Medicine & Health

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Now showing 1 - 10 of 10
  • (2022) Sloane, Jennifer
    Thesis
    From a child interrupting a conversation between her parents to ask "What's for dinner?" to a nurse interrupting a physician in the middle of a complex procedure with an urgent message, interruptions are an inevitable part of our daily lives no matter who we are, where we live, or what we do. Interruptions can have a variety of affects on people's performance and behavior. While interruptions may sometimes facilitate performance, often interruptions have negative consequences. For example, interruptions may result in people making more errors or forgetting to complete a prior task altogether. This thesis examines existing strategies to help mitigate interruption costs and explores the effects of interruptions within different decision environments. Chapter I introduces the topic by discussing a few theoretical frameworks of interruptions and reviewing prior research on what makes interruptions disruptive. One strategy to minimize interruption costs is to use what is called an interruption lag, which can be thought of as taking time to prepare for a pending interruption. Chapter II presents a novel experiment to systematically explore the potential benefits of interruptions lags and an alternative intervention (i.e. providing feedback) when interruption lags are not possible. Chapters III and IV discuss the results from three experiments and a final replication study that all focus on how interruptions affect people's decision making in unique environments. The environments consist of easy problems (i.e. basic arithmetic problems) and trick problems, designed in such a way to lead the reader down an incorrect path. Results from these studies were mixed. While there was some evidence that interruptions may make people more susceptible to falling for the trick answer, this finding was inconsistent across all the experiments. Chapter V applies the findings from the previous chapters to a medical context. This chapter presents novel medical cases that were developed with the help of a medical expert. These cases consisted of easy, hard, and trick cases designed for medical students. The goals of this chapter were to validate the cases and to investigate the effects of interruptions within the different case types. The final chapter (Chapter VI) concludes with a general discussion of the experimental findings, the theoretical implications of the results, and the broader implications of this research for the field of medicine.

  • (2022) Jamshidi, Javad
    Thesis
    Wellbeing, a key aspect of mental health, is defined as a state of positive subjective experience and optimal psychological functioning. This thesis presents a series of studies devised to comprehensively explore phenotypic, genetic, and neural correlates of wellbeing. The first study (Chapter 2) aimed to compare the heritability and stability of different wellbeing measures in the TWIN-E dataset (N~1600) to discern the most suitable approach for measuring wellbeing for subsequent gene discovery efforts. This twin-based study concluded that multi-item measures of wellbeing such as the COMPAS-W scale, were more heritable and stable than single-item measures. Wellbeing-associated variants were identified via genome-wide association studies (GWAS) and highlighted the need for larger sample size. The subsequent studies were conducted using population-scale data from the UK Biobank comprising ~130,000 participants with phenotypic and genetic data. Thus, in Chapter 3, I constructed a multi-item “wellbeing index” measure using UK Biobank data to investigate its relationship phenotypically and genetically (using GWAS, polygenic scores and LD score regression) with negative mental health indicators (e.g., neuroticism and loneliness), childhood maltreatment and psychiatric illness. I confirmed that SNP-heritability of wellbeing index was higher than both single-item measures and estimates previously reported (SNP-h2 = 8.6%). Moreover, I provide an overview of phenotypic and genetic correlations between wellbeing index and negative mental health indicators. In addition, childhood maltreatment and psychiatric illnesses were associated with reduced wellbeing, with evidence that genetic factors may influence their correlations. In Chapter 4, I investigated the genetic and phenotypic associations between wellbeing index and brain structure, using magnetic resonance image-derived phenotypes from the UK Biobank. This study found associations between wellbeing and volumes of brainstem, cerebellum and subcortical regions, and structural morphology of various cortical regions. Thus, wellbeing is associated with complex structural variations, each with a small effect. Together, this thesis explores the multifaceted nature of wellbeing, elucidating its phenotypic and genetic relationships with related phenotypes, childhood maltreatment, and psychiatric outcomes, and provides novel insights into the associations between wellbeing, its genetic signatures and brain structure.

