TY - THES A1 - Notz, Quirin Julius T1 - Der Einfluss von Fingolimod auf die autoreaktive B-Zell-Antwort in einem B-Zell-abhängigen Mausmodell der Multiplen Sklerose T1 - Effects of fingolimod on the autoreactive B cell response in a B cell-dependent mouse model of multiple sclerosis N2 - Die MP4-induzierte experimentelle autoimmune Encephalomyelitis (EAE) erlaubt eine fokussierte Betrachtung von B-Zellen, die eine wichtige Rolle bei der Pathogenese der Multiplen Sklerose (MS) spielen. Es konnte zum Beispiel gezeigt werden, dass das Vorhandensein von B-Zell-Aggregaten im zentralen Nervensystem (ZNS) von MS-Patienten mit einem aggravierten Krankheitsverlauf assoziiert war. Diese Follikel könnten dabei als ektope lymphatische Strukturen den Immunprozess aktiv gestalten und somit ein therapeutisches Ziel darstellen. In der vorliegenden Studie wurde der Effekt des Sphingosin-1-Phosphat-Rezeptor-Modulators Fingolimod (FTY720) auf die autoreaktive B-Zell-Antwort und speziell die Bildung von B-Zell-Aggregaten im Kleinhirn der MP4-EAE-Mäuse untersucht. N2 - MP4-induced experimental autoimmune encephalomyelitis (EAE) is a mouse model of multiple sclerosis (MS), which enables focused research on B cells, important protagonists in MS pathogenesis. This study is about the impact of the sphingosine-1-phosphate receptor modulator fingolimod (FTY720) on the autoreactive B cell response and the formation of B cell aggregates and lymphoid neogenesis in the murine central nervous system (CNS). KW - Multiple Sklerose KW - B-Zelle KW - Experimentelle autoimmune Encephalomyelitis KW - Fingolimod KW - B-Zell-Aggregat KW - Lymphoide Neogenese KW - Tertiär lymphatisches Organ Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-191540 ER - TY - JOUR A1 - Dresen, Ellen A1 - Lee, Zheng-Yii A1 - Hill, Aileen A1 - Notz, Quirin A1 - Patel, Jayshil J. A1 - Stoppe, Christian T1 - History of scurvy and use of vitamin C in critical illness: A narrative review JF - Nutrition in Clinical Practice N2 - In 1747, an important milestone in the history of clinical research was set, as the Scottish surgeon James Lind conducted the first randomized controlled trial. Lind was interested in scurvy, a severe vitamin C deficiency which caused the death of thousands of British seamen. He found that a dietary intervention with oranges and lemons, which are rich in vitamin C by nature, was effective to recover from scurvy. Because of its antioxidative properties and involvement in many biochemical processes, the essential micronutrient vitamin C plays a key role in the human biology. Moreover, the use of vitamin C in critical illness—a condition also resulting in death of thousands in the 21st century—has gained increasing interest, as it may restore vascular responsiveness to vasoactive agents, ameliorate microcirculatory blood flow, preserve endothelial barriers, augment bacterial defense, and prevent apoptosis. Because of its redox potential and powerful antioxidant capacity, vitamin C represents an inexpensive and safe antioxidant, with the potential to modify the inflammatory cascade and improve clinical outcomes of critically ill patients. This narrative review aims to update and provide an overview on the role of vitamin C in the human biology and in critically ill patients, and to summarize current evidence on the use of vitamin C in diverse populations of critically ill patients, in specific focusing on patients with sepsis and coronavirus disease 2019. KW - antioxidant KW - scurvy KW - sepsis KW - vitamin C KW - critical illness KW - COVID‐19 Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-318176 VL - 38 IS - 1 SP - 46 EP - 54 ER - TY - JOUR A1 - Schmidbauer, Moritz L. A1 - Ferse, Caroline A1 - Salih, Farid A1 - Klingner, Carsten A1 - Musleh, Rita A1 - Kunst, Stefan A1 - Wittstock, Matthias A1 - Neumann, Bernhard A1 - Schebesch, Karl-Michael A1 - Bösel, Julian A1 - Godau, Jana A1 - Lochner, Piergiorgio A1 - Adam, Elisabeth