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Hintergrund: Bisher existiert keine detaillierte Analyse von pädiatrischen Notfällen, die in Notaufnahmen versorgt werden. Im Rahmen der Kapazitätsplanung und anstehenden Reform der Notfallversorgung werden diese Daten aber dringend benötigt. Methode: Retrospektive multizentrische Querschnittsstudie für den Zeitraum vom 01.07.2013 bis zum 01.06.2014 der pädiatrischen Fälle in den Notaufnahmen Münchens. Ergebnisse: Es wurden insgesamt 103.830 Fälle analysiert (Alter: 6,9 ± 5,4 Jahre, Jungen/Mädchen 55 %/45 %). Es konnten 85,9 % der Fälle ambulant versorgt werden, 12,4 % (9,6 pro 100.000 Kinder) wurden auf die Normal- und 1,7 % (1,0 pro 100.000 Kinder) auf die Intensivstation aufgenommen. Der real benötigte Bettenbedarf überstieg jedoch diese Richtzahlen mit absolut benötigten 4,9 Intensiv- und 35,1 Normalstationsbetten pro Tag. Es zeigten sich Belastungsspitzen an den Nachmittagen des Mittwochs und des Freitags sowie an den Wochenenden. Jeder 8. Patient, der in einer Notaufnahme als Selbstzuweiser vorgestellt wurde, wurde stationär behandelt. Schlussfolgerung: Für die Kapazitätsplanung der stationären Notfallversorgung pädiatrischer Patienten müssen mehr Betten eingeplant werden als bevölkerungsbezogen zu erwarten sind. Die Verfügbarkeit der kassenärztlichen Versorgung beeinflusst das Patientenaufkommen in den Notaufnahmen (NA). Zur Verteilung der Patienten werden Instrumente zur medizinischen Ersteinschätzung des Behandlungsbedarfs und der Behandlungsdringlichkeit benötigt. Die im Rahmen der aktuellen Reform der Notfallversorgung geplanten Kindernotfallzentren müssen personell und finanziell angemessen ausgestattet werden, um – in enger Zusammenarbeit mit der kassenärztlichen Versorgung – den zu erwartenden Versorgungsbedarf bewältigen zu können.

The intensifying competitive pressures in manufacturing companies, combined with the expanding array of product variants, are propelling the integration of human-robot collaboration in operational frameworks. Effectively planning assembly processes demands particularly streamlined methods for assessing execution times, especially in the initial planning phases. While predetermined motion time systems are designed for human tasks, this contribution puts forth an approach for the time-economic analysis of robot movements without resorting to simulation.

Transposon-encoded tnpBand iscBgenes encode RNA-guided DNA nucleases that promote their own selfish spread through targeted DNA cleavage and homologous recombination1–4. These widespread gene families were repeatedly domesticated over evolutionary timescales, leading to the emergence of diverse CRISPR-associated nucleases including Cas9 and Cas12 (refs. 5,6). We set out to test the hypothesis that TnpB nucleases may have also been repurposed for novel, unexpected functions other than CRISPR–Cas adaptive immunity. Here, using phylogenetics, structural predictions, comparative genomics and functional assays, we uncover multiple independent genesis events of programmable transcription factors, which we name TnpB-like nuclease-dead repressors (TldRs). These proteins use naturally occurring guide RNAs to specifically target conserved promoter regions of the genome, leading to potent gene repression in a mechanism akin to CRISPR interference technologies invented by humans7. Focusing on a TldR clade found broadly in Enterobacteriaceae, we discover that bacteriophages exploit the combined action of TldR and an adjacently encoded phage gene to alter the expression and composition of the host flagellar assembly, a transformation with the potential to impact motility8, phage susceptibility9, and host immunity10. Collectively, this work showcases the diverse molecular innovations that were enabled through repeated exaptation of transposon-encoded genes, and reveals the evolutionary trajectory of diverse RNA-guided transcription factors.

