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  • Public defence: 2018-09-27 13:00 MA121, Umeå
    Yan, Chunli
    Umeå University, Faculty of Science and Technology, Department of Computing Science.
    Developing digital support for learning and diagnostic reasoning in clinical practice2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The two main purposes of clinical decision-support systems (CDSSs) are to provide healthcare professionals decision-making support based on evidence-based medical knowledge, and a continuing medical education. This thesis focuses on both purposes and shows how fundamental theory in the field of artificial intelligence can be developed, adapted and implemented in a CDSS for supporting learning and diagnostic reasoning in clinical practice. The main research problems addressed in this thesis are how to represent and manage uncertain, incomplete, inconsistent and distributed knowledge in automated reasoning and decision-making with the clinicians in the loop, how to facilitate the knowledge engineering and maintenance process, and how to detect and support learning and skill development in CDSS users.

    Research contributions include theories, methods, and algorithms based on possibilistic logic and formal argumentation for representing and managing uncertain, incomplete, inconsistent and distributed medical knowledge, and for supporting reasoning and decision-making when using a CDSS. The clinician is provided potentially conflicting arguments and their strength based on different diagnostic criteria and the available patient information in order to make an informed decision. The theoretical results were implemented in the Dementia Diagnosis and Management Support System - Web version (DMSS-W), in a multi-agent hypothesis-driven inquiry dialogue system, and in an inference engine serving as a module of ACKTUS.

    CDSS maintenance is challenging since new knowledge about diseases and treatments are continuously developed. Typically, knowledge and software engineers are needed to bridge medical experts and CDSSs, leading to time-consuming system development. ACKTUS (Activity-Centered Knowledge and Interaction Tailored to Users) was, as part of this research, further developed as a generic web-based platform for knowledge management and end-user development of CDSSs. It includes the inference engine and a content management system that the medical expert can use to manage knowledge, design and evaluate CDSSs. A graphical user interface generator synchronizes the interface to the ontology serving as the knowledge base. ACKTUS was used for developing DMSS-W, and facilitated the system development and maintenance.

    To offer person-tailored support for the clinician's learning, reasoning and decision-making, the CDSS design was based on theories of how novices and experts reason and make decisions. Pilot case studies involving physicians with different levels of expertise who applied DMSS-W in patient cases were conducted in clinical practice to explore methods for detecting skill levels and whether learning is taking place. The results indicated that the skill levels can be detected using the method. The novice was seen to develop reasoning strategies similar to an expert's, indicating that learning was taking place. In future work, tailored educational support will be developed, and evaluated using the methods.

  • Public defence: 2018-09-28 09:00 Aulan, Umeå
    Smulter, Nina
    Umeå University, Faculty of Medicine, Department of Nursing. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Delirium after cardiac surgery: risk factors, assessment methods and costs2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Cardiac surgery is considered safe, but postoperative delirium (POD) remains frequently reported. Delirium is characterised by fluctuations in consciousness and cognition, and can be subdivided into disturbed psychomotoric activity (hyperactive and hypoactive) and psychiatric symptom profiles (psychotic and emotional). Delirium has an underlying cause that can be prevented and treated, provided the condition is detected. Undetected delirium could lead to serious consequences for the patient.

    Aim: This thesis aims to understand the underlying risk factors of delirium, to compare different assessment methods and documentation, and to understand its effects on hospitalisation costs after cardiac surgery.

    Methods: Two cohorts of patients undergoing cardiac surgery at the Heart Centre, Umeå University Hospital, Sweden were analysed. Cohort-A (Studies I-IV) enrolled 142 patients, ≥70 years of age, scheduled in 2009 for surgery with cardiopulmonary bypass (CPB). POD was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders 4th ed, text rev (DSM-IV-TR), based on repetitive assessments with the Mini-Mental State Examination (MMSE) and the Organic Brain Syndrome (OBS) scale. This method was considered as reference. Predisposing and precipitating risk factors were explored (Study I), and a separate analysis was conducted with focus on CPB parameters (Study II). Patients were also assessed for POD with the Confusion Assessment Method (CAM), which was validated versus the reference method (Study III). Additionally in Study IV, data about how nurses assessed patients for POD symptoms using the Nursing Delirium Screening Scale (Nu-DESC) were analysed together with information extracted from the clinical database. Moreover, discharge summaries from both nurses and physicians were retrospectively reviewed for key words and expression associated with delirium. Cohort-B (Study V) included 1879 routine cardiac surgery patients (2014-2017) retrospectively extracted from the clinical database with concomitant Nu-DESC scoring. The association between the Nu-DESC and postoperative hospitalization costs was analysed.

    Results: In cohort-A, 54.9% (78/142) patients developed POD. Both predisposing and precipitating risk factors were significantly associated with POD, of which the ‘volume load during operation’ had the strongest predictive influence (Study I). Among CPB variables the ‘duration of mixed-venous oxygen saturation <75%’ predicted POD (Study II). Hypoactive was more common than hyperactive delirium. Those with hypoactive delirium were less likely to be detected by the CAM method (Study III), an observation also demonstrated from information found in the clinical database and in discharge summaries. Nu-DESC did not detect all patients with POD, but significantly increased the detection rate (Study IV). The major hospitalisation costs associated with Nu-DESC ≥2 occurred in the ICU and independently of the surgical procedure performed. There were no significant differences in costs among patients with Nu-DESC ≥2, between age groups (70-year cut-off) or genders (Study V).

