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  • Public defence: 2017-09-22 09:00 NUS 1D - Tandläkarhögskolan, Hörsal D, Umeå
    Nilsson, Ulf
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Cardiovascular aspects on chronic obstructive pulmonary disease: with focus on ischemic ECG abnormalities, QT prolongation and arterial stiffness2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background

    Chronic Obstructive Pulmonary disease (COPD) is an under-diagnosed disease with a prevalence of approximately 10%, highly dependent on age and smoking habits. Comorbidities are common in COPD and of these, cardiovascular diseases (CVD) are the most common. COPD is the fourth leading cause of death globally, and CVD probably contribute to the high mortality. Within CVD, Ischemic Heart Disease (IHD) is the most common. It is highly clinically relevant to identify signs of ischemic heart disease, other cardiac conditions, and risk factors for CVD in COPD. Electrocardiogram (ECG) is a simple but still major diagnostic tool in clinical cardiology, including disturbances in the electric conduction system and ischemia. Due to the under-diagnosis of COPD, there is limited knowledge regarding the prevalence and prognostic impact of ECG abnormalities in COPD. Arterial stiffness is a risk factor for CVD, which has raised an increased interest, however not evaluated in population based studies of COPD.

    Aim

    The overall aim was to describe cardiovascular aspects on COPD, with a specific focus on arterial stiffness, prevalence and prognostic impact of ischemic ECG abnormalities and prolonged QT interval, by comparing subjects with and without obstructive lung function impairment in a population-based cohort.

    Methods

    The thesis is based on the Obstructive Lung Disease in Northern Sweden (OLIN) COPD study; a population-based longitudinal cohort study. During the years 2002-2004, all participants in clinical examinations from previously recruited large population-based cohorts were invited to re-examination including spirometry and a structured interview. All subjects with obstructive lung function impairment (n=993) were identified, together with 993 age and sex-matched referents without airway obstruction. The study population (n=1986) has been invited to annual examinations since 2005 including spirometry and structured interview. Papers I-III are based on data from 2005 when electrocardiogram (ECG) was recorded in addition to the basic program. All ECGs were Minnesota coded and QT-time was measured. Paper IV is based data from 2010 when non-invasive measurements of arterial stiffness, assessed as pulse wave velocity (PWV), was added to the program. Spirometric data were classified as normal lung function (NLF), restrictive spirometric pattern (RSP) and airway obstruction (COPD). The following spirometric criteria for COPD were used: post-bronchodilator FEV1/VC<0.70 (papers I-IV, in paper III labelled GOLD-COPD) and lower limit of normal, LLN (LLN-COPD) (paper III). Spirometric classification of COPD severity was based on FEV1 % predicted as a continuous variable or according to the Global Initiative for Obstructive Lung Disease (GOLD), divided into GOLD 1-4.

    Results

    The prevalence of ischemic heart disease (IHD), both self-reported and assessed as probable and possible ischemic ECG abnormalities (I-ECG) according to the Whitehall criteria, was similar among subjects with NLF and COPD. The prevalence of both self-reported and probable (I-ECG) according to Whitehall increased by GOLD grade.  Among those with COPD, self-reported IHD was associated with disease severity, assessed as FEV1 % predicted also after adjustment for age and sex (paper I).

    In both COPD and NLF, those with I-ECG had a higher cumulative mortality over 5 years than those without I-ECG (29.6 vs. 10.6%, p<0.001 and 17.1 vs. 6.3 %, p=0.001). When analysed in a multivariate model, the Mortality Risk Ratio (MRR, 95%CI) was increased for subjects with COPD and I-ECG (2.4, 1.5-3.9), and non-significantly so for NLF with I-ECG (1.65, 0.94-2.90), when compared to NLF without I-ECG.  When analyzed separately among subjects with COPD, the increased risk for death associated with I-ECG persisted independent of age, sex, BMI-class, smoking habits and disease severity assessed as FEV1 % predicted (1.89, 1.20-2.99). The proportion without reported IHD was high among those with I-ECG; 72.4% in NLF and 67.3% in COPD. The pattern was similar also among them; I-ECG was associated with an increased risk for death in COPD and non-significantly so in NLF (paper II).

    Mean corrected QT-time (QTc) and prevalence of QTc prolongation was higher in RSP than NLF but similar in NLF and GOLD-COPD. The prevalence of borderline as well as prolonged QTc increased by GOLD grade (test for trend p=0.012 for both groups). Of those with GOLD-COPD, 52% fulfilled the LLN-criterion (LLN-COPD). When comparing LLN-COPD and NLF, the pattern was similar as when comparing NLF and GOLD-COPD. The cumulative mortality over 5 years was higher among subjects with borderline and prolonged QTc than those with normal QTc in subjects with GOLD-COPD and LLN-COPD but not in NLF and RSP (paper III).

    Arterial stiffness, assessed as PWV, was higher in GOLD 3-4 compared to non-COPD (10.52 vs. 9.13 m/s, p=0.042). Reported CVD and age >60 were both associated with significantly higher PWV in COPD as well as in non-COPD. In a multivariate model, GOLD 3-4 remained associated with higher PWV when compared with non-COPD, also when adjusted for sex, age group, smoking habits, blood pressure, reported CVD and pulse rate (paper IV).

    Conclusion

    In this population-based study, the prevalence of ischemic ECG abnormalities was similar among subjects with normal lung function and COPD, but increased by disease severity among subjects with COPD. Ischemic ECG abnormalities were associated with an increased mortality among subjects with COPD, independent of common confounders and disease severity, also among those without known heart disease. Whilst the prevalence of QTc prolongation was similar in NLF, COPD and LLN-COPD, it was associated with an increased mortality only in the COPD-groups. ECG is a simple non-invasive method and seems to identify findings of prognostic importance among subjects with COPD. Central arterial stiffness, a known risk factor for cardiovascular disease, was increased among subjects with severe and very severe COPD when compared to subjects without COPD independent of common confounders.

  • Public defence: 2017-09-22 09:00 föreläsningsal A103 (Astrid Fagreus-salen), byggnad 6A, Norrlands Universitetssjukhus, Umeå
    Vdovikova, Svitlana
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Roles of membrane vesicles in bacterial pathogenesis2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The production of membranous vesicles is observed to occur among organisms from all domains of the tree of life spanning prokaryotes (bacteria, archaea) and eukaryotes (plants, animals and fungi). Bacterial release of membrane-derived vesicles (MVs) has been studied most extensively in cases of Gram-negative species and implicating their outer membrane in formation of extracellular MVs. However, recent studies focusing on Gram-positive bacteria have established that they also undergo MV formation. Membrane vesicles are released during normal bacterial growth, they are derived from the bacterial membrane(s) and may function as transporters of different proteins, DNA and RNA to the neighbouring bacteria or to the cells of a mammalian host. The transport of virulence factors in a condensed manner via MVs to the host cells presumably protects these proteins from degradation and, thereby, targets the host cells in a specific manner.

