Genomweite Analysen der genetischen Architektur von Sepsis und Gewichtsregulation

Sepsis ist ein durch eine Infektion entstandener lebensbedrohlicher Zustand, bei dem der Körper die eigenen Organe schädigt (Singer et al. 2016). Eine optimale Behandlung oder sogar Vorsorge ist in vielen Fällen nicht möglich, was dazu führt, dass Sepsis immer noch der Hauptgrund für den Tod nach einer Infektion ist. Neben der Erforschung der Erreger wird auch der wirtsseitige Einfluss genetischer Faktoren untersucht. Es wurde festgestellt, dass genetische Aspekte weniger Einfluss auf das Auftreten einer Sepsis haben, sondern viel mehr auf ihren Verlauf (Petersen et al. 2010; Sørensen et al. 1988). In dieser Arbeit wurden zwei Strategien verfolgt, um molekulargenetische Faktoren, die mit dem Verlauf einer Sepsis assoziiert sind, zu identifizieren. Zunächst wurde eine genomweite Assoziationsstudie (GWAS) in 740 Sepsispatienten durchgeführt. Als Untersuchungsvariablen wurden die 28 und 90 Tage Mortalität sowie der SOFA-Score gewählt. Die Daten einer unabhängigen Exomsequenzierungsstudie in 74 Sepsispatienten mit extremen Krankheitsverläufen (Taudien et al. 2016) wurden anschließend analysiert und dienten zur Validierung der GWAS-Befunde sowie zur Identifizierung weiterer Kandidatengene. Als dritter Aspekt erfolgte eine Untersuchung des Übergewichtsparadoxons in Sepsen, da es nur relativ wenige molekulargenetische Arbeiten im Bereich Sepsis gibt. Hierbei wurden robust bestätigte genetische Assoziationen mit BMI-Variabilität (Locke et al. 2015; Turcot et al. 2018) in den vorliegenden GWAS- und Exomdatensätzen analysiert. Anhand der Analysen konnte eine Region auf Chromosom 9q21.2 im Gen VPS13A mit dem Verlauf einer Sepsis assoziiert werden. Assoziationen waren in den GWAS-Analysen zur 28 Tage Mortalität sowie im SOFA-Score zu beobachten und konnten in der unabhängigen Exomsequenzierungsstudie bestätigt werden. In einer weiteren Region auf Chromosom 16q24.1 befindet sich das Gen CRISPLD2, dessen Expression bei Patienten mit septischem Schock reduziert war und mit dem Biomarker Procalcitonin in Verbindung gebracht wurde (Wang et al. 2013b). Auf Basis der verfügbaren Daten konnte das Übergewichtsparadoxon in Sepsen leider kaum weiter beleuchtet werden, obwohl die erwartete Anreicherung von Risikoallelen auch bei Sepsispatienten mit höherem BMI festgestellt werden konnte

Optimization of grinding processes on fused silica components using in-process vibrometry and dynamometer measurements

The presented investigations deal with real-time evaluation and recording of vibrations and forces during a CNC grinding process, as well as the analysis and control of process influences on the surface quality of optical components. The experiments were carried out on a 5-axis CNC machine. Rapid subsequent analysis of the topography resulting from grinding is achieved with the aid of white light interferometry. The aim of the investigations is to reduce the surface deviations (roughness, mid-spatials, waviness) influenced by process factors. It is shown that the vibration data measured during the grinding process correlate to a high degree with the recorded topography data

The epidemiology of bloodstream infections and antimicrobial susceptibility patterns in Thuringia, Germany: a five-year prospective, state-wide surveillance study (AlertsNet)

Background!#!Monitoring pathogens of bloodstream infections (BSI) and their antibiotic susceptibility is important to guide empiric antibiotic treatment strategies and prevention programs. This study assessed the epidemiology of BSI and antibiotic resistance patterns at the German Federal State of Thuringia longitudinally.!##!Methods!#!A surveillance network consisting of 26 hospitals was established to monitor BSIs from 01/2015 to 12/2019. All blood culture results, without restriction of age of patients, of the participating hospitals were reported by the respective microbiological laboratory. A single detection of obligate pathogens and a repeated detection of coagulase-negative staphylococci, Bacillus spp., Corynebacterium spp., Micrococcus spp. and Propionibacterium spp., within 96 h were regarded as a relevant positive blood culture. If one of the aforementioned non-obligate pathogens has been detected only once within 96 h, contamination has been assumed. Logistic regression models were applied to analyse the relationship between resistance, year of BSI and hospital size. Generalized estimating equations were used to address potential clustering.!##!Results!#!A total of 343,284 blood cultures (BC) of 82,527 patients were recorded. Overall, 2.8% (n = 9571) of all BCs were classified as contaminated. At least one relevant pathogen was identified in 13.2% (n = 45,346) of BCs. Escherichia coli (25.4%) was the most commonly detected pathogen, followed by Staphylococcus aureus (15.2%), Staphylococcus epidermidis (8.1%) and Klebsiella pneumoniae (4.6%). In S. aureus, we observed a decline of methicillin resistance (MRSA) from 10.4% in 2015 to 2.5% in 2019 (p < 0.001). The rate of vancomycin resistance in Enterococcus faecium (VRE) has increased from 16.7% in 2015 to 26.9% in 2019 (p < 0.001), with a peak in 2018 (42.5%). In addition, we observed an increase of Cefotaxime (3GC) resistance in E. coli from 10.7% in 2015 to 14.5% in 2019 (p = 0.007) whereas 3GC resistance in K. pneumoniae was stable (2015: 9.9%; 2019: 7.4%, p = 0.35). Carbapenem resistance was less than 1% for both pathogens. These patterns were robustly observed across sensitivity analyses.!##!Conclusions!#!We observed evidence for a decline in MRSA, an increase in VRE and a very low rate of carbapenem resistance in gram-negative bacteria. 3GC resistance in E. coli increased constantly over time

Genetic Factors of the Disease Course After Sepsis: Rare Deleterious Variants Are Predictive

Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection. For its clinical course, host genetic factors are important and rare genomic variants are suspected to contribute. We sequenced the exomes of 59 Greek and 15 German patients with bacterial sepsis divided into two groups with extremely different disease courses. Variant analysis was focusing on rare deleterious single nucleotide variants (SNVs). We identified significant differences in the number of rare deleterious SNVs per patient between the ethnic groups. Classification experiments based on the data of the Greek patients allowed discrimination between the disease courses with estimated sensitivity and specificity > 75%. By application of the trained model to the German patients we observed comparable discriminatory properties despite lower population-specific rare SNV load. Furthermore, rare SNVs in genes of cell signaling and innate immunity related pathways were identified as classifiers discriminating between the sepsis courses. Sepsis patients with favorable disease course after sepsis, even in the case of unfavorable preconditions, seem to be affected more often by rare deleterious SNVs in cell signaling and innate immunity related pathways, suggesting a protective role of impairments in these processes against a poor disease course