    Conclusions: Both predisposing and precipitating risk factors contributed to POD and should be considered in future guidelines to prevent delirium after cardiac surgery. Hypoactive delirium was most common, but was the most difficult to detect without screening scales. Systematic assessment with Nu-DESC improved the detection rate of POD. Delirium after cardiac surgery has consequences on healthcare and is associated with increased costs.

  • Public defence: 2018-09-28 10:00 Hörsal B, Samhällsvetarhuset, Umeå
    Ek, Hans
    Umeå University, Faculty of Social Sciences, Department of Social Work.
    Psykiatriseringen av skolkaren: BUP och det institutionella omhändertagandet av ungdomar som inte går till skolan2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The main aim of the thesis was to investigate the nature of as well as critically review the institutional care of young people who do not go to school.

    The thesis consists of four studies. The first three studies are based on different empirical materials such as electronical journals and administrative patient databases, qualitative interviews with social workers at Child and Adolescent Psychiatry (CAP), and with managerial representatives in School, social services and CAP. The fourth study is mainly theoretical and problematizes the results from the first three studies.

    The results show several problematic aspects in the institutional care of young truants. When young truants enters CAP, a quick, and sometimes without psychological investigation, categorization is made with psychiatric terminology in the form of a diagnosis, and medicines are prescribed as treatment. Further, social workers, who shall have a systemic approach on family and relationships, seem to embrace a psychiatric diagnostic understanding of the problems. At the same time, it appears that school only has extra resources to help the truants if they have a psychiatric diagnosis. Although the idea of collaboration between different professionals is that several different perspectives should be used, the results shows that CAP’s psychiatric perspective dominates.

    The results of what happens to young people who do not go to school is discussed as an example of a special form of medicalization, in which social difficulties and existential problems are referred to psychiatry. It appears that help for them is completely individualised, by focusing on symptoms and diagnosis. What is not visible in this unilateral individualisation, for example, are organisational and educational problems in school, system problems in the family or among friends or lack of social contacts outside the family. By referring the truant to CAP can therefore miss further social circumstances in their life situation, which can have great importance in whether they attend school or not. Therefore, it is important to problematise this process of referring everything to psychiatry and to ask questions about what situations and events have contributed to this cultural pattern, which means that people’s difficulties in life are increasingly being solved with diagnosis and medications.

  • Public defence: 2018-09-28 10:15 N430, Umeå
    Monteux, Sylvain
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    A song of ice and mud: Interactions of microbes with roots, fauna and carbon in warming permafrost-affected soils2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Permafrost-affected soils store a large quantity of soil organic matter (SOM) – ca. half of worldwide soil carbon – and currently undergo rapid and severe warming due to climate change. Increased SOM decomposition by microorganisms and soil fauna due to climate change, poses the risk of a positive climate feedback through the release of greenhouse gases. Direct effects of climate change on SOM decomposition, through such mechanisms as deepening of the seasonally-thawing active layer and increasing soil temperatures, have gathered considerable scientific attention in the last two decades. Yet, indirect effects mediated by changes in plant, microbial, and fauna communities, remain poorly understood. Microbial communities, which may be affected by climate change-induced changes in vegetation composition or rooting patterns, and may in turn affect SOM decomposition, are the primary focus of the work described in this thesis.

    We used (I) a field-scale permafrost thaw experiment in a palsa peatland, (II) a laboratory incubation of Yedoma permafrost with inoculation by exotic microorganisms, (III) a microcosm experiment with five plant species grown either in Sphagnum peat or in newly-thawed permafrost peat, and (IV) a field-scale cold season warming experiment in cryoturbated tundra to address the indirect effects of climate change on microbial drivers of SOM decomposition. Community composition data for bacteria and fungi were obtained by amplicon sequencing and phospholipid fatty acid extraction, and for collembola by Tullgren extraction, alongside measurements of soil chemistry, CO2 emissions and root density.

    We showed that in situ thawing of a palsa peatland caused colonization of permafrost soil by overlying soil microbes. Further, we observed that functional limitations of permafrost microbial communities can hamper microbial metabolism in vitro. Relieving these functional limitations in vitro increased cumulative CO2 emissions by 32% over 161 days and introduced nitrification. In addition, we found that different plant species did not harbour different rhizosphere bacterial communities in Sphagnum peat topsoil, but did when grown in newly-thawed permafrost peat. Plant species may thus differ in how they affect functional limitations in thawing permafrost soil. Therefore, climate change-induced changes in vegetation composition might alter functioning in the newly-thawed, subsoil permafrost layer of northern peatlands, but less likely so in the topsoil. Finally, we observed that vegetation encroachment in barren cryoturbated soil, due to reduced cryogenic activity with higher temperatures, change both bacterial and collembola community composition, which may in turn affect soil functioning.

    This thesis shows that microbial community dynamics and plant-decomposer interactions play an important role in the functioning of warming permafrost-affected soils. More specifically, it demonstrates that the effects of climate change on plants can trickle down on microbial communities, in turn affecting SOM decomposition in thawing permafrost.

  • Public defence: 2018-09-28 13:00 Hörsal Betula, Norrlands Universitetssjukhus, Umeå
    Pietilä Holmner, Elisabeth
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Rehabilitation Medicine.
    Multimodal rehabilitation of patients with chronic musculoskeletal pain, focusing on primary care2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Chronic pain is a complex condition that has consequences both for individual people and for society. The individual often experiences impact on function, activity and participation. Society is affected by high healthcare and sick leave costs and a loss of workforce. Multimodal rehabilitation programmes (MMRP) have mainly been provided through specialist care but it is now also available through primary care. The overall aim of this thesis was to evaluate the effects of MMRP in patients with chronic musculoskeletal pain and to explore patients’ and healthcare professionals’ experiences of MMRP.

