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The ALICE Collaboration reports the measurement of the relative J/ψ yield as a function of charged particle pseudorapidity density dNch/dη in pp collisions at √s=7 TeV at the LHC. J/ψ particles are detected for pt>0, in the rapidity interval |y|<0.9 via decay into e+e−, and in the interval 2.5<y<4.0 via decay into μ+μ− pairs. An approximately linear increase of the J/ψ yields normalized to their event average (dNJ/ψ/dy)/〈dNJ/ψ/dy〉 with (dNch/dη)/〈dNch/dη〉 is observed in both rapidity ranges, where dNch/dη is measured within |η|<1 and pt>0. In the highest multiplicity interval with 〈dNch/dη(bin)〉=24.1, corresponding to four times the minimum bias multiplicity density, an enhancement relative to the minimum bias J/ψ yield by a factor of about 5 at 2.5<y<4 (8 at |y|<0.9) is observed.
The ALICE Zero Degree Calorimeter system (ZDC) is composed of two identical sets of calorimeters, placed at opposite sides with respect to the interaction point, 114 meters away from it, complemented by two small forward electromagnetic calorimeters (ZEM). Each set of detectors consists of a neutron (ZN) and a proton (ZP) ZDC. They are placed at zero degrees with respect to the LHC axis and allow to detect particles emitted close to beam direction, in particular neutrons and protons emerging from hadronic heavy-ion collisions (spectator nucleons) and those emitted from electromagnetic processes. For neutrons emitted by these two processes, the ZN calorimeters have nearly 100% acceptance.
During the √sNN = 2.76 TeV Pb-Pb data-taking, the ALICE Collaboration studied forward neutron emission with a dedicated trigger, requiring a minimum energy deposition in at least one of the two ZN. By exploiting also the information of the two ZEM calorimeters it has been possible to separate the contributions of electromagnetic and hadronic processes and to study single neutron vs. multiple neutron emission.
The measured cross sections of single and mutual electromagnetic dissociation of Pb nuclei at √sNN = 2.76 TeV, with neutron emission, are σsingle EMD = 187:4 ± 0.2 (stat.)−11.2+13.2 (syst.) b and σmutual EMD = 5.7 ± 0.1 (stat.) ±0.4 (syst.) b, respectively [1]. This is the first measurement of electromagnetic dissociation of 208Pb nuclei at the LHC energies, allowing a test of electromagnetic dissociation theory in a new energy regime. The experimental results are compared to the predictions from a relativistic electromagnetic dissociation model.
Introduction: Evidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkin's lymphoma in a real-life clinical setting.
Methods: Patients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases. The main outcome measures were safety and clinical response, as judged at the discretion of the investigators.
Results: A total of 370 patients (299 patient-years) with various autoimmune diseases (23.0% with systemic lupus erythematosus, 15.7% antineutrophil cytoplasmic antibody-associated granulomatous vasculitides, 15.1% multiple sclerosis and 10.0% pemphigus) from 42 centres received a mean dose of 2,440 mg of rituximab over a median (range) of 194 (180 to 1,407) days. The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy. Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus. There were 11 deaths (3.0% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections. Overall (n = 293), 13.3% of patients showed no response, 45.1% showed a partial response and 41.6% showed a complete response. Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab. Rituximab generally had a positive effect on patient well-being (physician's visual analogue scale; mean improvement from baseline of 12.1 mm).
Conclusions: Data from this registry indicate that rituximab is a commonly employed, well-tolerated therapy with potential beneficial effects in standard of care-refractory autoimmune diseases, and support the results from other open-label, uncontrolled studies.
Plants, fungi and algae are important components of global biodiversity and are fundamental to all ecosystems. They are the basis for human well-being, providing food, materials and medicines. Specimens of all three groups of organisms are accommodated in herbaria, where they are commonly referred to as botanical specimens.The large number of specimens in herbaria provides an ample, permanent and continuously improving knowledge base on these organisms and an indispensable source for the analysis of the distribution of species in space and time critical for current and future research relating to global biodiversity. In order to make full use of this resource, a research infrastructure has to be built that grants comprehensive and free access to the information in herbaria and botanical collections in general. This can be achieved through digitization of the botanical objects and associated data.The botanical research community can count on a long-standing tradition of collaboration among institutions and individuals. It agreed on data standards and standard services even before the advent of computerization and information networking, an example being the Index Herbariorum as a global registry of herbaria helping towards the unique identification of specimens cited in the literature.In the spirit of this collaborative history, 51 representatives from 30 institutions advocate to start the digitization of botanical collections with the overall wall-to-wall digitization of the flat objects stored in German herbaria. Germany has 70 herbaria holding almost 23 million specimens according to a national survey carried out in 2019. 87% of these specimens are not yet digitized. Experiences from other countries like France, the Netherlands, Finland, the US and Australia show that herbaria can be comprehensively and cost-efficiently digitized in a relatively short time due to established workflows and protocols for the high-throughput digitization of flat objects.Most of the herbaria are part of a university (34), fewer belong to municipal museums (10) or state museums (8), six herbaria belong to institutions also supported by federal funds such as Leibniz institutes, and four belong to non-governmental organizations. A common data infrastructure must therefore integrate different kinds of institutions.Making full use of the data gained by digitization requires the set-up of a digital infrastructure for storage, archiving, content indexing and networking as well as standardized access for the scientific use of digital objects. A standards-based portfolio of technical components has already been developed and successfully tested by the Biodiversity Informatics Community over the last two decades, comprising among others access protocols, collection databases, portals, tools for semantic enrichment and annotation, international networking, storage and archiving in accordance with international standards. This was achieved through the funding by national and international programs and initiatives, which also paved the road for the German contribution to the Global Biodiversity Information Facility (GBIF).Herbaria constitute a large part of the German botanical collections that also comprise living collections in botanical gardens and seed banks, DNA- and tissue samples, specimens preserved in fluids or on microscope slides and more. Once the herbaria are digitized, these resources can be integrated, adding to the value of the overall research infrastructure. The community has agreed on tasks that are shared between the herbaria, as the German GBIF model already successfully demonstrates.We have compiled nine scientific use cases of immediate societal relevance for an integrated infrastructure of botanical collections. They address accelerated biodiversity discovery and research, biomonitoring and conservation planning, biodiversity modelling, the generation of trait information, automated image recognition by artificial intelligence, automated pathogen detection, contextualization by interlinking objects, enabling provenance research, as well as education, outreach and citizen science.We propose to start this initiative now in order to valorize German botanical collections as a vital part of a worldwide biodiversity data pool.
Aim: In the CheckRad-CD8 trial patients with locally advanced head and neck squamous cell cancer are treated with a single cycle of induction chemo-immunotherapy (ICIT). Patients with pathological complete response (pCR) in the re-biopsy enter radioimmunotherapy. Our goal was to study the value of F-18-FDG PET/CT in the prediction of pCR after induction therapy.
Methods: Patients treated within the CheckRad-CD8 trial that additionally received FDG- PET/CT imaging at the following two time points were included: 3–14 days before (pre-ICIT) and 21–28 days after (post-ICIT) receiving ICIT. Tracer uptake in primary tumors (PT) and suspicious cervical lymph nodes (LN +) was measured using different quantitative parameters on EANM Research Ltd (EARL) accredited PET reconstructions. In addition, mean FDG uptake levels in lymphatic and hematopoietic organs were examined. Percent decrease (Δ) in FDG uptake was calculated for all parameters. Biopsy of the PT post-ICIT acquired after FDG-PET/CT served as reference. The cohort was divided in patients with pCR and residual tumor (ReTu).
Results: Thirty-one patients were included. In ROC analysis, ΔSUVmax PT performed best (AUC = 0.89) in predicting pCR (n = 17), with a decline of at least 60% (sensitivity, 0.77; specificity, 0.93). Residual SUVmax PT post-ICIT performed best in predicting ReTu (n = 14), at a cutpoint of 6.0 (AUC = 0.91; sensitivity, 0.86; specificity, 0.88). Combining two quantitative parameters (ΔSUVmax ≥ 50% and SUVmax PT post-ICIT ≤ 6.0) conferred a sensitivity of 0.81 and a specificity of 0.93 for determining pCR. Background activity in lymphatic organs or uptake in suspected cervical lymph node metastases lacked significant predictive value.
