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Abstract Precision oncology offers new cancer treatment options, yet sequencing methods vary in type and scope. In this study, we compared whole-exome/whole-genome (WES/WGS) and transcriptome sequencing (TS) with broad panel sequencing by resequencing the same tumor DNA and RNA as well as normal tissue DNA for germline assessment, from 20 patients with rare or advanced tumors, who were originally sequenced by WES/WGS ± TS within the DKFZ/NCT/DKTK MASTER program from 2015 to 2020. Molecular analyses resulted in a median number of 2.5 (gene panel) to 3.5 (WES/WGS ± TS) treatment recommendations per patient. Our results showed that approximately half of the therapy recommendations (TRs) of both sequencing programs were identical, while approximately one-third of the TRs in WES/WGS ± TS relied on biomarkers not covered by the panel. Eight of 10 molecularly informed therapy implementations were supported by the panel, the remaining two were based on biomarkers absent from the panel, highlighting the potential additional clinical benefit of WGS and TS.

Es widerspräche der Normhierarchie, wenn der einfache Gesetzgeber berechtigt wäre, ein verfassungsrechtlich als „friedlich“ qualifiziertes Verhalten mit dem entgegengesetzten Begriff der „Gewalt“ zu belegen. Wenn „Gewalttätigkeiten“ charakteristisch für die Unfriedlichkeit einer Versammlung sind, dann kann eine friedliche Versammlung nicht umgekehrt als „Gewalt“ qualifiziert werden.

Abstract Background and aims This study sought to determine the value of patient-derived organoids (PDOs) from esophago-gastric adenocarcinoma (EGC) for response prediction to neoadjuvant chemotherapy (neoCTx). Methods Endoscopic biopsies of patients with locally advanced EGC (n = 120) were taken into culture and PDOs expanded. PDOs' response towards the single substances of the FLOT regimen and the combination treatment were correlated to patients' pathological response using tumor regression grading. A classifier based on FLOT response of PDOs was established in an exploratory cohort (n = 13) and subsequently confirmed in an independent validation cohort (n = 13). Results EGC PDOs reflected patients' diverse responses to single chemotherapeutics and the combination regimen FLOT. In the exploratory cohort, PDOs response to single 5-FU and FLOT combination treatment correlated with the patients' pathological response (5-FU: Kendall's τ = 0.411, P = 0.001; FLOT: Kendall's τ = 0.694, P = 2.541e-08). For FLOT testing, a high diagnostic precision in receiver operating characteristic (ROC) analysis was reached with an AUCROC of 0.994 (CI 0.980 to 1.000). The discriminative ability of PDO-based FLOT testing allowed the definition of a threshold, which classified in an independent validation cohort FLOT responders from non-responders with high sensitivity (90%), specificity (100%) and accuracy (92%). Conclusion In vitro drug testing of EGC PDOs has a high predictive accuracy in classifying patients' histological response to neoadjuvant FLOT treatment. Taking into account the high rate of successful PDO expansion from biopsies, the definition of a threshold that allows treatment stratification paves the way for an interventional trial exploring PDO-guided treatment of EGC patients.

Despite the global trend of record temperatures and the increasing number of disasters caused by extreme weather events, the political impetus to combat global warming is weakening all over Europe. Not only far-right forces want to stop ambitious climate policy, but also other political parties tend to neglect this field. To counter those political forces, climate litigation tries to hold national governments accountable to their goals as enshrined in the Paris Agreement. Courts represent one of the arenas in the struggle for climate protection. However, the battle is ultimately won or lost in the legislative arena.

