Background: Cerebral small vessel disease (SVD) causes substantial cognitive, psychiatric and physical disabilities. Despite its common nature, SVD pathogenesis and molecular mechanisms remain poorly understood, and prevention and treatment are probably suboptimal. Identifying the genetic determinants of SVD will improve understanding and may help identify novel treatment targets. The aim of this thesis is to better understand genetic associations with SVD through investigating its pathological, radiological and clinical phenotypes. Methods: To unravel the genetic associations with SVD, I used three complementary approaches. First, I performed a systematic review looking at existing intracerebral haemorrhage (ICH) classification systems and their reliability, to help inform future studies of ICH genetics. Second, I performed a series of systematic reviews and meta-analyses, investigating associations between genetic polymorphisms and histopathologically confirmed cerebral amyloid angiopathy (CAA). Third, I performed meta-analyses of existing genome-wide datasets to determine associations of >1000 common single nucleotide polymorphisms (SNP) in the COL4A1/COL4A2 genomic region with clinico-radiological SVD phenotypes: ICH and its subtypes, ischaemic stroke and its subtypes, and white matter hyperintensities. Results: The reliability of existing ICH classification systems appeared excellent in eight studies conducted in specialist centres with experienced raters, although these existing systems have several limitations. In my systematic evaluation of CAA genetics, meta-analyses of 24 studies including 3520 participants showed robust evidence for a dose-dependent association between APOE ɛ4 and histopathological CAA. There was, however, no convincing association between APOE ɛ2 and presence of CAA in a meta-analysis of 11 studies including 1640 participants. Meta-analyses of five studies including 497 participants showed, contrary to an existing popular hypothesis, that while APOE 4 may increase the risk of developing severe CAA vasculopathy, there is no clear evidence to support a role of ɛ2. There were few data about the role of APOE in hereditary CAA, but in the three studies that had looked at this, there was no evidence for an association between APOE ɛ4 and CAA severity. There were too few studies and participants to draw firm conclusions about the effect of non-APOE ε2/ε3/ε4 genetic polymorphisms on CAA, but there were positive associations with TGF-β1, TOMM40 and CR1 genes in four studies. Finally, in my meta-analyses of the COL4A1/COL4A2 genomic region, three intronic SNPs in COL4A2 were associated with SVD phenotypes: significantly with deep ICH, and suggestively with lacunar ischaemic stroke and WMH. Conclusions: I have shown that while existing ICH classification systems appear to have very good reliability, further research is needed to determine their performance in different settings. For large population-based prospective studies of ICH genetics, anatomical systems are likely to be more feasible, scalable and appropriate, although they have limitations and will need to be further developed. Using systematic reviews and meta-analyses, I have confirmed a dose-related association between APOE ɛ4 and histopathological CAA, but also demonstrated that, despite popular acceptance, there is insufficient data to draw firm conclusions about the association with APOE ɛ2. I found some positive associations with CAA in other genes, which merit replication in further larger studies, and showed that there is currently insufficient data about the role of APOE in hereditary CAA. Finally, I identified a novel association between a locus in a known hereditary SVD gene – COL4A2 – and sporadic SVD. This highlights a new and successful approach for selecting candidate genes and can be expanded in future studies to include other known hereditary SVD genes.

Numerical simulation of noise production and propagation is a very complex problem. A methodology fitting for one particular problem can fail for another one. So there are no general guidelines on how to deal with such phenomena. In the present work, noise propagated in non-uniform mean-flow is considered. For most cases, in the propagation field, there is a rather significant region where the mean flow is not uniform, but the sound production is negligible compared to the noise emitted by the source region. In this<p>nearfield, a linear set of propagation equations may be considered (LEE). For such problems, the following simulation methodology is proposed:<p>1. Incompressible/compressible LES simulation in the source region.<p>2. Linearized Euler Equations to propagate the noise through the nonlinear mean flow.<p>3. Kirchhoff method in the farfield, if necessary.<p>This thesis deals with the second item of this system (LEE), including interfacing with the other two steps. / Doctorat en Sciences de l'ingénieur / info:eu-repo/semantics/nonPublished

Predicting and inhibiting aerodynamically generated noise for fast moving vehicles such as cars, aircraft and trains is increasingly important. The tonal noise generated by the shear-layer instability of air flowing around the cavity opening is especially one of the most significant and most intense sources of aerodynamically generated noise. Computational aeroacoustics (CAA) based on the CFD simulations of compressible Navier-Stokes equations offers the most general approach to predicting those aerodynamically induced sounds. Aeroacoustics is practically always associated with turbulent flow and turbulence is the major challenge for CFD simulations. Four different turbulence modelling approaches are examined in this work. Three of them belong to the LES method category and one uses the URANS approach. Appropriate numerical discretization and iteration schemes have been identified for each of these approaches and implemented in the OpenFOAM open source CFD platform. The accuracy, computational performance and convergence reliability of those schemes have been subsequently studied during three-dimensional CFD simulations on a model of a suitable real object. The CFD simulation results are validated by a measurement. An organ pipe has been chosen as the object of this CAA research because it uses self-sustained oscillations, commonly referred as shear-layer (Rossiter) modes, as the source of its tone generation. The numerical simulation of the shear layer modes, respectively the noise generated by instability in the shear layer, is the subject of this work.

