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Formation of pathological anti-FVIII antibodies, or “inhibitors,” is the most serious complication of therapeutic FVIII infusions, affecting up to 1/3 of severe Hemophilia A (HA) patients. Inhibitor formation is a classical T-cell dependent adaptive immune response. As such, it requires help from the innate immune system. However, the roles of innate immune cells and mechanisms of inhibitor development vs. immune tolerance, achieved with or without Immune Tolerance Induction (ITI) therapy, are not well-understood. To address these questions, temporal transcriptomics profiling of FVIII-stimulated peripheral blood mononuclear cells (PBMCs) was carried out for HA subjects with and without a current or historic inhibitor using RNA-Seq. PBMCs were isolated from 40 subjects in the following groups: HA with an inhibitor that resolved either following ITI or spontaneously; HA with a current inhibitor; HA with no inhibitor history and non-HA controls. PBMCs were stimulated with 5 nM FVIII and RNA was isolated 4, 16, 24, and 48 h following stimulation. Time-series differential expression analysis was performed and distinct transcriptional signatures were identified for each group, providing clues as to cellular mechanisms leading to or accompanying their disparate anti-FVIII antibody responses. Subjects with a current inhibitor showed differential expression of 56 genes and a clustering analysis identified three major temporal profiles. Interestingly, gene ontology enrichments featured innate immune modulators, including NLRP3, TLR8, IL32, CLEC10A, and COLEC12. NLRP3 and TLR8 are associated with enhanced secretion of the pro-inflammatory cytokines IL-1β and TNFα, while IL32, which has several isoforms, has been associated with both inflammatory and regulatory immune processes. RNA-Seq results were validated by RT-qPCR, ELISAs, multiplex cytokine analysis, and flow cytometry. The inflammatory status of HA patients suffering from an ongoing inhibitor includes up-regulated innate immune modulators, which may act as ongoing danger signals that influence the responses to, and eventual outcomes of, ITI therapy.
Angesichts des kürzlich von der Bundesregierung verabschiedeten Konjunkturpakets, stellen sich die Autoren des Policy Letters die Frage, ob und inwieweit die angekündigte Mehrwertsteuersenkung sowie der Kinderbonus zur substantiellen Ankurbelung des Binnenkonsums führt. Aus den für das Haushaltskrisenbarometer erhobenen Daten zu Einkommensänderungen sowie Einkommens- und Kündigungserwartungen, können die Ökonomen keine zu erwartende Schwächung der Binnennachfrage ableiten. Der überwiegende Teil der deutschen Wohnbevölkerung scheint kurzfristig nicht davon auszugehen, finanzielle Einbußen aufgrund der Pandemie zu erleiden. Die Erwartungen hinsichtlich der künftigen Einkommensentwicklung haben sich gar über die letzten vier Umfragewellen graduell verbessert. Ferner kann dargelegt werden, dass weder die Konsum- noch die Sparneigung durch die Corona-Krise zum gegenwärtigen Zeitpunkt langfristig stark beeinflusst wird. So geben derzeit lediglich 10 Prozent der Befragten an, größere Anschaffungen angesichts der Pandemie vollständig gestrichen zu haben. Anfang April 2020 lag dieser Wert noch bei 16 Prozent. Die Befragten berichteten in 71 Prozent der Fälle ihre Konsumpläne und in 78 Prozent der Fälle ihre Sparverhalten nicht geändert zu haben. Im Lichte dieser Ergebnisse lassen sich Maßnahmen, die auf eine unspezifische Stimulierung der Binnennachfrage abzielen, nicht substantiell begründen und rechtfertigen.
We study D and DS mesons at finite temperature using an effective field theory based on chiral and heavy-quark spin-flavor symmetries within the imaginary-time formalism. Interactions with the light degrees of freedom are unitarized via a Bethe-Salpeter approach, and the D and self-energies are calculated self-consistently. We generate dynamically the e D∗0(2300)and Ds(2317)state, and study their possible identification as the chiral We study Dand Dsmesons at finite temperature using an effective field theory based on chiral and heavy-quark spin-flavor symmetries within the imaginary-time formalism. Interactions with the light degrees of freedom are unitarized via a Bethe-Salpeter approach, and the Dand Dsself-energies are calculated self-consistently. We generate dynamically the D∗0(2300)and Ds(2317)states, and study their possible identification as the chiral partners of the Dand Dsground states, respectively. We show the evolution of their masses and decay widths as functions of temperature, and provide an analysis of the chiral-symmetry restoration in the heavy-flavor sector below the transition temperature. In particular, we analyse the very special case of the D-meson, for which the chiral partner is associated to the double-pole structure of the D∗0(2300).
The Masquelet technique for the treatment of large bone defects is a two-stage procedure based on an induced membrane. We eliminate the first surgical step by using a decellularized dermal skin graft (Epiflex®) populated with bone marrow mononuclear cells (BMC), as a replacement for the induced membrane. The aim of this study was to demonstrate the feasibility of this technology and provide evidence of equivalent bone healing in comparison to the induced membrane-technique. Therefore, 112 male Sprague–Dawley rats were allocated in six groups and received a 10 mm femoral defect. Defects were treated with either the induced membrane or decellularized dermis, with or without the addition of BMC. Defects were then filled with a scaffold (β-TCP), with or without BMC. After a healing time of eight weeks, femurs were taken for histological, radiological and biomechanical analysis. Defects treated with Epiflex® showed increased mineralization and bone formation predominantly in the transplanted dermis surrounding the defect. No significant decrease of biomechanical properties was found. Vascularization of the defect could be enhanced by addition of BMC. Considering the dramatic reduction of a patient’s burden by the reduced surgical stress and shortened time of treatment, this technique could have a great impact on clinical practice.
Reactive oxygen species (ROS) have been shown or at least suggested to play an essential role for cellular signaling as second messengers. NADPH oxidases represent a source of controlled ROS formation. Accordingly, understanding the role of individual NADPH oxidases bears potential to interfere with intracellular signaling cascades without disturbing the signaling itself. Many tools have been developed to study or inhibit the functions and roles of the NADPH oxidases. This short review summarizes diseases, potentially associated with NADPH oxidases, genetically modified animals, and inhibitors.
he Pauli Exclusion Principle (PEP) is one of the most basic concepts in physics, but also the most difficult to implement in many-fermion systems, which are common in nuclear physics. To investigate the consequences of ignoring the PEP, we discuss several algebraic models in nuclear structure physics, in particular cluster models. Sometimes they tend to ignore the Pauli Exclusion Principle for practical reasons, leading to flawed interpretations. Though at first sight there seems to be an agreement to experiment, often it is due to the limited number of states known experimentally. We discuss several models which include or not the PEP, illustrating through their differences the importance of the PEP. This contribution is also a review of recently published results.
First, we propose a scale-invariant modified gravity interacting with a neutral scalar inflaton and a Higgs-like SU(2)×U(1) iso-doublet scalar field based on the formalism of non-Riemannian (metric-independent) spacetime volume-elements. This model describes, in the physical Einstein frame, a quintessential inflationary scenario driven by the “inflaton” together with the gravity-“inflaton” assisted dynamical spontaneous SU(2)×U(1) symmetry breaking in the post-inflationary universe, whereas the SU(2)×U(1) symmetry remains intact in the inflationary epoch. Next, we find the explicit representation of the latter quintessential inflationary model with a dynamical Higgs effect as an Eddington-type purely affine gravity.
Suspected Blood Indicator (SBI) ist ein Modus in der RAPID® Reader 6 Software des Kapselendoskopie (KE) Systems, PillCam® SB2 (Given Imaging Ltd., seit 2015 Medtronic GmbH), welcher den Behandler bei der Auffindung potenzieller Dünndarmblutungen unterstützt. Ziel dieser Arbeit ist es, die Sensitivität sowie die Spezifität des SBI-Modus der zweiten Kapselgeneration (PillCam® SB2) zu evaluieren.
Es handelt sich um eine retrospektive Studie, bei der KE-Aufnahmen von insgesamt 199 Patienten, die sich in der Zeit von Juni 2008 bis März 2013 in der Universitätsklinik Frankfurt einer KE-Untersuchung unterzogen hatten, beurteilt wurden. Die Aufnahmen wurden von erfahrenen Behandlern konventionell durchgesehen und auf blutende sowie potenziell blutende Läsionen untersucht. Gleichzeitig wurden die SBI-Markierungen in diesen Aufnahmen von einem unabhängigen Mitarbeiter gezählt und die Ergebnisse den Befunden und Diagnosen der erfahrenen Behandler gegenüberge-stellt.
Das Patientenkollektiv bestand aus 64 weiblichen und 135 männlichen Patienten (mitt-leres Alter 59 Jahre, Spannweite 12–91 Jahre). Die häufigsten Indikationen zur KE-Untersuchung waren in 97/199 Fällen eine mittlere gastrointestinale Blutung und in 50/199 Fällen eine Eisenmangelanämie. In 157/199 Fällen hatten die erfahrenen Be-handler keine Blutung feststellen können. In 137/199 Aufnahmen setzte SBI jedoch mindestens eine Markierung (durchschnittlich 18,4 Markierungen pro Aufnahme) und in 20/199 Aufnahmen gab es keine Markierung. In 13/199 Untersuchungen stellten die Behandler wenig Blut fest, SBI fand hier ebenfalls Blut und setzte durchschnittlich 36,1 Markierungen. In 29 Aufnahmen wurde von dem Behandler viel Blut festgestellt, mit durchschnittlich 46,7 Markierungen pro Aufnahme. SBI setzte Markierungen in insge-samt 179 Aufnahmen, nur in 42 davon hatten auch die erfahrenen Behandler Blutun-gen festgestellt. Alle aktiven Blutungen wurden von SBI erkannt mit einer Sensitivität von 100 % und einer Spezifität von 13 %. Bei der ROC-Analyse wurde der optimale Grenzwert für die Bestimmung einer aktiven Blutung bei 51 SBI-Markierungen (viel Blut) und bei 31 SBI-Markierungen für kleinere Läsionen (wenig Blut) festgesetzt.
Zusammenfassend kann man sagen, dass der SBI-Modus eine hervorragende Hilfe zum Ausschluss einer aktiven Blutung ist. Die hohe Sensitivität Blutungen zu erkennen, kann im Klinikalltag von weniger geübten Mitarbeitern dazu genutzt werden, Patienten oh-ne aktive Blutung schneller zu erkennen und dadurch früher entlassen zu können. Für das Auffinden aktiver Blutungsquellen oder anderer Läsionen sowie für eine genaue Diagnosestellung ist jedoch eine Inspektion der Aufnahme durch einen erfahrenen Behandler weiterhin unabdingbar.
Derzeit breiten sich gebietsfremde Stechmücken (Diptera: Culicidae) aufgrund von Globalisierung und Klimawandel auf der ganzen Welt aus und bilden neue, stabile Populationen. Wegen ihrer hämatophagen Ernährungsweise sind sie Überträger von Pathogenen, die teilweise schwere bis tödliche Krankheiten beim Menschen, seinen Haustieren oder auch Wildtieren auslösen können. Mit den Stechmücken treten daher auch Infektionskrankheiten vermehrt in Gebieten auf, in denen sie vorher nicht vorkamen oder als bereits ausgerottet galten. Da die meisten im Menschen wirksamen Pathogene nicht durch Impfungen kontrolliert werden können, bleibt als eine der wenigen Möglichkeit der Krankheitsprävention die Dezimierung der Stechmückenpopulation. Daher sind Stechmücken momentan im Fokus von biologischer und epidemiologischer Forschung. Diese hat zum Ziel epidemische Krankheitsausbrüche vektorübertragener Krankheiten in der menschlichen Population zu verhindern. Eine Verringerung der lokalen Stechmückenpopulation bis hin zum Aussterben kann durch die Verwendung von Insektiziden, die Vernichtung von Bruthabitaten oder anderen Kontrollmaßnahmen erreicht werden. Jedoch sind diese Maßnahmen unterschiedlich effektiv, haben zum Teil unerwünsch-te ökologische und gesundheitsschädigende Folgen und sind unterschiedlich aufwendig und kostenintensiv in der Anwendung. Für die Entwicklung eines integrierten, effektiven, zielgerichteten und kostengünstigen Vektormanagements fehlen bislang jedoch die populationsbiologischen Grundlagen.
Ziel dieser Arbeit ist daher die Schaffung der Datengrundlage eines Integrierten Stechmückenmanagements für die Asiatische Buschmücke (Aedes japonicus japonicus THEOBALD 1901), die am weitesten verbreitete exotische Stechmücke in Deutschland. Schwerpunkte dafür wurden auf das zeitliche und räumliche Vorkommen, die Temperaturabhängigkeit des Lebenszyklus, sowie die Wirksamkeit von Kontrollmethoden gelegt.