„Vor diesem Hintergrund fordern wir als Wissenschaftlerinnen und Wissenschaftler des Verfassungs- und Völkerrechts die gesetzgebenden Organe des Bundes auf, das Klimaschutzgesetz nicht abzuschwächen. Wir fordern die Bundesregierung auf, ein effektives Klimaschutzprogramm mit ausreichenden Maßnahmen zur Einhaltung der Klimaschutzziele und damit der völker- und verfassungsrechtlichen Verpflichtungen zu beschließen.“

Heavy plates are indispensable semi-finished products. Quality is strongly linked with production, so the rolling process must be performed within well-defined narrow tolerances. To meet this challenge, adequate modeling has become a necessity. In contrast to continuous strip rolling, where the workpiece can be modeled as a semi-infinite strip and 2D modeling can be argued quite well, this strategy is insufficient for the comprehensive modeling of heavy plate rolling. The geometry of the heavy plate favors an inhomogeneous distribution of relevant state variables, such as temperature. In addition, if the process involves longitudinal and spreading passes, the required plate rotation spoils the assumption of a symmetric arrangement that might have been acceptable before rotation. Consequently, the derivation of suitably reduced models is not trivial, and modeling tailored to the specific objective of investigation is of utmost importance. Models intended to resolve the evolution of inhomogeneities in the field variables are demanding and computationally expensive. An effective modular modeling strategy was developed for such models to be used offline. Mutually complementing and interchangeable modules may constitute an efficient modeling strategy valid for the specific subject of interest. The presented approach reduces the enormous cost of complete 3D simulation as much as the model purpose allows for.

Financial markets are a source of non-stationary multidimensional time series which has been drawing attention for decades. Each financial instrument has its specific changing-over-time properties, making its analysis a complex task. Hence, improvement of understanding and development of more informative, generalisable market representations are essential for the successful operation in financial markets, including risk assessment, diversification, trading, and order execution.In this study, we propose a volume-price-based market representation for making financial time series more suitable for machine learning pipelines. We use a statistical approach for evaluating the representation. Through the research questions, we investigate, i) whether the proposed representation allows any improvement over the baseline (always-positive) performance; ii) whether the proposed representation leads to increased performance over the price levels market pattern; iii) whether the proposed representation performs better on the liquid markets, and iv) whether SHAP feature interactions are reliable to be used in the considered setting.Our analysis shows that the proposed volume-based method allows successful classification of the financial time series patterns, and also leads to better classification performance than the price levels-based method, excelling specifically on more liquid financial instruments. Finally, we propose an approach for obtaining feature interactions directly from tree-based models and compare the outcomes to those of the SHAP method. This results in the significant similarity between the two methods, hence we claim that SHAP feature interactions are reliable to be used in the setting of financial markets.

Der Beschluss des Bundesverfassungsgerichts vom 24. März 2021 wurde von der Deutschen Umwelthilfe als „die wohl bedeutendste Umweltschutz-Entscheidung in der Geschichte des Bundesverfassungsgerichts“ gelobt. Wenn man mit dem Abstand von zwei Jahren auf die Entscheidung und ihre (Nicht)Folgen sieht, muss die Bewertung deutlich nüchterner ausfallen. Zum einen wird meist übersehen, dass die unmittelbare Wirkung des Beschlusses denkbar gering war. Vor allem wird er aber von der Politik, von den Verwaltungsgerichten und sogar vom Bundesverfassungsgericht selbst nicht umgesetzt. Das Problem, wie effektiver Klimaschutz durchgesetzt werden kann, ist nach wie vor nicht gelöst.

Fusarium head blight (FHB) and the occurrence of mycotoxins is the largest food safety threat to malting and brewing grains. Worldwide surveys of commercial beers have reported that the trichothecene mycotoxin deoxynivalenol (DON) is the most frequent contaminant in beer. Although the DON content of grain generally declines during steeping due to its solubilization, Fusarium spp. can continue to grow and produce DON from steeping through the early kilning stage of malting. DON present on malt is largely extracted into beer. The objective of the current study was to localize the growth of Fusarium spp. within FHB-infected kernels by developing an improved method and to associate fungal growth with the production of DON during malting. FHB-infected barley, wheat, rye, and triticale grains that exhibited large increases in the amount of Fusarium Tri5 DNA and trichothecene mycotoxins following malting were screened for hyphal localization. The growth of fungal hyphae associated with grain and malt was imaged by scanning electron microscopy and confocal laser-scanning microscopy assisted with WGA-Alexa Fluor 488 staining, respectively. In barley, hyphae were present on or within the husk, vascular bundle, and pericarp cavities. Following malting, vast hyphal growth was observed not only in these regions but also in the aleurone layer, endosperm, and embryo. Extensive fungal growth was also observed following malting of wheat, rye, and triticale. However, these grains already had an extensive internal presence of Fusarium hyphae in the unmalted grain, thus representing an enhanced chance of fungal expansion during the malting.[Graphic: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY 4.0 International license.

