Publications by authors named "Matthias Klein"

155 Publications

IL-17 controls central nervous system autoimmunity through the intestinal microbiome.

Sci Immunol 2021 Feb;6(56)

Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.

Interleukin-17A- (IL-17A) and IL-17F-producing CD4 T helper cells (T17 cells) are implicated in the development of chronic inflammatory diseases, such as multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). T17 cells also orchestrate leukocyte invasion of the central nervous system (CNS) and subsequent tissue damage. However, the role of IL-17A and IL-17F as effector cytokines is still confused with the encephalitogenic function of the cells that produce these cytokines, namely, T17 cells, fueling a long-standing debate in the neuroimmunology field. Here, we demonstrated that mice deficient for IL-17A/F lose their susceptibility to EAE, which correlated with an altered composition of their gut microbiota. However, loss of IL-17A/F in T cells did not diminish their encephalitogenic capacity. Reconstitution of a wild-type-like intestinal microbiota or reintroduction of IL-17A specifically into the gut epithelium of IL-17A/F-deficient mice reestablished their susceptibility to EAE. Thus, our data demonstrated that IL-17A and IL-17F are not encephalitogenic mediators but rather modulators of intestinal homeostasis that indirectly alter CNS-directed autoimmunity.
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http://dx.doi.org/10.1126/sciimmunol.aaz6563DOI Listing
February 2021

Maternal and Cord Blood Metabolite Associations with Gestational Weight Gain and Pregnancy Health Outcomes.

J Proteome Res 2021 Mar 2;20(3):1630-1638. Epub 2021 Feb 2.

School of Human Kinetics, Faculty of Health Sciences, University of Ottawa, Ottawa, Ontario K1N 6N5, Canada.

Pre-pregnancy obesity and excessive gestational weight gain (GWG) are risk factors for future maternal and childhood obesity. Maternal obesity is potentially communicated to the fetus in part by the metabolome, altering the child's metabolic program in early development. Fasting maternal blood samples from 37 singleton pregnancies at 25-28 weeks of gestation were obtained from mothers with pre-pregnancy body mass indexes (BMIs) between 18 and 40 kg/m. Various health measures including GWG, diet, and physical activity were also assessed. At term (37-42 weeks), a venous umbilical cord sample was obtained. Serum metabolomic profiles were measured using nuclear magnetic resonance spectroscopy as well as a gut and metabolic hormone panel. Maternal and cord serum metabolites were tested for associations with pre-pregnancy BMI, GWG, health outcomes, and gut and metabolic hormones. While cord blood metabolites showed no significant correlation to maternal obesity status or other measured health outcomes, maternal serum metabolites showed distinct profiles for lean, overweight, and obese women. Additionally, four serum metabolites, namely, glutamate, lysine, pyruvate, and valine, allowed prediction of excessive GWG when pre-pregnancy BMI was controlled. Metabolic biomarkers predictive of GWG are reported and, if validated, could aid in the guidance of prenatal weight management plans as the majority of pregnancy weight gain occurs in the third trimester.
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http://dx.doi.org/10.1021/acs.jproteome.0c00854DOI Listing
March 2021

[Steroids in infection medicine].

Dtsch Med Wochenschr 2021 Feb 29;146(3):162-166. Epub 2021 Jan 29.

Universitätsklinikum Freiburg, Abteilung Infektiologie, Klinik für Innere Medizin II, Freiburg.

Corticosteroids have been found as useful adjunctive therapy in patients with various infections and hyperinflammation-associated disease. They are recommended in practice guidelines for patients with tuberculous and pneumococcal meningitis and patients with immune reconstitution syndrome associated with antiretroviral therapy. A new indication is severe COVID-19. Evidence from clinical trials is insufficient to allow the routine use of steroids among patients with septic shock, community-acquired pneumonia or tuberculous pericarditis.
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http://dx.doi.org/10.1055/a-1302-3530DOI Listing
February 2021

SOP: emergency workup in patients with suspected acute bacterial meningitis.

Neurol Res Pract 2021 Jan 7;3(1). Epub 2021 Jan 7.

Department of Neurology, LMU Klinikum, Ludwig Maximilians University Munich, Marchioninistr 15, 81377, Munich, Germany.

Introduction: Despite antibiotic therapy, adjunctive treatment with dexamethasone, and care on modern intensive care units, bacterial meningitis remains a life-threatening disease with a high mortality and morbidity. One of most critical factors that influences outcome is a targeted quick but profound workup and early initiation of therapy in the Emergency Department. This standardized operating procedure was designed to guide physicians through the workup of patients with suspected acute bacterial meningitis.

First Steps: In patients with suspected community-acquired bacterial meningitis, the first steps aim at establishing a diagnosis and at starting empiric therapy without delay. Therefore, physicians need to seek for an early lumbar puncture that can be done safely without prior imaging if clinical signs that point at contraindications of a lumbar puncture are absent. Immediately after lumbar puncture, empiric therapy with ceftriaxone, ampicillin and dexamethasone should be started. In regions with a critical resistance rate of pneumococci against third generation cephalosporines, vancomycin or rifampicin need to be added.

Comments: Clinical signs that are associated with intracranial conditions that are a contraindication for a lumbar puncture are severely decreased consciousness, new onset focal neurological signs, and epileptic seizures. If any of these clinical signs are present, cerebral imaging is recommended before lumbar puncture. Whenever lumbar puncture is delayed, empiric therapy needs to be begun before cerebrospinal fluid is obtained.

