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RNA modifications, such as methylation, can be detected with Oxford Nanopore Technologies direct RNA sequencing. One commonly used tool for detecting 5-methylcytosine (m5C) modifications is Tombo, which uses an “Alternative Model” to detect putative modifications from a single sample. We examined direct RNA sequencing data from diverse taxa including virus, bacteria, fungi, and animals. The algorithm consistently identified a 5-methylcytosine at the central position of a GCU motif. However, it also identified a 5-methylcytosine in the same motif in fully unmodifiedin vitrotranscribed RNA, suggesting that this a frequent false prediction. In the absence of further validation, several published predictions of 5-methylcytosine in human coronavirus and human cerebral organoid RNA in a GCU context should be reconsidered.IMPORTANCEThe detection of chemical modifications to RNA is a rapidly expanding field within epigenetics. Nanopore sequencing technology provides an attractive means of detecting these modifications directly on the RNA, but accurate modification predictions are dependent upon the software developed to interpret the sequencing results. One of these tools, Tombo, allows users to detect modifications using sequencing results from a single RNA sample. However, we find that this method falsely predicts modifications in a specific sequence context across a variety of RNA samples, including RNA that lacks modifications. Results from previous publications include predictions in human coronaviruses with this sequence context and should be reconsidered. Our results highlight the importance of using RNA modification detection tools with caution in the absence of a control RNA sample for comparison.

Aspergillus fumigatus is an environmental fungus that can cause life-threatening pulmonary disease. Infections initiate when conidia are inhaled and land deep inside the small airways and alveoli of the lungs, where they interact with epithelial cells. These cells provide a physical barrier and secrete chemokines to attract innate immune cells to the site of infection. Melanin, a key constituent of the conidial cell wall, is required for the establishment of invasive infection due to its ability to inhibit the function of innate immune cells recruited to clear the infection. Here, we provide evidence for an additional mechanism by which A. fumigatus can alter host innate immune responses. In vitro infection of a normal human small airway epithelial cell line (HSAEC1-KT) caused a decrease in extracellular protein levels of CXCL10 and CCL20, two proinflammatory chemokines that are required for the host defense against aspergillosis, despite a dramatic increase in the levels of each mRNA. A. fumigatus depleted recombinant human CXCL10 and CCL20 from medium in the absence of host cells, suggesting that the block in accumulation is downstream of protein translation and secretion. Melanin is both necessary and sufficient for this chemokine-depleting activity because a dihydroxynaphthalene (DHN)-melanin-deficient strain of A. fumigatus is defective in depleting chemokines and purified melanin ghosts retain potent depletion activity. We propose that A. fumigatus, through the action of melanin, depletes important chemokines, thereby dampening the innate immune response to promote infection. IMPORTANCE Aspergillus fumigatus is the major airborne fungal pathogen that affects humans. In order to cause an invasive infection, inhaled spores must avoid killing by innate immune cells that are recruited to the site of infection. Understanding how A. fumigatus achieves immune evasion is important for the development of novel therapeutics. We provide evidence that melanin, a pigment contained in the spore cell wall, can remove certain chemokines from the extracellular space to suppress the host inflammatory response that is responsible for clearing fungal infection.

This article deals with the implementation by teachers of secondary schools of the culture-creating and pedagogical potential of natural science museums with the help of the author's program. At the moment, there is a situation where society needs a holistic and informative potential of the museum. Modern education in the educational process is increasingly based on a number of museum disciplines. The museum, being a socio-cultural institution, directly influences the solution of crisis situations of civilization in the XXI century. It should be noted that the pedagogical position put forward by the authors on the potential of natural science museums, reflected in this article, is relevant not only for our country, but also for the whole world affected by globalization. The authors of the article, based on the findings of the study, compiled an author's program for teachers of secondary schools, in which they tried to reveal the main points on the implementation of the culture-creating and pedagogical potential of natural science museums.

Background The aim of this study was to evaluate mechanical circulatory support (MCS) for the treatment of non-ischemic cardiogenic shock (CS). Methods Data from 1,030 consecutive patients with non-ischemic CS treated with or without MCS at 16 tertiary-care centers were retrospectively collected. The association between MCS and 30-day mortality was assessed in a 1:1 propensity score matched cohort. Results MCS was used in 406 (39%) patients. MCS treated patients presented with more severe CS (lactate 5.4 vs. 4.1 mmol/l, systolic blood pressure 80 vs. 83 mmHg, higher SCAI class) and with more disease modifiers (prior cardiac arrest 42.4 vs. 36.1%, mechanical ventilation 78.4 vs. 56.5%). After matching, 272 patients treated with were compared vs. 272 patients treated without MCS. MCS was associated with a lower 30-day mortality (hazard ratio 0.77, 95% confidence interval 0.60–0.98, Figure 1). This finding was consistent through all tested sub-groups except when ejection fraction was considered, indicating an association especially in patients with an ejection fraction ≤20%. Complications occurred more frequently in patients with MCS; e.g. severe bleedings (21.8 vs. 9.2%) and access-site related ischemia (6.6 vs. 0%). Conclusion In patients with non-ischemic CS, MCS use was associated with lower 30-day mortality as compared to medical therapy only, particularly in patients with a lower ejection fraction. This provides rationale for randomized trials to validate these findings. Funding Acknowledgement Type of funding sources: None.

