Bakgrund Bukaortaaneurysm är en potentiell farlig sjukdom med en dödlighet på 80-90% vid bristning. I Sverige screenas således alla 65-åriga män med ultraljud för att upptäcka aneurysmen i tid innan den brister och erbjuda männen behandling.  Syfte Syftet med examensarbetet var att utvärdera den interindividuella mätosäkerheten hos legitimerade och erfarna biomedicinska analytiker vid screening av bukaorta med ultraljud på 65-åriga män.  Material och metod Den interindividuella mätosäkerheten har utvärderats hos två par erfarna biomedicinska analytiker (BMA). BMA-paren screenade och registrerade bukaortandiametern på 65-åriga män vid två olika fysiologiska kliniker med metoden leading edge to leading edge (LELE) i anteroposteiror riktning. Analysen av data har genomförts med programmet IBM SPSS Statistics.  Resultat Analysen av data visade ingen signifikant skillnad i mätosäkerhet mellan BMA eller mellan klinikerna. Skillnaden i medelvärde mellan BMA låg på -0,06 mm respektive -0,07 mm. Medianen för skillnaderna av mätresultaten för respektive BMA-par var 0,0 mm (-0,5 til 0,4 mm, 95% CI) och -0,3 mm (-0,6 till 0,5 mm, 95% CI). Mätosäkerheten påverkades inte av BMI.  Slutsatser Utbildade och erfarna BMA som följer samma undersökningsprotokoll uppnår en hög nivå av interindividuell mätsäkerhet vid screening av bukaortaaneurysm med ultraljud.  Nyckelord: Bukarotaaneurysm, biomedicinska analytiker, interindividuell variation, LELE

New technologies have greatly shaped the scientific and medical landscape within the last years. The unprecedented expansion of data and information on RNA biology has led to the discovery of new RNA classes with unique functions and unexpected modifications. Today, the biggest challenge is to transfer the large number of findings in basic RNA biology into corresponding clinical RNA-based therapeutics. Lately, this research begins to yield positive outcomes. RNA drugs advance to the final phases of clinical trials or even receive FDA approval. Furthermore, the introduction of the RNA-guided gene-editing technology CRISPR and advances in the delivery ofmessenger RNAs have triggered a major progression in the field of RNA-therapeutics. Especially short interfering RNAs and antisense oligonucleotides are promising examples for novel categories of therapeutics. However, several issues need to be addressed including intracellular delivery, toxicity, and immune responses before utilizing RNAs in a clinical setting. In this review, we provide an overview on opportunities and challenges for clinical translation of RNA-based therapeutics, with an emphasis on advances in novel delivery technologies and abdominal aortic aneurysm disease where non-coding RNAs have been shown to play a crucial regulatory role.

The hidden Markov model (HMM) is one of the workhorse tools in, for example, statistical signal processing and machine learning. It has found applications in a vast number of fields, ranging all the way from bioscience to speech recognition to modeling of user interactions in social networks. In an HMM, a latent state transitions according to Markovian dynamics. The state is only observed indirectly via a noisy sensor – that is, it is hidden. This type of model is at the center of this thesis, which in turn touches upon three main themes. Firstly, we consider how the parameters of an HMM can be estimated from data. In particular, we explore how recently proposed methods of moments can be combined with more standard maximum likelihood (ML) estimation procedures. The motivation for this is that, albeit the ML estimate possesses many attractive statistical properties, many ML schemes have to rely on local-search procedures in practice, which are only guaranteed to converge to local stationary points in the likelihood surface – potentially inhibiting them from reaching the ML estimate. By combining the two types of algorithms, the goal is to obtain the benefits of both approaches: the consistency and low computational complexity of the former, and the high statistical efficiency of the latter. The filtering problem – estimating the hidden state of the system from observations – is of fundamental importance in many applications. As a second theme, we consider inverse filtering problems for HMMs. In these problems, the setup is reversed; what information about an HMM-filtering system is exposed by its state estimates? We show that it is possible to reconstruct the specifications of the sensor, as well as the observations that were made, from the filtering system’s posterior distributions of the latent state. This can be seen as a way of reverse engineering such a system, or as using an alternative data source to build a model. Thirdly, we consider Markov decision processes (MDPs) – systems with Markovian dynamics where the parameters can be influenced by the choice of a control input. In particular, we show how it is possible to incorporate prior information regarding monotonic structure of the optimal decision policy so as to accelerate its computation. Subsequently, we consider a real-world application by investigating how these models can be used to model the treatment of abdominal aortic aneurysms (AAAs). Our findings are that the structural properties of the optimal treatment policy are different than those used in clinical practice – in particular, that younger patients could benefit from earlier surgery. This indicates an opportunity for improved care of patients with AAAs. / <p>QC 20180301</p>