    The aim of my thesis is to investigate secretion of MV-associated virulence factors and to study interactions of MVs produced by two selected Gram-negative and Gram-positive bacteria, i.e. Vibrio cholerae and Listeria monocytogenes, with eukaryotic host cells. Depending on whether the bacterium acts as an extracellular or intracellular pathogen, MVs may be considered to have specific functions, which may lead to the different outcomes of MV-host interactions.

    V. cholerae transport systems for virulence factors include the Type VI secretion system and MVs (also referred to as the “Type 0” secretion system). We have identified that the biologically active form of PrtV protease in different V. cholerae serogroups is transported via MVs. PrtV protease is essential for V. cholerae environmental survival and protection from natural predator grazing. We demonstrated that PrtV is primarily translocated via the inner membrane to the periplasmic space, where it undergoes autoproteolysis, and the truncated version of PrtV protein is packaged inside the MVs and released from the surface of bacteria. MV-associated PrtV protease showed a contribution to bacterial resistance towards the antimicrobial peptide LL-37, thereby, enhancing bacterial survival by avoiding this innate immune defense of the host.

    We also studied another virulence factor of V. cholerae, the pore-forming toxin VCC, which was found to be transported by MVs. MV-associated VCC is biologically active and triggers an autophagic response in the target cells. We suggested that autophagy serves as a cellular defense mechanism against the MV-associated bacterial virulence factor of V. cholerae.

    Listeria monocytogenes is a Gram-positive intracellular and facultative anaerobic food-borne pathogen causing listeriosis. It causes only sporadic outbreaks in healthy individuals, however, it is dangerous for a fetus or newborn child, and for pregnant and immunocompromised people, leading to a deadly infection in one third of the cases. We have analyzed MVs produced by L. monocytogenes and their interaction with eukaryotic cells. Confocal microscopy analysis showed that MVs are internalized into HeLa and HEK293 cells and are accumulated in lysosomes. Moreover, L. monocytogenes produces MVs inside the host cells and even inside the phagosomes. We found that the major virulence factor of L. monocytogenes, the cholesterol-dependent pore-forming protein listeriolysin O (LLO), is entrapped inside the MVs and resides there in an oxidized inactive state. LLO is known to induce autophagy by making pores in the phagosomal membrane of targeted eukaryotic cells. In our studies, we have shown that MVs effectively abrogated autophagy induced by Torin1, by purified LLO or by another pore-forming toxin from V. cholerae. We also found that MVs promote bacterial intracellular survival inside mouse embryonic fibroblasts. In addition, MVs have been shown to have a strong protective activity against host cell necrosis initiated by pore-forming toxin. Taken together, these findings suggested that in vivo MVs production from L. monocytogenes might be a relevant strategy of bacteria to manipulate host responses and to promote bacterial survival inside the host cells. 

  • Public defence: 2017-09-22 09:00 KBE303-Stora hörsalen, KBC-huset
    Zhou, Yang
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Regulation of pre-mRNA splicing and mRNA degradation in Saccharomyces cerevisiae2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Messenger RNAs are transcribed and co-transcriptionally processed in the nucleus, and transported to the cytoplasm. In the cytoplasm, mRNAs serve as the template for protein synthesis and are eventually degraded. The removal of intron sequences from a precursor mRNA is termed splicing and is carried out by the dynamic spliceosome. In this thesis, I describe the regulated splicing of two transcripts in Saccharomyces cerevisiae. I also describe a study where the mechanisms that control the expression of magnesium transporters are elucidated.

    The pre-mRNA retention and splicing (RES) complex is a spliceosome-associated protein complex that promotes the splicing and nuclear retention of a subset of pre-mRNAs. The RES complex consists of three subunits, Bud13p, Snu17p and Pml1p. We show that the lack of RES factors causes a decrease in the formation of N4-acetylcytidine (ac4C) in tRNAs. This phenotype is caused by inefficient splicing of the pre-mRNA of the TAN1 gene, which is required for the formation of ac4C in tRNAs. The RES mutants also show growth defects that are exacerbated at elevated temperatures. We show that the temperature sensitive phenotype of the bud13Δ and snu17Δ cells is caused by the inefficient splicing of the MED20 pre-mRNA. The MED20 gene encodes a subunit of the Mediator complex. Unspliced pre-mRNAs that enter the cytoplasm are usually degraded by the nonsense-mediated mRNA decay (NMD) pathway, which targets transcripts that contain premature translation termination codons. Consistent with the nuclear retention function of the RES complex, we find that NMD inactivation in the RES mutants leads to the accumulation of both TAN1 and MED20 pre-mRNAs. We also show that the cis-acting elements that promote RES-dependent splicing are different between the TAN1 and MED20 pre-mRNAs.

    The NMD pathway also targets transcripts with upstream ORFs (uORFs) for degradation. The ALR1 gene encodes the major magnesium importer in yeast, and its expression is controlled by the NMD pathway via a uORF in the 5’ untranslated region. We show that the ribosome reaches the downstream main ORF by a translation reinitiation mechanism. The NMD pathway was shown to control cellular Mg2+ levels by regulating the expression of the ALR1 gene. We further show that the NMD pathway targets the transcripts of the vacuolar Mg2+ exporter Mnr2p and the mitochondrial Mg2+ exporter Mme1p for degradation.

    In summary, we conclude that the RES complex has a role in the splicing regulation of a subset of transcripts. We also suggest a regulatory role for the NMD pathway in maintaining the cellular Mg2+ concentration by controlling the expression of Mg2+ transporters.

  • Public defence: 2017-09-22 10:00 Hörsal 1031, Norra beteendevetarhuset, Umeå
    Wedman, Jonathan
    Umeå University, Faculty of Social Sciences, Department of applied educational science, Departement of Educational Measurement.
    Theory and validity evidence for a large-scale test for selection to higher education2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Validity is a crucial part of all forms of measurement, and especially in instruments that are high-stakes to the test takers. The aim of this thesis was to examine theory and validity evidence for a recently revised large-scale instrument used for selection to higher education in Sweden, the Swedish Scholastic Assessment Test (SweSAT), as well as identify threats to its validity. Previous versions of the SweSAT have been intensely studied but when it was revised in 2011, further research was needed to strengthen the validity arguments for the test. The validity approach suggested in the most recent version of the Standards for education and psychological testing, in which the theoretical basis and five sources of validity evidence are the key aspects of validity, was adopted in this thesis.

    The four studies that are presented in this thesis focus on different aspects of the SweSAT, including theory, score reporting, item functioning and linking of test forms. These studies examine validity evidence from four of the five sources of validity: evidence based on test content, response processes, internal structure and consequences of testing.

