Zwei Beispiele aus der Praxis des Musikunterrichts

Die hier vorgestellten Beispiele aus der Praxis des Musikunterrichts in dritten und vierten Klassen stellen vielfältige Bezüge her zu den vier im Beitrag von Constanze Rora und Lutz Schäfer beschriebenen Dimensionen ästhetischer Erfahrung und möchten Anregung sein, ästhetische Erfahrungen im eigenen Unterricht zu ermöglichen. Es werden jeweils zunächst der Ablauf des Unterrichtsvorschlags vorgestellt und dann in einem weiteren Schritt die Bezüge zum theoretischen Rahmen aufgezeigt. (DIPF/Orig.

The Impact of Rubella Virus Infection on a Secondary Inflammatory Response in Polarized Human Macrophages

Macrophages (MF) are known to exhibit distinct responses to viral and bacterial infection, but how they react when exposed to the pathogens in succession is less well understood. Accordingly, we determined the effect of a rubella virus (RV)-induced infection followed by an LPS-induced challenge on cytokine production, signal transduction and metabolic pathways in human GM (M1-like)- and M (M2-like)-MF. We found that infection of both subsets with RV resulted in a low TNF-a and a high interferon (IFN, type I and type III) release whereby M-MF produced far more IFNs than GM-MF. Thus, TNF-a production in contrast to IFN production is not a dominant feature of RV infection in these cells. Upon addition of LPS to RV-infected MF compared to the addition of LPS to the uninfected cells the TNF-a response only slightly increased, whereas the IFN-response of both subtypes was greatly enhanced. The subset specific cytokine expression pattern remained unchanged under these assay conditions. The priming effect of RV was also observed when replacing RV by IFN-b one putative priming stimulus induced by RV. Small amounts of IFN-b were sufficient for phosphorylation of Stat1 and to induce IFN-production in response to LPS. Analysis of signal transduction pathways activated by successive exposure of MF to RV and LPS revealed an increased phosphorylation of NFkB (MMF), but different to uninfected MF a reduced phosphorylation of ERK1/2 (both subtypes). Furthermore, metabolic pathways were affected; the LPS-induced increase in glycolysis was dampened in both subtypes after RV infection. In conclusion, we show that RV infection and exogenously added IFN-b can prime MF to produce high amounts of IFNs in response to LPS and that changes in glycolysis and signal transduction are associated with the priming effect. These findings will help to understand to what extent MF defense to viral infection is modulated by a following exposure to a bacterial infection

Burden of disease in myasthenia gravis: taking the patient’s perspective

Background: Myasthenia gravis (MG) leads to exertion-dependent muscle weakness, but also psychological and social well-being are limited. We aim to describe the burden of disease in MG including sociodemographic, economical, psychosocial as well as clinical aspects, to compare health-related quality of life (HRQoL) of patients with MG to the general population (genP) and to explore risk factors for a lower HRQoL. Methods: This case-control study was conducted with MG patients of the German Myasthenia Association. A questionnaire-based survey included sociodemographic and clinical data as well as standardized questionnaires, e.g. the Short Form Health (SF-36). HRQoL was compared to genP in a matched-pairs analysis. Participants of the German Health Interview and Examination Survey for Adults (DEGS1) served as control group. Results: In our study, 1660 MG patients participated and were compared to 2556 controls from the genP. Patients with MG showed lower levels of physical functioning (SF-36 mean 56.0, SD 30.3) compared to the genP (mean 81.8, SD 22.1, adjusted difference: 25, 95% CI 22-29) and lower mental health sub-score (SF-36 mean 67.3, SD 19.8, vs. 74.1, SD 16.7, adjusted difference: 5, 95% CI 2-8). Female gender, higher age, low income, partnership status, lower activities of daily life, symptoms of depression, anxiety and fatigue and self-perceived low social support were associated with a lower HRQoL in MG patients. Discussion: HRQoL is lower in patients with MG compared to genP. The burden of MG on patients includes economic and social aspects as well as their emotional well-being. New therapies must achieve improvements for patients in these areas

Glutaminyl cyclase contributes to the formation of focal and diffuse pyroglutamate (pGlu)-Aβ deposits in hippocampus via distinct cellular mechanisms

