The role of elevated central-peripheral temperature difference in early detection of late-onset sepsis in preterm infants

Um die Mortalität und Morbidität von Sepsisepisoden bei Frühgeborenen zu verbessern, kommt einer frühen und sicheren Diagnosestellung besonderes Interesse entgegen. In dieser Arbeit wurde untersucht, inwiefern durch eine Analyse einfacher klinischer Symptome die Wahrscheinlichkeit einer Sepsisepisode korrekt vorausgesagt werden kann. In einer prospektiven Studie wurden in 83 Verdachtsmomenten einer Sepsis bei 67 Frühgeborenen die Basisdaten (Geburtsalter, Geburtsgewicht, etc.), die klinischen (kardiovaskuläre, pulmonale, gastrale und neurologische Symptome) und die paraklinischen (CRP, Blutkulturen, etc.) Variablen analysiert. In 39 Verdachtsmomenten konnte eine Sepsis bestätigt werden, darunter koagulase-negative Staphylokokken als häufigster Erreger. In 44 Fällen wurde keine Sepsis entdeckt. Die Studie zeigte, dass kardiovaskuläre Symptome bei Frühgeborenen frühzeitig auf eine Sepsis hinweisen können. Ein Novum stellte hierbei die Messung einer zentral-peripheren Temperaturdifferenz (cpTD) dar, deren Erhöhung mit einer deutlichen höheren Wahrscheinlichkeit für das Vorliegen einer Sepsis assoziiert war. Sie bietet eine kostengünstige, nicht-invasive und kontinuierlich messbare Methode zur verbesserten Diagnosestellung einer Neugeborenensepsis.:1. Einleitung 2. Hintergründe 3. Ableitung der Fragestellung (inklusive Hypothesen) 4. Publikation 5. Zusammenfassung der Arbeit 6. Aufnahme in die aktuellen Leitlinien 7. LiteraturverzeichnisThe study investigated the association between clinical symptoms and late-onset sepsis (LOS) in preterm infants with the aim of identifying a non-invasive tool for the early detection of LOS. This was a prospective study of 83 episodes of suspected LOS in 67 preterm infants. At the time LOS was suspected, we recorded a standardized set of clinical symptoms. A diagnosis of “clinical LOS” (Clin-LOS), “culture-proven LOS” (Prov-LOS) or “LOS not present” (No-LOS) was made on the basis of C-reactive protein (CrP) and blood culture results. We examined univariable associations between clinical signs and LOS using odds ratio (OR) analysis and then adjusted the odds ratio (adOR) through binary regression analysis. Clin-LOS was diagnosed in 20/83 episodes, 19 cases were found to have Prov-LOS. Clinical signs which had a significant association with Clin-LOS were capillary refill time > 2 s (OR 2.9) and decreased responsiveness (OR 5.2), whereas there was a negative association between gastric residuals and LOS (OR 0.35). However, the most marked association was found for a greater central-peripheral temperature difference (cpTD) > 2 °C (OR 9). In Prov-LOS an increased heart rate (OR 3.1), prolonged capillary refill time (OR 3.3) and again an increased cpTD (OR 16) had a significant association with LOS, whereas gastric residuals were negatively associated (OR 0.29). Regression analysis showed that cpTD was the most striking clinical sign associated with both Clin- (adOR 6.3) and Prov-LOS (adOR 10.5). Conclusions: Prolonged capillary refill time and – more impressive – elevated cpTD were the most useful clinical symptoms for detection of LOS in preterm infants. We especially suggest using cpTD as a predictor of LOS. It is a cheap, non-invasive and readily available tool for daily routines.:1. Einleitung 2. Hintergründe 3. Ableitung der Fragestellung (inklusive Hypothesen) 4. Publikation 5. Zusammenfassung der Arbeit 6. Aufnahme in die aktuellen Leitlinien 7. Literaturverzeichni

Hematopoietic stem cell involvement in BCR-ABL1-positive ALL as a potential mechanism of resistance to blinatumomab therapy

The bispecific T-cell engager blinatumomab targeting CD19 can induce complete remission in relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, some patients ultimately relapse with loss of CD19 antigen on leukemic cells, which has been established as a novel mechanism to escape CD19-specific immunotherapies. Here, we provide evidence that CD19-negative (CD19–) relapse after CD19-directed therapy in BCP-ALL may be a result of the selection of preexisting CD19– malignant progenitor cells. We present 2 BCR-ABL1 fusion–positive BCP-ALL patients with CD19– myeloid lineage relapse after blinatumomab therapy and show BCR-ABL1 positivity in their hematopoietic stem cell (HSC)/progenitor/myeloid compartments at initial diagnosis by fluorescence in situ hybridization after cell sorting. By using the same approach with 25 additional diagnostic samples from patients with BCR-ABL1–positive BCP-ALL, we identified HSC involvement in 40% of the patients. Patients (6 of 8) with major BCR-ABL1 transcript encoding P210BCR-ABL1 mainly showed HSC involvement, whereas in most of the patients (9 of 12) with minor BCR-ABL1 transcript encoding P190BCR-ABL1, only the CD19+ leukemia compartments were BCR-ABL1 positive (P = .02). Our data are of clinical importance, because they indicate that both CD19+ cells and CD19– precursors should be targeted to avoid CD19– relapses in patients with BCR-ABL1–positive ALL