Conclusion: Suspected acute bacterial meningitis is an emergency and requires attention with high priority in the emergency department to ensure a quick workup and early start of therapy.
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http://dx.doi.org/10.1186/s42466-020-00098-6DOI Listing
January 2021

Determining the effects of nutrition on the reproductive physiology of male mosquitoes.

J Insect Physiol 2021 Feb-Mar;129:104191. Epub 2021 Jan 9.

Department of Entomology, The Ohio State University, 2021 Coffey Rd, Columbus, OH 43210, United States. Electronic address:

Nutrition affects multiple aspects of insect physiology such as body size and fecundity, but we lack a detailed understanding of how nutrition influences the reproductive physiology of male insects such as mosquitoes. Given that female mosquitoes are vectors of many deadly diseases and can quickly proliferate, understanding how male nutrition impacts female fecundity could be of critical importance. To uncover the relationship between nutrition in adult male mosquitoes and its impacts on reproductive physiology, we reared larvae of the Northern house mosquito, Culex pipiens, on a standard lab diet and divided adult males among three different dietary treatments: low (3%), moderate (10%), and high (20%) sucrose. We found that although overall body size did not differ among treatments, one-week-old males raised on the 3% sucrose diet had significantly smaller male accessory glands (MAGs) compared to males that consumed the 10% and the 20% sucrose diets. Diet affected whole-body lipid content but did not affect whole-body protein content. Using nuclear magnetic resonance (NMR) spectroscopy, we found that diet altered the metabolic composition of the MAGs, including changes in lactic acid, formic acid, and glucose. We also observed changes in protein and lipid abundance and composition in MAGs. Females who mated with males on the 3% diet were found to produce significantly fewer larvae than females who had mated with males on the 10% diet. Taken together, our results demonstrate that the diet of adult male mosquitoes clearly affects male reproductive physiology and female fecundity.
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http://dx.doi.org/10.1016/j.jinsphys.2021.104191DOI Listing
January 2021

Affine Transformation of Negative Values for NMR Metabolomics Using the mrbin R Package.

Authors:
Matthias S Klein

J Proteome Res 2021 Feb 8;20(2):1397-1404. Epub 2021 Jan 8.

Department of Food Science and Technology, The Ohio State University, 2015 Fyffe Road, Columbus, Ohio 43210, United States.

Data from untargeted metabolomics studies employing nuclear magnetic resonance (NMR) spectroscopy oftentimes contain negative values. These negative values hamper data processing and analysis algorithms and prevent the use of such data in multiomics integration settings. New methods to deal with such negative values are thus an urgent need in the metabolomics community. This study presents affine transformation of negative values (ATNV), a novel algorithm for replacement of negative values in NMR data sets. ATNV was implemented in the R package mrbin, which features interactive menus for user-friendly application and is available for free for various operating systems within the free R statistical programming language. The novel algorithms were tested on a set of human urinary NMR spectra and were able to successfully identify relevant metabolites.
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http://dx.doi.org/10.1021/acs.jproteome.0c00684DOI Listing
February 2021

Prospective Longitudinal Serosurvey of Health Care Workers in the First Wave of the SARS-CoV-2 Pandemic in a Quaternary Care Hospital in Munich, Germany.

Clin Infect Dis 2021 Jan 3. Epub 2021 Jan 3.

Emergency Department, University Hospital, LMU Munich, Munich, Germany.

Background: High infection rates among health care personnel in an uncontained pandemic can paralyze health systems due to staff shortages. Risk constellations and rates of seroconversion for health care workers during the first wave of the SARS-CoV-2 pandemic are still largely unclear.

Methods: Health care personnel (n=300) on different organizational units in the LMU Munich University Hospital were included and followed in this prospective longitudinal study in the period of March 24 until July 7, 2020. Participants were monitored in intervals of two to six weeks using different antibody assays for serological testing and questionnaires to evaluate risk contacts. In a subgroup of infected participants, we obtained nasopharyngeal swabs to perform whole genome sequencing for outbreak characterization.

Results: Health care workers involved in patient care on dedicated COVID-19 wards or on regular non-COVID-19 wards showed a higher rate of SARS-CoV-2 seroconversion compared to staff in the emergency department and non-frontline personnel. The landscape of risk contacts in these units was dynamic, with a decrease of unprotected risk contacts in the emergency department and an increase on non-COVID-19 wards. Both, the intensity and number of risk contacts, were associated with higher rates of seroconversion. On regular wards, staff infections tended to occur in clusters, while infections on COVID-19 wards were less frequent and apparently independent of each other.

Conclusion: The risk of SARS-CoV-2 infection for front-line health care workers was increased during the first pandemic wave in Southern Germany. Stringent measures for infection control are essential to protect all patient-facing staff during the ongoing pandemic.
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http://dx.doi.org/10.1093/cid/ciaa1935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799305PMC
January 2021

Caffeine-Containing Energy Shots Cause Acute Impaired Glucoregulation in Adolescents.

Nutrients 2020 Dec 16;12(12). Epub 2020 Dec 16.

College of Food, Agricultural and Environmental Sciences, The Ohio State University, Columbus, OH 43210, USA.