    The results from the thesis as a whole show that there is validity evidence that supports some of the validity arguments for the intended interpretations and uses of SweSAT scores, and that there are potential threats to validity that require further attention. Empirical evidence supports the two-dimensional structure of the construct scholastic proficiency, but the construct requires a more thorough definition in order to better examine validity evidence based on content and consequences for test takers. Section scores provide more information about test takers' strengths and weaknesses than what is already provided by the total score and can therefore be reported, but subtest scores do not provide additional information and should not be reported. All four quantitative subtests, as well as the Swedish reading comprehension subtest, are essentially free of differential item functioning (DIF) but there is moderate DIF that could be bias in two of the four verbal subtests. Finally, the equating procedure, although it appears to be appropriate, needs to be examined further in order to determine whether it is the best practice available or not for the SweSAT.

    Some of the results in this thesis are specific to the SweSAT because only SweSAT data was used but the design of the studies and the methods that were applied serve as practical examples of validating a test and are therefore likely useful to different populations of people involved in test development, test use and psychometric research.

    Suggestions for further research include: (1) a study to create a more clear and elaborate definition of the construct, scholastic proficiency; (2) a large and empirically focused study of subscore value in the SweSAT using repeat test takers and applying Haberman’s method along with recently proposed effect size measures; (3) a cross-validation DIF-study using more recently administered test forms; (4) a study that examines the causes for the recurring score differences between women and men on the SweSAT; and (5) a study that re-examines the best practice for equating the current version of the SweSAT, using simulated data in addition to empirical data.

  • Public defence: 2017-09-22 10:15 Hörsal B, samhällsvetarhuset, Umeå
    Holm, Fanny
    Umeå University, Faculty of Social Sciences, Department of Law.
    Justice for victims of atrocity crimes: prosecution and reparations under international law2017Doctoral thesis, monograph (Other academic)
    Abstract [en]

    This thesis takes its starting point from the need for a comprehensive approach towards justice following atrocities, and where not only the states in which the crimes were committed have a role to play. The thesis discusses atrocity crime (genocide, crimes against humanity and war crimes) prosecution and reparations procedures concerning individuals as two appropriate courses of action, through which non-territorial states may contribute to atrocity prevention and justice for the victims of atrocities. The analysis addresses whether, under international law, non-territorial states are allowed to, required to, or prohibited from facilitating prosecution and reparations procedures and includes an assessment of the extent to which international law relating to reparations fails to correspond to that applicable to prosecution. The implications of the lack of correspondence are analysed in light of the historical connection and separation of the two courses of action, the procedural and substantive legal overlaps between prosecution and reparations, and the underlying aims and functions of prosecution and reparations. The study covers a wide spectrum of international legal sources, most of them to be found in human rights law, humanitarian law and international criminal law.

    The study shows that while non-territorial states are included in both conventional and customary law as regards prosecution of atrocity crimes, the same cannot be said in relation to reparations procedures. This serious deficit and inconsistency in international law, is explained by the framing of reparations, but not prosecution, as a matter concerning victims and human rights, thereby leaving the enforcement of the rules to the discretion of each state. Reparation is also considered a private matter and as such falls outside the scope of the far-reaching obligations regarding prosecution. The study suggests taking further the responsibilities of non-territorial states in relation to atrocity crimes. Most urgently, measures should be considered that bring the legal space for reparations procedures into line with that for prosecution in, for instance, future discussions by human rights treaty-monitoring bodies and in the drafting of new international victims' rights, atrocity crimes or civil procedure instruments.

  • Public defence: 2017-09-22 13:00 Hörsal A, Samhällsvetarhuset, Umeå
    Rezvani, Zeinab
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Business Administration.
    Drivers to and barriers against sustainable consumption: exploring the role of consumer anticipated emotions in the context of consumer adoption of alternative fuel vehicles2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    With the increasing environmental problems, sustainable consumption is an important consumer behavior. Therefore, it is important to investigate further the significant drivers to and barriers against sustainable consumption, in order to increase the share of sustainable consumption and understanding of consumer behavior. This dissertation identifies two gaps. The first is in understanding consumer positive and negative anticipated emotions as an important factor influencing high-involvement sustainable consumption. The second gap relates to the lack of understanding about the associations between anticipated emotions and personal moral norms in high-involvement sustainable consumption. Against this background, the aim is to contribute to the sustainable consumption literature by investigating the roles and relations of anticipated emotions, personal moral norms, and weighing costs and benefits as drivers to and barriers against consumer adoption of a high-involvement sustainable product. A literature review and two empirical studies were conducted. Consumer adoption of alternative fuel vehicles is the specific sustainable consumption. Using quantitative methods, this phenomenon is investigated in the empirical studies conducted in Sweden. It was shown that anticipated emotions have direct effects on consumers' intention to adopt alternative fuel vehicles. Moreover, positive anticipated emotions (e.g. pride, pleasure, happiness) are drivers of sustainable consumption, while negative anticipated emotions (e.g. regret, embarrassment) are barriers against the sustainable consumption. This dissertation suggests an extension to the norm activation model, and shows that moral norms, ascription of responsibility, and awareness of environmental problems influence consumers' intentions through consumers’ anticipated emotions. For people who perceive high social norms related to decreasing the environmental impacts of car driving, the influence of positive anticipated emotions and personal moral norms are stronger. This points toward the social aspect of sustainable consumption and suggests that targeting the consumers who perceive high social norms is an important step to promoting sustainable consumption. Findings would be of relevance to marketers, policymakers and environmental organizations. Creating awareness and communicating personal responsibilities and moral norms related to the environment and consumption are important drivers for consumer adoption of sustainable products. However, it is noteworthy that consumer anticipated emotions about high-involvement sustainable products (such as alternative fuel vehicle) have also important influence on the sustainable consumption. Thus, consumer anticipated emotions should be considered in designing promotion programs.

  • Public defence: 2017-09-27 09:00 Hörsal E, Humanisthuset, Umeå
    Prittinen, Juha
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Studies on various culture systems for chondrocytes and osteoblasts2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Osteoarthritis and osteochondral defects are ailments that are increasing in frequency as the lifespan of the population increases and sedentary lifestyle becomes more common. Osteoarthritis is an inflammatory disease that causes the progressive degeneration of articular surfaces and the underlying bone. Accidents and injuries can cause osteochondral defects similar to osteoarthritis. In both cases the structure of the articular cartilage fails, leading to pain and disability. Articular cartilage has a naturally poor ability to regenerate since there is no vasculature and it is aneural. The sparse chondrocytes mainly act to maintain the healthy extracellular matrix. Once the defect is severe enough, a surgical intervention becomes necessary. For small defects and young patients, a cell-based treatment can be used, whereas for larger defects and severe osteoarthritis a partial or whole joint arthroplasty is performed. Methods to repair osteochondral defects have been improving over the years as the inter-disciplinary understanding of joints, and what is required to repair them, has increased. However, there are still issues to solve in order to achieve consistently good results in both joint replacement and repair of cartilage. The main issue faced with current techniques used for joint replacement is poor integration of the artificial joint, leading to loosening at the bone interface over time, while cartilage repair techniques face the problem of generating mechanically inferior fibrocartilage. It is known that surface chemistry and structures at micro- and nanoscale influence cell behaviour, which can be utilised to guide their attachment, proliferation and phenotype. Scaffold-free approaches and mechanical stimulation have previously given promising results in generating articular neocartilage.

