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  • Public defence: 2019-04-26 09:00 Hörsal d Unod T 9, Umeå
    Espaillat, Akbar
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Uncovering novel cell wall chemistries in gram negative bacteria: from development or dedicated peptidoglycan chemometric tools to functional genomics2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Bacteria are surrounded by an external cell wall whose main component is a polymeric net-like structure called the peptidoglycan (PG) or murein sacculus. PG plays crucial roles in bacterial physiology (eg morphogenesis, growth fitness and regulation of innate immunity). Based on the characteristics of this macromolecule, bacteria are grouped as gram negative and positive. Gram negatives present a thin PG layer in the periplasmic space, while Gram positive bacteria contain one thick multi-layered sacculus covering the cytoplasmic membrane. Although the PG sacculus is widely conserved between bacteria, variations in its chemical structure (ie sugars and peptide components) have been reported as a coping mechanism to stress. For example, V. choleraeis able to downregulate PG biosynthesis through non-canonical D-amino acids (NCDAAs) cell wall editing when entering stationary phase. NCDAAs production relies on Bsr enzymes, broad spectrum racemases which are expressed in V. cholerae under the control of stress sigma factor RpoS. In this thesis, we present a comprehensive study that allows us to determine the basic structural and biochemical features required for prominent D-amino acid production by Bsr enzymes.

    V. cholerae’s PG editing by NCDAAs revealed the existence of previously unappreciated  chemical modification in the cell wall of bacteria. Such an observation made us question whether the latest technology could reveal, otherwise undetectable, novel PG traits and furthermore, revisit the existence of murein in bacteria which were previously defined as PG-less. Finally, these studies would promote a global assessment of the degree of PG-chemical variability at a Kingdom scale.

    On the search for novel functional chemistries and associated mechanisms of cell wall regulation, we analysed the cell wall of hundreds of different species. Here, I present two proof of concept studies: i) investigation of the existence of PG in the Plantomycetes Kuenenia stuttgartiensis, a species previously classified as PG-less; and ii) PG chemical diversity within Class Alphaproteobacteria. To do so, we developed and experimentally validated an innovative chemometric pipeline to rapidly analyse large PG datasets. Chemometric analyses revealed 3 PG clusters within Alphaproteobacteria, which included unprecedented PG modifications widely conserved in family Acetobacteria: amidation at the α-(L)-carboxyl of meso-diaminopimelic acid and the presence of (1–3) cross-linked muropeptides between L-Ala and D-(meso)-diaminopimelate residues from adjacent moieties. Fluctuations of the relative abundance of these PG traits were growth phase and media composition dependent. Functional studies demonstrated that Acetobacteria atypical muropeptides enabled cellular protection against Type VI secreted endopeptidases and negatively affected innate immune system recognition suggesting relevant functional roles in the environmental adaptability of these bacteria.

  • Public defence: 2019-04-26 09:00 Sal E04, Umeå
    Al-Alawi, Kamila
    Umeå University, Faculty of Medicine, Department of Epidemiology and Global Health.
    Team-based approach in the management of diabetes at primary health care level in Muscat, Oman: challenges and opportunities2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Introduction: The growth of type 2 diabetes is considered an alarming epidemic in Oman. The efficient team-based approach to diabetes management in primary health care is an essential component for providing ideal diabetic care. This thesis aimed to explore the current situation related to team-based management of type 2 diabetes in public Primary Health Care Centres (PHCCs) under the Ministry of Health (MOH) in Oman, including the various challenges associated with diabetes management and the most preferable Human Resources for Health (HRH) management mechanism, and to examine how this could be optimized from provider and patient perspectives.