Caffeine-containing, nutritionally fortified energy shots are consumed at high rates by adolescents, yet little is known about their metabolic impact. The purpose of this study was to examine the consequences of small format, caffeinated energy shots on glucose metabolism and gastrointestinal hormone secretion in adolescents. Twenty participants aged 13-19 years participated in a double-blind, randomized cross-over study consisting of two trials separated by 1-4 weeks. Participants consumed a volume-matched caffeinated energy shot (CAF, 5 mg/kg) or a decaffeinated energy shot (DECAF) followed by a 2 h oral glucose tolerance test. Blood samples were collected and area under the curve (AUC) calculated for glucose, insulin and gut and metabolic hormones. Consumption of CAF resulted in a 25% increase in glucose and a 26% increase in insulin area under the curve (AUC, = 0.037; < 0.0001) compared to DECAF. No impact on gut hormones was observed. To further characterize responses, individuals were classified as either slow or fast caffeine metabolizers based on an allele score. Glucose intolerance was greater in genetically fast vs. slow caffeine metabolizers and differences between groups were supported by distinct serum metabolomics separation. Consumption of caffeine-containing energy shots results in acute impaired glucoregulation in healthy adolescents as characterized by hyperinsulinemia following an oral glucose challenge.
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http://dx.doi.org/10.3390/nu12123850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766305PMC
December 2020

Multicenter Evaluation of the Unyvero Platform for Testing Bronchoalveolar Lavage Fluid.

J Clin Microbiol 2021 Feb 18;59(3). Epub 2021 Feb 18.

Beaumont Hospital, Royal Oak, Section of Infectious Diseases and International Medicine, Royal Oak, Michigan, USA

Bronchoalveolar lavage (BAL) culture is a standard, though time-consuming, approach for identifying microorganisms in patients with severe lower respiratory tract (LRT) infections. The sensitivity of BAL culture is relatively low, and prior antimicrobial therapy decreases the sensitivity further, leading to overuse of empirical antibiotics. The Unyvero LRT BAL Application (Curetis GmbH, Germany) is a multiplex molecular panel that detects 19 bacteria, 10 antibiotic resistance markers, and a fungus, , in BAL fluid in ∼4.5 h. Its performance was evaluated using 1,016 prospectively collected and 392 archived specimens from 11 clinical trial sites in the United States. Overall positive and negative percent agreements with culture results for identification of bacteria that grow in routine cultures were 93.4% and 98.3%, respectively, with additional potential pathogens identified by Unyvero in 21.7% of prospectively collected specimens. For detection of , the positive percent agreement with standard testing was 87.5%. Antibiotic resistance marker results were compared to standard antibiotic susceptibility test results to determine positive predictive values (PPVs). PPVs ranged from 80 to 100%, based on the microorganism and specific resistance marker(s). The Unyvero LRT BAL Application provides accurate detection of common agents of bacterial pneumonia and of The sensitivity and rapidity of this panel suggest significant clinical value for choosing appropriate antibiotics and for antibiotic stewardship.
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http://dx.doi.org/10.1128/JCM.02497-20DOI Listing
February 2021

In Activated Murine Mast Cells, NFATc2 Is Critical for the Production of Autocrine IL-3, Thereby Promoting the Expression of IL-9.

J Immunol 2021 Jan 2;206(1):67-76. Epub 2020 Dec 2.

Institute for Immunology, University Medical Center of the Johannes Gutenberg-University Mainz and Research Center for Immunotherapy, Paul-Klein-Center for Immune Intervention, 55131 Mainz, Germany

IL-9 has lent its numerical designation to the Th9 subset of CD4 Th cells, although it is also produced by additional cell types, including mast cells. It is a pleiotropic cytokine involved in allergic reactions, parasitic infections, autoimmune inflammation, and cancer immunity. In this article, we provide evidence that NFATc2 has contradictory functions in the expression of IL-9 in murine Th9 cells and bone marrow-derived mast cells (BMMC). The basis for this is our observation that the production of IL-9 in NFATc2-deficient Th9 cells is increased, whereas it is decreased in BMMC devoid of NFATc2. In addition, NFATc2 deficiency almost completely abrogates the expression of IL-3 in both cell types. However, selectively in BMMC, the production of IL-9 critically depends on autocrine IL-3 acting via the sustained activation of STAT5 on the expression of IL-9. Furthermore, we demonstrate that IL-3 acts independently and synergistically with IL-1β on the production of IL-9. Taken together, we highlight NFATc2-driven production of autocrine IL-3 as a critical and cell type-specific component for IL-9 expression in BMMC.
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http://dx.doi.org/10.4049/jimmunol.1900310DOI Listing
January 2021

German guidelines on the diagnosis and treatment of neurosyphilis.

Neurol Res Pract 2020 17;2:33. Epub 2020 Nov 17.

Department of Neurology, Klinikum Klagenfurt, Feschnigstraße 11, 9020 Klagenfurt am Wörthsee, Austria.

Introduction: In view of the importance of neurosyphilis and the difficulties encountered in diagnosing it, the S1 guideline "Neurosyphilis" has been published by the German Society for Neurology (DGN) in accordance with the stipulations of the Association of the Scientific Medical Societies in Germany (AWMF). The present article is an abridged translation of that German guideline.

Main Recommendations: (a) Neurosyphilis can manifest as early neurosyphilis (meningitis, meningovascular neurosyphilis or syphilitic gummas) or late neurosyphilis (tabes dorsalis, general paresis). (b) The following diagnostic criteria help to establish the presence of probable neurosyphilis (always point iv, accompanied by any two of points i to iii): (i) subacute or chronic neuro-psychiatric symptoms; (ii) increased cerebrospinal fluid (CSF) cell count or signs of blood-CSF barrier disruption; (iii) positive effect of anti-neurosyphilis antibiotic therapy on clinical course and CSF findings; (iv) positive TPHA/TPPA or FTA test in serum. (c) The diagnosis of neurosyphilis is confirmed by the subsequent detection of intrathecal production of antibodies against . (d) In neurosyphilis, treatment with intravenous penicillin or ceftriaxone for 14 days is recommended. (e) The following parameters can be used to assess a therapeutic effect: clinical findings, serum VDRL, and CSF cell count.

