10,549 research outputs found

    Computertomographie-basierte Bestimmung von Aortenklappenkalk und seine Assoziation mit Komplikationen nach interventioneller Aortenklappenimplantation (TAVI)

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    Background: Severe aortic valve calcification (AVC) has generally been recognized as a key factor in the occurrence of adverse events after transcatheter aortic valve implantation (TAVI). To date, however, a consensus on a standardized calcium detection threshold for aortic valve calcium quantification in contrast-enhanced computed tomography angiography (CTA) is still lacking. The present thesis aimed at comparing two different approaches for quantifying AVC in CTA scans based on their predictive power for adverse events and survival after a TAVI procedure.   Methods: The extensive dataset of this study included 198 characteristics for each of the 965 prospectively included patients who had undergone TAVI between November 2012 and December 2019 at the German Heart Center Berlin (DHZB). AVC quantification in CTA scans was performed at a fixed Hounsfield Unit (HU) threshold of 850 HU (HU 850 approach) and at a patient-specific threshold, where the HU threshold was set by multiplying the mean luminal attenuation of the ascending aorta by 2 (+100 % HUAorta approach). The primary endpoint of this study consisted of a combination of post-TAVI outcomes (paravalvular leak ≄ mild, implant-related conduction disturbances, 30-day mortality, post-procedural stroke, annulus rupture, and device migration). The Akaike information criterion was used to select variables for the multivariable regression model. Multivariable analysis was carried out to determine the predictive power of the investigated approaches.   Results: Multivariable analyses showed that a fixed threshold of 850 HU (calcium volume cut-off 146 mm3) was unable to predict the composite clinical endpoint post-TAVI (OR=1.13, 95 % CI 0.87 to 1.48, p=0.35). In contrast, the +100 % HUAorta approach (calcium volume cut-off 1421 mm3) enabled independent prediction of the composite clinical endpoint post-TAVI (OR=2, 95 % CI 1.52 to 2.64, p=9.2x10-7). No significant difference in the Kaplan-Meier survival analysis was observed for either of the approaches.   Conclusions: The patient-specific calcium detection threshold +100 % HUAorta is more predictive of post-TAVI adverse events included in the combined clinical endpoint than the fixed HU 850 approach. For the +100 % HUAorta approach, a calcium volume cut-off of 1421 mm3 of the aortic valve had the highest predictive value.Hintergrund: Ein wichtiger Auslöser von Komplikationen nach einer Transkatheter-Aortenklappen-Implantation (TAVI) sind ausgeprĂ€gte Kalkablagerung an der Aortenklappe. Dennoch erfolgte bisher keine Einigung auf ein standardisiertes Messverfahren zur Quantifizierung der Kalklast der Aortenklappe in einer kontrastverstĂ€rkten dynamischen computertomographischen Angiographie (CTA). Die vorliegende Dissertation untersucht, inwieweit die Wahl des Analyseverfahrens zur Quantifizierung von Kalkablagerungen in der Aortenklappe die Prognose von Komplikationen und der Überlebensdauer nach einer TAVI beeinflusst.   Methodik: Der Untersuchung liegt ein umfangreicher Datensatz von 965 Patienten mit 198 Merkmalen pro Patienten zugrunde, welche sich zwischen 2012 und 2019 am Deutschen Herzzentrum Berlin einer TAVI unterzogen haben. Die Quantifizierung der Kalkablagerung an der Aortenklappe mittels CTA wurde einerseits mit einem starren Grenzwert von 850 Hounsfield Einheiten (HU) (HU 850 Verfahren) und andererseits anhand eines individuellen Grenzwertes bemessen. Letzterer ergibt sich aus der HU-DĂ€mpfung in dem Lumen der Aorta ascendens multipliziert mit 2 (+100 % HUAorta Verfahren). Der primĂ€re klinische Endpunkt dieser Dissertation besteht aus einem aus sechs Variablen zusammengesetzten klinischen Endpunkt, welcher ungewĂŒnschte Ereignisse nach einer TAVI abbildet (paravalvulĂ€re Leckage ≄mild, Herzrhythmusstörungen nach einer TAVI, Tod innerhalb von 30 Tagen, post-TAVI Schlaganfall, Ruptur des Annulus und Prothesendislokation). Mögliche Störfaktoren, die auf das Eintreten der Komplikationen nach TAVI Einfluss haben, wurden durch den Einsatz des Akaike Informationskriterium ermittelt. Um die Vorhersagekraft von Komplikationen nach einer TAVI durch beide Verfahren zu ermitteln, wurde eine multivariate Regressionsanalyse durchgefĂŒhrt.   Ergebnisse: Die multivariaten logistischen Regressionen zeigen, dass die Messung der Kalkablagerungen anhand der HU 850 Messung (Kalklast Grenzwert von 146 mm3) die Komplikationen und die Überlebensdauer nicht vorhersagen konnten (OR=1.13, 95 % CI 0.87 bis 1.48, p=0.35). Die nach dem +100 % HUAorta Verfahren (Kalklast Grenzwert von 1421 mm3) individualisierte Kalkmessung erwies sich hingegen als sehr aussagekrĂ€ftig, da hiermit Komplikationen nach einer TAVI signifikant vorhergesagt werden konnten (OR=2, 95 % CI 1.52 bis 2.64, p=9.2x10-7). In Hinblick auf die postoperative Kaplan-Meier Überlebenszeitanalyse kann auch mit dem +100 % HUAorta Verfahren keine Vorhersage getroffen werden.   Fazit: Aus der Dissertation ergibt sich die Empfehlung, die Messung von Kalkablagerungen nach dem +100 % HUAorta Verfahren vorzunehmen, da Komplikationen wesentlich besser und zuverlĂ€ssiger als nach der gĂ€ngigen HU 850 Messmethode vorhergesagt werden können. FĂŒr das +100 % HUAorta Verfahren lag der optimale Kalklast Grenzwert bei 1421 mm3