Insertion sequences are compact and pervasive transposable elements found in bacteria, which encode only the genes necessary for their mobilization and maintenance1. IS200- and IS605-family transposons undergo ‘peel-and-paste’ transposition catalysed by a TnpA transposase2, but they also encode diverse, TnpB- and IscB-family proteins that are evolutionarily related to the CRISPR-associated effectors Cas12 and Cas9, respectively3,4. Recent studies have demonstrated that TnpB and IscB function as RNA-guided DNA endonucleases5,6, but the broader biological role of this activity has remained enigmatic. Here we show that TnpB and IscB are essential to prevent permanent transposon loss as a consequence of the TnpA transposition mechanism. We selected a family of related insertion sequences from Geobacillus stearothermophilusthat encode several TnpB and IscB orthologues, and showed that a single TnpA transposase was broadly active for transposon mobilization. The donor joints formed upon religation of transposon-flanking sequences were efficiently targeted for cleavage by RNA-guided TnpB and IscB nucleases, and co-expression of TnpB and TnpA led to substantially greater transposon retention relative to conditions in which TnpA was expressed alone. Notably, TnpA and TnpB also stimulated recombination frequencies, surpassing rates observed with TnpB alone. Collectively, this study reveals that RNA-guided DNA cleavage arose as a primal biochemical activity to bias the selfish inheritance and spread of transposable elements, which was later co-opted during the evolution of CRISPR–Cas adaptive immunity for antiviral defence.

Dieses Dokument zur „Struktur und Ausstattung von Intensivstationen“ der Deutschen Interdisziplinären Vereinigung für Intensiv- und Notfallmedizin e. V. (DIVI) soll Empfehlungen zur personellen Ausstattung, zur Infrastruktur und zur Organisation von Intensivstationen geben. Die Empfehlungen basieren auf einer systematischen Literaturrecherche und einem formalen Konsensprozess einer interdisziplinären und interprofessionellen Gruppe von Spezialisten der DIVI. Die Empfehlungen beschreiben eine Einteilung von Intensivstationen in 3 Stufen, eine Einteilung der Patienten entsprechend ihrer Erkrankungsschwere in 3 Stufen, die personelle Ausstattung mit Ärzten, Pflegekräften, Therapeuten ebenso wie mit Stationsapothekern, Psychologen und weiteren Spezialisten. Weiterhin werden Empfehlungen zur apparativen Ausstattung und zur baulichen Ausführung ausgesprochen

Bacterial transposons are pervasive mobile genetic elements that use distinct DNA-binding proteins for horizontal transmission. For example, Escherichia coliTn7homes to a specific attachment site using TnsD1, whereas CRISPR-associated transposons use type I or type V Cas effectors to insert downstream of target sites specified by guide RNAs2,3. Despite this targeting diversity, transposition invariably requires TnsB, a DDE-family transposase that catalyses DNA excision and insertion, and TnsC, a AAA+ ATPase that is thought to communicate between transposase and targeting proteins4. How TnsC mediates this communication and thereby regulates transposition fidelity has remained unclear. Here we use chromatin immunoprecipitation with sequencing to monitor in vivo formation of the type I-F RNA-guided transpososome, enabling us to resolve distinct protein recruitment events before integration. DNA targeting by the TniQ–Cascade complex is surprisingly promiscuous—hundreds of genomic off-target sites are sampled, but only a subset of those sites is licensed for TnsC and TnsB recruitment, revealing a crucial proofreading checkpoint. To advance the mechanistic understanding of interactions responsible for transpososome assembly, we determined structures of TnsC using cryogenic electron microscopy and found that ATP binding drives the formation of heptameric rings that thread DNA through the central pore, thereby positioning the substrate for downstream integration. Collectively, our results highlight the molecular specificity imparted by consecutive factor binding to genomic target sites during RNA-guided transposition, and provide a structural roadmap to guide future engineering efforts.

