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  • Public defence: 2018-11-16 09:00 Aulan Vårdvetarhuset, Umeå
    Bergman, Frida
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy.
    Active workstations: a NEAT way to prevent and treat overweight and obesity?2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Modern society is triggering sedentary behaviours in different domains. Different strategies can be used to reduce the time spent sitting and increase physical activity in the office environment, which is one domain where sedentary time is often high. One such strategy could be to install treadmill workstations. With these, the office workers can walk on a treadmill while performing their usual work tasks at the computer. However, the long-term effects of these workstations are not known. 

    Aim: The overall aim of this thesis was to investigate the long-term effects on sedentary behaviour, physical activity and associated health factors of installing treadmill workstations in offices compared to regular office work.

    Method: In this randomized controlled trial, 80 sedentary, middle-aged, healthy office workers with overweight or obesity were individually randomized into either an intervention or a control group. Those in the intervention group had a treadmill workstation installed at their sit-stand desk, to use for at least one hour per day for 13 months. They further received boosting e-mails at four time-points during the study. Participants in the control group continued to work as normal at their sit-stand office desk. All participants also received a health consultation at the beginning of the study, where they got to discuss physical activity and diet recommendations. Measurements reported include physical activity and sedentary behaviour, anthropometric measurements, body composition, metabolic outcomes, stress, depression and anxiety, cognitive function, structural brain images and interview data. Linear mixed models were used for the main statistical analyses of the quantitative data. An exploratory approach was also undertaken, using orthogonal partial least squares regression on the baseline data. Finally, interview data from participants in the intervention group were analysed using a modified Grounded Theory approach.

    Results: The intervention group increased their daily walking time and their number of steps at all follow-ups compared to the control group. Concomitantly, a decrease in moderate-to-vigorous intensity physical activity (MVPA) was observed within both groups, mainly during weekends. No intervention effects were observed on any of the body, cognitive or brain volume measurements. Our exploratory analyses revealed a significant association between smaller hippocampal volume and percentage sitting time among participants over 51 years of age. From the interview data, we discovered a core category, “The Capacity to Benefit”. The categories were described as the ideal types the Convinced, the Competitive, the Responsible and the Vacillating, based on the principal characteristics of the participants representing their different motivational status and strategies to reach the goal of benefitting from the intervention.  

    Conclusion: It is possible to increase daily physical activity in office environments by introducing treadmill workstations. Future interventions should adapt strategies for the individuals based on their motivational level, but should also workwith the social and physical environment and with factors within the organization to gain the best effects of these interventions.

    The full text will be freely available from 2019-11-16 00:00
  • Public defence: 2018-11-23 09:00 Stora hörsalen (KBE303), Umeå
    Fallah, Mahsa
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Plasminogen: a pleiotropic inflammatory regulator in radiation-induced wound formation and wound repair2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The plasminogen activator (PA) system plays important roles in many physiological and pathological processes, including inflammation and wound healing. Plasmin, the central component of the PA system, is a broad-spectrum serine protease that is derived from its inactive precursor form, plasminogen. The first aim of this thesis was to study the role of plasminogen in the formation of radiation-induced wounds, which are an inflammatory side effect of radiotherapy. The second aim was to investigate the molecular mechanisms behind the potentiating effect of plasminogen in the healing of radiation-induced wounds. The third aim was to explore the therapeutic potential of plasminogen in the healing of radiation-induced wounds.

    Radiation therapy in cancer patients is often limited by side effects such as radiation-induced skin damage (radiodermatitis). The mechanisms behind the formation of radiodermatitis are not fully elucidated, and there are no effective preventive therapies for clinical use. In this study, we show that irradiation of skin in WT (wild-type) mice induces plasminogen accumulation, which is followed by activation of TGF-β (transforming growth factor-beta) signaling and the development of inflammation that leads to skin damage. However, plasminogen-deficient mice and mice lacking PAs were mostly resistant to radiodermatitis. Moreover, treatment with a plasminogen inhibitor, tranexamic acid, decreases radiodermatitis in WT mice and prevented radiodermatitis in heterozygous mice. Thus, plasmin is required for the formation of radiodermatitis, and inhibition of plasminogen activation might be a novel treatment strategy to reduce or prevent radiodermatitis in patients undergoing radiotherapy.

    Wound healing consists of partially overlapping inflammatory, proliferation, and tissue remodeling phases, and failure to terminate inflammation leads to the formation of chronic wounds. Previous studies by our group have shown that plasminogen is transported to acute wounds by inflammatory cells where it potentiates inflammation and enhances wound healing. Here, we report that plasminogen-deficient mice, which have delayed wound healing, have extensive fibrin and neutrophil depositions in the wounded area long after re-epithelialization, indicating inefficient debridement and chronic inflammation. The delayed formation of granulation tissue suggests that fibroblast function is also impaired in the absence of plasminogen. Therefore, in addition to its role in the activation of inflammation, plasminogen is also crucial for the resolution of inflammation and the activation of the proliferation phase. Importantly, supplementation of plasminogen-deficient mice with human plasminogen leads to a restored healing capacity that is comparable to that in WT mice. Therefore, plasminogen might be an important future therapeutic agent for treatment of wounds.