    Strategies for Early Learners

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    Welcome to learning about how to effectively plan curriculum for young children. This textbook will address: ‱ Developing curriculum through the planning cycle ‱ Theories that inform what we know about how children learn and the best ways for teachers to support learning ‱ The three components of developmentally appropriate practice ‱ Importance and value of play and intentional teaching ‱ Different models of curriculum ‱ Process of lesson planning (documenting planned experiences for children) ‱ Physical, temporal, and social environments that set the stage for children’s learning ‱ Appropriate guidance techniques to support children’s behaviors as the self-regulation abilities mature. ‱ Planning for preschool-aged children in specific domains including o Physical development o Language and literacy o Math o Science o Creative (the visual and performing arts) o Diversity (social science and history) o Health and safety ‱ Making children’s learning visible through documentation and assessmenthttps://scholar.utc.edu/open-textbooks/1001/thumbnail.jp

    INVESTIGATING THE PERCEPTION OF EXPATRIATES TOWARDS IMMIGRATION SERVICE QUALITY IN SHARJAH, UNITED ARAB EMIRATES THROUGH MIXED METHOD APPROACH

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    The public sectors in UAE are under immense pressure to demonstrate that their services are customer-focused and that continuous performance improvement is being delivered. The United Arab Emirates is a favoured destination for expatriates due to its own citizens form a minority of the population and are barely represented in the private sector workforce. These highly unusual demographics confer high importance on the national immigration services. Recently, increased interest in international migration, specifically within the United Arab Emirates, has been shown both by government agencies and by the governments of industrialised countries. Given the importance of the expatriate labour force to economic stability and growth in the Emirates, this research investigates how immigration services are perceived, with the aim of contributing to their improvement, thus ultimately supporting economic growth. It proposes a service quality perception framework to improve understanding within SID of how to raise levels of service delivered to migrants and other persons directly or indirectly affected by SID services. Qualitative data were collected by means of semi-structured interviews and quantitative data by means of a questionnaire survey based on the abovementioned framework. The survey data, on the variables influencing participants’ experiences and perceptions of SID services, were subjected to statistical analysis. The framework was then used to evaluate quality of service in terms of general impressions, delivery, location, response, SID culture and behaviour. Numerical data were analysed using inferential and descriptive statistics. It was found that service quality positively influenced service behaviour and that this relationship was mediated by SID culture. This research makes an original contribution to knowledge as one of the few studies of immigration to the United Arab Emirates. By examining the workings of one immigration department, it adds to the literature on immigration departments and organisational development in developing countries. It illuminates the mechanics of immigration services and demonstrates their increasing importance to the world economy

