eine post hoc-Analyse der GM-CSF-Studie

Die schwere Sepsis und der septische Schock stellen schwere Verlaufsformen einer systemischen Infektion dar. Im Rahmen der adaptiven Immunantwort kommt es häufig zur Dysregulation pro- und anti-inflammatorischer Prozesse. Hierbei können Mikrozirkulationsstörungen und ein Multiorganversagen auftreten, was mit einer hohen Sterblichkeitsrate einhergeht. Der typische klinische Verlauf beginnt mit einer hyper-inflammatorischen Frühphase, die – vermutlich durch anti-inflammatorische Kompensationsmechanismen – in eine hypo-inflammatorische Spätphase übergehen kann. Die prolongierte Hypoinflammation ist mit einem Verlust der zellulären und humoralen angeborenen und adaptiven Immunantwort verbunden. Es resultiert eine „sepsis-assoziierte Immunsuppression“ mit erhöhter Suszeptibilität für sekundäre, nosokomiale und opportunistische Infektionen, welche wiederum mit erhöhter Mortalität assoziiert sind. Die vorliegende Arbeit untersucht den Einfluss von GM-CSF auf die Entwicklung sekundärer Infektionen bei Patienten mit sepsis-assoziierter Immunsuppression. Es wurde eine retrospektive Analyse der prospektiven randomisierten multizentrischen Doppelblind-Studie von Meisel und Schefold et al. (2009) durchgeführt. Im Rahmen der Studie erhielt ein Kollektiv von 38 Patienten mit schwerer Sepsis/septischem Schock und sepsis-assoziierter Immunsuppression neben der leitliniengerechten intensivmedizinischen Standardtherapie subkutan 4 µg/kg KG GM-CSF oder Placebo (0,9 % NaCl-Lösung) für acht Tage. Bei fehlender Rekonvaleszenz der monozytären Immunkompetenz (definiert als < 15000 mHLA-DR Moleküle/Zelle an Tag 5) wurde die GM-CSF-Dosis an Tag 6-8 auf 8µg/kg KG erhöht. Ziel und primärer Endpunkt war die Wiederherstellung der monozytären Immunkompetenz. Unter Intervention mit GM-CSF zeigten sich keine signifikanten Unterschiede hinsichtlich der Anzahl, Art und des Erregerspektrums der sekundären nosokomialen Infektionen. Die Verumgruppe wies hinsichtlich der zeitlichen Verteilung eine geringere Sekundärinfektrate während des Interventionszeitraumes (V1-V9) auf (p = 0,04). Zusätzlich traten urogenitale, gastrointestinale und dermale Sekundärinfekte verzögert auf. Ein nicht statistisch signifikant verlängertes infekt-freies Intervall innerhalb der ersten 28 Tage ab Studieneinschluss sowie temporär zwischen später auftretenden Sekundärinfekten wurde beobachtet. Die antimikrobielle Therapie der Primär- und Sekundärinfektionen unterschied sich zwischen den Studiengruppen bezüglich der Auswahl und Applikationsdauer der eingesetzten Antiinfektiva nicht. Zusammenfassend ließen sich in der vorliegenden Studie unter GM-CSF keine signifikante Reduktion sekundärer Infektionen und kein signifikanter Einfluss auf die antimikrobielle Therapie nachweisen. Zu beobachten war, dass Sekundärinfekte in der Interventionsgruppe mit geringerer Anzahl/Rate im Interventionszeitraum sowie über den Verlauf temporär verzögert auftraten, was ein infekt-präventives Potential von GM-CSF vermuten lässt. Weiterführende größere Untersuchungen sollten durchgeführt werden, um eine Reproduzierbarkeit dieser Ergebnisse und einen etwaigen Effekt der Intervention auf klinische Endpunkte bei schwerer Sepsis/septischem Schock mit sepsis-assoziierter Immunsuppression zu überprüfen.Sepsis and septic shock are the worst progressive form of an infection and rest upon dysregulation of overwhelming pro- and anti-inflammatory processes. This may result in tissue damages, microcirculatory disorders, and/or multiple-organ failure with high mortality rates. The course of disease is often characterized by an initial systemic (hyper-) inflammatory response syndrome (SIRS) followed by a subsequent compensatory anti-inflammatory response syndrome with a loss of innate and adaptive immune system. In sepsis-associated immunosuppression, the susceptibility for secondary, nosocomial and opportunistic infections is increased. The present thesis investigates how GM-CSF influences the progress, reconvalescence and course of disease of secondary infections/antimicrobial therapy in patients with severe sepsis/shock and sepsis-associated immunosuppression. Therefore, a retrospective analysis of patients’ charts of the prospective double-blind, randomized multicentre study performed by Meisel and Schefold et al. (2009) was performed, in which 38 patients with sepsis and/or without septic shock and sepsis-associated immunosuppression received GM-CSF in a dose of 4 µg/kg body weight or placebo (0,9 % NaCl-solution) subcutaneously for 8 days in addition to the standard guideline therapy. The dose of GM-CSF was increased to 8 µg/kg body weight in cases of < 15000 mHLA-DR molecules/cell at day five. The primary endpoint of trial was restoration of monocytic immunocapacity in septic patients with sepsis-associated immunosuppression. Between the study groups, there were no significant changes related to frequency and types of secondary nosocomial infections and their pathogens. However, a significantly reduced rate of infections was noted during the intervention period compared to after GM-CSF therapy in the GM-CSF group (p = 0.04). Moreover, a longer infection-free interval regarding secondary infections in the first 28 days after enrollment and a delayed occurrence of urogenital, gastrointestinal and dermal infections were observed in the GM-CSF group when compared to control group. The study groups did not differ in regard to time of antimicrobial therapy or applied anti-infectious agents. In summary, secondary infections did not differ in intervention vs. control group. Regarding the temporal distribution the infection rate was significantly reduced during the intervention period in the GM-CSF group. A different temporal pattern of secondary infections was noted in patients treated with GM-CSF, underlining a potential of GM-CSF for prevention of infection. Larger multicenter studies should be performed to prove potential patient-centered outcome effects of GM-CSF in patients with sepsis-associated immunosuppression