Abstract Background Novel coronavirus disease 2019 (COVID-19) has been the subject of a numerous research projects over the past year. In cases with a severe disease course or threatening long-term impairment due to disease, the German health care system offers insured persons the possibility of medical rehabilitation. In contrast to what was observed and expected at the beginning of the pandemic, COVID-19 patients with varying degrees of disease severity are represented in rehabilitation. To date, there is no common consensus on the content and aftercare of rehabilitation nor is there any knowledge about the short- and long-term effects of such a rehabilitation programme. In addition, these aspects were not considered with regard to the varying severity of the course of the disease. The present research project investigates this question. Methods The study sample will consist of N = 350 rehabilitants after COVID-19 and a comparison group (CG) with N = 230 rehabilitants suffering from an obstructive respiratory disease. The participants will be recruited at five German rehabilitation facilities and undergo medical rehabilitation. This prospective, exploratory, multicentre, mixed-methods study will be evaluated as follows: (A) The quantitative portion includes questionnaires at different points in time (at the beginning and end of rehabilitation, after six and twelve months) and contains standardised measurement instruments. For example, participation limitations, quality of life, health status, fatigue, psychomental limitations and disorders, performance in different areas of life and ability to work are measured. (B) Qualitative interviews are held at different times (end of rehabilitation, after six and twelve months), and an expert workshop is conducted. Topics are rehabilitation content, satisfaction and aftercare as well as different outcomes on subjective health and participation impairments. Discussion Studies on other indications have already shown that pneumological rehabilitation has positive effects. Thus, it is expected that an improvement in different dimensions will be observed at the end of rehabilitation in both groups. With regard to the different severities of COVID-19, this study evaluates the long-term developments. Subsequently, the authors will elaborate concrete recommendations for medical rehabilitation after different courses of disease with regard to existing pneumological rehabilitation concepts. Trial Registration German Register of Clinical Trials, www.drks.de .Identifier: DRKS00023642; Registered: 01.12.2020.Date and version identifier: 08.04.2021; version 4.

Abstract Background Red clover (Trifolium pratense) is globally used as a fodder plant due its high nutritional value and soil improving qualities. In response to mowing, red clover exhibits specific morphological traits to compensate the loss of biomass. The morphological reaction is well described, but the underlying molecular mechanisms and its role for plants grown in the field are unclear. Results Here, we characterize the global transcriptional response to mowing of red clover by comparing plants grown under greenhouse conditions with plants growing on agriculturally used fields. Unexpectedly, we found that biotic and abiotic stress related changes of plants grown in the field overlay their regrowth related transcriptional changes and characterized transcription related protein families involved in these processes. Further, we can show that gibberellins, among other phytohormones, also contribute to the developmental processes related to regrowth after biomass-loss. Conclusions Our findings show that massive biomass loss triggers less transcriptional changes in field grown plants than their struggle with biotic and abiotic stresses and that gibberellins also play a role in the developmental program related to regrowth after mowing in red clover. Our results provide first insights into the physiological and developmental processes of mowing on red clover and may serve as a base for red clover yield improvement.

In this work we address the main issues of Information Technology (IT) consumerization that are related to security risks, and vulnerabilities of devices used within Bring Your Own Device (BYOD) strategy in particular. We propose a ‘soft’ mitigation strategy for user actions based on nudging, widely applied to health and social behavior influence. In particular, we propose a complementary, less strict, more flexible Information Security policies, based on risk assessment of device vulnerabilities and threats to corporate data and devices, combined with a strategy of influencing security behavior by nudging. We argue that nudging, by taking into account the context of the decision-making environment, and the fact that the employee may be in better position to make a more appropriate decision, may be more suitable than strict policies in situations of uncertainty of security-related decisions. Several examples of nudging are considered for different tested and potential scenarios in security context.