    RNA pull-down-confocal nanoscanning (RP-CONA), a novel method for studying RNA/protein interactions in cell extracts that detected potential drugs for Parkinson’s disease targeting RNA/HuR complexes

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    MicroRNAs (miRNAs, miRs) are a class of small non-coding RNAs that regulate gene expression through specific base-pair targeting. The functional mature miRNAs usually undergo a two-step cleavage from primary miRNAs (pri-miRs), then precursor miRNAs (pre-miRs). The biogenesis of miRNAs is tightly controlled by different RNA-binding proteins (RBPs). The dysregulation of miRNAs is closely related to a plethora of diseases. Targeting miRNA biogenesis is becoming a promising therapeutic strategy. HuR and MSI2 are both RBPs. MiR-7 is post-transcriptionally inhibited by the HuR/MSI2 complex, through a direct interaction between HuR and the conserved terminal loop (CTL) of pri-miR-7-1. Small molecules dissociating pri-miR-7/HuR interaction may induce miR-7 production. Importantly, the miR-7 levels are negatively correlated with Parkinson’s disease (PD). PD is a common, incurable neurodegenerative disease causing serious motor deficits. A hallmark of PD is the presence of Lewy bodies in the human brain, which are inclusion bodies mainly composed of an aberrantly aggregated protein named α-synuclein (α-syn). Decreasing α-syn levels or preventing α-syn aggregation are under investigation as PD treatments. Notably, α-syn is negatively regulated by several miRNAs, including miR-7, miR-153, miR-133b and others. One hypothesis is that elevating these miRNA levels can inhibit α-syn expression and ameliorate PD pathologies. In this project, we identified miR-7 as the most effective α-syn inhibitor, among the miRNAs that are downregulated in PD, and with α-syn targeting potentials. We also observed potential post-transcriptional inhibition on miR-153 biogenesis in neuroblastoma, which may help to uncover novel therapeutic targets towards PD. To identify miR-7 inducers that benefit PD treatment by repressing α-syn expression, we developed a novel technique RNA Pull-down Confocal Nanoscaning (RP-CONA) to monitor the binding events between pri-miR-7 and HuR. By attaching FITC-pri-miR-7-1-CTL-biotin to streptavidin-coated agarose beads and incubating them in human cultured cell lysates containing overexpressed mCherry-HuR, the bound RNA and protein can be visualised as quantifiable fluorescent rings in corresponding channels in a confocal high-content image system. A pri-miR-7/HuR inhibitor can decrease the relative mCherry/FITC intensity ratio in RP-CONA. With this technique, we performed several small-scale screenings and identified that a bioflavonoid, quercetin can largely dissociate the pri-miR-7/HuR interaction. Further studies proved that quercetin was an effective miR-7 inducer as well as α-syn inhibitor in HeLa cells. To understand the mechanism of quercetin mediated α-syn inhibition, we tested the effects of quercetin treatment with miR-7-1 and HuR knockout HeLa cells. We found that HuR was essential in this pathway, while miR-7 hardly contributed to the α-syn inhibition. HuR can directly bind an AU-rich element (ARE) at the 3’ untranslated region (3’-UTR) of α-syn mRNA and promote translation. We believe quercetin mainly disrupts the ARE/HuR interaction and disables the HuR-induced α-syn expression. In conclusion, we developed and optimised RP-CONA, an on-bead, lysate-based technique detecting RNA/protein interactions, as well as identifying RNA/protein modulators. With RP-CONA, we found quercetin inducing miR-7 biogenesis, and inhibiting α-syn expression. With these beneficial effects, quercetin has great potential to be applied in the clinic of PD treatment. Finally, RP-CONA can be used in many other RNA/protein interactions studies

    Early Neanderthal social and behavioural complexity during the Purfleet Interglacial: handaxes in the latest Lower Palaeolithic.

