| 1. |
- Elm Svensson, Erik, 1976-
(författare)
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Nanotemplated High-Temperature Materials for Catalytic Combustion
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Catalytic combustion is a promising technology for heat and power applications, especially gas turbines. By using catalytic combustion ultra low emissions of nitrogen oxides (NOX), carbon monoxide (CO) and unburned hydrocarbons (UHC) can be reached simultaneously, which is very difficult with conventional combustion technologies. Besides achieving low emission levels, catalytic combustion can stabilize the combustion and thereby be used to obtain stable combustion with low heating-value gases. This thesis is focused on the high-temperature part of the catalytic combustor. The level of performance demanded on this part has proven hard to achieve. In order to make the catalytic combustor an alternative to the conventional flame combustor, more stable catalysts with higher activity have to be developed. The objective of this work was to develop catalysts with higher activity and stability, suitable for the high-temperature part of a catalytic combustor fueled by natural gas. Two template-based preparation methods were developed for this purpose. One method was based on soft templates (microemulsion) and the other on hard templates (carbon). Supports known for their stability, magnesia and hexaaluminate, were prepared using the developed methods. Catalytically active materials, perovskite (LaMnO3) and ceria (CeO2), were added to the supports in order to obtain catalysts with high activities and stabilities. The supports were impregnated with active materials by using a conventional technique as well as by using the microemulsion technique. It was shown that the microemulsion method can be used to prepare catalysts with higher activity compared to the conventional methods. Furthermore, by using a microemulsion to apply active materials onto the support a significantly higher activity was obtained than when using the conventional impregnation technique. Since the catalysts will operate in the catalytic combustor for extended periods of time under harsh conditions, an aging study was performed on selected catalysts prepared by the microemulsion technique. The stability of the catalysts was assessed by measuring the activity before and after aging at 1000 C in humid air for 100 h. One of the most stable catalysts reported in the literature, LMHA (manganese-substituted lanthanum hexaaluminate), was included in the study for comparative purposes. The results showed that LMHA deactivated much more strongly compared to several of the catalysts consisting of ceria supported on lanthanum hexaaluminate prepared by the developed microemulsion method. Carbon templating was shown be a very good technique for the preparation of high-surface-area hexaaluminates with excellent sintering resistance. It was found that the pore size distribution of the carbon used as template was a crucial parameter in the preparation of hexaaluminates. When a carbon with small pores was used as template, the formation of the hexaaluminate crystals was strongly inhibited. This resulted in a material with poor sintering resistance. On the other hand, if a carbon with larger pores was used as template, it was possible to prepare materials with hexaaluminate as the major phase. These materials were, after accelerated aging at 1400 C in humid air, shown to retain surface areas twice as high as reported for conventionally prepared materials.
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| 2. |
- Grzymala-Lubanski, Bartosz, 1980-
(författare)
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Anticoagulation treatment in patients with a mechanical heart valve
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundEvery year about 2,500 patients in Sweden undergo surgery for heart valve disease, primarily in the aortic valve. In contrast to the mitral valve, which can be repaired in 70% of the cases, the aortic valve is normally replaced by a mechanical or biological prosthesis. A mechanical heart valve (MHV) necessitates lifelong anticoagulation treatment with a vitamin K antagonist, most commonly warfarin, due to the high thrombogenicity of the prosthesis. The quality of the warfarin treatment is crucial in these patients. Compared to other countries, treatment quality in Sweden is very high; nonetheless, there is always room for improvement. One of the ways to achieve this improvement is to implement computerized dosing assistance. Treatment recommendations for anticoagulation intensity are based on few and old studies, making these recommendations uncertain. There is therefore a need for studies designed to establish the appropriate level of anticoagulation therapy.AimThe aim of these studies was to investigate the efficacy and safety of anticoagulation treatment among patients with mechanical heart valve prostheses in Sweden; to assess whether computerized dosing can increase the treatment quality; to investigate the influence of the treatment quality, measured by Time in Therapeutic Range (TTR) and INR variability, on the risk of complications and, finally, to establish the optimal intensity of anticoagulation treatment in this group of patients.MethodsData were obtained from AuriculA – a national quality registry established in 2006, which currently includes approximately 50% of all patients treated with oral anticoagulation in Sweden.Study II used only data from AuriculA. 