Conclusion: The German guideline on the diagnosis and treatment of neurosyphilis is a practical tool to support clinicians in diagnosing and treating patients with neurosyphilis. This article is an abridged translation of this guideline (Klein MW, J.; Angstwurm, K.; Esser, S.; Hahn, K.; Matschke, M.; Scheithauer, S.; Schoefer, H.; Sturzenegger, M.; Wildemann, B. Neurosyphilis, S1-Leitlinie. Deutsche Gesellschaft für Neurologie, Leitlinien für Diagnostik und Thearpie in der Neurologie 2020).
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http://dx.doi.org/10.1186/s42466-020-00081-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669305PMC
November 2020

Specific Management of Patients with Acute Abdomen during the COVID-19 Pandemic: A Surgical Perspective from Germany.

Visc Med 2020 Oct 11;36(5):417-420. Epub 2020 Jun 11.

Department of General, Visceral, and Transplant Surgery, Hospital of the Ludwig Maximilian University of Munich, Munich, Germany.

During the current COVID-19 pandemic, the triage, assessment, and management of patients presenting to the emergency department with critical conditions has become -challenging. The clinical features of COVID-19 are heterogeneous and subtle in many cases. They may easily be overlooked in the case of other acute diseases. Gastrointestinal symptoms are common in patients with COVID-19 as SARS-CoV-2 is able to enter gastrointestinal epithelial cells. However, these complaints can also be caused by a COVID-19-independent concomitant abdominal pathology. Therefore, patients with acute abdominal pain and fever need to be assessed very thoroughly. Based on a clinical case, we present our approach of managing emergency patients with acute abdomen and concomitant suspicion of -COVID-19.
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http://dx.doi.org/10.1159/000509122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360493PMC
October 2020

[Psychosocial support during the COVID-19 pandemic: interdisciplinary concept of care at a university hospital].

Nervenarzt 2020 Oct 6. Epub 2020 Oct 6.

Klinik für Psychiatrie und Psychotherapie, LMU Klinikum, Nußbaumstraße 7, 80336, München, Deutschland.

Background: Since the beginning of the outbreak, the COVID-19 pandemic has caused an increased demand for psychosocial support for patients, their family members, and healthcare workers. Concurrently, possibilities to provide this support have been hindered. Quarantine, social isolation, and SARS-CoV‑2 infections represent new and severe stressors that have to be addressed with innovative psychosocial care.

Objective And Method: This article describes the COVID-19 psychosocial first aid concept at the University Hospital Munich (LMU Klinikum) developed by an interdisciplinary team of psychiatric, psychological, spiritual care, psycho-oncological, and palliative care specialists.

Results: A new psychosocial first aid model has been implemented for COVID-19 inpatients, family members, and hospital staff consisting of five elements.

Conclusion: The concept integrates innovative and sustainable ideas, e.g. telemedicine-based approaches and highlights the importance of multidisciplinary collaboration to cope with challenges in the healthcare system.
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http://dx.doi.org/10.1007/s00115-020-01014-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538057PMC
October 2020

Lack of NFATc1 SUMOylation prevents autoimmunity and alloreactivity.

J Exp Med 2021 Jan;218(1)

Institute of Pathology, University of Wuerzburg, Wuerzburg, Germany.

Posttranslational modification with SUMO is known to regulate the activity of transcription factors, but how SUMOylation of individual proteins might influence immunity is largely unexplored. The NFAT transcription factors play an essential role in antigen receptor-mediated gene regulation. SUMOylation of NFATc1 represses IL-2 in vitro, but its role in T cell-mediated immune responses in vivo is unclear. To this end, we generated a novel transgenic mouse in which SUMO modification of NFATc1 is prevented. Avoidance of NFATc1 SUMOylation ameliorated experimental autoimmune encephalomyelitis as well as graft-versus-host disease. Elevated IL-2 production in T cells promoted T reg expansion and suppressed autoreactive or alloreactive immune responses. Mechanistically, increased IL-2 secretion counteracted IL-17 and IFN-γ expression through STAT5 and Blimp-1 induction. Then, Blimp-1 repressed IL-2 itself, as well as the induced, proliferation-associated survival factor Bcl2A1. Collectively, these data demonstrate that prevention of NFATc1 SUMOylation fine-tunes T cell responses toward lasting tolerance. Thus, targeting NFATc1 SUMOylation presents a novel and promising strategy to treat T cell-mediated inflammatory diseases.
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http://dx.doi.org/10.1084/jem.20181853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953626PMC
January 2021

Specialized regulatory T cells control venous blood clot resolution through SPARC.

Blood 2021 Mar;137(11):1517-1526

Department of Dermatology.

The cells and mechanisms involved in blood clot resorption are only partially known. We show that regulatory T cells (Tregs) accumulate in venous blood clots and regulate thrombolysis by controlling the recruitment, differentiation and matrix metalloproteinase (MMP) activity of monocytes. We describe a clot Treg population that forms the matricellular acid- and cysteine-rich protein SPARC (secreted protein acidic and rich in cysteine) and show that SPARC enhances monocyte MMP activity and that SPARC+ Tregs are crucial for blood clot resorption. By comparing different treatment times, we define a therapeutic window of Treg expansion that accelerates clot resorption.
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http://dx.doi.org/10.1182/blood.2020005407DOI Listing
March 2021

Diagnostic potential of circulating cell-free microRNAs for community-acquired pneumonia and pneumonia-related sepsis.

J Cell Mol Med 2020 10 11;24(20):12054-12064. Epub 2020 Sep 11.

Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany.

Cell-free microRNAs (miRNAs) are transferred in disease state including inflammatory lung diseases and are often packed into extracellular vesicles (EVs). To assess their suitability as biomarkers for community-acquired pneumonia (CAP) and severe secondary complications such as sepsis, we studied patients with CAP (n = 30), sepsis (n = 65) and healthy volunteers (n = 47) subdivided into a training (n = 67) and a validation (n = 75) cohort. After precipitating crude EVs from sera, associated small RNA was profiled by next-generation sequencing (NGS) and evaluated in multivariate analyses. A subset of the thereby identified biomarker candidates was validated both technically and additionally by reverse transcription quantitative real-time PCR (RT-qPCR). Differential gene expression (DGE) analysis revealed 29 differentially expressed miRNAs in CAP patients when compared to volunteers, and 25 miRNAs in patients with CAP, compared to those with sepsis. Sparse partial-least discriminant analysis separated groups based on 12 miRNAs. Three miRNAs proved as a significant biomarker signature. While expression levels of miR-1246 showed significant changes with an increase in overall disease severity from volunteers to CAP and to sepsis, miR-193a-5p and miR-542-3p differentiated patients with an infectious disease (CAP or sepsis) from volunteers. Cell-free miRNAs are potentially novel biomarkers for CAP and may help to identify patients at risk for progress to sepsis, facilitating early intervention and treatment.
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http://dx.doi.org/10.1111/jcmm.15837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578906PMC
October 2020

Medical Emergencies During the COVID-19 Pandemic.

Dtsch Arztebl Int 2020 08;117(33-34):545-552

Departments of Emergency and Acute Medicine, Campus Mitte and Virchow-Klinikum Charité-Universitätsmedizin Berlin

Background: In this study, we investigate the number of emergency room consultations during the COVID-19 pandemic of 2020 in Germany compared to figures from the previous year.

Methods: Case numbers from calendar weeks 1 through 22 of the two consecutive years 2019 and 2020 were obtained from 29 university hospitals and 7 non-university hospitals in Germany. Information was also obtained on the patients' age, sex, and urgency, along with the type of case (outpatient/inpatient), admitting ward, and a small number of tracer diagnoses (I21, myocardial infarction; J44, COPD; and I61, I63, I64, G45, stroke /TIA), as well as on the number of COVID-19 cases and of tests performed for SARS-CoV-2, as a measure of the number of cases in which COVID-19 was suspected or at least included in the differential diagnoses.

Results: A total of 1 022 007 emergency room consultations were analyzed, of which 546 940 took place in 2019 and 475 067 in 2020. The number of consultations with a positive test for the COVID-19 pathogen was 3122. The total number of emergency room consultations in the observation period was 13% lower in 2020 than in 2019, with a maximum drop by 38% coinciding with the highest number of COVID-19 cases (calendar week 14; 572 cases). After the initiation of interpersonal contact restrictions in 2020, there was a marked drop in COVID-19 case numbers, by a mean of -240 cases per week per emergency room (95% confidence interval [-284; -128]). There was a rise in case numbers thereafter, by a mean of 17 patients per week [14; 19], and the number of cases of myocardial infarction returned fully to the level seen in 2019.

Conclusion: In Germany, the COVID-19 pandemic led to a significant drop in medical emergencies of all kinds presenting to the nation's emergency departments. A recovery effect began to be seen as early as calendar week 15, but the levels seen in 2019 were not yet reached overall by calendar week 22; only the prevalence of myocardial infarction had renormalized by then. The reasons for this require further investigation.
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http://dx.doi.org/10.3238/arztebl.2020.0545DOI Listing
August 2020

Basic life support knowledge in Germany and the influences of demographic factors.

PLoS One 2020 20;15(8):e0237751. Epub 2020 Aug 20.

Clinic of Plastic, Reconstructive, Hand and Burn Surgery, Hospital Cologne Merheim, University of Witten-Herdecke, Witten, Germany.

Background: In the developed world, cardiovascular diseases still contribute to mortality and morbidity, leading to significantly increased deaths in recent years. Thus, it is necessary for a layperson to provide the best possible basic life support (BLS) until professional help is available. Since information on current BLS knowledge in Germany is not available, but necessary to be able to make targeted improvements in BLS education, we conducted this study.

Methods: A cohort survey using convenience sampling (non-probability) method was conducted with questions found in emergency medicine education. People coming to the emergency room of two big university hospitals located in the South (Munich) and western part (Cologne) of Germany were asked to participate in the survey between 2016 and 2017. Primary outcome measures were the proportion of correct answers for each emergency scenario in relationship to age, region, profession and first-aid training.

Results: Altogether 1003 people (504 from Cologne; 499 from Munich) took part in the questionnaire. 54.7% were female and 45.3% were male aging from 19 to 52 with a mean of 37.2 years. Although over 90% had taken part in first aid training, many people were lacking first aid knowledge, with less than 10% choosing the correct frequency for chest compression. Hereby demographic factors had a significant influence (p<0.05) in the given answers (Friedmann-and-Wilcoxon Test).

Conclusion: Overall, results of our survey indicate a clear lack of BLS knowledge. With this information, targeted measures for improving BLS knowledge should be conducted. Additionally, further studies on the feasibility and efficiency of teaching methods are needed.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237751PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446818PMC
October 2020

Circulating Metabolites Differentiate Acute Ischemic Stroke from Stroke Mimics.

Ann Neurol 2020 10 29;88(4):736-746. Epub 2020 Aug 29.

Institute for Stroke and Dementia Research, University Hospital, LMU Munich, Munich, Germany.