    In radiation-induced wounds, inflammation often cannot resolve and the wounds become chronic and fibrotic. Currently, there is no gold standard for the treatment of radiation-induced wounds. In this study, we have shown that radiation-induced wounds treated with plasminogen healed faster than placebo-treated wounds, had diminished inflammation and granulation tissue formation, and had enhanced re-epithelialization and collagen maturation. Transcriptome analysis showed that plasminogen has a pleiotropic effect on gene expression during wound healing, influencing the expression of 33 genes out of the 84 genes studied. In particular, plasminogen decreased the expression of 11 pro-inflammatory genes early in the healing process. Later, plasminogen decreased WNT (Wingless/Integrated) and TGF-β signaling, as well as the expression of 5 growth factors and 13 factors involved in granulation tissue formation. From the genes downregulated by plasminogen, 19 genes are known to be involved in fibrosis. These results show that in radiation-induced wounds with excessive inflammation and tissue formation plasminogen is able to direct the healing process to a normal outcome without the risk for developing fibrosis. This makes plasminogen an attractive drug candidate for treating radiodermatitis in cancer patients. Taken together, our results indicate that plasminogen is a pleiotropic inflammatory regulator involved in radiation-induced wound formation as well as in wound repair.

  • Public defence: 2018-11-23 09:00 Hörsal D, Unod T9, plan 9 Tandläkarhögskolan, Umeå
    Westborg, Inger
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Safety and  efficacy in the cataract surgery process2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background

    Cataract and age-related macular degeneration (AMD) are two major causes for visual impairment in the elderly. Cataract surgery is one of the most common surgical interventions performed in the western world. As a consequence of the increasing number of operations performed, postoperative visits are a large workload for surgical units. It is important that all parts of the cataract surgery procedure are appropriate and cost-effective. During the last 20 years the trend is towards fewer visits both pre- as well as postoperatively. The number and timing of postoperative visits are also a subject of an ongoing debate. Few studies have previously evaluated safety perspectives concerning the number and timing of post-operative visits.

    The last decade, new treatments for wet AMD have evolved and the number of patients receiving treatment has increased. It has been debated if blue-blocking intraocular lenses (IOL) have a protective effect on the development of wet AMD and decreasing the need for AMD-treatment after cataract surgery.

    Aims

    To analyse parts of the modern cataract surgery process including peri- and post-operative routines from a safety and efficacy perspective. To analyse pre- and perioperative risk factors as well as protective factors associated with the need for wet AMD-treatment after cataract surgery.

    Methods

    I, II. These prospective, observational cohort studies included all cataract surgery cases (n=1249) during a 1-year period, at one institution. The cohort was analysed regarding the use of a standardized anaesthetic regimen and the safety perspectives, when the standard routine is no planned postoperative visit in uncomplicated cases without ocular comorbidity.

    III. The above-mentioned cohort (study group), was compared with a cohort from another clinic (control group) with a different follow-up routine, i.e. each case with first eye cataract surgery had a planned postoperative visit. In the control group all patients (n= 1162 cases) had surgery during the same 1-year period. The number of planned and unplanned visits was recorded, and the surgical outcome from the two institutions was compared.

    IV. A register-based cohort study included all patients registered in the Swedish National Cataract Register and the Swedish Macula Register in 2010 - 2017, to find all eyes with past cataract surgery that were subsequently treated for wet AMD. Complete registry data was used for comparisons and analyses of pre- and peri-operative risk- and protective factors for wet AMD treatment after cataract surgery.

    Results

    I. A standardized anaesthetic method with topical and intracameral anaesthetics without sedation was used in most cases (90%). Median pain score after surgery was 0.7 (VAS 0-10) and most patients (97%) would choose the same anaesthetic method again.

    II, III. Evaluation of all medical records 2 years after the cataract surgery procedure, found no report of missed adverse events. Significantly less patients in the study group (9% vs 16%; p=0.000036) initiated a postoperative unplanned contact compared with the control group. Patients with 70 km or longer to the hospital were less inclined to seek unplanned care (p=0.016).

    IV. Female gender and high age are associated with an increased risk of needing treatment for wet AMD ≥1 year after cataract surgery. Eyes with a diagnosis of AMD preoperatively, and subsequently treated for wet AMD, had a significantly (p=0.023) lower degree of blue-blocking IOLs implanted at their previous cataract surgery.

    Conclusion

    I. A standardized anaesthetic method with topical and intracameral anaesthetics without sedation seems well tolerated by the patients, and is effective at cataract surgery, also in cases when complications/adverse events occur.

    II, III. Without compromising patient safety, it is possible to refrain from standard postoperative visits after cataract surgery in patients with uncomplicated surgery and no ocular comorbidity. A significant reduction in postoperative visits is only obtained if the standard routine applies to both first and second eye surgery.

    IV. Patients without preoperative AMD have no benefit from the use of blue-blocking IOLs. In patients with preoperatively diagnosed AMD, blue-blocking IOLs may offer some protection from the subsequent development of AMD.

  • Public defence: 2018-11-23 09:00 Aulan, Vårdvetarhuset, Umeå
    Linander, Ida
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Umeå University, Faculty of Social Sciences, Umeå Centre for Gender Studies (UCGS).
    “It was like I had to fit into a category”: people with trans experiences navigating access to trans-specific healthcare and health2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Trans issues have received increased attention over the last couple of years and important changes have been made in the legislation relating to gender reassignment and in trans-specific healthcare practices. At the same time, many people with trans experiences report poor mental health, bad experiences when encountering the healthcare and a tendency to postpone seeking care due to being badly treated. Previous research has also shown that gender norms guide the evaluation that precedes access to gender-confirming medical procedures. Critical studies examining practices within trans-specific healthcare in the Swedish context and health among people with trans experiences are limited, especially qualitative interview studies involving people with trans experiences.

