-69%) had antibodies against each individual VAR2CSA DBL domain, and antibodies to DBLs correlated with each other, but not with antibody to CS2VSA or history of infection. We did not find a significant association between antibodies to CS2VSA with pregnancy outcomes. However, antibodies to individual VAR2CSA DBLs and certain P. falciparum merozoite antigens were significantly associated with lower odds of maternal anaemia (OR range 0.38-0.54, p<0.038). Aim 2 explored whether exposure to P. vivax antigens could lead to the production of cross-reactive antibodies to VAR2CSA. The acquisition of antibodies specific to VAR2CSA is generally assumed to occur through exposure to P. falciparum during pregnancy. More recent evidence has suggested that individuals exposed to P. vivax can also acquire antibodies to VAR2CSA. However, this evidence is based on antibodies to recombinant proteins and may be an artifact of the protein expression system. Therefore, in chapter 6 of this thesis, we investigated a hypothesis that P. vivax exposure does not result in antibodies that bind to VAR2CSA on the surface of the IEs and the acquisition of antibodies to VAR2CSA is restricted to pregnancy. The study cohort included P. vivax only infected primigravid women, P. falciparum infected multigravid women, uninfected pregnant women, men, and children from Brazil. When antibodies were measured to surface antigens on P. falciparum IEs, the P. vivax infected women showed significantly lower levels of antibodies to whole parasite CS2VSA in comparison to P. falciparum-infected women (p<0.0001). Additionally, the levels of CS2VSA-specific IgG in primigravid women infected with P. vivax was not significantly different compared to antibody levels in plasma samples from uninfected women. However, it was observed that pregnant women regardless of infection status and gravidity exhibited comparable levels of IgG response to recombinant VAR2CSA DBL3 expressed in P. pastoris and VAR2CSA DBL5 expressed in Chinese hamster ovary (CHO) cells. Intriguingly, men and children also exhibited antibodies against the recombinant VAR2CSA DBL3 domain at levels similar to those observed in pregnant women. In summary, antibodies to CS2VSA did not appear to result from exposure to P. vivax. Nonetheless, antibodies to individual recombinant VAR2CSA domains are not restricted to pregnancy or exposure to P. falciparum. Aim 3 investigated the effect of allotypic variations on the transplacental transfer and functions of malaria-specific IgG3 antibodies. Antibody allotypes are polymorphisms in the constant regions of immunoglobulin heavy and light chains. IgG3 allotypic variations can have a significant impact on associated Fc-mediated effector functions and transplacental transfer of malaria specific antibodies. We identified a novel IgG3 allotype in a cohort of pregnant women from PNG which has a histidine-to-glutamine replacement at residue 433 (IgG3-Q433). The maternal IgG3 gene was sequenced in a total 558 women to identify the IgG3-Q433 polymorphism. A total of 298 pairs of maternal and cord serum samples were analysed to investigate the effect of this allotypic variation on transplacental transfer of IgG3 antibodies. Mother to cord transfer ratios were calculated. We used four VAR2CSA DBL3-specific monoclonal antibodies with different heavy chain constant regions (IGHG1*01, IGHG3*01, IGHG3*30 and IGHG3*30-H435R) to assess the effect of IgG3-Q433 polymorphism on the FC-mediated effector functions, including complement fixation and antibody dependent cellular phagocytosis. In brief, the novel IgG3 variant displayed enhanced ability to induce phagocytosis by neutrophils and THP-1 cells, but it did not show an increased ability to activate the complement system. Additionally, there was no significant difference in antibody transfer from mother to baby between the novel variant and common IgG3 and IgG1 allotypes (Chapter 7). In summary, this thesis analysed diverse aspects of antibody responses to malaria in pregnancy and investigated factors that may affect acquisition and Fc- mediated effector functions of these antibodies. It explored whether these antibodies confer protection against malaria associated pregnancy outcomes or just serve as markers of prior exposure. Furthermore, this thesis investigated the effects of IgG3 allotypic variations on the transplacental transfer of antibodies and the associated Fc-mediated functions. Continued research in this area will add to our understanding of pregnancy associated malaria and potentially reveal novel therapy and vaccine strategies to combat this disease.