C-reactive protein for diagnosing late-onset infection in newborn infants

BACKGROUND: Late-onset infection is the most common serious complication associated with hospital care for newborn infants. Because confirming the diagnosis by microbiological culture typically takes 24 to 48 hours, the serum level of the inflammatory marker C-reactive protein (CRP) measured as part of the initial investigation is used as an adjunctive rapid test to guide management in infants with suspected late-onset infection. OBJECTIVES: To determine the diagnostic accuracy of serum CRP measurement in detecting late-onset infection in newborn infants. SEARCH METHODS: We searched electronic databases (MEDLINE, Embase, and Science Citation Index to September 2017), conference proceedings, previous reviews, and the reference lists of retrieved articles. SELECTION CRITERIA: We included cohort and cross-sectional studies evaluating the diagnostic accuracy of serum CRP levels for the detection of late-onset infection (occurring more than 72 hours after birth) in newborn infants. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility for inclusion, evaluated the methodological quality of included studies, and extracted data to estimate diagnostic accuracy using hierarchical summary receiver operating characteristic (SROC) models. We assessed heterogeneity by examining variability of study estimates and overlap of the 95% confidence interval (CI) in forest plots of sensitivity and specificity. MAIN RESULTS: The search identified 20 studies (1615 infants). Most were small, single-centre, prospective cohort studies conducted in neonatal units in high- or middle-income countries since the late 1990s. Risk of bias in the included studies was generally low with independent assessment of index and reference tests. Most studies used a prespecified serum CRP threshold level as the definition of a 'positive' index test (typical cut-off level between 5 mg/L and 10 mg/L) and the culture of a pathogenic micro-organism from blood as the reference standard.At median specificity (0.74), sensitivity was 0.62 (95% CI 0.50 to 0.73). Heterogeneity was evident in the forest plots but it was not possible to conduct subgroup or meta-regression analyses by gestational ages, types of infection, or types of infecting micro-organism. Covariates for whether studies used a predefined threshold or not, and whether studies used a standard threshold of between 5 mg/L and 10 mg/L, were not statistically significant. AUTHORS' CONCLUSIONS: The serum CRP level at initial evaluation of an infant with suspected late-onset infection is unlikely to be considered sufficiently accurate to aid early diagnosis or select infants to undergo further investigation or treatment with antimicrobial therapy or other interventions

Human embryonic stem cell-derived neurons as a tool for studying neuroprotection and neurodegeneration.

The capacity to generate myriad differentiated cell types, including neurons, from human embryonic stem cell (hESC) lines offers great potential for developing cell-based therapies and also for increasing our understanding of human developmental mechanisms. In addition, the emerging development of this technology as an experimental tool represents a potential opportunity for neuroscientists interested in mechanisms of neuroprotection and neurodegeneration. Potentially unlimited generation of well-defined functional neurons from hES and patient specific induced pluripotent (iPS) cells offers new systems to study disease mechanisms, signalling pathways and receptor pharmacology within a human cellular environment. Such systems may help in overcoming interspecies differences. Far from replacing rodent in vivo and primary culture systems, hES and iPS cell-derived neurons offer a complementary resource to overcome issues of interspecies differences, accelerate drug discovery, study of disease mechanism as well as provide basic insight into human neuronal physiology