BackgroundThe Global Trigger Tool (GTT) has become a worldwide used method for estimating adverse events through a retrospective patient record review. However, little is known about the facilitators and the challenges in the GTT-implementation process. Thus, this study followed two aims: First, to apply a comprehensive set of feasibility criteria to qualitatively and systematically assess the GTT-implementation process in three departments of German university hospitals. Second, to identify the facilitators and the obstacles met in the GTT-implementation process and to derive recommendations for supporting other hospitals in implementing the GTT in clinical practice.MethodsThe study used a qualitative documentary method based on process documentation, with written and verbal feedback from the reviewer, as well as evaluating the study sites during the implementation process. The study was conducted in three departments, each in a different German university hospital. The authors applied a comprehensive set of 22 feasibility criteria assessing the level of challenge in GTT implementation. The results were synthesized and they focused on the facilitators and the challenges.ResultsOf these 22 feasibility criteria, nine were assessed as a low-level challenge, eleven regarded as a moderate-level challenge, and two with a problematic level of challenge. In particular, the lack of time and staff resources, the quality of the information in the patient records, organizational procedures, and local issues, posed major challenges in the implementation process. By contrast, the use of local coordinators and an external expert made important contributions to the GTT implementation.ConclusionsConsidering the facilitators and the obstacles beforehand may help with the implementation of the GTT in routine practice. In particular, early and effective planning can reduce or prevent critical challenges in terms of time, staff resources, and organizational aspects.

Abstract Background Puccinia graminis f. sp. tritici (Pgt) race TTKSK and its lineage pose a threat to barley production world-wide justifying the extensive efforts to identify, clone, and characterize the rpg4-mediated resistance locus (RMRL), the only effective resistance to virulent Pgt races in the TTKSK lineage. The RMRL contains two nucleotide-binding domain and leucine-rich repeat (NLR) resistance genes, Rpg5 and HvRga1, which are required for resistance. The two NLRs have head-to-head genome architecture with one NLR, Rpg5, containing an integrated C-terminal protein kinase domain, characteristic of an “integrated sensory domain” resistance mechanism. Fast neutron mutagenesis of line Q21861 was utilized in a forward genetics approach to identify genetic components that function in the RMRL or Rpg1 resistance mechanisms, as Q21861 contains both genes. A mutant was identified that compromises both RMRL and Rpg1-mediated resistances and had stunted seedling roots, designated required for P. graminis resistance 9 (rpr9). Results The rpr9 mutant generated in the Q21861 background was crossed with the Swiss landrace Hv584, which carries RMRL but contains polymorphism across the genome compared to Q21861. To map Rpr9, a Hv584 x rpr9 F6:7 recombinant inbred line (RIL) population was developed. The RIL population was phenotyped with Pgt race QCCJB. The Hv584 x rpr9 RIL population was genotyped with the 9 k Illumina Infinium iSelect marker panel, producing 2701 polymorphic markers. A robust genetic map consisting of 563 noncosegregating markers was generated and used to map Rpr9 to an ~ 3.4 cM region on barley chromosome 3H. The NimbleGen barley exome capture array was utilized to capture rpr9 and wild type Q21861 exons, followed by Illumina sequencing. Comparative analysis, resulting in the identification of a 1.05 Mbp deletion at the chromosome 3H rpr9 locus. The identified deletion contains ten high confidence annotated genes with the best rpr9 candidates encoding a SKP1-like 9 protein and a F-box family protein. Conclusion Genetic mapping and exome capture rapidly identified candidate gene/s that function in RMRL and Rpg1 mediated resistance pathway/s. One or more of the identified candidate rpr9 genes are essential in the only two known effective stem rust resistance mechanisms, present in domesticated barley.