769,933 warfarin-dosing suggestions proposed by the dosing algorithm in AuriculA were analysed. Accepted dose suggestions (590,939) were compared with 178,994 manually-changed doses in regard to the resultant INR value, measured as mean error (deviation from target INR) and hit rate (number of INR samples within the target range 2-3).In study III, AuriculA was used to identify patients in Sundsvall and Malmö in the period 2008 – 2011 who were receiving warfarin for a mechanical heart valve prosthesis, as well as to retrieve their INR data. Data on background characteristics and bleedings or thromboembolic complications were manually retrieved from medical records by two investigators. A total of 534 patients with mechanical heart valve prostheses were divided into quartiles based on TTR and were compared regarding the risk of complications.For Studies I and IV, data from AuriculA were merged with the Swedish National Patient Register, SWEDEHEART/ Heart surgery, and the Swedish Cause of Death Register, comprising in total 77,423 patients on warfarin with 217,804 treatment years. Every treatment period registered in AuriculA was given an individual identification number. During the study period a patient could have any number of treatment periods. The number of complications in total and in different patient groups within the study population was investigated. Complications were defined by ICD-10 codes. Major bleeding was defined as an event necessitating hospital treatment and given a discharge diagnosis with one of the ICD-10 codes reflecting bleeding, as listed in the Appendix. Bleeding events were divided into intracranial, gastrointestinal and other bleedings. Thromboembolic complications consist of venous events (deep vein thrombosis, pulmonary embolism, venous stroke) or arterial events (stroke, TIA, acute myocardial infarction, peripheral arterial embolism).Data were analysed using both simple, descriptive statistical methods and various tests such as Mann-Whitney (or two sample Wilcoxon), T-test, Chi 2 test, ANOVA, multivariate analysis with logistic regression and survival analysis with Cox Regression with proportional hazard assumption.ResultsTreatment quality Mean TTR among all patients in Study I was 76.5% whereas patients with mechanical heart valve prostheses had a TTR of 74.5%. The annual incidence of major bleeding or thromboembolic events among all patients was 2.24% and 2.65%, respectively. The incidence of intracranial bleeding was 0.37% per year in the general population and 0.51% among patients with mechanical heart valve prostheses, who also had a higher bleeding rate in total (3.37% per year).Both the mean and median errors were smaller (0.44 vs. 0.48 and 0.3 vs. 0.4, respectively) and the hit rate was higher (0.72 vs. 0.67) when the dose suggested by the algorithm was accepted, compared to when it was manually changed.TTR In Study III there was no significant difference in the risk of thromboembolism regardless of TTR level. Risk of bleeding in quartiles I and II was more than two times higher than in the quartile with TTR >82.9.In Study IV, lower TTR (≤70%) was associated with a significantly higher rate of complications when compared with TTR >70%. Bleeding risk was higher in the group with lower TTR (HR=2.43, CI 2.02-2.89, p<0.001). After dividing patients into TTR quartiles, the rate of complications in total was significantly higher in quartiles I to III compared with quartile IV, which had the highest TTR. Risk of thromboembolism, major bleeding and death was higher in the first and second quartile compared to the quartile with the highest TTR.INR variability Higher INR variability above mean (≥0.40) was related to a higher rate of complications compared with lower INR variability (<0.40) as shown in Study IV. Bleeding risk was higher in the group with INR variability ≥0.40 (HR = 2.15, CI 1.75-2.61, p<0.001).Comparison of quartile IV, which had the lowest INR variability, with the other three revealed that quartiles I and II, which had the highest INR variability, had significantly worse outcomes for all complications except for thromboembolic events, plus also death in quartile II.TTR and INR variability combined High variability and low TTR combined was associated with a higher risk of bleedings (HR 2.50, CI 1.99-3.15), death (3.34, CI 2.62-4-27) and thrombosis (1.55, CI 1.21-1.99) compared to the best group.Level of anticoagulation Higher warfarin treatment intensity (mean INR 2.8-3.2 vs. 2.2-2.7) was associated with a higher rate of bleedings (HR 1.29, CI 1.06-1.58), death (1.73, CI 1.38-2.16) and complications in total (1.24, CI 1.06-1.41) after adjustment for MHV position, age and comorbidity.ConclusionWarfarin treatment quality is crucial for patients with mechanical heart valve prostheses. Computerized dosing assistance could help maintain high warfarin treatment quality.Well-managed treatment with TTR ≥70% and INR variability below mean <0.40 is associated with a lower risk of serious complications compared with a lower TTR and higher INR variability.No benefit of higher warfarin treatment intensity was found for any valve type or position.