H. A1 - Jahnke, Kolja A1 - Knier, Benjamin A1 - Schirotzek, Ingo A1 - Müllges, Wolfgang A1 - Notz, Quirin A1 - Dengl, Markus A1 - Güldner, Andreas A1 - Onur, Oezguer A. A1 - Garcia Borrega, Jorge A1 - Dimitriadis, Konstantinos A1 - Günther, Albrecht T1 - COVID-19 and intracranial hemorrhage: a multicenter case series, systematic review and pooled analysis JF - Journal of Clinical Medicine N2 - Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) profoundly impacts hemostasis and microvasculature. In the light of the dilemma between thromboembolic and hemorrhagic complications, in the present paper, we systematically investigate the prevalence, mortality, radiological subtypes, and clinical characteristics of intracranial hemorrhage (ICH) in coronavirus disease (COVID-19) patients. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we performed a systematic review of the literature by screening the PubMed database and included patients diagnosed with COVID-19 and concomitant ICH. We performed a pooled analysis, including a prospectively collected cohort of critically ill COVID-19 patients with ICH, as part of the PANDEMIC registry (Pooled Analysis of Neurologic Disorders Manifesting in Intensive Care of COVID-19). Results: Our literature review revealed a total of 217 citations. After the selection process, 79 studies and a total of 477 patients were included. The median age was 58.8 years. A total of 23.3% of patients experienced the critical stage of COVID-19, 62.7% of patients were on anticoagulation and 27.5% of the patients received ECMO. The prevalence of ICH was at 0.85% and the mortality at 52.18%, respectively. Conclusion: ICH in COVID-19 patients is rare, but it has a very poor prognosis. Different subtypes of ICH seen in COVID-19, support the assumption of heterogeneous and multifaceted pathomechanisms contributing to ICH in COVID-19. Further clinical and pathophysiological investigations are warranted to resolve the conflict between thromboembolic and hemorrhagic complications in the future. KW - COVID-19 KW - intracranial hemorrhage KW - prognosis KW - anticoagulation Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-255236 SN - 2077-0383 VL - 11 IS - 3 ER - TY - JOUR A1 - Bail, Kathrin A1 - Notz, Quirin A1 - Rovituso, Damiano M. A1 - Schampel, Andrea A1 - Wunsch, Marie A1 - Koeniger, Tobias A1 - Schropp, Verena A1 - Bharti, Richa A1 - Scholz, Claus-Juergen A1 - Foerstner, Konrad U. A1 - Kleinschnitz, Christoph A1 - Kuerten, Stefanie T1 - Differential effects of FTY720 on the B cell compartment in a mouse model of multiple sclerosis. JF - Journal of Neuroinflammation N2 - Background: MP4-induced experimental autoimmune encephalomyelitis (EAE) is a mouse model of multiple sclerosis (MS), which enables targeted research on B cells, currently much discussed protagonists in MS pathogenesis. Here, we used this model to study the impact of the S1P1 receptor modulator FTY720 (fingolimod) on the autoreactive B cell and antibody response both in the periphery and the central nervous system (CNS). Methods: MP4-immunized mice were treated orally with FTY720 for 30 days at the peak of disease or 50 days after EAE onset. The subsequent disease course was monitored and the MP4-specific B cell/antibody response was measured by ELISPOT and ELISA. RNA sequencing was performed to determine any effects on B cell-relevant gene expression. S1P\(_{1}\) receptor expression by peripheral T and B cells, B cell subset distribution in the spleen and B cell infiltration into the CNS were studied by flow cytometry. The formation of B cell aggregates and of tertiary lymphoid organs (TLOs) was evaluated by histology and immunohistochemistry. Potential direct effects of FTY720 on B cell aggregation were studied in vitro. Results: FTY720 significantly attenuated clinical EAE when treatment was initiated at the peak of EAE. While there was a significant reduction in the number of T cells in the