1,506 research outputs found
Effects of municipal smoke-free ordinances on secondhand smoke exposure in the Republic of Korea
ObjectiveTo reduce premature deaths due to secondhand smoke (SHS) exposure among non-smokers, the Republic of Korea (ROK) adopted changes to the National Health Promotion Act, which allowed local governments to enact municipal ordinances to strengthen their authority to designate smoke-free areas and levy penalty fines. In this study, we examined national trends in SHS exposure after the introduction of these municipal ordinances at the city level in 2010.MethodsWe used interrupted time series analysis to assess whether the trends of SHS exposure in the workplace and at home, and the primary cigarette smoking rate changed following the policy adjustment in the national legislation in ROK. Population-standardized data for selected variables were retrieved from a nationally representative survey dataset and used to study the policy action’s effectiveness.ResultsFollowing the change in the legislation, SHS exposure in the workplace reversed course from an increasing (18% per year) trend prior to the introduction of these smoke-free ordinances to a decreasing (−10% per year) trend after adoption and enforcement of these laws (β2 = 0.18, p-value = 0.07; β3 = −0.10, p-value = 0.02). SHS exposure at home (β2 = 0.10, p-value = 0.09; β3 = −0.03, p-value = 0.14) and the primary cigarette smoking rate (β2 = 0.03, p-value = 0.10; β3 = 0.008, p-value = 0.15) showed no significant changes in the sampled period. Although analyses stratified by sex showed that the allowance of municipal ordinances resulted in reduced SHS exposure in the workplace for both males and females, they did not affect the primary cigarette smoking rate as much, especially among females.ConclusionStrengthening the role of local governments by giving them the authority to enact and enforce penalties on SHS exposure violation helped ROK to reduce SHS exposure in the workplace. However, smoking behaviors and related activities seemed to shift to less restrictive areas such as on the streets and in apartment hallways, negating some of the effects due to these ordinances. Future studies should investigate how smoke-free policies beyond public places can further reduce the SHS exposure in ROK
Analytical validation of innovative magneto-inertial outcomes: a controlled environment study.
peer reviewe
Evaluating Symbolic AI as a Tool to Understand Cell Signalling
The diverse and highly complex nature of modern phosphoproteomics research produces a high volume of data. Chemical phosphoproteomics especially, is amenable to a variety of analytical approaches. In this thesis we evaluate novel Symbolic AI based algorithms as potential tools in the analysis of cell signalling. Initially we developed a first order deductive, logic-based model. This allowed us to identify previously unreported inhibitor-kinase relationships which could offer novel therapeutic targets for further investigation. Following this we made use of the probabilistic reasoning of ProbLog to augment the aforementioned Prolog based model with an intuitively calculated degree of belief. This allowed us to rank previous associations while also further increasing our confidence in already established predictions. Finally we applied our methodology to a Saccharomyces cerevisiae gene perturbation, phosphoproteomics dataset. In this context we were able to confirm the majority of ground truths, i.e. gene deletions as having taken place as intended. For the remaining deletions, again using a purely symbolic based approach we were able to provide predictions on the rewiring of kinase based signalling networks following kinase encoding gene deletions. The explainable, human readable and white-box nature of this approach were highlighted, however its brittleness due to missing, inconsistent or conflicting background knowledge was also examined
Comparative genomics of recent adaptation in Candida pathogens
[eng] Fungal infections pose a serious health threat, affecting >1,000 million people and causing ~1.5 million deaths each year. The problem is growing due to insufficient diagnostic and therapeutic options, increased number of susceptible patients, expansion of pathogens partly linked to climate change and the rise of antifungal drug resistance. Among other fungal pathogens, Candida species are a major cause of severe hospital-acquired infections, with high mortality in immunocompromised patients. Various Candida pathogens constitute a public health issue, which require further efforts to develop new drugs, optimize currently available treatments and improve diagnostics. Given the high dynamism of Candida genomes, a promising strategy to improve current therapies and diagnostics is to understand the evolutionary mechanisms of adaptation to antifungal drugs and to the human host. Previous work using in vitro evolution, population genomics, selection inferences and Genome Wide Association Studies (GWAS) have partially clarified such recent adaptation, but various open questions remain. In the three research articles that conform this PhD thesis we addressed some of these gaps from the perspective of comparative genomics.
