Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Background Although abdominal aortic aneurysm (AAA) growth is non-linear, serial measurements of aneurysm diameter are the mainstay of aneurysm surveillance and contribute to decisions on timing of intervention. Aneurysm biology plays a key part in disease evolution but is not currently routinely assessed in clinical practice. Magnetic Resonance Imaging (MRI) and Positron Emission Tomography-Computed Tomography (PET-CT) provide insight into disease processes on a cellular or molecular level, and represent exciting new imaging biomarkers of disease activity. Macrophage-mediated inflammation may be assessed using ultrasmall superparamagnetic particles of iron oxide (USPIO) MRI and the PET radiotracer 18FSodium Fluoride (18F-NaF) identifies microcalcification which is a response to underlying necrotic inflammation. The central aim of this thesis was to investigate these imaging modalities in patients with AAA. Methods and Results USPIO MRI: MULTI-CENTRE STUDY In a prospective multi-centre observational cohort study, 342 patients (85.4% male, mean age 73.1±7.2 years, mean AAA diameter 49.6±7.7mm) with asymptomatic AAA ≥4 cm anteroposterior diameter underwent MRI before and 24-36 hours after intravenous administration of USPIO. Colour maps (depicting the change in T2* caused by USPIO) were used to classify aneurysms on the basis of the presence of USPIO uptake in the aneurysm wall, representing mural inflammation. Intra- and inter-observer agreement were found to be very good, with proportional agreement of 0.91 (kappa 0.82) and 0.83 (kappa 0.66), respectively. At 1 year, there was 29.3% discordant classification of aneurysms on repeated USPIO MRI and at 2 years, discordance was 65%, suggesting that inflammation evolves over time. In the observational study, after a mean of 1005±280 days of follow up, there were 126 (36.8%) aneurysm repairs and 17 (5.0%) ruptures. Participants with USPIO enhancement (42.7%) had increased aneurysm expansion rates (3·1±2·5 versus 2·5±2·4 mm/year; difference 0·6 [95% confidence intervals (CI), 0·02 to 1·2] mm/year, p=0·0424) and had higher rates of aneurysm rupture or repair (69/146=47·3% versus 68/191=35·6%; difference 11·7%, 95% CI 1·1 to 22·2%, p=0·0308). USPIO MRI was therefore shown to predict AAA expansion and the composite of rupture or repair, however this was not independent of aneurysm diameter (c-statistic, 0·7924 to 0·7926; unconditional net reclassification -13·5%, 95% confidence intervals -36·4% to 9·3%). 18F-NaF PET-CT: SINGLE-CENTRE STUDY A sub-group of 76 patients also underwent 18F-NaF PET-CT, which was evaluated using the maximum tissue-to-background ratio (TBRmax) in the most diseased segment (MDS), a technique that showed very good intra- (ICC 0.70-0.89) and inter-observer (ICC 0.637-0.856) agreement. Aneurysm tracer uptake was compared firstly in a case-control study, with 20 patients matched to 20 control patients for age, sex and smoking status. 18F-NaF uptake was higher in aneurysm when compared to control aorta (log2TBRmax 1.712±0.560 vs. 1.314±0.489; difference 0.398 (95% CI 0.057, 0.739), p=0.023), or to non-aneurysmal aorta in patients with AAA (log2TBRmax 1.647±0.537 vs. 1.332±0.497; difference 0.314 (95% CI 0.0685, 0.560), p=0.004). An ex vivo study was performed on aneurysm and control tissue, which demonstrated that 18F-NaF uptake on microPET-CT was higher in the aneurysm hotspots and higher in aneurysm tissue compared to control tissue. Histological analysis suggested that 18F-NaF was highest in areas of focal calcification and necrosis. In an observational cohort study, aneurysms were stratified by tertiles of TBRmax in the MDS and followed up for 510±196 days, with 6 monthly serial ultrasound measurements of diameter. Those in the highest tertile of tracer uptake expanded more than 2.5 times more rapidly than those in the lowest tertile (3.10 [3.58] mm/year vs. 1.24 [2.41] mm/year, p=0.008) and were also more likely to experience repair or rupture (15.3% vs. 5.6%, log-rank p=0.043). In multivariable analyses, 18F-NaF uptake on PET-CT emerged as an independent predictor of AAA expansion (p=0.042) and rupture or repair (HR 2.49, 95% CI1.07, 5.78; p=0.034), even when adjusted for age, sex, body mass index, systolic blood pressure, current smoking and, crucially, aneurysm diameter. Conclusion These are the largest USPIO MRI and PET-CT studies in AAA disease to date and the first to investigate 18F-NaF. Both USPIO MRI and 18F-NaF PET-CT are able to predict AAA expansion and the composite of rupture and repair, with 18F-NaF PETCT emerging as the first imaging biomarker that independently predicts expansion and AAA events, even after adjustment for aneurysm diameter. This represents an exciting new predictor of disease progression that adds incremental value to standard clinical assessments. Feasibility and randomised clinical trials are now required to assess the potential of this technique to change the management and outcome of patients with AAA.