    Study I: Aim: To evaluate the effects of an interdisciplinary team assessment and MMRP for patients with chronic pain in a specialist care setting. Design: Longitudinal cohort study. Method: Pain intensity, pain dimensions, anxiety and depression were measured at assessment and at the start and end of MMRP.  A total of 93 women were evaluated. Result: Pain and pain-related measures were significantly improved both after the interdisciplinary assessment and after MMRP.

    Study II: Aim: To explore healthcare professionals’ experiences of MMRP in primary care. Design: Individual interviews, analysed with qualitative content analysis. Method: Fourteen healthcare professionals (11 women, 3 men) were interviewed about their work with MMRP. Result: Healthcare professionals considered that MMRP was useful but also challenging. It was difficult to select appropriate patients, and health care professionals felt they were torn between following healthcare legislation and the goals of MMRP. They had to deal with ethical dilemmas as well as decide what constitutes good results.

    Study III: Aim: To explore patients’ experiences of participating in MMRP in primary care. Design: Individual interviews, analysed with qualitative content analysis. Method: Twelve former patients (7 women and 5 men) were interviewed about their experiences of MMRP in primary care. Result: Patients in primary care experienced a complex, ongoing process of accepting chronic pain. Obtaining redress, learning about chronic pain, and experiencing fellowship with others with the same condition contributed to the acceptance process.

    Study IV: Aim: To evaluate the effects of MMRP in primary care at one-year follow-up for all patients together and for men and women separately and to identify predictive factors for being employable at follow-up. Design: Prospective longitudinal cohort study. Method: Pain, physical and emotional functioning, coping, health-related quality of life, work-related factors, sick leave extent and sickness compensation were evaluated prior to and one year after MMRP in 234 patients, 34 men and 200 women. Result: All patients improved significantly in most measures at one-year follow-up, and the effect was larger in women. Sick leave decreased while no significant difference was found for total sickness compensation. Patients’ self-reported rating of current work ability before MMRP was significantly associated with being employable at follow-up.

    General conclusions and implications: 

    MMRP seems to be effective for patients with chronic musculoskeletal pain, both in specialist care and in primary care. MMRP was more effective for women than for men, and the reasons for this need to be investigated further. An interdisciplinary team assessment could also be beneficial for decreasing pain and pain-related measures. Patients in primary care experience a complex, ongoing process of accepting chronic pain. Healthcare professionals have to deal with conflicting emotions with regard to different commitments from healthcare legislation and the goals of MMRP.                         

  • Public defence: 2018-10-01 13:30 MA121, MIT-huset, Umeå
    Mehta, Amardeep
    Umeå University, Faculty of Science and Technology, Department of Computing Science.
    Resource allocation for Mobile Edge Clouds2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Recent advances in Internet technologies have led to the proliferation of new distributed applications in the transportation, healthcare, mining, security, and entertainment sectors. The emerging applications have characteristics such as being bandwidth-hungry, latency-critical, and applications with a user population contained within a limited geographical area, and require high availability, low jitter, and security.

    One way of addressing the challenges arising because of these emerging applications, is to move the computing capabilities closer to the end-users, at the logical edge of a network, in order to improve the performance, operating cost, and reliability of applications and services. These distributed new resources and software stacks, situated on the path between today's centralized data centers and devices in close proximity to the last mile network, are known as Mobile Edge Clouds (MECs). The distributed MECs provides new opportunities for the management of compute resources and the allocation of applications to those resources in order to minimize the overall cost of application deployment while satisfying end-user demands in terms of application performance.

    However, these opportunities also present three significant challenges. The first challenge is where and how much computing resources to deploy along the path between today's centralized data centers and devices for cost-optimal operations. The second challenge is where and how much resources should be allocated to which applications to meet the applications' performance requirements while minimizing operational costs. The third challenge is how to provide a framework for application deployment on resource-constrained IoT devices in heterogeneous environments. 

    This thesis addresses the above challenges by proposing several models, algorithms, and simulation and software frameworks. In the first part, we investigate methods for early detection of short-lived and significant increase in demand for computing resources (also called spikes) which may cause significant degradation in the performance of a distributed application. We make use of adaptive signal processing techniques for early detection of spikes. We then consider trade-offs between parameters such as the time taken to detect a spike and the number of false spikes that are detected. In the second part, we study the resource planning problem where we study the cost benefits of adding new compute resources based on performance requirements for emerging applications. In the third part, we study the problem of allocating resources to applications by formulating as an optimization problem, where the objective is to minimize overall operational cost while meeting the performance targets of applications. We also propose a hierarchical scheduling framework and policies for allocating resources to applications based on performance metrics of both applications and compute resources. In the last part, we propose a framework, Calvin Constrained, for resource-constrained devices, which is an extension of the Calvin framework and supports a limited but essential subset of the features of the reference framework taking into account the limited memory and processing power of the resource-constrained IoT devices.

  • Public defence: 2018-10-05 09:00 Sal Betula, 901 87 Umeå
    Linder, Robert
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Proteolytic imbalance in COPD: epidemiological and clinical aspects2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: The complete pathologic mechanism behind the development of chronic obstructive pulmonary disease (COPD) remains unclear, but several risk factors have been identified, of which smoking is the most common. Proteolytic imbalance contributes to lung tissue degradation and is related to both smoking and COPD symptoms. Spirometry and symptomatic assessments are the standard diagnostics, but COPD has varying clinical features, that hamper clinical management and research assessment. Evaluating proteolytic markers' relationship to COPD and its clinical presentation could reveal proteolytic imbalance as an important disease mechanism.