The CREMA collaboration is pursuing a measurement of the ground-state hyperfine splitting (HFS) in muonic hydrogen ($\mu$p) with 1 ppm accuracy by means of pulsed laser spectroscopy to determine the two-photon-exchange contribution with $2\times10^{-4}$ relative accuracy. In the proposed experiment, the $\mu$p atom undergoes a laser excitation from the singlet hyperfine state to the triplet hyperfine state, {then} is quenched back to the singlet state by an inelastic collision with a H$_2$ molecule. The resulting increase of kinetic energy after the collisional deexcitation is used as a signature of a successful laser transition between hyperfine states. In this paper, we calculate the combined probability that a $\mu$p atom initially in the singlet hyperfine state undergoes a laser excitation to the triplet state followed by a collisional-induced deexcitation back to the singlet state. This combined probability has been computed using the optical Bloch equations including the inelastic and elastic collisions. Omitting the decoherence effects caused by {the laser bandwidth and }collisions would overestimate the transition probability by more than a factor of two in the experimental conditions. Moreover, we also account for Doppler effects and provide the matrix element, the saturation fluence, the elastic and inelastic collision rates for the singlet and triplet states, and the resonance linewidth. This calculation thus quantifies one of the key unknowns of the HFS experiment, leading to a precise definition of the requirements for the laser system and to an optimization of the hydrogen gas target where $\mu$p is formed and the laser spectroscopy will occur., Comment: 21 pages, 4 figures

Background Even an ultraprotective ventilation strategy in severe acute respiratory distress syndrome (ARDS) patients treated with extracorporeal membrane oxygenation (ECMO) might induce ventilator-induced lung injury and apneic ventilation with the sole application of positive end-expiratory pressure may, therefore, be an alternative ventilation strategy. We, therefore, compared the effects of ultraprotective ventilation with apneic ventilation on oxygenation, oxygen delivery, respiratory system mechanics, hemodynamics, strain, air distribution and recruitment of the lung parenchyma in ARDS patients with ECMO. Methods In a prospective, monocentric physiological study, 24 patients with severe ARDS managed with ECMO were ventilated using ultraprotective ventilation (tidal volume 3 ml/kg of predicted body weight) with a fraction of inspired oxygen (FiO2) of 21%, 50% and 90%. Patients were then treated with apneic ventilation with analogous FiO2. The primary endpoint was the effect of the ventilation strategy on oxygenation and oxygen delivery. The secondary endpoints were mechanical power, stress, regional air distribution, lung recruitment and the resulting strain, evaluated by chest computed tomography, associated with the application of PEEP (apneic ventilation) and/or low VT (ultraprotective ventilation). Results Protective ventilation, compared to apneic ventilation, improved oxygenation (arterial partial pressure of oxygen, p 2 of 50% and 90%) and reduced cardiac output. Both ventilation strategies preserved oxygen delivery independent of the FiO2. Protective ventilation increased driving pressure, stress, strain, mechanical power, as well as induced additional recruitment in the non-dependent lung compared to apneic ventilation. Conclusions In patients with severe ARDS managed with ECMO, ultraprotective ventilation compared to apneic ventilation improved oxygenation, but increased stress, strain, and mechanical power. Apneic ventilation might be considered as one of the options in the initial phase of ECMO treatment in severe ARDS patients to facilitate lung rest and prevent ventilator-induced lung injury. Trial registration: German Clinical Trials Register (DRKS00013967). Registered 02/09/2018. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00013967.