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    Medication use of anti-cholesterol drugs and cognitive decline in ageing
    Chin, Tze Jian ( 2022-08)
    Projections estimate 131.5 million will be living with dementia by the year 2050. Alzheimer’s disease is the leading cause of dementia, accounting for about two-thirds of all cases and is a global public health priority. Alzheimer’s disease risk escalates with age and lacks efficacious drugs. Statins are prescribed to lower cholesterol levels and the risk of adverse cardiovascular events. Some epidemiological studies have linked statin use to improved cognitive functioning. Nonetheless, literature in this field is conflicting. Thus, investigations of long-term statin use from midlife have been suggested in recent systematic reviews. To the best of our knowledge, only one study has examined a female-specific cohort, and only few studies have investigated this relationship over a period of at least ten years, and prior to this thesis, no study has examined this relationship in women over a 24-year period. Chapters 1 and 2 examined the current literature regarding statin-cognition relationship. Previous systematic review suggests a mixed and inconclusive relationship between statins and cognitive outcome: however, this thesis provided the first evidence of this relationship extending to the prodromal phase of neuropathological change. A comprehensive systematic review and meta-analysis into statin and cognition found that the significant difference reported in the current statin studies was mainly driven by male statin users. This review highlighted the importance of having long-term statin studies and the urgent need to focus on female statin users. Chapter 4 presented a cross-sectional analysis of the relationship between statin and cognition in participants of the Women’s Healthy Ageing Project. Independent of underlying vascular risk, current statin users, initiation of statin use by women (1-4 years of use) was associated with the greatest deterioration in global cognitive function. This effect is not simply reflective of the lipid levels in the women. Chapters 5 and 6 investigated the longitudinal effect of statin consumption on the cognition of Australian ageing women over time. Participants from the longitudinal Women’s Healthy Ageing Project completed assessments from 1992 to 2016. Statin use by women was associated with greatest decline in episodic memory, global cognitive function and visuospatial ability. Non-statin users were also mostly seen to have a better cognition than statin users across this 24-year period. Type of statins do appear important and the effect of statins on cognition could take up to many years before it is noticeable, highlighting the importance of needing an extensive duration (more than 20 years) of longitudinal studies. This thesis presented the first systematic review and meta-analysis in highlighting the paucity of statin studies with long duration and lack of inclusion of female participants, who are at a much greater risk than their male counterparts. This thesis was the first to examine this relationship in a female only cohort in more than 20 years of follow-up. The results of this thesis, in concert with previous literature, suggest statin has a substantial role in jeopardizing our cognition and the detrimental effects of statins could take many years to be apparent. However; it is clear that the complex connection between statin and brain health requires further research to elucidate the underlying mechanism governing this relationship.
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    Understanding mechanisms enabling long-lasting immunity to malaria
    Horton, Jessica Louise ( 2023-07)
    An efficacious vaccine that generates long-lasting immunity is critically needed to reduce the global burden of malaria and protect young children in high transmission areas, who are most at risk of severe disease and death. However, despite four decades of development, the most advanced malaria vaccine induces only moderate and short-lived protection and other candidate vaccines are yet to demonstrate more sustained efficacy. Advancement in malaria vaccine design is impeded by an absence of established correlates of immunity, limiting targets for directed vaccine improvements. Host-specific factors, such as age, previous malaria infection and nutritional status, may modulate immune function and impair vaccine responsiveness, highlighting the need for an extensive characterisation of immune function in children in malaria endemic regions. In this thesis, we explored correlates and determinants of sustained immunity to malaria and examined how vaccine modification may improve long-lasting protection. We first considered immune and host factors associated with antibody-mediated protection and antibody maintenance in clinical samples. We investigated the value of antibody avidity, previously reported as a marker of robust and high-quality immune induction, as a possible correlate of long-lasting malaria immunity following vaccination in children and adults. Our findings suggest that avidity is an unreliable marker of antibody maintenance and antibody functional properties. In malaria, monocytes may be key effector cells of antibody-mediated functions which have shown protective associations in vaccine trials. We found that monocytes in children with malaria infection expressed high levels of cell surface receptors relevant to functions in malaria immunity. Given the importance of potent antibody responses to generate protective and sustained immunity, we also explored the role of undernutrition in IgG responses to routine vaccinations in children living in regions of endemic malaria transmission and found that underweight and wasting were associated with reduced vaccine-induced antibody levels. Finally, we used mouse models to investigate vaccine strategies and dietary modifications that may alter the magnitude and longevity of antibodies induced by malaria vaccines. We demonstrated differences in antibody maintenance generated by different vaccine approaches, including varying adjuvants and antigens, and that deficiencies in critical micronutrients, such as zinc, may impair the antibody response to vaccination, an effect modulated by adjuvant selection. The work in this thesis supports the role of monocytes in immunity, shows that nutritional factors impact vaccine antibody levels, and demonstrates that vaccine formulation – including adjuvant and antigen selection – and host factors, such as zinc deficiency, interact to modulate the induction and maintenance of antibody responses to vaccination. In summary, we illustrate the challenges and complexity of inducing sustained immunity with malaria vaccines, providing foundations for future work characterising the interplay of host factors, the immune system and vaccine features to support vaccine-induced immunity to malaria.