Conclusion: FDG-PET/CT can identify patients with pCR after ICIT via residual FDG uptake levels in primary tumors and the related changes compared to baseline. FDG-uptake in LN + had no predictive value.
Trial registry: ClinicalTrials.gov identifier: NCT03426657.
The Coulomb Dissociation (CD) cross sections of the stable isotopes 92,94,100Mo and of the unstable isotope 93Mo were measured at the LAND/R3B setup at GSI Helmholtzzentrum für Schwerionenforschung in Darmstadt, Germany. Experimental data on these isotopes may help to explain the problem of the underproduction of 92,94Mo and 96,98Ru in the models of p-process nucleosynthesis. The CD cross sections obtained for the stable Mo isotopes are in good agreement with experiments performed with real photons, thus validating the method of Coulomb Dissociation. The result for the reaction 93Mo(γ,n) is especially important since the corresponding cross section has not been measured before. A preliminary integral Coulomb Dissociation cross section of the 94Mo(γ,n) reaction is presented. Further analysis will complete the experimental database for the (γ,n) production chain of the p-isotopes of molybdenum.
The project focuses on the efficiency of combined technologies to reduce the release of micropollutants and bacteria into surface waters via sewage treatment plants of different size and via stormwater overflow basins of different types. As a model river in a highly populated catchment area, the river Schussen and, as a control, the river Argen, two tributaries of Lake Constance, Southern Germany, are under investigation in this project. The efficiency of the different cleaning technologies is monitored by a wide range of exposure and effect analyses including chemical and microbiological techniques as well as effect studies ranging from molecules to communities.
Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).
We report progress in our exploration of the finite-temperature phase structure of two-flavour lattice
QCD with twisted-mass Wilson fermions and a tree-level Symanzik-improved gauge action
for a temporal lattice size Nt = 8. Extending our investigations to a wider region of parameter
space we gain a global view of the rich phase structure. We identify the finite temperature transition/
crossover for a non-vanishing twisted-mass parameter in the neighbourhood of the zerotemperature
critical line at sufficiently high b . Our findings are consistent with Creutz’s conjecture
of a conical shape of the finite temperature transition surface. Comparing with NLO lattice
cPT we achieve an improved understanding of this shape.
We discuss the use of Wilson fermions with twisted mass for simulations of QCD thermodynamics.
As a prerequisite for a future analysis of the finite-temperature transition making use
of automatic O(a) improvement, we investigate the phase structure in the space spanned by the
hopping parameter k , the coupling b , and the twisted mass parameter m. We present results for
Nf = 2 degenerate quarks on a 163×8 lattice, for which we investigate the possibility of an Aoki
phase existing at strong coupling and vanishing m, as well as of a thermal phase transition at
moderate gauge couplings and non-vanishing m.
Pseudo-Critical Temperature and Thermal Equation of State from Nf = 2 Twisted Mass Lattice QCD
(2012)
We report about the current status of our ongoing study of the chiral limit of two-flavor QCD at finite temperature with twisted mass quarks. We estimate the pseudo-critical temperature Tc for three values of the pion mass in the range of mPS ~ 300 and 500 MeV and discuss different chiral scenarios. Furthermore, we present first preliminary results for the trace anomaly, pressure and energy density. We have studied several discretizations of Euclidean time up to Nt = 12 in order to assess the continuum limit of the trace anomaly. From its interpolation we evaluate the pressure and energy density employing the integral method. Here, we have focussed on two pion masses with mPS ~ 400 and 700 MeV.
In this study, we aimed to comparatively evaluate high-resolution 3D ultrasonography (hrUS), in-vivo micro-CT (μCT) and 9.4T MRI for the monitoring of tumor growth in an orthotopic renal cell carcinoma (RCC) xenograft model since there is a lack of validated, non-invasive imaging tools for this purpose. 1 × 106 Caki-2 RCC cells were implanted under the renal capsule of 16 immunodeficient mice. Local and systemic tumor growth were monitored by regular hrUS, μCT and MRI examinations. Cells engrafted in all mice and gave rise to exponentially growing, solid tumors. All imaging techniques allowed to detect orthotopic tumors and to precisely calculate their volumes. While tumors appeared homogenously radiolucent in μCT, hrUS and MRI allowed for a better visualization of intratumoral structures and surrounding soft tissue. Examination time was the shortest for hrUS, followed by μCT and MRI. Tumor volumes determined by hrUS, μCT and MRI showed a very good correlation with each other and with caliper measurements at autopsy. 10 animals developed pulmonary metastases being well detectable by μCT and MRI. In conclusion, each technique has specific strengths and weaknesses, so the one(s) best suitable for a specific experiment may be chosen individually.
Simple Summary: Treatment of metastatic renal cell carcinoma (mRCC) remains a challenge due to the lack of biomarkers indicating the optimal drug for each patient. This study analyzed blood samples of patients with predominant clear cell mRCC who were treated with the mTOR inhibitor everolimus after failure of one prior tumor therapy. In an exploratory approach, predictive blood biomarkers were searched. We found lower levels of the protein thrombospondin-2 (TSP-2) at the start of the therapy and higher lactate dehydrogenase (LDH) levels in serum two weeks after therapy initiation to be associated with therapy response. Of note, these blood biomarkers had a higher predictive value than baseline patient parameters or risk classifications. Polymorphisms in the mTOR gene appeared to be associated with therapy response, but were not significant. To conclude, it seems feasible to identify patients showing longtime responses to everolimus and possible to increase tumor therapy response rates based on biomarkers for individual therapy selection.
Abstract: There is an unmet need for predictive biomarkers in metastatic renal cell carcinoma (mRCC) therapy. The phase IV MARC-2 trial searched for predictive blood biomarkers in patients with predominant clear cell mRCC who benefit from second-line treatment with everolimus. In an exploratory approach, potential biomarkers were assessed employing proteomics, ELISA, and polymorphism analyses. Lower levels of angiogenesis-related protein thrombospondin-2 (TSP-2) at baseline (≤665 parts per billion, ppb) identified therapy responders with longer median progression-free survival (PFS; ≤665 ppb at baseline: 6.9 months vs. 1.8, p = 0.005). Responders had higher lactate dehydrogenase (LDH) levels in serum two weeks after therapy initiation (>27.14 nmol/L), associated with a longer median PFS (3.8 months vs. 2.2, p = 0.013) and improved overall survival (OS; 31.0 months vs. 14.0 months, p < 0.001). Baseline TSP-2 levels had a stronger relation to PFS (HR 0.36, p = 0.008) than baseline patient parameters, including IMDC score. Increased serum LDH levels two weeks after therapy initiation were the best predictor for OS (HR 0.21, p < 0.001). mTOR polymorphisms appeared to be associated with therapy response but were not significant. Hence, we identified TSP-2 and LDH as promising predictive biomarkers for therapy response on everolimus after failure of one VEGF-targeted therapy in patients with clear cell mRCC.