In the hippocampal formation of Alzheimer’s disease (AD) patients, both focal and diffuse deposits of Aβ peptides appear in a subregion- and layer-specific manner. Recently, pyroglutamate (pGlu or pE)-modified Aβ peptides were identified as a highly pathogenic and seeding Aβ peptide species. Since the pE modification is catalyzed by glutaminyl cyclase (QC) this enzyme emerged as a novel pharmacological target for AD therapy. Here, we reveal the role of QC in the formation of different types of hippocampal pE-Aβ aggregates. First, we demonstrate that both, focal and diffuse pE-Aβ deposits are present in defined layers of the AD hippocampus. While the focal type of pE-Aβ aggregates was found to be associated with the somata of QC-expressing interneurons, the diffuse type was not. To address this discrepancy, the hippocampus of amyloid precursor protein transgenic mice was analysed. Similar to observations made in AD, focal (i.e. core-containing) pE-Aβ deposits originating from QC-positive neurons and diffuse pE-Aβ deposits not associated with QC were detected in Tg2576 mouse hippocampus. The hippocampal layers harbouring diffuse pE-Aβ deposits receive multiple afferents from QC-rich neuronal populations of the entorhinal cortex and locus coeruleus. This might point towards a mechanism in which pE-Aβ and/or QC are being released from projection neurons at hippocampal synapses. Indeed, there are a number of reports demonstrating the reduction of diffuse, but not of focal, Aβ deposits in hippocampus after deafferentation experiments. Moreover, we demonstrate in neurons by live cell imaging and by enzymatic activity assays that QC is secreted in a constitutive and regulated manner. Thus, it is concluded that hippocampal pE-Aβ plaques may develop through at least two different mechanisms: intracellularly at sites of somatic QC activity as well as extracellularly through seeding at terminal fields of QC expressing projection neurons

Lysimeter-based full fertilizer 15N balances corroborate direct dinitrogen emission measurements using the 15N gas flow method

The $^{15}$N gas flux ($^{15}$NGF) method allows for direct in situ quantification of dinitrogen (N$_2$) emissions from soils, but a successful cross-comparison with another method is missing. The objectives of this study were to quantify N$_2$ emissions of a wheat rotation using the $^{15}$NGF method, to compare these N$_2$ emissions with those obtained from a lysimeter-based $^{15}$N fertilizer mass balance approach, and to contextualize N$_2$ emissions with $^{15}$N enrichment of N$_2$ in soil air. For four sampling periods, fertilizer-derived N$_2$ losses ($^{15}$NGF method) were similar to unaccounted fertilizer N fates as obtained from the $^{15}$N mass balance approach. Total N$_2$ emissions ($^{15}$NGF method) amounted to 21 ± 3 kg N ha− 1, with 13 ± 2 kg N ha− 1 (7.5% of applied fertilizer N) originating from fertilizer. In comparison, the $^{15}$N mass balance approach overall indicated fertilizer-derived N$_2$ emissions of 11%, equivalent to 18 ± 13 kg N ha− 1. Nitrous oxide (N$_2$O) emissions were small (0.15 ± 0.01 kg N ha− 1 or 0.1% of fertilizer N), resulting in a large mean N$_2$:(N$_2$O + N$_2$) ratio of 0.94 ± 0.06. Due to the applied drip fertigation, ammonia emissions accounted for < 1% of fertilizer-N, while N leaching was negligible. The temporal variability of N$_2$ emissions was well explained by the δ$^{15}$N$_2$ in soil air down to 50 cm depth. We conclude the $^{15}$NGF method provides realistic estimates of field N$_2$ emissions and should be more widely used to better understand soil N$_2$ losses. Moreover, combining soil air δ$^{15}$N$_2$ measurements with diffusion modeling might be an alternative approach for constraining soil N$_2$ emissions

Retrospektive Phaseneinteilung der COVID-19-Pandemie in Deutschland bis Februar 2021

Seit Anfang März 2020 wurde in Deutschland eine deutliche Zunahme der COVID-19-Fälle beobachtet, mit einem Höhepunkt von etwa 35.000 Fällen in der Meldewoche 14/2020. Im folgenden Sommer wurden zunächst deutlich rückläufige Fallzahlen beobachtet. Diese waren insbesondere auf Ausbrüche in Gemeinschaftsunterkünften, fleischverarbeitenden Betrieben und auf Einreisende zurückzuführen. Im Spätsommer stieg die Anzahl übermittelter Fälle erneut an und mündete in einem starten exponentiellen Anstieg zum Herbst 2020. Um Änderungen im Gesamtgeschehen erkennen und interpretieren zu können, ist es erforderlich den Verlauf basierend auf den verfügbaren Daten in klar definierte Phasen einzuteilen. Dazu sind objektive Kriterien notwendig, die unterschiedliche Zeiträume möglichst klar voneinander trennen. Die Phaseneinteilung anhand epidemiologischer Parameter soll eine Grundlage für zukünftige Auswertungen und Darstellungen schaffen und Vergleiche (z. B. zur Transmission, individuellen klinischen Schwere und zur Belastung des Gesundheitswesen) innerhalb der verschiedenen Phasen ermöglichen