    This thesis aims at exploring tools and solutions to the problems involved in implant integration, chondrocyte expansion and neocartilage tissue engineering. We hypothesised that 1) ultra-short pulsed laser deposition can be used to create biocompatible coatings; 2) micropillars with nanoscale features can improve the maintenance of the chondrocyte phenotype in culture and 3) hypergravity can aid in the production of more native-like neocartilage constructs.

    Our studies showed that ultra-short pulsed laser ablation can be used to create various surfaces for studying cell behaviour. Cell viability was slightly higher on a rough titanium oxide, whereas the cell area was significantly smaller on rough titanium oxide, indicating a lower amount of focal adhesions. Nanopatterned microstructures were not capable of maintaining the chondrocyte phenotype in culture, but they were not disadvantageous either. Hypergravity might help in creating a native-like distribution of collagen and proteoglycans. The constructs were more uniform in shape, but biomechanically the constructs were not different from non-centrifuged controls.

  • Public defence: 2017-09-28 09:00 Major Groove, building 6L, Umeå
    Forsgren, Elin
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Using patient-derived cell models to investigate the role of misfolded SOD1 in ALS2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Protein misfolding and aggregation underlie several neurodegenerative proteinopathies including amyotrophic lateral sclerosis (ALS). Superoxide dismutase 1 (SOD1) was the first gene found to be associated with familial ALS. Overexpression of human mutant or wild type SOD1 in transgenic mouse models induces motor neuron (MN) degeneration and an ALS-like phenotype. SOD1 mutations, leading to the destabilization of the SOD1 protein is associated with ALS pathogenesis. However, how misfolded SOD1 toxicity specifically affects human MNs is not clear. The aim of this thesis was to develop patient-derived, cellular models of ALS to help understand the pathogenic mechanisms underlying SOD1.

    To understand which cellular pathways impact on the level of misfolded SOD1 in human cells, we established a model using patient-derived fibroblasts and quantified misfolded SOD1 in relation to disturbances in several ALS-related cellular pathways. Misfolded SOD1 levels did not change following reduction in autophagy, inhibition of the mitochondrial respiratory chain, or induction of endoplasmic reticulum (ER)-stress. However, inhibition of the ubiquitin-proteasome system (UPS) lead to a dramatic increase in misfolded SOD1 levels. Hence, an age-related decline in proteasome activity might underlie the late-life onset that is typically seen in SOD1 ALS.

    To address whether or not SOD1 misfolding is enhanced in human MNs, we used mixed MN/astrocyte cultures (MNCs) generated in vitro from patient-specific induced pluripotent stem cells (iPSCs). Levels of soluble misfolded SOD1 were increased in MNCs as well as in pure iPSC-derived astrocytes compared to other cell types, including sensory neuron cultures. Interestingly, this was the case for both mutant and wild type human SOD1, although the increase was enhanced in SOD1 FALS MNCs. Misfolded SOD1 was also found to exist in the same form as in mouse SOD1 overexpression models and was identified as a substrate for 20S proteasome degradation. Hence, the vulnerability of motor areas to ALS could be explained by increased SOD1 misfolding, specifically in MNs and astrocytes.

    To investigate factors that might promote SOD1 misfolding, we focussed on the stability of SOD1 mediated by a crucial, stabilizing C57-C146 disulphide bond and its redox status. Formation of disulphide bond is dependent on oxidation by O2 and catalysed by CCS. To investigate whether low O2 tension affects the stability of SOD1 in vitro we cultured fibroblasts and iPSC-derived MNCs under different oxygen tensions. Low oxygen tension promoted disulphide-reduction, SOD1 misfolding and aggregation. This response was much greater in MNCs compared to fibroblasts, suggesting that MNs may be especially sensitive to low oxygen tension and areas with low oxygen supply could serve as foci for ALS initiation.

    SOD1 truncation mutations often lack C146, and cannot adopt a native fold and are rapidly degraded. We characterized soluble misfolded and aggregated SOD1 in patient-derived cells carrying a novel SOD1 D96Mfs*8 mutation as well as in cells fom an unaffected mutation carrier. The truncated protein has a C-terminal fusion of seven non-native amino acids and was found to be extremely prone to aggregation in vitro. Since not all mutation carriers develop ALS, our results suggested this novel mutation is associated with reduced penetrance.

    In summary, patient derived cells are useful models to study factors affecting SOD1 misfolded and aggregation. We show for the first time that misfolding of a disordered and disease associated protein is enhanced in disease-related cell types. Showing that misfolded SOD1 exists in human cells in the same form as in transgenic mouse models strengthens the translatability of results obtained in the two species. Our results demonstrate disulphide-reduction and misfolding/aggregation of SOD1 and suggest that 20S proteasome could be an important therapeutic target for early stages of disease. This model provides a great opportunity to study pathogenic mechanisms of both familial and sporadic ALS in patient-derived models of ALS. 

  • Public defence: 2017-09-29 09:00 Sal 1031, Norra Beteendevetarhuset, Umeå universitet, Umeå
    Hansson, Jonas
    Umeå University, Faculty of Social Sciences, Police Education Unit at Umeå University. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Mind the blues: Swedish police officers' mental health and forced deportation of unaccompanied refugee children2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Introduction: Policing is a public health issue. The police often encounter vulnerable populations. Police officers have wide discretionary powers, which could impact on how they support vulnerable populations. In encountering vulnerable populations the police officers are required to be professional; maintaining mental health in the face of challenges is part of professionalism. Their encounters with vulnerable populations might influence their mental health which in turn might influence the way they use their discretion when making decisions.

    Background/context: Sweden receives more unaccompanied, asylum-seeking refugee children than any other country in Europe. The number of asylum applications for such children increased from 400 in 2004 to 7000 in 2014 to over 35,000 in 2015. These children come to Sweden and apply for asylum without being under the care of their parents or other legal guardian. Some are denied asylum. If they do not return to their country of origin voluntarily the police are responsible for their deportation. The Swedish government wants an increasing number of deportations and wants them carried out with dignity. This thesis is about the police officers’ perceptions of how to interpret the seemingly contradictory demands for more deportations, that is, efficiency; and concerns for human rights during the deportation process, that is, dignity. This is conceptualized using three theoretical frameworks: a) street-level bureaucracy, b) job demand-control-social support model and c) coping. These theoretical frameworks indicate the complexity of the issue and function as constructions by means of which understanding can be brought to the police officers’ perceptions of deportation work involving unaccompanied, asylum-seeking refugee children and how such work is associated to their mental health.