  • (2022) Shvetcov, Artur
    Thesis
    Rodents learn to fear a stimulus (e.g., a light) that signals the imminent arrival of an innate source of danger (typically an aversive foot shock). They also learn to fear a stimulus (e.g., a noise) that signals a learned source of danger (e.g., the already conditioned fear-eliciting light). Following Pavlov (1927), the former type of fear is termed first-order conditioned fear, because the stimulus is paired with an aversive unconditioned stimulus (US). The latter is termed second-order conditioned fear, because the stimulus is paired, not with a US, but with an already conditioned stimulus. There are both commonalities and differences in the neural substrates underlying these two forms of fear. Both require neuronal activity in the basolateral amygdala complex (BLA), including activation of NMDA receptors, for their encoding, and both require CaMK signalling, gene expression and DNA methylation for their consolidation. However, de novo protein synthesis is required for consolidation of first-order fear but not for consolidation of second-order fear.

  • (2022) Aung, Htein Linn
    Thesis
    With widespread access to combination anti-retroviral therapy (cART) and HIV suppression, life expectancy among people living with HIV (PLHIV) is increasing more than ever. According to UNAIDS, there were 8.1 million older PLHIV (i.e., 50 years of age and over) in 2020 globally. Although HIV-associated dementia has become rare in the cART era, mild neurocognitive impairments remain prevalent among PLHIV (~30% in virally suppressed). With aging, there is an increasing concern that HIV may precipitate neurocognitive abnormal aging because HIV is associated with increased markers of aging (e.g., immunosenescence and hyper-coagulopathy) and multiple age and HIV-related comorbidities (e.g., cardiovascular diseases). Importantly, these comorbidities occur at an earlier age and at a higher rate among PLHIV compared to age-matched HIV-negative persons. Earlier, more severe and more rapidly progressing neurocognitive impairment would have major public health consequences for the millions of PLHIV and the healthcare system. The overarching aim of this PhD thesis is to determine whether having chronic stable HIV infection and suppressive ART is associated with abnormal cognitive aging including premature cognitive aging (HIV and age synergistically/addictively lead to much lower cognitive performance at a younger age compared to controls), accentuated cognitive aging (HIV and age synergistically/addictively lead to much greater prevalence and severity of neurocognitive impairment), and/or accelerated cognitive aging (HIV and age synergistically/ addictively lead to much more rapid progression of neurocognitive impairment). To address these questions, we used a range of scientific methodologies including a systematic review, and several types of advanced statistical analyses using national and international longitudinal cohort data. First, to contextualise the potential public health consequences of cognitive aging in PLHIV, we conducted a narrative review of the burden of established dementia risk factors among PLHIV. We identified that the burden of several major dementia risk factors is much greater among PLHIV than in the general population. Second, we conducted the first-ever systematic review evaluating the current evidence for premature, accentuated and accelerated cognitive aging among PLHIV. We determined moderate evidence for premature cognitive aging and strong evidence for accelerated cognitive aging, while accentuated cognitive aging had not been optimally assessed. Lastly, addressing the previous literature major limitations (low sample size, cross-sectional study design, low proportion of older PLHIV, and inadequate controls/norms), we quantified the profiles of cognitive aging in four longitudinal studies of PLHIV. We demonstrated robust trends for premature cognitive aging among PLHIV compared to age-matched HIV-negative persons. We also demonstrated that older PLHIV had a higher risk for both neurocognitive impairment and neurocognitive decline compared to younger PLHIV, while controlling for normative age effect. These results are indicative of both accentuated and accelerated aging, although our research identified the need for longer-term studies using very large sample size to assess these trends especially in PLHIV older than 70+. Based on these findings, we discussed implications for clinical practice and future research directions.

  • (2022) Joubert, Amy
    Thesis
    Targeting and reducing the processes underlying the development and maintenance of depression and anxiety disorders, such as repetitive negative thinking (RNT), is a promising approach suggested to improve the efficacy and durability of psychological treatment. Delivering treatment online overcomes many of the barriers to accessing mental health treatment and improves treatment coverage. This thesis therefore involved the development and evaluation of a novel internet-delivered treatment targeting RNT. Study 1 involved an online qualitative survey to gain insight into how individuals define, experience, and understand rumination and worry. The findings from Study 1 were used to inform the development of the online intervention evaluated in subsequent chapters. Study 2 outlines the pilot evaluation of the online intervention. The results of Study 2 demonstrated the preliminary efficacy and acceptability of the intervention in adults, with significant reductions in participants self-reported levels of RNT, rumination, and worry, as well as symptoms of depression and generalised anxiety. Treatment effects were maintained at 1-month follow-up. Study 3 aimed to extend these preliminary findings using a randomised controlled trial design and compared the intervention when it was delivered with and without clinician guidance to a treatment-as-usual (TAU) control group. Participants in both the clinician guided and self-help groups had significantly lower levels of RNT, rumination, and worry, as well as symptoms of depression and anxiety compared to TAU at both post-treatment and 3-month follow-up. Treatment effects were significantly larger in the clinician guided group compared to self-help. This thesis provided the first evidence that targeting rumination and worry, both types of RNT, using an online intervention is efficacious, feasible, and acceptable in adults. This thesis also provided the first direct comparison of treatment outcomes and adherence between guided and self-help intervention formats and, in doing so, is the first to demonstrate the superiority of the clinician guided format. These findings add to the growing body of literature suggesting that internet-delivered interventions can successfully simultaneously target rumination and worry and that doing so is associated with significant improvements in depression and anxiety symptoms.