Einleitung: Die konventionelle Galaktografie stellte jahrzehntelang das einzige bildgebende Verfahren zur Darstellung von Milchgängen in der Brust dar. Heute verfügen wir in der Diagnostik über ein multimodales Konzept aus hochauflösendem Ultraschall, der Magnetresonanz-(MR-)Mammografie und der Duktoskopie/Galaktoskopie mit Sensitivitäten und Spezifitäten bis zu 95%. Ziel unserer Untersuchung war es, erstmalig die Tomosynthesetechnik in der Galaktografie einzusetzen und die daraus generierten synthetischen digitalen 2-D-Vollfeld-Mammografien mit der etablierten Methode der duktusorientierten Sonografie zu vergleichen. Es sollen mit beiden Methoden invasive Mammakarzinome und deren Vorstufen wie duktale Carcinoma in situ (DCIS) sowie benigne Befunde erkannt werden. Material und Methoden: Wir führten bei 5 Patientinnen mit pathologischer Mamillensekretion sowohl eine duktusorientierte Sonografie, eine kontrastmittelunterstützte Galaktografie mithilfe der Tomosynthese in 3-D sowie auch den daraus generierten synthetischen digitalen 2-D-Vollfeld-Mammografien durch. Die Auswertung der unterschiedlichen Untersuchungsmodalitäten erfolgte durch 3 in der komplementären Mammadiagnostik erfahrene Untersucher (1, 5 und 15 Jahre) und wurde mit der endgültigen Histologie korreliert. Ergebnisse: Alle 3 Untersucher beurteilten unabhängig voneinander die Bilder des duktusorientierten Ultraschalls und der kontrastmittelunterstützten Galaktografie in Tomosynthesetechnik in 3-D und den daraus generierten, synthetischen digitalen 2-D-Vollfeld-Mammografien. Die Ergebnisse wurden mit den histopathologischen Befunden der Operationspräparate korreliert, wobei sich bei den 5 Patientinnen 1 invasives Mammakarzinom, 2-mal ein duktales Carcinoma in situ (DCIS) und 2 benigne Befunde ergaben. Alle drei Untersucher lagen bei der Verdachtsdiagnose in der Standardbildgebung der duktusorientierten Sonografie seltener richtig als bei der erstmalig durchgeführten, kontrastmittelunterstützten Galaktografie in Tomosynthesetechnik und den daraus generierten, synthetischen digitalen 2-D-Vollfeld-Mammografien. Schlussfolgerung: Erstmalig wurde die Brusttomosynthese in der Galaktografie (Galaktomosynthese) eingesetzt und ermöglichte eine digitale, 3-dimensionale Darstellung von suspekten Befunden. Zusammen mit den daraus synthetisierten, digitalen 2-D-Vollfeld-Mammografien könnte dies in Zukunft eine sinnvolle Ergänzung der komplementären Mammadiagnostik sein – und eine Renaissance dieser Methode. Im Vergleich mit dem duktusorientierten Ultraschall in Hochauflösung erzielten die Untersucher mit der kontrastmittelunterstützten Galaktografie in Tomosynthesetechnik und den daraus generierten, synthetischen digitalen 2-D-Vollfeld-Mammografien bessere Ergebnisse in Korrelation mit den histopathologischen Befunden.
Introduction: For decades, conventional galactography was the only imaging technique capable of showing the mammary ducts. Today, diagnosis is based on a multimodal concept which combines high-resolution ultrasound with magnetic resonance (MR) mammography and ductoscopy/galactoscopy and has a sensitivity and specificity of up to 95%. This study used tomosynthesis in galactography for the first time and compared the synthetic digital 2D full-field mammograms generated with this technique with the images created using the established method of ductal sonography. Both methods should be able to detect invasive breast cancers and their precursors such as ductal carcinoma in situ (DCIS) as well as being able to identify benign findings.
Material and Methods: Five patients with pathological nipple discharge were examined using ductal sonography, contrast-enhanced 3D galactography with tomosynthesis and the synthetic digital 2D full-field mammograms generated with the latter method. Evaluation of the images created with the different imaging modalities was done by three investigators with varying levels of experience with complementary breast diagnostics (1, 5 and 15 years), and their evaluations were compared with the histological findings.
Results: All 3 investigators independently evaluated the images created with ductal sonography, contrast-enhanced 3D galactography with tomosynthesis, and generated synthetic digital 2D full-field mammograms. Their evaluations were compared with the histopathological assessment of the surgical specimens resected from the 5 patients. There was 1 case of invasive breast cancer, 2 cases with ductal carcinoma in situ and 2 cases with benign findings. All 3 investigators made more mistakes when they used the standard imaging technique of ductal sonography to diagnose suspicious lesions than when they used contrast-enhanced galactography with tomosynthesis and the generated synthetic digital 2D full-field mammograms.
Conclusion: This is the first time breast tomosynthesis was used in galactography (galactomosynthesis) to create digital 3-dimensional images of suspicious findings. When used together with the generated synthetic digital 2D full-field mammograms, it could be a useful complementary procedure for the diagnosis of breast anomalies and could herald a renaissance of this method. Compared with high-resolution ductal ultrasound, the investigators achieved better results with contrast-enhanced galactography using tomosynthesis and the generated synthetic digital 2D full-field mammograms, as confirmed by histopathological findings.
Very-long-baseline interferometry (VLBI) observations of active galactic nuclei at millimetre wavelengths have the power to reveal the launching and initial collimation region of extragalactic radio jets, down to 10–100 gravitational radii (rg ≡ GM/c2) scales in nearby sources. Centaurus A is the closest radio-loud source to Earth. It bridges the gap in mass and accretion rate between the supermassive black holes (SMBHs) in Messier 87 and our Galactic Centre. A large southern declination of −43° has, however, prevented VLBI imaging of Centaurus A below a wavelength of 1 cm thus far. Here we show the millimetre VLBI image of the source, which we obtained with the Event Horizon Telescope at 228 GHz. Compared with previous observations, we image the jet of Centaurus A at a tenfold higher frequency and sixteen times sharper resolution and thereby probe sub-lightday structures. We reveal a highly collimated, asymmetrically edge-brightened jet as well as the fainter counterjet. We find that the source structure of Centaurus A resembles the jet in Messier 87 on ~500 rg scales remarkably well. Furthermore, we identify the location of Centaurus A’s SMBH with respect to its resolved jet core at a wavelength of 1.3 mm and conclude that the source’s event horizon shadow should be visible at terahertz frequencies. This location further supports the universal scale invariance of black holes over a wide range of masses.
Background: The focus of this study is to identify particular microRNA (miRNA) signatures in exosomes derived from plasma of 435 human epidermal growth factor receptor 2 (HER2)-positive and triple-negative (TN) subtypes of breast cancer (BC).
Methods: First, miRNA expression profiles were determined in exosomes derived from the plasma of 15 TNBC patients before neoadjuvant therapy using a quantitative TaqMan real-time PCR-based microRNA array card containing 384 different miRNAs. Forty-five miRNAs associated with different clinical parameters were then selected and mounted on microRNA array cards that served for the quantification of exosomal miRNAs in 435 BC patients before therapy and 20 healthy women. Confocal microscopy, Western blot, and ELISA were used for exosome characterization.
Results: Quantification of 45 exosomal miRNAs showed that compared with healthy women, 10 miRNAs in the entire cohort of BC patients, 13 in the subgroup of 211 HER2-positive BC, and 17 in the subgroup of 224 TNBC were significantly deregulated. Plasma levels of 18 exosomal miRNAs differed between HER2-positive and TNBC subtypes, and 9 miRNAs of them also differed from healthy women. Exosomal miRNAs were significantly associated with the clinicopathological and risk factors. In uni- and multivariate models, miR-155 (p = 0.002, p = 0.003, respectively) and miR-301 (p = 0.002, p = 0.001, respectively) best predicted pathological complete response (pCR).
Conclusion: Our findings show a network of deregulated exosomal miRNAs with specific expression patterns in exosomes of HER2-positive and TNBC patients that are also associated with clinicopathological parameters and pCR within each BC subtype.
Purpose: To evaluate the efficacy of the virtual reality training simulator Eyesi to prepare surgeons for performing pars plana vitrectomies and its potential to predict the surgeons’ performance.
Methods: In a preparation phase, four participating vitreoretinal surgeons performed repeated simulator training with predefined tasks. If a surgeon was assigned to perform a vitrectomy for the management of complex retinal detachment after a surgical break of at least 60 hours it was randomly decided whether a warmup training on the simulator was required (n = 9) or not (n = 12). Performance at the simulator was measured using the built-in scoring metrics. The surgical performance was determined by two blinded observers who analyzed the video-recorded interventions. One of them repeated the analysis to check for intra-observer consistency. The surgical performance of the interventions with and without simulator training was compared. In addition, for the surgeries with simulator training, the simulator performance was compared to the performance in the operating room.
Results: Comparing each surgeon’s performance with and without warmup trainingshowed a significant effect of warmup training onto the final outcome in the operating room. For the surgeries that were preceeded by the warmup procedure, the performance at the simulator was compared with the operating room performance. We found that there is a significant relation. The governing factor of low scores in the simulator were iatrogenic retinal holes, bleedings and lens damage. Surgeons who caused minor damage in the simulation also performed well in the operating room.
Conclusions: Despite the large variation of conditions, the effect of a warmup training as well as a relation between the performance at the simulator and in the operating room was found with statistical significance. Simulator training is able to serve as a warmup to increase the average performance.
Background; Salivary gland carcinomas (SGC) cover a heterogeneous group of malignancies with a lack of data of high-level evidence.
Methods; Clinical data of 127 patients treated for SGC at a university cancer center between 2002 and 2017 were analyzed retrospectively. The association of clinicopathological characteristics, treatment modalities, adverse events, and outcome was assessed.