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| 3. |
- Själander, Sara, 1981-
(författare)
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Stroke prevention in atrial fibrillation
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: The Framingham Study from 1991 showed a clear correlation between atrial fibrillation (AF) and ischemic stroke, where patients with AF had an almost fivefold increase in risk of stroke compared with patients without AF. Since then, several trials have evaluated different antithrombotic treatments to reduce the risk of stroke in patients with AF. Other trials have investigated factors that increase the risk of stroke in patients with AF and risk score systems have been developed to categorize patients into low or increased risk of stroke to help clinicians to decide which patients benefit from antithrombotic treatment and in whom it can be abstained, not to expose patients with low stroke risk to an increased risk of bleeding conferred by antithrombotic treatment. The aims of this thesis were: [1] to evaluate if a warfarin dosing algorithm can increase hit rate and decrease mean error compared with manually changed doses; [2] to assess the prevalence and net clinical benefit of aspirin as monotherapy for stroke prevention in AF; [3] to investigate the risk of thromboembolic and haemorrhagic complications within 30 days after electrical cardioversion (ECV) of AF in patients with and without oral anticoagulation (OAC) pre-treatment; and [4] to assess the proportion of patients discontinuing OAC after pulmonary vein isolation (PVI), identify factors predicting stroke after PVI and to investigate risk of complications after PVI with and without OAC.Materials and methods: All studies are retrospective and based on data from Swedish national quality registries. In paper I, data from Auricula was used to compare the resulting INR values after algorithmic warfarin dose suggestions and manually changed doses. In paper II data was extracted from the Swedish National Patient Register, the Dispensed Drugs Register and the Cause of Death Register. Patients with aspirin treatment were compared with patients without any antithrombotic treatment regarding risk of thromboembolic and haemorrhagic complications. In paper III data was collected from the Swedish National Patient Register and the Dispensed Drugs Register to examine risk of complications (thromboembolic and haemorrhagic events) within 30 days after cardioversion, comparing patients with and without oral anticoagulation pre-treatment. In paper IV data from six different Swedish national quality registries were used (Swedish Catheter Ablation Register, Auricula, Swedish National Patient Register, Dispensed Drugs Register, Cause of Death Register and Riksstroke). Patients undergoing pulmonary vein isolation (PVI) were investigated for adherence to guidelines regarding oral anticoagulation, predictors for stroke after PVI, as well as risk of ischemic stroke or intracranial haemorrhage after PVI in patients with and without treatment.Results: Paper I showed that a computerized dosing algorithm for warfarin in most cases perform as well or better compared with doses that have been changed manually, with a better hit-rate (0.72 vs. 0.67) and a lower mean error (0.44 vs. 0.48). Paper II showed that 32% of 182.678 patients with a diagnosis of AF were on monotherapy with aspirin for stroke prevention. A total of 115.185 patients were included, 58.671 with aspirin treatment and 56.514 without antithrombotic treatment at baseline. After stratification after CHA2DS2-VASc score and after multivariable adjustment, aspirin treatment did not confer a decrease in thromboembolic events. After propensity score mathcing, rate of ischemic stroke was 7.4%/year (95% CI 7.1-7.6) in aspirin treated patients and 6.6%/year (95% CI 6.4-6.9) in patients without antithrombotic treatment. In paper III 22.874 patients undergoing electrical cardioversion were included, 10.722 with and 12.152 without OAC pre-treatment. In patients with low stroke risk (CHA2DS2-VASc 0-1), no thromboembolic complication was seen within 30 days after cardioversion. In patients with CHA2DS2-VASc ≥2, the risk of thromboembolic complications was increased when no oral anticoagulation pre-treatment was used, results that remained after propensity score matching. No difference regarding haemorrhagic complications was seen. Paper IV included a total of 1585 patients undergoing PVI with a mean follow up of 2.6 years. Adherence to current guidelines regarding oral anticoagulation was good in patients with CHA2DS2-VASc ≥2. Previous ischemic stroke was a predictor for a new stroke after PVI. In patients with CHA2DS2-VASc ≥2 stroke risk was increased in patients discontinuing OAC compared to those continuing OAC (1,60%/year vs. 0.34%/year).Conclusion: Oral anticoagulation is still underutilized for prevention of stroke and systemic embolism in patients with atrial fibrillation. Patients with risk factors for stroke (CHA2DS2-VASc ≥2p) benefit from continuous oral anticoagulation treatment to prevent stroke, also in conjunction with electrical cardioversion and after pulmonary vein isolation. If warfarin is chosen, a computerised dosing algorithm can facilitate and standardize warfarin dosing and lead to better resulting INR values than manually changed doses. Aspirin should not be used for stroke prevention in patients with atrial fibrillation.
