Coming dissertations at Uppsala university
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Analysis of Gamma and Neutron Emission for Predicting Decay Heat in Spent Nuclear Fuel
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-535938
Geological repositories are the preferred option for many countries for the disposal of spent nuclear fuel assemblies. The thesis work has been part of the European program EURAD, which aims to contribute to increasing the safety of nuclear waste management. The thesis is focused on the Swedish geological repository system due to the availability of the data.
In Sweden, the spent nuclear fuel assemblies will be placed in copper canisters and positioned 500 m underground. The filling of the canisters is limited by safety, safeguards and operational constraints. In order to verify some of these limitations, experimental measurements will be performed on every spent nuclear fuel assembly before their encapsulation. An important part of this thesis is the analysis of data from previously performed measurements of spent nuclear fuel assemblies’ neutron and gamma emissions at the Swedish interim storage. The neutron and gamma measurements are complementary and give different information about the spent nuclear fuel. These types of measurements are extremely scarce, and they have previously been realized using an HPGe detector and a prototype DDSI instrument. The analyses performed as part of this thesis quantify the measurement uncertainties, assess the reproducibility of the results, and identify potential signatures that could aid in determining safety parameters. This thesis is particularly focused on one safety parameter, namely the decay heat. From the signatures obtained from the analyzed experimental measurements, a machine-learning model has been developed to predict the decay heat for the spent nuclear fuel assemblies. The predicted decay heat is compared to results from previously conducted calorimetric measurements, and the developed machine learning model demonstrates a strong predictive capability. An additional aim of this thesis is to understand the measurable signatures needed to predict the decay heat. Therefore, this thesis also focuses on making recommendations on the type of signatures needed from the experimental measurements, with the ultimate goal of guiding the selection of measurements for spent nuclear fuel assemblies both in Sweden and internationally.
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Invasive Candida infections : Treatment of the critically ill and patients with infective endocarditis
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-535842
Invasive Candida infections have a major impact on morbidity and mortality in critically ill patients. Prompt initiation of effective antifungal therapy and source control are cornerstones in management. The echinocandin caspofungin is first-line treatment in invasive Candida infections and dosage is based on the Child-Pugh liver scoring system, developed for patients with chronic liver disease. Pathophysiological changes in the critically ill, e.g. hypoalbuminemia, may affect antifungal pharmacokinetics (PK) and drug exposure, calling into question if dosage regimens are adequate for this group. Candida infective endocarditis (CIE) is a rare but serious form of deep-seated Candida infection, burdened with high mortality rates. The standard of care has been antifungal therapy combined with cardiac valve surgery.
The overall aim of this thesis was to study aspects of invasive Candida infections in relation to caspofungin pharmacokinetics and pharmacodynamics (PK/PD) and the management of patients with CIE.
In a prospective study of critically ill patients, we investigated the prevalence of hepatic impairment, the effect of Child-Pugh score on caspofungin PK and whether caspofungin PK/PD targets were achieved. The prevalence of patients with pathological liver function tests was high, but the Child-Pugh score did not significantly impact caspofungin PK. The PK/PD target was reached, but with small margins. No dose reduction is warranted in critically ill patients with hepatic impairment, in the absence of chronic liver disease.
The impact of plasma protein levels on the antifungal activity of caspofungin at clinically relevant concentrations was studied in time-kill experiments. Reduced plasma protein levels in vitro increased caspofungin’s fungicidal effect on Candida glabrata.
In a retrospective observational study, we compared the effect of echinocandins, mainly caspofungin, on the outcome in patients with CIE with those of other antifungal regimens. We found no significant differences in outcome between regimens.
Further investigation of the CIE cohort showed that Candida parapsilosis was overrepresented in CIE compared with candidemia, indicating a higher propensity to cause CIE. In the overall CIE cohort, surgery did not improve outcome. Therefore, the recommendation of surgery in all patients with CIE may be questioned. Long-term suppressive antifungal therapy reduced the number of relapses.
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Faecal biomarkers of neutrophil and eosinophil origin in the evaluation of inflammatory bowel disease : Providing insights into the patophysiology
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-535509
Inflammatory bowel disease (IBD), encompassing Crohn’s disease (CD) and ulcerative colitis (UC), is characterised by chronic inflammation of the gastrointestinal tract. The gold standard for diagnosing and monitoring IBD is by endoscopy, but biomarkers, like the clinically established faecal calprotectin (FC), can function as non-invasive surrogate markers reflecting disease activity. As FC has some known limitations, it is worthwhile to investigate the performance of alternative faecal markers. Therefore, we aimed to evaluate eosinophil and neutrophil granule proteins as potential faecal biomarkers for different aspects of IBD. An additional aim was to study the association of eosinophils with IBD onset.
In Paper I, we explored the role of eosinophils in the pathophysiology of IBD by studying faecal eosinophil markers in a cohort of discordant twin pairs. This study showed that, unlike neutrophils, eosinophils are not active in the pre-clinical state of IBD. Thus, activation of eosinophils is a consequence of inflammation rather than a primary event triggering the onset of disease. In Paper II, the diagnostic association and predictive performance of neutrophil and eosinophil faecal markers were evaluated in a cohort of newly-onset IBD patients. We showed that Myeloperoxidase (MPO) and FC have comparable diagnostic capacities in IBD and that combining FC and MPO could enhance diagnostic accuracy. We also demonstrated that neutrophil markers were predictive of an aggressive disease course in UC. Paper III showed that faecal MPO, human neutrophil lipocalin (HNL) and eosinophil-derived neurotoxin (EDN) – similar to FC – are functioning biomarkers for monitoring clinical remission in IBD patients treated with biologics. The study also demonstrated that faecal EDN and HNL are influenced by corticosteroids, indicating a response mechanism different from that of FC and MPO. In Paper IV we proposed that faecal HNL, reflecting both intestinal neutrophils and epithelial cells, can differentiate patients with gastroenteritis (GE) from new-onset IBD patients.
This comprehensive exploration of faecal biomarkers suggests interesting alternatives or adjuncts to FC in the diagnostics, monitoring and prediction of disease course in IBD. By studying these biomarkers, we have also uncovered parts of the IBD pathophysiology and increased the knowledge of the eosinophils in the early state of IBD.