    Aim: The current research aims to investigate and analyse Swedish police officers’ mental health in the context of deportations of unaccompanied, asylum-seeking refugee children.

    Methods: This thesis uses both qualitative and quantitative methodology. The qualitative approach comprised interviews conducted to achieve a deeper understanding of the phenomenon of police officers’ perceptions of deportations of unaccompanied, asylum-seeking refugee children. The quantitative method involved the use of validated questionnaires to investigate the association between police officers’ mental health and psychosocial job characteristics and coping. This approach made it possible to study a complex issue in a complex environment and to present relevant recommendations. A total of 14 border police officers were interviewed and 714 police officers responded to a survey.

    Results: The police officers utilize their wide discretionary powers and perceive that they are doing what is best in the situation, trying to listen to the child and to be aware of the child’s needs. Police officers with experience of deportations of unaccompanied, asylum-seeking refugee children were not found to have poorer mental health than police officers with no such experience. Furthermore, high job demand, low decision latitude, low levels of work-related social support, shift work and being single are associated with poor mental health. Coping moderates the association between mental health and the experience of carrying out deportations of unaccompanied, asylum-seeking, refugee children, and the police officers seem to utilize both emotional and problem-solving coping during the same complex deportation process.

    Implications / conclusions: The general conclusion reached in this thesis is that if police officers are subject to reasonable demands, have high decision latitude, access to work-related social support, and utilize adaptable coping, the deportation work does not seem to affect their mental health. When police officers meet vulnerable people, they utilize their discretionary powers to deal with seemingly contradictory demands, that is, efficiency and dignity. The executive role in the deportations of unaccompanied, asylum-seeking refugee children and the awareness of dealing with a child threatened with deportation might give rise to activation of a sense of protection, safety and security. Discretion might make it possible to act on this sense of protection, safety and security and to combine efficiency and dignity. Further studies, which integrate cognitive and emotional discretion with coping, need to be undertaken.

  • Public defence: 2017-09-29 09:00 Vårdvetarhuset Aula, Umeå
    Björk, Sabine
    Umeå University, Faculty of Medicine, Department of Nursing.
    Exploring resident thriving in Swedish nursing homes: the Umeå Ageing and Health Research Programme (U-Age) Thesis I2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background

    The population living in nursing homes is generally characterized by high age and female sex, as well as by physical and cognitive impairments. Also, negative symptoms such as pain and neuropsychiatric symptoms are reportedly common. Care in Swedish nursing homes is regulated by law and national guidelines implying that care is to be tailored to resident preferences and needs in order to facilitate their well-being. However, there is no national data source on the characteristics of nursing home residents or on measures of their well-being. Thriving and not merely surviving in nursing homes has been described as a subjective experience of place-related well-being resulting from interaction between residents and the nursing home environment in terms of the quality of care and caregivers, as well as from the physical and psychosocial environment. However, there is a gap in knowledge of whether and, if so, to what extent resident characteristics and factors in the nursing home environment are associated with resident thriving in nursing homes.

    Aim

    The overall aim of this thesis is to explore resident thriving in Swedish nursing homes, and the extent to which resident characteristics, neuropsychiatric symptoms, activities, and environmental factors are associated with resident thriving.

    Methods

    This thesis is based on cross-sectional baseline data from a national inventory of health and care in Swedish nursing homes collected in 2013–2014. The resident sample covered 4831 residents in 548 units from 172 nursing homes in 35 Swedish municipalities. The data were explored using descriptive statistics, as well as simple and multiple linear regression analyses and multilevel linear regression analyses. Resident characteristics and symptom prevalence as well as their associations with thriving; and engagement in everyday activities and their associations with thriving were explored in a sample comprising 4831 nursing home residents from 172 nursing homes. Associations between resident thriving and resident living conditions, nursing home facility and unit characteristics, and the psychosocial climate of units were explored in a sample comprising 4205 residents from 147 nursing homes.

    Results

    Engagement in everyday activities was positively associated with resident thriving, the strongest associations being found for engagement in an activity programme, dressing nicely, and spending time with someone the resident likes. 

    Environmental factors associated with thriving were a positive psychosocial climate at the unit, having access to newspapers, residing in a special care unit, and residing in a facility that was unlocked during the day. Cognitive functioning was strongly associated with resident thriving. Aggressive and depressive symptoms were found to be negatively associated with resident thriving regardless of levels of cognitive functioning.

    Conclusions

    Engagement in everyday activities can support thriving and can be conceptualized and implemented as nursing interventions to facilitate thriving in nursing homes. Factors in the nursing home environment can support resident thriving; in particular, the psychosocial climate of units seems to have a great influence. Aggressive and depressive symptoms were associated with lower levels of thriving. Targeting these symptoms would therefore seem to be a priority in nursing homes. The population living in Swedish nursing homes has a high prevalence of neuropsychiatric symptoms and cognitive impairment. Residents with cognitive impairment also commonly resided in general units. As all data were cross-sectional, longitudinal studies would be valuable to further explore causality. As resident data were based on proxy ratings, future research exploring residents’ perspectives on thriving would be valuable. The present findings contribute to our understanding of nursing home residents’ complex care needs and identify factors that could have an impact on their well-being. These findings can provide benchmark estimates for further research, quality assessment activities, as well as further clinical development work. 

    The full text will be freely available from 2018-08-29 00:00
  • Public defence: 2017-09-29 09:35 Sal 933, Umeå
    Jonasson, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR).
    Aerobic fitness and healthy brain aging: cognition, brain structure, and dopamine2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Performing aerobic exercise and maintaining high levels of aerobic fitness may have positive effects on both brain structure and function in older adults. Despite decades of research however, there is still a rather poor understanding of the neurocognitive mechanisms explaining the positive effects of aerobic exercise on cognition. Changes in prefrontal gray matter as well as dopaminergic neurotransmission in striatum are both candidate neurocognitive mechanisms. The main aims of this thesis are: 1. To investigate the effects of aerobic exercise and fitness on cognition and magnetic resonance imaging (MRI) derived gray matter volumes using data from a 6 month physical exercise intervention in older adults (Study I). 2. To simulate the effect of atrophy in longitudinal positron emission tomography (PET) which could pose a challenge to interpreting changes in longitudinal PET imaging (Study II). 3. To study the influence of aerobic exercise and fitness on the dopamine D2-receptor (D2R) system in striatum using [11C]raclopride PET as a potential mechanism for improved cognition (Study III).

    Results: In Study I, aerobic exercise was found to improve cognitive performance in a broad, rather than domain-specific sense. Moreover, aerobic fitness was related to prefrontal cortical thickness, and improved aerobic fitness over 6 months was related to increased hippocampal volume. In Study II, we identified areas in the striatum vulnerable to the effect of shrinkage, which should be considered in longitudinal PET imaging. Finally, in Study III, the effect of being aerobically fit, and improving fitness levels was found to impact dopaminergic neurotransmission in the striatum, which in turn mediated fitness-induced improvements in working memory updating performance.