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Hintergrund: Während der Einsatz mechanischer Reanimationshilfen für Reanimationen des Erwachsenen erwogen werden kann, wird dies für die kindliche Reanimation noch nicht in der Leitlinie des European Resuscitation Council (ERC) erwähnt. Eine begrenzte Zulassung für den kindlichen Bereich liegt lediglich für ein verfügbares Gerät vor, weitere Anwendungen bei Kindern erfolgen im Rahmen von Off-label-Therapieversuchen. Die ethischen Aspekte, die sich durch den Einsatz von mechanischen Reanimationshilfen ergeben, sind bisher nicht strukturiert dargestellt worden. Ziel: Erarbeitung ethischer Aspekte in der Entwicklungsphase mechanischer Reanimationshilfen für Kinder. Methoden: Anhand von fiktiven Fallberichten wurde eine interdisziplinäre Expertendiskussion mit anschließender moderierter Ergebnissicherung durchgeführt. Unter Einbeziehung bestehender Literatur erfolgt die Formulierung von Leitsätzen und Forschungsdesideraten. Ergebnisse: Ethische Implikationen mechanischer Reanimationshilfen in der Pädiatrie ergeben sich für die Experten insbesondere für die Frage nach Indikationsstellung und Abbruchkriterien. Psychosoziale Aspekte betroffener Familien und Einsatzteams bedürfen einer differenzierten Betrachtung nicht zuletzt auch unter ethischen Gesichtspunkten. Diskussion: Über die hier dargestellten Aspekte zum Einsatz mechanischer Reanimationshilfen im noch im Entwicklungsstadium befindlichen pädiatrischen Kontext hinaus ergeben sich auch für die außerklinischen Reanimationsentscheidungen bei Erwachsenen praxisrelevante Implikationen. Für ethische Aspekte außerklinischer Reanimationsentscheidungen insbesondere unter Einsatz mechanischer Reanimationshilfen besteht ein hoher Bedarf an empirischer Begleitforschung.

We aim to describe the variability and identify gaps in preparedness and response to the coronavirus disease 2019 pandemic in European emergency departments (EDs) caring for children.

The dispersion of individual returns to experience, often referred to as heterogeneity of income profiles (HIP), is a key parameter in empirical human capital models, in studies of life‐cycle income inequality, and in heterogeneous agent models of life‐cycle labor market dynamics. It is commonly estimated from age variation in the covariance structure of earnings. In this study, I show that this approach is invalid and tends to deliver estimates of HIP that are biased upward. The reason is that any age variation in covariance structures can be rationalized by age‐dependent heteroscedasticity in the distribution of earnings shocks. Once one models such age effects flexibly the remaining identifying variation for HIP is the shape of the tails of lag profiles. Credible estimation of HIP thus imposes strong demands on the data since one requires many earnings observations per individual and a low rate of sample attrition. To investigate empirically whether the bias in estimates of HIP from omitting age effects is quantitatively important, I thus rely on administrative data from Germany on quarterly earnings that follow workers from labor market entry until 27 years into their career. To strengthen external validity, I focus my analysis on an education group that displays a covariance structure with qualitatively similar properties like its North American counterpart. I find that a HIP model with age effects in transitory, persistent and permanent shocks fits the covariance structure almost perfectly and delivers small and insignificant estimates for the HIP component. In sharp contrast, once I estimate a standard HIP model without age‐effects the estimated slope heterogeneity increases by a factor of thirteen and becomes highly significant, with a dramatic deterioration of model fit. I reach the same conclusions from estimating the two models on a different covariance structure and from conducting a Monte Carlo analysis, suggesting that my quantitative results are not an artifact of one particular sample.