In the large field of research on nanoplatelets (NPLs), their strong tendency to self-assemble into ordered stacks and the resulting changes in their properties are of great interest. The assembly reveals new characteristics such as the charge carrier transport through the NPL assembly or altered optical properties. In particular, a reduced distance should enhance the charge carrier transport due to higher electronic coupling of neighboring NPLs, and therefore, is the focus of this work. To modify the inter-particle distances, the straightforward method of ligand exchange is applied. Various CdSe and CdSe/CdX (hetero-) NPLs serve as building blocks, which not only display different material combinations but also different types of hetero-structures. The surface-to-surface distance between the stacked NPLs can be reduced to below 1 nm, thus, to less than the half compared to assemblies of pristine NPLs. Moreover, for certain NPLs stacking is only enabled by the ligand exchange. To characterize the ligand exchanges and to investigate the influences of the reduced distances, photo-electrochemical measurements, fluorescence spectroscopy, energy dispersive X-ray spectroscopy, nuclear magnetic resonance, and X-ray photoelectron spectroscopy are performed. It is possible to show higher photocurrents for smaller distances, indicating enhanced charge transport ability within those stacks.

Background Prone positioning in combination with the application of low tidal volume and adequate positive end-expiratory pressure (PEEP) improves survival in patients with moderate to severe acute respiratory distress syndrome (ARDS). However, the effects of PEEP on end-expiratory transpulmonary pressure (Ptpexp) during prone positioning require clarification. For this purpose, the effects of three different PEEP titration strategies on Ptpexp, respiratory mechanics, mechanical power, gas exchange, and hemodynamics were evaluated comparing supine and prone positioning. Methods In forty consecutive patients with moderate to severe ARDS protective ventilation with PEEP titrated according to three different titration strategies was evaluated during supine and prone positioning: (A) ARDS Network recommendations (PEEPARDSNetwork), (B) the lowest static elastance of the respiratory system (PEEPEstat,RS), and (C) targeting a positive Ptpexp (PEEPPtpexp). The primary endpoint was to analyze whether Ptpexp differed significantly according to PEEP titration strategy during supine and prone positioning. Results Ptpexp increased progressively with prone positioning compared with supine positioning as well as with PEEPEstat,RS and PEEPPtpexp compared with PEEPARDSNetwork (positioning effect p p Estat,RS and PEEPPtpexp (positioning effect p p Estat,RS and PEEPPtpexp compared with PEEPARDSNetwork, and prone positioning attenuated this effect (positioning effect p p p p Conclusions Prone positioning increased transpulmonary pressures while improving oxygenation and hemodynamics in patients with moderate to severe ARDS when PEEP was titrated according to the ARDS Network lower PEEP table. This PEEP titration strategy minimized parameters associated with ventilator-induced lung injury induction, such as transpulmonary driving pressure and mechanical power. We propose that a lower PEEP strategy (PEEPARDSNetwork) in combination with prone positioning may be part of a lung protective ventilation strategy in patients with moderate to severe ARDS. Trial registration German Clinical Trials Register (DRKS00017449). Registered June 27, 2019. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00017449

Cadmium chalcogenide nanoplatelets (NPLs) have gained tremendous attention in the past decade due to their extremely narrow optical features and their special electronic properties. For the application of the NPLs as optical emitters, in (photo) catalysis or sensing, further modification of the pristine (core) NPLs can be required. Therefore, many procedures for the synthesis of crowns (lateral extension of the core NPLs), shells and particle domains on the NPLs have already been developed. CdSe/CdS core/crown NPLs are characterised by extremely short photoluminescence (PL) lifetimes and high PL quantum yields (PLQYs) and might therefore be ideal candidates for lighting applications. In this work, we show how the optical properties of CdSe/CdS core/crown NPLs, especially their PLQYs, can be strongly improved by applying a sulphur precursor with a low reactivity. Under optimised conditions, the new procedure allows the growth of uniform CdS crowns around CdSe core NPLs with various lateral sizes, thicknesses and shapes. In addition, the modified growth kinetics was investigated by various methods, including UV/vis and PL spectroscopy as well as transmission electron microscopy. This journal is © The Royal Society of Chemistry.

Background Renal cell carcinomas (RCC) represent a heterogeneous group of hypo- and hypervascularized malignancies. Using contrast-enhanced ultrasound (CEUS) specific imaging features of clear cell (ccRCC), papillary (pRCC) and chromophobe RCC (chRCC) subtypes have been demonstrated. However, some RCCs show atypical imaging features making it difficult to distinguish between the subtypes. Objective This study was performed to evaluate the observed enhancement features of pRCC in CEUS and to assess the sensitivity in the diagnosis of suspected renal malignancies in a 10 year retrospective analysis at our institution. Methods The study population consisted of 60 patients with histologically confirmed pRCC. All patients underwent CEUS imaging between 2005 and 2015 as part of their diagnostic workup. Results In 45 out of 60 (75%) cases the examined pRCC showed typical hypoenhancement and wash-out. 15 out of 60 (25%) pRCC showed atypical enhancement features; in 14 cases the contrast enhancement indicated a ccRCC. 1 complex cyst was falsely reported as IIF lesion. 59 out of 60 malignancies were reported as malignant using CEUS resulting in a sensitivity of 98.4%. Conclusions CEUS is an eligible imaging technique to visualize the contrast enhancement features of pRCC. However, up to 25% of pRCCs show an atypical enhancement pattern making it difficult to distinguish it from other renal lesions.