    Aim: To analyse how constructions of trans experiences and gender can affect trans-specific healthcare practices, experiences of navigating access to gender- confirming medical procedures, inhabitancy of different spaces and, ultimately, health.

    Conceptual framework: Three areas of theory are used for the conceptual framework: trans studies, queer phenomenology and Foucauldian theories of power and governmentality.

    Methods: The thesis includes three sub-studies (generating four articles): two interview studies that build on interviews with 18 people with trans experiences, and a policy analysis of the guidelines for trans-specific healthcare published by the Swedish National Board of Health and Welfare. For the interview studies, grounded theory and thematic analysis were used as the analytical method. The guidelines were analysed using Bacchi’s method: “What’s the problem represented to be?”.

    Results: The participants experienced trans-specific healthcare as difficult to navigate due to waiting times, lack of knowledge and/or support and relationships of dependency between healthcare users and providers. In the evaluation, gender is reconstructed as linear – stereotypical, binary and stable – and the space for action available to care-seekers is affected by discourses existing both inside and outside trans-specific healthcare. The difficulties in navigating access to care were experienced as creating ill-health. In order to negotiate access to gender-confirming medical procedures, the participants took responsibility for the care process by, for example, ordering hormones from abroad, acquiring medical knowledge and finding alternative support. The linear gendered positioning was variously resisted, negotiated and embraced by the participants.

    The analysis of the guidelines showed that gender identity is constructed as a fixed linear essence but that the guidelines also open up space for a non-linear embodiment. Gender dysphoria is closely constructed in relation to psychiatric knowledge and mental health and the gate-keeping function among mental healthcare professionals is reconstituted in the guidelines. Hence, care-seekers are constructed as not competent enough to make decisions concerning access to gender-confirming medical procedures.

    The participants experienced several different spaces, such as bars, public toilets and changing rooms, gyms and cafés, as unsafe and as contributing to ill-health. In order to overcome the barriers to comfortably inhabiting spaces, the participants performed a kind of labour; for example, preparing in order to visit public baths and to answer transphobic comments and questions. Some spaces, such as trans-separatist, feminist and queer spaces, were experienced as safer and contributed to improved health through experiences of belonging, being able to share bad experiences and being able to relax.

    Conclusions: Trans-specific healthcare practices need to become more affirming and change so that care-seekers have more space for self- determination. Trans-specific healthcare needs more resources in order to decrease waiting times, improve knowledge and support, and hence to improve access to gender-confirming medical procedures. Actions need to be initiated to make spaces safer in order to improve the health of people with trans experiences.

  • Public defence: 2018-11-23 10:00 Hörsal B, Samhällsvetarhuset, Umeå
    Hane-Weijman, Emelie
    Umeå University, Faculty of Social Sciences, Department of Geography and Economic History.
    Returning to Work: geographies of Employment in Turbulent Times2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis adds to theorizations of resilience, by placing workers and employment on the center stage. This has been addressed by contextualizing gross employment changes and workers’ way back to employment after redundancy. Swedish longitudinal microdata from 1990-2010 were used. This made it possible to study employer-employee links that disappeared and appeared, and to follow redundant workers over time and space. 

    The empirical findings conclude there are big regional differences in resilience, absorptive capacity and employment growth. The trajectories of regional net employment growth are diverging – an unequal spatial development that might become reinforced with time as the empirical results show that resilience is a path-dependent phenomenon. Moreover, industry proximity is an important factor when analyzing both regional absorptive capacity and labour matching, thus significantly affecting worker adaptability in times of turbulence.

    This is explained by the frictions and skill (mis)matching that arise in the labour market and in new employment positions due to industry proximities. A cohesive and diverse region is more resistant to shocks as well as adaptable in the aftermath of the crisis, while a specialized region is more sensitive and less resilient in general. In addition, a worker facing redundancy in a region where there is a big share of the same or related industries to the industry she became redundant from decreases the time to re-employment as there is a big supply of jobs that need similar skills and competences. However, there are significant differences in the mobilities of redundant workers, where some groups are more inclined to diversify into new regions and industries, while some have more invested in the industry and region. However, staying in the same industry that experienced the major lay-off means a less stable employment, but moving into unrelated industries increases the workers’ chances of experiencing skill mismatch and becoming underemployed. Finding a new job in related industries means a more stable employment and increases the chances of upward mobility. 

    In conclusion, based on these findings, it is argued in the thesis that regional branching into related industries is a good regional resilience strategy. However, it needs to be combined with policies aiming for related labour branching as well in order to be able to reallocate skills into new parts of the economy while avoiding skill mismatch. This provides a good base for regional diversification that can result in path re-orientation and renewal.