Results: Patients received surgery (n = 65), surgery followed by (chemo-)radiotherapy (n = 56), or primary (chemo-)radiotherapy (n = 6). Injury to the cranial nerves or their branches was the most frequent surgical complication affecting 40 patients (33.1%). Ten year overall and progression-free survival rates were 73.2% and 65.4%, respectively. Parotid tumor site, advanced tumor, and positive nodal stage remained independent negative prognostic factors for overall survival, loco-regional and distant tumor control in multivariate analysis.
Conclusions: Optimizing treatment strategies for SGC, depending on distinct clinicopathological factors, remains challenging due to the low incidence rates of the disease.
GATA2 deficiency is a heterogeneous multi-system disorder characterized by a high risk of developing myelodysplastic syndrome (MDS) and myeloid leukemia. We analyzed the outcome of 65 patients reported to the registry of the European Working Group (EWOG) of MDS in childhood carrying a germline GATA2 mutation (GATA2mut) who had undergone hematopoietic stem cell transplantation (HSCT). At 5 years the probability of overall survival and disease-free survival (DFS) was 75% and 70%, respectively. Non-relapse mortality and relapse equally contributed to treatment failure. There was no evidence of increased incidence of graft-versus-host-disease or excessive rates of infections or organ toxicities. Advanced disease and monosomy 7 (−7) were associated with worse outcome. Patients with refractory cytopenia of childhood (RCC) and normal karyotype showed an excellent outcome (DFS 90%) compared to RCC and −7 (DFS 67%). Comparing outcome of GATA2mut with GATA2wt patients, there was no difference in DFS in patients with RCC and normal karyotype. The same was true for patients with −7 across morphological subtypes. We demonstrate that HSCT outcome is independent of GATA2 germline mutations in pediatric MDS suggesting the application of standard MDS algorithms and protocols. Our data support considering HSCT early in the course of GATA2 deficiency in young individuals.
Despite multidisciplinary local and systemic therapeutic approaches, the prognosis for most patients with brain metastases is still dismal. The role of adaptive and innate anti-tumor response including the Human Leukocyte Antigen (HLA) machinery of antigen presentation is still unclear. We present data on the HLA class II-chaperone molecule CD74 in brain metastases and its impact on the HLA peptidome complexity.
We analyzed CD74 and HLA class II expression on tumor cells in a subset of 236 human brain metastases, primary tumors and peripheral metastases of different entities in association with clinical data including overall survival. Additionally, we assessed whole DNA methylome profiles including CD74 promoter methylation and differential methylation in 21 brain metastases. We analyzed the effects of a siRNA mediated CD74 knockdown on HLA-expression and HLA peptidome composition in a brain metastatic melanoma cell line.
We observed that CD74 expression on tumor cells is a strong positive prognostic marker in brain metastasis patients and positively associated with tumor-infiltrating T-lymphocytes (TILs). Whole DNA methylome analysis suggested that CD74 tumor cell expression might be regulated epigenetically via CD74 promoter methylation. CD74high and TILhigh tumors displayed a differential DNA methylation pattern with highest enrichment scores for antigen processing and presentation. Furthermore, CD74 knockdown in vitro lead to a reduction of HLA class II peptidome complexity, while HLA class I peptidome remained unaffected.
In summary, our results demonstrate that a functional HLA class II processing machinery in brain metastatic tumor cells, reflected by a high expression of CD74 and a complex tumor cell HLA peptidome, seems to be crucial for better patient prognosis.
An ever-increasing demand for novel antimicrobials to treat life-threatening infections caused by the global spread of multidrug-resistant bacterial pathogens stands in stark contrast to the current level of investment in their development, particularly in the fields of natural-product-derived and synthetic small molecules. New agents displaying innovative chemistry and modes of action are desperately needed worldwide to tackle the public health menace posed by antimicrobial resistance. Here, our consortium presents a strategic blueprint to substantially improve our ability to discover and develop new antibiotics. We propose both short-term and long-term solutions to overcome the most urgent limitations in the various sectors of research and funding, aiming to bridge the gap between academic, industrial and political stakeholders, and to unite interdisciplinary expertise in order to efficiently fuel the translational pipeline for the benefit of future generations.
Significant reductions in stratospheric ozone occur inside the polar vortices each spring when chlorine radicals produced by heterogeneous reactions on cold particle surfaces in winter destroy ozone mainly in two catalytic cycles, the ClO dimer cycle and the ClO/BrO cycle. Chlorofluorocarbons (CFCs), which are responsible for most of the chlorine currently present in the stratosphere, have been banned by the Montreal Protocol and its amendments, and the ozone layer is predicted to recover to 1980 levels within the next few decades. During the same period, however, climate change is expected to alter the temperature, circulation patterns and chemical composition in the stratosphere, and possible geo-engineering ventures to mitigate climate change may lead to additional changes. To realistically predict the response of the ozone layer to such influences requires the correct representation of all relevant processes. The European project RECONCILE has comprehensively addressed remaining questions in the context of polar ozone depletion, with the objective to quantify the rates of some of the most relevant, yet still uncertain physical and chemical processes. To this end RECONCILE used a broad approach of laboratory experiments, two field missions in the Arctic winter 2009/10 employing the high altitude research aircraft M55-Geophysica and an extensive match ozone sonde campaign, as well as microphysical and chemical transport modelling and data assimilation. Some of the main outcomes of RECONCILE are as follows: (1) vortex meteorology: the 2009/10 Arctic winter was unusually cold at stratospheric levels during the six-week period from mid-December 2009 until the end of January 2010, with reduced transport and mixing across the polar vortex edge; polar vortex stability and how it is influenced by dynamic processes in the troposphere has led to unprecedented, synoptic-scale stratospheric regions with temperatures below the frost point; in these regions stratospheric ice clouds have been observed, extending over >106km2 during more than 3 weeks. (2) Particle microphysics: heterogeneous nucleation of nitric acid trihydrate (NAT) particles in the absence of ice has been unambiguously demonstrated; conversely, the synoptic scale ice clouds also appear to nucleate heterogeneously; a variety of possible heterogeneous nuclei has been characterised by chemical analysis of the non-volatile fraction of the background aerosol; substantial formation of solid particles and denitrification via their sedimentation has been observed and model parameterizations have been improved. (3) Chemistry: strong evidence has been found for significant chlorine activation not only on polar stratospheric clouds (PSCs) but also on cold binary aerosol; laboratory experiments and field data on the ClOOCl photolysis rate and other kinetic parameters have been shown to be consistent with an adequate degree of certainty; no evidence has been found that would support the existence of yet unknown chemical mechanisms making a significant contribution to polar ozone loss. (4) Global modelling: results from process studies have been implemented in a prognostic chemistry climate model (CCM); simulations with improved parameterisations of processes relevant for polar ozone depletion are evaluated against satellite data and other long term records using data assimilation and detrended fluctuation analysis. Finally, measurements and process studies within RECONCILE were also applied to the winter 2010/11, when special meteorological conditions led to the highest chemical ozone loss ever observed in the Arctic. In addition to quantifying the 2010/11 ozone loss and to understand its causes including possible connections to climate change, its impacts were addressed, such as changes in surface ultraviolet (UV) radiation in the densely populated northern mid-latitudes.
The international research project RECONCILE has addressed central questions regarding polar ozone depletion, with the objective to quantify some of the most relevant yet still uncertain physical and chemical processes and thereby improve prognostic modelling capabilities to realistically predict the response of the ozone layer to climate change. This overview paper outlines the scope and the general approach of RECONCILE, and it provides a summary of observations and modelling in 2010 and 2011 that have generated an in many respects unprecedented dataset to study processes in the Arctic winter stratosphere. Principally, it summarises important outcomes of RECONCILE including (i) better constraints and enhanced consistency on the set of parameters governing catalytic ozone destruction cycles, (ii) a better understanding of the role of cold binary aerosols in heterogeneous chlorine activation, (iii) an improved scheme of polar stratospheric cloud (PSC) processes that includes heterogeneous nucleation of nitric acid trihydrate (NAT) and ice on non-volatile background aerosol leading to better model parameterisations with respect to denitrification, and (iv) long transient simulations with a chemistry-climate model (CCM) updated based on the results of RECONCILE that better reproduce past ozone trends in Antarctica and are deemed to produce more reliable predictions of future ozone trends. The process studies and the global simulations conducted in RECONCILE show that in the Arctic, ozone depletion uncertainties in the chemical and microphysical processes are now clearly smaller than the sensitivity to dynamic variability.