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Modern silencers for heavy vehicle applications are designed to cancel out the sound generated by the effects of combustion and propagation of exhaust gases through the engine after-treatment system. The complex geometry within the compact silencer give rise to self generated (or flow-) noise that contribute to the total sound power radiated at the exhaust outlet. To evaluate the magnitude and spectral frequency content of this self-generated noise, accurate non-reflective boundary conditions need to be applied along with a solver optimized for low dissipation and dispersion of acoustic waves. Parametric studies have been preformed to construct and evaluate the non-reflectiveness of stretched grids in combination with the buffer-zone technique for low- to mid- frequency noise. The Proudman noise source model have been used to identify the sources of sound within the computational domain and Detached Eddy Simulations have been used with full silencer geometries. Finally, the non-reflective performance of the stretched grid and buffer-zone technique have been evaluated using the acoustic beamforming method to spatially filter out and estimate the amount of reflections present in the final simulations. Detached Eddy Simulations can with success be used to resolve flow noise in exhaust gas geometries and allow reasonable comparisons. Steady models have been included in the comparisons but can only be used to estimate the amount of production of acoustic energy, not the radiated sound pressure levels related to the suppression of sound due to flow characteristics within the silencer geometries. Finally, the rough beamforming method confirmed the function of the non-reflective boundary conditions by finding major differences in magnitude for the sound being radiated towards the measurement point in different directions. / Ljuddämpare för lastbilar och bussar är konstruerade för att dämpa det ljud som genereras i förbränningsmotorn och i avgasreningssystemet. Moderna ljuddämpare består av komplexa geometrier som avgaserna flödar igenom och som släcker ut oönskat ljud. När avgaserna, bärandes ljud ifrån förbränningsmotorn flödar i hög hastighet genom den komplexa geometrin alstras ytterligare buller, så kallat själv-genererat ljud. För att ta fram frekensspektrat och ljudtrycksnivån ifrån detta bidragande ljud kan Detached Eddy Simulations utföras. Denna metod av strömningsmekaniska beräkningar kräver dock icke-reflektiva randvilkor. Randvilkor som uppfyller kraven har konstruerats genom parameterstudier tillsammans med en numerisk lösare som med låg dissipation och dispersion beräknar de akustiska pertubationerna i fjärfältet på ett fysikaliskt korrekt sätt. Vidare har även akustiska källmetoder används för att uppskatta närfältets storlek. Magnituden hos de kvarvarande reflektionerna har sedan uppskattas med hjälp av en förenklad Beamforming metod. Detached Eddy Simulations kan på ett framgångsfullt sätt användas för att ta fram det egengenererade ljudet ifrån ljuddämpargeometrier och möjliggör därigenom rimliga jämförelser mellan olika avgasgeometrier. De akusiska källmetoderna kan med säkerhet anvädas för att uppskatta den akustiska effekten som genereras i geometrierna men kan inte användas för att ta fram de dämpande effekterna som turbulenta strukturer eller hastighetsgradienter medför. Den förenklade Beamforming metoden har även bekräftat funtionen hos de icke-reflectiva randvilkoren genom att påvisa stora skillander i den ljudnivån som radierars ifrån olika riktingar mot den punkt som anvädas för att extrahera ljuddämparens ljudtrycksnivå.

The thesis objective is to analyze existing situation concerning reporting of the aviation accidents or incidents in national level and according the outputs from the analyses to develop recommendations, how database system ECCAIRS can by used for reporting on the national base. The focus of the thesis is investigation and evaluation of the existing national situation / from theoretical point of view and practical point of view/ and develop recommendation. As source of the investigation ware used existing legislation documents and foreign experience. For collection of the foreign experience was designed special type of questioner. The questioners ware distributed to the pre-selected number of authorities represented pre-selected states. During all process of analysis and investigation situation was discussed with local Czech authorities too. International law / ICAO Annex 13 of the Chicago Convention and EU Directive 94/56 / ware considers as one of the basic sources for the information.

The thesis objective is considerations of effect safety campaigns, which are issued by CAA CZ, on safety of air traffic in Czech Republic. In thesis are considered categories of aircrafts from 0 to 5700 kg except for Ultralight Aircrafts in period 1993 to 2011. Recognition involves describe given campaigns, assurance of information, processing and final assessment of efficiency published safety campaigns.

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