    Aims: 1) To evaluate proteolytic markers in COPD and non-COPD. 2) To study the relationship between proteolytic markers and both lung function decline and prognosis. 3) To recruit subjects from a longitudinal study to a clinical study of disease mechanisms. 4) To study proteolytic markers in airways and serum and their relation to rate of decline in lung function.

    Methods: Spirometry, serum matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinase-1 (TIMP-1) were evaluated in a population-based study comprising 993 COPD subjects and 993 age- and sex-matched non-COPD referents. In addition, data from 2005 to 2010 were surveyed comprising longitudinal spirometry data and mortality records. For a clinical study, we described the recruitment process of COPD subjects with a FEV1 decline of ≥60 or ≤30 mL/year, along with ever- and never-smoking controls with normal lung function. MMP-9, MMP-12, and TIMP-1 data from bronchial wash (BW), bronchoalveolar lavage (BAL) and serum (collected from 2012 to 2014) were assessed in the clinical study.

    Results: COPD subjects presented higher serum concentrations of MMP- 9 compared to non-COPD subjects (p = 0.017). MMP-9 and MMP- 9/TIMP-1 ratio had a negative linear association with the forced expiratory volume in one second (FEV1) percentage predicted in COPD. Associating the 2005 levels of MMP-9 and MMP-9/TIMP-1 ratio to decline in FEV1 and FEV1% predicted, revealed a similar negative association pattern in both non-COPD and COPD, however, this was only significant for non-COPD. A non-response analysis comparing proteolytic marker values from 2005 between participating and non-participating subjects at follow-up in 2010 (excluding deceased individuals) demonstrated significantly higher MMP-9 and MMP-9/TIMP-1 ratios in both non-COPD and COPD, and significantly lower TIMP-1 concentration in non-participants compared to participants. Among the deceased, MMP-9 levels and MMP-9/TIMP-1 ratios were higher in COPD compared to non-COPD. In the longitudinal study, all-cause mortality was higher in the COPD group (16%), than in the non-COPD (10%) (p = 0.008).

    For the clinical study, 15 subjects were recruited to the two normal lung function groups, while this goal was unachieved for the two COPD groups. The most prevalent reasons for exclusion in the COPD groups were comorbidities. BW- and BAL-MMP-12 concentrations were higher in the COPD group comprising current- and ex-smokers, compared to both ever-smokers (BW: p = 0.001, BAL: p = 0.001) and non-smokers with normal lung function (BW: p = 0.001, BAL: p = 0.001). To evaluate the impact of smoking, COPD ex-smokers were compared to COPD current smokers, with no significant difference in BW- and BAL-MMP- 12. In contrast COPD-ex smokers had higher BW- and BAL-MMP-12 compared to ex-smokers with normal lung function, thus suggesting increased BW- and BAL-MMP-12 as markers of COPD rather than of smoking. MMP-12 concentrations in serum were higher for COPD current smokers compared to COPD ex-smokers (p = 0.028), but there was no significant difference between COPD ex-smokers and ex-smokers with normal lung function. BAL-MMP-12 in COPD was associated with annual decline in FEV1 (r = 0.61, p = 0.005).

    Conclusion: Extrapolating the data on MMP-9 and MMP-9/TIMP-1 ratio suggests increased proteolytic activity is related to airflow limitation and consequently to COPD severity. Considering the population-based nature of the study, the association of both MMP-9 and MMP-9/TIMP-1-ratio in COPD to mortality risk could be translated to the general population. Identifying COPD subjects with specific phenotypes proved difficult despite the large number of available individuals. Increased airway levels of MMP-12 indicated a state of increased proteolytic activity and were associated with rapid lung function decline in COPD. These findings imply that proteolytic imbalance is related to symptoms, lung function decline and prognosis, suggesting it represents a relevant disease mechanism in COPD.

  • Public defence: 2018-10-05 09:00 KB.E3.01, Umeå
    Wessels, Bernard
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    The significance of ethylene and ETHYLENE RESPONSE FACTORS in wood formation of hybrid aspen2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The woody tissues serve to stabilise plants, store nutrients and translocate water and minerals. The formation of wood, or ’secondary xylem’, follows a well-defined developmental gradient which is initiated by cell division activity in the vascular cambium. The ’xylem cambial derivatives’ then expand before deposition of the secondary cell wall (SCW), which is where most of the biomass of wood originates. After this, some cells of the xylem typically undergo programmed cell death (PCD). Cellulose and lignin are chemical components of the SCW that provide structural support and water impermeability, respectively. The chemical composition of the SCWs is also important economically since it affects the efficiency of wood processing during pulping and enzymatic hydrolysis. Two dominant xylem cell types of angiosperm tree species like Populus are the fibers and the vessel elements. Fibers are important for the mechanical strength of the wood and provide the majority of the wood biomass. Vessel elements join endwise to form hollow tubes, or vessels, for the purposes of water and solute transport in the stem.


    Formation of wood is a complex process, subject to multiple levels of regulation. Plant hormones are important for wood formation, and ethylene signalling has been shown to stimulate cambial activity, affect the ratio between fibers and vessel elements, as well as the expansion of the cambial derivatives. Ethylene is also involved in the ‘tension wood’ response of stems that are displaced from their original vertical position. Formation of ’tension wood’ generates a force that lifts the stem back to the upright growing position. What remains unknown is the molecular link between ethylene signalling and wood formation. The work in this thesis focuses on providing this link using the model tree species hybrid aspen (Populus tremula x tremuloides).