Background: Perioperative anaemia leads to impaired oxygen supply with a risk of vital organ ischaemia. In healthy and fit individuals, anaemia can be compensated by several mechanisms. Elderly patients, however, have less compensatory mechanisms because of multiple co-morbidities and age-related decline of functional reserves. The purpose of the study is to evaluate whether elderly surgical patients may benefit from a liberal red blood cell (RBC) transfusion strategy compared to a restrictive transfusion strategy.
Methods: The LIBERAL Trial is a prospective, randomized, multicentre, controlled clinical phase IV trial randomising 2470 elderly (≥ 70 years) patients undergoing intermediate- or high-risk non-cardiac surgery. Registered patients will be randomised only if Haemoglobin (Hb) reaches ≤9 g/dl during surgery or within 3 days after surgery either to the LIBERAL group (transfusion of a single RBC unit when Hb ≤ 9 g/dl with a target range for the post-transfusion Hb level of 9–10.5 g/dl) or the RESTRICTIVE group (transfusion of a single RBC unit when Hb ≤ 7.5 g/dl with a target range for the post-transfusion Hb level of 7.5–9 g/dl). The intervention per patient will be followed until hospital discharge or up to 30 days after surgery, whichever occurs first. The primary efficacy outcome is defined as a composite of all-cause mortality, acute myocardial infarction, acute ischaemic stroke, acute kidney injury (stage III), acute mesenteric ischaemia and acute peripheral vascular ischaemia within 90 days after surgery. Infections requiring iv antibiotics with re-hospitalisation are assessed as important secondary endpoint. The primary endpoint will be analysed by logistic regression adjusting for age, cancer surgery (y/n), type of surgery (intermediate- or high-risk), and incorporating centres as random effect.
Discussion: The LIBERAL-Trial will evaluate whether a liberal transfusion strategy reduces the occurrence of major adverse events after non-cardiac surgery in the geriatric population compared to a restrictive strategy within 90 days after surgery.
Trial registration: ClinicalTrials.gov (identifier: NCT03369210).
Background: Simultaneous pancreas kidney transplantation (SPK), pancreas transplantation alone (PTA) or pancreas transplantation after kidney (PAK) are the only curative treatment options for patients with type 1 (juvenile) diabetes mellitus with or without impaired renal function. Unfortunately, transplant waiting lists for this indication are increasing because the current organ acceptability criteria are restrictive; morbidity and mortality significantly increase with time on the waitlist. Currently, only pancreas organs from donors younger than 50 years of age and with a body mass index (BMI) less than 30 are allocated for transplantation in the Eurotransplant (ET) area. To address this issue we designed a study to increase the available donor pool for these patients.
Methods/Design: This study is a prospective, multicenter (20 German centers), single blinded, non-randomized, two armed trial comparing outcome after SPK, PTA or PAK between organs with the currently allowed donor criteria versus selected organs from donors with extended criteria. Extended donor criteria are defined as organs procured from donors with a BMI of 30 to 34 or a donor age between 50 and 60 years. Immunosuppression is generally standardized using induction therapy with Myfortic, tacrolimus and low dose steroids. In principle, all patients on the waitlist for primary SPK, PTA or PAK are eligible for the clinical trial when they consent to possibly receiving an extended donor criteria organ. Patients receiving an organ meeting the current standard criteria for pancreas allocation (control arm) are compared to those receiving extended criteria organ (study arm); patients are blinded for a follow-up period of one year. The combined primary endpoint is survival of the pancreas allograft and pancreas allograft function after three months, as an early relevant outcome parameter for pancreas transplantation.
Discussion: The EXPAND Study has been initiated to investigate the hypothesis that locally allocated extended criteria organs can be transplanted with similar results compared to the currently allowed standard ET organ allocation. If our study shows a favorable comparison to standard organ allocation criteria, the morbidity and mortality for patients waiting for transplantation could be reduced in the future.
Trial registered at: NCT01384006
Background: Eligibility criteria are a critical part of clinical trials, as they define the patient population under investigation. Besides certain patient characteristics, clinical trials often include biomarker testing for eligibility. However, patient-identification mostly relies on the trial site itself and is often a time-consuming procedure, which could result in missing out on potentially eligible patients. Pre-selection of those patients using a registry could facilitate the process of eligibility testing and increase the number of identified patients. One aim with the PRAEGNANT registry (NCT02338167) is to identify patients for therapies based on clinical and molecular data. Here, we report eligibility testing for the SHERBOC trial using the German PRAEGNANT registry.
Methods:Heregulin (HRG) has been reported to identify patients with better responses to therapy with the anti-HER3 monoclonal antibody seribantumab (MM-121). The SHERBOC trial investigated adding seribantumab (MM-121) to standard therapy in patients with advanced HER2-negative, hormone receptor–positive (HR-positive) breast cancer and HRG overexpression. The PRAEGNANT registry was used for identification and tumor testing, helping to link potential HRG positive patients to the trial. Patients enrolled in PRAEGNANT have invasive and metastatic or locally advanced, inoperable breast cancer. Patients eligible for SHERBOC were identified by using the registry. Study aims were to describe the HRG positivity rate, screening procedures, and patient characteristics associated with inclusion and exclusion criteria.
Results: Among 2769 unselected advanced breast cancer patients, 650 were HER2-negative, HR-positive and currently receiving first- or second-line treatment, thus potentially eligible for SHERBOC at the end of current treatment; 125 patients also met further clinical eligibility criteria (e.g. menopausal status, ECOG). In the first/second treatment lines, patients selected for SHERBOC based on further eligibility criteria had a more favorable prognosis than those not selected. HRG status was tested in 38 patients, 14 of whom (36.8%) proved to be HRG-positive.
Conclusion: Using a real-world breast cancer registry allowed identification of potentially eligible patients for SHERBOC focusing on patients with HER3 overexpressing, HR-positive, HER2-negative metastatic breast cancer. This approach may provide insights into differences between patients eligible or non-eligible for clinical trials.
Trial registration: Clinicaltrials, NCT02338167, Registered 14 January 2015 - retrospectively registered.
This study presents comprehensive real-world data on the use of anti-human epidermal growth factor receptor 2 (HER2) therapies in patients with HER2-positive metastatic breast cancer (MBC). Specifically, it describes therapy patterns with trastuzumab (H), pertuzumab + trastuzumab (PH), lapatinib (L), and trastuzumab emtansine (T-DM1). The PRAEGNANT study is a real-time, real-world registry for MBC patients. All therapy lines are documented. This analysis describes the utilization of anti-HER2 therapies as well as therapy sequences. Among 1936 patients in PRAEGNANT, 451 were HER2-positive (23.3%). In the analysis set (417 patients), 53% of whom were included in PRAEGNANT in the first-line setting, 241 were treated with H, 237 with PH, 85 with L, and 125 with T-DM1 during the course of their therapies. The sequence PH → T-DM1 was administered in 51 patients. Higher Eastern Cooperative Oncology Group (ECOG) scores, negative hormone receptor status, and visceral or brain metastases were associated with more frequent use of this therapy sequence. Most patients received T-DM1 after treatment with pertuzumab. Both novel therapies (PH and T-DM1) are utilized in a high proportion of HER2-positive breast cancer patients. As most patients receive T-DM1 after PH, real-world data may help to clarify whether the efficacy of this sequence is similar to that in the approval study.
Background: The incidence of central nervous system (CNS) metastases in breast cancer patients is rising and has become a major clinical challenge. Only few data are published concerning risk factors for the development of CNS metastases as a first site of metastatic disease in breast cancer patients. Moreover, the incidence of CNS metastases after modern neoadjuvant treatment is not clear.
Methods: We analyzed clinical factors associated with the occurrence of CNS metastases as the first site of metastatic disease in breast cancer patients after neoadjuvant treatment in the trials GeparQuinto and GeparSixto (n = 3160) where patients received targeted treatment in addition to taxane and anthracycline-based chemotherapy.
Results: After a median follow-up of 61 months, 108 (3%) of a total of 3160 patients developed CNS metastases as the first site of recurrence and 411 (13%) patients had metastatic disease outside the CNS. Thirty-six patients (1%) developed both CNS metastases and other distant metastases as the first site of metastatic disease. Regarding subtypes of the primary tumor, 1% of luminal A-like (11/954), 2% of luminal B-like (7/381), 4% of HER2-positive (34/809), and 6% of triple-negative patients (56/1008) developed CNS metastases as the first site of metastatic disease.