Plants react to various biotic and abiotic factors by adjusting their growth pattern. This process, called phenotypic plasticity, can also be observed in the agronomical important fodder plant Trifolium pratense L. (red clover) which is grown worldwide for its high pro-tein content and soil improving ability. After cutting it changes its growth pattern due to phenotypic plasticity and initiates a second growth phase. Here, we analyze the regrowth dynamics of red clover in response to grazing or mowing by recording the plant’s architecture, leaf morphology, and growth performance in different cutting experiments. As previous studies were limited in the number of individuals and carried out via common garden experiments, we analyzed the regrowth reaction of T. pratense under standard agricul-tural field conditions. T. pratense forms smaller and rounder leaflets after repeated cutting, compensated by the production of more bio-mass. Nitrogen contents were subjected to seasonal changes, rather than by changes through cutting. As middle to late cut plants had higher regrowth capacities and regrew more biomass than early cut plants, an optimal time point for biomass harvest can be suggested to maximize the total yield of red clover biomass.

Topic Detection and Tracking (TDT) is a very active research question within the area of text mining, generally applied to news feeds and Twitter datasets, where topics and events are detected. The notion of "event" is broad, but typically it applies to occurrences that can be detected from a single post or a message. Little attention has been drawn to what we call "micro-events", which, due to their nature, cannot be detected from a single piece of textual information. The study investigates the feasibility of micro-event detection on textual data using a sample of messages from the Stack Overflow Q&A platform and Free/Libre Open Source Software (FLOSS) version releases from Libraries.io dataset. We build pipelines for detection of micro-events using three different estimators whose parameters are optimized using a grid search approach. We consider two feature spaces: LDA topic modeling with sentiment analysis, and hSBM topics with sentiment analysis. The feature spaces are optimized using the recursive feature elimination with cross validation (RFECV) strategy. In our experiments we investigate whether there is a characteristic change in the topics distribution or sentiment features before or after micro-events take place and we thoroughly evaluate the capacity of each variant of our analysis pipeline to detect micro-events. Additionally, we perform a detailed statistical analysis of the models, including influential cases, variance inflation factors, validation of the linearity assumption, pseudo R2 measures and no-information rate. Finally, in order to study limits of micro-event detection, we design a method for generating micro-event synthetic datasets with similar properties to the real-world data, and use them to identify the micro-event detectability threshold for each of the evaluated classifiers.

Advances in genetic sequencing and other diagnostic technologies have enabled the use of precision medicine in clinical cancer care, as well as the development of novel therapies that are targeted to specific molecular drivers of cancer. Developing these new agents and making them accessible to patients requires global clinical studies and regulatory review and approval by different national regulatory agencies. Whereas these global trials present challenges for drug developers who conduct them and regulatory agencies who oversee them, they also raise practical issues about patients with low-frequency cancers who need these therapies. A lack of uniform standards in both regulatory approval for marketing and reimbursement for approved agents across countries may make the newly developed agent either unavailable or inaccessible to patients in certain countries or regions, even if patients from those countries or regions participated in the clinical research that established the safety and efficacy of the agent. In an effort to further understand and address this need, we convened an international workshop in 2017 in North Bethesda, MD. After presentations of the individual regulatory pathways for marketing approval and reimbursement for individual nations, participants discussed expedited pathways and specific challenges for uncommon cancers. As a matter of justice, agents being developed for rare cancers, pediatric cancers, or uncommon molecular subsets of common cancers need a pragmatic, science-based regulatory policy framework to clearly specify the type and quantity of evidence needed to demonstrate efficacy from these trials and evidence to support accessibility.

Abstract Background The Quality of Life after Brain Injury (QOLIBRI) score was developed to assess disease-specific health-related quality of life (HRQoL) after traumatic brain injury (TBI). So far, validation studies on the QOLIBRI were only conducted in cohorts with traumatic brain injury. This study investigated the longer-term residuals in severely injured patients, focusing specifically on the possible impact of major TBI. Methods In a prospective questionnaire investigation, 199 survivors with an injury severity score (ISS) > 15 participated in one-year follow-up. Patients who had sustained major TBI (abbreviated injury scale, AIS head > 2) were compared with patients who had no or only mild TBI (AIS head ≤ 2). Univariate analysis (ANOVA, Cohen’s kappa, Pearson’s r) and stepwise linear regression analysis (B with 95% CI, R, R2) were used. Results The total QOLIBRI revealed no differences in one-year outcomes between patients with versus without major TBI (75 and 76, resp.; p = 0.68). With regard to the cognitive subscore, the group with major TBI demonstrated significantly more limitations than the one with no or mild TBI (p