Hybrid semiconductor-based nanocrystals (NCs) are generally synthesized in organic media prior to their assembly into catalytically promising nanostructures via multistep methods. Here, a tunable, easy-to-adapt and versatile approach for the preparation of hybrid nanoparticle networks from aqueous nanocrystal solutions is demonstrated. The networks consist of interconnected semiconductor NC backbones (made of CdSe/CdS dot-in-rods or core/crown nanoplatelets) decorated with noble metal (Au and Pt) or with metal-based domains (Co2+ and Ni2+) demonstrating a powerful synthetic control over a variety of hybrid nanostructures. The deposition of the domains and the formation of the network take place simultaneously (one-step method) at room temperature in dark conditions without any external trigger. Beside the in-depth structural characterization of the gel-like hybrid networks, the wavelength-dependent optical features are studied to reveal an efficient charge carrier separation in the systems and a controllable extent of fluorescence quenching through the domain sizes. Photoluminescence quantum yields and decay dynamics highlight the importance of fine-tuning the conduction band/Fermi level offset between the semiconductors and the various deposited metals playing central role in the electron–hole separation processes. This procedure provides a novel platform toward the preparation of photo(electro)catalytically promising hybrid nanostructures (acetogels and xerogels) without the need of presynthetic hybrid particle design.

Given the limited efficacy of current medical treatments in trauma-related necrotizing mucormycosis, there is a dire need to better understand the Mucoralean pathophysiology in order to develop novel strategies to counteract fungal tissue invasion following severe trauma. Here, we describe that tornadic shear stress challenge transiently induces a hypervirulent phenotype in various pathogenic Mucorales species but not in other molds known to cause wound infections. Pharmacological and genetic inhibition of calcineurin signaling abrogated hypervirulence in shear stress-challenged Mucorales, encouraging further evaluation of (topical) calcineurin inhibitors to improve therapeutic outcomes of NMM after combat-related blast injuries or violent storms., Trauma-related necrotizing myocutaneous mucormycosis (NMM) has a high morbidity and mortality in victims of combat-related injuries, geometeorological disasters, and severe burns. Inspired by the observation that several recent clusters of NMM have been associated with extreme mechanical forces (e.g., during tornados), we studied the impact of mechanical stress on Mucoralean biology and virulence in a Drosophila melanogaster infection model. In contrast to other experimental procedures to exert mechanical stress, tornadic shear challenge (TSC) by magnetic stirring induced a hypervirulent phenotype in several clinically relevant Mucorales species but not in Aspergillus or Fusarium. Whereas fungal growth rates, morphogenesis, and susceptibility to noxious environments or phagocytes were not altered by TSC, soluble factors released in the supernatant of shear-challenged R. arrhizus spores rendered static spores hypervirulent. Consistent with a rapid decay of TSC-induced hypervirulence, minimal transcriptional changes were revealed by comparative RNA sequencing analysis of static and shear-challenged Rhizopus arrhizus. However, inhibition of the calcineurin/heat shock protein 90 (hsp90) stress response circuitry by cyclosporine and tanespimycin abrogated the increased pathogenicity of R. arrhizus spores following TSC. Similarly, calcineurin loss-of-function mutants of Mucor circinelloides displayed no increased virulence capacity in flies after undergoing TSC. Collectively, these results establish that TSC induces hypervirulence specifically in Mucorales and point out the calcineurin/hsp90 pathway as a key orchestrator of this phenotype. Our findings invite future studies of topical calcineurin inhibitor treatment of wounds as an adjunct mitigation strategy for NMM following high-energy trauma.