In multivariate analysis, risk factors for the development of CNS metastases were larger tumor size (cT3–4; HR 1.63, 95% CI 1.08–2.46, p = 0.021), node-positive disease (HR 2.57, 95% CI 1.64–4.04, p < 0.001), no pCR after neoadjuvant chemotherapy (HR 2.29, 95% CI 1.32–3.97, p = 0.003), and HER2-positive (HR 3.80, 95% CI 1.89–7.64, p < 0.001) or triple-negative subtype (HR 6.38, 95% CI 3.28–12.44, p < 0.001).
Conclusions: Especially patients with HER2-positive and triple-negative tumors are at risk of developing CNS metastases despite effective systemic treatment. A better understanding of the underlying mechanisms is required in order to develop potential preventive strategies.
Purpose: The PELICAN trial evaluates for the first time efficacy and safety of pegylated liposomal doxorubicin (PLD) versus capecitabine as first-line treatment of metastatic breast cancer (MBC).
Methods: This randomized, phase III, open-label, multicenter trial enrolled first-line MBC patients who were ineligible for endocrine or trastuzumab therapy. Cumulative adjuvant anthracyclines of 360 mg/m2 doxorubicin or equivalent were allowed. Left ventricular ejection fraction of >50 % was required. Patients received PLD 50 mg/m2 every 28 days or capecitabine 1250 mg/m2 twice daily for 14 days every 21 days. The primary endpoint was time-to-disease progression (TTP).
Results: 210 patients were randomized (n = 105, PLD and n = 105, capecitabine). Adjuvant anthracyclines were given to 37 % (PLD) and 36 % (capecitabine) of patients. No significant difference was observed in TTP [HR = 1.21 (95 % confidence interval, 0.838–1.750)]. Median TTP was 6.0 months for both PLD and capecitabine. Comparing patients with or without prior anthracyclines, no significant difference in TTP was observed in the PLD arm (log-rank P = 0.64). For PLD versus capecitabine, respectively, overall survival (median, 23.3 months vs. 26.8 months) and time-to-treatment failure (median, 4.6 months vs. 3.7 months) were not statistically significantly different. Compared to PLD, patients on capecitabine experienced more serious adverse events (P = 0.015) and more cardiac events among patients who had prior anthracycline exposure (18 vs. 8 %; P = 0.31).
Conclusion: Both PLD and capecitabine are effective first-line agents for MBC.
In this report, we present the contributions, outcomes, ideas, discussions and conclusions obtained at the PaleoMaps Workshop 2019, that took place at the Institute of Geography of the University of Cologne on 23 and 24 September 2019. The twofold aim of the workshop was: (1) to provide an overview of approaches and methods that are presently used to incorporate paleoenvironmental information in human–environment interaction modeling applications, and building thereon; (2) to devise new approaches and solutions that might be used to enhance the reconstruction of past human–environmental interconnections. This report first outlines the presented papers, and then provides a joint protocol of the often extensive discussions that came up following the presentations or else during the refreshment intervals. It concludes by adressing the open points to be resolved in future research avenues, e.g., implementation of open science practices, new procedures for reviewing of publications, and future concepts for quality assurance of the often complex paleoenvironmental data. This report may serve as an overview of the state of the art in paleoenvironment mapping and modeling. It includes an extensive compilation of the basic literature, as provided by the workshop attendants, which will itself facilitate the necessary future research.
In psychiatry, there has been a growing focus on identifying at-risk populations. For schizophrenia, these efforts have led to the development of early recognition and intervention measures. Despite a similar disease burden, the populations at risk of bipolar disorder have not been sufficiently characterized. Within the BipoLife consortium, we used magnetic resonance imaging (MRI) data from a multicenter study to assess structural gray matter alterations in N = 263 help-seeking individuals from seven study sites. We defined the risk using the EPIbipolar assessment tool as no-risk, low-risk, and high-risk and used a region-of-interest approach (ROI) based on the results of two large-scale multicenter studies of bipolar disorder by the ENIGMA working group. We detected significant differences in the thickness of the left pars opercularis (Cohen’s d = 0.47, p = 0.024) between groups. The cortex was significantly thinner in high-risk individuals compared to those in the no-risk group (p = 0.011). We detected no differences in the hippocampal volume. Exploratory analyses revealed no significant differences in other cortical or subcortical regions. The thinner cortex in help-seeking individuals at risk of bipolar disorder is in line with previous findings in patients with the established disorder and corresponds to the region of the highest effect size in the ENIGMA study of cortical alterations. Structural alterations in prefrontal cortex might be a trait marker of bipolar risk. This is the largest structural MRI study of help-seeking individuals at increased risk of bipolar disorder.
Men and women differ substantially regarding height, weight, and body fat. Interestingly, previous work detecting genetic effects for waist-to-hip ratio, to assess body fat distribution, has found that many of these showed sex-differences. However, systematic searches for sex-differences in genetic effects have not yet been conducted. Therefore, we undertook a genome-wide search for sexually dimorphic genetic effects for anthropometric traits including 133,723 individuals in a large meta-analysis and followed promising variants in further 137,052 individuals, including a total of 94 studies. We identified seven loci with significant sex-difference including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were significant in women, but not in men. Of interest is that sex-difference was only observed for waist phenotypes, but not for height or body-mass-index. We found no evidence for sex-differences with opposite effect direction for men and women. The PPARG locus is of specific interest due to its link to diabetes genetics and therapy. Our findings demonstrate the importance of investigating sex differences, which may lead to a better understanding of disease mechanisms with a potential relevance to treatment options.
A wide variety of enzymatic pathways that produce specialized metabolites in bacteria, fungi and plants are known to be encoded in biosynthetic gene clusters. Information about these clusters, pathways and metabolites is currently dispersed throughout the literature, making it difficult to exploit. To facilitate consistent and systematic deposition and retrieval of data on biosynthetic gene clusters, we propose the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard.
The consequences of the current COVID-19 pandemic for mental health remain unclear, especially regarding the effects on suicidal behaviors. To assess changes in the pattern of suicide attempt (SA) admissions and completed suicides (CS) in association with the COVID-19 pandemic. As part of a longitudinal study, SA admissions and CS are systematically documented and analyzed in all psychiatric hospitals in Frankfurt/Main (765.000 inhabitants). Number, sociodemographic factors, diagnoses and methods of SA and CS were compared between the periods of March–December 2019 and March–December 2020. The number of CS did not change, while the number of SA significantly decreased. Age, sex, occupational status, and psychiatric diagnoses did not change in SA, whereas the percentage of patients living alone while attempting suicide increased. The rate and number of intoxications as a SA method increased and more people attempted suicide in their own home, which was not observed in CS. Such a shift from public places to home is supported by the weekday of SA, as the rate of SA on weekends was significantly lower during the pandemic, likely because of lockdown measures. Only admissions to psychiatric hospitals were recorded, but not to other institutions. As it seems unlikely that the number of SA decreased while the number of CS remained unchanged, it is conceivable that the number of unreported SA cases increased during the pandemic. Our data suggest that a higher number of SA remained unnoticed during the pandemic because of their location and the use of methods associated with lower lethality.
Children’s and adolescents’ lives drastically changed during COVID lockdowns worldwide. To compare accident- and injury-related admissions to pediatric intensive care units (PICU) during the first German COVID lockdown with previous years, we conducted a retrospective multicenter study among 37 PICUs (21.5% of German PICU capacities). A total of 1444 admissions after accidents or injuries during the first lockdown period and matched periods of 2017–2019 were reported and standardized morbidity ratios (SMR) were calculated. Total PICU admissions due to accidents/injuries declined from an average of 366 to 346 (SMR 0.95 (CI 0.85–1.05)). Admissions with trauma increased from 196 to 212 (1.07 (0.93–1.23). Traffic accidents and school/kindergarten accidents decreased (0.77 (0.57–1.02 and 0.26 (0.05–0.75)), whereas household and leisure accidents increased (1.33 (1.06–1.66) and 1.34 (1.06–1.67)). Less neurosurgeries and more visceral surgeries were performed (0.69 (0.38–1.16) and 2.09 (1.19–3.39)). Non-accidental non-suicidal injuries declined (0.73 (0.42–1.17)). Suicide attempts increased in adolescent boys (1.38 (0.51–3.02)), but decreased in adolescent girls (0.56 (0.32–0.79)). In summary, changed trauma mechanisms entailed different surgeries compared to previous years. We found no evidence for an increase in child abuse cases requiring intensive care. The increase in suicide attempts among boys demands investigation.