Die Kenntnis der räumlichen Verbreitung und saisonalen Häufigkeit der Stechmücken ist notwendig, um befallene Standorte und Zeitpunkte des größten Populationszuwachses definieren zu können. Die Verbreitung und die Häufigkeit der endothermen Stechmücken sind stark von der Umgebungstemperatur abhängig, die beispielsweise deren Entwicklungsdauer und Sterblichkeit beeinflusst. Dabei entwickeln sich die verschiedenen Stadien (Ei, Larven, Puppe, Imago), die eine Stechmücke während ihres Lebens durchläuft, in Abhängigkeit von der Umgebungstemperatur unterschiedlich und haben jeweils andere Temperaturpräferenzen. Lebenszyklustabellen geben die Entwicklungsdauer und Mortalität pro Stadium in Abhängigkeit von der Temperatur an. Mit ihrer Hilfe können somit die räumlichen und zeitlichen Vorkommen und Häufigkeiten einer Stechmückenart berechnet werden. Dies ist insbesondere für Stechmücken in Gebieten mit jahreszeitlichen Temperaturveränderungen wichtig. Um Daten für eine solche Lebenszyklustabelle aufnehmen zu können, ist es notwendig Laborexperimente bei festgelegten Temperaturen durchzuführen. Die Voraussetzung dafür ist, dass die Stechmückenart im Labor optimale Bedingungen erhält, um ihren Lebenszyklus abschließen zu können. In dieser Arbeit wurde daher ein Laborprotokoll entwickelt, mithilfe dessen der Lebenszyklus der Asiatischen Buschmücke im Labor untersucht werden kann. Dazu wurden systematisch die Fütterung, die innerartliche Konkurrenz und das Wasservolumen des Brutge-fäßes für die aquatischen Stadien erprobt. Auf Basis dieses Protokolls wurden anschließend die Temperatureinflüsse auf die Entwicklung aller Stadien aufgenommen. Diese Daten dienten der Parametrisierung eines populationsdynamischen Modells. Dieses wurde verwendet, um Standorte mehrjähriger Populationen zu definieren, saisonale Häufigkeiten für Deutschland zu berechnen, durch Temperaturveränderungen hervorgerufene zukünftige Verbreitungsgebiete vorherzusagen, sowie Effekte von Kontrollmaßnahmen auf die Häufigkeit der Asiatischen Buschmücke zu modellieren.
Um eine dauerhafte Kontrolle der Stechmückenvektoren zu gewährleisten, ist weiterhin die permanente Neuentwicklung von wirksamen Kontrollmethoden notwendig. Dazu gehört die präventive Vermeidung von Bruthabitaten der aquatischen Stadien von Stechmücken. Die exotischen Stechmücken, die in Deutschland etabliert sind, gehören mehrheitlich der Gattung Aedes an und sind sogenannte Gefäßbrüter. Ihre bevorzugten Bruthabitate sind kleine Was-seransammlungen wie sie in Baumhöhlen, Gesteinsauswaschungen, Gießkannen, Regentonnen und Blumenuntersetzern vorkommen. In dieser Arbeit wurde untersucht, welche Farben und Volumina von Plastikbechern die Asiatische Buschmücke zur Eiablage bevorzugt, um präferierte Bruthabitate gezielt zu identifizieren und verringern zu können. Auch die Bereitstellung von Insektiziden wird durch in Stechmücken auftretende Insektizidresistenzen erschwert. Insektizide sollen dabei umweltfreundlich, spezifisch für den Zielorganismus und nicht gesundheitsschädlich für den Menschen sein. Weiterhin sind eine gute Anwendbarkeit, geringe Kosten und eine hohe Effizienz wünschenswert. Eine Quelle für potentielle Insektizide sind pflanzliche Stoffe, zum Beispiel ätherische Öle. Diese sind leicht erhältlich, natürlichen Ursprungs und wirksame Vergrämungsmittel gegen stechbereite Stechmückenweibchen. In dieser Arbeit wurde nach einer Literaturrecherche Nelkenöl ausgewählt und als Insektizid gegen Larven der Asiatischen Buschmücke getestet. Dafür wurden die akute toxische Wirkung von Nelkenöl bei drei Temperaturen untersucht und zusätzlich die Wirkung von Nelkenöl auf die Eiablage im Freiland. Nelkenöl zeigte dabei sowohl eine larvizide als auch eine eiablagehemmende Wirkung. Weiterhin wurde Kupfer in Form von kupferhaltigen Euromünzen als Larvizid untersucht. Kupfer ist ein wirksamer Stoff gegen die aquatischen Stadien von Stechmücken. Allerdings wurde der Stoff noch nicht in Form der einfach zu handhabenden, leicht erhältlichen Kupfermünzen getestet. Dazu wurden Vorexperimente durchgeführt, um herauszufinden, wieviel Kupferionen sich aus den Münzen lösen lassen. Anschließend wurde der akut toxische Effekt auf Larven der Asiatischen Buschmücke untersucht.
Ein Integriertes Stechmückenmanagement hat zum Ziel, die lokale Stechmückenpopulation zu kontrollieren, um so Stichen und daraus resultierender Krankheitsübertragung vorzubeugen. Dies erfolgt über die Aufklärung von Betroffenen, der Überwachung der Stechmückenpopulation, dem Testen auf Pathogenbefall und der direkten Kontrolle von Stechmücken. Diese Arbeit leistet einen Beitrag zu den Kenntnissen über die Laborhaltung einer exotischen Stechmückenart, zur Identifizierung von Bruthabitaten, zur zeitlichen und räumlichen Festlegung von Kontrollmaßnahmen und zur Anwendung von Larviziden und eines Vergrämungsmittels. Mit dieser Arbeit wurde die Grundlage eines faktenbasierten Integrativen Stechmückenmanagements für die Asiatische Buschmücke entwickelt, das eventuell auch auf weitere Aedes-Arten übertragbar ist, und als Handlungsempfehlung für politische Entscheidungstragende dienen kann.
The widely varying therapeutic response of patients with inflammatory bowel disease (IBD) continues to raise questions regarding the unclarified heterogeneity of pathological mechanisms promoting disease progression. While biomarkers for the differentiation of Crohn’s disease (CD) versus ulcerative colitis (UC) have been suggested, specific markers for a CD subclassification in ileal CD versus colonic CD are still rare. Since an altered signature of the tryptophan metabolism is associated with chronic inflammatory disease, we sought to characterize potential biomarkers by focusing on the downstream enzymes and metabolites of kynurenine metabolism. Using immunohistochemical stainings, we analyzed and compared the mucosal tryptophan immune metabolism in bioptic samples from patients with active inflammation due to UC or CD versus healthy controls. Localization-specific quantification of immune cell infiltration, tryptophan-metabolizing enzyme expression and mucosal tryptophan downstream metabolite levels was performed. We found generally increased immune cell infiltrates in the tissue of all patients with IBD. However, in patients with CD, significant differences were found between regulatory T cell and neutrophil granulocyte infiltration in the ileum compared with the colon. Furthermore, we observed decreased kynurenine levels as well as strong kynureninase (KYNU) expression specifically in patients with ileal CD. Correspondingly, significantly elevated levels of the kynurenine metabolite 3-hydroxyanthranilic acid were detected in the ileal CD samples. Highlighting the heterogeneity of the different phenotypes of CD, we identified KYNU as a potential mucosal biomarker allowing the localization-specific differentiation of ileal CD versus colonic CD.
Current evidence indicates that acute aerobic exercise might increase domain-specific cognitive performance. However, only a small number of studies deduced the impact on lower and higher cognitive functions systematically or analyzed dose–response relationships and the underlying mechanisms. This study aimed to expose the dose–response relationships by investigating the influence of exercise duration on subjective and objective arousal, cognitive attention and visual recognition memory tasks. Nineteen participants (eight female; 25.69 ± 3.11 years) were included in a randomized, three-armed intervention study in a cross-over design. The participants completed three different interventions consisting of either 15, 30 or 45 min of cycling at 60–70% VO2max. Arousal and cognitive measurements were taken before and immediately after (<2 min) exercise. All three interventions led to significant but comparable effects on self-perceived arousal, heart rate (HR) and rating of perceived exertion (RPE) (p < 0.05). Analysis of variance (ANOVA) indicated significant effects of exercise duration on visual recognition memory accuracy. Reaction times for higher and lower cognitive tasks did not change after exercise. Fifteen minutes of aerobic exercise was feasible to induce beneficial changes in self-perceived arousal. Processing speed of visual recognition memory and attention remained unaltered. Exercise exceeding fifteen minutes seemed to negatively impact visual recognition memory accuracy.
Macrophages facilitate essential homeostatic functions e.g., endocytosis, phagocytosis, and signaling during inflammation, and express a variety of scavenger receptors including CD163 and CD206, which are upregulated in response to inflammation. In healthy individuals, soluble forms of CD163 and CD206 are constitutively shed from macrophages, however, during inflammation pathogen- and damage-associated stimuli induce this shedding. Activation of resident liver macrophages viz. Kupffer cells is part of the inflammatory cascade occurring in acute and chronic liver diseases. We here review the existing literature on sCD163 and sCD206 function and shedding, and potential as biomarkers in acute and chronic liver diseases with a particular focus on Acute-on-Chronic Liver Failure (ACLF). In multiple studies sCD163 and sCD206 are elevated in relation to liver disease severity and established as reliable predictors of morbidity and mortality. However, differences in expression- and shedding-stimuli for CD163 and CD206 may explain dissimilarities in prognostic utility in patients with acute decompensation of cirrhosis and ACLF.
Background and purpose: The aim of the study was to determine the effects of post-traumatically released High Mobility Group Box-1 protein (HMGB1) and extracellular histones on cardiomyocytes (CM). We also evaluated a therapeutic option to capture circulating histones after trauma, using a hemadsorption filter to treat CM dysfunction. Experimental Approach: We evaluated cell viability, calcium handling and mitochondrial respiration of human cardiomyocytes in the presence of HMGB-1 and extracellular histones. In a translational approach, a hemadsorption filter was applied to either directly eliminate extracellular histones or to remove them from blood samples obtained from multiple injured patients. Key results: Incubation of human CM with HMGB-1 or histones is associated with changes in calcium handling, a reduction of cell viability and a substantial reduction of the mitochondrial respiratory capacity. Filtrating plasma from injured patients with a hemadsorption filter reduces histone concentration ex vivo and in vitro, depending on dosage. Conclusion and implications: Danger associated molecular patterns such as HMGB-1 and extracellular histones impair human CM in vitro. A hemadsorption filter could be a therapeutic option to reduce high concentrations of histones.
The UN's sustainable development goals (SDGs), which aim to solve important economic, social, and environmental problems of humanity, are to be supported by education for sustainable development (ESD). Empirical studies on the success of the implementation of the SDGs in the field of education are still pending. For this reason, using the loss of global biodiversity as an example, this study examined the extent to which high school students, teacher trainees in biology, and biology bachelor students can identify the causes of the global biodiversity loss. A new questioning tool was developed and tested on 889 participants. In addition, the relationship between connection to nature and the personal assessment about biodiversity threats was examined. The factor analysis of the scale used showed that 11 out of 16 items were assigned to the intended factor. The comparison between high school students, teacher trainees in biology, and biology bachelor students showed no significant difference in overall assessment of the reasons for global biodiversity loss. When comparing the three risk levels in which the risk factors for biodiversity could be divided, across the three student groups, only minor differences were found. Therefore, a specific education of prospective teachers is necessary, as they have to pass on the competence as multipliers to their students. No significant difference could be found when examining the relationship between connection to nature and the overall scores of the assessment scale for the reasons of biodiversity loss. However, it was found that people who felt more connected to nature were more capable of assessing the main causes of risk for global biodiversity, while people who felt less connected to nature achieved better scores for the medium factors
The occupation of dental assistants (DAs) involves many health risks of the musculoskeletal system due to static and prolonged work, which can lead to musculoskeletal disorders (MSDs). The aim of the study was to investigate the prevalence of MSDs in DAs in Germany. Methods: For this purpose, an online questionnaire analyzed 406 (401 female participants and 5 male participants, 401w/5m) DAs. It was based on the Nordic Questionnaire (lifetime, 12-month, and seven-day MSDs’ prevalence separated into neck, shoulder, elbow, wrist, upper back, lower back, hip, knee, and ankle), and occupational and sociodemographic questions as well as questions about specific medical conditions. Results: 98.5% of the participants reported complaints of at least one body region in their lives, 97.5% reported at least one complaint in the last 12 months and 86.9% affirmed at least one complaint in the last seven days. For lifetime, 12-month and seven-day prevalence, the neck was the region that was most affected followed by the shoulder, the upper back and the lower back. Conclusion: The prevalence of MSDs among German (female) DAs was very high. The most affected area is the neck, followed by the shoulder, the lower back, and the upper back. It, therefore, seems necessary to devote more attention to ergonomics at the working practice of DAs as well in education and in dental work.