Zusammenfassung Im Rahmen der Tagung „Wurzel und Rhizosphäre: Ökophysiologie, Humushaushalt und Bodenmanagement” im September 2015 wurden Wurzelfreilegungen von Hopfen und Mais in Wolnzach (Bayern) durchgeführt. Das Hauptziel der Untersuchungen war, die Möglichkeiten und den Wert von Wurzelfreilegungen im Feld zu demonstrieren. Für die Hopfenfreilegungen konnten die sichtbaren oberirdischen Unterschiede auch durch die Bewurzelungsweise erklärt werden. Der Einfluss der Bewässerung auf das Wurzelwachstum wurde ebenfalls untersucht. Die schwächer entwickelten Hopfenpflanzen wiesen eine Wurzeltiefe von ca. 130 cm auf, während die Wurzeln der gut entwickelten Pflanzen bis in eine Tiefe von 370 cm verfolgt werden konnten. Weiters wurden Maispflanzen bei konservierender Bodenbearbeitung mit Direktsaat untersucht. Im Gegensatz zu anderen Standorten konnten mehr Sprosswurzeln und lange Seitenwurzeln bis in eine Bodentiefe von 140 cm gefunden werden.

Background: Fish is one of the most important, allergenic foods worldwide. Parvalbumin is the well characterized, major allergen in fish muscle. In this study, we developed a protein- and a DNA-based method for the sensitive detection and authentication of eight commonly consumed fishes in food and compared their applicability. Methods: Fish parvalbumins were purified. Polyclonal, anti-parvalbumin antibodies were raised in rabbits and mice. Protein extracts from food were analyzed by quantitative ELISA. Parvalbumin genes were cloned and sequenced for the design of parvalbumin gene-specific PCR-primers. DNA extracted from food was subjected to specific PCR. Results: Increasing parvalbumin contents were quantified by ELISA in fresh fish, in the order of tuna < mackerel < cod < salmon/trout < redfish < carp < herring. The parvalbumin content of processed fish was up to 67% lower than in fresh fish. In spiked food samples, 1 to 15 ppm fresh fish and 30 to 170 ppm processed fish were still detectable by ELISA. The eight fishes were identified by specific PCR using 0.2 to 10 ng fish DNA. PCRs detected still 3 ppm fresh fish and 30 to 150 ppm processed fish in spiked samples. Conclusions: Both the protein- and the DNA-based method have sufficient sensitivity to protect fish-allergic consumers. The ELISA allows allergen quantification, while the PCR identifies the fish present in the food. The detection limits of both methods vary depending on different factors. Both methods need to be carefully validated for each fish and fish product when used in detection assays.

Background: Procollagen peptides have been associated with lung fibroproliferation and poor outcomes in patients with acute respiratory distress syndrome (ARDS). Therefore, serum procollagen concentrations might have prognostic value in ARDS patients treated with extracorporeal membrane oxygenation (ECMO). Methods: In a prospective cohort study, serum N-terminal procollagen I-peptide (PINP) and N-terminal procollagen III-peptide (PIIINP) concentrations in twenty-three consecutive patients with severe ARDS treated with ECMO were measured at the time of ECMO initiation and during the course of treatment. The predictive value of PINP and PIIINP at the time of ECMO initiation was tested with a univariable logistic regression and a receiver operating characteristic (ROC) curve analysis. Results: Thirteen patients survived to intensive care unit (ICU) discharge. Non-survivors had higher serum PINP and PIIINP concentrations at all points in time during the course of treatment. Serum PIIINP at the day of ECMO initiation showed an odds ratio of 1.37 (95% CI 1.10–1.89, p = 0.017) with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.87 (95% CI 0.69–1.00, p = 0.0029) for death during the course of treatment. Conclusions: PINP and PIIINP concentrations differ between survivors and non-survivors in ARDS treated with ECMO. This exploratory hypothesis generating study suggests an association between PIIINP serum concentrations at ECMO initiation and an unfavorable clinical outcome.

Das hamodynamische Monitoring in der kardiovaskularen Intensivmedizin wird unterteilt in Komponenten des Basismonitorings und des erweiterten Monitorings. Unverzichtbares Basismonitoring ist die Kombination aus EKG, Korpertemperatur, Sauerstoffsattigung, nichtinvasivem Blutdruck, Urinproduktion und dem „klinischen Blick“, bestehend aus grundlicher klinischer Untersuchung und Anamnese. Das Basismonitoring kann mit einer Vielfalt differenzierter erweiterter Monitoringverfahren erganzt werden, die im Einzelfall fur den in der Anwendung Geubten extrem nutzlich sein konnen, aber, wenn undifferenziert eingesetzt, mehr schaden als helfen. Fur kritische Phasen der Akuttherapie auf der Intensivstation, insbesondere fur das Nichtansprechen auf etablierte Therapieformen mussen differenzierte Optionen erwogen werden. Hierzu werden in dieser Arbeit Empfehlungen abgegeben. Der bettseitige, moglichst zeitnah verfugbare Einsatz der Echokardiographie bzw. Sonographie ist das zentrale Modul in der Diagnostik, Uberwachung und Therapiesteuerung kritisch kranker Intensivpatienten und kann Volumenreagibilitat und hamodynamischen Unterstutzungsbedarf abschatzen. Die Ausbildung und Expertise in diesen Verfahren ist daher unverzichtbar und unterstreicht die zentrale Rolle des internistisch-kardiologisch ausgebildeten Intensivmediziners.