Objective.The volumetric interpolated breath-hold examination (VIBE) magnetic resonance imaging (MRI) technique can visualize erosive cartilage defects in peripheral joints. We evaluated the ability of VIBE to detect erosions in sacroiliac joints (SIJ) of patients with axial spondyloarthritis (axSpA) compared to the established T1-weighted MRI sequence and computed tomography (CT).Methods.MRI (T1-weighted and VIBE) and CT scans of SIJ of 109 patients with axSpA were evaluated by 2 blinded readers based on SIJ quadrants (SQ). Erosions were defined according to Assessment of Spondyloarthritis international Society (ASAS) definitions. Scores were recorded if readers were in agreement.Results.Erosions were less frequently detected by CT (153 SQ) than by T1-weighted MRI (182 SQ; p = 0.008) and VIBE-MRI (199 SQ; p < 0.001 vs CT and p = 0.031 vs T1-weighted MRI). Taking CT as the gold standard, the sensitivity of VIBE-MRI (71.2%) was higher than that for T1-weighted MRI (63.4%), with similar specificity (87.3% vs 88%, respectively). In linear regression analysis, younger age was significantly associated with occurrence of erosions independently in VIBE-MRI (β = 0.384, p < 0.001) and T1-weighted MRI (β = 0.369, p < 0.001) compared to CT.Conclusion.The VIBE-MRI sequence was more sensitive than T1-weighted MRI in identifying erosive damage in the SIJ, especially in younger patients. This might be due to the ability of VIBE-MRI to identify structural changes in the cartilage that have not yet extended to the underlying bone, where CT seems to be superior.

The lithium–sulfur battery is a promising electrochemical storage solution, especially for aviation and aeronautical applications, due to its high‐gravimetric energy density (specific energy) and the abundance of sulfur. In recent years, the number of reported prototype cells and their realized energy have increased. This underlines the progress of technology readiness of the lithium–sulfur system. However, the influence of the cathode porosity as well as the porosity of the carbon material on the performance of prototype cells is still not fully understood. Consequently, in this study, the porosity of solvent‐free processed cathodes is investigated, with varying carbon matrix composition, via mercury intrusion porosimetry and synchrotron tomography. Moreover, the swelling behavior of the S/C dry‐film cathodes is investigated and mitigated. These cathodes are then electrochemically evaluated at pouch cell level with ether‐based electrolytes with varying E/S ratios. The combination of the gained findings in pouch cells enables specific energies of 425 Wh kg−1and 558 Wh L−1at cell level. The impact of the carbon host matrix on the performance of solvent‐free‐processed S/C cathodes is investigated at pouch cell level. Furthermore, the morphology and porosity of the cathodes are investigated inter alia via synchrotron tomography. After the adaption of the carbon host matrix composition, energy densities at cell level of 425 Wh kg−1and 588 Wh L−1are achieved.

The safe and stable utilization of lithium metal as an anode in rechargeable batteries is still a major challenge. One way to improve the performance of lithium anodes is the modification of its surface. Here we report two possible methods for lithium surface modification using a combination of tris(N,N-tetramethylene)phosphoric acid triamide and an alcohol for dip coating. The coatings lead to a thin and homogenous surface layer on the electrodes which causes diminished cell resistance and enhanced life time in symmetrical transference cells as well as enhanced capacity retention in Li-S batteries. Surface analyses by XPS and SIMS prove the incorporation of phosphorus and nitrogen into the SEI and the presence of highly lithium ion conductive Li3N.

Begrenzte Zeit für den Patienten und allgegenwärtige administrative Verpflichtungen kennzeichnen das Arbeitsprofil von klinisch tätigen ÄrztInnen in der Erwachsenenmedizin.

Copyright of brand eins is the property of brand eins Medien AG and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Pulmonary disease caused by nontuberculous mycobacteria in healthy children is rare, and its pathogenesis is unknown in most cases and standardized treatment is lacking. Here, we report various endobronchial manifestations in 5 patients including hitherto undescribed diffuse tracheobronchial granulomas in 2 patients. Bronchoscopic debulking was performed in all patients and tuberculostatic treatment in 4. All patients including 1 without tuberculostatic treatment showed remission.

The crystal structure of tropylium bromide, C7H7+Br-, was solved and refined in space group type R¯3m with rotationally disordered C7rings. Restraints of identical 1,2- and 1,7-C-C bond lengths as well as identical 1,3- and 1,6-C-C separations within a flat C7H7moiety were applied. The refinement converged to a regular C7heptagon with C-C bond lengths of 139.1(1) pm. C7H7+Br-reacts with Mo(CO)3(CH3CN)3to form C7H7Mo(CO)2Br.