Ziel der hier pointiert zusammenfassenden Gesamtschau der Beobachtungen aus den unterschiedlichen Forschungsmodulen des 'Monitoringsystem Drogentrends' (MoSyD) ist es, sich abzeichnende Veränderungen (Trends) und Muster des Konsums legaler und illegaler Drogen in Frankfurt am Main herauszustellen. Die Darstellung abstrahiert weitgehend von konkreten Daten und Einzelbeobachtungen - diese finden sich ausführlich in den einzelnen Berichtsteilen dokumentiert, die jeweils mit detaillierten Zusammenfassungen enden. Eine Ausnahme bilden hier die punktuellen Vergleiche mit Beobachtungen aus Hamburg, die im Rahmen der dort erstmalig in der Intention eines Trendmonitorings durchgeführten Schülerbefragung gemacht wurden (vgl. Baumgärtner 2004, s. auch 3.2.3). Damit können die Ergebnisse unmittelbar mit aktuellen Daten aus einer in vielerlei Hinsicht vergleichbaren deutschen Großstadt verglichen werden. Zwecks weiterer Vergleichbarkeit werden die Ergebnisse der MoSyD-Schülerbefragung im Abschnitt zu Jugendlichen/ jungen Erwachsenen in Bezug zu den Ergebnissen der ersten deutschen Erhebungen im Rahmen der europäischen Schülerbefragung ESPAD (vgl. Hibel et al. 2000, Kraus et al. 2004) gesetzt.
Background: The newly introduced German pediatric screening examination at the end of the third year of life (U7a) incorporates visual function testing in particular; there is no ophthalmic screening during childhood in Germany. The purpose of this study is to investigate the relationship between participation in U7a and visual function at the preschool health examination (PHE) in the sixth year of life. Methods: This study evaluated PHE data from school enrollment years 2009/2010 to 2014/2015 of Rhineland-Palatinate, Germany. Visual acuity (VA) at PHE was assessed with Rodenstock visual acuity test device (tumbling E) wearing glasses if present. The relationship between participation in U7a and VA <0.7 at PHE was calculated for reduced monocular and binocular VA using multiple logistic regression adjusted for potential confounders. Results: Data from 189,704 children (91,041 girls) in 35 out of 36 districts were included. The first children to participate in U7a were enrolled in 2011/2012 school year. In total, 90,339 children (47.6%) had U7a before PHE, while 99,365 (52.4%) had not. VA <0.7 in at least one eye was measured at PHE in 8429 (4.4%) children, and in both eyes in 4345 (2.3%) children. Participation in U7a was not associated with VA <0.7 at PHE (odds ratio 0.99; 95% confidence interval: 0.94–1.04). Conclusions: The proportion of children with VA <0.7 at PHE was high. No beneficial effect of newly introduced German U7a pediatric screening examination was found for reduced VA at PHE.
In der heutigen Zeit ist der Konsum von Drogen wie THC und Amphetaminen insbe-sondere unter Jugendlichen weit verbreitet. Vor allem durch die aufputschende Wirkung der Amphetamine und deren Ruf als Partydroge kommt es gehäuft an Wochenenden zu vermehrten Autofahrten unter Drogeneinfluss. Die vorliegende Arbeit untersucht die Auswirkungen von THC- und Amphetaminkon-sum auf verschiedene Sehleistungen. Zu diesem Zweck wurde eine Gruppe von Kraft-fahrzeugführern, die unter Drogeneinfluss standen, mit einem nicht beeinflussten Kol-lektiv verglichen. Es zeigten sich signifikante Unterschiede im Bereich der Testzeit sowie des Stereose-hens, wobei die Gruppe der Drogenkonsumenten und hier vorrangig die Amphetamin-konsumenten deutlich schlechter abschnitten. Die Beeinträchtigungen im Bereich der Testzeit dürften auf eine deutlich eingeschränkte Konzentrationsfähigkeit unter Amphetamin- und THC- Konsum zurück zu führen sein, vermutlich hervorgerufen durch Wirkungen im Bereich des Hypothalamus und Hippo-campus, welche im Bereich der Aufmerksamkeit sowie des Lernverhaltens eine wich-tige Rolle spielen. Verbindungen dieser beiden Hirnareale zur Sehbahn könnten eine Erklärung für die Einschränkungen im Bereich des Stereosehens vor allem der Amphetamingruppe sein, da diese Substanzgruppe sowohl Hippocampus, Hypothalamus als auch die Mandel-kerne beeinflusst, THC hingegen nur den Hippocampus. Insgesamt muss anhand der vorliegenden Ergebnisse von einer Beeinträchtigung der Fahrtüchtigkeit unter THC und Amphetaminen unabhängig von der konsumierten Dro-genmenge ausgegangen werden. Hieraus lässt sich ableiten, dass die Einführung eines Grenzwertes aufgrund der sehr individuellen Beeinträchtigungen auf die kognitiven und optischen Fähigkeiten einer einzelnen Person als äußerst problematisch zu bewerten ist und somit die Fahrsicherheit und Fahreignung nur bei einem völligen Verzicht auf jeg-lichen Cannabis- oder Amphetaminkonsum gewährleistet ist.
Die "Digitalisierung" ist ein gesamtgesellschaftlicher und globaler Trend, der nahezu alle Bereiche der Lebens- und Arbeitswelt durchzieht und insofern auch das Studieren an (allen) Hochschulen betrifft. Das Schlagwort "Digitalisierung" verweist auch auf alle Varianten der Nutzung von digitalen Technologien im Bereich Studium und Lehre. Lange Zeit stand vor allem das E-Learning im Vordergrund der Diskussion und damit die Nutzung von digitalen Technologien im engeren Lehr-Lernkontext zur Unterstützung der Interaktion von Lehrenden und Studierenden. Heute werden an den Hochschulen zunehmend die weiteren Möglichkeiten der digitalen Technik für Studium und Lehre erkannt und immer mehr in der Praxis an Hochschulen genutzt: Von der Werbung um Studierende bis hin zur Ansprache von Alumni können sie die Qualität, die Leistungsfähigkeit, die Öffnung, Vermarktung und Internationalisierung der Hochschullehre unterstützen (Kerres 2013, Bischof und von Stuckrad 2013); und einige Hochschulen nutzen die Digitalisierung von Lehre und Studium zur Profilbildung und zur besseren Positionierung im nationalen und internationalen Wettbewerb zwischen Hochschulen. ...
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.
Background and objectives: Preoperative anaemia is an independent risk factor for a higher morbidity and mortality, a longer hospitalization and increased perioperative transfusion rates. Managing preoperative anaemia is the first of three pillars of Patient Blood Management (PBM), a multidisciplinary concept to improve patient safety. While various studies provide medical information on (successful) anaemia treatment pathways, knowledge of organizational details of diagnosis and management of preoperative anaemia across Europe is scarce.
Materials and methods: To gain information on various aspects of preoperative anaemia management including organization, financing, diagnostics and treatment, we conducted a survey (74 questions) in ten hospitals from seven European nations within the PaBloE (Patient Blood Management in Europe) working group covering the year 2016.
Results: Organization and activity in the field of preoperative anaemia management were heterogeneous in the participating hospitals. Almost all hospitals had pathways for managing preoperative anaemia in place, however, only two nations had national guidelines. In six of the ten participating hospitals, preoperative anaemia management was organized by anaesthetists. Diagnostics and treatment focused on iron deficiency anaemia which, in most hospitals, was corrected with intravenous iron.
Conclusion: Implementation and approaches of preoperative anaemia management vary across Europe with a primary focus on treating iron deficiency anaemia. Findings of this survey motivated the hospitals involved to critically evaluate their practice and may also help other hospitals interested in PBM to develop action plans for diagnosis and management of preoperative anaemia.