On behalf of the Medical/Psychological Pain Associations, Pain Patients Alliance and the Professional Association of Pain Physicians and Psychologists, the Joint Commission of Professional Societies and Organizations for Quality in Pain Medicine, working in close collaboration with the respective presidents, has developed verifiable structural and process-related criteria for the classification of medical and psychological pain treatment facilities in Germany. Based on the established system of graded care in Germany and on existing qualifications, these criteria also argue for the introduction of a basic qualification in pain medicine. In addition to the first-ever comprehensive description of psychological pain facilities, the criteria presented can be used to classify five different levels of pain facilities, from basic pain management facilities, to specialized institutions, to the Centre for Interdisciplinary Pain Medicine. The recommendations offer binding and verifiable criteria for quality assurance in pain medicine and improved pain treatment.

Mucormycosis is a life-threatening, invasive fungal infection that is caused by various species belonging to the order Mucorales. Rhizopus species are the most common cause of the disease, responsible for approximately 70% of all cases of mucormycosis. During pulmonary mucormycosis, inhaled Rhizopus spores must adhere to and invade airway epithelial cells in order to establish infection. The molecular mechanisms that govern this interaction are poorly understood. We performed an unbiased survey of the host transcriptional response during early stages of Rhizopus arrhizus var. delemar (R. delemar) infection in a murine model of pulmonary mucormycosis using transcriptome sequencing (RNA-seq). Network analysis revealed activation of the host’s epidermal growth factor receptor (EGFR) signaling. Consistent with the RNA-seq results, EGFR became phosphorylated upon in vitro infection of human alveolar epithelial cells with several members of the Mucorales, and this phosphorylated, activated form of EGFR colocalized with R. delemar spores. Inhibition of EGFR signaling with cetuximab or gefitinib, specific FDA-approved inhibitors of EGFR, significantly reduced the ability of R. delemar to invade and damage airway epithelial cells. Furthermore, gefitinib treatment significantly prolonged survival of mice with pulmonary mucormycosis, reduced tissue fungal burden, and attenuated the activation of EGFR in response to pulmonary mucormycosis. These results indicate EGFR represents a novel host target to block invasion of alveolar epithelial cells by R. delemar, and inhibition of EGFR signaling provides a novel approach for treating mucormycosis by repurposing an FDA-approved drug., IMPORTANCE Mucormycosis is an increasingly common, highly lethal fungal infection with very limited treatment options. Using a combination of in vivo animal models, transcriptomics, cell biology, and pharmacological approaches, we have demonstrated that Mucorales fungi activate EGFR signaling to induce fungal uptake into airway epithelial cells. Inhibition of EGFR signaling with existing FDA-approved drugs significantly increased survival following R. arrhizus var. delemar infection in mice. This study enhances our understanding of how Mucorales fungi invade host cells during the establishment of pulmonary mucormycosis and provides a proof-of-concept for the repurposing of FDA-approved drugs that target EGFR function.

Der kardiogene Schock ist mit einer Mortalitat von bis zu 50 % weiterhin der schwerwiegendste prognoserelevante Faktor beim akuten Myokardinfarkt. In der Fruhphase dieser Erkrankung vor und nach fruher Revaskularisation spielt vor allem die hamodynamische Unterstutzung der Patienten eine Rolle. Die Katecholamintherapie mit Inotropika und Vasopressoren, aber auch die Erwagung mechanischer Unterstutzungssysteme wie intraaortaler Ballonpumpen (IABP), perkutaner linksventrikularer Unterstutzungssysteme und extrakorporaler Membranoxygenation (ECMO) sind hier wichtige Eckpunkte der Therapie. Die Anlage einer IABP ist aufgrund der aktuellen Datenlage nicht mehr generell zu empfehlen, aber die Datenlage zur Implantation perkutaner linksventrikularer Assist-Devices (LVAD) bei Patienten im kardiogenen Schock ist sehr limitiert und bedarf weiterer Untersuchung. Ein Vergleich von perkutanen LVAD-Systemen mit einer medikamentosen Standardtherapie in grosen randomisierten Studien ist bislang nicht erfolgt. Ein direkter Vergleich der verschiedenen mechanischen Unterstutzungssysteme untereinander existiert ebenfalls nicht. Aus diesen Grunden gibt es in den deutschen und internationalen Leitlinien derzeit nur eine Empfehlung fur Patienten im kardiogenen Schock, die refraktar gegenuber der medikamentosen Standardtherapie sind. Diese Ubersicht soll die Moglichkeiten der mechanischen Kreislaufunterstutzung im kardiogenen Schock beleuchten und die aktuelle (Leitlinien-)Empfehlungslage zur Anwendung der verschiedenen Systeme reflektieren.