First, we addressed methodological issues regarding the analysis of Candida genomes. Studying recent adaptation in these pathogens requires adequate bioinformatic tools for variant calling, filtering and functional annotation. Among other reasons, current methods are suboptimal due to limited accuracy to identify structural variants from short read sequencing data. In addition, there is a need for easy-to-use, reproducible variant calling pipelines. To address these gaps we developed the “personalized Structural Variation detection” pipeline (perSVade), a framework to call, filter and annotate several variant types, including structural variants, directly from reads. PerSVade enables accurate identification of structural variants in any species of interest, such as Candida pathogens. In addition, our tool automatically predicts the structural variant calling accuracy on simulated genomes, which informs about the reliability of the calling process. Furthermore, perSVade can be used to analyze single nucleotide polymorphisms and copy number-variants, so that it facilitates multi-variant, reproducible genomic studies. This tool will likely boost variant analyses in Candida pathogens and beyond.
Second, we addressed open questions about recent adaptation in Candida, using perSVade for variant identification. On the one hand, we investigated the evolutionary mechanisms of drug resistance in Candida glabrata. For this, we used a large-scale in vitro evolution experiment to study adaptation to two commonly-used antifungals: fluconazole and anidulafungin. Our results show rapid adaptation to one or both drugs, with moderate fitness costs and through few mutations in a narrow set of genes. In addition, we characterize a novel role of ERG3 mutations in cross-resistance towards fluconazole in
anidulafungin-adapted strains. These findings illuminate the mutational paths leading to drug resistance and cross-resistance in Candida pathogens. On the other hand, we reanalyzed ~2,000 public genomes and phenotypes to understand the signs of recent selection and drug resistance in six major Candida species: C. auris, C. glabrata, C. albicans, C. tropicalis, C. parapsilosis and C. orthopsilosis. We found hundreds of genes under recent selection, suggesting that clinical adaptation is diverse and complex. These involve species-specific but also convergently affected processes, such as cell adhesion, which could underlie conserved adaptive mechanisms. In addition, using GWAS we predicted known drivers of antifungal resistance alongside potentially novel players. Furthermore, our analyses reveal an important role of generally-overlooked structural variants, and suggest an unexpected involvement of (para)sexual recombination in the spread of resistance. Taken together, our findings provide novel insights on how Candida pathogens adapt to human-related environments and suggest candidate genes that deserve future attention. In summary, the results of this thesis improve our knowledge about the mechanisms of recent adaptation in Candida pathogens, which may enable improved therapeutic and diagnostic applications.[cat] Les infeccions fúngiques representen una greu amenaça per a la salut, afectant a més de 1.000 milions de persones i causant aproximadament 1,5 milions de morts cada any. El problema està augmentant a causa d’unes opcions terapèutiques i diagnòstiques insuficients, l'increment del nombre de pacients susceptibles, l'expansió dels patògens parcialment vinculada al canvi climàtic i l'augment de la resistència als fàrmacs antifúngics. D’entre diversos fongs patògens, els llevats del gènere Candida són una causa important d'infeccions nosocomials, amb una alta mortalitat en pacients immunodeprimits. Diverses espècies de Candida constitueixen un problema de salut pública, cosa que requereix més esforços per a desenvolupar nous medicaments, optimitzar els tractaments disponibles i millorar els diagnòstics. Tenint en compte el dinamisme genòmic d’aquests patògens, una estratègia prometedora per millorar les teràpies i diagnòstics actuals és comprendre els mecanismes evolutius d'adaptació als fàrmacs antifúngics i a l’hoste humà. Treballs anteriors utilitzant l'evolució in vitro, la genòmica de poblacions, les inferències de selecció i els estudis d'associació de genoma complet (GWAS, per les sigles en anglès) han aclarit parcialment aquesta adaptació recent, però encara hi ha diverses preguntes obertes. En els tres articles que conformen aquesta tesi doctoral, hem abordat algunes d'aquestes preguntes des de la perspectiva de la genòmica comparativa.