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| 4. |
- Sjögren, Vilhelm, 1968-
(författare)
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Oral anticoagulation and stroke risk
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: The risk of ischaemic stroke in patients with atrial fibrillation (AF) and mechanical heart valve (MHV) prostheses can be reduced by oral anticoagulation (OAC), which increases the risk of serious bleeding. The aims of this thesis were [1] to find out how effective and safe warfarin is where treatment quality is high, i.e. Sweden, with proportion of time that patients spend within the therapeutic range (TTR) >70%, [2] whether there is evidence for administering low-molecular-weight heparin (LMWH) during temporary interruptions of OAC (bridging therapy), and whether non-vitamin K-dependent oral anticoagulants (NOACs) as a group, [3] or individually, [4] are more effective and safer than warfarin when used for stroke prevention in patients with AF.Materials and methods: All four studies were retrospective, based on the Swedish anticoagulation register Auricula, and done with merging of data from some or all of the National Patient Register, the Prescribed Drug Register, the Swedish Stroke Register (Riksstroke), and the Cause of Death Register. In studies 2–4, propensity score matching was performed to obtain treatment groups with similar risk profiles. Outcomes were defined as haemorrhages or thromboses requiring specialist care, or death. Haemorrhages were intracranial, gastrointestinal, or other. Thromboses were ischaemic stroke, systemic embolism, myocardial infarction, or venous thromboembolism (VTE).Study 1 described all patients on warfarin during 2006–2011, which was before the introduction of NOACs. Study 2 was a cohort study of all patients who had a planned interruption of warfarin during the same period. Study 3 included all 49,011 patients starting OAC for stroke prevention due to AF between 1 July 2011 and 31 December 2014, and study 4 all 64,382 patients with the same indication between 1 January 2013 and 31 December 2015.Results: Study 1 showed that for the 77,423 patients on warfarin with 217,804 treatment years, TTR was 77.4% for patients with AF, 74.5% with MHV, and 75.9% with VTE. Annual rates of intracranial bleeding were 0.38%, 0.51%, and 0.30%. In study 2, with 14,556 warfarin interruptions, the 30-day risk of a bleeding requiring specialist care was 0.64% for LMWH treated and 0.46% for controls. For patients with VTE as indication for OAC, bleeding rate with LMWH was significantly higher at 0.85% vs. 0.16% (hazard ratio 5.24, 95% confidence interval 1.39–19.77), but with no difference for patients with MHV or AF. The incidence of ischaemic complications was higher in the LMWH bridging group overall and for patients with MHV and AF, but not for patients with VTE. In study 3, for the 12,694 patients starting NOAC (10,392 treatment years) or matched warfarin patients (9,835 treatment years, TTR 70%) due to AF, annual incidence of ischaemic stroke and systemic embolism did not differ between the groups (1.35% vs. 1.58%), but risks of major bleedings and intracranial bleedings were significantly lower: 2.76% vs. 3.61% and 0.40% vs. 0.69%. In study 4, patients on individual NOACs (6,574 dabigatran, 8,323 rivaroxaban, 12,311 apixaban) were compared to 37,174 patients starting warfarin (in total 81,176 treatment years). No NOAC showed any difference in risk of ischaemic stroke or systemic embolism, but there were fewer intracranial bleedings, serious bleedings overall, and deaths for dabigatran and apixaban compared to warfarin. For patients starting rivaroxaban the risk of gastrointestinal bleeding was higher than for matched warfarin counterparts, with no significant differences in other bleeding risks, or mortality.Conclusions: Swedish warfarin treatment shows TTR levels that are high by international standards, correlating to low incidences of ischaemic and haemorrhagic events. LMWH bridging has not been proven beneficial, even for patients with MHV, meaning that bridging in general cannot be recommended. NOACs as a group were safer than high-quality warfarin treatment. Efficacy did not differ, even when comparing individual NOACs to warfarin, but there were fewer bleedings on dabigatran and apixaban. Although not more efficient than warfarin with a high TTR, NOACs should be the recommended first choice for OAC in AF, on the merit of lower bleeding risks.
