7,245 research outputs found

    Mathematical models to evaluate the impact of increasing serotype coverage in pneumococcal conjugate vaccines

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    Of over 100 serotypes of Streptococcus pneumoniae, only 7 were included in the first pneumo- coccal conjugate vaccine (PCV). While PCV reduced the disease incidence, in part because of a herd immunity effect, a replacement effect was observed whereby disease was increasingly caused by serotypes not included in the vaccine. Dynamic transmission models can account for these effects to describe post-vaccination scenarios, whereas economic evaluations can enable decision-makers to compare vaccines of increasing valency for implementation. This thesis has four aims. First, to explore the limitations and assumptions of published pneu- mococcal models and the implications for future vaccine formulation and policy. Second, to conduct a trend analysis assembling all the available evidence for serotype replacement in Europe, North America and Australia to characterise invasive pneumococcal disease (IPD) caused by vaccine-type (VT) and non-vaccine-types (NVT) serotypes. The motivation behind this is to assess the patterns of relative abundance in IPD cases pre- and post-vaccination, to examine country-level differences in relation to the vaccines employed over time since introduction, and to assess the growth of the replacement serotypes in comparison with the serotypes targeted by the vaccine. The third aim is to use a Bayesian framework to estimate serotype-specific invasiveness, i.e. the rate of invasive disease given carriage. This is useful for dynamic transmission modelling, as transmission is through carriage but a majority of serotype-specific pneumococcal data lies in active disease surveillance. This is also helpful to address whether serotype replacement reflects serotypes that are more invasive or whether serotypes in a specific location are equally more invasive than in other locations. Finally, the last aim of this thesis is to estimate the epidemiological and economic impact of increas- ing serotype coverage in PCVs using a dynamic transmission model. Together, the results highlight that though there are key parameter uncertainties that merit further exploration, divergence in serotype replacement and inconsistencies in invasiveness on a country-level may make a universal PCV suboptimal.Open Acces

    Full stack development toward a trapped ion logical qubit

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    Quantum error correction is a key step toward the construction of a large-scale quantum computer, by preventing small infidelities in quantum gates from accumulating over the course of an algorithm. Detecting and correcting errors is achieved by using multiple physical qubits to form a smaller number of robust logical qubits. The physical implementation of a logical qubit requires multiple qubits, on which high fidelity gates can be performed. The project aims to realize a logical qubit based on ions confined on a microfabricated surface trap. Each physical qubit will be a microwave dressed state qubit based on 171Yb+ ions. Gates are intended to be realized through RF and microwave radiation in combination with magnetic field gradients. The project vertically integrates software down to hardware compilation layers in order to deliver, in the near future, a fully functional small device demonstrator. This thesis presents novel results on multiple layers of a full stack quantum computer model. On the hardware level a robust quantum gate is studied and ion displacement over the X-junction geometry is demonstrated. The experimental organization is optimized through automation and compressed waveform data transmission. A new quantum assembly language purely dedicated to trapped ion quantum computers is introduced. The demonstrator is aimed at testing implementation of quantum error correction codes while preparing for larger scale iterations.Open Acces

    Unraveling the effect of sex on human genetic architecture

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    Sex is arguably the most important differentiating characteristic in most mammalian species, separating populations into different groups, with varying behaviors, morphologies, and physiologies based on their complement of sex chromosomes, amongst other factors. In humans, despite males and females sharing nearly identical genomes, there are differences between the sexes in complex traits and in the risk of a wide array of diseases. Sex provides the genome with a distinct hormonal milieu, differential gene expression, and environmental pressures arising from gender societal roles. This thus poses the possibility of observing gene by sex (GxS) interactions between the sexes that may contribute to some of the phenotypic differences observed. In recent years, there has been growing evidence of GxS, with common genetic variation presenting different effects on males and females. These studies have however been limited in regards to the number of traits studied and/or statistical power. Understanding sex differences in genetic architecture is of great importance as this could lead to improved understanding of potential differences in underlying biological pathways and disease etiology between the sexes and in turn help inform personalised treatments and precision medicine. In this thesis we provide insights into both the scope and mechanism of GxS across the genome of circa 450,000 individuals of European ancestry and 530 complex traits in the UK Biobank. We found small yet widespread differences in genetic architecture across traits through the calculation of sex-specific heritability, genetic correlations, and sex-stratified genome-wide association studies (GWAS). We further investigated whether sex-agnostic (non-stratified) efforts could potentially be missing information of interest, including sex-specific trait-relevant loci and increased phenotype prediction accuracies. Finally, we studied the potential functional role of sex differences in genetic architecture through sex biased expression quantitative trait loci (eQTL) and gene-level analyses. Overall, this study marks a broad examination of the genetics of sex differences. Our findings parallel previous reports, suggesting the presence of sexual genetic heterogeneity across complex traits of generally modest magnitude. Furthermore, our results suggest the need to consider sex-stratified analyses in future studies in order to shed light into possible sex-specific molecular mechanisms