blood after FTY720 treatment, B cells were only slightly diminished. Yet, there was evidence for the modulation of B cell receptor-mediated signaling upon FTY720 treatment. In addition, we detected a significant increase in the percentage of B220\(^{+}\) B cells in the spleen both in acute and chronic EAE. Whereas acute treatment completely abrogated B cell aggregate formation in the CNS, the numbers of infiltrating B cells and plasma cells were comparable between vehicle- and FTY720-treated mice. In addition, there was no effect on already developed aggregates in chronic EAE. In vitro B cell aggregation assays suggested the absence of a direct effect of FTY720 on B cell aggregation. However, FTY720 impacted the evolution of B cell aggregates into TLOs. Conclusions: The data suggest differential effects of FTY720 on the B cell compartment in MP4-induced EAE. KW - B cells KW - EAE KW - FTY720 KW - fingolimod KW - multiple sclerosis KW - TLO Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-157869 VL - 14 IS - 148 ER - TY - JOUR A1 - Herrmann, Johannes A1 - Adam, Elisabeth Hannah A1 - Notz, Quirin A1 - Helmer, Philipp A1 - Sonntagbauer, Michael A1 - Ungemach-Papenberg, Peter A1 - Sanns, Andreas A1 - Zausig, York A1 - Steinfeldt, Thorsten A1 - Torje, Iuliu A1 - Schmid, Benedikt A1 - Schlesinger, Tobias A1 - Rolfes, Caroline A1 - Reyher, Christian A1 - Kredel, Markus A1 - Stumpner, Jan A1 - Brack, Alexander A1 - Wurmb, Thomas A1 - Gill-Schuster, Daniel A1 - Kranke, Peter A1 - Weismann, Dirk A1 - Klinker, Hartwig A1 - Heuschmann, Peter A1 - Rücker, Viktoria A1 - Frantz, Stefan A1 - Ertl, Georg A1 - Muellenbach, Ralf Michael A1 - Mutlak, Haitham A1 - Meybohm, Patrick A1 - Zacharowski, Kai A1 - Lotz, Christopher T1 - COVID-19 Induced Acute Respiratory Distress Syndrome — A Multicenter Observational Study JF - Frontiers in Medicine N2 - Background: Proportions of patients dying from the coronavirus disease-19 (COVID-19) vary between different countries. We report the characteristics; clinical course and outcome of patients requiring intensive care due to COVID-19 induced acute respiratory distress syndrome (ARDS). Methods: This is a retrospective, observational multicentre study in five German secondary or tertiary care hospitals. All patients consecutively admitted to the intensive care unit (ICU) in any of the participating hospitals between March 12 and May 4, 2020 with a COVID-19 induced ARDS were included. Results: A total of 106 ICU patients were treated for COVID-19 induced ARDS, whereas severe ARDS was present in the majority of cases. Survival of ICU treatment was 65.0%. Median duration of ICU treatment was 11 days; median duration of mechanical ventilation was 9 days. The majority of ICU treated patients (75.5%) did not receive any antiviral or anti-inflammatory therapies. Venovenous (vv) ECMO was utilized in 16.3%. ICU triage with population-level decision making was not necessary at any time. Univariate analysis associated older age, diabetes mellitus or a higher SOFA score on admission with non-survival during ICU stay. Conclusions: A high level of care adhering to standard ARDS treatments lead to a good outcome in critically ill COVID-19 patients. KW - COVID-19 KW - ARDS (acute respiratory distress syndrome) KW - intensive care medicine KW - pandemia KW - Germany Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219834 SN - 2296-858X VL - 7 ER - TY - JOUR A1 - Herrmann, Johannes A1 - Notz, Quirin A1 - Schlesinger, Tobias A1 - Stumpner, Jan A1 - Kredel, Markus A1 - Sitter, Magdalena A1 - Schmid, Benedikt A1 - Kranke, Peter A1 - Schulze, Harald A1 - Meybohm, Patrick A1 - Lotz, Christopher T1 - Point of care diagnostic of hypercoagulability and platelet function in COVID-19 induced acute respiratory distress syndrome: a retrospective observational study JF - Thrombosis Journal N2 - Background Coronavirus disease 2019 (COVID-19) associated coagulopathy (CAC) leads to thromboembolic