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| 5. |
- Svensson, J. Peter, 1975-
(författare)
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Systematic Modular Approaches to Reveal DNA Damage Responses in Mammalian Cells
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cancer therapy operates by inflicting damage in malignant cells. The most lethal target is the genomic DNA. As a single double strand DNA break has the potential to kill the cell, mechanisms have evolved to detect and block propagation of the damage. Genes and their products function in a highly connected network-structure with ample cross-talk between different pathways. This interplay can be studied by genome-wide experiments, such as expression profiling. The aim of this thesis is to study the cellular effects of DNA damaging agents.A theoretical framework is explored to improve understanding of expression profiling results. To analyse large datasets, computational methods were developed to model the data. Further, the response to DNA damage was investigated in different cellular systems. As late radiation toxicity is a severe limitation of radiotherapy of cancer patients, patients were enrolled in a study to search for a molecular signature to identify high-risk patients. Ex vivo irradiation of lymphocytes revealed a signature of functionally related gene sets that were capable to separate patients with regard to toxicity status. The gene set analysis was also applied to a dataset where mouse embryonic stem cells had been exposed to various doses of cisplatin. At several time-points after administration of the drug, expression profiles were determined. In addition to the expected increase of genes related to apoptosis and cell cycle progression, damaged cells also seemed to have embarked upon a p53-dependent differentiation programme. Finally, in a study of cardiac rodent cells, the genotoxic treatment with irradiation was compared to the mechanical stress induced in heart tissue.In conclusion, this thesis presents evidence for the advantage of using functionally related sets of genes in analysis and interpretation of genome-wide experiments. This strategy may improve clinical understanding of the effects of DNA damaging agents used for cancer therapeutics.
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| 6. |
- Svensson, J. Robin, 1979
(författare)
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Ecological disturbances: the good, the bad and the ugly
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Abstract. This thesis focuses on the definitions, characterizations and quantifications of ecological disturbances, as well as hypotheses on their impacts on biological communities. The most prominent model on effects of disturbance on diversity is the Intermediate Disturbance Hypothesis (IDH), which is utilized in management of national reserves, has received over 3300 citations and has been corroborated by a multitude of studies from terrestrial and aquatic systems. According to the predictions of the IDH, diversity is high at intermediate levels of disturbance due to coexistence of competitors and colonizers. At low levels of disturbance diversity will be low due to competitive exclusion and few species can persist at high levels of disturbance. In an extension of the IDH, the Dynamic Equilibrium Model (DEM) predicts that the effects of disturbance depend on the productivity of communities, because at high growth rates a stronger disturbance is required to counteract increased rates of competitive exclusion. The IDH and the DEM were tested in a field experiment on effects of physical disturbance (scraping) and productivity (nutrient availability) on hard-substratum assemblages in paper I, where the patterns predicted by the IDH, but not the DEM, were observed. This outcome shows the importance of the nature of productivity alterations, as the productivity treatment had a general positive effect on growth rates but only marginal effects on the dominant species, thereby leaving rates of competitive exclusion unaffected. In paper II I tested another extension of the IDH, which predicts that smaller, more frequent disturbances will have different effects on diversity compared to larger, less frequent disturbances. In this experiment I used two different regimes of disturbance, small and frequent vs. large and infrequent disturbances, while the overall rate (the product of area and frequency) was kept equal for both regimes. At the site where the IDH was supported, the regime with a large proportion of the area disturbed infrequently showed higher richness, due to a stronger decrease of dominants, compared to the regime with a small proportion disturbed frequently. In addition to these significant differences in diversity effects between different disturbance regimes, it may also matter what agent of disturbance that is causing the damage. In paper III I contrasted the effects of a physical disturbance (wave-action) to that of a biological disturbance (grazing), as well as their respective interactions with productivity in a multifactorial design tested on natural epilithic assemblages. The composition of assemblages and the total species richness was significantly affected by physical disturbance and interactively by biological disturbance and productivity. The algal richness was significantly affected by productivity and biological disturbance, whereas the invertebrate richness was affected by physical disturbance. The results show, for the first time, that biological disturbance and physical disturbance interact differently with productivity due to differences in the distribution and selectivity among disturbances. In paper IV I investigate how the choice of diversity measure may impact the outcomes of tests of the IDH, which, surprisingly, has not previously been discussed. This was done by an extensive literature review and meta-analysis on published papers as well as by two different approaches to mathematical modelling. Both models support the IDH when biodiversity is measured as species richness, but not evenness. The meta-analysis showed that two-thirds of the published studies in the survey present different results for different diversity measures. Hence, the choice of diversity measure is vital for the outcome of tests of the IDH and related models.