A rupturing abdominal aortic aneurysm (AAA) has a mortality rate of 50% while an elective repair has a mortality rate of 3-8%. Screening programmes with ultrasound are used in some countries to detect AAA at an early stage. Ultrasound is however very observer bias and dependent on the observer's experience. The study was performed in Vietnam, a country that have experienced exceptional economic growth with increasing risk factors for cardiovascular diseases but has no national screening programme. The aim of this study was to examine the interobserver variability when measuring the abdominal aorta with ultrasound on young adults in Vietnam. The abdominal aorta was measured in the longitudinal and the transverse axis by two different observers using the leading edge to leading edge method. Participants in this study were 31 voluntary students, 16 men and 15 women in the ages 18-26 years, from the Da Nang university of medical technology and pharmacy and the design was a cross-sectional study with a quantitative approach. The study showed a significant difference between the longitudinal measurements but not between the transverse measurements. Despite this statistical significance, the observers' differences were within the recommended limit of 5 mm. / Ett rupturerande bukaortaaneurysm har en dödlighet på 50% medan förebyggande vaskulär kirurgi har en dödlighet på 3-8%. Screeingprogram med ultraljud används i vissa länder för att upptäcka bukaortaaneurysm i ett tidigt skede innan de rupterar. Ultraljudsundersökningen är dock väldigt beroende på utövarens erfarenhet och utbildning. Studien genomfördes i Vietnam, ett land som genomgått stor ekonomisk tillväxt men även en ökning av riskfaktorer för kardiovaskulära sjukdomar. Vietnam har dock inget nationellt screeningprogram för bukaortaaneurysm. Syftet med studien var att undersöka observatörsvariationen vid mätning av bukaortan med ultraljud på unga vuxna i Vietnam. Populationen var ung för att minska patologiska fynd. Bukaortan mättes med metoden leading edge to leading edge, både i det longitudinella och i det transversella snittet av två olika utövare. Observatörerna var två studenter från Biomedicinska analytikerprogrammet med inriktning klinisk fysiologi, Jönköpings Universitet. Deltagare i studien var 31 frivilliga studenter, 16 män och 15 kvinnor i åldrarna 18-26 år, från Da Nang University of medical technology and pharmacy och designen var en tvärsnittsstudie med kvantitativ ansats. Studien visade en signifikant skillnad i de longitudinella mätningarna men inte i de transversella mätningarna. Trots denna statistiska signifikans var observatörernas differenser inom den rekommenderade gränsen på 5 mm.

Objectives: Cardiovascular disease is the leading cause of mortality and morbidity in the developed world. Surgery can improve prognosis and relieve symptoms. Risk prediction models are increasingly being used to inform clinicians and patients about the risks of surgery, to facilitate clinical decision making and for the risk-adjustment of surgical outcome data. The importance of risk prediction models in cardiovascular surgery has been highlighted by the publication of cardiovascular surgery outcome data and the need for risk-adjustment. The overall objective of this thesis is to advance risk prediction modelling in cardiovascular surgery with a focus on the development of models for elective AAA repair and assessment of models for cardiac surgery. Methods: Three large clinical databases (two elective AAA repair and one cardiac surgery) were utilised. Each database was cleaned prior to analysis. Logistic regression was used to develop both regional and national risk prediction models for mortality following elective AAA repair. A regional model to identify the risk of developing renal failure following elective AAA repair was also developed. The performance of a widely used cardiac surgery risk prediction model (the logistic EuroSCORE) over time was evaluated using a national cardiac database. In addition an updated model version (EuroSCORE II) was validated and both models’ performance in emergency cardiac surgery was evaluated. Results: Regional risk models for mortality following elective AAA repair (VGNW model) and a model to predict post-operative renal failure were developed. Validation of the model for mortality using a national dataset demonstrated good performance compared to other available risk models. To improve generalisability a national model (the BAR score) with better discriminatory ability was developed. In a prospective validation of both models using regional data, the BAR score demonstrated excellent discrimination overall and good discrimination in procedural sub-groups. The EuroSCORE was found to have lost calibration over time due to a fall in observed mortality despite an increase in the predicted mortality of patients undergoing cardiac surgery. The EuroSCORE II demonstrated good performance for contemporary cardiac surgery. Both EuroSCORE models demonstrated inadequate performance for emergency cardiac surgery. Conclusions: Risk prediction models play an important role in cardiovascular surgery. Two accurate risk prediction models for mortality following elective AAA repair have been developed and can be used to risk-adjust surgical outcomes and facilitate clinical decision making. As surgical practice changes over time risk prediction models may lose accuracy which has implications for their application. Cardiac risk models may not be sufficiently accurate for high-risk patient groups such as those undergoing emergency surgery and specific emergency models may be required. Continuing research into new risk factors and model outcomes is needed and risk prediction models may play an increasing role in clinical decision making in the future.