  • (2023) Rossi Nogueira Rizzo, Rodrigo
    Thesis
    Low back pain is the leading cause of years lived with disability and is associated with personal suffering and societal and economic burden. The burden of low back pain has not improved since 1990, partially because most current interventions are ineffective, and patients do not have access to many adequate treatments. The findings of this thesis have provided new evidence on the effects of a promising pharmacological intervention, the effects of contemporary nonpharmacological interventions, and the mechanisms and acceptability of novel interventions with new treatment targets for low back pain. This thesis has six chapters. Chapter One introduced problems and evidence gaps in the literature on low back pain addressed in the following thesis chapters. Chapter Two provided evidence that the most promising and advanced pharmacological intervention in the development pipeline for chronic pain, anti-NGF, does not provide clinically meaningful improvements in pain and function and is associated with an increased risk of experiencing an adverse event in adults with low back pain. Chapter Three summarised the findings from all Cochrane systematic reviews that investigated the effects of nonpharmacological interventions for low back pain, providing an accessible synthesis for consumers of the high-quality evidence of current treatments for low back pain. Chapter Four investigated the importance of targeting pain catastrophising to reduce pain intensity for chronic low back pain. Chapter Five presented the facilitators and barriers for the acceptability of an effective nonpharmacological intervention involving new treatment targets to treat chronic low back pain. Chapter Six summarised the main findings and provided the clinical and research implications for the management of low back pain. This doctoral thesis provides new evidence to optimise the management of low back pain. It is unlikely that a new and effective pharmacological intervention will be available for the management of low back pain in the following years. There are nonpharmacological options that probably provide benefits for chronic low back pain. Higher-quality randomised controlled trials are necessary to clarify the effects of nonpharmacological interventions on acute low back pain. Treatment optimisation for chronic low back pain depends on identifying new treatment targets and interventions. The identification of effective treatment targets requires high-quality mediation studies. The successful implementation of interventions with new treatment targets will depend on strategies to address common barriers to the acceptability of the treatment.

  • (2023) Chen, Wenting
    Thesis
    Hoarding disorder (HD) is associated with social impairment, including isolation, loneliness, and reduced social support. Social factors also play a role in the maintenance of hoarding symptoms. However, current treatments for HD do not include an interpersonal component. One potential treatment target for hoarding is empathy. Empathy is fundamental to the development of successful social bonds, and disrupted empathy has been implicated in the social difficulties in other disorders. As such, the aim of this current thesis is to explore the relationship between hoarding and empathy and examine whether empathy could be an interpersonal target in hoarding treatment. In Study 1, I investigated the relationship between hoarding and empathy in an unselected sample. Hoarding was positively associated with emotional contagion, a core component of emotional empathy, and negatively related to cognitive empathy. Self-reported emotional empathy and a behavioural measure of cognitive empathy predicted hoarding beyond depression, and a clinical subgroup of participants showed mild-to-moderate impairments in the behavioural cognitive empathy task. Studies 2-4 expanded upon these findings to investigate empathy-related concepts in relation to hoarding. In Study 2, I examined the relationship between hoarding with social motivation and social support, two variables that represent a predecessor and consequence of normal empathy development, respectively. Hoarding was associated with greater social anhedonia, enjoyment of both positive and negative social rewards, and reduced social support. In Study 3, I aimed to investigate if those with high and low hoarding symptoms differ in prosocial behaviour, a common behavioural component of empathy. No significant differences were found between groups. In Study 4, I aimed to clarify if hoarding was associated with experiences and expressions of anger. Dysregulations in emotional and cognitive empathy may reflect in unhelpful emotional and cognitive experiences of anger. Moreover, aggression is a common behavioural consequence of dysregulated empathy, so was potentially relevant to hoarding. Hoarding was positively associated with angry feelings, hostility, and direct aggression, as well as related concepts of angry rumination and displaced aggression. Lastly, Study 5 was a pilot intervention investigating a social cognition intervention for individuals diagnosed with HD. Participants showed improvements in primary outcomes of cognitive empathy and hostility bias and secondary outcomes of hoarding symptoms and loneliness from pre- to post-treatment. This dissertation provides preliminary evidence that empathy may represent a promising construct to improve the understanding and treatment of psychosocial difficulties in hoarding.