events in a high number of critically ill COVID-19 patients. However, specific diagnostic or therapeutic algorithms for CAC have not been established. In the current study, we analyzed coagulation abnormalities with point-of-care testing (POCT) and their relation to hemostatic complications in patients suffering from COVID-19 induced Acute Respiratory Distress Syndrome (ARDS). Our hypothesis was that specific diagnostic patterns can be identified in patients with COVID-19 induced ARDS at risk of thromboembolic complications utilizing POCT. Methods This is a single-center, retrospective observational study. Longitudinal data from 247 rotational thromboelastometries (Rotem®) and 165 impedance aggregometries (Multiplate®) were analysed in 18 patients consecutively admitted to the ICU with a COVID-19 induced ARDS between March 12th to June 30th, 2020. Results Median age was 61 years (IQR: 51–69). Median PaO2/FiO2 on admission was 122 mmHg (IQR: 87–189), indicating moderate to severe ARDS. Any form of hemostatic complication occurred in 78 % of the patients with deep vein/arm thrombosis in 39 %, pulmonary embolism in 22 %, and major bleeding in 17 %. In Rotem® elevated A10 and maximum clot firmness (MCF) indicated higher clot strength. The delta between EXTEM A10 minus FIBTEM A10 (ΔA10) > 30 mm, depicting the sole platelet-part of clot firmness, was associated with a higher risk of thromboembolic events (OD: 3.7; 95 %CI 1.3–10.3; p = 0.02). Multiplate® aggregometry showed hypoactive platelet function. There was no correlation between single Rotem® and Multiplate® parameters at intensive care unit (ICU) admission and thromboembolic or bleeding complications. Conclusions Rotem® and Multiplate® results indicate hypercoagulability and hypoactive platelet dysfunction in COVID-19 induced ARDS but were all in all poorly related to hemostatic complications.. KW - COVID-19 KW - acute Respiratory Distress Syndrome KW - point of care testing KW - thromboelastometry KW - impedance aggregometry; WHOLE-BLOOD THROMBOELASTOMETRY; DEFINITION; DISEASE Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-260739 VL - 19 IS - 1 ER - TY - JOUR A1 - Notz, Quirin A1 - Lotz, Christopher A1 - Herrmann, Johannes A1 - Vogt, Marius A1 - Schlesinger, Tobias A1 - Kredel, Markus A1 - Muellges, Wolfgang A1 - Weismann, Dirk A1 - Westermaier, Thomas A1 - Meybohm, Patrick A1 - Kranke, Peter T1 - Severe neurological complications in critically ill COVID‑19 patients JF - Journal of Neurology N2 - No abstract available. KW - COVID-19 KW - neurological complications Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232429 SN - 0340-5354 ER - TY - JOUR A1 - Lotz, Christopher A1 - Notz, Quirin A1 - Kranke, Peter A1 - Kredel, Markus A1 - Meybohm, Patrick T1 - Unconventional approaches to mechanical ventilation - step-by-step through the COVID-19 crisis JF - Critical Care N2 - No abstract available. KW - COVID 19 KW - mechanical ventilation Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229868 VL - 24 ER - TY - JOUR A1 - Schlesinger, Tobias A1 - Weißbrich, Benedikt A1 - Wedekink, Florian A1 - Notz, Quirin A1 - Herrmann, Johannes A1 - Krone, Manuel A1 - Sitter, Magdalena A1 - Schmid, Benedikt A1 - Kredel, Markus A1 - Stumpner, Jan A1 - Dölken, Lars A1 - Wischhusen, Jörg A1 - Kranke, Peter A1 - Meybohm, Patrick A1 - Lotz, Christpher T1 - Biodistribution and serologic response in SARS-CoV-2 induced ARDS: A cohort study JF - PLoS One N2 - Background The viral load and tissue distribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain important questions. The current study investigated SARS-CoV-2 viral load, biodistribution and anti-SARS-CoV-2 antibody formation in patients suffering from severe corona virus disease 2019 (COVID-19) induced acute respiratory distress syndrome (ARDS). Methods This is a retrospective single-center study in 23 patients with COVID-19-induced ARDS. Data were collected within routine intensive