Objective: Early discrimination of patients with ischemic stroke (IS) from stroke mimics (SMs) poses a diagnostic challenge. The circulating metabolome might reflect pathophysiological events related to acute IS. Here, we investigated the utility of early metabolic changes for differentiating IS from SM.

Methods: We performed untargeted metabolomics on serum samples obtained from patients with IS (N = 508) and SM (N = 349; defined by absence of a diffusion weighted imaging [DWI] positive lesion on magnetic resonance imaging [MRI]) who presented to the hospital within 24 hours after symptom onset (median time from symptom onset to blood sampling = 3.3 hours; interquartile range [IQR] = 1.6-6.7 hours) and from neurologically normal controls (NCs; N = 112). We compared diagnostic groups in a discovery-validation approach by applying multivariable linear regression models, machine learning techniques, and propensity score matching. We further performed a targeted look-up of published metabolite sets.

Results: Levels of 41 metabolites were significantly associated with IS compared to NCs. The top metabolites showing the highest value in separating IS from SMs were asymmetrical and symmetrical dimethylarginine, pregnenolone sulfate, and adenosine. Together, these 4 metabolites differentiated patients with IS from SMs with an area under the curve (AUC) of 0.90 in the replication sample, which was superior to multimodal cranial computed tomography (CT; AUC = 0.80) obtained for routine diagnostics. They were further superior to previously published metabolite sets detected in our samples. All 4 metabolites returned to control levels by day 90.

Interpretation: A set of 4 metabolites with known biological effects relevant to stroke pathophysiology shows unprecedented utility to identify patients with IS upon hospital arrival, thus encouraging further investigation, including multicenter studies. ANN NEUROL 2020;88:736-746.
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http://dx.doi.org/10.1002/ana.25859DOI Listing
October 2020

Interleukin-1 promotes autoimmune neuroinflammation by suppressing endothelial heme oxygenase-1 at the blood-brain barrier.

Acta Neuropathol 2020 10 11;140(4):549-567. Epub 2020 Jul 11.

Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.

The proinflammatory cytokine interleukin 1 (IL-1) is crucially involved in the pathogenesis of multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Herein, we studied the role of IL-1 signaling in blood-brain barrier (BBB) endothelial cells (ECs), astrocytes and microglia for EAE development, using mice with the conditional deletion of its signaling receptor IL-1R1. We found that IL-1 signaling in microglia and astrocytes is redundant for the development of EAE, whereas the IL-1R1 deletion in BBB-ECs markedly ameliorated disease severity. IL-1 signaling in BBB-ECs upregulated the expression of the adhesion molecules Vcam-1, Icam-1 and the chemokine receptor Darc, all of which have been previously shown to promote CNS-specific inflammation. In contrast, IL-1R1 signaling suppressed the expression of the stress-responsive heme catabolizing enzyme heme oxygenase-1 (HO-1) in BBB-ECs, promoting disease progression via a mechanism associated with deregulated expression of the IL-1-responsive genes Vcam1, Icam1 and Ackr1 (Darc). Mechanistically, our data emphasize a functional crosstalk of BBB-EC IL-1 signaling and HO-1, controlling the transcription of downstream proinflammatory genes promoting the pathogenesis of autoimmune neuroinflammation.
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http://dx.doi.org/10.1007/s00401-020-02187-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498485PMC
October 2020

The potential for CXCL13 in CSF as a differential diagnostic tool in central nervous system infection.

Expert Rev Anti Infect Ther 2020 09 1;18(9):875-885. Epub 2020 Jun 1.

Department of Neurology, University Hospital, Ludwig Maximilian University , Munich, Germany.

: Central nervous system (CNS) infections can be life-threatening and are often associated with disabling sequelae. One important factor in most CNS infections is a timely pathogen-specific treatment. The diagnostic methods available, however, do not always reach a satisfying sensitivity and specificity. In these cases, there is need for additional diagnostic biomarkers. Chemokines represent potential candidates as biomarkers, since they are an important pillar of the host immune response. The aim of this review is to discuss the diagnostic potential of cerebrospinal fluid (CSF) CXCL13 in patients with CNS infections. : Data were obtained from a literature search in PubMed up to October 2019. This review focusses on articles on the potential of CXCL13 as a diagnostic tool. The majority of identified studies aimed to characterize its role in two diseases, namely Lyme neuroborreliosis and neurosyphilis. : CSF CXCL13 has a significant potential as a diagnostic and monitoring add-on marker in Lyme neuroborreliosis. Differences in study design, control groups and clinical parameters between studies, however, affect sensitivity, specificity and cutoff values, underlining the need of further studies to address these issues and pave the way for a generalized clinical practice.
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http://dx.doi.org/10.1080/14787210.2020.1770596DOI Listing
September 2020

Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19.

J Allergy Clin Immunol 2020 Jul 18;146(1):128-136.e4. Epub 2020 May 18.

Emergency Department, University Hospital, LMU Munich, Munich, Germany; Department of Medicine I, University Hospital, LMU Munich, Munich, Germany; German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.

Background: Coronavirus disease 2019 (COVID-19) can manifest as a viral-induced hyperinflammation with multiorgan involvement. Such patients often experience rapid deterioration and need for mechanical ventilation. Currently, no prospectively validated biomarker of impending respiratory failure is available.

Objective: We aimed to identify and prospectively validate biomarkers that allow the identification of patients in need of impending mechanical ventilation.

Methods: Patients with COVID-19 who were hospitalized from February 29 to April 9, 2020, were analyzed for baseline clinical and laboratory findings at admission and during the disease. Data from 89 evaluable patients were available for the purpose of analysis comprising an initial evaluation cohort (n = 40) followed by a temporally separated validation cohort (n = 49).