Strain-specific genes of Helicobacter pylori: genome evolution driven by a novel type IV secretion system and genomic island transfer

The availability of multiple bacterial genome sequences has revealed a surprising extent of variability among strains of the same species. The human gastric pathogen Helicobacter pylori is known as one of the most genetically diverse species. We have compared the genome sequence of the duodenal ulcer strain P12 and six other H. pylori genomes to elucidate the genetic repertoire and genome evolution mechanisms of this species. In agreement with previous findings, we estimate that the core genome comprises about 1200 genes and that H. pylori possesses an open pan-genome. Strain-specific genes are preferentially located at potential genome rearrangement sites or in distinct plasticity zones, suggesting two different mechanisms of genome evolution. The P12 genome contains three plasticity zones, two of which encode type IV secretion systems and have typical features of genomic islands. We demonstrate for the first time that one of these islands is capable of self-excision and horizontal transfer by a conjugative process. We also show that excision is mediated by a protein of the XerD family of tyrosine recombinases. Thus, in addition to its natural transformation competence, conjugative transfer of genomic islands has to be considered as an important source of genetic diversity in H. pylori

Using the R Package Spatstat to Assess Inhibitory Effects of Microregional Hypoxia on the Infiltration of Cancers of the Head and Neck Region by Cytotoxic T Lymphocytes

(1) Background: The immune system has physiological antitumor activity, which is partially mediated by cytotoxic T lymphocytes (CTL). Tumor hypoxia, which is highly prevalent in cancers of the head and neck region, has been hypothesized to inhibit the infiltration of tumors by CTL. In situ data validating this concept have so far been based solely upon the visual assessment of the distribution of CTL. Here, we have established a set of spatial statistical tools to address this problem mathematically and tested their performance. (2) Patients and Methods: We have analyzed regions of interest (ROI) of 22 specimens of cancers of the head and neck region after 4-plex immunofluorescence staining and whole-slide scanning. Single cell-based segmentation was carried out in QuPath. Specimens were analyzed with the endpoints clustering and interactions between CTL, normoxic, and hypoxic tumor areas, both visually and using spatial statistical tools implemented in the R package Spatstat. (3) Results: Visual assessment suggested clustering of CTL in all instances. The visual analysis also suggested an inhibitory effect between hypoxic tumor areas and CTL in a minority of the whole-slide scans (9 of 22, 41%). Conversely, the objective mathematical analysis in Spatstat demonstrated statistically significant inhibitory interactions between hypoxia and CTL accumulation in a substantially higher number of specimens (16 of 22, 73%). It showed a similar trend in all but one of the remaining samples. (4) Conclusion: Our findings provide non-obvious but statistically rigorous evidence of inhibition of CTL infiltration into hypoxic tumor subregions of cancers of the head and neck. Importantly, these shielded sites may be the origin of tumor recurrences. We provide the methodology for the transfer of our statistical approach to similar questions. We discuss why versions of the Kcross and pcf.cross functions may be the methods of choice among the repertoire of statistical tests in Spatstat for this type of analysis