  • (2023) Sucquart, Irene
    Thesis
    Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age and the leading cause of anovulatory infertility. PCOS has a complicated pathophysiology that encompasses endocrine, reproductive, metabolic, and psychological traits. Hyperandrogenism is a key trait driving the pathogenesis of PCOS through androgen receptor related actions. The brain has recently been revealed as an important site of androgen action in PCOS. Currently, PCOS has no cure and treatment options are suboptimal and are all symptom based. PCOS significantly impacts a woman’s quality of life and therefore there is a necessity to understand the underlying mechanism of neural androgen signaling in PCOS in the hopes of finding a cure or effective therapeutic options. The main aim of this research was to investigate the involvement of different androgen mediated neuron pathways in the development of PCOS using an established PCOS androgenized mouse model. The first study investigated the effect of therapeutic inhibition of kisspeptin-neurokinin B- dynorphin (KNDy) neurons on the development of PCOS traits. The results revealed that inhibition of KNDy neuron activity ameliorated PCOS associated weight gain, adiposity and increased respiratory exchange ratio in the mouse model. The second study examined the role of androgen signaling gamma-aminobutyric acid (GABA) neurons in PCOS development using genetically modified GABA neuron androgen receptor (AR) knock-out mice. The findings revealed that the development of PCOS traits was not affected in these mice despite the lack of GABA AR signaling. The third chapter aimed to investigate the role of agouti-related protein (AgRP) expressing neurons in the pathogenesis of PCOS. In this study, AgRP neurons were chemogenetically inhibited following the establishment of PCOS traits in the mouse model. The study found that while overall AgRP inhibition did not impact PCOS trait development, the results suggest that a hyperandrogenic environment may disrupt the role of AgRP neurons in glucose metabolism and cholesterol homeostasis. Overall, these results support the use of targeted neuroendocrine therapies for PCOS, narrow down the likely neuron pathways involved in pathogenic androgen actions, and add to the growing knowledge of neuroendocrine androgen driven disruption in PCOS.