  • Public defence: 2018-11-30 09:00 Betula, målpunkt L, by 6M, plan 0, Umeå
    Toppe, Cecilia
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    End stage renal disease in type 1 diabetes: time trends and risk factors2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background and aims: Sweden has a high incidence of type 1 diabetes (T1D) and the incidence is increasing worldwide. The incidence is now twice as high as when the registration of childhood onset T1D in Sweden started in 1977. One of the major risk factors for developing late complications such as renal failure (ESRD) is duration of T1D. With a disease onset early in life this could lead to young patients with serious complications. It is therefore of interest to follow these patients to see how the risk for complications develops over time. In the first study, time trends in onset of ESRD due to diabetes (type 1 and 2) and other causes of kidney failure were studied as well as the age at onset of ESRD. To follow up on this, the aim of the second study was to look at cumulative incidence in ESRD and analyse possible time trends and gender differences in a younger diabetes population with known T1D duration. An earlier study had shown a low incidence of ESRD and now 8 more years of follow up could be added. Besides genetics, metabolic control is a factor with strong impact on the future risk of complications. The social environment of the child and adolescent with diabetes influence the understanding and management of the disease and hence the blood glucose control. Social vulnerability and/or low education imposes even more stress on the individual which could negatively influence disease management. The aim of the third study was therefore to study the impact of socio-economic status (SES) on the risk of developing ESRD in the young diabetes population. The aim of the fourth study was to analyse time trends in the treatment choices once the patients develop ESRD, the survival and cause of death in treatment and how it has developed over time.

    Study population: In all studies, data from the Swedish Renal Register (SRR) were used. The data on the T1D patients with onset before the age of 15, used in studies II-IV, came from the Swedish Childhood Diabetes Register (SCDR).  In study II we also retrieved data from the Swedish National Diabetes Register (NDR) and the Diabetes Incidence Study in Sweden (DISS). All registers have national coverage. The diabetes registers were linked to the SRR to find the patients who had developed ESRD. In study III we used the linkage between the SCDR, the SRR and Longitudinal integration database for health insurance and labour market studies (LISA).

    Results: Even though the incidence of ESRD in Sweden remained stable, the incidence of ESRD due to T1D decreased over the studied years, 1991-2010. We did not see a concurrent change for T2D. The age when the T1D patients developed ESRD had increased by 3 years and this was not seen in patients with other causes of ESRD. For patients in the SCDR the increase in age was almost 6 years. The cumulative incidence of ERSD in Sweden due to T1D is still low, 5.6% at a maximum follow up of 38 years (median 23). The incidence of ESRD is decreasing when comparing onset of T1D in the 1970´s and 80´s to onset in the 90´s, even when adjusting for T1D duration. Once they had developed ESRD, the survival in renal replacement therapy (RRT) had also improved over the years. The longest survival was seen after receiving a kidney transplant which about 50% of the patients do.

    When analysing social risk factors for development of ESRD we found that the educational level of both parents, but especially the mothers, affected the child’s risk of developing ESRD. The strongest association of education however was seen in the T1D patients own education. There was also an increased risk of developing ESRD if any or both of the parents had received income support.

    Conclusion: The incidence of ESRD due to T1D is decreasing in Sweden and the age at onset of ESRD has increased by at least 3 years. There was a significant decrease in development of ESRD over time. The patients have a longer survival once in RRT today and many of them are transplanted, further improving their survival. Growing up in families with a lower SES increases the risk of later developing ESRD, a finding worthy of recognition in the clinical setting.

  • Public defence: 2018-11-30 09:00 E04, R-1, Norrlands Universitetssjukhus, byggnad 6E, Umeå
    Ling, Agnes
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Immune cell infiltration and prognosis in colorectal cancer2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Colorectal cancer (CRC) is globally the second most common form of cancer among women, and third in men. It is also one of the most common causes of cancer-related death in high-income countries. Surgical resection is the basis for curative therapy but still almost half of the patients die from metastatic disease. It is therefore imperative to strive on in the search for more efficient strategies to improve patient survival. The success scores for accurate prediction of patient prognosis remain discouraging and novel markers to identify high-risk patients are called for.

    The tumour immune response has proven critical to prognosis in CRC. A high amount of tumour infiltrating lymphocytes have in studies been found to significantly improve patient outcome. The opposite has been seen in patients with sparsely infiltrated tumours. Findings in this area have driven forth the design of the Immunoscore® system, which may be implemented in clinic as a complement to the TNM staging system. Ongoing research is also focusing on which immune evading mechanisms CRC might deploy in order to progress and metastasize.

    Aim: To study immune cell infiltration in relation to prognosis in CRC. More specifically the aim has been to investigate the prognostic importance of different subsets of immune cells infiltrating the tumour, not only according to quantity but also to intratumoural subsite (tumour invasive front, tumour centre and within the tumour epithelium). The tumour immune response was also evaluated in different molecular subgroups of CRC. Another part of this thesis concerns possible molecular mechanisms involved in tumour immune escape in CRC.

    Methods: CRC cases in the Colorectal Cancer in Umeå Study (CRUMS) were evaluated using immunohistochemistry, gene expression analyses as well as methylation analyses. Cytokine and chemokine expression was evaluated in CRC tumour tissues and one CRC cell line (Caco2) and derivatives using semi-quantitative real-time PCR. Methylation was analysed using methylation-specific pyrosequencing.

    Results: We found high quantities of both cytotoxic T cells (CTLs) as well as of regulatory T cells (Tregs) to associate with a better patient outcome. The infiltration of CTLs within the tumour epithelium provided the strongest prognostic information, whilst Tregs withheld the strongest association to prognosis at the tumour invasive front and tumour centre. We could further show that a high Th1 lymphocyte infiltration was strongly associated with a better prognosis in patients with CRC, independently of intratumoural subsite. Another finding was that the extent of Th1 infiltration and patient outcome differed in different molecular subgroups of CRC. We also found down-regulation of TAP1, a protein involved in antigen presentation by MHC class I, to be significantly associated with low infiltration of various subtypes of immune cells. Down-regulation of TAP1 was also correlated to poor prognosis in patients with early stages of CRC. Furthermore, we found TAP1 expression to be inversely correlated with methylation at sites close to the TAP1 promoter region.