Background The single-use supraglottic airway device i-gel™ has been described in several case reports as a conduit for intubation, but no prospective data about success rates of blind intubation are available. Therefore, we performed this prospective randomized controlled trial to compare the success rate of blind tracheal intubation with a Magill PVC tube through the i-gel™ with intubation using an sILMA™ PVC tube through the single-use intubating laryngeal mask airway (sILMA™). Methods With ethics committee approval and written informed consent, 80 patients with predictors of a difficult airway were computer randomized to either supraglottic airway device (SAD). The corresponding tracheal tube (TT) was introduced through the SAD under fibreoptic visualization but without fibreoptic guidance. Primary outcome was blind intubation success rate. Times, airway leak pressure, fibreoptic view, and adverse events were recorded. To control for the influence of the TT, we compared data from 40 patients described in an accompanying study (sILMA™ with Magill TT and i-gel™ with sILMA™ TT). Results Blind intubation success rate through the sILMA™ (69%) was higher than with the i-gel™ (15%, P

In recent years, the widespread use of partial mechanical cardiac support and even temporary complete replacement of cardiac function has been established in many intensive care units in the treatment of refractory cardiogenic shock. There is a difference between partial left-ventricular assist devices (LVAD) and the possibility of complete heart (and lung) replacement by extra corporeal life support (ECLS). Despite the use of mechanical support devices, the mortality of cardiogenic shock remains high. The consideration of using percutaneous LVAD and ECLS in cardiogenic shock should be considered in refractory cardiogenic shock patients in addition to support by catecholamines and after early revascularization in acute coronary syndromes. However, there are no large randomized studies evaluating mechanical support systems with respect to outcome in cardiogenic shock patients. German and international guidelines do not recommend the routine use of mechanical support as a first-line treatment in cardiogenic shock patients and emphasize that their application should be restricted to patients with therapy refractory shock. In other cases of noninfarct-related cardiogenic shock (e. g., poisoning, myocarditis), ECLS use should be considered as bridging therapy. ECLS may also be considered in cardiopulmonary resuscitation which is termed E‑CPR. According to registry data, E‑CPR may reduce mortality in selected patients. A possible application of ECLS is severe accidental hypothermia with cardiac arrest despite limited data. In these rare cases, early ECLS should be considered for rewarming and stabilization.

In this paper we investigate the propagation of conical waves in nonlinear media. In particular, we are interested in the effects resulting from applying a Gaussian apodization to an ideal nondiffracting wave. First, we present a multiple scales approach to derive amplitude equations for weakly nonlinear conical waves from a governing equation of cubic nonlinear Schrodinger type. From these equations we obtain asymptotic solutions for the linear and the weakly nonlinear problem for which we state several uniform estimates that describe the deviation from the ideal nondiffracting solution. Moreover, we show numerical simulations based on an implementation of our amplitude equations to support and illustrate our analytical results.

On behalf of the Medical/Psychological Pain Associations, Pain Patients Alliance and the Professional Association of Pain Physicians and Psychologists, the Joint Commission of Professional Societies and Organizations for Quality in Pain Medicine, working in close collaboration with the respective presidents, has developed verifiable structural and process-related criteria for the classification of medical and psychological pain treatment facilities in Germany. Based on the established system of graded care in Germany and on existing qualifications, these criteria also argue for the introduction of a basic qualification in pain medicine. In addition to the first-ever comprehensive description of psychological pain facilities, the criteria presented can be used to classify five different levels of pain facilities, from basic pain management facilities, to specialized institutions, to the Centre for Interdisciplinary Pain Medicine. The recommendations offer binding and verifiable criteria for quality assurance in pain medicine and improved pain treatment.

Systematic evaluation of ferroelectric memory (FRAM) data retention mechanisms under high temperature exposure are reported. The FRAM devices are embedded on ultra-low power, analog-enhanced 130nm and 180nm CMOS technologies. Capability of the FRAM to retain data through 260°C Pb-free solder assembly reflow is demonstrated. The 130nm FRAM is shown to achieve the equivalent of 10 years data retention at 125°C, with intrinsic margin comparable to the 180nm FRAM, previously shown to achieve 10 years at 125°C retention.