    Conclusion: The findings in this thesis provide novel evidence regarding the neurocognitive mechanisms of aerobic exercise-induced improvements in cognition, and impacts the interpretation of longitudinal PET imaging. Performing aerobic exercise and staying aerobically fit at an older age have positive effects on cognition and brain systems important for memory and cognition. Specifically, fitness-induced changes to the dopaminergic system stands out as one novel neurocognitive mechanism explaining the positive effects of aerobic fitness on working-memory performance in healthy older adults.

  • Public defence: 2017-09-29 13:00 N430, Naturvetarhuset, Umeå
    Zechner, Niklas
    Umeå University, Faculty of Science and Technology, Department of Computing Science.
    A novel approach to text classification2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis explores the foundations of text classification, using both empirical and deductive methods, with a focus on author identification and syntactic methods. We strive for a thorough theoretical understanding of what affects the effectiveness of classification in general. 

    To begin with, we systematically investigate the effects of some parameters on the accuracy of author identification. How is the accuracy affected by the number of candidate authors, and the amount of data per candidate? Are there differences in how methods react to the changes in parameters? Using the same techniques, we see indications that methods previously thought to be topic-independent might not be so, but that syntactic methods may be the best option for avoiding topic dependence. This means that previous studies may have overestimated the power of lexical methods. We also briefly look for ways of spotting which particular features might be the most effective for classification. Apart from author identification, we apply similar methods to identifying properties of the author, including age and gender, and attempt to estimate the number of distinct authors in a text sample. In all cases, the techniques are proven viable if not overwhelmingly accurate, and we see that lexical and syntactic methods give very similar results. 

    In the final parts, we see some results of automata theory that can be of use for syntactic analysis and classification. First, we generalise a known algorithm for finding a list of the best-ranked strings according to a weighted automaton, to doing the same with trees and a tree automaton. This result can be of use for speeding up parsing, which often runs in several steps, where each step needs several trees from the previous as input. Second, we use a compressed version of deterministic finite automata, known as failure automata, and prove that finding the optimal compression is NP-complete, but that there are efficient algorithms for finding good approximations. Third, we find and prove the derivatives of regular expressions with cuts. Derivatives are an operation on expressions to calculate the remaining expression after reading a given symbol, and cuts are an extension to regular expressions found in many programming languages. Together, these findings may be able to improve on the syntactic analysis which we have seen is a valuable tool for text classification.

  • Public defence: 2017-09-29 13:00 Humanisthuset hörsal F, Umeå
    Deldén, Maria
    Umeå University, Faculty of Arts, Department of historical, philosophical and religious studies. Högskolan Dalarna.
    Perspektiv på historiefilmslitteracitet: en didaktisk studie av gymnasieelevers historiska och emotionella meningsskapande i mötet med spelfilm2017Doctoral thesis, monograph (Other academic)
    Abstract [en]

    The present study addresses what happens when historical feature film is used in history education. The purpose of this thesis is to develop new knowledge of historical film literacy through a study of the feature film's didactical potential in an educa­tional context. This is carried out through an analysis of the historical meaning making among upper secondary students when viewing historical feature films, and special attention is paid to the importance of emotions in the students' meaning making through historical feature film. A focus of the study is the didactical dilemma, previously addressed in historical film research, that arises in the use of feature film in history or social studies education, in relation to educational context, film experience, and historical understanding.

    The present thesis is an independent continuation of my licentiate thesis History as Fiction (2014). The empirical material consists of interviews with students and teachers from two upper secondary schools in Sweden, as well as documentation from students' assessments and selected scenes from feature films experienced by the students as they were used in history class.

    The theoretical framework for the study takes an interdisciplinary approach. It is based on Jörn Rüsens under­standing of historical meaning and histo­ri­cal culture, as well as on transaction theory described by John Dewey and Louise M. Rosenblatt. Film reception theory is equally important, represented by theories from David Bordwell and Carl Plantinga.

    The main research question focused on how the concept of historical film literacy could be developed theoretically. Historical film literacy is understood in this thesis as an advanced consciousness of how historical meaning making is created through the individual's transaction with film's narration in a specific context, and how meaning making ideally links historical disciplinary thinking with practical orientation in life. The core of theoretically developed historical film literacy is an understanding of the individual's emotional and aesthetic experience of historical feature film, and elaborated theoretical knowledge about the close relationship between the affective response and the more distanced cognitive activity during and after watching a film. Also crucial for historical film literacy is an under­standing of the historical film's representation of the past as a conflation of facts and fiction. The knowledge of history that students' gain from historical feature film should be constructed in a synthesis of an aesthetic and an efferent stance in the transaction process. This is because the feature film has the capacity to stimulate both a feeling of empathy and of nearness in the viewer as well as a movement of the viewer away from the narration and towards more distanced cognition. This movement helps the viewer to analyze and interpret the historical meaning making from a critical perspective, when the experience of the feature film is transformed to a reflected experience.

  • Public defence: 2017-10-06 09:00 Vårdvetarhuset, Aulan, Umeå
    Svedmark, Åsa
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy.
    Neck pain in women: effect of tailored treatment and impact of work environment2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Introduction: Musculoskeletal pain is a common problem in the working population. In Sweden, 40% of women and 30% of men report suffering from neck and shoulder pain weekly. The underlying cause for neck pain is often not known and the treatment is commonly guided by the individual’s symptoms. However, there is a lack of knowledge on how to receive the best effect based on the individual’s symptoms and functional limitations, and therefore this has been scarcely evaluated in research. Furthermore, the impact of work exposure and stress on long-term treatment for persons with neck pain is not clear.

    Aims: To develop (paper 1) and to evaluate a decision model for tailored treatment in women with neck pain (paper 2). Moreover, to determine if risk factors at work and stress influence intermediate and long-term treatment results (paper 3). Further, to investigate if changes in self-reported pain and disabilities are associated with changes of physical test outcomes of the neck and shoulder region after treatment (paper 4).

    Methods: In an RCT, 120 working women with non-specific neck pain were randomized to three different groups – tailored treatment (TT), non-tailored treatment (NTT) or treatment-as-usual (TAU) for an 11 weeks intervention with short-term, intermediate-term and long-term follow-ups. The TT group was guided by a decision model with cut-off levels to indicate impairments. The NTT group received two established treatment components randomly from those not indicated, and TAU group did not receive any treatment within the study. The RCT primary outcomes were self-reported neck pain and neck disability. A linear mixed model was used for analysing the effects. One week after the end of intervention work exposure and stress were assessed at a work-place visit and associations to treatment results were tested for, and mixed models were used to estimate longitudinal associations. Associations between self-reported neck problems and physical outcomes were estimated with univariate and multiple regressions analysis.