The aim of this study is to create CFD tools and models capable of simulating pulsatile blood flow in abdominal aortic aneurysm (AAA) and stent graft. It helps to increase the current physiological understanding of rupture risk of AAA and stent graft fixation or migration. Firstly, in order to build a general solver for the AAA modeling with reasonable accuracy, a third/fourth order modified OCI scheme is originally developed for general numerical simulation. The modified OCI scheme has a wider cell Reynolds number limitation. This high order scheme performs well with general rectangular mesh for incompressible fluid. Second, a velocity based finite volume method is originally developed to calculate the stress field for solid in order to capture the transient changes of the blood vessel since the artery is a rubber like material. All one, two and three dimensional classical cases for solid are tested and good results are obtained. The velocity based finite volume method show good potential to calculate the stress field for solid and easy to blend with the finite volume fluid solver. It has been recognized that fluid structure interaction (FSI) is very crucial in biomechanics. In this regard, the velocity based finite volume method is then further developed for FSI application. A well known one dimensional piston problem is studied to understand the feasibility of the fluid structure coupling. The numerical prediction matches the analytical solution very well. The velocity based method introduces less numerical damping compared with a stagger method and a monolithic method. Finally, the work focuses on practical pulsatile boundary conditions, non-Newtonian blood viscous properties and bifurcating geometry, and provides an overview of the hemodynamic within the AAA model. A modified Womersley inlet and imbalance pressure outlet boundary conditions are originally used in this study. The Womersley inlet boundary represents better approximation for pulsatile flow compared with the parabolic inlet condition. Numerical results are presented providing comparison between different boundary conditions using different viscous models in both 2D and 3D aneurysms. Good agreement between the numerical predictions and the experimental data is achieved for 2D case. 3D stent models with different bifurcation angles are also tested. The Womersley inlet boundary condition improves the existing inlet conditions significantly and it can reduce the Aneurysm neck computation domain. The influence of the non-Newtonian model to the wall shear stress (WSS) and strain-rate is also studied. The non-Newtonian model tends to produce higher WSS at both proximal and distal end of the aneurysm as compared with the Newtonian model (both 2D and 3D cases). The computed strain-rate distribution at the centre of the aneurysm is different between these two models. The influence of imbalance outlet pressure at the iliac arteries to the blood flow is originally investigated. The imbalance outlet pressure boundary conditions affect the computed wall shear stress significantly near the bifurcation point. All the pulsatile Womersley inlet, non-Newtonian viscosity properties and the imbalance pressure outlet need to be considered in blood flow simulation of AAA.

Bakgrund: I Sverige avlider varje år cirka 600 män och 200 kvinnor till följd av ett brustet abdominalt aortaaneurysm. Mellan 1.5 och 4.0 procent av alla män över 65 år drabbas av ett abdominalt aortaaneurysm och sedan år 2015 erbjuds samtliga 65-åriga män screening för aortaaneurysm. De som diagnostiseras är således vanligen äldre personer, och i takt med stigande ålder ökar även risken att drabbas av andra sjukdomar. Patientgruppen kan därför vårdas på olika typer av vårdavdelningar, vilket gör att den grundutbildade sjuksköterskan kan möta dessa patienter på många olika vårdinstanser. För att kunna ge en god och personcentrerad vård krävs en förståelse för patienternas upplevelser relaterat till sitt aneurysm samt hur det påverkar det dagliga livet för patienterna.  Syfte: Litteraturöversiktens syfte var att beskriva vuxna patienters upplevelser relaterat till deras abdominala aortaaneurysm, både under konservativ behandling samt postoperativt och hur det påverkar det dagliga livet. Metod: Litteraturöversikten är baserad på tolv vetenskapliga artiklar med kvalitativ studiedesign. Artiklarna hämtades från tre olika databaser med medicin- och omvårdnadsfokus och analyserades därefter induktivt med en förenklad form av metasyntes. Resultat: Fem huvudkategorier och sju underkategorier av upplevelser hos patienter identifierades. Huvudkategorierna var: upplevelser kring behovet av information; upplevelser av att kunna lita på hälso- och sjukvården; oro, rädsla och ångest relaterat till AAA; AAAs påverkan på det dagliga livet; och möjlighet att vara delaktig i vårdprocessen. Konklusion: Litteraturöversikten visade att AAA upplevs med stor variation av patienter. Men framförallt upplever patienter en brist i information och kunskap om sitt AAA där ytterligare stöd, information och kunskap önskas av patienter.  