This study proposes a novel multi-network architecture consisting of a multi-scale convolution neural network (MSCNN) with fully connected graph convolution network (GCN), named MSCNN-GCN, for the detection of musculoskeletal abnormalities via musculoskeletal radiographs. To obtain both detailed and contextual information for a better description of the characteristics of the radiographs, the designed MSCNN contains three subnetwork sequences (three different scales). It maintains high resolution in each sub-network, while fusing features with different resolutions. A GCN structure was employed to demonstrate global structure information of the images. Furthermore, both the outputs of MSCNN and GCN were fused through the concat of the two feature vectors from them, thus making the novel framework more discriminative. The effectiveness of this model was verified by comparing the performance of radiologists and three popular CNN models (DenseNet169, CapsNet, and MSCNN) with three evaluation metrics (Accuracy, F1 score, and Kappa score) using the MURA dataset (a large dataset of bone X-rays). Experimental results showed that the proposed framework not only reached the highest accuracy, but also demonstrated top scores on both F1 metric and kappa metric. This indicates that the proposed model achieves high accuracy and strong robustness in musculoskeletal radiographs, which presents strong potential for a feasible scheme with intelligent medical cases.
Long non-coding RNAs (lncRNAs) contribute to cardiac (patho)physiology. Aging is the major risk factor for cardiovascular disease with cardiomyocyte apoptosis as one underlying cause. Here, we report the identification of the aging-regulated lncRNA Sarrah (ENSMUST00000140003) that is anti-apoptotic in cardiomyocytes. Importantly, loss of SARRAH (OXCT1-AS1) in human engineered heart tissue results in impaired contractile force development. SARRAH directly binds to the promoters of genes downregulated after SARRAH silencing via RNA-DNA triple helix formation and cardiomyocytes lacking the triple helix forming domain of Sarrah show an increase in apoptosis. One of the direct SARRAH targets is NRF2, and restoration of NRF2 levels after SARRAH silencing partially rescues the reduction in cell viability. Overexpression of Sarrah in mice shows better recovery of cardiac contractile function after AMI compared to control mice. In summary, we identified the anti-apoptotic evolutionary conserved lncRNA Sarrah, which is downregulated by aging, as a regulator of cardiomyocyte survival.
Proper speech production requires auditory speech feedback control. Models of speech production associate this function with the right cerebral hemisphere while the left hemisphere is proposed to host speech motor programs. However, previous studies have investigated only spectral perturbations of the auditory speech feedback. Since auditory perception is known to be lateralized, with right-lateralized analysis of spectral features and left-lateralized processing of temporal features, it is unclear whether the observed right-lateralization of auditory speech feedback processing reflects a preference for speech feedback control or for spectral processing in general. Here we use a behavioral speech adaptation experiment with dichotically presented altered auditory feedback and an analogous fMRI experiment with binaurally presented altered feedback to confirm a right hemisphere preference for spectral feedback control and to reveal a left hemisphere preference for temporal feedback control during speaking. These results indicate that auditory feedback control involves both hemispheres with differential contributions along the spectro-temporal axis.
Let me start with a reminiscence: a few weeks ago, I was sitting in one of my preferred cafés in Paris, le Café Odéon- Théâtre de l’Europe, a vivid place near the Jardin de Luxembourg in the heart of the university quarter. I realised that the waiter was wearing a shirt with the letters "Defend Paris", which he explained to be a statement against the forces that make Paris an uneasy place to live, a defiance against the powerful and social injustice. With a mixture of rebellion and idealism, he added that he understands himself as part of a "Reclaim Your City" Movement, thus representing what is central for urban citizenship today: a republican defence against forces that make a metropolitan city a trademark to be sold to people who can afford it, but increasingly less a home for ordinary people who want to live in the city. Walking through the streets, passing a small jewelry shop, a place of distinguished understatement showing a picture of Meghan Markle wearing "rose"-earrings displayed in the window, the term "zombie urbanism" came to my mind – a term used by Jonny Aspen, professor at the Institute of Urbanism and Landscape in Oslo (See Bjerkeset and Aspen (forthcoming 2020) and here), to describe a cliché-like way of dealing with urban environment by developers and designers – a "staged urbanism", in which urban features are used as a means for selling, marketing and branding. This kind of city-marketing can prove quite successful: whereas the burning of Notre Dame mobilised hundreds of millions of donations within a short period of time, the burning of the National Museum in Rio de Janeiro soon after, extinguishing 200 years of documentation of cultural memory, mobilised only 225.000 Euros (state 1.4.2019). ...
Mit einem um die Behandlungskapazität des Gesundheitssystems erweiterten epidemiologischen SIRD-Modell werden Mechanismen und Dynamik einer Virusepidemie wie Corona anhand von stilisierten politischen Reaktionsmustern (Ignore, Shutdown, Ignore-Shutdown-Relax) simuliert. Ferner werden aus dem Modell Lehren für die statistische Analyse von Corona gezogen, wie die Aussagekraft publizierter Verdopplungszeiten und Reproduktionszahlen. Die Dunkelziffer unbestätigter Fälle und die im Epidemieverlauf variable Genauigkeit von medizinischen Infektionstests werden diskutiert. Zur Messung der medizinischen Kosten von Corona sowie für regionale und internationale Vergleiche wird ein Schadensindex der verlorenen Lebenszeit vorgeschlagen. Zuletzt geht die Arbeit kurz auf die ökonomischen Kosten von Corona in Deutschland ein.
We are students, scholars, and academics at European universities who unequivocally condemn the violent attacks on student and faculty members of Jawaharlal Nehru University (JNU), New Delhi that took place on 5th January 2020. We see the attacks as part of the larger pattern of systematic violence that is being consistently inflicted on students across Indian universities for the past month by the Indian police in collusion with far-right organisations. We are shocked by the proclivity of the Indian State to turn upon its own students, and by the failure of universities and other academic institutions to protect their members; the cases are too many to be all listed here, but along with JNU, this inhumane orchestration of violence has extended to Aligarh Muslim University, Banaras Hindu University in Uttar Pradesh, and Jamia Millia Islamia in New Delhi. ...
Body dysmorphic disorder (BDD), together with its subtype muscle dysmorphia (MD), has been relocated from the Somatoform Disorders category in the DSM-IV to the newly created Obsessive-Compulsive and Related Disorders category in the DSM-5. Both categorizations have been criticized, and an empirically derived classification of BDD is lacking. A community sample of N = 736 participants completed an online survey assessing different psychopathologies. Using a structural equation modeling approach, six theoretically derived models, which differed in their allocation of BDD symptoms to various factors (i.e. general psychopathology, somatoform, obsessive-compulsive and related disorders, affective, body image, and BDD model) were tested in the full sample and in a restricted sample (n = 465) which indicated primary concerns other than shape and weight. Furthermore, measurement invariance across gender was examined. Of the six models, only the body image model showed a good fit (CFI = 0.972, RMSEA = 0.049, SRMR = 0.027, TLI = 0.959), and yielded better AIC and BIC indices than the competing models. Analyses in the restricted sample replicated these findings. Analyses of measurement invariance of the body image model showed partial metric invariance across gender. The findings suggest that a body image model provides the best fit for the classification of BDD and MD. This is in line with previous studies showing strong similarities between eating disorders and BDD, including MD. Measurement invariance across gender indicates a comparable presentation and comorbid structure of BDD in males and females, which also corresponds to the equal prevalence rates of BDD across gender.
The teaching of professional roles in medical education is an interdisciplinary concern. However, surgeons require specific standards of professionalism for certain context-based situations. In addition to communication, studies require collaboration, leadership, error-/conflict-management, patient-safety and decision-making as essential competencies for surgeons. Standards for corresponding competencies are defined in special chapters of the German National Competency-based Learning Objectives for Undergraduate Medical Education (NKLM; chapter 8, 10). The current study asks whether these chapters are adequately taught in surgical curricula. Eight German faculties contributed to analysing mapping data considering surgical courses of undergraduate programs. All faculties used the MERlin mapping platform and agreed on procedures for data collection and processing. Sub-competency and objective coverage, as well as the achievement of the competency level were mapped. Overall counts of explicit citations were used for analysis. Collaboration within the medical team is a strongly represented topic. In contrast, interprofessional cooperation, particularly in healthcare sector issues is less represented. Patient safety and dealing with errors and complications is most emphasized for the Manager/Leader, while time management, career planning and leadership are not addressed. Overall, the involvement of surgery in teaching the competencies of the Collaborator and Manager/Leader is currently low. However, there are indications of a curricular development towards explicit teaching of these roles in surgery. Moreover, implicitly taught roles are numerous, which indicates a beginning awareness of professional roles.
Introduction: Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) occurs approximately 1 in 3.500 live births representing the most common malformation of the upper digestive tract. Only half a century ago, EA/TEF was fatal among affected newborns suggesting that the steady birth prevalence might in parts be due to mutational de novo events in genes involved in foregut development.
Methods: To identify mutational de novo events in EA/TEF patients, we surveyed the exome of 30 case-parent trios. Identified and confirmed de novo variants were prioritized using in silico prediction tools. To investigate the embryonic role of genes harboring prioritized de novo variants we performed targeted analysis of mouse transcriptome data of esophageal tissue obtained at the embryonic day (E) E8.5, E12.5, and postnatal.
Results: In total we prioritized 14 novel de novo variants in 14 different genes (APOL2, EEF1D, CHD7, FANCB, GGT6, KIAA0556, NFX1, NPR2, PIGC, SLC5A2, TANC2, TRPS1, UBA3, and ZFHX3) and eight rare de novo variants in eight additional genes (CELSR1, CLP1, GPR133, HPS3, MTA3, PLEC, STAB1, and PPIP5K2). Through personal communication during the project, we identified an additional EA/TEF case-parent trio with a rare de novo variant in ZFHX3. In silico prediction analysis of the identified variants and comparative analysis of mouse transcriptome data of esophageal tissue obtained at E8.5, E12.5, and postnatal prioritized CHD7, TRPS1, and ZFHX3 as EA/TEF candidate genes. Re-sequencing of ZFHX3 in additional 192 EA/TEF patients did not identify further putative EA/TEF-associated variants.
Conclusion: Our study suggests that rare mutational de novo events in genes involved in foregut development contribute to the development of EA/TEF.
Background: A web-based malaria reporting information system (MRIS) has the potential to improve malaria reporting and management. The aim of this study was to evaluate the existing manual paper-based MRIS and to provide a way to overcome the obstacles by developing a web-based MRIS in Indonesia.
Methods: An exploratory study was conducted in 2012 in Lahat District, South Sumatra Province of Indonesia. We evaluated the current reporting system and identified the potential benefits of using a web-based MRIS by in-depth interviews on selected key informants. Feasibility study was then conducted to develop a prototype system. A web-based MRIS was developed, integrated and synchronized, with suitability ranging from Primary Healthcare Centres (PHCs) to the Lahat District Health Office.
Results: The paper-based reporting system was sub-optimal due to a lack of transportation, communication, and human capacity. We developed a web-based MRIS to replace the current one. Although the web-based system has the potential to improve the malaria reporting information system, there were some barriers to its implementation, including lack of skilled operators, computer availability and lack of internet access. Recommended ways to overcome the obstacles are by training operators, making the application in an offline mode and able to be operated by mobile phone text messaging for malaria reporting.
Conclusion: The web-based MRIS has the potential to be implemented as an enhanced malaria reporting information system and investment in the system to support timely management responses is essential for malaria elimination. The developed application can be cloned to other areas that have similar characteristics and MRIS with a built-in web base to aid its application in the 5G future.
This Policy White Paper assesses several main elements of ECB’s upcoming review of its monetary policy strategy, announced in January 2020. Four aspects of the review are discussed in detail: i) ECB’s definition of price stability and the arguments for and against inflation targeting; ii) the scope of ECB’s objectives, considering financial stability, employment and the sustainability of the environment; iii) an update of ECB’s economic and monetary analyses to assess the risks to price stability; iv) the ECB’s communication practice. Furthermore, an overview of the ECB’s monetary policy strategy and its last evaluation in 2003 is given.