En primer lloc, hem abordat qüestions metodològiques relatives a l'anàlisi dels genomes de les espècies Candida. L'estudi de l'adaptació recent en aquests patògens requereix eines bioinformàtiques adequades per a la detecció, filtratge i anotació funcional de variants genètiques. Entre altres raons, els mètodes actuals són subòptims a causa de la limitada precisió per identificar variants estructurals a partir de dades de seqüenciació amb lectures curtes. A més, hi ha una necessitat d’eines computacionals per a la detecció de variants que siguin senzilles d'utilitzar i reproduibles. Per abordar aquestes mancances, hem desenvolupat el mètode bioinformàtic "personalized Structural Variation detection" (perSVade), una eina que permet la detecció, filtratge i anotació de diversos tipus de variants, incloent-hi les variants estructurals, directament des de les lectures. PerSVade permet la identificació precisa de les variants estructurals en qualsevol espècie d'interès, com ara els patògens Candida. A més, la nostra eina prediu automàticament la precisió de la detecció d’aquestes variants en genomes simulats, la qual cosa informa sobre la fiabilitat del procés. Finalment, perSVade es pot utilitzar per analitzar altres tipus de variants, com els polimorfismes de nucleòtid únic o els canvis en el nombre de còpies, facilitant així estudis genòmics integrals i reproduibles. Aquesta eina probablement impulsarà les anàlisis genòmiques en els patògens Candida i també en altres espècies.
En segon lloc, hem abordat algunes de les preguntes obertes sobre l'adaptació recent en els llevats Candida, utilitzant perSVade per a la identificació de variants. D'una banda, hem investigat els mecanismes evolutius de resistència als fàrmacs antifúngics en Candida glabrata. Per a això, hem utilitzat un experiment
d'evolució in vitro a gran escala per estudiar l'adaptació a dos antifúngics comuns: el fluconazol i l’anidulafungina. Els nostres resultats mostren una adaptació ràpida a un o ambdós fàrmacs, amb un cost per al creixement moderat i a través de poques mutacions en un nombre reduït de gens. A més, hem caracteritzat un paper nou de les mutacions en ERG3 en la resistència creuada al fluconazol en soques adaptades a anidulafungina. Aquests descobriments aclareixen els processos mutacionals que condueixen a la resistència als fàrmacs i a la resistència creuada en els patògens Candida. D'altra banda, hem re-analitzat aproximadament 2.000 genomes i fenotips disponibles en repositoris públics per a comprendre els senyals genòmics de selecció recent i de resistència a fàrmacs antifúngics, en sis espècies rellevants de Candida: C. auris, C. glabrata, C. albicans, C. tropicalis, C. parapsilosis i C. orthopsilosis. Hem trobat centenars de gens sota selecció recent, suggerint que l'adaptació clínica és diversa i complexa. Aquests gens estan relacionats amb funcions específiques de cada espècie, però també trobem processos alterats de manera similar en diferents patògens, com per exemple l’adhesió cel·lular, cosa que indica fenòmens d’adaptació conservats. A part, utilitzant GWAS hem predit mecanismes esperats de resistència a antifúngics i també possibles nous factors. A més, les nostres anàlisis revelen un paper important de les variants estructurals, generalment poc estudiades, i suggereixen una implicació inesperada de la recombinació (para)sexual en la propagació de la resistència. En conjunt, els nostres descobriments proporcionen noves perspectives sobre com els patògens Candida s'adapten als entorns humans, i suggereixen gens candidats que mereixen investigacions futures. En resum, els resultats d’aquesta tesi milloren el nostre coneixement sobre els mecanismes d'adaptació recent en els patògens Candida, cosa que pot permetre el disseny de noves teràpies i diagnòstics
Digital Traces of the Mind::Using Smartphones to Capture Signals of Well-Being in Individuals
General context and questions Adolescents and young adults typically use their smartphone several hours a day. Although there are concerns about how such behaviour might affect their well-being, the popularity of these powerful devices also opens novel opportunities for monitoring well-being in daily life. If successful, monitoring well-being in daily life provides novel opportunities to develop future interventions that provide personalized support to individuals at the moment they require it (just-in-time adaptive interventions). Taking an interdisciplinary approach with insights from communication, computational, and psychological science, this dissertation investigated the relation between smartphone app use and well-being and developed machine learning models to estimate an individual’s well-being based on how they interact with their smartphone. To elucidate the relation between smartphone trace data and well-being and to contribute to the development of technologies