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| 7. |
- Svensson, Malin J., 1978-
(författare)
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Thioredoxins and gene regulation in the Drosophila germline
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Spermatogenesen är i många organismer en av de mest dramatiska förvandlingar som en cell kan genomgå – en vanlig, rund, diploid cell omvandlas till en nålformad, haploid cell med ett tätt packat cellmaskineri. I bananfluga, Drosophila melanogaster, innebär denna process flera karaktäristiska stadier. Ett av dessa är det primära spermatocyt-stadiet, som infaller innan cellen påbörjar meios-delning. Stadiet karaktäriseras av en uppluckrad kromatinstruktur i cellens kärna och ovanligt höga transkriptions- och translationshastigheter, för att producera allt det mRNA och de proteiner som behövs senare under spermatidomvandlingen. Två av de proteiner som uttrycks i höga nivåer i primära spermatocyter är ThioredoxinT (TrxT) och Painting of fourth (POF). Thioredoxiner är små proteiner som har som funktion att reducera disulfidbryggor i andra proteiner, en mekanism som används i många olika fysiologiska sammanhang. I denna avhandling visar jag att TrxT-genen kodar för ett testikelspecifikt thioredoxin som binder specifikt till Y-kromosom-loopar i primära spermatocyter. TrxT-genen ligger precis bredvid deadhead (dhd), en gen som kodar för ett hon-specifikt thioredoxin som är lokaliserat till cellkärnorna i flugans äggstockar. Ett tredje thioredoxin i Drosophila är det allmänt uttryckta Thioredoxin-2 (Trx-2). Jag har upptäckt att flugor som saknar Trx-2 är livsdugliga, men att de lever kortare än vildtypsflugor, medan flugor med extra mycket Trx-2 har en ökad tålighet mot oxidativ stress. Slående nog är en total avsaknad av alla tre thioredoxiner inte förenat med letalitet, tvärtemot vad man skulle kunnat vänta sig. Alla tre thioredoxiner finns i de olika Drosophilider som undersökts och den ovanliga genorganisation som delas av TrxT och dhd är generellt konserverad. Gen-namnet Painting of fourth härstammar från upptäckten att POF binder till (”målar”) Drosophilas kromosom 4. Jag visar i min avhandling att POFs bindning till den fjärde kromosomen är bevarad i olika Drosophila-arter och att POF kolokaliserar med både ett protein och en histon-modifiering, som är förknippade med doskompensation, i arter där POF också binder till hanens X-kromosom. POF uttrycks överallt i både honor och hanar, men i väldigt höga nivåer i hanens testiklar. Jag visar här att POF finns i cellkärnan hos primära spermatocyter, men också i kärnan på mognande spermatider, och att avsaknad av POF in hanens könsceller orsakar en global nedreglering av gener som ligger på kromosom 4. Kombinationen av mina POF- resultat tyder på att POF har en viktig funktion i det första kända fallet av genreglering av en hel autosomal kromosom.