    Results: No differences between TT and NTT were revealed for neck pain and disability. In comparison to TAU, the TT and NTT groups both showed improvements at short-term follow-up, but not at intermediate and long-term follow-up. High stress level and low self-estimated control at work were associated with more pain and disability at the intermediate and long-term follow-ups. After intervention and at the intermediate-term follow-up, reduced neck pain, disability and frequency of symptoms were associated with increased peak speed of head rotation and cervical range of motion.

    Conclusion: Tailored treatment according to the decision model was not superior to the non-tailored treatment in women with non-specific neck pain. One explanation for this can be the weak relationships found between neck pain and disability and physical test outcomes. Further, perceived stress and psychosocial work exposure were associated with self-reported neck problems and should be taken into account to optimize the effects in neck pain rehabilitation.

  • Public defence: 2017-10-06 13:00 Hörsal F, Humanisthuset, Umeå
    Hentschel, Linn
    Umeå University, Faculty of Arts, Department of Creative Studies (Teacher Education).
    Sångsituationer: en fenomenologisk studie av sång i musikämnet under grundskolans senare år2017Doctoral thesis, monograph (Other academic)
    Abstract [en]

    This thesis explores how the phenomena of ”singing situations” are made visible through pupils and music teachers' experiences of music education in a Swedish school, through an existential philosofical gender perspective. A basic point of departure in the thesis is that singing development is possible to evolve for all humans, similar to the latest curriculum for the music subject in elementary school in Sweden. The thesis can be positioned within four research areas: gender research in Swedish school, vocal- and voice research, gender related music education research and gender related music education research on singing. The latter research area constitutes the area in which the present dissertation is closest positioned to. Several researchers whose research is positioned in the area of gender related music education research expresses the need for more research similar to their own contributions.

     

    Within the study, five field visits have been conducted over two years involving seventyone students and five music teachers. The study includes observations and interviews, as well as sound recording and notes, and has focused solely on singing situations - situations in which singing appears in the participants' experiences in different ways. It was of research interest to meet pupils with experience of voice changes during puberty, as the majority of previous research presents the voice change as an experience that primarily or only boys experience. A very limited minority of research investigates how girls experience the voice change during puberty. The empirical data has been analyzed through seven phenomenological steps.

     

    The overall results show that all students sing and that many enjoy singing in school, with exception for one girl. The teachers' basic starting point in their teaching is to treat singing ability as possible to develop for all students. According to the teachers' basic view of singing ability as transcendence, the result shows that different gendered normative and structural aspects surround the pupils and teachers. The results also show how these aspects impacts pupils choices in the singing situations, and that some students are given greater opportunities to transcend in their vocal learning than others. The results are discussed through themes that arise within the results, mainly: subjective and intersubjective experience through singing, habitual singing, norms of restraint and imitation, girls' and boys' singing situations, views on the singing body as factuality or freedom in relation to gender, as well as the creation of alternative rooms in singing situations. 

  • Public defence: 2017-10-06 13:00 Flexhallen on Bildmuseet's lower floor, Umeå
    Holmstedt, Janna
    Umeå University, Faculty of Arts, Umeå Academy of Fine Arts. Malmö Faculty of Fine and Performing Arts.
    Are you ready for a wet live-in?: explorations into listening2017Doctoral thesis, monograph (Other academic)
    Abstract [en]

    Listen. If I ask you to listen, what is it that I ask of you—that you will understand, or perhaps obey? Or is it some sort of readiness that is requested? What occurs with a body in the act of listening? How do sound and voice structure audio-visual-spatial relations in concrete situations?

    This doctoral thesis in fine arts consists of six artworks and an essay that documents the research process, or rather, acts as a travelogue as it stages and narrates a series of journeys into a predominantly sonic ecology. One entry into this field is offered by the animal “voice” and attempts to teach animals to speak human language. The first journey concerns a specific case where humanoid sounds were found to emanate from an unlikely source—the blowhole of a dolphin. Another point of entry is offered by the acousmatic voice, a voice split from its body, and more specifically, my encounter with the disembodied voice of Steve Buscemi in a prison in Philadelphia. This listening experience triggered a fascination with, and an inquiry into, the voices that exist alongside us, the parasitic relation that audio technology makes possible, and the way an accompanying voice changes one’s perceptions and even one’s behavior. In the case of both the animal and the acousmatic, the seemingly trivial act of attending to a voice quickly opens up a complex space of embodied entanglements with the potential to challenge much of what we take for granted. At the heart of my inquiry is a series of artworks made between 2012 and 2016, which constitute a third journey: the performance Limit-Cruisers (#1 Sphere), the praxis session Limit-Cruisers (#2 Crowd), the installations Therapy in Junkspace, Fluorescent You, and “Then, ere the bark above their shoulders grew,” and the lecture performance Articulations from the Orifice (The Dry and the Wet).

    The relationship between what is seen and heard is being explored and renegotiated in the arts and beyond. We are increasingly addressed by prerecorded and synthetic voices in both public and private spaces. Simultaneously, our notions of human communication are challenged and complicated by recent research in animal communication. My work attempts to address the shifts and complexities embodied in these developments. The three journeys are deeply entwined with theoretical inquiries into human-animal relationships, technology, and the philosophy of sound. In the essay, I consider as well how other artistic practices are exploring this same complex space. What I put forward is a materialist and concrete approach to listening understood as a situated practice. Listening is both a form of co-habitation and an ecology. In and through listening, I claim, one could be said to perform in concert with the things heard while at the same time being changed by them.

  • Public defence: 2017-10-06 17:00 Sal D, 9 tr, Norrlands universitetssjukhus, Umeå
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    The heart in hereditary transthyretin amyloidosis: clinical studies on the impact of amyloid fibril composition2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background Hereditary transthyretin amyloid (ATTRm) amyloidosis is a systemic disease mainly affecting the peripheral nervous system and the heart. The disease is inherited in an autosomal dominant manner with a varying penetrance. It is caused by mutations in the transthyretin (TTR) gene. Today more than 100 disease causing mutations are known. The V30M mutation that is endemic in northern Sweden is the best studied and comprises the majority of the reported disease cases in the world. In ATTRm amyloidosis caused by the V30M mutation two distinct sub populations are seen, one with disease onset early in life and a mainly neuropathic disease and the other with late onset disease and both neuropathic disease and a progressive cardiomyopathy. These phenotypical findings have in Swedish patients been tied to differences in amyloid fibril composition. Generally, patients with early onset disease have amyloid fibrils containing only full length transthyretin (type B) whereas patients with late onset disease have amyloid containing both full length and fragmented transthyretin (type A). Until recently, the only available treatment for the disease has been liver transplantation. Patients with type A fibrils, especially males, have significantly worse survival after liver transplant due to progressive amyloid cardiomyopathy. Furthermore, it appears that type A fibrils may be the most common finding in other mutations.