for monitoring well-being in future clinical practice, this dissertation addressed two overarching questions:RQ1: Can we find empirical support for theoretically motivated relations between smartphone trace data and well-being in individuals? RQ2: Can we use smartphone trace data to monitor well-being in individuals?Aims The first aim of this dissertation was to quantify the relation between the collected smartphone trace data and momentary well-being at the sample level, but also for each individual, following recent conceptual insights and empirical findings in psychological, communication, and computational science. A strength of this personalized (or idiographic) approach is that it allows us to capture how individuals might differ in how smartphone app use is related to their well-being. Considering such interindividual differences is important to determine if some individuals might potentially benefit from spending more time on their smartphone apps whereas others do not or even experience adverse effects. The second aim of this dissertation was to develop models for monitoring well-being in daily life. The present work pursued this transdisciplinary aim by taking a machine learning approach and evaluating to what extent we might estimate an individual’s well-being based on their smartphone trace data. If such traces can be used for this purpose by helping to pinpoint when individuals are unwell, they might be a useful data source for developing future interventions that provide personalized support to individuals at the moment they require it (just-in-time adaptive interventions). With this aim, the dissertation follows current developments in psychoinformatics and psychiatry, where much research resources are invested in using smartphone traces and similar data (obtained with smartphone sensors and wearables) to develop technologies for detecting whether an individual is currently unwell or will be in the future. Data collection and analysis This work combined novel data collection techniques (digital phenotyping and experience sampling methodology) for measuring smartphone use and well-being in the daily lives of 247 student participants. For a period up to four months, a dedicated application installed on participants’ smartphones collected smartphone trace data. In the same time period, participants completed a brief smartphone-based well-being survey five times a day (for 30 days in the first month and 30 days in the fourth month; up to 300 assessments in total). At each measurement, this survey comprised questions about the participants’ momentary level of procrastination, stress, and fatigue, while sleep duration was measured in the morning. Taking a time-series and machine learning approach to analysing these data, I provide the following contributions: Chapter 2 investigates the person-specific relation between passively logged usage of different application types and momentary subjective procrastination, Chapter 3 develops machine learning methodology to estimate sleep duration using smartphone trace data, Chapter 4 combines machine learning and explainable artificial intelligence to discover smartphone-tracked digital markers of momentary subjective stress, Chapter 5 uses a personalized machine learning approach to evaluate if smartphone trace data contains behavioral signs of fatigue. Collectively, these empirical studies provide preliminary answers to the overarching questions of this dissertation.Summary of results With respect to the theoretically motivated relations between smartphone trace data and wellbeing (RQ1), we found that different patterns in smartphone trace data, from time spent on social network, messenger, video, and game applications to smartphone-tracked sleep proxies, are related to well-being in individuals. The strength and nature of this relation depends on the individual and app usage pattern under consideration. The relation between smartphone app use patterns and well-being is limited in most individuals, but relatively strong in a minority. Whereas some individuals might benefit from using specific app types, others might experience decreases in well-being when spending more time on these apps. With respect to the question whether we might use smartphone trace data to monitor well-being in individuals (RQ2), we found that smartphone trace data might be useful for this purpose in some individuals and to some extent. They appear most relevant in the context of sleep monitoring (Chapter 3) and have the potential to be included as one of several data sources for monitoring momentary procrastination (Chapter 2), stress (Chapter 4), and fatigue (Chapter 5) in daily life. Outlook Future interdisciplinary research is needed to investigate whether the relationship between smartphone use and well-being depends on the nature of the activities performed on these devices, the content they present, and the context in which they are used. Answering these questions is essential to unravel the complex puzzle of developing technologies for monitoring well-being in daily life.<br/