Historique et Objectif : La littérature est conflictuelle sur le rôle des calcifications aortiques dans la rupture d’anévrisme de l’aorte abdominale (AAA). La prédiction de rupture d’AAA basée sur le sexe et le diamètre est peu précise. Le but de ce projet était donc de déterminer si les calcifications permettent de mieux prédire la rupture d’AAA que le sexe et le diamètre à eux seuls. Méthodologie : Lors de cette étude rétrospective, 80 patients traités pour rupture d’AAA entre Janvier 2001 et Août 2018 ont été appariés à 80 patients non-rompus sur la base du diamètre maximal d’AAA, de l’âge, du sexe et de la présence de contraste lors du scan. La charge et la répartition des calcifications de la paroi aortique ainsi que certaines variables morphologiques d’anévrisme ont été comparées entre les deux groupes par analyse univariée et apprentissage machine. Résultats : L’âge moyen des patients était de 74.0 ± 8.4 ans et 89% étaient des hommes. Les diamètres d’AAA étaient équivalents entre groupes (80.9 ± 17.5 vs 79.0 ± 17.3 mm, p= 0.505). Selon l’analyse univariée, les anévrismes rompus comportaient significativement moins d’agrégats de calcifications (18.0 ± 17.9 vs 25.6 ± 18.9, p=0.010) et étaient moins enclins à avoir un collet (45.0% vs 76.3%, p<0.0001). Les 5 variables les plus importantes délivrées par l’apprentissage machine étaient: collet, antiplaquettaires, nombre de calcifications, distance d’Euler entre calcifications et finalement l’écart-type de la distance d’Euler entre calcifications. Le modèle à 5 variables a produit une aire sous la courbe (AUC) de 0.81 ± 0.02 (sensibilité 83% et spécificité 71%), supérieure à une AUC de 0.67(IC 95%, 0.58-0.77%) (sensibilité 60% et spécificité 77%) obtenues dans une étude antérieure avec une population similaire à celle-ci et ne tenant compte que du sexe et du diamètre. Conclusion : La charge en calcifications des anévrismes rompus était moins bien répartie que celle des non-rompus. Le modèle d’apprentissage machine a mieux prédit la rupture que le modèle basé uniquement sur le diamètre et le sexe. / Background and Purpose: Literature is conflictual regarding the role of aortic calcification in AAA rupture. AAA rupture prediction based on sex and diameter could be improved. The goal of this project was to assess whether aortic calcification could better predict AAA rupture. Methods: In this retrospective study, 80 patients treated for a ruptured AAA between January 2001 and August 2018 were matched with 80 non-ruptured patients based on maximal AAA diameter, age, sex and contrast enhancement status of the CT scan. Calcification load and dispersion, morphologic and clinical variables were compared between both groups using a univariable analysis and machine learning. Results: Mean age of patients was 74.0 ± 8.4 years and 89% were men. AAA diameters were equivalent in both groups (80.9 ± 17.5 vs 79.0 ± 17.3 mm, p= 0.505). Ruptured aneurysms contained a smaller number of calcification chunks than the non-ruptured (18.0 ± 17.9 vs 25.6 ± 18.9, p=0.010) and were less likely to have a proximal neck than the non-ruptured (45.0% vs 76.3%, p<0.0001). In the machine learning analysis, 5 variables were associated to AAA rupture: proximal neck, antiplatelets, calcification number, Euler distance between calcifications and standard deviation of the Euler distance between calcifications. The model including these 5 variables yielded an area under the curve (AUC) of 0.81 ± 0.02 (83% sensitivity and 71% specificity) which was better than a previous study with a similar population reporting a 0.67 AUC (95% CI, 0.58-0.77%) (60% sensitivity and 77% specificity) for sex and diameter only. Conclusion: Ruptured aneurysms were more likely to have their calcification load concentrated in a small number of clusters closer to each other. Our 5-variable model predicted rupture better than the model based on age and sex.

No description available.