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    Only a handful of ‘flagship’ sites from the Purfleet Interglacial (Marine Isotope Stage 9, c. 350-290,000 years ago) have been properly examined, but the archaeological succession at the proposed type-site at Purfleet suggests a period of complexity and transition, with three techno-cultural groups represented in Britain. The first was a simple toolkit lacking handaxes (the Clactonian), and the last a more sophisticated technology presaging the coming Middle Palaeolithic (simple prepared core or proto-Levallois technology). Sandwiched between were Acheulean groups, whose handaxes comprise the great majority of the extant archaeological record of the period – these are the focus of this study. It has previously been suggested that some features of the Acheulean in the Purfleet Interglacial were chronologically restricted, particularly the co-occurrence of ficrons and cleavers. These distinctive forms may have exceeded pure functionality and were perhaps imbued with a deeper social and cultural meaning. This study supports both the previously suggested preference for narrow, pointed morphologies, and the chronologically restricted pairing of ficrons and cleavers. By drawing on a wide spatial and temporal range of sites these patterns could be identified beyond the handful of ‘flagship’ sites previously studied. Hypertrophic ‘giants’ have now also been identified as a chronologically restricted form. Greater metrical variability was found than had been anticipated, leading to the creation of two new sub-groups (IA and IB) which are tentatively suggested to represent spatial and perhaps temporal patterning. The picture in the far west of Britain remains unclear, but the possibility of different Acheulean groups operating in the Solent area, and a late survival of the Acheulean, are both suggested. Handaxes with backing and macroscopic asymmetry may represent prehensile or ergonomic considerations not commonly found on handaxes from earlier interglacial periods. It is argued that these forms anticipate similar developments in the Late Middle Palaeolithic in an example of convergent evolution

    Development of in-vitro in-silico technologies for modelling and analysis of haematological malignancies

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    Worldwide, haematological malignancies are responsible for roughly 6% of all the cancer-related deaths. Leukaemias are one of the most severe types of cancer, as only about 40% of the patients have an overall survival of 10 years or more. Myelodysplastic Syndrome (MDS), a pre-leukaemic condition, is a blood disorder characterized by the presence of dysplastic, irregular, immature cells, or blasts, in the peripheral blood (PB) and in the bone marrow (BM), as well as multi-lineage cytopenias. We have created a detailed, lineage-specific, high-fidelity in-silico erythroid model that incorporates known biological stimuli (cytokines and hormones) and a competing diseased haematopoietic population, correctly capturing crucial biological checkpoints (EPO-dependent CFU-E differentiation) and replicating the in-vivo erythroid differentiation dynamics. In parallel, we have also proposed a long-term, cytokine-free 3D cell culture system for primary MDS cells, which was firstly optimized using easily-accessible healthy controls. This system enabled long-term (24-day) maintenance in culture with high (>75%) cell viability, promoting spontaneous expansion of erythroid phenotypes (CD71+/CD235a+) without the addition of any exogenous cytokines. Lastly, we have proposed a novel in-vitro in-silico framework using GC-MS metabolomics for the metabolic profiling of BM and PB plasma, aiming not only to discretize between haematological conditions but also to sub-classify MDS patients, potentially based on candidate biomarkers. Unsupervised multivariate statistical analysis showed clear intra- and inter-disease separation of samples of 5 distinct haematological malignancies, demonstrating the potential of this approach for disease characterization. The work herein presented paves the way for the development of in-vitro in-silico technologies to better, characterize, diagnose, model and target haematological malignancies such as MDS and AML.Open Acces