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    Biomarkers of Treatment Response in Multiple Sclerosis
    Moradi, Nahid ( 2023-04)
    Timely initiation of efficacious disease modifying therapy is the cornerstone of therapeutic management in multiple sclerosis (MS) as it preserves brain functional reserve by attenuating the underlying inflammatory processes. Achieving this goal however, is complicated by the individuality of disease trajectories and heterogenous response to therapies. In this context, it is imperative to identify patients that are at a higher risk for experiencing aggressive MS in the form of recurrent relapses or rapid worsening of disability and consider a more proactive treatment strategy. Various clinical outcome prediction tools have been proposed to date for this purpose with a few clinicodemographic predictors that they share in common such as number of prior relapses, imaging markers of disease activity, older age and male sex. However, these tools have been limited in their ability to provide a comprehensive adjustment for all the possible markers and predictors of disease activity due to the risk of model overparameterisation by including too many variables. A recently developed model of treatment outcome prediction in MS utilised homogeneity analysis to summarise a wide array of background clinicodemographic variables into three principal components to predict probability of clinical outcomes for individual patients over a four-year prediction horizon. This model provides a framework that can be further optimised by experimental inclusion of newly emerging biomarkers in the field to firstly determine their additive predictive value when considered alongside a comprehensive clinical model and secondly to enhance overall model performance. In this thesis, firstly external validity of the developed base model was evaluated using a non-overlapping underrepresented cohort from the Middle East. Once its generalisability was established, models were developed and adjusted to assess the additive predictive value of three emerging biomarkers in the field of MS. Neurofilament light chain was investigated as an acute marker of neuronal injury while volumetric magnetic resonance (vMRI) imaging parameters were investigated markers of chronic neurodegeneration. Lastly, vitamin D was assessed a proposed modulator of treatment response especially in those treated with interferon beta. We found that while higher NfL was associated with worse clinical outcomes in models without the clinicodemographic predictors, it failed to contribute unique prognostic information toward predicting medium-term outcomes in comparison with the solely clinical models. Findings for vMRI showed that lower brain volumes both globally and regionally were associated with higher disease activity in models without the clinicodemographic information. Similarly, however, these associations did not translate into superior predictive performance when compared with the base models. Lastly, we found no evidence of the association between vitamin D and medium-term clinical outcomes in any of the performed analyses. These findings suggest that continued utilisation of background and routinely collected clinicodemographic information is crucial for clinical decision making and that the utility of new biomarkers need to be assessed alongside real-world routine clinical practice before their widespread adoption. Such studies will also help elucidate the pragmatic clinical use of such biomarkers by clarifying their clinical trajectories in real world settings.
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    Malnutrition and nutrition interventions in older adults
    Hettiarachchi, Jeewanadee Isurika Kumari ( 2023-05)
    Malnutrition is highly prevalent in older adults and is characterised by unintentional weight and muscle mass loss among others. Malnutrition increases the risk of sarcopenia, a condition defined as low muscle mass and muscle strength below a clinically relevant threshold. Both conditions are associated with poor functional performance in older adults. Nutrition interventions are shown to be effective in the treatment of malnutrition, specifically when combined with an exercise intervention. The effect of nutrition interventions may be enhanced by methods such as using indirect calorimetry to determine energy targets and strategies such as specific patterns of protein intake. This thesis focuses on malnutrition and its intervention on body composition and functional outcomes in older adults. In a cohort of geriatric rehabilitation inpatients, malnutrition at admission was associated with poor functional recovery. During the geriatric rehabilitation admission, body weight and muscle mass improved in patients with malnutrition, sarcopenia or underweight. At least a quarter of patients with malnutrition, sarcopenia or underweight did not receive dietetic interventions as part of routine clinical care and the patients who received dietetic interventions did not have greater improvements in body weight or body composition. In a quasi-experimental study in a sub-sample of this population, using indirect calorimetry to determine energy targets in nutrition interventions did not lead to greater improvements in clinical outcomes. Inadequate dietary intake remained a major challenge for the success of nutrition interventions in geriatric rehabilitation patients. A systematic review and a meta-analysis showed that protein supplementation alone is effective in improving muscle mass in community-dwelling older adults, but the gain in muscle mass was not associated with the dose, frequency or timing of supplementation. This thesis highlights the importance of diagnosing malnutrition and the need for improved personalised nutritional care in geriatric patients. Ensuring adequate dietary intake remains critical in clinical care and in future studies investigating the effect of strategies optimising nutrition interventions in older adults.