Effects of Spermidine Supplementation on Cognition and Biomarkers in Older Adults With Subjective Cognitive Decline : Decline A Randomized Clinical Trial

IMPORTANCE Developing interventions against age-related memory decline and for older adults experiencing neurodegenerative disease is one of the greatest challenges of our generation. Spermidine supplementation has shown beneficial effects on brain and cognitive health in animal models, and there has been preliminary evidence of memory improvement in individuals with subjective cognitive decline. OBJECTIVE To determine the effect of longer-term spermidine supplementation on memory performance and biomarkers in this at-risk group. DESIGN, SETTING, AND PARTICIPANTS This 12-month randomized, double-masked, placebocontrolled phase 2b trial (the SmartAge trial) was conducted between January 2017 and May 2020. The study was a monocenter trial carried out at an academic clinical research center in Germany. Eligible individuals were aged 60 to 90 years with subjective cognitive decline who were recruited from health care facilities as well as through advertisements in the general population. Data analysis was conducted between January and March 2021. INTERVENTIONS One hundred participants were randomly assigned (1:1 ratio) to 12 months of dietary supplementation with either a spermidine-rich dietary supplement extracted from wheat germ (O.9 mg spermidine/d) or placebo (microcrystalline cellulose). Eighty-nine participants (89%) successfully completed the trial intervention. MAIN OUTCOMES AND MEASURES Primary outcome was change in memory performance from baseline to 12-month postintervention assessment (intention-to-treat analysis), operationalized by mnemonic discrimination performance assessed by the Mnemonic Similarity Task. Secondary outcomes included additional neuropsychological, behavioral, and physiological parameters. Safety was assessed in all participants and exploratory per-protocol, as well as subgroup, analyses were performed. RESULTS A total of 100 participants (51 in the spermidine group and 49 in the placebo group) were included in the analysis (mean [SD] age, 69 [5] years; 49 female participants [49%]). Over 12 months, no significant changes were observed in mnemonic discrimination performance (between-group difference, -0.03; 95% CI, -0.11 to 0.05; P = .47) and secondary outcomes. Exploratory analyses indicated possible beneficial effects of the intervention on inflammation and verbal memory. Adverse events were balanced between groups. CONCLUSIONS AND RELEVANCE In this randomized clinical trial, longer-term spermidine supplementation in participants with subjective cognitive decline did not modify memory and biomarkers compared with placebo. Exploratory analyses indicated possible beneficial effects on verbal memory and inflammation that need to be validated in future studies at higher dosage.Peer reviewe

Die verschiedenen Phasen der COVID-19-Pandemie in Deutschland: Eine deskriptive Analyse von Januar 2020 bis Februar 2021

Am 27.01.2020 wurde in Deutschland der erste Fall mit einer SARS-CoV-2-Infektion diagnostiziert. Für die Beschreibung des Pandemieverlaufs im Jahr 2020 wurden 4 epidemiologisch verschiedene Phasen betrachtet und Daten aus dem Meldesystem gemäß Infektionsschutzgesetz (IfSG) sowie hospitalisierte COVID-19-Fälle mit schwerer akuter respiratorischer Infektion aus der Krankenhaus-Surveillance eingeschlossen. Phase 0 umfasst den Zeitraum von Kalenderwoche (KW) 5/2020 bis 9/2020, in dem vor allem sporadische Fälle <60 Jahre und regional begrenzte Ausbrüche beobachtet wurden. Insgesamt wurden 167 Fälle übermittelt, die vorwiegend mild verliefen. Dem schloss sich in Phase 1 (KW 10/2020 bis 20/2020) die erste COVID-19-Welle mit 175.013 Fällen im gesamten Bundesgebiet an. Hier wurden vermehrt Ausbrüche in Krankenhäusern, Alten- und Pflegeheimen sowie ein zunehmender Anteil an älteren und schwer erkrankten Personen verzeichnet. In Phase 2, dem „Sommerplateau“ mit eher milden Verläufen (KW 21/2020 bis 39/2020), wurden viele reiseassoziierte COVID-19-Fälle im Alter von 15–59 Jahren und einzelne größere, überregionale Ausbrüche in Betrieben beobachtet. Unter den 111.790 Fällen wurden schwere Verläufe seltener beobachtet als in Phase 1. Phase 3 (KW 40/2020 bis 8/2021) war gekennzeichnet durch die zweite COVID-19-Welle in Deutschland, die sich zum Jahresende 2020 auf dem Höhepunkt befand. Mit 2.158.013 übermittelten COVID-19-Fällen und insgesamt deutlich mehr schweren Fällen in allen Altersgruppen verlief die zweite Welle schwerer als die erste Welle. Unabhängig von den 4 Phasen waren v. a. Ältere und auch Männer stärker von einem schweren Krankheitsverlauf betroffen.The first case of coronavirus SARS-CoV‑2 infection in Germany was diagnosed on 27 January 2020. To describe the pandemic course in 2020, we regarded four epidemiologically different periods and used data on COVID-19 cases from the mandatory reporting system as well as hospitalized COVID-19 cases with severe acute respiratory infection from the syndromic hospital surveillance. Period 0 covers weeks 5 to 9 of 2020, where mainly sporadic cases of younger age were observed and few regional outbreaks emerged. In total, 167 cases with mostly mild outcomes were reported. Subsequently, the first COVID-19 wave occurred in period 1 (weeks 10 to 20 of 2020) with a total of 175,013 cases throughout Germany. Increasingly, outbreaks in hospitals and nursing homes were registered. Moreover, elderly cases and severe outcomes were observed more frequently. Period 2 (weeks 21 to 39 of 2020) was an interim period with more mild cases, where many cases were younger and often travel-associated. Additionally, larger trans-regional outbreaks in business settings were reported. Among the 111,790 cases, severe outcomes were less frequent than in period 1. In period 3 (week 40 of 2020 to week 8 of 2021), the second COVID-19 wave started and peaked at the end of 2020. With 2,158,013 reported cases and considerably more severe outcomes in all age groups, the second wave was substantially stronger than the first wave. Irrespective of the different periods, more elderly persons and more men were affected by severe outcomes.Peer Reviewe