Results: We identified markers of inflammation, lactate dehydrogenase, and creatinine as the variables most predictive of respiratory failure in the evaluation cohort. Maximal IL-6 level before intubation showed the strongest association with the need for mechanical ventilation, followed by maximal CRP level. The respective AUC values for IL-6 and CRP levels in the evaluation cohort were 0.97 and 0.86, and they were similar in the validation cohort (0.90 and 0.83, respectively). The calculated optimal cutoff values during the course of disease from the evaluation cohort (IL-6 level > 80 pg/mL and CRP level > 97 mg/L) both correctly classified 80% of patients in the validation cohort regarding their risk of respiratory failure.

Conclusion: The maximal level of IL-6, followed by CRP level, was highly predictive of the need for mechanical ventilation. This suggests the possibility of using IL-6 or CRP level to guide escalation of treatment in patients with COVID-19-related hyperinflammatory syndrome.
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http://dx.doi.org/10.1016/j.jaci.2020.05.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233239PMC
July 2020

Microbiota-Induced Type I Interferons Instruct a Poised Basal State of Dendritic Cells.

Cell 2020 05 6;181(5):1080-1096.e19. Epub 2020 May 6.

Institute of Immunology, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany; Research Centre for Immunotherapy, University Medical Center Mainz, Langenbeckstraße 1, 55131 Mainz, Germany. Electronic address:

Environmental signals shape host physiology and fitness. Microbiota-derived cues are required to program conventional dendritic cells (cDCs) during the steady state so that they can promptly respond and initiate adaptive immune responses when encountering pathogens. However, the molecular underpinnings of microbiota-guided instructive programs are not well understood. Here, we report that the indigenous microbiota controls constitutive production of type I interferons (IFN-I) by plasmacytoid DCs. Using genome-wide analysis of transcriptional and epigenetic regulomes of cDCs from germ-free and IFN-I receptor (IFNAR)-deficient mice, we found that tonic IFNAR signaling instructs a specific epigenomic and metabolic basal state that poises cDCs for future pathogen combat. However, such beneficial biological function comes with a trade-off. Instructed cDCs can prime T cell responses against harmless peripheral antigens when removing roadblocks of peripheral tolerance. Our data provide fresh insights into the evolutionary trade-offs that come with successful adaptation of vertebrates to their microbial environment.
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http://dx.doi.org/10.1016/j.cell.2020.04.022DOI Listing
May 2020

ERK3/MAPK6 controls IL-8 production and chemotaxis.

Elife 2020 04 21;9. Epub 2020 Apr 21.

Cell Biology Unit, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.

ERK3 is a ubiquitously expressed member of the atypical mitogen activated protein kinases (MAPKs) and the physiological significance of its short half-life remains unclear. By employing gastrointestinal 3D organoids, we detect that ERK3 protein levels steadily decrease during epithelial differentiation. ERK3 is not required for 3D growth of human gastric epithelium. However, ERK3 is stabilized and activated in tumorigenic cells, but deteriorates over time in primary cells in response to lipopolysaccharide (LPS). ERK3 is necessary for production of several cellular factors including interleukin-8 (IL-8), in both, normal and tumorigenic cells. Particularly, ERK3 is critical for AP-1 signaling through its interaction and regulation of c-Jun protein. The secretome of ERK3-deficient cells is defective in chemotaxis of neutrophils and monocytes both in vitro and in vivo. Further, knockdown of ERK3 reduces metastatic potential of invasive breast cancer cells. We unveil an ERK3-mediated regulation of IL-8 and epithelial secretome for chemotaxis.
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http://dx.doi.org/10.7554/eLife.52511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7192585PMC
April 2020

Burn first aid knowledge in Germany and the influences of social-economic factors.

Burns 2020 09 16;46(6):1458-1465. Epub 2020 Apr 16.

Clinic of Plastic, Reconstructive, Hand and Burn Surgery, Hospital Cologne Merheim, University of Witten-Herdecke, Germany.

Background: Optimal management of burns always starts with the first aid. Results of numerous studies carried out in different countries indicated in general a low awareness of first aid of burns irrespective of whether the income of the country was high, middle or low. The aim of the study was to investigate the knowledge in burn first aid in Germany and compare it to an Australian study from 2013.

Methods: From January 2016 until August 2017 patients, visitors and medical personnel in the emergency room of two large hospitals in Southern and the Western part of Germany were asked to take part in a paper based multiple-choice survey.

Results: Altogether 1229 people took part in the questionnaire, 588 from Bavaria and 641 from North Rhine-Westphalia; 45,2% males and 54.8% females. Their age ranged from 19 to 52 with a mean of 37.2 years. Hereby participants that had taken part in first aid training and people working in health care had significant more correct answers. Overall, only approximately a third of the given answers were correct.

Conclusion: Our study suggests that there is room for improvement since only a minority of the German population is familiar with first aid principles dealing with burns. Although more than 40% had taken part in a first aid training, the questioned people gave less correct answers than the Australians in 2013.
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http://dx.doi.org/10.1016/j.burns.2020.03.006DOI Listing
September 2020

Species Identification and Antibiotic Resistance Prediction by Analysis of Whole-Genome Sequence Data by Use of ARESdb: an Analysis of Isolates from the Unyvero Lower Respiratory Tract Infection Trial.

J Clin Microbiol 2020 06 24;58(7). Epub 2020 Jun 24.