    Using a state-of-the-art transcriptomic database that spans all phases of xylem differentiation in hybrid aspen wood, from cell division through xylem cell expansion to xylem maturation (SCW deposition and PCD), the expression of the ethylene pathway related genes was investigated during normal wood formation. The analyses reveal ethylene perception and transcriptional reprogramming is possible across all zones of wood formation. Previously uncharacterised components were identified that may be important contributors to wood formation. Furthermore, although ethylene is known to affect the ratio between the abundance of the vessel elements and the fibers, genetic evidence is lacking. Using the tension wood response and transgenic trees modified in ethylene signalling, it was shown that ethylene is a negative regulator of vessel formation and important for a functional tension wood response. Furthermore, characterisation of two transcription factors (TFs), belonging to the ethylene response factor (ERF) gene family, suggests that aspects of xylem cell division, expansion and subsequent SCW formation, including lignification, can be affected by ERF85 and ERF139 in an ethylene-dependent manner. Phase transitions during wood formation need to be controlled spatiotemporally, and transcriptional regulation by these ERFs seems to be part of such control to establish correct transitions between cell expansion, secondary cell wall formation and lignification. The work presented here also identifies promising additions to the toolkit available for forest tree biotechnology and molecular breeding programmes.

  • Public defence: 2018-10-05 09:00 Major Groove, Umeå
    Lopes, José Pedro
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Candida albicans adaption to host microenvironments drives immune evasion2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Immunosuppressed patients are frequently afflicted with severe mycoses caused by opportunistic fungal pathogens. Besides being a commensal colonizing predominantly skin and mucosal surfaces, Candida albicans is the most common human fungal pathogen. Mast cells are present in tissues prone to fungal colonization being expectedly among the first immune cells to get into contact with C. albicans. Here we describe how mast cells acted as tissue sentinels and modulated initial antifungal immune responses. Mast cells response was able to reduce fungal viability and signaled for neutrophil infiltration to the tissue. Upon chemokine sensing circulating neutrophils are rapid infiltrating to the mucosal to help fight infection. A high number of infiltrating cells coupled with the formation of multicellular structures such as biofilm comes with induction of hypoxic and anoxic micro niches. We found that a persistence anoxia hampered neutrophil responses by affecting fungi sensing and consequent antifungal due to cell wall masking. Adaption to low oxygen seems is important for a successful host infection. Hypoxic and anoxic environments do not allow neutrophils to efficiently produce ROS. Neutrophil oxidative burst is essential for antifungal activity and many fungal pathogens evolved antioxidative factors to mediate survival during infection. We reasoned that targeting of fungal redox balances could be a new therapy approach. We have tested tempol, a redox-cycling nitroxide Tempol as a new antifungal drug. Tempol proved an efficient compound in our testing. We found that Tempol affected fundamental pathways for fungal homeostases such as glycolysis and steroid biosynthesis. Additionally, Tempol helped curve fungal infectivity in a mouse model and leads for an enhanced immune system cytokine profile in human blood. The results obtained proposed tempol as a valid new antifungal compound and open new opportunities for the future development of therapies. Efficient antifungal therapies are still urgent since only 6 classes of antimycotics exist and all with few restricted fungal targets. Since primarily fungal infections affect patients with other immunosuppressive conditions, which are undergoing treatment, we reasoned that repurposing drugs could offer clinical benefits. We performed a screening of two US Food and Drug Administration (FDA)–approved compound libraries for compounds with anti-Candida activity. From 844 drugs, 26 agents showed activity against C. albicans. We identified 7 new off-target drugs all with potent anti- C. albicans activity. The use of these new drugs could be prophylactic or to treat both conditions simultaneously offering, therefore the intended benefit.

    Overall, in this thesis work, we have focused on the sensing clearing and management of fungal pathogens. These findings open new doors for understanding better fungal pathogenicity and purpose valid new antifungal compounds that pave the way for future development of therapies.

  • Public defence: 2018-10-05 13:00 Sundsvalls sjukhus Aulan, plan 1, hiss 8, Sundsvall
    Wadsten, Charlotta
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    DCIS of the breast: aspects on treatment and prognosis2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Breast cancer is the most common cancer form and a leading cause of death in women worldwide. Ductal breast carcinoma in situ (DCIS) is characterized by a proliferation of malignant cells confined within the mammary ducts and is a potential precursor of invasive breast cancer. The risk estimations of a DCIS to develop into invasive cancer over a 10 year period range from 30-50%. In the past 25 years, concomitant with the implementation of screening mammography, the incidence of DCIS has increased dramatically and presently almost 1 000 women are diagnosed with DCIS each year in Sweden. The increased incidence poses concerns of overtreatment and current research aim at identifying clinical or pathological markers that can reliably distinguish hazardous from harmless DCIS.                                        The overall aim of this thesis was to explore the prognostic significance of clinical and tumourbiological characteristics of DCIS and to assess the benefits and harms of adjuvant treatment.

    In a population-based cohort of 2 952 women with primary DCIS, we analysed trends in incidence, treatment and outcome over a 20-year period (paper I). Information was obtained from the regional breast cancer register in Uppsala-Örebro healthcare region between 1992 and 2012. A validation of 300 randomly selected women revealed high overall completeness and reliability of most key variables, whereas follow-up data were of moderate quality with only 65% of the recurrences reported to the register.

