12 Chapter 1 1. Can we classify the diagnoses of study participants reliable and valid? 2. Does the higher accuracy of ULDCT for pneumonia affect clinical management and outcomes? 3. Are circulating levels of ferritin amongst patients hospitalized with pneumonia associated with clinical features, outcomes and key host response pathways? OPTIMACT trial: Patients suspected of non-traumatic pulmonary disease at the Emergency Department n = 2418 Randomized Study questions Patients with pneumonia ULDCT n = 1208 CXR n = 1210 ULDCT n = 225 CXR n = 169 1. Are there host response differences shortly after ICU admission between those that do and those that do not develop ICU-acquired pneumonia? 2. Are there host response aberrations at the time of ICUacquired pneumonia? 3. What is the change in host response from ICU admission to the day of ICU-acquired pneumonia? ASPIRE-ICU trial: Patients in the Intensive Care Unit (ICU) who do or do not develop ICU-acquired pneumonia n = 1997 ICU-acquired pneumonia Study questions Patients at risk for ICU-acquired pneumonia Yes n = 316 No n = 1681 Hospitals n = 30 Countries n = 11 1. Does modulation of the gut microbiome by broad-spectrum antibiotics of adults with allergic asthma influence lung inflammation in a house dust mite plus lipopolysaccharide provocation model? Human proof-of-concept intervention trial: Microbiome modulation in adults with allergic asthma n = 20 Gut microbiome modulation Study question Type of antibiotics Yes n = 7 No n = 13 Ciprofloxacin Vancomycin Metronidazole Figure 1. Overview of clinical trials. The three clinical trials summarized in the figure were the backbone of the studies discussed in this thesis. The number of study participants (n) and study questions are provided per trial. ASPIRE-ICU = Advanced understanding of Staphylococcus aureus and Pseudomonas aeruginosa Infections in EuRopE - Intensive Care Units; CXR = chest X-ray; ICU = intensive care unit; OPTIMACT = OPTimal IMAging strategy in patients suspected of nontraumatic pulmonary disease at the ED: chest X-ray or CT; ULDCT = ultra-low dose computed tomography. First, the OPTimal IMAging strategy in patients suspected of non-traumatic pulmonary disease at the ED: chest X-ray or CT (OPTIMACT) was a multicentre randomized clinical trial (RCT) designed to study the value of a novel imaging technique – ultra-low-dose chest computed tomography (CT) – in 2418 patients presenting at the Emergency Department (ED) and suspected of pulmonary disease [19,20]. During randomly assigned periods of one calendar month, either ultra-low dose CT or conventional chest X-ray was used. Eligible for inclusion were ED patients aged 18 years and older, suspected of non-traumatic pulmonary disease and requiring chest X-ray according to the attending physician. Valid and reliable classification of the clinical diagnosis of study participants in this RCT was a prerequisite for the evaluation of outcome of both imaging strategies, as well as for biomarker research. Presented in this thesis, we developed a structured approach in which study participants were assigned diagnostic labels using a carefully designed reference standard, which could be used by a team of medical students, residents and an expert panel, and which we hypothesized to be efficient and valid for diagnostic classification in large clinical trials. Also, we performed a preplanned subgroup analysis, where we hypothesized that the known
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