Developing and Examining Validity Evidence for the Writing Rubric to Inform Teacher Educators (WRITE)

Assessment is an under-researched challenge of writing development, instruction, and teacher preparation. One reason for the lack of research on writing assessment in teacher preparation is that writing achievement is multi-faceted and difficult to measure consistently. Additionally, research has reported that teacher educators and preservice teaches may have limited assessment literacy knowledge. In previous studies, researchers have struggled to provide strong evidence of validity, reliability, and fairness across raters, writing samples, and rubric items. In the present study, we fill several gaps in the research literature by developing a rubric, the Writing Rubric to Inform Teacher Educators (WRITE), which utilizes a structure that promotes assessment literacy while raters score samples. Furthermore, using modern measurement theory, we strengthen the field’s understanding of writing assessment by providing evidence of validity, reliability, and fairness of scores to support the interpretation and use of the WRITE

Vesicular stomatitis virus replicon expressing the VP2 outer capsid protein of bluetongue virus serotype 8 induces complete protection of sheep against challenge infection.

Bluetongue virus (BTV) is an arthropod-borne pathogen that causes an often fatal, hemorrhagic disease in ruminants. Different BTV serotypes occur throughout many temperate and tropical regions of the world. In 2006, BTV serotype 8 (BTV-8) emerged in Central and Northern Europe for the first time. Although this outbreak was eventually controlled using inactivated virus vaccines, the epidemic caused significant economic losses not only from the disease in livestock but also from trade restrictions. To date, BTV vaccines that allow simple serological discrimination of infected and vaccinated animals (DIVA) have not been approved for use in livestock. In this study, we generated recombinant RNA replicon particles based on single-cycle vesicular stomatitis virus (VSV) vectors. Immunization of sheep with infectious VSV replicon particles expressing the outer capsid VP2 protein of BTV-8 resulted in induction of BTV-8 serotype-specific neutralizing antibodies. After challenge with a virulent BTV-8 strain, the vaccinated animals neither developed signs of disease nor showed viremia. In contrast, immunization of sheep with recombinant VP5 - the second outer capsid protein of BTV - did not confer protection. Discrimination of infected from vaccinated animals was readily achieved using an ELISA for detection of antibodies against the VP7 antigen. These data indicate that VSV replicon particles potentially represent a safe and efficacious vaccine platform with which to control future outbreaks by BTV-8 or other serotypes, especially in previously non-endemic regions where discrimination between vaccinated and infected animals is crucial

The relevance of private actors in the transnational sphere for just peace governance

"Vor dem Hintergrund der Bedeutungszunahme privater Akteure in den internationalen Beziehungen (wird im) Arbeitspapier systematisch (aufgezeigt), welche Rolle diese nicht-staatlichen Akteure in Konflikten um Anerkennung, um prozedurale oder distributive Gerechtigkeit spielen. Rebellengruppen, kriminelle Organisationen, transnationale Unternehmen, zivilgesellschaftliche Organisationen oder ethnische Diasporas - sie tragen einerseits zur Multiplikation von Gerechtigkeitsansprüchen im transnationalen Raum bei; andererseits beteiligen sie sich an neuen, innovativen Governance-Formen, um Gerechtigkeitskonflikte beizulegen. Im Working Paper wird die Frage gestellt, unter welchen Bedingungen die Einbeziehung der Gerechtigkeitsansprüche privater Akteure einer friedlichen Konfliktlösung zuträglich ist oder sie behindert. Diese Ambivalenz nichtstaatlicher Akteure wird im Hinblick auf die Begriffstrias Frieden, Governance und Gerechtigkeit konzeptionalisiert." (Autorenreferat