    The major finding of the study was a trend towards more intensified treatment over time. The frequency of mastectomy increased from 23.0% to 39.0% and the proportion of patients receiving adjuvant radiotherapy after breast-conserving surgery increased from 30.1% to 67.6%. This did not, however, translate into any noteable improvements in outcome. Relative survival was >97% after 10 years with no significant variation over time. In conclusion, these results may reflect adequate treatment selection, but may also indicate a significant overtreatment.

    In paper II and III, a nested case-control study was conducted from a cohort of 6 964 women with primary DCIS to identify clinical characteristics in DCIS associated with subsequent breast cancer death. Ninety-six women who later died from breast cancer were compared to 318 controls selected by incidence density sampling. Information was obtained from medial records and histopathology reports.

    Tumour size over 25 mm or multifocal DCIS (OR 2⋅55; 95%CI 1⋅53 to 4⋅25), a positive or uncertain margin status (OR 3⋅91; 95%CI 1⋅59 to 9⋅61) and detection outside the screening programme (OR 2⋅12; 95%CI 1⋅16 to 3⋅86) increased the risk of death from breast cancer. In the multivariable analysis, tumour size (OR 1⋅95; 95%CI 1⋅06 to 3⋅67) and margin status (OR 2⋅69; 95%CI 1⋅15 to 7⋅11) remained significant. More extensive treatment was not associated with lower risk, which may be due to confounding by indication, or indicate that some DCIS have an inherent potential for metastatic spread.                                    

    In paper III, to further explore the association of tumour biology and risk of breast cancer death, archival tumour blocks were collected. Freshly cut hematoxylin and eosin (H&E) stained sections of the primary DCIS were histopathologically evaluated for nuclear grade, presence of comedonecrosis and lymphocytic infiltration (LI). Tissue microarrays were constructed for immunohistochemical analysis (IHC) of oestrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and Ki67. Using the results of the IHC analyses, tumours were classified into surrogate molecular subtypes.

    Presence of intense periductal LI was associated with an increased risk of subsequent breast cancer death (OR 2.25; 95%CI 1.02 to 4.99). None of the other biomarkers were individually related to breast cancer death, nor were there any statistically significant differences in risk between the molecular subtypes. In multivariable analysis, stepwise adjusting for age, tumour size and treatment, PR negativity in combination with LI; PR negativity, LI and presence of comedonecrosis and the combination of PR negativity, LI, comedonecrosis and HER2 positivity were all independently associated with increased risk of breast cancer death. The significance of features in the peritumoral stroma need further investigation and may have implications for targeted treatments.

    In paper IV, we studied the risk of ischemic heart disease (IHD) after treatment for DCIS. Postoperative radiotherapy (RT) in DCIS reduces recurrence rates by half but confers no benefits in terms of survival. It is thus of major importance to consider long-term adverse effects. Left-sided breast irradiation may involve exposure of the heart to ionising radiation with an associated risk of subsequent cardiovascular disease. The cumulative incidence of IHD was analysed in a population-based cohort of 6270 women with DCIS compared 31 257 women without a history of breast cancer. Of the women with DCIS, 38.9% had received adjuvant RT.

    After a median follow-up of 8 years, there was no increased risk of IHD for women with DCIS versus the comparison cohort. The risk was lower for women with DCIS allocated to RT compared to non-irradiated women and to the comparison cohort, probably due to patient selection. Comparison of RT by laterality did not show any over-risk for irradiation of the left breast. These results are reassuring, but longer follow-up may be warranted considering the continuously increasing use of RT in DCIS management.

  • Public defence: 2018-10-05 13:00 Hörsal D, Unod T9, Umeå
    Sirili, Nathanael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Health workforce development post-1990s health sector reforms: the case of medical doctors in Tanzania2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Health systems in many low- and middle-income countries suffer from critical shortages and inequitable geographical distribution of the health workforce. Since the 1940s, many low- and middle-income countries have passed through different regimes of health sector reforms; the most recent one was in the 1990s. Tanzania is a good example of these countries. From the 1990s, Tanzania has been implementing the third generation of health sector reforms. This thesis analysed the health workforce development following the 1990s health sector reforms in Tanzania.

    Methods: An exploratory case study employing both quantitative and qualitative research approaches was used to analyse the training, deployment, and retention of medical doctors about two decades following the 1990s healthsector reforms. The quantitative approach involved analysis of graduation books and records from the Medical Council of Tanganyika to document the number of doctors who graduated locally and abroad, a countrywide survey of available doctors as of July 2011, and analysis of staffing levels to document the number of doctors recommended for the health sector as of 2012. The gap between the number of available and required doctors was computed by subtracting available from required in that period. The qualitative approach involved key informant interviews, focus group discussions, and a documents review. Key informants were recruited from districts, regions, government ministries, national hospitals, medical training institutions in both the public and private sectors, Christian Social Services Commission and the Association of Private Health Facilities in Tanzania. Focused group discussion participants were members of Council Health Management Teams in three selected districts. Documents reviewed included country human resources for health profiles, health sector strategic plans, human resources for health strategic plans and published and grey literature on health sector reforms, health workforce training, and deployment and retention documentation. For the training, analysis of data was done thematically with the guide of policy analysis framework. For deployment and retention, qualitative content analysis was adopted.