    Materials and methods: The entire project was conducted in Muscat Governorate and was based on one quantitative and three qualitative studies. In the quantitative study, 26 public PHCCs were approached through cross-sectional study. The core diabetes management team recommended by the MOH for PHCCs in Oman was explored in terms of their competencies, values, skills, and resources related to the team-based approach to diabetes management. For the qualitative studies, five public purposely-selected PHCCs were approached. The diabetes consultations conducted by the core members and other supportive members involved in diabetes management were observed and later the Primary Health Care Providers (PHCPs) were interviewed. The different approaches explored challenges related to diabetes management and the most preferable HRH mechanism by PHCPs. Seven type 2 diabetes patients with different gender, employment status, and education were consequently interviewed to explore their perceptions towards the current diabetes management service and their opinions towards nurse-led clinics.

    Results: The survey provided significant and diverse perceptions of PHCPs towards their competencies, values, skills, and resources related to diabetes management. Physicians considered themselves to have better competencies than nurses and dieticians. Physicians also scored higher on team-related skills and values compared with health educators. In terms of team-related skills, the difference between physicians and nurses was statistically significant and showed that physicians perceived themselves to have better skills than nurses. Confusion about the leadership concept among PHCPs with a lack of pharmacological, technical, and human resources was also reported. The observations and interviews with PHCPs disclosed three different models of service delivery at diabetes management clinics. The challenges explored involved PHCCs’ infrastructure, nurses’ knowledge, skills, and non-availability of technical and pharmaceutical support. Other challenges that evolved into the community were cultural beliefs, traditions, health awareness, and public transportation. Complete implementation of task-sharing mechanisms within the team-based approach was selected by all PHCPs as the most preferable HRH mechanism. The selection was discussed in the context of positive outcomes, worries, and future requirements. The physicians stated that nurses’ weak contribution to the team within the selected mechanism could be the most significant aspect. Other members supported the task-sharing mechanism between physicians and nurses. However, type 2 diabetes patients’ non-acceptance of a service provided by the nurses created worries for the nurses. The interviews with type 2 diabetes patients disclosed positive perceptions towards the current diabetes management visits; however, opinions towards nurse-led clinics varied among the patients.

    Conclusions and recommendations: The team-based approach at diabetes management clinics in public PHCCs in Oman requires thoughtful attention. Diverse presence of the team members can form challenges during service delivery. Clear roles for team members must be outlined through a solid HRH management mechanism in the context of a sharp leadership concept. Nurse-led clinics are an important concept within the team; however, their implementation requires further investigation. The concept must involve clear understandings of independence and interdependence by the team members, who must be educated to provide a strong gain for team-based service delivery.

  • Public defence: 2019-05-10 09:00 Sal 933, Umeå
    Wahlin, Bengt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Atherosclerotic cardiovascular disease in rheumatoid arthritis: aspects of pathogenesis and risk2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Patients with rheumatoid arthritis (RA) have an increased prevalence and severity of atherosclerosis, and a corresponding increased risk of cardiovascular disease. The mechanisms causing this are not well elucidated, but both traditional cardiovascular risk factors and RA-associated factors have been associated with atherosclerosis and increased risk of cardiovascular events in patients with RA. Cardiovascular risk estimation based on traditional cardiovascular risk factors, often underestimates the risk in patients with RA. The aims of this thesis were to examine factors and biomarkers associated with atherosclerosis in patients with RA, and to evaluate an algorithm for cardiovascular risk estimation in patients with RA.

    Methods Patients with early RA in the four northernmost counties of Sweden have since 1995 been included in a prospective study of both the progress of RA and comorbidities. Besides clinical data, radiographs, genetic markers and autoantibodies are registered. Paper I includes 665 patients aged 40-80 years from that cohort, in whom the 10-year risk of a first cardiovascular event was estimated with both Expanded Cardiovascular Risk Prediction Score in Rheumatoid Arthritis (ERS-RA), and the general population based ACC/AHA algorithm. The estimations were then compared to the actual outcomes. Paper II examines factors associated with coronary artery calcification (CAC) in 22 patients with long-standing RA. Papers III and IV use data from a cohort of patients <60 years of age at diagnosis of RA (n=79), in whom development of atherosclerosis has been prospectively followed since diagnosis of RA. This is a subset of patients from the larger cohort in paper I. Controls matched for age and sex (n=44) are examined as well. In paper III, phenotypes of T-cells and IgG-antibodies against cytomegalovirus (CMV) are analysed in relation to carotid intima-media thickness (IMT). In paper IV, bone mineral density and markers and regulators of bone metabolism are analysed in relation to IMT.