Mit dem Ziel, Erkenntnisse zum individuellen Mobilitätsverhalten im Zusammenhang mit der Gestaltung des umgebenden Verkehrssystems zu gewinnen, wurde im Rahmen des vom Land Hessen geförderten LOEWE-Schwerpunkts „Infrastruktur – Design – Gesellschaft“ im März und April 2019 eine schriftliche Haushaltsbefragung in einem innerstädtischen Gebiet der Großstadt Offenbach am Main durchgeführt (n=701). Der vorliegende Bericht beschreibt die methodische Vorgehensweise bei der Umsetzung und Datenerfassung dieser Erhebung. Dabei wird auf die vorbereitenden Maßnahmen mit Hinblick auf die Erstellung des Fragebogens und weiterer Befragungsmaterialen sowie die Durchführung des Pretests und der eigentlichen Hauptbefragung eingegangen. Um die Bereitschaft einer Teilnahme zu erhöhen, wurden die Haushalte mittels Vorankündigungsschreiben, Pressemitteilung und Erinnerungsrundgang mehrfach kontaktiert. Außerdem wurde ein Teil der Rücksendeumschläge mit Sonderbriefmarken versehen. Abschließend befasst sich der Bericht mit dem Erhebungsrücklauf, der Dateneingabe und -aufbereitung sowie dem ermittelten Antwortverhalten und der Repräsentativität der Stichprobe.
NKG2D is a potent activating immunoreceptor expressed on nearly all cytotoxic lymphocytes promoting their cytotoxicity against self-cells expressing NKG2D ligands (NKG2DLs). NKG2DLs are MHC class I-like glycoproteins that usually are not expressed on “healthy” cells. Rather, their surface expression is induced by various forms of cellular stress, viral infection, or malignant transformation. Hence, cell surface NKG2DLs mark “dangerous” cells for elimination by cytotoxic lymphocytes and therefore can be considered as “kill-me” signals. In addition, NKG2DLs are up-regulated on activated leukocytes, which facilitates containment of immune responses. While the NKG2D receptor is conserved among mammals, NKG2DL genes have rapidly diversified during mammalian speciation, likely due to strong selective pressures exerted by species-specific pathogens. Consequently, NKG2DL genes are not conserved in man and mice, although their NKG2D-binding domains maintained structural homology. Human NKG2DLs comprise two members of the MIC (MICA/MICB) and six members of the ULBP family of glycoproteins (ULBP1–6) with MICA representing the best-studied human NKG2DLs by far. Many of these studies implicate a role of MICA in various malignant, infectious, or autoimmune diseases. However, conclusions from these studies often were limited in default of supporting in vivo experiments. Here, we report a MICA transgenic (MICAgen) mouse model that replicates central features of human MICA expression and function and, therefore, constitutes a novel tool to critically assess and extend conclusions from previous in vitro studies on MICA. Similarly to humans, MICA transcripts are broadly present in organs of MICAgen mice, while MICA glycoproteins are barely detectable. Upon activation, hematopoietic cells up-regulate and proteolytically shed surface MICA. Shed soluble MICA (sMICA) is also present in plasma of MICAgen mice but affects neither surface NKG2D expression of circulating NK cells nor their functional recognition of MICA-expressing tumor cells. Accordingly, MICAgen mice also show a delayed growth of MICA-expressing B16F10 tumors, not accompanied by an emergence of MICA-specific antibodies. Such immunotolerance for the xenoantigen MICA ideally suits MICAgen mice for anti-MICA-based immunotherapies. Altogether, MICAgen mice represent a valuable model to study regulation, function, disease relevance, and therapeutic targeting of MICA in vivo.
Risk evaluations for agricultural chemicals are necessary to preserve healthy populations of honey bee colonies. Field studies on whole colonies are limited in behavioural research, while results from lab studies allow only restricted conclusions on whole colony impacts. Methods for automated long-term investigations of behaviours within comb cells, such as brood care, were hitherto missing. In the present study, we demonstrate an innovative video method that enables within-cell analysis in honey bee (Apis mellifera) observation hives to detect chronic sublethal neonicotinoid effects of clothianidin (1 and 10 ppb) and thiacloprid (200 ppb) on worker behaviour and development. In May and June, colonies which were fed 10 ppb clothianidin and 200 ppb thiacloprid in syrup over three weeks showed reduced feeding visits and duration throughout various larval development days (LDDs). On LDD 6 (capping day) total feeding duration did not differ between treatments. Behavioural adaptation was exhibited by nurses in the treatment groups in response to retarded larval development by increasing the overall feeding timespan. Using our machine learning algorithm, we demonstrate a novel method for detecting behaviours in an intact hive that can be applied in a versatile manner to conduct impact analyses of chemicals, pests and other stressors.
Metabolites such as lactate and free fatty acids (FFAs) abundantly occur in high concentrations in tumor and stromal cells of solid malignancies. Their known functions comprise the allocation of nutrients and intermediates for the generation of cell components, the evasion of immune destruction, the induction of vessel formation and the stimulation of cell migration in order to promote tumor growth, progression and metastasis. However, the role of metabolites as signaling molecules and the downstream mechanisms of metabolite receptor mediated signaling in tumor and stromal cells is poorly understood. Our study confirms the expression of Hydroxycarboxylic acid receptor 1 (HCA1) in solid human breast tumors and the expression of Free fatty acid receptor 4 (FFA4) in solid human colorectal tumors. In addition, the expression of HCA1 in human breast cancer cell lines as well as the expression of FFA4 in human colorectal cancer cell lines was proved. Moreover, our research reveals the expression HCA2, FFA2 and FFA4 in tumor associated macrophages (TAMs).
To test whether the loss of any of the metabolite receptors affects tumor growth and progression we utilized a syngeneic Lewis lung cancer (LLC1) tumor model, an azoxymethane (AOM) – dextran sulfate (DSS) colorectal cancer model and a Mouse mammary tumor virus Polyoma Virus middle T antigen (MMTV-PyMT) breast cancer model. The loss of HCA2 did not lead to a changed outcome compared to wild type littermates in any of the models. Likewise, the deletion of FFA4 had no influence on the LLC1 model and, surprisingly, tumor number and area in the AOM-DSS model also remained unaltered. The impact of HCA1 deficiency was investigated utilizing the MMTV-PyMT model and revealed a moderately improved tumor growth. The absence of FFA2 did not affect tumor growth in the LLC1 model but led to an increased number of colorectal tumors in the AOM-DSS model while the tumor area remained unchanged. The most compelling results were obtained upon the deletion of FFA2 in the MMTV-PyMT model. Here, we demonstrate that the loss of FFA2 significantly reduces tumor latency and also significantly improves tumor growth. Nevertheless, the formation of metastases in the LLC1 model and the MMTV-PyMT model did not show any changes upon the loss of any of the metabolite receptors.
Together, our results describe a tumor-protective effect of FFA2 with an unclear impact on metastatic processes. Considerations about putative mechanisms of short chain fatty acid (SCFA) mediated FFA2 signaling suggest potential targets for pharmacological interventions to treat mammary tumors.
Article 4 of Protocol No. 4 to the European Convention on Human Rights (ECHR) is short. Its title reads "Prohibition of collective expulsion of aliens", its text reads: "Collective expulsion of aliens is prohibited." It comes as a historical disappointment that the European Court of Human Rights (ECtHR) in its decision in the case N.D. and N.T. v. Spain from 13 February 2020 distorts this clear guarantee to exclude apparently "unlawful" migrants from its protection. The decision is a shock for the effective protection of rights in Europe and at its external borders. Consequently the Guardian titled that the Court is "under fire". Reading the majority opinion is at times a puzzling experience, to say the least.
Connectomic analysis of apical dendrite innervation in pyramidal neurons of mouse cerebral cortex
(2020)
The central goal of this study was to generate synapse-resolution maps of local and long-range innervation on apical dendrites (AD) in mouse cerebral cortex. We used three-dimensional electron microscopy (3D-EM) to first measure the cell-type specific balance in the excitatory and inhibitory input on ADs. Further, we found two inhibitory axon populations with preference for apical dendrites originating from layer 2 and 3/5. Additionally, we used a combination of large-scale volumetric light and electron microscopy to investigate the innervation preference of long-range cortical projections onto ADs. To generate such large-scale 3D-EM datasets, we also developed a software package to automate aberration adjustment.
The balance of excitation and inhibition defines the computational properties of neurons. We, therefore, generated 6 datasets and annotated 26,548 excitatory and inhibitory synapses to map the relative inhibitory strength on the AD of pyramidal neurons in layers 1 and 2 (L1 and 2) of the cortex. We found consistent and cell-type specific patterns of inhibitory strength along the apical dendrite of L2-5 pyramidal neurons in primary somatosensory (S1), secondary visual (V2), posterior parietal (PPC) and anterior cingulate (ACC) cortices. L2 and L5 pyramidal neurons had inhibitory hot-zones at their main bifurcation and distal apical dendrite tuft, respectively. In contrast, L3 neurons had a baseline (~10%) level of inhibition along their apical dendrite. As controls, we quantified the effect of synapse strength (size), dendrite diameter, AD classification and synapse identification methods on the cell-type specific synapse densities. To classify L5 pyramidal subtypes, we performed hierarchical clustering using morphological properties that were described to differentiate slender- and thick-tufted L5 neurons.
We also investigated the distance to soma as a predictor of fractional inhibition around the main bifurcation of apical dendrites. Interestingly, we found a strong exponential relationship that was absent in density of either synapse type. This suggests a distance dependent control mechanism designed specifically for the balance (in synapse numbers) of excitation and inhibition.
Next, we focused on the inhibitory innervation preference for apical dendrite of pyramidal neuron. We, therefore, annotated 5,448 output synapses of AD-targeting inhibitory axons and found two populations specific for either L2 or L3/5 apical dendrites. Together with previous findings on preferential innervation of sub-cellular structures by inhibitory axons, this suggests two distinct inhibitory circuits for control of AD activity in L2 vs. deep-layer pyramidal neurons. This innervation preference was surprisingly consistent across S1, V2, PPC and ACC cortices.
3D-EM data acquisition is a laborious process that is made easier and more popular everyday by technical progress in the laboratory and industrial settings. To make data acquisition robust using our custom-built 3D-EM microscopes, an automatic aberration software was implemented to adjust the objective lens and the stigmators of the electron microscope. This method was used in multiple month-long experiments across 2 microscopes and 10 datasets. The aberration adjustment used the reduction in image details (high-frequency elements) to estimate the level of deviation from optimal focus and stigmator parameters. However, large objects in EM micrographs such as blood vessel and nuclei cross-sections generated anomalous results. We, therefore, added image processing routines based on edge detection combined with morphological operations to exclude such large objects.
Finally, we performed a correlative three-dimensional (3D) light (LM) and electron (EM) microscopy experiment to map the long-range primary visual (V1) and secondary motor (M2) cortical input to ADs in layer 1 of PPC using the “FluoEM” approach. This method allows for identification of the long-range source of projection axons in EM volumes without the need for EM-dense label conversion or heat-induced markings. The long-range source of an axon in EM is identified based on the fluorescent protein that is expressed in its LM counterpart. In comparison to M2 input, Long-range axons from V1 had a higher tendency to target L3 pyramidal neurons in PPC according to our preliminary analysis. In combination with the difference observed in the synapse composition of L2 and L3 apical dendrites, this suggests the need for separate functional and structural analysis of L2 and 3 pyramidal neurons.
Bacteria constantly attempt to hold up ion gradients across their membranes to maintain their resting potential for routine cell function, while coping with sudden environmental changes. Under abrupt hyperosmotic conditions, as faced when invading a host, most bacteria restore their turgor pressure by taking up potassium ions to prevent death by plasmolysis. Here, the potassium transporter AB, or KtrAB for short, is a key player. KtrAB consists of the membrane-embedded KtrB dimer, which includes two pores organized in tandem, and a cytoplasmic, octameric KtrA ring, which regulates these two pores. The KtrB subunits alone were suggested to function as rather non-selective ion channels translocating potassium and sodium ions. The KtrA subunits confer transport velocity, K+ selectivity as well as Na+ and nucleotide dependency to the Ktr system. The nucleotide regulation by binding to KtrA is rather well characterized. In contrast, the regulatory role of Na+ remains elusive. Controversially discussed is how selective the ion translocation by KtrB is and how KtrA affects it. Although there are several functional and structural data available of KtrAB and its homolog TrkAH, the selectivity of the ion translocation was never thoroughly addressed. The functional characterization of whether KtrAB is a selective ion channel and how selectivity is achieved is in the focus of this thesis. Since selectivity is usually defined by the ion channels’ selectivity filter contained in the pore-forming domain, a particular attention was laid on the ion-translocating subunits KtrB.