Personalisierte Optionsauswahl im Fahrzeuginformationssystem

Moderne Fahrzeuginformationssysteme ermöglichen es dem Fahrer, während der Fahrt auf eine Vielzahl an geographischen Informationen wie Sonderziele zuzugreifen. Die Auswahl einer Option aus solch umfangreichen Angeboten während der Fahrt kann jedoch zu einem erheblichen Sicherheitsrisiko werden, welches eine Unterstützung des Fahrers bei der Optionsauswahl erforderlich macht. Eine vielversprechende Möglichkeit der Unterstützung liegt im Anbieten von Assistenzsystemen zur personalisierten Sonderzielauswahl. Ziel der hier vorliegenden Dissertation ist die Optimierung der Akzeptanz solcher Assistenzsysteme im fahrzeugspezifischen Nutzungskontext. Hierzu wurde in einer qualitativen Studie zunächst der Nutzungskontext untersucht. Aufbauend auf den Ergebnissen und der Taxonomie für Assistenzsysteme nach Wandke (2005) wurden drei Assistenzarten mit verschiedenen Assistenzgraden identifiziert, die potentiell für die personalisierte Optionsauswahl im Fahrzeug in Frage kommen (adaptierbare Filterassistenz, adaptive Filterassistenz, adaptive Delegationsassistenz). In zwei Szenariobefragungen konnte mit Hilfe des UbiTAM nach Rothensee (2010) aufgezeigt werden, dass alle drei Assistenzarten positiv bewertet wurden. Innerhalb dieser positiven Bewertungen wurden höhere Assistenzgrade signifikant besser bewertet. Basierend auf den Erkenntnissen wurden die Assistenzarten prototypisch realisiert und in zwei Fahrsimulationsstudien hinsichtlich ihrer Auswirkung auf die Fahrleistung und die Güte der Aufgabenbearbeitung untersucht. In den Studien konnten die Ergebnisse zur Akzeptanzbeurteilung bestätigt werden. Zusätzlich wurde deutlich, dass die adaptiven Assistenzarten das höchste Maß an Unterstützung in der Nebenaufgabe boten. Gleichzeitig zeigten sie auch die geringste Auswirkung auf die Fahrleistung. Die Ergebnisse dieser Arbeit legen für die Gestaltung von Auswahlassistenzsystemen im Fahrzeug nahe, eine Kombination aus adaptiven Filter- und Delegationsassistenzen anzustreben.Modern vehicle information systems allow the driver to access a variety of geographical information, like points-of-interest, whilst driving. However, selecting an option from an extensive list of options, whilst driving, can pose a significant safety hazard. Thus, it becomes essential to support the driver in this selection process. A promising solution lies in supplying an assistance system that includes a personalised points-of-interest selection. The purpose of this doctoral thesis is to optimise the acceptance of those assistance systems. Firstly, a qualitative study was carried out to examine the context of use. The results were analysed using the taxonomy for assistance systems developed by Wandke (2005). This identified three suitable types of option selection assistance systems, with varying levels of support; adaptable filter assistance, adaptive filter assistance, adaptive delegation assistance. Secondly, the assistance systems were analysed by means of scenario surveys based on the UbiTAM, by Rothensee (2010). The results showed that all three assistance systems were rated positive. Within these positive ratings, those systems offering higher levels of support received significantly better ratings. Based on the findings all three assistance systems were implemented as prototypes. The prototypes were evaluated in two driving simulator studies, in order to assess their effects on both the driving performance and the quality of task processing. The simulator studies verified the results uncovered by the scenario surveys. Additionally, it became clear that adaptive assistance systems provided drivers with the most support during the fulfilment of secondary tasks. Finally, they showed that driving performance was only slightly affected by the use of the adaptive assistance systems. In terms of the development of assistance systems, the results of this thesis suggest that a combination of adaptive filter and delegation assistance should be implemented

Standardized angiographic projections allow evaluation of coronary artery side branches with quantitative flow ratio (QFR)

Quantitative flow ratio (QFR) is a novel, software-based noninvasive method for the quantitative evaluation of coronary physiology. QFR results correlate with invasive FFR measurements in the three main epicardial coronary arteries. However, QFR data for the evaluation of coronary side branches (SB) are scarce. The evaluation of QFR-performance of SB was retrospective and prospective. Eighty-seven patients with suspected chronic coronary syndrome, who received angiography using routine core lab projections, were retrospectively analyzed. On the second part 37 patients, who received angiography using recommended standardized coronary angiography projections, were prospectively analyzed. Quantitative analysis was performed for SB with a maximum lumen diameter proximal of ≥2 mm based on quantitative coronary angiography (QCA) by two certified experts with the software QAngio XA 3D 3.2. Using routine projections, QFR computation in 55 % of the SB were obtained (123 out of 224). Using standardized projections, 85 % of SB were computed by QFR (64 out of 75; p < 0.001 vs routine projections). The fluoroscopy time for recommended projections was not significantly different as opposed to routine projections (3.75 ± 2.2 vs. 4.58 ± 3.00 min, p = 2.6986). Using the standardized projections was associated with a higher amount of contrast medium (53.44 ± 24.23 vs. 87.95 ± 43.73 ml, p < 0.01), longer overall procedure time (23.23 ± 16.35 vs. 36.14 ± 17.21 min, p < 0.01) and a higher dose area product (1152.28 ± 576.70 vs. 2540.68 ± 1774.07 cGycm2, p < 0.01). Our study shows that the blood flow of the vast majority of coronary SB can be determined non-invasively by QFR in addition to the main epicardial coronary arteries when standardized projections are used