Nyckelord: Abdominalt aortaaneurysm, Dagligt liv, Patienter, Personcentrerad vård, Upplevelser / Background: In Sweden, approximately 600 men and 200 women die each year as a result of a ruptured abdominal aortic aneurysm. Between 1.5 and 4.0 percent of all men over the age of 65 years suffer from an abdominal aortic aneurysm and since year 2015, all 65-years-old men have been offered a screening for aortic aneurysm. Those who are diagnosed are thus elderly and alongside an increasing age, the risk of being subject to other diseases also increases. The patient group can therefore be cared for in different types of care wards, which means that the undergraduate nurse can meet these patients in many different care institutions. In order to be able to provide good and person-centred care, an understanding of the patients' experiences of their aneurysm, and how it affects their daily lives, is required. Aim: The aim of this literature study was to describe adult patients' experiences related to abdominal aortic aneurysm, both during conservative treatment and postoperatively and how it affects daily life. Method: A literature study which is based on twelve scientific articles with qualitative study design. The articles were retrieved from three different databases with a focus on medicine and nursing and were thereafter analysed inductively with a simplified form of metasynthesis. Result: Five main categories and seven subcategories of patient experiences were identified. The main categories were: experiences around the need for information; experiences of being able to trust the health care; worry, fear and anxiety related to AAA; AAA's impact on daily life; and the possibility to be involved in the care process. Conclusion: The literature review shows that AAA is experienced with a large variety of patients. But above all, patients experience a lack of information and knowledge about their AAA where further support, information and knowledge is desired by patients.  Keywords: Abdominal aortic aneurysm, Daily life, Experiences, Patients, Person-centred care.

La physiopathologie de l’anévrysme de l’aorte abdominale (AAA) est multifactorielle. De la plaque athéro-thrombotique jusqu’à l’anévrisme menaçant, les phénomènes hémodynamiques, protéolytiques, oxydatifs et inflammatoires jouent un rôle aussi complexe qu’interdépendant. Aucun traitement pharmacologique n’a fait la preuve de son efficacité. Dans ce travail, nous étudions 2 voies pharmacologiques potentielles, et développons un modèle murin d’exclusion endovasculaire. La rapamycine est utilisée en oncologie. Ses propriétés anti-inflammatoires, antiprolifératives et anti-angiogéniques stabilisaient la progression anévrismale dans un modèle établi d’AAA. L’AZD9668 est un inhibiteur sélectif de l’élastase. Sécrétée par les neutrophiles, cette protéase joue un rôle clé dans la physiopathologie anévrismale. Les propriétés thérapeutiques ont été étudiées sur un modèle murin potentialisé par l’injection systémique de Porphyromonas Gingivalis, entretenant la réaction inflammatoire et protéolytique pariétale. Dans un second temps, nous avons développé un modèle murin d’exclusion endovasculaire. La spécificité de ce traitement a soulevé de nouvelles problématiques, soulignant le rôle crucial de l’activité biologique du thrombus. L’exclusion endovasculaire d’un AAA sur les modèles de grands animaux est complexe et coûteuse. Nous avons ainsi décrit la technique sur un modèle reconnu d’AAA chez le rat. Le traitement pharmacologique des AAAs a démontré son efficacité sur modèles murins, mais est difficilement transposable à l’homme en raison des effets secondaires. Un traitement endoluminal véhiculant un principe actif délivré in-situ permettrait de stabiliser durablement les AAA. / Abdominal aortic aneurysm (AAA) pathophysiology is multifactorial. From the athero-thrombotic plaque to a threatening aneurysm, hemodynamic, proteolysis, oxidation and inflammation play a complex but interdependent role. No pharmacological treatment has yet proved to be efficient. In this work, we study 2 potential pharmacological targets, and develop a murine model of endovascular abdominal aneurysm repair (EVAR). Rapamycine is used in oncology. Its anti-inflammatory, anti-proliferative and antiangiogenic properties stabilized aneurysm progression on an established AAA. AZD9668 is an elastase selective inhibitor. Secreted by neutrophils, this protease plays a key role in aneurysmal pathophysiology. Its therapeutic benefits have been study on a murine AAA model potentiated by Porphyromonas Gingivalis systemic injection, maintaining inflammatory reaction and wall proteolysis. Then, we developed a murine endovascular aneurysm exclusion model. EVAR raised new concern, underlining the crucial role of the thrombus biological activity. Endovascular AAA exclusion on big animals is complex and expensive. We hence described the technic on a rat AAA well known model. Pharmacological AAAs treatment has proved to be efficient on murine models, but is hard to transpose to humans because of systemic side effects. An endoluminal treatment carrying active drugs, and delivered in-situ, could durably stabilize AAAs.

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>