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| 8. |
- Svensson, Robin J., 1989-
(författare)
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Pharmacometric Models to Improve the Treatment and Development of Drugs against Tuberculosis
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- With 10 million new infections yearly, tuberculosis has a major impact on the human well-being of the world. Most patients have infections susceptible to a first-line treatment with a treatment success rate of 80%, a number that can potentially be improved by optimising the first-line treatment. Besides susceptible disease, each year half a million patients are infected by tuberculosis with resistance to first-line treatment where only 50% of patients get cured. Thus, new drugs against resistant tuberculosis are desperately needed but given the inefficiency of developing new anti-tuberculosis drugs, enough new drugs will not reach patients in time. The aim of this thesis was to develop pharmacometric models to optimise the development and use of current and future drugs for treating tuberculosis.A population pharmacokinetic model for rifampicin, the most prominent first-line drug, was developed and later used for developing exposure-response models followed by clinical trial simulations. The developed exposure-response models were based on liquid culture data and were expanded to describe the relationship between liquid culture results and a new biomarker, the molecular bacterial load assay which is a quicker alternative to liquid culture and is also contamination-free.The in vitro-derived semi-mechanistic Multistate Tuberculosis Pharmacometric (MTP) model was applied to clinical rifampicin and clofazimine colony forming unit datasets. This novel application of the MTP model allowed detection of statistically significant exposure-response relationships between rifampicin and clofazimine for the specific killing of non-multiplying, persister bacteria. Furthermore, the MTP model was compared to conventional statistical analyses for detecting drug effects in Phase IIa. If designing and analysing Phase IIa using the MTP model, the required sample size for detecting drug effects can be lowered. An improved design and analysis of pre-clinical treatment outcome assessments was developed which increased the information gain compared to a conventional design yet kept the animal use at a minimum. Lastly, a therapeutic drug monitoring approach was suggested based on updated targets for rifampicin, a framework easily expandable to second-line drugs.In conclusion this thesis presents the development of pharmacometric models which will streamline both the development and use of drugs against tuberculosis.
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| 9. |
- Toma-Dasu, Iuliana, 1972-
(författare)
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Theoretical modelling of tumour oxygenation and influences on treatment outcome
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- One of the main problems in curing cancer resides in the different microenvironment existing in tumours compared to the normal tissues. The mechanisms of failure are different for radiotherapy and chemotherapy, but they all relate to the poor blood supply known to exist in tumours. It is therefore very important to know the tumour microenvironmental conditions in order to devise techniques that will overcome the problems and will therefore improve the result of the treatment.The aims of the thesis were the modelling of tumour oxygenation and the simulation of polarographic oxygen measurements in order to assess and possibly to improve the accuracy of the electrode in measuring tumour oxygenation. It also aimed to evaluate the implications of tumour microenvironment for the radiotherapy outcome.The project used theoretical modelling as the main tool. The processes of oxygen diffusion and consumption were described mathematically for different conditions, the result being very accurate distributions of oxygen in tissues. A first simple model of tissue oxygenation was based on the oxygen diffusion around a single blood vessel. A more complex model built from the basic physical processes and measurable parameters allowed the simulation of realistical tissues with heterogeneous vasculature. This model also allowed the modelling of the two types of hypoxia known to appear in tumours and their influence on the tumour microenvironment. The computer simulation of tissues was also used for assessing the accuracy of the polarographic technique for measuring tumour oxygenation.The results of this study have shown that it is possible to model theoretically the tissue oxygenation starting from the basic physical processes. The particular application of our theoretical simulation to the polarographic oxygen electrode has shown that this experimental method does not give the oxygen values in individual cells. Because the electrode measures the average oxygenation in a relatively large tissue volume, the resulting oxygen distributions are different from the real ones and the extreme high and low values are not detected. It has further been found that the polarographic electrode cannot make distinction between various types of hypoxia existing in tumours, the geometrical distribution of the hypoxic cells influencing mostly the accuracy of the measurement.It was also shown that because of the averaging implied by the measurement process, electrode results should not be used directly to predict the response to radiation. Thus, the differences between the predictions in clinical tumour control obtained from the real or the measured oxygenations are of the order of tens of percents in absolute value. A method to improve the accuracy of the electrode, i.e. to improve the correlation between the results of the measurements and the actual tissue oxygenation, was proposed.In conclusion, theoretical modelling has been shown to be a very powerful tool for predicting the outcome of radiotherapy and it has the advantage of describing the tumour oxygenation in the least invasive manner. Furthermore it allows the investigation of the invasiveness and the accuracy of various experimental methods.
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