[pt] Aneurisma arterial é definido como uma dilatação excessiva do diâmetro normal de uma artéria. O aneurisma da aorta ascendente é geralmente assintomático, portanto, é frequentemente identificado acidentalmente durante exames de imagem de rotina. Após a identificação do aneurisma, caso não haja indicação cirúrgica, o paciente deve ser acompanhado de maneira adequada, pois a ruptura arterial pode ser fatal. A influência do fluxo sanguíneo no remodelamento aórtico é uma importante área de investigação. O objetivo deste estudo é identificar padrões hemodinâmicos em aneurismas de aorta ascendente que possam estar relacionados com o aumento do aneurisma. Cada paciente do estudo foi avaliado em dois momentos distintos. Um modelo tridimensional do aneurisma de aorta ascendente foi gerado para cada paciente a partir de exames de angiotomografia de aorta. O padrão de fluxo foi determinado numericamente com a utilização de um software comercial. Foi demonstrado que o ângulo entre a entrada do fluxo principal e o tronco braquiocefálico pode induzir a uma incidência de um jato incidente na parede da aorta, ocasionado áreas de recirculação na região posterior do jato, além de altos valores de pressão e tensão cisalhante. Os presentes achados hemodinâmicos podem estar relacionados com o remodelamento da aorta ascendente. / [en] Arterial aneurysmal is defined as an excessive dilation of the normal diameter of an artery. Ascending aortic aneurysm is generally asymptomatic, so it is often accidentally identified during routine imaging examinations. After the aneurysm has been identified, if there is no surgical indication, the patient should be followed adequately, since arterial rupture can be fatal. The influence of blood flow on aortic remodeling is an important area of investigation. The aim of this study is to identify hemodynamic patterns in ascending aortic aneurysms that may be related to aneurysm enlargement. Each patient in the study was evaluated at two different times. A three-dimensional model of the ascending aortic aneurysm was generated for each patient from aortic angiotomography examinations. The flow field was numerically determined with a commercial software. It has been shown that the angle between the entrance of the main flow and the brachiocephalic trunk can induce an incident jet on the aortic wall, causing areas of recirculation in the posterior region of the jet, besides high values of pressure and wall shear stress. The present hemodynamics findings may be related to remodeling of the ascending aorta.

Extracellular matrix (ECM) is a key component and regulator of many biological tissues. Several cardiovascular pathologies are associated with significant changes in the composition of the matrix. Better understanding of these pathologies and the physiological phenomenon behind their development depends on reliable methods that can measure and characterize ECM content and structure. In this dissertation, infrared spectroscopic methodologies are developed to study the changes in extracellular matrix of cardiovascular tissue in two cardiovascular pathologies; myocardial infarction and abdominal aortic aneurysm. The specific aims of this dissertation were: 1. To develop a Fourier transform infrared imaging spectroscopy (FT-IRIS) methodology for creating distribution maps of collagen in remodeled cardiac tissue sections after myocardial infarction, and to quantitatively compare maps created by FT-IRIS with conventional staining techniques. 2. To develop an FT-IRIS method to assess elastin and collagen composition in the aortic wall. This will be accomplished using ex vivo animal aorta samples, where the primary ECM components of the wall will be systematically enzymatically degraded. 3. To apply the newly developed FTIR imaging methodology to evaluate changes in the primary ECM components (collagen and elastin) in the wall of human AAA tissues. The infrared absorbance band centered at 1338 cm-1, was used to map collagen deposition across heart tissue sections of a rat model of myocardial infarction, and was correlated strongly in the size of the scar (R=0.93) and local intensity of collagen deposition (R=0.86). In enzymatically degraded pig aorta samples, as a model of ECM degradation in abdominal aortic aneurysm (AAA), partial least squares (PLS) models were created to predict collagen and elastin content in aorta based on collected FTIR spectra and biochemically measured values. PLS models based on FT-IRIS spectra were able to predict elastin and collagen content of the samples with strong correlations (R2=0.90 and 0.70 respectively). Elastin content prediction from IFOP spectra was successful through a PLS regression model with high correlation (R2=0.81). The PLS regression coefficient from the FT-IRIS models were used to map collagen and elastin human AAA biopsy tissue sections, creating a similar map of each component compared to histologically stained images. The mean value of collagen deposition in each tissue was calculated for 13 pairs of AAA samples where stress had been calculated using finite element modeling. In most pairs with stress values higher than 5 N/m2, collagen content was lower in the sample with higher stress value. Collagen maturity had a weak negative correlation (R=-0.35) with collagen content in these samples. These results confirm that infrared spectroscopy is a powerful tool that can be applied to replace or complement conventional methods such as histology and biochemical analysis to characterize ECM components in cardiovascular tissues. Furthermore, infrared spectroscopy has the potential for translation to a clinical environment to examine ECM changes in aorta in a minimally invasive fashion using fiber optic technology. / Mechanical Engineering