care. SARS-CoV-2 viral load was assessed via reverse transcription quantitative polymerase chain reaction (RT-qPCR). Overall, 478 virology samples were taken. Anti-SARS-CoV-2-Spike-receptor binding domain (RBD) antibody detection of blood samples was performed with an enzyme-linked immunosorbent assay. Results Most patients (91%) suffered from severe ARDS during ICU treatment with a 30-day mortality of 30%. None of the patients received antiviral treatment. Tracheal aspirates tested positive for SARS-CoV-2 in 100% of the cases, oropharyngeal swabs only in 77%. Blood samples were positive in 26% of the patients. No difference of viral load was found in tracheal or blood samples with regard to 30-day survival or disease severity. SARS-CoV-2 was never found in dialysate. Serologic testing revealed significantly lower concentrations of SARS-CoV-2 neutralizing IgM and IgA antibodies in survivors compared to non-survivors (p = 0.009). Conclusions COVID-19 induced ARDS is accompanied by a high viral load of SARS-CoV-2 in tracheal aspirates, which remained detectable in the majority throughout intensive care treatment. Remarkably, SARS-CoV-2 RNA was never detected in dialysate even in patients with RNAemia. Viral load or the buildup of neutralizing antibodies was not associated with 30-day survival or disease severity. KW - viral load Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-231348 VL - 15, 2020 IS - 11 ER - TY - JOUR A1 - Menger, Johannes A1 - Lee, Zheng-Yii A1 - Notz, Quirin A1 - Wallqvist, Julia A1 - Hasan, M. Shahnaz A1 - Elke, Gunnar A1 - Dworschak, Martin A1 - Meybohm, Patrick A1 - Heyland, Daren K. A1 - Stoppe, Christian T1 - Administration of vitamin D and its metabolites in critically ill adult patients: an updated systematic review with meta-analysis of randomized controlled trials JF - Critical Care N2 - Background The clinical significance of vitamin D administration in critically ill patients remains inconclusive. The purpose of this systematic review with meta-analysis was to investigate the effect of vitamin D and its metabolites on major clinical outcomes in critically ill patients, including a subgroup analysis based on vitamin D status and route of vitamin D administration. Methods Major databases were searched through February 9, 2022. Randomized controlled trials of adult critically ill patients with an intervention group receiving vitamin D or its metabolites were included. Random-effect meta-analyses were performed to estimate the pooled risk ratio (dichotomized outcomes) or mean difference (continuous outcomes). Risk of bias assessment included the Cochrane tool for assessing risk of bias in randomized trials. Results Sixteen randomized clinical trials with 2449 patients were included. Vitamin D administration was associated with lower overall mortality (16 studies: risk ratio 0.78, 95% confidence interval 0.62–0.97, p = 0.03; I2 = 30%), reduced intensive care unit length of stay (12 studies: mean difference − 3.13 days, 95% CI − 5.36 to − 0.89, n = 1250, p = 0.006; I2 = 70%), and shorter duration of mechanical ventilation (9 studies: mean difference − 5.07 days, 95% CI − 7.42 to − 2.73, n = 572, p < 0.0001; I2 = 54%). Parenteral administration was associated with a greater effect on overall mortality than enteral administration (test of subgroup differences, p = 0.04), whereas studies of parenteral subgroups had lower quality. There were no subgroup differences based on baseline vitamin D levels. Conclusions Vitamin D supplementation in critically ill patients may reduce mortality. Parenteral administration might be associated with a greater impact on mortality. Heterogeneity and assessed certainty among the studies limits the generalizability of the results. KW - critically ill KW - vitamin D KW - nutrition KW - meta-analysis KW - mortality KW - mechanical ventilator weaning Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-299700 VL - 26 IS - 1 ER -