    Conclusion: Tumour infiltrating T lymphocytes have a significant positive impact on prognosis in CRC patients. Different subsets of T lymphocytes vary in their dependency on intratumoural subsite, in to what extent they exert their prognostic influence. We moreover found varying Th1 lymphocyte infiltration rates as well as prognostic impact thereof, in different molecular subgroups of CRC. Our results also show down-regulation of TAP1 to be a mechanism of tumour immune escape in CRC. Further findings suggest methylation of the TAP1 gene to be a putative mechanism for TAP1 down-regulation.

  • Public defence: 2018-11-30 10:00 Hörsal E, Humanisthuset, Umeå
    Lind Pantzare, Anna
    Umeå University, Faculty of Social Sciences, Department of applied educational science, Departement of Educational Measurement.
    Dimensions of validity: studies of the Swedish national tests in mathematics2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The main purpose for the Swedish national tests was from the beginning to provide exemplary assessments in a subject and support teachers when interpreting the syllabus. Today, their main purpose is to provide an important basis for teachers when grading their students. Although the results from tests do not entirely decides a student’s grade, they are to be taken into special account in the grading process. Given the increasing importance and raise of the stakes, quality issues in terms of validity and reliability is attracting greater attention. The main purpose of this thesis is to examine evidence demonstrating the validity for the Swedish national tests in upper secondary school mathematics and thereby identify potential threats to validity that may affect the interpretations of the test results and lead to invalid conclusions. The validation is made in relation to the purpose that the national tests should support fair and equal assessment and grading. More specifically, the focus was to investigate how differences connected to digital tools, different scorers and the standard setting process affect the results, and also investigate if subscores can be used when interpreting the results. A model visualized as a chain containing links associated with various aspects of validity, ranging from administration and scoring to interpretation and decision-making, is used as a framework for the validation.

    The thesis consists of four empirical studies presented in the form of papers and an introduction with summaries of the papers. Different parts of the validation chain are examined in the studies. The focus of the first study is the administration and impact of using advanced calculators when answering test items. These calculators are able to solve equations algebraically and therefore reduce the risk of a student making mistakes. Since the use of such calculators is allowed but not required and since they are quite expensive, there is an obvious threat to validity since the national tests are supposed to be fair and equal for all test takers. The results show that the advanced calculators were not used to a great extent and it was mainly those students who were high-achieving in mathematics that benefited the most. Therefore the conclusion was that the calculators did not affect the results.

    The second study was an inter-rater reliability study. In Sweden, teachers are responsible for scoring their own students’ national tests, without any training, monitoring or moderation. Therefore it was interesting to investigate the reliability of the scoring since there is a potential risk of bias against one’s own students. The analyses showed that the agreement between different raters, analyzed with percent-agreement and kappa, is rather high but some items have lower agreement. In general, items with several correct answers or items where different solution strategies are available are more difficult to score reliably.

    The cut scores set by a judgmental Angoff standard setting, the method used to define the cut scores for the national tests in mathematics, was in study three compared with a statistical linking procedure using an anchor test design in order to investigate if the cut scores for two test forms were equally demanding. The results indicate that there were no large differences between the test forms. However, one of the test taker groups was rather small which restricts the power of the analysis. The national tests do not include any anchor items and the study highlights the challenges of introducing equating, that is comparing the difficulty of different test forms, on a regular basis.

    In study four, the focus was on subscores and whether there was any value in reporting them in addition to the total score. The syllabus in mathematics has been competence-based since 2011 and the items in the national tests are categorized in relation to these competencies. The test grades are only connected to the total score via the cut scores but the result for each student is consolidated in a result profile based on those competencies. The subscore analysis shows that none of the subscores have added value and the tests would have to be up to four times longer in order to achieve any significant value.

    In conclusion, the studies indicate that several of the potential threats do not appear to be significant and the evidence suggests that the interpretations made and decisions taken have the potential to be valid. However, there is a need for further studies. In particular, there is a need to develop a procedure for equating that can be implemented on a regular basis.

  • Public defence: 2018-11-30 10:00 N450, Naturvetarhuset, Umeå
    Hausmaninger, Thomas
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Mid- and near-infrared NICE-OHMS: techniques for ultra-sensitive detection of molecules in gas phase2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Noise-immune cavity-enhanced optical heterodyne molecular spectrometry (NICE-OHMS) is a technique for ultra-sensitive detection of molecular absorption and dispersion. For highest performance, the technique combines cavity enhancement (CE) with frequency modulation (FM); while the former increases the effective interaction length between the light and the analyte by several orders of magnitudes, the latter removes the in-coupling of 1/f noise and makes the signals background free. The combination of CE and FM also gives the technique an immunity to amplitude noise caused by the jitter of the laser frequency relative to the cavity resonance frequencies. All these properties make the technique suitable for ultra sensitive trace gas detection in the sub-parts-per-trillion (ppt) range. The aim of this thesis is to improve the performance of the NICE-OHMS technique and to increase its range of applications.