This thesis consists of four self-contained papers. Essay I (with Linuz Aggeborn): Fluoridation of the drinking water is a public policy whose aim is to improve dental health. Although the evidence is clear that fluoride is good for dental health, concerns have been raised regarding potential negative effects on cognitive development. We study the effects of fluoride exposure through the drinking water in early life on cognitive and non-cognitive ability, education and labor market outcomes in a large-scale setting. We use a rich Swedish register dataset for the cohorts born 1985-1992, together with drinking water fluoride data. To estimate the effects, we exploit intra-municipality variation of fluoride, stemming from an exogenous variation in the bedrock. First, we investigate and confirm the long-established positive relationship between fluoride and dental health. Second, we find precisely estimated zero-effects on cognitive ability, non-cognitive ability and education for fluoride levels below 1.5 mg/l. Third, we find evidence that fluoride improves later labor market outcomes, which indicates that good dental health is a positive factor on the labor market. Essay II: I study the associations between cognitive and non-cognitive abilities and mortality using a population-wide dataset of almost 700,000 Swedish men born between 1950 and 1965. The abilities were measured at the Swedish military enlistment at age 18-20. In addition, I investigate if income and education are good proxies for the abilities. The results suggest that both cognitive and non-cognitive abilities are strongly associated with mortality, but that non-cognitive ability is a stronger predictor. The associations are only partly mediated through income and education. For middle and high income earners and individuals with a college education there are no associations with mortality. However, for low income earners and individuals without a college education, both abilities are strongly associated with mortality. The associations are mainly driven by the bottom of the distributions. Essay III (with Matz Dahlberg, Kevin Mani and Anders Wanhainen): We examine how health information affects individuals' well-being using a regression discontinuity design on data from a screening program for an asymptomatic disease, abdominal aortic aneurysm (AAA). The information provided to the individuals is guided by the measured aorta size and its relation to pre-determined levels. When comparing individuals that receive information that they are healthy with those that receive information that they are in the risk zone for AAA, we find no effects. However, when comparing those that receive information that they have a small AAA, and will be under increased surveillance, with those who receive information that they are in the risk zone, we find a weak positive effect on well-being. This indicates that the positive information about increased surveillance may outweigh the negative information about worse health. Essay IV: I estimate the effect of SSRI antidepressants on the risk of mortality for myocardial infarction (MI) patients using Propensity Score Matching on individual health variables such as pharmaceutical drug prescription, patient history and severity of the MI. The effect of antidepressants on mortality is a heavily debated topic. MI patients have an elevated risk of developing depression, and antidepressants are among the most common treatments for depression and anxiety. However, there are indications that some classes of antidepressants may have drug-induced cardiovascular effects and could be harmful for individuals with heart problems, but there is a lack of large-scale studies using credible identification strategies. My findings indicate no increased risk of two-year mortality for MI patients using SSRI. The results are stable for several specifications and robustness checks.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

Tato práce se zabývá problematikou aneurysmat břišní aorty a možností využít konečnoprvkovou deformačně-napěťovou analýzu těchto aneurysmat ke stanovení rizika ruptury. První část práce je věnována úvodu do problematiky, popisu kardiovaskulární soustavy člověka s důrazem na abdominální aortu, anatomii, fyziologii a patologii stěny tepny s důrazem na procesy vedoucí ke vzniku aneurysmatu. Dále se práce věnuje rizikovým faktorům přispívajících ke vzniku aneurysmat spolu s analýzou současných klinických postupů ke stanovení rizika ruptury spolu se srovnáním navrhovaného kritéria maximálního napětí. Dominantní část této disertace je věnována identifikaci faktorů ovlivňujících napjatost a deformaci stěny aneurysmatu spolu s návrhem nových postupů, prezentací vlastních poznatků vedoucích ke zpřesnění určení rizika ruptury pomocí deformačně- napěťové analýzy a metody konečných prvků. Nejprve je analyzován vliv geometrie, vedoucí k závěru, že je nezbytné používání individuálních geometrií pacienta. Dále je pozornost zaměřena na odbočující tepny, které ve stěně působí jako koncentrátor napětí a mohou tedy ovlivňovat napjatost v ní. Jako další podstatný faktor byl identifikován vliv nezatížené geometrie a bylo napsáno makro pro její nalezení, které bylo opět zahrnuto jako standardní součást do výpočtového modelu. Mechanické vlastnosti jak stěny aneurysmatu, tak intraluminálního trombu jsou experimentálně testovány pomocí dvouosých zkoušek. Také je zde analyzován vliv modelu materiálu, kde je ukázáno, že srovnávání maximálních napětí u jednotlivých modelů materiálu není vhodné díky zcela rozdílným gradientům napětí ve stěně aneurysmatu. Dále je zdůrazněna potřeba znalosti distribuce kolagenních vláken ve stěně a navržen program k jejímu získání. Intraluminální trombus je analyzován ve dvou souvislostech. Jednak je ukázán vliv jeho ruptury na napětí ve stěně a jednak je analyzován vliv jeho poroelastické struktury na totéž. Posledním identifikovaným podstatným faktorem je zbytková napjatost ve stěně. Její významnost je demonstrována na několika aneurysmatech a i tato je zahrnuta jako integrální součást do našeho výpočtového modelu.Na závěr jsou pak navrženy další možné směry výzkumu.