Safe Brain Tumor Resection Does not Depend on Surgery Alone - Role of Hemodynamics

Aim of this study was to determine if perioperative hemodynamics have an impact on perioperative infarct volume and patients' prognosis. 201 cases with surgery for a newly diagnosed or recurrent glioblastoma were retrospectively analyzed. Clinical data and perioperative hemodynamic parameters, blood tests and time of surgery were recorded. Postoperative infarct volume was quantitatively assessed by semiautomatic segmentation. Mean diastolic blood pressure (dBP) during surgery (rho -0.239, 95% CI -0.11 - -0.367, p = 0.017), liquid balance (rho 0.236, 95% CI 0.1-0.373, p = 0.017) and mean arterial pressure (MAP) during surgery (rho -0.206, 95% CI -0.07 - -0.34, p = 0.041) showed significant correlation to infarct volume. A rank regression model including also age and recurrent surgery as possible confounders revealed mean intraoperative dBP, liquid balance and length of surgery as independent factors for infarct volume. Univariate survival analysis showed mean intraoperative dBP and MAP as significant prognostic factors, length of surgery also remained as significant prognostic factor in a multivariate model. Perioperative close anesthesiologic monitoring of blood pressure and liquid balance is of high significance during brain tumor surgery and should be performed to prevent or minimize perioperative infarctions and to prolong survival

Potential der Biolandwirtschaft zur Steigerung der ökologischen Nachhaltigkeit des Agrarsektors in Luxemburg

Organic agriculture is often hailed as an environmentally friendly food production system. The aim of this study was to analyse the effect of the management system (organic (org.)/conventional (conv.)) on the sustainability performance of farms and derive the possible environmental impact of a 100% conversion to organic agriculture in Luxembourg. During a sustainability assessment at farm level using the SMART-Farm Tool, org. farms achieved significantly higher goal achievements in 13 of the 14 sub-themes of the sustainability dimension “Environmental Integrity”. Thus, org. agriculture shows promise for improvement of the Luxembourgish agricultural sector. However, some differences in goal achievement between the org. and conv. farms, especially in the sub-theme Greenhouse Gases, are relatively small and show that org. agriculture also still has a large potential for improvement when we want to tackle environmental challenges such as climate change.SustEATabl

Retrospective Analysis of Radiological Recurrence Patterns in Glioblastoma, Their Prognostic Value And Association to Postoperative Infarct Volume

Recent studies suggested that postoperative hypoxia might trigger invasive tumor growth, resulting in diffuse/multifocal recurrence patterns. Aim of this study was to analyze distinct recurrence patterns and their association to postoperative infarct volume and outcome. 526 consecutive glioblastoma patients were analyzed, of which 129 met our inclusion criteria: initial tumor diagnosis, surgery, postoperative diffusion-weighted imaging and tumor recurrence during follow-up. Distinct patterns of contrast-enhancement at initial diagnosis and at first tumor recurrence (multifocal growth/progression, contact to dura/ventricle, ependymal spread, local/distant recurrence) were recorded by two blinded neuroradiologists. The association of radiological patterns to survival and postoperative infarct volume was analyzed by uni-/multivariate survival analyses and binary logistic regression analysis. With increasing postoperative infarct volume, patients were significantly more likely to develop multifocal recurrence, recurrence with contact to ventricle and contact to dura. Patients with multifocal recurrence (Hazard Ratio (HR) 1.99, P = 0.010) had significantly shorter OS, patients with recurrent tumor with contact to ventricle (HR 1.85, P = 0.036), ependymal spread (HR 2.97, P = 0.004) and distant recurrence (HR 1.75, P = 0.019) significantly shorter post-progression survival in multivariate analyses including well-established prognostic factors like age, Karnofsky Performance Score (KPS), therapy, extent of resection and patterns of primary tumors. Postoperative infarct volume might initiate hypoxia-mediated aggressive tumor growth resulting in multifocal and diffuse recurrence patterns and impaired survival