    This thesis work aims to in depth investigate the impact amyloid fibril composition has on cardiac manifestations of the disease and on the outcome of available and novel modalities for cardiac amyloid imaging.

    Methods The four studies included in the thesis were done as part of the on going clinical research at the Swedish centre for transthyretin amyloidosis in Umeå.  Patients in whom amyloid fibril composition had been determined were included. Available echocardiographic data were analysed to find predictors for left ventricular hypertrophy and systolic function as measured by strain analysis in a large cohort of 105 patients (paper I). Serial 12-lead electrocardiograms from 98 patients were gathered and retrospectively interpreted and analysed to investigate the impact of amyloid fibril composition and disease progression on frequency and development of ECG abnormalities (paper IV).  DPD scintigraphy, cardiac biomarkers, clinical data and echocardiograms were analysed in a cohort of 53 consecutive patients. to assess the impact of amyloid fibril composition on the outcome of DPD scintigraphy and its relationship with cardiac hypertrophy. (paper II). To evaluate the usefulness of positron emission tomography (PET) using the amyloid specific tracer PIB, 10 patients, five with each fibril type, were selected and examined. The patients selected had a similar age of onset and similar echocardiographic findings (paper III).

    Results Paper I: Type A fibrils, male gender and age were independent factors associated with increased LV thickness. The distribution of amyloid fibril composition did not differ between the sexes, but in patients with type A fibrils, females had lower median cardiac wall thickness (p<0.01and better left ventricular septal strain (p=0.04).The gender differences were not apparent in patients with type B fibrils.

    Paper II: Ninety-seven per cent of patients with type A fibrils had pathological cardiac DPD uptake compared to none of the patients with type B fibrils. Among patients with normal septal thickness, none of 15 patients with type B fibrils had positive scintigraphy compared with 2 out of 2 with type A fibrils (P<0.01) Cardiac biomarkers, demographic data and cardiac biomarkers were significantly different, but could not differentiate between type A and type B fibrils in individual patients.

    Paper III: All patients had pathological cardiac PIB retention. In patients with type B fibrils the retention was significantly higher (p<0.01) than in patients with type A fibrils. Based on the selection criteria, no significant differences were seen in various echocardiographic measurements.

    Paper IV: All patients had a high prevalence of AV-blocks, LAH and anterior infarction pattern. Patients with type A fibrils had significantly more electrocardiographic abnormalities compared to those with type B fibrils, both at an early stage of diseases and at later follow up.

    Conclusion Type A fibrils are associated with more pronounced cardiac involvement, which appear to be more severe in males than in females. In study II we showed that DPD scintigraphy appears to be a very good tool for non-invasive determination of amyloid fibril composition. Papers III and IV show that patients with type B amyloid have cardiac involvement even without echocardiographic or DPD-scintigraphic evidence of amyloid cardiomyopathy and that ECG abnormalities are common irrespectively of amyloid fibril composition, and increase with time for both groups. 

  • Public defence: 2017-10-10 10:00 Hörsal G, Humanisthuset, Umeå
    Fowler, Philip
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Methods for improving covariate balance in observational studies2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis contributes to the field of causal inference, where the main interest is to estimate the effect of a treatment on some outcome. At its core, causal inference is an exercise in controlling for imbalance (differences) in covariate distributions between the treated and the controls, as such imbalances otherwise can bias estimates of causal effects. Imbalance on observed covariates can be handled through matching, where treated and controls with similar covariate distributions are extracted from a data set and then used to estimate the effect of a treatment.

    The first paper of this thesis describes and investigates a matching design, where a data-driven algorithm is used to discretise a covariate before matching. The paper also gives sufficient conditions for if, and how, a covariate can be discretised without introducing bias.

    Balance is needed for unobserved covariates too, but is more difficult to achieve and verify. Unobserved covariates are sometimes replaced with correlated counterparts, usually referred to as proxy variables. However, just replacing an unobserved covariate with a correlated one does not guarantee an elimination of, or even reduction of, bias. In the second paper we formalise proxy variables in a causal inference framework and give sufficient conditions for when they lead to nonparametric identification of causal effects.

    The third and fourth papers both concern estimating the effect an enhanced cooperation between the Swedish Social Insurance Agency and the Public Employment Service has on reducing sick leave. The third paper is a study protocol, where the matching design used to estimate this effect is described. The matching was then also carried out in the study protocol, before the outcome for the treated was available, ensuring that the matching design was not influenced by any estimated causal effects. The third paper also presents a potential proxy variable for unobserved covariates, that is used as part of the matching. The fourth paper then carries out the analysis described in the third paper, and uses an instrumental variable approach to test for unobserved confounding not captured by the supposed proxy variable.

  • Public defence: 2017-10-10 10:30 N320, Naturvetarhuset, Umeå
    Khan, Muhammad Sikandar Lal
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics.
    Presence through actions: theories, concepts, and implementations2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    During face-to-face meetings, humans use multimodal information, including verbal information, visual information, body language, facial expressions, and other non-verbal gestures. In contrast, during computer-mediated-communication (CMC), humans rely either on mono-modal information such as text-only, voice-only, or video-only or on bi-modal information by using audiovisual modalities such as video teleconferencing. Psychologically, the difference between the two lies in the level of the subjective experience of presence, where people perceive a reduced feeling of presence in the case of CMC. Despite the current advancements in CMC, it is still far from face-to-face communication, especially in terms of the experience of presence.

    This thesis aims to introduce new concepts, theories, and technologies for presence design where the core is actions for creating presence. Thus, the contribution of the thesis can be divided into a technical contribution and a knowledge contribution. Technically, this thesis details novel technologies for improving presence experience during mediated communication (video teleconferencing). The proposed technologies include action robots (including a telepresence mechatronic robot (TEBoT) and a face robot), embodied control techniques (head orientation modeling and virtual reality headset based collaboration), and face reconstruction/retrieval algorithms. The introduced technologies enable action possibilities and embodied interactions that improve the presence experience between the distantly located participants. The novel setups were put into real experimental scenarios, and the well-known social, spatial, and gaze related problems were analyzed.

    The developed technologies and the results of the experiments led to the knowledge contribution of this thesis. In terms of knowledge contribution, this thesis presents a more general theoretical conceptual framework for mediated communication technologies. This conceptual framework can guide telepresence researchers toward the development of appropriate technologies for mediated communication applications. Furthermore, this thesis also presents a novel strong concept – presence through actions - that brings in philosophical understandings for developing presence- related technologies. The strong concept - presence through actions is an intermediate-level knowledge that proposes a new way of creating and developing future 'presence artifacts'. Presence- through actions is an action-oriented phenomenological approach to presence that differs from traditional immersive presence approaches that are based (implicitly) on rationalist, internalist views.