KtrB belongs to the superfamily of K+ transporters (SKT). Each KtrB monomer consists of four covalently attached M1-P-M2 motifs, each motif is made of two transmembrane (TM or M) helices that are connected by a pore (P) helix. The four motifs, referred to as domains D1 to D4, are arranged in a pseudo-fourfold symmetry and together form the pore for potassium ion translocation. Each pore contains two structural features thought to be involved in ion selectivity and ion gating. These are the non-canonical selectivity filter and the intramembrane loop. The selectivity filter is localized at the extracellular side of the pore and mostly shaped by the backbone carbonyl groups of the loops connecting the P and M2 helices in each domain. In KtrB, each P-loop contains only one highly conserved glycine residue instead of the classical -TVGYG- signature sequence of a K+ channel. This simple constructed selectivity filter led to the hypothesis that KtrAB would only have low ion selectivity. The intramembrane loop is formed by broken helix D3M2 and is located directly under the selectivity filter. It consists mostly of polar residues and acts as a molecular gate restricting ion fluxes. The intramembrane loop has been shown to be regulated by nucleotide binding to KtrA. Additionally, it could directly or indirectly be affected by Na+ binding. Further, the loop might even be involved in ion selectivity because it presents a physical barrier inside the pore.
To address the ion selectivity of the Ktr system, first, the ion binding specificity of KtrB was investigated. Binding affinities of different cations to KtrB were determined using isothermal titration calorimetry (ITC). For this, KtrB from Vibrio alginolyticus was heterologously produced in and purified from Escherichia coli. 12 L of culture roughly yielded 4 to 8 mg of the functional KtrB dimer in detergent solution. ITC measurements were performed in two different buffers, one choline-Cl-based and one LiCl-based buffer. No differences in the affinity between Na+ (KD = 1.8 mM), K+ (KD = 2.9 mM), Rb+ (KD = 1.9 mM) or Cs+ (KD = 1.6 mM) were detected in the choline-Cl-based buffer; only Li+ did not bind. In contrast, ITC measurements in LiCl-based buffer revealed a significant preference for K+ (KD = 91 µM) over Rb+ (KD = 2.4 mM), Cs+ (KD = 1.7 mM) and particularly Na+ (for which no binding was observed). Similarly, the presence of low millimolar NaCl concentrations in the choline-Cl-based buffer led to a decreased KD value of 260 µM. Hence, small cations, which usually are present in the natural environment, seem to modulate the selectivity filter for a better binding of K+ ions providing K+ selectivity. In fact, the low binding affinities of the other ions could indicate that they do not even bind to the selectivity filter but to the cavity. However, ITC competition experiments showed that all four ions compete for the same or overlapping binding sites, with Rb+ and Cs+ even blocking K+ binding at concentrations 10-fold above their binding affinities. Importantly, at physiological NaCl concentrations of 200 mM, the apparent binding affinity for K+ to KtrB was still 3.5 mM. This suggested that Na+ can also bind to KtrB’s selectivity filter but with a comparably low binding affinity providing an unexpectedly high preference for K+ ions.
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Consuming dividends
(2020)
This paper studies why investors buy dividend-paying assets and how they time their consumption accordingly. We combine administrative bank data linking customers’ consumption transactions and income to detailed portfolio data and survey responses on financial behavior. We find that private consumption is excessively sensitive to dividend income. Investors across wealth, income, and age distributions increase spending precisely around days of dividend receipt. Importantly, the consumption response is driven by financially prudent investors who select dividend portfolios, anticipate dividend income, and plan consumption accordingly. Our results contribute to the literature on a dividend clientele and provide evidence of ‘planned’ excess sensitivity.
We survey a representative sample of US households to study how exposure to the COVID-19 stock market crash a↵ects expectations and planned behavior. Wealth shocks are associated with upward adjustments of expectations about retirement age, desired working hours, and household debt, but have only small e↵ects on expected spending. We provide correlational and experimental evidence that beliefs about the duration of the stock market recovery shape households’ expectations about their own wealth and their planned investment decisions and labor market activity. Our findings shed light on the implications of household exposure to stock market crashes for expectation formation.
This working paper suggests to analyse agencification as a double process of institutional and policy centralisation. To that end, it develops a categorisation of agencies that incorporates these two dimensions. More specifically, it is argued that mixed outcomes where the levels of institutional and policy centralisation diverge can be expected to be the rule rather than the exception, in line with the hybrid nature of EU agencies as inbetweeners. Moreover, the fiduciary setting hits important legal constraints given the limits to delegation in the EU context. Against this backdrop a process whereby institutional centralisation develops incrementally and remains limited, yet is accompanied by a process of substantial policy centralisation, appears as the most promising path for EU agencification. A fiduciary setting, where a strong agency enjoys a high degree of independence and operates in a centralised policy space, by contrast, should be the exception. The comparative study of the process of agencification in the energy and banking sector is insightful in the light of these expectations. The incremental nature of institutional change in energy exemplifies the usual path of agencification, which is conducive to a weak agency operating in a relatively centralised policy space. Agencification in banking, by contrast, has led to a rather unusual outcome where the strong agency model combines with a fragmented policy context.
This Policy Letter outlines a pandemic insurance solution through a pandemic-related “Insurance Linked Bond”. It would be originated by governments, with a principal amount to cover significant costs resulting from a pandemic. These bonds, which would be traded on a secondary market, generate a risk-adequate return for private and institutional investors that is financed through the insurance premiums paid by the public domain. In case of a pre-defined pandemic trigger event, the principal of the bond becomes available for the originating governments to cover pandemic-related costs. Through this approach, governments can insure themselves against future pandemic-related risks, while funding comes primarily from private and institutional investors.
leporello #4
(2020)
Background and Objectives: Delirium is a common and major complication subsequent to cardiac surgery. Despite scientific efforts, there are no parameters which reliably predict postoperative delirium. In delirium pathology, natriuretic peptides (NPs) interfere with the blood–brain barrier and thus promote delirium. Therefore, we aimed to assess whether NPs may predict postoperative delirium and long-term outcomes. Materials and Methods: To evaluate the predictive value of NPs for delirium we retrospectively analyzed data from a prospective, randomized study for serum levels of atrial natriuretic peptide (ANP) and the precursor of C-type natriuretic peptide (NT-proCNP) in patients undergoing coronary artery bypass grafting (CABG) with or without cardiopulmonary bypass (off-pump coronary bypass grafting; OPCAB). Delirium was assessed by a validated chart-based method. Long-term outcomes were assessed 10 years after surgery by a telephone interview. Results: The overall incidence of delirium in the total cohort was 48% regardless of the surgical approach (CABG vs. OPCAB). Serum ANP levels >64.6 pg/mL predicted delirium with a sensitivity (95% confidence interval) of 100% (75.3–100) and specificity of 42.9% (17.7–71.1). Serum NT-proCNP levels >1.7 pg/mL predicted delirium with a sensitivity (95% confidence interval) of 92.3% (64.0–99.8) and specificity of 42.9% (17.7–71.1). Both NPs could not predict postoperative survival or long-term cognitive decline. Conclusions: We found a positive correlation between delirium and preoperative plasma levels of ANP and NT-proCNP. A well-powered and prospective study might identify NPs as biomarkers indicating the risk of delirium and postoperative cognitive decline in patients at risk for postoperative delirium.
Within the context of eHealth interventions, a shared understanding of what constitutes engagement in and with eHealth technologies is missing. A clearer understanding of engagement could provide a valuable starting point for guidelines relating to the design and development of eHealth technologies. Given the cross-disciplinary use of the term “engagement,” investigating how engagement (and its components) is conceptualized in different domains could lead to determining common components that are deemed important for eHealth technological design. As such, the aim of this paper was 3-fold: (a) to investigate in which domains engagement features, (b) to determine what constitutes engagement in these different domains, and (c) to determine whether there are any common components that seem to be important. A comprehensive systematic scoping review of the existing literature was conducted in order to identify the domains in which engagement is used, to extract the associated definitions of engagement, and to identify the dimensionality or components thereof. A search of five bibliographic databases yielded 1,231 unique records. All titles, abstracts, and full texts were screened based on specific inclusion and exclusion criteria. This led to 69 articles being included for further analyses. The results showed that engagement is used in seven functional domains, categorized as follows: student (n = 18), customer (n = 12), health (n = 11), society (n = 10), work (n = 9), digital (n = 8), and transdisciplinary (n = 1) domains. It seems that some domains are more mature regarding their conceptualization and theorizing on engagement than others. Further, engagement was found to be predominantly conceptualized as a multidimensional construct with three common components (behavior, cognition, and affective) shared between domains. Although engagement is prolifically used in different disciplines, it is evident that little shared consensus as to its conceptualization within and between domains exists. Despite this, engagement is foremost seen as a state of being engaged in/with something, which is part of, but should not be confused with, the process of engagement. Behavior, cognition, and affect are important components of engagement and should be specified for each new context.
A list of authors and their affiliations appears at the end of the paper New-particle formation is a major contributor to urban smog, but how it occurs in cities is often puzzling. If the growth rates of urban particles are similar to those found in cleaner environments (1–10 nanometres per hour), then existing understanding suggests that new urban particles should be rapidly scavenged by the high concentration of pre-existing particles. Here we show, through experiments performed under atmospheric conditions in the CLOUD chamber at CERN, that below about +5 degrees Celsius, nitric acid and ammonia vapours can condense onto freshly nucleated particles as small as a few nanometres in diameter. Moreover, when it is cold enough (below −15 degrees Celsius), nitric acid and ammonia can nucleate directly through an acid–base stabilization mechanism to form ammonium nitrate particles. Given that these vapours are often one thousand times more abundant than sulfuric acid, the resulting particle growth rates can be extremely high, reaching well above 100 nanometres per hour. However, these high growth rates require the gas-particle ammonium nitrate system to be out of equilibrium in order to sustain gas-phase supersaturations. In view of the strong temperature dependence that we measure for the gas-phase supersaturations, we expect such transient conditions to occur in inhomogeneous urban settings, especially in wintertime, driven by vertical mixing and by strong local sources such as traffic. Even though rapid growth from nitric acid and ammonia condensation may last for only a few minutes, it is nonetheless fast enough to shepherd freshly nucleated particles through the smallest size range where they are most vulnerable to scavenging loss, thus greatly increasing their survival probability. We also expect nitric acid and ammonia nucleation and rapid growth to be important in the relatively clean and cold upper free troposphere, where ammonia can be convected from the continental boundary layer and nitric acid is abundant from electrical storms.
The aim of this observational study was to follow-up patients with bedtime basal insulin (NPH insulin) added to metformin. In 285 patients with type 2 diabetes, a therapy with bedtime basal insulin added to metformin was started due to failure to achieve a glycaemic goal. Up until July 2019, 272 patients (95.4%) were followed-up (59.5 y, 92.6 kg, diabetes duration 6.6 y, HbA1c 8.4%/68.6 mmol/mol). HbA1c decreased by −1.2% and bodyweight by −1.7 kg after a duration of 31.7 ± 29.1 (range 2–133) months. Severe hypoglycaemia did not occur. In 144/272 patients (52.9%), the therapeutic goal for HbA1c was achieved over 32.7 months. In 69/272 patients (25.4%), the HbA1c target was achieved over 25.0 months (afterwards, therapy with basal insulin was discontinued because HbA1c was under target). In 36/272 patients (13.2%), the HbA1c goal was achieved until the submission of this manuscript (mean duration of treatment 57.4 ± 28.2 (range 13–121) months). Over 90% of patients with type 2 diabetes and failure of metformin reached their HbA1c goal with additional basal insulin at bedtime over several years in association with a reduction of bodyweight and without any event of severe hypoglycaemia.
Young neurons in the adult brain are key to some types of learning and memory. They integrate in the dentate gyrus (DG) of the hippocampus contributing to such cognitive processes following timely developmental events. While experimentally impairing GABAergic transmission through the blockade or elimination of the ionic cotransporter NKCC1 leads to alterations in the proper maturation of young neurons, it is still unknown if the in vivo administration of common use diuretic drugs that block the cotransporter, alters the development of young hippocampal neurons and affects DG-related functions. In this study, we delivered chronically and intracerebroventricularly the NKCC1 blocker bumetanide to young-adult rats. We analyzed doublecortin density and development parameters (apical dendrite length and angle and dendritic arbor length) in doublecortin positive neurons from different subregions in the DG and evaluated the performance of animals in contextual fear learning and memory. Our results show that in bumetanide-treated subjects, doublecortin density is diminished in the infra and suprapyramidal blades of the DG; the length of primary dendrites is shortened in the infrapyramidal blade and; the growth angle of primary dendrites in the infrapyramidal blade is different from control animals. Behaviorally, treated animals showed the typical learning curve in a contextual fear task, and freezing-time displayed during contextual fear memory was not different from controls. Thus, in vivo icv delivery of bumetanide negatively alters DCX density associated to young neurons and its proper development but not to the extent of affecting a DG dependent task as aversive context learning and memory.