    Omics measures of ageing and disease susceptibility

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    While genomics has been a major field of study for decades due to relatively inexpensive genotyping arrays, the recent advancement of technology has also allowed the measure and study of various “omics”. There are now numerous methods and platforms available that allow high throughput and high dimensional quantification of many types of biological molecules. Traditional genomics and transcriptomics are now joined by proteomics, metabolomics, glycomics, lipidomics and epigenomics. I was lucky to have access to a unique resource in the Orkney Complex Disease Study (ORCADES), a cohort of individuals from the Orkney Islands that are extremely deeply annotated. Approximately 1000 individuals in ORCADES have genomics, proteomics, lipidomics, glycomics, metabolomics, epigenomics, clinical risk factors and disease phenotypes, as well as body composition measurements from whole body scans. In addition to these cross-sectional omics and health related measures, these individuals also have linked electronic health records (EHR) available, allowing the assessment of the effect of these omics measures on incident disease over a ~10-year follow up period. In this thesis I use this phenotype rich resource to investigate the relationship between multiple types of omics measures and both ageing and health outcomes. First, I used the ORCADES data to construct measures of biological age (BA). The idea that there is an underlying rate at which the body deteriorates with age that varies between individuals of the same chronological age, this biological age, would be more indicative of health status, functional capacity and risk of age-related diseases than chronological age. Previous models estimating BA (ageing clocks) have predominantly been built using a single type of omics assay and comparison between different omics ageing clocks has been limited. I performed the most exhaustive comparison of different omics ageing clocks yet, with eleven clocks spanning nine different omics assays. I show that different omics clocks overlap in the information they provide about age, that some omics clocks track more generalised ageing while others track specific disease risk factors and that omics ageing clocks are prognostic of incident disease over and above chronological age. Second, I assessed whether individually or in multivariable models, omics measures are associated with health-related risk factors or prognostic of incident disease over 10 years post-assessment. I show that 2,686 single omics biomarkers are associated with 10 risk factors and 44 subsequent incident diseases. I also show that models built using multiple biomarkers from whole body scans, metabolomics, proteomics and clinical risk factors are prognostic of subsequent diabetes mellitus and that clinical risk factors are prognostic of incident hypertensive disorders, obesity, ischaemic heart disease and Framingham risk score. Third, I investigated the genetic architecture of a subset of the proteomics measures available in ORCADES, specifically 184 cardiovascular-related proteins. Combining genome-wide association (GWAS) summary statistics from ORCADES and 17 other cohorts from the SCALLOP Consortium, giving a maximum sample size of 26,494 individuals, I performed 184 genome-wide association meta-analyses (GWAMAs) on the levels of these proteins circulating in plasma. I discovered 592 independent significant loci associated with the levels of at least one protein. I found that between 8-37% of these significant loci colocalise with known expression quantitative trait loci (eQTL). I also find evidence of causal associations between 11 plasma protein levels and disease susceptibility using Mendelian randomisation, highlighting potential candidate drug targets

    Socio-endocrinology revisited: New tools to tackle old questions

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    Animals’ social environments impact their health and survival, but the proximate links between sociality and fitness are still not fully understood. In this thesis, I develop and apply new approaches to address an outstanding question within this sociality-fitness link: does grooming (a widely studied, positive social interaction) directly affect glucocorticoid concentrations (GCs; a group of steroid hormones indicating physiological stress) in a wild primate? To date, negative, long-term correlations between grooming and GCs have been found, but the logistical difficulties of studying proximate mechanisms in the wild leave knowledge gaps regarding the short-term, causal mechanisms that underpin this relationship. New technologies, such as collar-mounted tri-axial accelerometers, can provide the continuous behavioural data required to match grooming to non-invasive GC measures (Chapter 1). Using Chacma baboons (Papio ursinus) living on the Cape Peninsula, South Africa as a model system, I identify giving and receiving grooming using tri-axial accelerometers and supervised machine learning methods, with high overall accuracy (~80%) (Chapter 2). I then test what socio-ecological variables predict variation in faecal and urinary GCs (fGCs and uGCs) (Chapter 3). Shorter and rainy days are associated with higher fGCs and uGCs, respectively, suggesting that environmental conditions may impose stressors in the form of temporal bottlenecks. Indeed, I find that short days and days with more rain-hours are associated with reduced giving grooming (Chapter 4), and that this reduction is characterised by fewer and shorter grooming bouts. Finally, I test whether grooming predicts GCs, and find that while there is a long-term negative correlation between grooming and GCs, grooming in the short-term, in particular giving grooming, is associated with higher fGCs and uGCs (Chapter 5). I end with a discussion on how the new tools I applied have enabled me to advance our understanding of sociality and stress in primate social systems (Chapter 6)

    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
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