Abstract Background No consensus exists in the literature on the use of uniform emergency room trauma team activation criteria (ERTTAC). Today excessive over- or undertriage rates continue to be a challenge for most trauma centres. Application of ERTTAC, published for use in the German TraumaNetwork DGU®, at a Swiss trauma centre resulted in a high overtriage rate. The aim of the investigation was to analyse the ERTTAC in detail with the intention of possible improvement. Methods The investigation included consecutive adult (age > 15 years) trauma patients treated at the emergency department of a level II trauma centre from 01.01.2013–31.12.2015. All data were collected prospectively. To identify over- and undertriage, patients with an Injury Severity Score (ISS) > 15 were defined as requiring specific emergency room (ER) management. ANOVA, Student’s t-test and chi-square analysis were used for statistical analysis with mean values ± standard deviation. Results 1378 adult injured (64% male) received ER trauma team treatment (mean age 48.3 ± 21.2 years; ISS 9.7 ± 9.6) during the observation period. Of those, 326 ER patients (23.7%) were diagnosed with an ISS > 15, which proved to be an overtriage of 76.3%. 80/406 trauma patients with an ISS > 15 were not referred to the ER, resulting in an actual undertriage rate of 19.7%, mainly because the criteria list was not observed. Effectively applying ERTTAC according to the protocol in all cases would have reduced undertriage to 2.0% (8/406). The most frequent trigger for trauma team activation was injury mechanism (65%). A simulation revealed that omitting the criterion ‘passenger of car or truck’ (n = 326) would have prevented overtriage in 257 cases, as such lowering overtriage rate to 62.4% and at the same time increasing undertriage by only 8 cases to 7.1%. Conclusion Application of ERTTAC as published for TraumaNetwork DGU® resulted in a lower undertriage but higher overtriage rate than recommended by the American College of Surgeons. Omitting the criterion ‘passenger of car or truck’ markedly improved overtriage with only a minimal increase in undertriage. Trial registration NCT02165137; retrospectively registered 11. June 2014.

Permanent magnets based on FePrCuB were realized on a laboratory scale through additive manufacturing (laser powder bed fusion, L-PBF) and book mold casting (reference). A well-adjusted two-stage heat treatment of the as-cast/as-printed FePrCuB alloys produces hard magnetic properties without the need for subsequent powder metallurgical processing. This resulted in a coercivity of 0.67 T, remanence of 0.67 T and maximum energy density of 69.8 kJ/m3 for the printed parts. While the annealed book-mold-cast FePrCuB alloys are easy-plane permanent magnets (BMC magnet), the printed magnets are characterized by a distinct, predominantly directional microstructure that originated from the AM process and was further refined during heat treatment. Due to the higher degree of texturing, the L-PBF magnet has a 26% higher remanence compared to the identically annealed BMC magnet of the same composition.

The transcription factor Gcn4 is known to regulate yeast amino acid synthesis. Here, the authors show that Gcn4 also acts as a repressor of protein biosynthesis in a range of conditions that enhance yeast lifespan, such as ribosomal protein knockout, calorie restriction or mTOR inhibition.

Abstract Insect-derived antifungal peptides have a significant economic potential, particularly for the engineering of pathogen-resistant crops. However, the nonspecific antifungal activity of such peptides could result in detrimental effects against beneficial fungi, whose interactions with plants promote growth or increase resistance against biotic and abiotic stress. The antifungal peptide metchnikowin (Mtk) from Drosophila melanogaster acts selectively against pathogenic Ascomycota, including Fusarium graminearum, without affecting Basidiomycota such as the beneficial symbiont Piriformospora indica. Here we investigated the mechanism responsible for the selective antifungal activity of Mtk by using the peptide to probe a yeast two-hybrid library of F. graminearum cDNAs. We found that Mtk specifically targets the iron-sulfur subunit (SdhB) of succinate–coenzyme Q reductase (SQR). A functional assay based on the succinate dehydrogenase (SDH) activity of mitochondrial complex II clearly demonstrated that Mtk inhibited the SDH activity of F. graminearum mitochondrial SQR by up to 52%, but that the equivalent enzyme in P. indica was unaffected. A phylogenetic analysis of the SdhB family revealed a significant divergence between the Ascomycota and Basidiomycota. SQR is one of the key targets of antifungal agents and we therefore propose Mtk as an environmentally sustainable and more selective alternative to chemical fungicides.