Ende November hat Bundesjustizministerin Christine Lamprecht (SPD) vorgeschlagen, das Grundgesetz zu ändern und darin ausdrücklich Kinderrechte zu verankern. Der Vorschlag befindet sich derzeit in der Ressortabstimmung. Auf dem Verfassungsblog hat sich Friederike Wapler kritisch mit diesem Entwurf auseinandergesetzt und am Ende empfohlen, statt einer schlechten Grundgesetzänderung lieber gar keine zu verabschieden. Ich hingegen halte eine solche Grundgesetzänderung für ebenso sinnvoll wie möglich.
Maintaining biodiversity and ecosystem function is critical on national and global scales. However, while only a fraction of the global biodiversity is known, its current decline is unprecedented, making biodiversity hotspots a conservation priority. The Sierra Gorda Biodiversity Reserve (SGBR) in Central Mexico is known for its rich biodiversity. It is an example of the juxtaposition between species discovery and extinction: aquatic species richness is mostly unknown as no efforts have investigated aquatic communities so far, but are already anthropogenically stressed. We hypothesized that invasive species are already well established in various protected areas and investigated this by assessing the threat of invasive species that are already established within the SGBR on the native biodiversity. By combining field sampling with peer-reviewed literature and local reports, we identify the presence of various non-native species in SGBR. Among these non-native species identified were opportunistic predatory fish and potentially-pathogen transmitting molluscs, but also, a habitat engineer capable of modifying ecosystem functions. Moreover, we highlight that these species were introduced despite legislation and without any knowledge among authorities. As a result, we underline the necessity to describe native species, control invasive and prevent the introduction of further non-native species. If accelerated action is not taken, we risk losing a considerable amount of described and unknown freshwater biota. Keywords: Anthropocene, Biodiversity loss, Freshwater, Invasive species, Mexico, Nature reserve.
Der Zweifel muss schweigen, soll ein richterliches Urteil überzeugen. Gewissheit zu verbreiten, ist das nicht allzu heimliche Ziel der juristischen Ausbildung. Der Charme der Gutachtentechnik, alles Mögliche zu erwägen und zu prüfen, wird in der Referendarausbildung durch die Relationstechnik ersetzt und in der richterlichen Urteilspraxis vollends desavouiert. Gewissheitsdenken und Erledigungsökonomie gehen in Führung. Vieles bleibt "dahingestellt", wenn die Entscheidung einmal feststeht. Und die Gutachten von Rechtsexperten hängen dem Interesse der Auftraggeber häufig einen mehr als fadenscheinigen Mantel um. Ungewissheit, das scheint gewiss, ist Sache der juristischen Zunft nicht. ...
In the present paper, we tested the ability of individuals to judge correctly whether athletes are lying or telling the truth. For this purpose, we first generated 28 videos as stimulus material: in half of the videos, soccer players were telling the truth, while in the other half, the same soccer players were lying. Next, we tested the validity of these video clips by asking N = 65 individuals in a laboratory experiment (Study 1a) and N = 52 individuals in an online experiment (Study 1b) to rate the level of veracity of each video clip. Results suggest that participants can distinguish between true and false statements, but only for some clips and not for others, indicating that some players were better at deceiving than others. In Study 2, participants again had to make veracity estimations, but we manipulated the level of information given, as participants (N = 145) were randomly assigned to one of three conditions (regular video clips, mute video clips, and only the audio stream of each statement). The results revealed that participants from the mute condition were less accurate in their veracity ratings. The theoretical and practical implications of these findings are discussed.
Mechanistic understanding of dynamic membrane proteins such as transporters, receptors, and channels requires accurate depictions of conformational ensembles, and the manner in which they interchange as a function of environmental factors including substrates, lipids, and inhibitors. Spectroscopic techniques such as electron spin resonance (ESR) pulsed electron–electron double resonance (PELDOR), also known as double electron–electron resonance (DEER), provide a complement to atomistic structures obtained from x-ray crystallography or cryo-EM, since spectroscopic data reflect an ensemble and can be measured in more native solvents, unperturbed by a crystal lattice. However, attempts to interpret DEER data are frequently stymied by discrepancies with the structural data, which may arise due to differences in conditions, the dynamics of the protein, or the flexibility of the attached paramagnetic spin labels. Recently, molecular simulation techniques such as EBMetaD have been developed that create a conformational ensemble matching an experimental distance distribution while applying the minimal possible bias. Moreover, it has been proposed that the work required during an EBMetaD simulation to match an experimentally determined distribution could be used as a metric with which to assign conformational states to a given measurement. Here, we demonstrate the application of this concept for a sodium-coupled transport protein, BetP. Because the probe, protein, and lipid bilayer are all represented in atomic detail, the different contributions to the work, such as the extent of protein backbone movements, can be separated. This work therefore illustrates how ranking simulations based on EBMetaD can help to bridge the gap between structural and biophysical data and thereby enhance our understanding of membrane protein conformational mechanisms.
Human-induced changes in the environment have increased the number of stressors impacting aquatic organism. In the light of climate change and plastic pollution, thermal stress and microplastics (MP) have become two of the most intensively studied stressors in aquatic ecosystems. Previous studies, however, mostly evaluated the impacts of thermal and MP stress in isolation, thereby neglecting joint effects.
To examine the combined effects of both, we exposed the freshwater mussel Dreissena polymorpha to irregular polystyrene MP (6.4, 160, 4000, 100,000 p mL−1) at either 14, 23 or 27 °C for 14 days and analyzed mortality, mussel activity and clearance rate, energy reserves, oxidative stress and the immunological state. Further, we exposed the mussels to diatomite (natural particle equivalent, 100,000 p mL−1) at each of the three water temperatures to compare MP and natural particle toxicity.
An increase in water temperature has a pronounced effect on D. polymorpha and significantly affects the activity, energy reserves, oxidative stress and immune function. In contrast, the effects by MP are limited to a change in the antioxidative capacity without any interactive effects between MP and thermal exposure. The comparison of the MP with a diatomite exposure revealed only limited influence of the particle type on the response of D. polymorpha to high concentrations of suspended particles.
The results indicate that MPs have minor effects on a freshwater mussel compared to thermal stress, neither alone nor as interactive effect. Limited MP toxicity could be based on adaptation mechanism of dreissenids to suspended solids. Nonetheless, MP may contribute to environmental impacts of multiple anthropogenic stressors, especially if their levels increase in the future. Therefore, we suggest integrating MP into the broader context of multiple stressor studies to understand and assess their joint impacts on freshwater ecosystems.
Krisen als Normalität
(2020)
Es gibt in Krisenzeiten wenig Verlässliches. Doch auf eines kann man immer zählen: Irgendwann, und meistens früher als später, fällt der Begriff der Ausnahme oder einer seiner zahlreichen Verwandten. Hierzu gehört vor allem die große Schwester der Ausnahme: der Ausnahmezustand. Da unterscheidet sich die Corona-Krise nicht von der Eurozonenkrise, die Eurozonenkrise nicht von der globalen Finanzkrise und diese nicht von der durch die Terroranschläge vom 11. September ausgelöste Sicherheitskrise. Auch wenn wir über den Corona-Virus selbst nicht viel wissen, scheint vieler Orten Gewissheit darüber zu herrschen, dass wir derzeit im Ausnahmezustand leben. ...
Angesichts der in Deutschland und anderswo präzedenzlosen Eingrenzung des rechtlich Erlaubten stehen die begrenzenden Rechtsverordnungen, Allgemeinverfügungen und vollziehenden Maßnahmen des Staates im Zentrum grundrechtlicher Aufmerksamkeit. Freiheitsschonendere Alternativen werden in erster Linie durch das Prisma der Erforderlichkeit in den Blick genommen. Sich in einer Pandemielage gegen Beschränkungen zu entscheiden, erscheint grundrechtlich unverdächtig. Doch wäre es das tatsächlich? Im Folgenden werden zwei unterschiedliche Szenarien einer solchen Entscheidung vorgestellt und es wird ein näherer Blick auf die Folgen für den individuellen Grundrechtsgebrauch geworfen. Es zeigen sich Grundrechtsfragen, die im Ergebnis auch für die Beurteilung des beschränkenden Staates aufgeworfen sind.
Wenn die Bedrohung, wie im Fall des Virus, als natürliche Gegebenheit auftritt, kommen leicht auch die Maßnahmen, um ihn zu beseitigen, als natürliche, d.h. fraglos vorgegebene Maßnahmen in Betracht. Eine Gefahr liegt hier darin, von einer Natürlichkeit des Zwecks auf die Natürlichkeit der Mittel zu schließen. Dass die Maßnahmen aber nicht natürlich gegeben, sondern politisch entschieden sind, muss demgegenüber im Blick bleiben.
Social insects dominate arthropod communities worldwide due to cooperation and division of labor in their societies. This, however, makes them vulnerable to exploitation by social parasites, such as slave‐making ants. Slave‐making ant workers pillage brood from neighboring nests of related host ant species. After emergence, host workers take over all nonreproductive colony tasks, whereas slavemakers have lost the ability to care for themselves and their offspring. Here, we compared transcriptomes of different developmental stages (larvae, pupae, and adults), castes (queens and workers), and sexes of two related ant species, the slavemaker Temnothorax americanus and its host Temnothorax longispinosus. Our aim was to investigate commonalities and differences in group‐specific transcriptomes, whereupon across‐species differences possibly can be explained by their divergent lifestyles. Larvae and pupae showed the highest similarity between the two species and upregulated genes with enriched functions of translation and chitin metabolism, respectively. Workers commonly upregulated oxidation‐reduction genes, possibly indicative of their active lifestyle. Host workers, but not workers of the slavemaker, upregulated a “social behavior” gene. In slavemaker queens and workers, genes associated with the regulation of transposable elements were upregulated. Queens of both species showed transcriptomic signals of anti‐aging mechanisms, with hosts upregulating various DNA repair pathways and slavemaker queens investing in trehalose metabolism. The transcriptomes of males showed enriched functions for quite general terms realized in different genes and pathways in each species. In summary, the strong interspecific commonalities in larvae, pupae, and workers were reflected in the same enriched Gene Ontology (GO) terms. Less commonalities occurred in the transcriptomes of queens and males, which apparently utilize different pathways to achieve a long life and sperm production, respectively. We found that all analyzed groups in this study show characteristic GO terms, with similar patterns in both species.
Seit Wochen nun beobachten wir, wie Menschen auf sehr unterschiedliche Weise auf die COVID-19-Pandemie reagieren. Die unmittelbare Gefahrenursache ist zwar für das bloße Auge nicht sichtbar. Sichtbar hingegen sind die von der Weltgesundheitsorganisation, der Johns Hopkins Universität oder dem Robert-Koch-Institut veröffentlichten Daten. Täglich steigende Zahlen von Infizierten, täglich steigende Zahlen von Toten. Vielleicht ist es nachvollziehbar, dass "in diesen Zeiten" Regelungsmaßnahmen "mit heißer Nadel gestrickt" (noch so eine Phrase) sind. Selbst wenn in der Theorie Krisenszenarien vielleicht irgendwann einmal durchgespielt worden sind (siehe BT Drs. 17/12051, S. 57 ff.), lässt sich nicht jede Variante einer Krise antizipieren – genauso wenig wie der tatsächliche Stressmodus, in dem andere und man selbst sich befinden werden. In diesem Modus sind nun Entscheidungen getroffen worden. Entscheidungen, deren Konsequenzen ohne jegliche Übertreibung als der "massivste kollektive Grundrechtseingriff in der Geschichte der Bundesrepublik" bezeichnet werden können. ...
Background: Data on Candida bloodstream infections in pediatric patients in Europe are limited. We performed a retrospective multicenter European study of the epidemiology and outcome of neonatal and pediatric candidemia.
Material and Methods: All first positive blood cultures from patients ≤ 18 years of age with candidemia were registered. Patients’ demographic and clinical characteristics and causative Candida species were collected and analyzed. Regression analysis was used to identify factors independently associated with mortality.
Results: One thousand three hundred ninety-five episodes of candidemia (57.8% male) were reported from 23 hospitals in 10 European countries. Of the 1395 episodes, 36.4% occurred in neonates (≤ 44 weeks postmenstrual age), 13.8% in infants (> 44 weeks postmenstrual age to 1 year) and 49.8% in children and adolescents. Candida albicans (52.5%) and Candida parapsilosis (28%) were the predominant species. A higher proportion of candidemia caused by C. albicans was observed among neonatal patients (60.2%) with highest rates of C. parapsilosis seen among infants (42%). Children admitted to hematology-oncology wards presented the highest rates of non-albicans Candida species. Candidemia because of C. albicans was more frequent than non-albicans Candida in Northern versus Southern Europe (odds ratio, 2.3; 95% confidence interval, 1.8–2.9; P < 0.001). The all-cause mortality at 30 days was 14.4%. All-cause mortality was higher among patients admitted to the neonatal or pediatric intensive care units than other wards. Over time, no significant changes in species distribution were observed.