Machine Learning Approaches for the Prioritisation of Cardiovascular Disease Genes Following Genome- wide Association Study
Genome-wide association studies (GWAS) have revealed thousands of genetic loci, establishing itself as a valuable method for unravelling the complex biology of many diseases. As GWAS has grown in size and improved in study design to detect effects, identifying real causal signals, disentangling from other highly correlated markers associated by linkage disequilibrium (LD) remains challenging. This has severely limited GWAS findings and brought the method’s value into question. Although thousands of disease susceptibility loci have been reported, causal variants and genes at these loci remain elusive. Post-GWAS analysis aims to dissect the heterogeneity of variant and gene signals. In recent years, machine learning (ML) models have been developed for post-GWAS prioritisation. ML models have ranged from using logistic regression to more complex ensemble models such as random forests and gradient boosting, as well as deep learning models (i.e., neural networks). When combined with functional validation, these methods have shown important translational insights, providing a strong evidence-based approach to direct post-GWAS research. However, ML approaches are in their infancy across biological applications, and as they continue to evolve an evaluation of their robustness for GWAS prioritisation is needed. Here, I investigate the landscape of ML across: selected models, input features, bias risk, and output model performance, with a focus on building a prioritisation framework that is applied to blood pressure GWAS results and tested on re-application to blood lipid traits
An evaluation of the role of biomarkers in Alzheimer’s disease and age-related cognitive decline
An ageing population will lead to an increase in age-related cognitive decline and
dementia syndromes such as Alzheimer’s disease (AD), which can seriously limit an
individual’s independence and quality of life. Identifying biomarkers associated with
cognitive impairment in both ageing and AD are needed as they will improve our
understanding of underlying pathophysiology and may eventually improve prognoses
via the identification of at-risk individuals and the development of novel therapeutics.
Several pathological changes in the brain which are typically seen in AD can be
detected in the cerebrospinal fluid (CSF) and plasma of middle- and late-life adults
without dementia. Previous work has identified associations between CSF markers
and cognitive functions, although a synthesis of the large number of studies is needed.
Furthermore CSF marker levels may also differ with AD risk factors, however evidence
is mixed. Increasingly, research has shifted to focus on blood-based biomarkers which
provide the benefit of being less invasive and more accessible. Several plasma
biomarkers have been associated with cognitive functions in ageing, although few
studies use appropriate cognitive tests, and even fewer have examined these proteins
in the brain. There remains no gold-standard biomarkers associated with cognitive
functions in either AD or age-related cognitive decline, therefore additional
approaches are needed to fully understand their relationship. The aims of the current
thesis are to: investigate CSF biomarkers associated with cognition in dementia and
ageing; assess the relationship between CSF biomarkers and AD risk factors;
examine whether plasma biomarkers are associated with age-related cognitive
decline; and lastly, to examine the level of proteins (which have previously been
investigated as biomarkers) in post-mortem brain tissue.
Cerebrospinal fluid biomarkers associated with cognition have been investigated
across a range of dementia syndromes and age-related cognitive decline. While much
of the work has focused on tau and amyloid-beta (Aβ), there is burgeoning research
around markers such as neurogranin and neurofilament-light. Due to a wide range of
markers investigated across several dementia syndromes and ageing, the roles of
each marker are less clear. Therefore, a systematic review was conducted examining
the association between CSF synaptic/axonal markers, and cognitive functions across
dementia syndromes and typical ageing. Sixty-seven studies were included in the
review in Chapter 3. Despite substantial heterogeneity in the field, there was evidence
for an association between CSF neurofilament-light and cognition in AD,
frontotemporal dementia, and typical cognitive ageing. Cerebrospinal fluid
neurogranin tended to be associated with cognition in those with CSF tau and CSF
Aβ profiles indicative of AD.