The selective synthesis of functional alkynylsilanes RC≡C–SiMe2m–X m= 1, 3 was investigated. Monofunctionalization with or without protecting groups gave moderate to good yields of alkynyldimethylmonosilanes RC≡CMe2SiX [R = Ph, X = Cl 1, NEt22, OMe 3, H 4, Br 5, I 6, Cp 8, C5H4Li 10, Ph 11; R = Pr, X = Ph 12]. Compounds 4and 8were converted into the alkynetransitionmetal complexes 4·Cp2Mo2CO413 and 8·Co2CO614, respectively, which were characterized by Xray diffraction. Stepwise extension and functionalization of the silane chain starting from 1chloro2diethylaminotetramethyldisilane Et2NMe2Si–SiMe2Cl yielded the trisilanes Ph–SiMe23–X [X = NEt218, OMe 19, Cl 20, H 21, C≡CPh 22, C≡CPr 23]. The synthesized compounds were characterized by NMR and IR spectroscopy, 4, 11, 13, and 14also by UVVis spectroscopy.

The nickel cyclohexasilyl complex CpNi(PPh3)Si6Me11was synthesized from nickelocene, triphenylphosphine, and undecamethylcyclohexasilyl potassium and was fully characterized. It shows a relationship between its Si-Si bond lengths and its reactivity towards oxygen. The cleavage of one cyclopentadienyl ligand from nickelocene by silyl anions in the presence of additional ligands opens a promising new pathway to nickel silyl complexes of the type CpNi(L)-SiR3

Therapeutic effects of dietary flavonoids have been attributed mainly to their antioxidant capacity. Xanthohumol (1), a prominent flavonoid of the hop plant, Humulus lupulus, was investigated for its antioxidant potential and for its effect on NF-κB activation. To examine the biological relevance of 1, a hepatic ischemia/reperfusion model was chosen as a widely accepted model of oxidative stress generation. The impact of 1on endogenous antioxidant systems, on the NF-κB signal transduction pathway as well as on apoptotic parameters, and on hepatic tissue damage was evaluated. Compound 1markedly decreased the level of reactive oxygen species in vitro. Furthermore, levels of enzymatic and nonenzymatic antioxidants were restored after pretreatment in postischemic hepatic tissue, and lipid peroxidation was attenuated. NF-κB activity was reduced in vitro as well as in hepatic tissue after ischemia/reperfusion upon pretreatment with 1. In addition, the phosphorylation of Akt was markedly inhibited. Surprisingly, 1decreased the expression of the antiapoptotic protein Bcl-X and increased caspase-3 like-activity, a proapoptotic parameter. Moreover, hepatic tissue damage as well as TNF-α levels increased in xanthohumol-pretreated liver tissue after ischemia/reperfusion. In summary, xanthohumol did not protect against ischemia/reperfusion injury in rat liver, despite its antioxidant and NF-κB inhibitory properties.

Endothelial barrier dysfunction is a hallmark of many severe pathologies, including sepsis or atherosclerosis. The cardiovascular hormone atrial natriuretic peptide (ANP) has increasingly been suggested to counteract endothelial leakage. Surprisingly, the precise in vivo relevance of these observations has never been evaluated. Thus, we aimed to clarify this issue and, moreover, to identify the permeability-controlling subcellular systems that are targeted by ANP. Histamine was used as important pro-inflammatory, permeability-increasing stimulus. Measurements of fluorescein isothiocyanate (FITC)-dextran extravasation from venules of the mouse cremaster muscle and rat hematocrit values were performed to judge changes of endothelial permeability in vivo. It is noteworthy that ANP strongly reduced the histamine-evoked endothelial barrier dysfunction in vivo. In vitro, ANP blocked the breakdown of transendothelial electrical resistance (TEER) induced by histamine. Moreover, as judged by immunocytochemistry and Western blot analysis, ANP inhibited changes of vascular endothelial (VE)-cadherin, β-catenin, and p120ctnmorphology; VE-cadherin and myosin light chain 2 (MLC2) phosphorylation; and F-actin stress fiber formation. These changes seem to be predominantly mediated by the natriuretic peptide receptor (NPR)-A, but not by NPR-C. In summary, we revealed ANP as a potent endothelial barrier protecting agent in vivo and identified adherens junctions and the contractile apparatus as subcellular systems targeted by ANP. Thus, our study highlights ANP as an interesting pharmacological compound opening new therapeutic options for preventing endothelial leakage.