    The work in this thesis can be divided into three areas:Firstly, a mid-infrared (MIR)-NICE-OHMS instrumentation was developed. In a first realization an unprecedented white-noise equivalent absorption limit for Doppler broadened (Db) detection in the MIR of 3×10-9 cm-1Hz-1/2was demonstrated. This was subsequently improved to 2.4×10-10 cm-1Hz-1/2allowing for detection methane and its two main isotopologues (CH3D and 13CH4) at their natural abundance.Secondly, further development of an existing near-infrared NICE-OHMS system was performed. This resulted in an improved longtime stability and the first shot-noise limited NICE-OHMS system for Db detection with a noise equivalent absorption limit of 2.3×10-14 cm-1detected over 200 s. Thirdly, models and theoretical descriptions of NICE-OHMS signals under strong absorption conditions and from methane under high laser power were developed. It was experimentally verified that the models allow for a more accurate evaluation of NICE-OHMS signals under a wide range of conditions.

  • Public defence: 2018-11-30 13:00 Sal B, 9 tr, byggnad 1D, Norrlands Universitetssjukhus, Umeå
    Lampa, Ewa
    Umeå University, Faculty of Medicine, Department of Odontology.
    Pain and disability in the jaw and neck regions after whiplash trauma: a short- and long-term perspective2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Whiplash trauma, a hyperextension-flexion trauma to the neck that is often related to a car accident, affects tens of thousands in Sweden every year. A significant proportion will develop long-term symptoms including neck pain and dysfunction – this is embraced as Whiplash associated disorders (WAD). Some individuals also develop pain and dysfunction in the orofacial region that is denoted as Temporomandibular disorder (TMD). TMD is common in the population with a prevalence of about 10% but the relation to whiplash trauma is still unclear. The limited number of prospective studies on TMD after whiplash trauma show diverging results, but it has been suggested that TMD develops over time and not in close proximity to the trauma. Prospective studies are needed to determine the course of jaw pain and disability after whiplash trauma.

    The general aim of this thesis was to evaluate the presence and course of pain and disability in the jaw and neck regions at the acute and chronic stages after whiplash trauma.

    This prospective cohort study included at baseline 176 cases with a recent whiplash trauma, and 116 age and gender matched controls without a history of neck trauma that were recruited from the general population. The cases had visited the emergency department at Umeå university hospital, Sweden, with neck pain within 72 hours following a car accident and had been diagnosed with neck distortion by a physician. The cases were examined within one month after the trauma (December 2010 to January 2016) and at a 2-year followup (December 2012 to January 2018). All participants completed questionnaires regarding pain and disability in the jaw and neck regions, physical symptoms (pain and non-pain items), and depression. At baseline, 80 of the cases and 80 of the controls also completed a 5-minute chewing capacity test. At the 2- year follow-up, 119 cases (68%) and 104 controls (90%) were re-examined with the same questionnaires.

    Compared to controls, within one month after a whiplash trauma cases reported significantly more pain in the jaw and neck regions with a positive correlation between the intensity of pain in these regions (Paper I). In the acute stage after trauma, cases, compared to controls, showed a reduced chewing capacity, and this was related to the severity of neck disability (Paper II). For cases, jaw and neck pain correlated positively to each other, to non-specific physical symptoms, and to depression at both the acute (Paper III) and chronic stages (Paper IV). About one third (34%) of the cases reported orofacial pain at baseline, and for a majority of these, the pain persisted at the 2-year follow-up (Paper IV).

    The presence of orofacial pain early after a whiplash trauma indicates involvement of central sensitization and spread of pain between the jaw and neck regions. The positive correlations between pain in the jaw and neck regions, and to psychosocial factors, underline the integration of these regions and the importance of a biopsychosocial perspective. The impaired jaw function shortly after a neck trauma further underlines the close sensorimotor relationship between the trigeminal and cervical regions. The finding that orofacial pain is common shortly after whiplash trauma, and often persists into the chronic stage, indicates that assessment in the acute stage should include both the neck and jaw regions. From this, it follows that multidisciplinary teams that entail both medical professions and dentists specialised in orofacial pain can be beneficial in the early assessment after whiplash trauma.

  • Public defence: 2018-11-30 13:00 HumlabX, Umeå Arts Campus
    Kuenen, Stoffel
    Umeå University, Faculty of Science and Technology, Umeå Institute of Design.
    Aesthetics of being together2018Doctoral thesis, monograph (Other academic)
    Abstract [en]

    Design deals with matters of aesthetics. Historically, aesthetics in industrial design refers to the designed artifact: aesthetics of objects. When designed artifacts include digital technologies, aesthetics in design refers to what happens between people and artifacts as well: aesthetics of interaction. Now that these artifacts increasingly mediate our social lives, what aesthetics in design quite obviously also refers to, is what happens between people.

    This dissertation proposes an aesthetic of being together, as a necessary addition to current notions of aesthetics in interaction design practice, when it engages with digital systems that are part of people’s social life. It does not answer the question what Aesthetics is in general, instead it examines the work that particular notions of aesthetics do in interaction design practice.

    The practice based design research assembled in this dissertation starts from current notions of aesthetics in interaction design to explore the social experiences that mediated interactions between groups of people offer. What I found, through designing digital systems, is that current notions of aesthetics in interaction design are not conducive to addressing the kind of social experience people have with such systems. On the contrary, current notions actually inhibit interaction design to approach any experiences that cannot in the first place be conceived of as useful in terms of instrumental task performance. Yet, being social is hardly like performing a task or using other people in that sense.