    Results Cardiovascular risk estimation with the RA-specific algorithm ERS-RA is not superior to estimation with the ACC/AHA algorithm. Both algorithms underestimate the risk in patients with a high grade of inflammation and in patients with an estimated moderate risk. In patients with long-standing RA, presence of CAC is associated with inflammatory activity, both at time of examination and in earlier stages of RA. Presence of anti-CMV IgG antibodies and altered T-cells (both CD4+ and CD8+) lacking the co-stimulatory molecule CD28 (CD28null) are associated with a higher IMT, and patients IgG-positive for CMV have a rapid increase in IMT after onset of RA. Regulators of bone metabolism (sclerostin, osteoprotegerin and osteocalcin) are associated with a higher IMT in patients with RA.

    Conclusion Cardiovascular risk estimation in patients with RA still needs to be improved. The fact that CMV-positivity, altered populations of T-cells and IMT all are associated, and that also regulators of bone metabolism reflect IMT, suggests that the pathogenesis of atherosclerosis in patients with RA is multifactorial.  This thesis provides knowledge of the accelerated development of atherosclerosis in RA and could possibly be relevant also in other chronic inflammatory diseases, where markers of accelerated atherosclerosis and increased cardiovascular risk are lacking.

  • Public defence: 2019-05-17 12:30 N420, Umeå
    Sidenvall, Johan
    Umeå University, Faculty of Science and Technology, Umeå Mathematics Education Research Centre (UMERC). Umeå University, Faculty of Science and Technology, Department of Science and Mathematics Education.
    Lösa problem: om elevers förutsättningar att lösa problem och hur lärare kan stödja processen2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In mathematics education, there is generally too much emphasis on rote learning and superficial reasoning. If learning is mostly done by rote and imitation, important mathematical competencies such as problem-solving, reasoning, and conceptual understanding are not developed. Previous research has shown that students who work with problems (i.e. constructs a new solution method to a task), to a greater extent increase their mathematical understanding than students who only solve routine tasks.

    The aim of the thesis was to further understand why teaching is dominated by rote learning and imitation of procedures and investigate how opportunities for students to solve tasks through problem-solving could be improved. This was done through the following studies. (1) Investigating the relation between types of solution strategy required, used, and the rate of correct task solutions in students’ textbook task-solving. (2) Studying the relationship between students’ beliefs and choice of solution strategy when working on problems. (3) Conducting a textbook analysis of mathematics textbooks from 12 countries, to determine the proportions of tasks that could be solved by mimicking available templates and of tasks where a solution had to be constructed without guidance from the textbook. (4) Conducting a literature review in order to characterize teaching designs intended to enhance students to develop mathematical understanding through problem solving and reasoning. (5) Conducting an intervention study were a teacher guide, structured in line with central tenets of formative assessment, was developed, tested, and evaluated in real classroom settings. The teacher guide was designed to support teachers in their support of students’ in their problem-solving process. Studies I, II and V were conducted in Swedish upper secondary school settings. 

    The students’ opportunities to solve tasks through problem-solving were limited: by the low proportion of problems among the easier tasks in the textbooks; by the students' choice of using imitative solution strategies; and by the guidance of solution methods that students received from other students and their teachers. The students’ opportunities were also limited by the students' beliefs of mathematics and the fact that a solution method of problem tasks was not always within reach for the students, based on the students' knowledge. In order to improve students’ opportunities, teachers should allow students to work with more problems in a learning environment that lets students engage in problem-solving and support students' work on problems by adapting their support to students' difficulties. The results also give implications for the construction and use of textbooks and how the use of the teacher guide could be part of teachers’ professional development and a tool that teacher students may meet within their education.