    Results: Re-introduction of the private sector in the form of public-private partnerships has boosted the number of doctors graduating annually sevenfold in 2010 compared to that in 1992. Despite the increase in the number of doctors graduating annually, their training faces some challenges, including the erosion of university autonomies prescribed by the law; coercive admission of many medical students greater than the capacity of the medical schools, thus threatening the quality of the graduates; and lack of coordination between trainers and employers. Tanzania requires a minimum of 3,326 doctors to attain the minimum threshold of 0.1 doctor per 1,000 population, as recommended by the World Health Organization. However, a countrywide survey has revealed the existence of around 1,300 doctors working in the health sector—almost the same as the number before the reforms. Failure to offer employment to all graduating doctors, uncertainties around the first appointment, failure to respect doctors’ preferences for first appointment workplaces, and the feelings of insecurity in going to districts are among the major challenges haunting the deployment of doctors in Tanzania. For those who went to the districts, the issues of unfavourable working conditions, unsupportive environment in the community, and resource scarcity have all challenged their retention.

    Conclusions: The development of human resources for health after the 1990s health sector reforms have to some extent been contradictory. On the one hand, Tanzania has succeeded in training more doctors than the minimum it requires, despite some challenges facing the training institutions. On the other hand, failure to deploy and retain an adequate number of doctors in its health system has left the country to continue suffering from a shortage and inequitable distribution of doctors in favour of urban areas. For health sector reforms to bring successes with minimal challenges in health workforce development, a holistic approach that targets doctors’ training, deployment, and retention is recommended.

  • Public defence: 2018-10-05 13:15 L 212, Lärarhuset, Umeå
    Ewa, Axelsson Lantz
    Umeå University, Faculty of Social Sciences, Department of Geography and Economic History.
    Naturresurser, sågverksbolag och bönder: konflikter i Västernorrland 1863-19062018Doctoral thesis, monograph (Other academic)
    Abstract [en]

    During the nineteenth century, competition over forestland and waterways grew in Northern Sweden. This increased the pressure on existing institutions of natural resource governance. It culminated with a ban on private acquisition of woodland from smallholders in 1906. This thesis deals with how the local communities handled the institutional challenges of this process. I study two geographical areas connected to different stages in the chain of production, from the inland of standing timber to the downstream sawmills. Previous research states that the sawmill industry in this region used its position in local governments to gain economic advantages. The number of votes were related to the value of one’s property and income, which put forest and factory owners in a favorable political position. Another claim from previous works is that the local courts, in general, constituted a place for settling local natural resource conflicts in the eighteenth and nineteenth centuries. The two research questions extracted from this are: What role did formal political and legal institutions play in managing conflicts about natural resource use? What disagreements occurred in the different parts of the sawmill industry's production chain? The aim is to better understand natural resource conflicts between the local community and the sawmill industry, across the production chain, in the county of Västernorrland, 1863-1906. To capture the regional differences, I study one industrial municipality – Gudmundrå, and one raw material municipality – Junsele. An iterative methodological approach is used. I find that the local government was not a significant arena for natural resource matters, in contrast to what could be intuitively expected from the literature. Sawmill companies did use their politically dominant position to influence the local community, however not in matters of resource management in this case. The local court was more important. These conflicts were often about property rights regarding contracts and the use of waterways and forestland, and damages imposed by this. Local farmers often initiated cases. This is in line with what the literature suggested on the role of local courts as the arena for settling private economic matters among locals. However, the nature of the conflicts changed over time and differed vastly between the two geographical areas. The results show that the conflict types were different in Gudmundrå and Junsele due to their geographical location, which provided a ground for different links of the sawmill value chain. The results also reveals that key institutional changes were characterized of both top-down and bottom-up processes. One example is local farmers who were involved in the processes of setting the terms for log driving routes. They served as an important link of the value chain that connected the raw materials to the saw mill industry’s production.

  • Public defence: 2018-10-11 09:00 Hörsal 933 Unod B9, Umeå
    Islam, Koushikul
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Identification and evaluation of antiviral compounds targeting Rift Valley fever virus2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Rift Valley fever virus (RVFV), a negative-stranded RNA virus, is the etiological agent of the vector-borne zoonotic disease Rift Valley fever (RVF). RVFV causes significant morbidity and mortality in humans and livestock throughout Africa and the Arabian Peninsula. RVFV is an emerging virus and is capable of infecting a broad range of mosquito species distributed around the world, so it poses a potential threat globally. A wide range of livestock animals (e.g. sheep, goats, cows, and camels) and some wild animals become highly affected by RVFV. In humans, RVFV infection presents as an acute self-limiting febrile illness that may lead to more severe hemorrhagic fever and encephalitis. The severity of the disease is mostly dependent on age and the species of mammal, but other factors are also important.

    There are no licensed RVFV vaccines for humans, and there is a lack of effective antiviral drugs. Moreover, due to the severe pathogenicity, higher-level facilities are needed―biosafety level 3 (BSL-3) or more―to work with RVFV, which makes antiviral drug development more challenging. Because RVFV causes severe disease in Africa and the Arabian Peninsula, and has the potential to spread globally, it is essential that safe, efficient antiviral drugs against this virus are developed.

    The previously reported antiviral compound benzavir-2 inhibits the replication of several DNA viruses, i.e. human adenoviruses, herpes simplex virus (HSV) type 1, and HSV type 2, indicating a broadranging activity. We wanted to evaluate whether benzavir-2 had an effect against the RNA virus RVFV. For these and subsequent studies, we used a recombinant, modified RVFV strain with a deleted NSs gene, which was replaced by a reporter gene (rRVFVΔNSs::Katushka), enabling the studies to be conducted under BSL-2 conditions. The NSs gene is the main virulence factor for RVFV and without it, RVFV become less pathogenic. The reporter gene made it possible for us to quantify infection with the help of the red fluorescent protein. We found that benzavir-2 effectively inhibited RVFV infection in cell culture at an effective concentration showing 50% inhibition (EC50) of 0.6 μM. Benzavir-2 also inhibited the production of progeny virus. When we studied the pharmacokinetic properties, we found that benzavir-2 had good in vitro solubility, permeability, and metabolic stability. When we investigated the oral bioavailability in mice by administering benzavir-2 in peanut butter pellets, high systemic distribution was observed without any adverse toxic effects. Benzavir-2 thus inhibited RVFV infection in cell culture and showed excellent pharmacokinetic properties, suggesting the possibility of evaluating its effectiveness in an animal model. Since benzavir-2 has a broad effect against both RNA and DNA viruses, we speculated that the antiviral mechanism affects cellular targets.