Ares Genetics GmbH, Vienna, Austria

Whole-genome sequencing (WGS) is now routinely performed in clinical microbiology laboratories to assess isolate relatedness. With appropriately developed analytics, the same data can be used for prediction of antimicrobial susceptibility. We assessed WGS data for identification using open-source tools and antibiotic susceptibility testing (AST) prediction using ARESdb compared to matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) identification and broth microdilution phenotypic susceptibility testing on clinical isolates from a multicenter clinical trial of the FDA-cleared Unyvero lower respiratory tract infection (LRTI) application (Curetis). For the trial, more than 2,000 patient samples were collected from intensive care units across nine hospitals and tested for LRTI. The isolate subset used in this study included 620 clinical isolates originating from 455 LRTI culture-positive patient samples. Isolates were sequenced using the Illumina Nextera XT protocol and FASTQ files with raw reads uploaded to the ARESdb cloud platform (ares-genetics.cloud; released for research use in 2020). The platform combines Ares Genetics' proprietary database ARESdb with state-of-the-art bioinformatics tools and curated public data. For identification, WGS showed 99 and 93% concordance with MALDI-TOF MS at the genus and species levels, respectively. WGS-predicted susceptibility showed 89% categorical agreement with phenotypic susceptibility across a total of 129 species-compound pairs analyzed, with categorical agreement exceeding 90% in 78 species-compound pairs and reaching 100% in 32. Results of this study add to the growing body of literature showing that, with improvement of analytics, WGS data could be used to predict antimicrobial susceptibility.
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http://dx.doi.org/10.1128/JCM.00273-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315026PMC
June 2020

[Herpes simplex virus enzephalitis].

MMW Fortschr Med 2020 02;162(3):37-40

Neurologische Klinik und Poliklinik Klinikum Großhadern, Ludwig-Maximilians-Universität, Marchioninistr. 15, D-81377, München, Deutschland.

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http://dx.doi.org/10.1007/s15006-020-0158-8DOI Listing
February 2020

Oscillometric versus invasive blood pressure measurement in patients with shock: a prospective observational study in the emergency department.

J Clin Monit Comput 2021 Apr 13;35(2):387-393. Epub 2020 Feb 13.

Department of Anaesthesiology, University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany.

In emergency medicine, blood pressure is often measured by an oscillometric device using an upper arm cuff. However, measurement accuracy of this technique in patients suffering from hypotensive shock has not been sufficiently evaluated. We designed a prospective observational study investigating the accuracy of an oscillometric device in hypotensive patients admitted to the resuscitation area of the emergency department. Patients admitted to the resuscitation area of a university hospital, who were equipped with an arterial catheter and found to be hypotensive (mean arterial pressure (MAP) < 60 mmHg) were eligible for the study. Blood pressure was measured simultaneously via upper arm cuff and invasively under routine clinical conditions. After data extraction, Bland-Altman analysis, correlation coefficient and percentage error of mean and systolic blood pressure pairs were performed. We analysed 75 simultaneously obtained blood pressure measurements of 30 patients in hypotension, 11 (37%) were female, median age was 76.5 years (IQR 63-82). Oscillometric MAP was markedly higher than invasive MAP with a mean of the differences of 13 ± 15 mmHg (oscillometric-invasive), 95% limits of agreement - 16 to 41 mmHg, percentage error was 76%. In 64% of readings, values obtained by the upper arm cuff were not able to detect hypotension. Oscillometric blood pressure measurement is not able to reliably detect hypotension in emergency patients. Therefore, direct measurement of blood pressure should be established as soon as possible in patients suffering from shock.
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http://dx.doi.org/10.1007/s10877-020-00482-2DOI Listing
April 2021

Microglial A20 Protects the Brain from CD8 T-Cell-Mediated Immunopathology.

Cell Rep 2020 02;30(5):1585-1597.e6

Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University of Mainz, 55131 Mainz, Germany. Electronic address:

Tumor-necrosis-factor-alpha-induced protein 3 (TNFAIP3), or A20, is a ubiquitin-modifying protein and negative regulator of canonical nuclear factor κB (NF-κB) signaling. Several single-nucleotide polymorphisms in TNFAIP3 are associated with autoimmune diseases, suggesting a role in tissue inflammation. While the role of A20 in peripheral immune cells has been well investigated, less is known about its role in the central nervous system (CNS). Here, we show that microglial A20 is crucial for maintaining brain homeostasis. Without microglial A20, CD8 T cells spontaneously infiltrate the CNS and acquire a viral response signature. The combination of infiltrating CD8 T cells and activated A20-deficient microglia leads to an increase in VGLUT1 terminals and frequency of spontaneous excitatory currents. Ultimately, A20-deficient microglia upregulate genes associated with the antiviral response and neurodegenerative diseases. Together, our data suggest that microglial A20 acts as a sensor for viral infection and a master regulator of CNS homeostasis.
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http://dx.doi.org/10.1016/j.celrep.2019.12.097DOI Listing
February 2020

[Update on important CNS infections].

Dtsch Med Wochenschr 2020 02 4;145(3):155-160. Epub 2020 Feb 4.

Neurologische Klinik und Poliklinik, Klinikum der Ludwig-Maximilians-Universität München.

Infections of the central nervous system (CNS) are a diagnostic and therapeutic challenge in daily clinical practice. In most cases, an early and efficient empiric therapy is crucial for the prognosis. Here, an update on current developments concerning the following CNS infections is presented:- Herpes simplex virus (HSV) encephalitis,- bacterial meningitis,- tick borne encephalitis,- neuroborreliosis.
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http://dx.doi.org/10.1055/a-0968-1063DOI Listing
February 2020