Brain metastasis and survival outcomes after first-line therapy in metastatic melanoma: a multicenter DeCOG study on 1704 patients from the prospective skin cancer registry ADOREG

Background Despite the availability of effective systemic therapies, a significant number of advanced melanoma patients develops brain metastases. This study investigated differences in incidence and time to diagnosis of brain metastasis and survival outcomes dependent on the type of first-line therapy.Methods Patients with metastatic, non-resectable melanoma (AJCCv8 stage IIIC–V) without brain metastasis at start of first-line therapy (1L-therapy) were identified from the prospective multicenter real-world skin cancer registry ADOREG. Study endpoints were incidence of brain metastasis, brain metastasis-free survival (BMFS), progression-free survival (PFS), and overall survival (OS).Results Of 1704 patients, 916 were BRAF wild-type (BRAFwt) and 788 were BRAF V600 mutant (BRAFmut). Median follow-up time after start of 1L-therapy was 40.4 months. BRAFwt patients received 1L-therapy with immune checkpoint inhibitors (ICI) against CTLA-4+PD-1 (n=281) or PD-1 (n=544). In BRAFmut patients, 1L-therapy was ICI in 415 patients (CTLA-4+PD-1, n=108; PD-1, n=264), and BRAF+MEK targeted therapy (TT) in 373 patients. After 24 months, 1L-therapy with BRAF+MEK resulted in a higher incidence of brain metastasis compared with PD-1±CTLA-4 (BRAF+MEK, 30.3%; CTLA-4+PD-1, 22.2%; PD-1, 14.0%). In multivariate analysis, BRAFmut patients developed brain metastases earlier on 1L-therapy with BRAF+MEK than with PD-1±CTLA-4 (CTLA-4+PD-1: HR 0.560, 95% CI 0.332 to 0.945, p=0.030; PD-1: HR 0.575, 95% CI 0.372 to 0.888, p=0.013). Type of 1L-therapy, tumor stage, and age were independent prognostic factors for BMFS in BRAFmut patients. In BRAFwt patients, tumor stage was independently associated with longer BMFS; ECOG Performance status (ECOG-PS), lactate dehydrogenase (LDH), and tumor stage with OS. CTLA-4+PD-1 did not result in better BMFS, PFS, or OS than PD-1 in BRAFwt patients. For BRAFmut patients, multivariate Cox regression revealed ECOG-PS, type of 1L-therapy, tumor stage, and LDH as independent prognostic factors for PFS and OS. 1L-therapy with CTLA-4+PD-1 led to longer OS than PD-1 (HR 1.97, 95% CI 1.122 to 3.455, p=0.018) or BRAF+MEK (HR 2.41, 95% CI 1.432 to 4.054, p=0.001), without PD-1 being superior to BRAF+MEK.Conclusions In BRAFmut patients 1L-therapy with PD-1±CTLA-4 ICI resulted in a delayed and less frequent development of brain metastasis compared with BRAF+MEK TT. 1L-therapy with CTLA-4+PD-1 showed superior OS compared with PD-1 and BRAF+MEK. In BRAFwt patients, no differences in brain metastasis and survival outcomes were detected for CTLA-4+PD-1 compared with PD-1