    We also wanted to explore a large number of small chemical compounds with unknown properties and identify any anti-RVFV activities. Thus, we developed a whole-cell-based high-throughput reporter-based assay, and screened 28,437 small chemical compounds. The assay was established after optimization of several parameters. After primary and secondary screening, we identified 63 compounds that inhibited RVFV infection by 60% at a concentration of 3.12 μM and showed ≥ 50% cell viability at 25 μM. After a dose-dependent screening of these 63 compounds, several compounds were identified with highly efficient anti-RVFV properties. Finally, N1-(2-(biphenyl-4-yloxy)ethyl)propane-1,3-diamine (compound 1) was selected as the lead compound. We performed a structure-activity relationship (SAR) analysis of compound 1 by replacing and changing component after component of the chemical compound to see how this affected the antiviral activity. After the SAR analysis, the antiviral activity did not change, but we could improve the cytotoxicity profile. Our studies suggested that the improved compound, 13a, might be targeting the early phase of the RVFV lifecycle.

    In conclusion, we developed an efficient and reliable screening method that creates possibilities for discovering and developing antivirals against RVFV under BSL-2 conditions. We also identified several chemical compounds with anti-RVFV activities, which might lead to development of therapies for RVFV infection.

  • Public defence: 2018-10-12 09:00 Sal 260, Umeå
    Myte, Robin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Metabolic Risk Factors and Molecular Subtypes of Colorectal Cancer2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Colorectal cancer (CRC) is a heterogeneous disease developing from distinct pathways, resulting in tumor subtypes with large differences in clinical and molecular characteristics. Molecular characteristics are increasingly being used clinically to guide therapy. However, whether molecular subtypes of CRC differ in etiology or risk factors is not clear. Clarifying such potential differences may lead to an improved understanding of CRC etiology, with implications for CRC prevention and screening.

    Aim: The aim of this thesis was to investigate whether risk factors related to energy metabolism, such as body fatness, and one-carbon metabolism, such as circulating B-vitamin status, were associated with specific subtypes of CRC defined by molecular characteristics of the tumor. 

    Methods: These prospective studies are based on data and blood samples from cohorts within the population-based Northern Sweden Health and Disease Study (NSHDS). Prospective CRC cases with available archived tumor tissue were analyzed for key molecular features (KRAS and BRAF mutation status, Microsatellite instability (MSI) status, and CpG Island Methylator Phenotype (CIMP) status). Paper I was a cohort study of metabolic factors related to the metabolic syndrome (117 687 participants). Paper II was a nested-case control study on circulating insulin resistance-markers and adipokines (1010 cases and 1010 matched controls). Papers III and IV were nested case-control studies of one-carbon metabolism biomarkers and genetic variants (613 cases and 1190 matched controls).

    Results: In paper I, we observed associations between metabolic factors, such as BMI, blood pressure, and blood lipids, and CRC risk consistent with previous studies. These associations were similar regardless of tumor KRAS and BRAF mutation status. In paper II, circulating biomarkers of insulin resistance and adipokines were not associated with the risk of CRC or specific molecular subtypes of CRC defined by KRAS and BRAF mutation or MSI status. In paper III, higher circulating levels of metabolites involved in the methionine cycle (namely, betaine and methionine) were associated with a lower CRC risk. In paper IV, we found no support for clear subtype-specific roles of any circulating one-carbon metabolism biomarker or genetic variants in CRC development.

    Conclusions: The result of these prospective studies suggests that metabolic factors related to energy metabolism and one-carbon metabolism are generally associated with the risk of CRC, regardless of major subtypes defined by key molecular tumor features. If causal, metabolic risk factors likely influence the risk of colorectal cancer through more than one carcinogenic pathway.

  • Public defence: 2018-10-12 09:00 Sal 260, Röntgenklinik, Umeå
    Al-Amiry, Bariq
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Radiological measurements in total hip arthroplasty2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Every year, about 1 million patients worldwide and 20000 patients in Sweden undergo total hip arthroplasty (THA). This type of operation is considered a successful, safe and cost-effective procedure to regain mobility and restore hip joint function in patients suffering from severe hip joint disease or trauma. The main goals of the operation are to relief the pain, improve quality of life (QoL) and to restore the biomechanical forces around the hip with appropriate femoral offset (FO), leg length and proper component position and orientation. The radiographic preoperative planning and postoperative evaluation of these parameters require good validity, interobserver reliability and intraobserver reproducibility. Most patients are satisfied after THA, although this treatment still has its complications. About 10 % of THA patients report persistent pain and suboptimal functional outcome and QoL at long-term follow-up. The absolute number of dissatisfied patients is expected to rise given the increase in the annual number of THA performed. Therefore, every effort should be made to investigate factors that possibly influence THA outcome. The data available about the influence of preoperative radiological severity and symptom duration of OA on the outcome of THA are scarce and contradictory. Further studies even needed to evaluate the effect of obesity on post-operative THA radiological measurements