The growing number of older patients presenting to Emergency Departments (EDs) requires better risk stratification to guide treatment and dispositiondecisions. Therefore, it is essential to... Show moreThe growing number of older patients presenting to Emergency Departments (EDs) requires better risk stratification to guide treatment and dispositiondecisions. Therefore, it is essential to understand the effect of age on the associations between physiological variables and outcomes. More importantly, most risk tools are not age or sex adjusted and are not based on a statistical approach. An age and sex adjusted risk tool could improve risk stratification in the ED.This thesis is divided into three parts and has four aims, regarding ageadjusted interpretation of physiological variables for risk stratification in ED patients, developing a new age- and sex-adjusted risk tool for the hospital, and describing potential bias if risk tools are used for comparing the quality of care among departments. Show less
Sepsis is a life-threatening condition caused by a dysregulated host response to infection, it is associated with significant morbidity, mortality, and with a high financial burden on global... Show moreSepsis is a life-threatening condition caused by a dysregulated host response to infection, it is associated with significant morbidity, mortality, and with a high financial burden on global healthcare systems. Bacterial infections are the primary cause of sepsis, but the growing prevalence of antimicrobial resistance complicates the effectiveness of antimicrobial treatments. Moreover, limited understanding of the host immune response during sepsis hinders the discovery of valuable biomarkers and drug targets. As such, there is an urgent need to improve the treatment of sepsis. To tackle this challenge, we have concentrated our efforts on optimizing current treatment strategies and on facilitating the discovery of novel host inflammatory response directed therapeutics. In this thesis, we have utilized quantitative pharmacological modeling approaches to assess the adequacy of current dose regimens and to evaluate antibiotic pharmacokinetic variability, thereby optimizing antimicrobial therapies for sepsis. Additionally, our researches had aimed to deepen our understanding of the underlying dynamics of sepsis pathology, enabling the identification of promising biomarkers and therapeutic targets for sepsis. Our work demonstrated how quantitative modeling strategies can support the design of optimized treatment strategies, and how systematic model-based integration of disease mechanisms can help to overcome the translational challenges in sepsis drug development. Show less
A significant proportion of the in-hospital antimicrobial consumption is used in the empiric setting, making empiric therapy an important target of stewardship interventions.Empiric antimicrobial... Show moreA significant proportion of the in-hospital antimicrobial consumption is used in the empiric setting, making empiric therapy an important target of stewardship interventions.Empiric antimicrobial therapy is the antimicrobial regimen that is started when the definite clinical diagnosis, causative agent and/or resistance pattern are yet unknown. Empiric therapy is accompanied by a varying level of uncertainty. In daily clinical practice, this uncertainty about the source, pathogen and susceptibility pattern are often managed by prescribing relatively broad-spectrum antimicrobial therapy. This has potential negative effects, such as toxicity and selective pressure resulting in antimicrobial resistance. Balancing the potential benefits and drawbacks of more broad-spectrum therapy is a substantial challenge, in particular when the level of uncertainty is high.This thesis aims to address the uncertainties most relevant in daily clinical practice in empiric antimicrobial therapy, to determine how they affect daily decision making, and to explore how this can be translated in antimicrobial policy making and antimicrobial stewardship. Show less
Cells, their fragments and secreted factors may all be transported to distant sites via the blood circulatory system and exert their action far away from the site of origin. Identification of these... Show moreCells, their fragments and secreted factors may all be transported to distant sites via the blood circulatory system and exert their action far away from the site of origin. Identification of these mediating factors and unraveling of the pathogenesis resulting in organ damage will contribute to our general understanding and may ultimately result in new treatment strategies. The studies included in this thesis focus on mechanisms of coagulopathy and other blood abnormalities in patients with cancer or inflammation. Show less
Aim of this thesis was to provide evidence for the clinical implication of biomarkers in blood and urine, as well as genetic markers, for the prediction of the severity and course of febrile UTI.... Show moreAim of this thesis was to provide evidence for the clinical implication of biomarkers in blood and urine, as well as genetic markers, for the prediction of the severity and course of febrile UTI. Furthermore, this thesis focused on optimization of antimicrobial treatment of febrile UTI. The main results are: 1. Recent hospitalization, indwelling urinary catheter and especially individual fluoroquinolone (FQ) use are independent risk factors for a FQ-resistant Escherichia coli febrile UTI. 2. Women with febrile UTI, including postmenopausal women and those with comorbidities, can be safely and successfully treated with a 7-day course of oral ciprofloxacin. In men, however, treatment duration should be at least 14 days. 3. Diabetes mellitus does not affect the clinical presentation and course of febrile UTI; concurrent illnesses and higher age of the diabetic population attribute to a more complicated course. 4. MR-proADM more accurately predicts a complicated course of disease than currently available inflammatory biomarkers. Importantly, biomarkers derived directly from host defense mechanisms are not suitable to distinguish between febrile UTI patients with and without bacteremia. 5. MP-TF activity is related to disease severity and bacteraemia in febrile E. coli UTI and may contribute to the prothrombotic state in gram-negative sepsis. Show less
The research described in this thesis focussed on the role of apolipoproteins in lipid metabolism, inflammation and bacterial sepsis, with specific emphasis on apoCI. From studies in human APOC1_... Show moreThe research described in this thesis focussed on the role of apolipoproteins in lipid metabolism, inflammation and bacterial sepsis, with specific emphasis on apoCI. From studies in human APOC1_-transgenic and apoc1-/- mice, we were able to identify apoCI as a potent inhibitor of triglyceride hydrolysis by inhibiting lipoprotein lipase. Since APOC1 mice have thus increased VLDL levels, and VLDL protects against bacterial infection, we studied whether apoCI could play a role in inflammation and infection. We found that apoCI was able to bind lipopolysaccharide (LPS), the main toxic component of Gram-negative bacteria. Interestingly, although other apolipoproteins which have been studied have anti-inflammatory properties, we found that apoCI is a pro-inflammatory protein. By enhancing the biological response towards LPS and Gram-negative bacteria, apoCI dose-dependently improved the anti-bacterial attack, and protected against intrapulmonal Klebsiella pneumoniae-induced sepsis. Consistent with these experimental findings we also found that subjects with high plasma apoCI levels were less prone to infection-related mortality during follow-up, independent of plasma lipid levels. Likewise, survivors of severe sepsis showed higher plasma apoCI levels as compared to non-survivors, again independent of lipid levels. Taken together, our findings indicate that apoCI is an important determinant of the inflammatory response in mice and humans. Show less