Conclusions: This first multicenter European study shows unique characteristics of the epidemiology of pediatric candidemia. The insights obtained from this study will be useful to guide clinical management and antifungal stewardship.
Non-random connectivity can emerge without structured external input driven by activity-dependent mechanisms of synaptic plasticity based on precise spiking patterns. Here we analyze the emergence of global structures in recurrent networks based on a triplet model of spike timing dependent plasticity (STDP) which depends on the interactions of three precisely-timed spikes and can describe plasticity experiments with varying spike frequency better than the classical pair-based STDP rule. We derive synaptic changes arising from correlations up to third-order and describe them as the sum of structural motifs which determine how any spike in the network influences a given synaptic connection through possible connectivity paths. This motif expansion framework reveals novel structural motifs under the triplet STDP rule, which support the formation of bidirectional connections and ultimately the spontaneous emergence of global network structure in the form of self-connected groups of neurons, or assemblies. We propose that under triplet STDP assembly structure can emerge without the need for externally patterned inputs or assuming a symmetric pair-based STDP rule common in previous studies. The emergence of non-random network structure under triplet STDP occurs through internally-generated higher-order correlations, which are ubiquitous in natural stimuli and neuronal spiking activity, and important for coding. We further demonstrate how neuromodulatory mechanisms that modulate the shape of the triplet STDP rule or the synaptic transmission function differentially promote structural motifs underlying the emergence of assemblies, and quantify the differences using graph theoretic measures.
In a 40-year-old caucasian patient with stress incontinence was a TVT operation performed with an autologous semitendinosus tendon transplant. The operation was done with spinal anesthesia. The tendon of the right musculus semitendinosus was stripped from the popliteal fossa and used instead of a synthetic tape as midurethral sling, as it is done in a classical retropubic TVT procedure. The operation was performed successfully. On the first day after the operation the transurethral catheter was removed, continence was reached, and no urinary retention was seen. Mobility and power of the affected leg did not change.
Background: The back pain screening tool Risk-Prevention-Index Social (RPI-S) identifies the individual psychosocial risk for low back pain chronification and supports the allocation of patients at risk in additional multidisciplinary treatments. The study objectives were to evaluate (1) the prognostic validity of the RPI-S for a 6-month time frame and (2) the clinical benefit of the RPI-S. Methods: In a multicenter single-blind 3-armed randomized controlled trial, n = 660 persons (age 18-65 years) were randomly assigned to a twelve-week uni- or multidisciplinary exercise intervention or control group. Psychosocial risk was assessed by the RPI-S domain social environment (RPI-SSE) and the outcome pain by the Chronic Pain Grade Questionnaire (baseline M1, 12-weeks M4, 24-weeks M5). Prognostic validity was quantified by the root mean squared error (RMSE) within the control group. The clinical benefit of RPI-SSE was calculated by repeated measures ANOVA in intervention groups. Results: A subsample of n = 274 participants (mean = 38.0 years, SD 13.1) was analyzed, of which 30% were classified at risk in their psychosocial profile. The half-year prognostic validity was good (RMSE for disability of 9.04 at M4 and of 9.73 at M5; RMSE for pain intensity of 12.45 at M4 and of 14.49 at M5). People at risk showed significantly stronger reduction in pain disability and intensity at M4/M5, if participating in a multidisciplinary exercise treatment. Subjects at no risk showed a smaller reduction in pain disability in both interventions and no group differences for pain intensity. Regarding disability due to pain, around 41% of the sample would gain an unfitted treatment without the back pain screening. Conclusion: The RPI-SSE prognostic validity demonstrated good applicability and a clinical benefit confirmed by a clear advantage of an individualized treatment possibility.
The Specialised Information Service Performing Arts (SIS PA) is part of a funding programme by the German Research Foundation that enables libraries to develop tailor-made services for individual disciplines in order to provide researchers direct access to relevant materials and resources from their field. For the field of performing arts, the SIS PA is aggregating metadata about theater and dance resources from currently, mostly, German-speaking cultural heritage institutions in a VuFind-based search portal.
In this article, we focus on metadata quality and its impact on the aggregation workflow by describing the different, possibly data provider-specific, process stages of improving data quality in order to achieve a searchable, interlinked knowledge base. We also describe lessons learned and limitations of the process.
Bevor der Bundesgesundheitsminister mit der Corona-Bewältigung in das Rampenlicht der Öffentlichkeit treten konnte, versuchte er in einer Reihe von Gesetzgebungsvorhaben und Maßnahmen, die deutsche gesetzliche Krankenversicherung (GKV) zu verändern. Eine seiner Maßnahmen war das Digitale-Versorgung-Gesetz, das der Bundestag im Dezember 2019 verabschiedete (DVG, BGBl. I, S. 2562) und die medizinische Versorgung durch Digitalisierung und Innovation verbessern sollte. Es sieht u.a. vor, Gesundheits-Apps auf Rezept zu verschreiben und Videosprechstunden und Telemedizin zum Alltag werden zu lassen. Vor allem aber sollen umfangreiche medizinische Daten der Versicherten in einem Forschungsdatenzentrum zusammengeführt und effektiv ausgewertet werden, um bessere Erkenntnisse in der Gesundheitsforschung zu erlangen.
Dagegen hatte ein Versicherter Beschwerde erhoben, und das Bundesverfassungsgericht hat im Verfahren des einstweiligen Rechtsschutzes entschieden, dass Teile dieses Gesetzes – nämlich §§ 68a Abs. 5 und 303a-303f SGB V – in der Tat erhebliche verfassungsrechtliche Bedenken aufwerfen. Dennoch hat das Gericht den Vollzug dieser Regelungen nicht ausgesetzt (Rn. 6 ff.) und noch nicht einmal die hilfsweise beantragte Reduktion des Datenumgangs angeordnet. Das ist im Ergebnis, vor allem aber in seiner Begründung unter mindestens zwei Aspekten kritisch zu betrachten.
Datenschutz versus Katastrophenschutz : Standortdaten als Mittel zur Bekämpfung der Corona-Pandemie
(2020)
Einige Länder setzen Standortdaten jetzt schon gezielt ein, um die weitere Ausbreitung von Covid-19 einzudämmen. Ein Gesetzentwurf von Bundesgesundheitsminister Jens Spahn, der weitreichende Befugnisse vorsah, um mithilfe von Standortdaten Kontaktpersonen von Infizierten über deren Handys zu orten, stieß auf teilweise heftige Kritik. Der Gesetzentwurf wurde daraufhin zurückgezogen, ohne dass nähere Einzelheiten an die Öffentlichkeit gelangt sind. Ein genauer Blick zeigt jedoch, dass eine Verarbeitung von Standortgesundheitsdaten nicht nur tatsächlich nützlich sein kann, sondern auch rechtlich möglich ist.
This paper summarizes key elements of the German Federal Constitutional Court’s decision on the European Central Bank’s Public Sector Asset Purchase Programme. It briefly explains how it is possible for the German Court to disagree with the ruling of the Court of Justice of the European Union. Finally, it makes suggestions concerning a practical way forward for the Governing Council of the ECB in light of these developments.
Diamond formation in the Earth has been extensively discussed in recent years on the basis of geochemical analysis of natural materials, high-pressure experimental studies, or theoretical aspects. Here, we demonstrate experimentally for the first time, the spontaneous crystallization of diamond from CH4-rich fluids at pressure, temperature and redox conditions approximating those of the deeper parts of the cratonic lithospheric mantle (5-7 GPa) without using diamond seed crystals or carbides. In these experiments the fluid phase is nearly pure methane, even though the oxygen fugacity was significantly above metal saturation. We propose several previously unidentified mechanisms that may promote diamond formation under such conditions and which may also have implications for the origin of sublithospheric diamonds. These include the hydroxylation of silicate minerals like olivine and pyroxene, H2 incorporation into these phases and the "etching" of graphite by H2 and CH4 and reprecipitation as diamond. This study also serves as a demonstration of our new high-pressure experimental technique for obtaining reduced fluids, which is not only relevant for diamond synthesis, but also for investigating the metasomatic origins of diamond in the upper mantle, which has further implications for the deep carbon cycle.
Hintergrund: Die chronische metabolischen Azidose (cmA) ist eine häufige Komplikation bei chronischer Niereninsuffizienz, deren Behandlung bei niereninsuffizienten Patienten mit Diabetes mellitus die Insulinresistenz verbessern kann. Um die aktuelle Therapiesituation der cmA im diabetologischen Umfeld abzubilden und mehr über die Zusammenarbeit von Diabetologen und Nephrologen zu erfahren, wurden diabetologisch tätige Haus- und Fachärzte zur cmA befragt.
Methoden An 5863 Ärzten mit diabetologischer Zusatzqualifikation wurde postalisch ein Fragebogen versandt. Alle 97 erhaltenen Antwortbögen wurden deskriptiv ausgewertet.
Ergebnisse Die meisten Teilnehmer sind Internisten mit diabetologischer Zusatzqualifikation (46 %) und behandeln im Median 50 (10; 112) Patienten mit Typ-1-Diabetes bzw. 210 (100; 450) Patienten mit Typ-2-Diabetes pro Quartal. Eine cmA wurde von 12 % der Teilnehmer in den letzten 12 Monaten bei median 4 (2; 6) Patienten mit Typ-1-Diabetes und 10 (3; 30) Patienten mit Typ-2-Diabetes beobachtet. Die cmA wird überwiegend durch Bestimmung des Serum-Bikarbonats (27; 28 %) und des Base Excess (19; 20 %) diagnostiziert. 38 (39 %) der Teilnehmer erhalten regelmäßig von Nephrologen die Empfehlung zur Behandlung der cmA. Sie wird von knapp 1 Drittel als relevant (29 %) und gut umsetzbar (27 %) betrachtet. Zur Behandlung der cmA wird vor allem orales Bikarbonat empfohlen (Bikarbonat: 39 %, Zitrat: 5 %, sonst: keine Angabe). Maßnahmen, die die Mehrheit der Diabetologen in der Verantwortung der Nephrologen sehen, sind ergänzende Diagnostik (87; 90 %) einschließlich Blutgasanalyse (59 %) sowie die Behandlung der cmA (62 %) und renalen Anämie (53 %). 34 % der Diabetologen gaben an, bisher noch keine cmA-Fälle in der Praxis behandelt zu haben. Die meisten Diabetologen überlassen die Behandlung und Überwachung der cmA dem Nephrologen (38 %). Dabei wird die Zusammenarbeit mit den Nephrologen als zufriedenstellend (81 %) bewertet. 38 % der Befragten haben in der täglichen Praxis beobachtet, dass die Einstellung der cmA auch die Insulinresistenz positiv beeinflusst. Eine CME-Fortbildung in der Diabetologie speziell zur cmA würden 76 (78 %) begrüßen.
Diskussion Bei der Behandlung der cmA wird die Kooperation zwischen Diabetologen und Nephrologen generell gut bewertet, wobei die Diagnose, Behandlung und Überwachung einer cmA in der Verantwortung des Nephrologen gesehen werden. Da die Behandlung der cmA die Insulinresistenz verringern kann, sollte der Stellenwert der cmA-Therapie im diabetologischen Umfeld nicht unterschätzt werden. Um die cmA-Behandlung bei diabetischer Nephropathie zu optimieren, wären CME-Fortbildungen zur cmA geeignet. Zudem könnten Schulungen im Rahmen einer interdisziplinären Kooperation mit Diätberatern die Umsetzbarkeit diätetischer Interventionen zur Behandlung der cmA verbessern.
Background & Aims: Spontaneous portosystemic shunts (SPSS) frequently develop in liver cirrhosis. Recent data suggested that the presence of a single large SPSS is associated with complications, especially overt hepatic encephalopathy (oHE). However, the presence of >1 SPSS is common. This study evaluates the impact of total cross-sectional SPSS area (TSA) on outcomes in patients with liver cirrhosis.
Methods: In this retrospective international multicentric study, CT scans of 908 cirrhotic patients with SPSS were evaluated for TSA. Clinical and laboratory data were recorded. Each detected SPSS radius was measured and TSA calculated. One-year survival was the primary endpoint and acute decompensation (oHE, variceal bleeding, ascites) was the secondary endpoint.