Chapter 4 focuses on the interaction between Apolipoprotein E (APOE) and sex on
CSF tau levels in a middle-life cohort without dementia. Females account for an
estimated 60% of those diagnosed with AD and the APOE4 allele is widely recognised
to be the strongest genetic risk factor for late-onset AD. However, evidence for the
interaction between these two risk factors is mixed. In this chapter, a significant
interaction between APOE, sex, and CSF AD biomarkers was found, suggesting that
tau accumulation may be independent of Ab in females, but not males. This has
potential implications for the implementation of CSF AD biomarkers in clinical practice
and pharmacological interventions which target cortical Ab.
Chapter 5 focuses on the relationship between plasma biomarkers and cognitive
functions in typical ageing. Previous studies have focused on this relationship,
however, few use appropriate cognitive tests for a sample without dementia. In this
chapter, the association between cognitive ability and plasma phosphor-tau 181 (ptau181),
Ab, neurofilament-light (NfL), and glial fibrillary acidic protein (GFAP) were
investigated in the Lothian Birth Cohort 1936. A significant relationship was observed
between baseline p-tau181, NfL, GFAP and cognitive decline up to ~ 10-years later.
Further, increasing levels of p-tau181 over time were associated with steeper cognitive
decline. The results of this chapter suggest that plasma p-tau181, NfL, and GFAP may
be useful biomarkers of age-related cognitive decline.
In Chapter 6, several of the aforementioned markers that were previously investigated
in the CSF and plasma are examined in post-mortem brain tissue. While previous
work has focused on these markers in the CSF and plasma, few studies have
investigated them in post-mortem tissue and how levels differ between AD and
typically ageing participants. Relative differences in neurogranin, p-tau181, p-tau231,
total tau, and SNAP-25 were examined by western blot in AD cases, healthy ageing
cases, and mid-life cases. The results of this chapter provide evidence of a reduction
of neurogranin and SNAP-25 at the synapse in AD, as well as an increase of p-tau231.
This suggests that the elevations of CSF neurogranin, SNAP-25, and p-tau231 seen
in AD may reflect both the loss of neurogranin/SNAP-25 and the accumulation of ptau231
in synapses.
The final chapter of the thesis summarise the findings of the previous chapters, their
limitations, and the impact of this work on the field
The efficacy of a language intervention on the acquisition of past tense in children with Down syndrome
Background: Individuals with Down syndrome (DS) experience difficulties with receptive and expressive grammar and specifically morphosyntax. Despite these difficulties, there have been few studies to evaluate the effectiveness of intervention and limited evidence of generalisation to untaught items. /
Aim: To evaluate the efficacy of a language intervention on the acquisition of the regular simple past tense (RSPT) in children with DS aged 7-11 years and to explore whether any gains in the use of this grammatical rule will generalise. /
Method: A randomised controlled trial evaluated a 10-week intervention, using explicit and implicit methods, designed for children with DS. Fifty-two children with DS aged 7-11 years were randomly allocated into two groups: 1) intervention group and 2) delayed intervention group. All children were assessed at three timepoints: preintervention (t1), after the intervention group had received the intervention (t2), and 12-14 weeks later (after the delayed intervention group had received the intervention) (t3). The intervention was delivered by trained teaching assistants (TAs) in daily 20-minute sessions. /
Results: The intervention group made significantly greater gains at t2 on a composite measure of the use of the RSPT (d=1.63). These gains were maintained 12-14 weeks later at t3 when the delayed intervention group also made similar gains. The use of the RSPT generalised to untaught regular verbs. In addition, the children made errors of overregularisation on irregular verbs demonstrating they had learnt the grammatical rule. Generalisation to other tense morphemes (e.g., the third person singular) did not occur. /
Conclusions: An intervention, using explicit and implicit methods, was successful in teaching children with DS to use a grammatical rule. Furthermore, the children were able to generalise this rule to untaught items. This provides evidence for intervention targeting morphosyntax and the feasibility of training TAs to deliver this intervention
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