In this paper we present first-order reversal curve (FORC) diagrams of ensembles of three-dimensional Co3Fe nanostructures as 2 × 2 arrays of nano-cubes and nano-trees. The structures are fabricated and investigated by an advanced platform of focused electron beam induced deposition combined with high-resolution detection of magnetic stray fields using a home-built micro-Hall magnetometer based on an AlGaAs/GaAs heterostructure. The experimental FORC diagrams are compared to macrospin simulations for both geometries at different angles of the externally applied magnetic field. The measured FORC diagrams are in good agreement with the simulated ones and reflect non-uniform magnetization reversal dominated by multi-vortex states within, and strong magnetic coupling between, the building blocks of our nanostructures. Thus, a FORC analysis of small arrays of 3D magnetic nanostructures provides more detailed insights into the mechanisms of magnetization reversal beyond standard major hysteresis loop measurements.
By the fabrication of periodically arranged nanomagnetic systems it is possible to engineer novel physical properties by realizing artificial lattice geometries that are not accessible via natural crystallization or chemical synthesis. This has been accomplished with great success in two dimensions in the fields of artificial spin ice and magnetic logic devices, to name just two. Although first proposals have been made to advance into three dimensions (3D), established nanofabrication pathways based on electron beam lithography have not been adapted to obtain free-form 3D nanostructures. Here we demonstrate the direct-write fabrication of freestanding ferromagnetic 3D nano-architectures. By employing micro-Hall sensing, we have determined the magnetic stray field generated by our free-form structures in an externally applied magnetic field and we have performed micromagnetic and macro-spin simulations to deduce the spatial magnetization profiles in the structures and analyze their switching behavior. Furthermore we show that the magnetic 3D elements can be combined with other 3D elements of different chemical composition and intrinsic material properties.
Three-dimensional (3D) nanomagnetism, where spin configurations extend into the vertical direction of a substrate plane allow for more complex, hierarchical systems and the design of novel magnetic effects. As an important step towards this goal, we have recently demonstrated the direct-write fabrication of freestanding ferromagnetic 3D nano-architectures of ferromagnetic CoFe in shapes of nano-tree and nano-cube structures by means of focused electron beam induced deposition. Here, we present a comprehensive characterization of the magnetic properties of these structures by local stray-field measurements using a high-resolution micro-Hall magnetometer. Measurements in a wide range of temperatures and different angles of the externally applied magnetic field with respect to the surface plane of the sensor are supported by corresponding micromagnetic simulations, which explain the overall switching behavior of in part rather complex magnetization configurations remarkably well. In particular, the simulations yield coercive and switching fields that are in good quantitative correspondence with the measured coercive and switching fields assuming a bulk metal content of 100 at % consisting of bcc Co 3 Fe. We show that thermally-unstable magnetization states can be repetitively prepared and their lifetime controlled at will, a prerequisite to realizing dynamic and thermally-active magnetic configurations if the building blocks are to be used in lattice structures.
Continuous blood glucose monitoring reveals enormous circadian variations in pregnant diabetic rats
(2018)
Aim: Diabetes in pregnancy is a major burden with acute and long-term consequences. Its treatment requires adequate diagnosis and monitoring of therapy. Many experimental research on diabetes during pregnancy has been performed in rats. Recently, continuous blood glucose monitoring of non-pregnant diabetic rats revealed an increased circadian variability of blood glucose that made a single blood glucose measurement per day inappropriate to reflect glycemic status. Continuous blood glucose measurement has never been performed in pregnant rats. We wanted to perform continuous blood glucose monitoring in pregnant rats to decipher the influence of pregnancy on blood glucose in diabetic and normoglycemic status.
Methods: We used the transgenic Tet29 diabetes rat model with an inducible knock down of the insulin receptor via RNA interference upon application of doxycycline (DOX) leading to insulin resistant type II diabetes. All Tet29 rats received a HD-XG telemetry implant (Data Sciences International, USA) that measured blood glucose and activity continuously. Rats were divided into four groups and blood glucose was monitored until end of pregnancy or the corresponding period: Tet29 + DOX (diabetic) non-pregnant, Tet29 + DOX (diabetic) pregnant, Tet29 (normoglycemic) non-pregnant, Tet29 (normoglycemic) pregnant.
Results: All analyzed rats displayed a circadian variation in blood glucose concentration. Circadian variability was much more pronounced in pregnant diabetic rats than in normoglycemic pregnant rats. Pregnancy ameliorated variation in blood glucose in diabetic situation. Pregnancy continuously decreased blood glucose during normoglycemic pregnancy. Diabetic rats were less active than normoglycemic rats. We performed a calculation showing that application of continuous blood glucose measurement reduces animal numbers needed to detect a given effect in experimental setting by decreasing variability and SD.
Interpretation: Continuous blood glucose monitoring via a telemetry device in pregnant rats provides a more informative picture of the glycemic situation in comparison to single measurements. This could improve diagnosis and therapy of diabetes, decrease animal numbers within experimental settings, and add another physiological parameter (activity) to the analysis that could be helpful in testing therapeutic concepts targeting blood glucose levels and peripheral muscle function. We propose continuous glucose monitoring as a new tool for the evaluation of pregnant diabetic rats.
Stimulation of renal collecting duct principal cells with antidiuretic hormone (arginine-vasopressin, AVP) results in inhibition of the small GTPase RhoA and the enrichment of the water channel aquaporin-2 (AQP2) in the plasma membrane. The membrane insertion facilitates water reabsorption from primary urine and fine-tuning of body water homeostasis. Rho guanine nucleotide exchange factors (GEFs) interact with RhoA, catalyze the exchange of GDP for GTP and thereby activate the GTPase. However, GEFs involved in the control of AQP2 in renal principal cells are unknown. The A-kinase anchoring protein, AKAP-Lbc, possesses GEF activity, specifically activates RhoA, and is expressed in primary renal inner medullary collecting duct principal (IMCD) cells. Through screening of 18,431 small molecules and synthesis of a focused library around one of the hits, we identified an inhibitor of the interaction of AKAP-Lbc and RhoA. This molecule, Scaff10-8, bound to RhoA, inhibited the AKAP-Lbc-mediated RhoA activation but did not interfere with RhoA activation through other GEFs or activities of other members of the Rho family of small GTPases, Rac1 and Cdc42. Scaff10-8 promoted the redistribution of AQP2 from intracellular vesicles to the periphery of IMCD cells. Thus, our data demonstrate an involvement of AKAP-Lbc-mediated RhoA activation in the control of AQP2 trafficking.
Protein kinases are highly tractable targets for drug discovery. However, the biological function and therapeutic potential of the majority of the 500+ human protein kinases remains unknown. We have developed physical and virtual collections of small molecule inhibitors, which we call chemogenomic sets, that are designed to inhibit the catalytic function of almost half the human protein kinases. In this manuscript we share our progress towards generation of a comprehensive kinase chemogenomic set (KCGS), release kinome profiling data of a large inhibitor set (Published Kinase Inhibitor Set 2 (PKIS2)), and outline a process through which the community can openly collaborate to create a KCGS that probes the full complement of human protein kinases.
Background: The present study aims to elucidate the state of gender equality in high-quality research by analyzing the representation of female authorships in the last decade (from 2008 to 2016).
Methods: Based on the Gendermetrics platform, 293,557 research articles from 54 journals listed in the Nature Index were considered covering the categories Life Science, Multidisciplinary, Earth & Environmental and Chemistry. The core method was the combined analysis of the proportion of female authorships and the female-to-male odds ratio for first, co- and last authorships. The distribution of prestigious authorships was measured by the Prestige Index.
Results: 29.8% of all authorships and 33.1% of the first, 31.8% of the co- and 18.1% of the last authorships were held by women. The corresponding female-to-male odds ratio is 1.19 (CI: 1.18–1.20) for first, 1.35 (CI: 1.34–1.36) for co- and 0.47 (CI: 0.46–0.48) for last authorships. Women are underrepresented at prestigious authorships compared to men (Prestige Index = -0.42). The underrepresentation accentuates in highly competitive articles attracting the highest citation rates, namely, articles with many authors and articles that were published in highest-impact journals. More specifically, a large negative correlation between the 5-Year-Impact-Factor of a journal and the female representation at prestigious authorships was revealed (r(52) = -.63, P < .001). Women publish fewer articles compared to men (39.0% female authors are responsible for 29.8% of all authorships) and are underrepresented at productivity levels of more than 2 articles per author. Articles with female key authors are less frequently cited than articles with male key authors. The gender-specific differences in citation rates increase the more authors contribute to an article. Distinct differences at the journal, journal category, continent and country level were revealed. The prognosis for the next decades forecast a very slow harmonization of authorships odds between the two genders.