Results: A total of 301 patients (169 male) were included in the training cohort. Thirty percent of all patients presented with >1 SPSS. A TSA cut-off of 83 mm2 was used to classify patients with small or large TSA (S-/L-TSA). Patients with L-TSA presented with higher model for end-stage liver disease score (11 vs. 14) and more commonly had a history of oHE (12% vs. 21%, p <0.05). During follow-up, patients with L-TSA experienced more oHE episodes (33% vs. 47%, p <0.05) and had lower 1-year survival than those with S-TSA (84% vs. 69%, p <0.001). Multivariate analysis identified L-TSA (hazard ratio 1.66; 95% CI 1.02–2.70, p <0.05) as an independent predictor of mortality. An independent multicentric validation cohort of 607 patients confirmed that patients with L-TSA had lower 1-year survival (77% vs. 64%, p <0.001) and more oHE development (35% vs. 49%, p <0.001) than those with S-TSA.
Conclusion: This study suggests that TSA >83 mm2 increases the risk for oHE and mortality in patients with cirrhosis. Our results support the clinical use of TSA/SPSS for risk stratification and decision-making in the management of patients with cirrhosis.
Lay summary: The prevalence of spontaneous portosystemic shunts (SPSS) is higher in patients with more advanced chronic liver disease. The presence of more than 1 SPSS is common in advanced chronic liver disease and is associated with the development of hepatic encephalopathy. This study shows that total cross-sectional SPSS area (rather than diameter of the single largest SPSS) predicts survival in patients with advanced chronic liver disease. Our results support the clinical use of total cross-sectional SPSS area for risk stratification and decision-making in the management of SPSS.
Cryptocurrencies have received growing attention from individuals, the media, and regulators. However, little is known about the investors whom these financial instruments attract. Using administrative data, we describe the investment behavior of individuals who invest in cryptocurrencies with structured retail products. We find that cryptocurrency investors are active traders, prone to investment biases, and hold risky portfolios. In line with attention effects and anticipatory utility, we find that the average cryptocurrency investor substantially increases log-in and trading activity after his or her first cryptocurrency purchase. Our results document which investors are more likely to adopt new financial products and help inform regulators about investors' vulnerability to cryptocurrency investments.
The transition from local to global patterns governs the differentiation of mouse blastocysts
(2020)
During mammalian blastocyst development, inner cell mass (ICM) cells differentiate into epiblast (Epi) or primitive endoderm (PrE). These two fates are characterized by the expression of the transcription factors NANOG and GATA6, respectively. Here, we investigate the spatio-temporal distribution of NANOG and GATA6 expressing cells in the ICM of the mouse blastocysts with quantitative three-dimensional single cell-based neighbourhood analyses. We define the cell neighbourhood by local features, which include the expression levels of both fate markers expressed in each cell and its neighbours, and the number of neighbouring cells. We further include the position of a cell relative to the centre of the ICM as a global positional feature. Our analyses reveal a local three-dimensional pattern that is already present in early blastocysts: 1) Cells expressing the highest NANOG levels are surrounded by approximately nine neighbours, while 2) cells expressing GATA6 cluster according to their GATA6 levels. This local pattern evolves into a global pattern in the ICM that starts to emerge in mid blastocysts. We show that FGF/MAPK signalling is involved in the three-dimensional distribution of the cells and, using a mutant background, we further show that the GATA6 neighbourhood is regulated by NANOG. Our quantitative study suggests that the three-dimensional cell neighbourhood plays a role in Epi and PrE precursor specification. Our results highlight the importance of analysing the three-dimensional cell neighbourhood while investigating cell fate decisions during early mouse embryonic development.
How is semantic information stored in the human mind and brain? Some philosophers and cognitive scientists argue for vectorial representations of concepts, where the meaning of a word is represented as its position in a high-dimensional neural state space. At the intersection of natural language processing and artificial intelligence, a class of very successful distributional word vector models has developed that can account for classic EEG findings of language, that is, the ease versus difficulty of integrating a word with its sentence context. However, models of semantics have to account not only for context-based word processing, but should also describe how word meaning is represented. Here, we investigate whether distributional vector representations of word meaning can model brain activity induced by words presented without context. Using EEG activity (event-related brain potentials) collected while participants in two experiments (English and German) read isolated words, we encoded and decoded word vectors taken from the family of prediction-based Word2vec algorithms. We found that, first, the position of a word in vector space allows the prediction of the pattern of corresponding neural activity over time, in particular during a time window of 300 to 500 ms after word onset. Second, distributional models perform better than a human-created taxonomic baseline model (WordNet), and this holds for several distinct vector-based models. Third, multiple latent semantic dimensions of word meaning can be decoded from brain activity. Combined, these results suggest that empiricist, prediction-based vectorial representations of meaning are a viable candidate for the representational architecture of human semantic knowledge.
Background: Naturalistic developmental behavioural interventions (NDBI) have been shown to improve autism-specific symptoms in young children with Autism Spectrum Disorder (ASD). NDBI approaches, such as the ASD-specific Frankfurt Early Intervention Programme for ASD (A-FFIP), are based on ASD-specific developmental and learning aspects. A-FFIP is a low-intensity intervention which can easily be implemented in the local health care/social welfare system. The aim of the present study is to establish 1-year efficacy of the manualised early intervention programme A-FFIP in toddlers and preschool children with ASD. It is hypothesised that A-FFIP will result in improved ASD-specific symptoms compared to early intervention as usual (EIAU). Child- and family-specific secondary outcomes, as well as moderators and mediators of outcome, will be explored.
Methods/design: A prospective, multi-centre, parallel-group, randomised controlled, phase-III trial comparing A-FFIP versus EIAU. A total of 134 children (A-FFIP: 67, EIAU: 67) aged 24–66 months at baseline assessment meeting the criteria for ASD (DSM-5) will be included. The primary outcome is the absolute change of the total score of the Brief Observation of Social Communication Change (BOSCC-AT) between baseline (T2) and 1-year follow-up (T6). The treatment effect will be tested, adjusted for relevant covariates applying a mixed model for repeated measures. Secondary outcomes are BOSCC social communication and repetitive-behaviour scores, single ASD symptoms, language, cognition, psychopathology, parental well-being and family quality of life. Predictors, moderators and mediating mechanisms will be explored.
Discussion: If efficacy of the manualised A-FFIP early intervention is established, the current study has the potential to change clinical practice strongly towards the implementation of a low-intensity, evidence-based, natural early intervention in ASD. Early intervention in ASD requires specialist training, which subsequently needs to be developed or included into current training curricula.
Trial registration: German Registry for Clinical Trials (Deutscher Register Klinischer Studien, DRKS); ID: 00016330. Retrospectively registered on 4 January 2019. URL: https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00016330.
Background: Depression is a widespread disorder with severe impacts for individuals and society, especially in its chronic form. Current treatment approaches for persistent depression have focused primarily on reducing negative affect and have paid little attention to promoting positive affect. Previous studies have shown that metta meditation increases positive affect in chronically depressed patients. Results from previous trials provide evidence for the efficacy of a stand-alone metta meditation group treatment in combination with mindfulness-based approaches. Further research is needed to better understand the implementation of meditation practice into everyday life. Therefore, mindfulness and metta meditation in a group setting are combined with individual cognitive behavioral therapy (CBT) into a new, low-intensity, cost-effective treatment (“MeCBT”) for chronic depression. Methods/design: In this single-center, randomized, observer-blinded, parallel-group clinical trial we will test the efficacy of MeCBT in reducing depression compared to a wait-list control condition. Forty-eight participants in a balanced design will be allocated randomly to a treatment group or a wait-list control group. Metta-based group meditation will be offered in eight weekly sessions and one additional half-day retreat. Subsequent individual CBT will be conducted in eight fortnightly sessions. Outcome measures will be assessed at four time points: before intervention (T0); after group meditation (T1); after individual CBT (T2); and, in the treated group only, at 6-month follow-up (T3). Changes in depressive symptoms (clinician rating), assessed with the Quick Inventory of Depressive Symptoms (QIDS-C) are the primary outcome. We expect a significant decline of depressive symptoms at T2 compared to the wait-list control group. Secondary outcome measures include self-rated depression, mindfulness, benevolence, rumination, emotion regulation, social connectedness, social functioning, as well as behavioral and cognitive avoidance. We will explore changes at T1 and T2 in all these secondary outcome variables. Discussion: To our knowledge this is the first study to combine a group program focusing on Metta meditation with stateof-the art individual CBT specifically tailored to chronic depression. Implications for further refinement and examination of the treatment program are discussed. Trial registration: ISRCTN, ISRCTN97264476. Registered 29 March 2018 (applied on 14 December 2017)—retrospectively registered.
High-quality single crystals of the unconventional superconductor NdFeAsO1 − xFx were grown. We developed a new optimized flux technique to overcome the difficulties in single-crystal growth and the sample quality limitations of NdFeAsO1 − xFx. The normal state of the F-doped samples exhibits simple metallic behavior upon cooling down from room temperature, followed by a sharp superconducting transition. The values of residual resistivity ratio (RRR) is 3.2, 6.4, and 10.3 for x = 0.1, 0.15, and 0.2, respectively. Both the large RRR and the narrow superconducting transition signpost the high quality of the crystals. We have examined the in- and out-of-plane lower critical fields, and the field at which vortices penetrate the sample of NdFeAsO1 − xFx (x = 0.1). The anisotropy ratio [γHc1 (0)] increased slightly with increasing temperature from 0.8 Tc to Tc. The temperature dependence of the first vortex penetration field was obtained under the static magnetic field, H, parallel to the c- and ab- axis, and pronounced changes in the Hc1(T) curvature were observed, which are attributed to the multi-band superconductivity.
Ferroptosis, a newly discovered form of cell death mediated by reactive oxygen species (ROS) and lipid peroxidation, has recently been shown to have an impact on various cancer types; however, so far there are only few studies about its role in hepatocellular carcinoma (HCC). The delicate equilibrium of ROS in cancer cells has found to be crucial for cell survival, thus increased levels may trigger ferroptosis in HCC.In our study, we investigated the effect of different ROS modulators and ferroptosis inducers on a human HCC cell line and a human hepatoblastoma cell line. We identified a novel synergistic cell death induction by the combination of Auranofin and buthionine sulfoxime (BSO) or by Erastin and BSO at subtoxic concentrations. We found a caspase-independent, redox-regulated cell death, which could be rescued by different inhibitors of ferroptosis. Both cotreatments stimulated lipid peroxidation. All these findings indicated ferroptotic cell death. Both cotreatments affected the canonical ferroptosis pathway through GPX4 downregulation. We also found an accumulation of Nrf2 and HO-1, indicating an additional effect on the non-canonical pathway. Our results implicate that targeting these two main ferroptotic pathways simultaneously can overcome chemotherapy resistance in HCC.
The production of light (anti-)(hyper-)nuclei in heavy-ion collisions at the LHC is considered in the framework of the Saha equation, making use of the analogy between the evolution of the early universe after the Big Bang and that of “Little Bangs” created in the lab. Assuming that disintegration and regeneration reactions involving light nuclei proceed in relative chemical equilibrium after the chemical freeze-out of hadrons, their abundances are determined through the famous cosmological Saha equation of primordial nucleosynthesis and show no exponential dependence on the temperature typical for the thermal model. A quantitative analysis, performed using the hadron resonance gas model in partial chemical equilibrium, shows agreement with experimental data of the ALICE collaboration on d, 3He, HΛ3, and 4He yields for a very broad range of temperatures at T≲155 MeV. The presented picture is supported by the observed suppression of resonance yields in central Pb–Pb collisions at the LHC. Keywords: Light (anti-)(hyper-)nuclei production, Saha equation, Partial chemical equilibrium.
Children with reading and/or spelling disorders have increased rates of behavioral and emotional problems and combinations of these. Some studies also find increased rates of attention-deficit/hyperactivity disorder (ADHD), conduct disorder, anxiety disorder, and depression. However, the comorbidities of, e.g., arithmetic disorders with ADHD, anxiety disorder, and depression have been addressed only rarely. The current study explored the probability of children with specific learning disorders (SLD) in reading, spelling, and/or arithmetic to also have anxiety disorder, depression, ADHD, and/or conduct disorder. The sample consisted of 3,014 German children from grades 3 and 4 (mean age 9;9 years) who completed tests assessing reading, spelling as well as arithmetic achievement and intelligence via a web-based application. Psychopathology was assessed using questionnaires filled in by the parents. In children with a SLD we found high rates of anxiety disorder (21%), depression (28%), ADHD (28%), and conduct disorder (22%). Children with SLD in multiple learning domains had a higher risk for psychopathology and had a broader spectrum of psychopathology than children with an isolated SLD. The results highlight the importance of screening for and diagnosing psychiatric comorbidities in children with SLD.