    Graphical scaffolding for the learning of data wrangling APIs

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    In order for students across the sciences to avail themselves of modern data streams, they must first know how to wrangle data: how to reshape ill-organised, tabular data into another format, and how to do this programmatically, in languages such as Python and R. Despite the cross-departmental demand and the ubiquity of data wrangling in analytical workflows, the research on how to optimise the instruction of it has been minimal. Although data wrangling as a programming domain presents distinctive challenges - characterised by on-the-fly syntax lookup and code example integration - it also presents opportunities. One such opportunity is how tabular data structures are easily visualised. To leverage the inherent visualisability of data wrangling, this dissertation evaluates three types of graphics that could be employed as scaffolding for novices: subgoal graphics, thumbnail graphics, and parameter graphics. Using a specially built e-learning platform, this dissertation documents a multi-institutional, randomised, and controlled experiment that investigates the pedagogical effects of these. Our results indicate that the graphics are well-received, that subgoal graphics boost the completion rate, and that thumbnail graphics improve navigability within a command menu. We also obtained several non-significant results, and indications that parameter graphics are counter-productive. We will discuss these findings in the context of general scaffolding dilemmas, and how they fit into a wider research programme on data wrangling instruction

    Endogenous mechanisms of vascular regeneration following myocardial infarction

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    Ischaemic heart disease remains one of the leading causes of death worldwide, responsible for over 8.9 million deaths in 2017 according to the Global Burden of Disease Study. Restoring blood perfusion in the ischaemic border via a functional vascular network may enhance myocardial perfusion, limit infarct expansion and promote cardiac regeneration. However, the pathways driving endogenous vascular regeneration following myocardial infarction (MI) remain poorly understood. The aim of this thesis was twofold; First, to investigate the origin and clonal dynamics of cardiac endothelial cells (EC) post-MI. Secondly, to analyse the transcriptional profiles of pro-angiogenic EC in MI using single cell RNA sequencing in the post-ischaemic adult mouse heart, and investigate potential therapeutic targets in human patient samples. MI was induced in an EC-specific multispectral lineage-tracing mouse, “Pdgfb-iCreERT2-Brainbow2.1”, by permanent ligation of the left anterior descending coronary artery. Blood vessel formation via clonal proliferation by resident Pdgfb-lineage EC was significantly upregulated in the ischaemic border at 7 days post-MI, compared to the healthy heart. Minimal contribution from the bone marrow was observed. Bioinformatics analyses revealed 10 transcriptionally discrete heterogeneous EC states in the 7 days post-MI heart and revealed molecular pathways through which each cluster was likely to mediate neovasculogenesis following MI. Plasmalemma Vesicle–Associated Protein (Plvap) gene expression was upregulated in MI, specifically in clusters of cells from the MI group, indicating its potential relevance to neovasculogenic pathways. I validated increased Plvap expression at the protein level, which was EC-specific and was significantly higher in the infarct border of the post-ischaemic mouse heart compared to the healthy heart. PLVAP expression was also significantly increased in EC adjacent to regions of fibrosis and scarring in the ischaemic human heart, compared to healthy human hearts. Moreover, in vitro silencing using RNAi in human umbilical vein ECs showed that PLVAP may play a direct functional role in regulating EC proliferation. The single cell gene expression atlas of cardiac resident ECs presented in this thesis can be used to unravel the neovasculogenesis pathways that are activated 7 days post-MI. Cluster specific PLVAP was identified as a possible target for augmenting endogenous myocardial perfusion following ischaemia and validated in human cardiac ischaemic tissue. Future studies will involve further interrogation of the activated neovasculogenesis pathways from cardiac ECs using the single cell gene expression atlas as well as investigation of the molecular mechanisms of the role of PLVAP in EC proliferation

    The applied psychology of addictive orientations : studies in a 12-step treatment context.