The Molecular and Crystal Structures of (η5‐Cyclopentadienyl)bis‐(triphenylphosphane)cobalt(I)–(hexane/toluene) (2/1), (η5‐Cyclopentadienyl)‐{1,1′‐[(1,2‐η)‐ethyne‐1,2‐diyl]bis(benzene)}(triphenylphosphane)cobalt(I), and (η5‐Cyclopentadienyl)(1,2,3,4‐tetraphenyl‐buta‐1,3‐diene‐1,4‐diyl)(triphenyl‐phosphane)cobalt(I)

In this retrospective study we compared the antiretroviral effect of regimens consisting of simultaneous administration of two protease inhibitors (PI) with at least one nucleoside reverse transcriptase inhibitor on plasma viral load (VL) and CD4 cell count in HIV-infected children intensively pretreated with nucleoside reverse transcriptase inhibitors and PIs.

The effects of two antiretroviral triple combinations including the protease inhibitor indinavir on the surrogate markers, viral load and CD4 cells were evaluated.

The activity of thalidomide monotherapy in relapsed or refractory disease is widely accepted but many haematologists have observed better response rates with combination therapies. This communication aims to give an overview on the efficacy of these alternatives. Methods: Our group has performed two systematic reviews (thalidomide monotherapy: Glasmacher et al., Brit. J. Haematol., 2005; 129 suppl 1: 24; thalidomide and dexamethasone combination therapy: submitted to ASH 2005). Furthermore a search of trials combining thalidomide, cyclophosphamide and dexamethasone (with or without further drugs) was performed. Only trials that included patients with relapsed or refractory multiple myeloma could be evaluated. Response was defined as a reduction of the monoclonal component by more than 50% in the absence of any sign of disease progression. Proportions and 95% confidence intervals were reported (Confidence Interval Analysis, Version 2.1.1, Southampton, UK, 2000). Results: Thalidomide monotherapy was administered in doses between 50–600 mg/d (median doses). Thalidomide in combination with dexamethasone was given in doses of 100–400 mg/d (median doses), dexamethasone was given 40 mg/d d1–4 every 3–4 weeks in 7 of 8 trials. Thalidomide dosage and combination therapy of trials adding Cy to thalidomide and dexamethasone are shown in Table 1. The response rates of the three different thalidomide applications are demonstrated Table 2. Conclusion: This compilation of data from phase II trials cannot replace a randomized trial and may be biased. With this limitation it seems that thalidomide combined with dexamethasone (response rate 51%) is more effective than monotherapy (response rate 29%) as the 95% confidence intervals for the response rates do not overlap. Whether a combination of thalidomide, dexamethasone and cyclophosphamide is more effective than thalidomide and dexamethasone alone cannot be decided from the current data. Table 1: Studies with thalidomide and combination chemotherapy Study Intervention No. of pts. Response (95%CI) Abb.: Cy, cyclophosphamide; Eto, etoposide; T, thalidomide; Dex, dexamethasone; Ida, idarubicin. Values are mg/m2 per course for Cy, Eto, Ida; mg per course for Dex, mg/d for T. Moehler et al. 2003 Cy 1600, Eto 160, T 400, Dex 160 119 55% (46–65) Kropff et al., 2003 Cy 1800, T 400, Dex 240 60 70% (57–81) Dimopoulos et al. 2003 Cy 1500, T 400, Dex 160 43 67% (51–81) Gracia-Sanz et al. 2004 Cy 50 daily, T 800, Dex 160 71 57% (45–67) Glasmacher et al. 2005 Cy 800, Ida 40, T 400, Dex 320 39 57% (41–73) Table 2: Response of different thalidomide combinations Intervention No. of trials No. of pts. Response (95%CI) Abb.: see Table 1 T monotherapy 42 1629 29% (27–32) T + Dex 8 283 51% (45–57) T + Cy + Dex 5 332 60% (55–65)