Die arterielle Hypertonie ist der haufigste und wichtigste Risikofaktor fur die koronare Herzkrankheit (KHK). Arterielle Hypertonie und KHK treten somit haufig koinzident auf und fuhren additiv nicht nur zu einer myokardialen Mikrozirkulationstorung, sondern uber die permanente Druckuberlastung des Herzens sowie die KHK-bedingte Ischamie auch zu einer permanenten Schadigung des linksventrikularen Myokards. Therapeutisch ist sowohl in der Primar- als auch in der Sekundarpravention eine gute Einstellung des systemischen Blutdrucks notwendig. Hier stehen nichtpharmakologische Masnahmen an erster Stelle. Allerdings kann auf eine Medikation in der Regel nicht verzichtet werden, wobei Antihypertensiva in Kombination mit ASS und Statinen als sichere und in grosen internationalen Studien erprobte Mono- und Kombinationspraparate fur Patienten mit Hypertonie und KHK zur Verfugung stehen. Dabei sollte die genaue Einstellung auf Zielblutdruckwerte in Abhangigkeit vom Schweregrad der KHK erfolgen. Besondere Beachtung findet dabei der diastolische Blutdruck, der eine J-formige Beziehung zu koronaren Endpunkten zeigt und bei Werten zwischen 70 und 90 mmHg optimal eingestellt ist.

The German Society for the Study of Pain has formed an interdisciplinary committee to answer urgent ethical questions on the diagnosis and treatment of pain and to give an ethical orientation on the care of pain and palliative patients. The treatment of pain is a fundamental objective of medicine. Competent and adequate relief of pain in all stages of life is a basic characteristic of a humane medicine oriented to the quality and meaning of life for people. However, there are substantial deficits in all areas, especially in the knowledge of physicians and patients, in training and further education, diagnosis and therapy. Freedom from pain is a substantial element of quality of life. A central duty of all physicians is an adequate diagnosis and treatment of acute pain and thereby the prophylaxis of chronic pain. If pain persists over a longer period of time, it loses the warning function and becomes taken for granted. Alterations, disabilities and limitations of the physical, psychic and social levels are the consequences. For these patients an interdisciplinary approach is necessary by which various medical disciplines, psychologists and physiotherapists are involved and all collaborate on the diagnosis and therapy of pain. All patients have the right to sufficient and individually tailored treatment of pain. Special attention must be paid to vulnerable patient groups, such as newborns, children and adolescents, as well as aged and mentally retarded patients. For cancer patients pain relief of their tumor pain is totally in the forefront. Indications of "unbearable pain" must not lead to resignation or even be seen as an argument for legalization of "death on request". The nursing of terminally ill patients necessitates a special measure not only of clinical, but also ethical competence, communication and multiprofessional collaboration. The modern options for palliative care are real alternatives to demands for legalization of "death on request". Physician-assisted suicide does not belong to the scope of functions of palliative medicine. The basic constitutional law makes an appropriate treatment of pain obligatory. Neglect of pain treatment fulfils the elements of criminal bodily harm. As a consequence, there is a legal right to a comprehensive pain diagnosis and a pain treatment corresponding to the appropriate standard. The state is obliged to provide the legal, social and financial prerequisites for an adequate treatment of pain. Continuous efforts in research are necessary to fill the existing gaps in our knowledge. The transfer between basic research and clinical application of pain therapy must be urgently improved. Of central importance for the German Pain Society are therefore: Improvement of training and further education in pain therapy. Chronic pain must be accepted and coded as an autonomous sickness. Graded structures for care of pain patients must be realized. Interdisciplinary structures of care must be made available to patients with chronic pain. Palliative medical care is a basic right of all terminally ill patients. Politics and health care providers must establish prerequisites for adequate pain diagnosis, pain therapy and palliative medicine.

Human cannabinoid type 1 (CB1) G-protein coupled receptor is a potential therapeutic target for obesity. The previously predicted and experimentally validated ensemble of ligand-free conformations of CB1 [Scott, C. E. et al. Protein Sci.2013, 22, 101−11323184890; Ahn, K. H. et al. Proteins2013, 81, 1304–131723408552] are used here to predict the binding sites for known CB1-selective inverse agonists including rimonabant and its seven known derivatives. This binding pocket, which differs significantly from previously published models, is used to identify 16 novel compounds expected to be CB1 inverse agonists by exploiting potential new interactions. We show experimentally that two of these compounds exhibit inverse agonist properties including inhibition of basal and agonist-induced G-protein coupling activity, as well as an enhanced level of CB1 cell surface localization. This demonstrates the utility of using the predicted binding sites for an ensemble of CB1 receptor structures for designing new CB1 inverse agonists.