    An aesthetic of being together is a proposition of a different fundament for interaction design practice. In addition to referring to properties of things and qualities of interacting with things, it refers to the kind of relations that come to expression between people interacting with each other with these things. Consequently, interaction design needs to resolve basic issues in what it considers and brings to expression, i.e. people’s relations with things and people at the same time. This requires (re-) considering what the designed thing is, what interaction is about and what the role of design is in bringing those to expression.

    My work contributes to the field of interaction design research an example of how, through practice, fundamental issues can be addressed. By orienting one set of concepts, ways of working and objectives into a different design situation, tensions built up that exposed foundational issues with that frame of reference, while pointing to the different fundaments needed to enable design practice to engage such situations.

    The results of the practical experimentation led to the articulation of a series of structural mechanisms of mediating systems.  These mechanisms provide material handles for interaction designers on how experiences of being present with others take shape. They configure the relations of artifacts and people in different ways than current notions of aesthetics afford. This theoretical investigation is then synthesised in the form of a new logic of expression for interaction design practice: an aesthetic of being together.

  • Public defence: 2018-12-04 09:00 Betula, Byggnad 6M, Umeå
    Rawcliffe, Denise F. R.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    The regulation of incorrect splicing of ISCU in hereditary myopathy with lactic acidosis2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Patients suffering from hereditary myopathy with lactic acidosis (HML) can be found in the northern Swedish counties of Ångermanland and Västerbotten. HML is a rare autosomal recessive disease where patients display a low tolerance to exercise at an early age. Exercise can trigger symptoms such as palpitations, tachycardia, muscle cramps and dyspnoea. Extensive exercise or strict diets can result in myoglobinuria and life-threatening levels of lactic acid. The disease is caused by a nonsense G > C mutation (c.418 + 328G < C) in the last intron of the iron-sulphur (FeS) cluster assembly gene (ISCU), resulting in nonsense-mediated decay (NMD) of the transcript due to incorrect splicing. The ISCU protein is involved in the assembly of FeS clusters, which are essential cofactors for a wide range of proteins. Patient muscles display decreased levels of several FeS cluster proteins: mitochondrial aconitase in the tricarboxylic acid (TCA) cycle and Complex I, II (succinate dehydrogenase [SDH]) and III in the electron transport chain (ETC). The incorrect splicing of ISCU occurs to the highest extent in HML patient skeletal muscle, restricting the loss of ISCU protein to muscles, thereby preventing a more severe phenotype.

    We found that the incorrect splicing occurs to the highest extent in slow-fibre muscle, which may be caused by the serine/arginine-rich splicing factor (SRSF3) as it is expressed at higher levels in slow-fibre muscle compared to other muscles, and since it is able to activate the incorrect splicing of ISCU. Following muscle, there is a gradual decrease of the incorrect splicing in heart, brain, liver and kidney, which is negatively correlated with the levels of the splicing inhibitor polypyrimidine-tract binding protein 1 (PTBP1). Overexpression of PTBP1 in HML patient myoblasts resulted in a drastic decrease in the incorrect splicing, while a PTBP1 knockdown had the opposite effect. Our results suggest that PTBP1 acts as a dominant inhibitor of the incorrect splicing and is likely the main cause for the tissue-specific splicing of ISCU in HML. We also identified RBM39 and MBNL1 as activators of the incorrect splicing of ISCU, which, together with the low levels of PTBP1, could explain the high levels of incorrect splicing in muscle.

    Since almost 95% of all human gene transcripts are alternatively spliced, it is not surprising that a wide range of diseases are caused by mutations that affect splicing. Further knowledge of the function of splicing, such as tissue-specific splicing, can provide vital information for the development of therapies for diseases caused by splicing.

  • Public defence: 2018-12-06 13:00 Norrlands universitetssjukhus, Unod R1, Hörsal E04,, Umeå
    Lécrivain, Anne-Laure
    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 Molecular Biology (Faculty of Medicine).
    Post-transcriptional regulation by RNases in Streptococcus pyogenes2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Ribonucleases (RNases) are proteins that adjust cellular RNA levels by processing RNA transcripts, leading to their stabilization or degradation. RNases are grouped based on their ability to cleave the transcript internally (endoRNases) or degrade the transcript starting from the ends (exoRNases). Specificities of RNA degradation vary among bacterial species, attributable to different sets of endo- and exoRNases. Most of the current knowledge gathered about the roles of RNases and their targets relies on the study of a few model bacteria, such as Escherichia coli and Bacillus subtilis. The aim of this thesis was to understand how Streptococcus pyogenes, a strict human pathogen, controls and adjusts gene expression by characterizing in vivo RNase activities.

    The transcriptome of S. pyogenes was inspected to identify cleavages in vivo performed by RNases of interest using RNA sequencing. For this purpose, we developed a method to compare transcript 5′ and 3′ ends in RNase deletion mutants with those in the parental strain. We first applied our method for the study of endoRNase III, which cleaves ds RNA, and endoRNase Y, which is specific for ss RNA. We accurately retrieved RNase III cleavage positions in structured regions, characterized by 2 nucleotide (nt) 3′ overhangs, and we showed RNase III nicking activity in vivo. We observed that RNase Y processed transcripts after a guanosine. The upstream and downstream fragments generated by a single cleavage event were never both identified, indicating that RNase Y processing always led to the degradation of one of the two fragments. To investigate further the degradation of the upstream fragment subsequent to RNase Y processing, we characterized the 3′-to-5′ exoRNases R, YhaM, and PNPase. RNase R did not have any detectable activity in standard laboratory conditions. YhaM is an intriguing enzyme that removed on average 3 nt of the majority of cellular transcripts. PNPase fully degraded fragments originating from endoRNase processing and is the main 3′-to-5′ exoRNase involved in RNA decay in S. pyogenes.