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    The clinical data for the studies was collected at The PROMIS Recovery Centre, a Minnesota Model treatmentc entre for addictions,w hich encouragesth e membership and use of the 12 step Anonymous Fellowships, and is abstinence based. The area of addiction is contextualised in a review chapter which focuses on research relating to the phenomenon of cross addiction. A study examining the concept of "addictive orientations" in male and female addicts is described, which develops a study conductedb y StephensonM, aggi, Lefever, & Morojele (1995). This presents study found a four factor solution which appeared to be subdivisions of the previously found Hedonism and Nurturance factors. Self orientated nurturance (both food dimensions, shopping and caffeine), Other orientated nurturance (both compulsive helping dimensions and work), Sensation seeking hedonism (Drugs, prescription drugs, nicotine and marginally alcohol), and Power related hedonism (Both relationship dimensions, sex and gambling. This concept of "addictive orientations" is further explored in a non-clinical population, where again a four factor solution was found, very similar to that in the clinical population. This was thought to indicate that in terms of addictive orientation a pattern already exists in this non-clinical population and that consideration should be given to why this is the case. These orientations are examined in terms of gender differences. It is suggested that the differences between genders reflect power-related role relationships between the sexes. In order to further elaborate the significance and meaning behind these orientations, the next two chapters look at the contribution of personality variables and how addictive orientations relate to psychiatric symptomatology. Personality variables were differentially, and to a considerable extent predictably involved with the four factors for both males and females.Conscientiousness as positively associated with "Other orientated Nurturance" and negatively associated with "Sensation seeking hedonism" (particularly for men). Neuroticism had a particularly strong association with the "Self orientated Nurturance" factor in the female population. More than twice the symptomatology variance was explained by the factor scores for females than it was for males. The most important factorial predictors for psychiatric symptomatology were the "Power related hedonism" factor for males, and "Self oriented nurturance" for females. The results are discussed from theoretical and treatment perspectives

    Effects of spatial and temporal heterogeneity on the genetic diversity of the alpine butterfly Parnassius smintheus

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    Genetic diversity represents a population’s evolutionary potential, as well as its demographic and evolutionary history. Advances in DNA sequencing have allowed the development of new and potentially powerful methods to quantify this diversity. However, when using these methods best practices for sampling populations and analyzing data are still being developed. Furthermore, while effects of the landscape on spatial patterns of genetic variation have received considerable attention, we have a poorer understanding of how genetic diversity changes as a result of temporal variation in environmental and demographic variables. Here, I take advantage of advances in DNA sequencing to investigate genetic diversity at single nucleotide polymorphisms (SNPs) across space and time in a model system of the butterfly, Parnassius smintheus. I used double digest restriction site associated DNA sequencing to genotype SNPs in P. smintheus from populations in Alberta, Canada. To develop recommendations for analyzing data, I tested the effect of varying the maximum amount of missing data (and therefore the number of SNPs) on common population genetic analyses. Most analyses were robust to varying amounts of missing data, except for population assignment tests where larger datasets (with more missing data) revealed higher-resolution population structure. I also examined the effect of sample size on the same set of analyses, finding that some (e.g., estimation of genetic differentiation) required as few as five individuals per population, while others (e.g., population assignment) required at least 15. I used the SNP dataset to investigate factors shaping patterns of genetic diversity at different spatial scales and across time. At a larger spatial scale but a single time point, both weather (snow depth and mean minimum temperatures) and land cover (the distance between meadow patches) predicted genetic diversity and differentiation. At a smaller spatial but longer temporal scale, I used a smaller SNP dataset to show that genetic diversity is lost over repeated demographic bottlenecks driven by winter weather, and subsequently recovered through gene flow. My work contributes to understanding how genetic diversity is shaped in natural populations, and points to the importance of both land cover and weather (and specifically, variability in weather) to this process
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