  • (2022) Das, Abhijit
    Thesis
    The homeostatic regulation of amino acid concentrations is crucial for optimal brain function and development. Different amino acid transporters at cell membranes work together to facilitate the movement of amino acids into and out of the brain. Despite countless in vitro and in vivo research on these amino acids' activities, many fundamental concerns about their metabolic function in different brain areas and pathophysiological conditions remain unanswered. In the framework of this thesis, the effects of exogenous administration of several non-essential amino acids and the participation of their specific transporters in brain metabolism were investigated in Guinea pig cortical brain slices and mouse brain tissues using a targeted neuropharmacological and metabolomic strategy. Alterations in brain metabolism were analyzed using 1H and 13C nuclear magnetic resonance spectroscopy to evaluate changes in metabolite pools and 13C-enriched substrates. All the amino acid transporters mentioned in this study were addressed by the existing solute carrier (SLC) gene nomenclature system for amino acid transporters. The effect of exogenous L-aspartate, L-ornithine, and their salt, L-aspartate-L-ornithine (LOLA), on brain metabolism was investigated with or without an intact blood-brain barrier (BBB). The results indicated that neither L-aspartate, L-ornithine, nor LOLA, affected brain metabolism with an intact BBB. In cortical tissue slices L-aspartate increased brain metabolism concentration-dependently, L-ornithine significantly slowed it at higher concentrations (100 μmol/L), and the effects of LOLA was largely dependent on the balance of its two constituent amino acids. D-aspartate, another isoform of aspartate, produced a range of metabolic impacts, particularly on glutamatergic and GABAergic systems, with varying concentrations. In principal component analysis, the effects of D-aspartate were clearly distinguished from those of L-aspartate, indicating a metabolic pattern distinct from that of excitatory mechanisms. L-Proline administration significantly inhibited brain metabolism in Guinea pig cortical tissue slices, indicating a GABA-like effect; however, it was not a significant metabolic substrate. While it was actively taken up by cells in a concentration-dependent manner but was not completely metabolized. The metabolic pattern revealed that L-proline's effects clustered with 3-aminopropyl(methyl)phosphinic acid (SKF 97541), GABA, 1,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA) and (5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepine-3-carboxylic acid) 1,1-dimethylethyl ester (RO194603) at lower concentrations (10 μmol/L) and with vigabatrin and RO194603 at higher concentrations (100 μmol/L); indicating that proline may act as a GABAB receptor agonist or GABAArho antagonist. Deletion of SLC6A17/NTT4 (neurotransmitter transporter 4) gene significantly impaired glutamate-glutamine cycle, reduced incorporation of 13C into Krebs cycle intermediates, and increased incorporation into lactate in the brain of mice lacking the gene. NTT4 knockout also altered several important metabolites in glutamatergic neurones, implying that it is a crucial transporter for maintaining brain amino acid homeostasis. Investigation of glutamine transport in cerebellum demonstrated that system A dominates glutamine transport in the cerebellum, with contributions from system N, which is inhibited by histidine and 2-(Methylamino)-2-methylpropionic acid (MeAIB) exerting the most metabolic influence. Inhibition of systems A and L by L-γ-Glutamyl-p-nitroanilide (GPNA) and 2-amino-4-bis(aryloxybenzyl)aminobutanoic acid (AABA) did not influence glutamine transport due to their low affinity for the transporters. Inhibition of systems L and B0 by 2-Aminobicyclo[2.2.1]heptane-2-carboxylic acid (BCH) showed little effect on fluxes from [1-13C]D-glucose but increased the flux of [1,2-13C]acetate into Glu C4,5 and Gln C4,5. Effects of cycloleucine were comparable to BCH but less powerful. This study provided new insight into the role of several non-essential amino acids in brain metabolism and also showed how brain metabolism is regulated in different brain regions.

  • (2023) Hagos, Amanuel Kidane
    Thesis
    In most developed countries, the rapid increase in the number of older incarcerated adults along with their complex health and social service needs has become a challenge for both correctional and health systems. Existing evidence consists of largely secondary data and addresses single issues such as mental health. The purpose of this body of work was to explore current practices in the care and management of older people in prison and those transitioning to community and provide recommendations for policy, practice, and future research in the field. The body of work employed a combination of exploratory sequential and concurrent mixed methods study design. The work started with a scoping review to identify international best practices in the care and management of older incarcerated adults. This review further informed two subsequent qualitative studies and a collective mixed methods case study in New South Wales, Australia. The two qualitative studies used focus group discussions with Corrective Services New South Wales (CSNSW) staff and applied thematic analysis to analyse the data. The collective mixed methods case study used interviews and online survey with CSNSW and Justice Health and Forensic Mental Health Network staff and older incarcerated adults. A constant comparative analysis was applied to analyse interviews using NVivo version 12. Qualtrics and SPSS version 26.0 were used to administer and analyse the quantitative data. The series of studies in this thesis have resulted to key empirical and conceptual contributions including: i) best practices to optimise the care and management of older incarcerated adults in mainstream prisons, ii) barriers and enablers to in-prison care and the transition to community, iii) attributes of competing logics (e.g. differing power and priorities) between health and custody in the care and management of older incarcerated adults, iv) sub-optimal application of the principles of equivalence of care, v) weak communication and relationships among prison staff (Relational Coordination index of 2.9 (SD = 0.7), and vi) ad hoc approaches to the care and management of the older incarcerated adult population. In a summary, the evidence from this body of work revealed that the care and management of older incarcerated adults operates through an intersecting triad of correctional safety and security requirements, prison health services ethos and older incarcerated adults’ needs where safety and security considerations take precedence over health services, limiting older incarcerated adults’ involvement and preferences and compromising equivalence of care. More collaborative work between health and custody can improve the organisation and provision of care to older incarcerated adults and achieve equivalence of care in correctional centres.