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Coming dissertations at MedFak

  • Fluid Management in Haemodialysis : Studies on current practices and new methods Author: Jenny Stenberg Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-407956 Publication date: 2020-05-06 10:20

    Chronic fluid overload has been identified as an independent predictor of mortality in haemodialysis patients, and 30% remain fluid overloaded at dry weight. The use of bioimpedance spectroscopy (BIS) in fluid management may improve blood pressure control and cardiovascular status. However, the importance of regular and careful clinical assessment of fluid balance is repeatedly emphasised.

    This thesis is based on five papers and the overall aim was to investigate current practices and new methods for fluid management in haemodialysis, and to develop a management tool for dry weight determination, based on multiple complementary methods. The purpose was to contribute to reduced prevalence of fluid overload and intradialytic symptoms in haemodialysis patients, by providing the healthcare team and the patient with a tool, that facilitates communication and enables informed decision-making in dry weight determination.

    In the initial, cross-sectional study, clinical praxis for dry weight assessment in Sweden and Denmark was investigated. A wide variation in routines was found. Despite high access, BIS was sparsely used. Instead, nurses’ authorisation to adjust haemodialysis patients’ dry weight was associated with improved fluid status. The second study had a qualitative approach. Focus group interviews, with healthcare professionals, were carried out to achieve a deeper understanding of the factors preventing or facilitating the use of BIS. In the third study, the usefulness of a biomarker, brain natriuretic peptide (BNP), for assessing fluid status in haemodialysis patients, was investigated. An association between BNP and fluid overload was established. The between-individual variation in BNP levels was greater than the within-individual variation over time. Therefore, if BNP is to be used as a marker for fluid overload, repeated measurements are required. In the fourth study, we developed and validated a multifactorial decision aid, Recova®, that incorporates BIS in dry weight determination. Recova® is based on physiological parameters routinely measured in haemodialysis and provides guidance on when and how to respond to recognised fluid alterations. In the fifth study, the decision aid’s effect on volume status was tested in a cohort of haemodialysis patients. Implementation of Recova® had effect on fluid status symptoms, BIS-measured hydration status and NT-proBNP levels.

  • Studies of drug safety in the treatment of rheumatoid arthritis Author: Johanna Karlsson Sundbaum Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-407866 Publication date: 2020-05-04 14:17

    Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting mainly smaller joints. Patients are at risk for complications as joint destruction, but starting treatment soon after onset of disease, has reduced the risk for complications. Methotrexate (MTX) is the anchor drug in the treatment of RA and has proven effects on both inflammatory symptoms and joint destruction. apy. Identifying patients at risk for MTX-induced hepatotoxicity before treatment could be a way to minimize the risk for Adverese effects.Following the introduction of pre-treatment screening, the risk of tuberculosis (TB) among patients with RA starting biologic treatment has decreased. By contrast, the risk remains several-fold increased in RA patients non-exposed to biological treatment. Knowledge about risk factors for TB and TB characteristics in this group of patients, and thus optimal clinical risk stratification and preven-tion, is still limited.In Paper I, only a small number of ALT tests (7%) performed during MTX therapy in RA patients, capture an elevation of ALT > upper limit of normal (ULN). ALT >1.5 × ULN was observed in 44 (21%) patients and the strongest predictor was a pre-treatment elevation of ALT. Recurrent elevations occurred in 70% of patients who continued treatment, and the proportion was similar in those with and without interventions. The results support a more individualized approach to monitoring and handling of ALT elevations during MTX therapy. In Paper II MTHFR A1298C (rs1801131) was nominally associated with ALT >1.5 x ULN within 6 months after the start of MTX (OR=1.7 [95% CI 1.04-2.9], p=0.03). In a multi-ple regression analysis for ALT >1.5 X ULN within 6 months of treatment start, including known risk factors for ALT elevation and MTHFR A1298C, the C-statistic was 0.734. A mod-el containing clinical risk factors and MTHFR A1298C might be used for prediction of ALT elevation in MTX treated patients. In Paper III a Genome-Wide Association Study (GWAS) and analysis of candidate Single Nucleotide Polymorphisms (SNPs) were performed. Four SNPs in and upstream of the ribonucleoprotein, PTB Binding 2 gene on chromosome 1 were associated with max ALT within 6 months on a genome wide level (p<5x10-8). Our results indicate that the RAVER2 and/or JAK1 genes might play a role in MTX- induced hepatotoxici-ty, but further studies are necessary for confirmation of the results. In Paper IV, we performed a population based case-control study. Several RA-associated risk factors (treatment with leflunomide, azathioprine or prednisolone and concomitant obstructive lung disease) may contribute to the increased TB risk in biologics-naïve RA patients. We could not confirm previous findings of an association with the use of moderate to high doses of prednisolone (≥15 mg). TB risk seems difficult to predict with precision in the individual biologics-naïve patient based on RA-associated risk factors. This suggests TB screening should be considered in biologics-naïve patients.

    In conclusion, results from these studies suggest that several factors could increase the risk of AEs in RA patients. The risk might be reduced by utilizing prediction models that include knowledge about the medical history of the individual patient and genetic data in combination with screening for TB.

  • Membrane-bound proteins : Characterization, evolution, and functional analysis Author: Misty M. Attwood Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-407778 Publication date: 2020-05-04 09:36

    Alpha-helical transmembrane proteins are important components of many essential cell processes including signal transduction, transport of molecules across membranes, protein and membrane trafficking, and structural and adhesion activities, amongst others. Their involvement in critical networks makes them the focus of interest in investigating disease pathways, as candidate drug targets, and in evolutionary analyses to identify homologous protein families and possible functional activities. Transmembrane (TM) proteins can be categorized into major groups based the same gross structure, i.e., the number of transmembrane helices, which are often correlated with specific functional activities, for example as receptors or transporters. The focus of this thesis was to analyze the evolution of the membrane proteome from the last holozoan common ancestor (LHCA) through metazoans to garner insight into the fundamental functional clusters that underlie metazoan diversity and innovation. Twenty-four eukaryotic proteomes were analyzed, with results showing more than 70% of metazoan transmembrane protein families have a pre-metazoan origin. In concert with that, we characterized the previously unstudied groups of human proteins with three, four, and five membrane-spanning regions (3TM, 4TM, and 5TM) and analyzed their functional activities, involvement in disease pathways, and unique characteristics. Combined, we manually curated and classified nearly 11% of the human transmembrane proteome with these three studies. The 3TM data set included 152 proteins, with nearly 45% that localize specifically to the endoplasmic reticulum (ER), and are involved in membrane biosynthesis and lipid biogenesis, proteins trafficking, catabolic processes, and signal transduction due to the large ionotropic glutamate receptor family. The 373 proteins identified in the 4TM data set are predominantly involved in transport activities, as well as cell communication and adhesion, and function as structural elements. The compact 5TM data set includes 58 proteins that engage in localization and transport activities, such as protein targeting, membrane trafficking, and vesicle transport. Notably, ~60% are identified as cancer prognostic markers that are associated with clinical outcomes of different tumour types. This thesis investigates the evolutionary origins of the human transmembrane proteome, characterizes formerly dark areas of the membrane proteome, and extends the fundamental knowledge of transmembrane proteins.

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