    To conclude, in this work, we developed a novel method to analyze RNA sequencing data. This method was successfully applied to the study of both endo- and exoRNases. Most importantly, we identified the targetomes of RNases III, Y, R, YhaM, and PNPase and we highlighted the distinctive features of these enzymes.

    The full text will be freely available from 2019-12-06 00:01
  • Public defence: 2018-12-07 09:00 Sal D, byggnad 1D, Tandläkarhögskolan, Umeå
    Isehed, Catrine
    Umeå University, Faculty of Medicine, Department of Odontology. Folktandvården Gävleborg AB, Region Gävleborg.
    Peri-implantitis: treatment and effects of enamel matrix derivative2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Biological complications affecting osseointegrated dental implants are a growing treatment problem in clinical practice. Since the number of implant carriers has increased in recent decades, this is an urgent topic in dentistry. Peri-implantitis, inflammatory degradation of the implant-supporting jawbone, affects approximately 20% of all implant carriers and approximately 10% of all implants.

    Implant surfaces are colonised by microbes that may cause an inflammatory process in the soft tissue around the implant. In some sensitive individuals, the inflammatory response leads to disturbed jawbone remodelling, with increased recruitment and activity of bone-resorbing osteoclasts, which could ultimately lead to implant loss. The corresponding degradation of the bone supporting the teeth is denoted as periodontitis. The current view is that factors such as proinflammatory cytokines and prostaglandins, produced by leukocytes and cells of mesenchymal origin in the inflamed connective tissue, are responsible for local osteoclast recruitment and activation. Pro-inflammatory factors and tissue degradation products will leak into the exudate in the peri-implant sulci and the gingival pockets around the teeth. Analysis of the exudate could be of use for predicting and monitoring peri-implantitis, as well as identifying new targets for treatment.

    The standard treatment for peri-implantitis is surgery in combination with mechanical cleaning of the implant surface and optimisation of oral hygiene, with the goal of achieving infection control and pocket reduction. This treatment has a moderate effect on healing of the peri-implantitis lesion around the dental implant. The use of adjunctive bone grafts, membranes and antimicrobials has thus far not been shown to achieve a more successful outcome. Adjunctive treatment with enamel matrix derivative (EMD) during regenerative periodontal surgery contributes to wound healing and increased tissue support, but the adjunctive effect of EMD during surgical treatment of peri-implantitis remains unknown.

    The overall aim of this thesis was to investigate the outcome of a regenerative surgical treatment approach with and without adjunctive EMD treatment from the short- and long-term perspectives and to increase our knowledge of microbial flora and biomarkers in the peri-implant sulci before and after treatment. Furthermore, an additional aim of this work was to investigate whether EMD could directly affect osteoclast formation and activity.

    We performed a randomised controlled clinical trial of a surgical intervention for peri-implantitis with and without EMD. In multivariate modelling, an increased marginal bone level at the implant site 12 months after surgery was significantly associated with EMD, the number of osseous walls in the peri-implant bone defect and a gram-positive/aerobic microbial flora, whereas a reduced bone level was associated with a gram-negative/anaerobic microbial flora and the presence of bleeding and pus, with a cross-validated predictive capacity (Q2) of 36.4%. Similar trends were observed for bone level, pocket depth, plaque, pus and bleeding, but these associations were statistically non-significant in the univariate analysis. Five years after treatment, no significant differences in bone level changes were observed between groups, but fewer implants were lost to follow-up due to reinfections in the EMD-treated group.

    We used mass spectrometry to analyse the protein content in peri-implant crevicular fluid (PICF) before and up to 12 months after treatment. The total protein amount and diversity displayed decreasing trends 3, 6 and 12 months after treatment. Multivariate analysis of the PICF protein content revealed two major groups, cluster 2 and cluster 3, of which cluster 2 was associated with an increased risk of implant loss. EMD treatment was associated with cluster 3, which was in turn associated with increased implant survival.

    To test whether EMD affects osteoclast formation or bone resorption, we added purified EMD to RANKL-stimulated mouse bone marrow macrophage cultures in plastic dishes and counted the number of osteoclasts. We also cultured the cells on bone slices and measured the secretion of TRAP5b and the release of CTX-1 into the culture medium as biomarkers of osteoclast numbers and bone resorption, respectively, but no effect of EMD was observed.

    In conclusion, adjunctive EMD during surgical treatment of peri-implantitis changed the microbial flora to a less pathogenic microbiota, and similar changes in the inflammatory protein profile of PICF were observed; these effects were associated with implant survival. However, the trend toward a positive healing response after EMD treatment was not associated with a significant radiographic bone gain in this study and needs to be further explored. In addition, our finding that EMD did not affect osteoclast formation or bone resorption in vitro indicates that the effect of EMD on bone regeneration, as seen in periodontitis treatment, does not seem to depend on a direct inhibitory effect on osteoclast formation or bone resorption.