AIMS OF THE STUDY Given the lack of information on the relation between baseline patient, injury and treatment data and longer-term outcomes for survivors of significant trauma, the objective of this evaluation was to examine the degree to which these characteristics might predict working constraints and expenses. METHODS 1183 significantly injured patients (New Injury Severity Score >8) of working age were treated at a Swiss trauma centre. Only patients insured by the largest national accident insurer, Suva, were included. Their sociodemographic, trauma, treatment and early clinical status data were evaluated against insurance variables for 4 years post-injury (uni- and multivariate analysis, R2). RESULTS 346 out of 363 surviving Suva-insured patients were eligible for analysis, constituting a 95% complete 4-year longitudinal follow-up. Overall, 121 (35%) presented with a reduced capacity to work (RCW) 1 to 4 years after the trauma. Patients experienced a mean percentage RCW (PRCW) of 27% 1 year after injury and of 14% at 4 years. In multivariate analysis all investigated parameters together explained 40% of the adjusted variance of patients’ mean PRCW over the 4-year surveillance period, with the highest association found for the block of injury-related variables (17%). Sixty percent of variance was explained for total insurance costs, found to be on average CHF 417,000 per case in patients with a RCW compared with CHF 47,000 per case without RCW (p

Background The Transcatheter Valve Therapy (TVT) Coordinated Registry Network (CRN) supported 23 regulatory decisions and ensured evidence-based evaluation of the application of TVT technology. However, there are cost concerns that require value assessment of the TVT CRN compared with traditional study designs.Objectives We aimed to determine the value created by the TVT CRN based on (1) Return on investment (ROI), (2) Time saved (TS) in conducting necessary regulatory studies.Methods For both ROI and TS analyses, we compared studies that used the TVT CRN with those that would have been required if the registry did not exist (counterfactual studies). To estimate ROI, we accounted for the costs of investment and gain from investment. Both the counterfactual costs and length of studies were projected using design specifications determined by US Food and Drug Administration (FDA) reviewers.Results We identified 21 studies using the TVT CRN (supporting 23 FDA decisions) that generated evidence on TVT for three device manufacturers. ROI is estimated to be greater than 550%. TS by using the CRN ranged from months to years.Conclusions The CRN method to evidence generation creates value for manufacturers and the broader device ecosystem, demonstrated with this example of the TVT CRN. The public health benefits of evidence created by this CRN outweighs the difference in data quality between traditional clinical studies and the CRN method.

Stem rust, caused by Puccinia graminis f. sp. tritici (Pgt) is an economically important disease of wheat and barley. Rpg1 is the only resistance gene deployed in Midwestern US barley varieties and provides remarkable resistance to most North American races, except Pgt race QCCJB. Rpg1 is also ineffective against Pgt race TTKSK and its lineage that originated in Africa. The barley rpg4-mediated resistance locus (RMRL) conferring resistance to Pgt races QCCJB and TTKSK was isolated from line Q21861, which is resistant to all known Pgt races due to Rpg1 and RMRL. To develop elite barley varieties RMRL was pyramided into the varieties, Pinnacle and Conlon (both contain Rpg1), producing the near isogenic lines (NILs), Pinnacle RMRL-NIL (PRN) and Conlon RMRL-NIL (CRN). The CRN was resistant to Pgt races QCCJB (RMRL specific) and HKHJC (Rpg1 specific) at the seedling stage and Pgt race TTKSK (RMRL specific) at the adult stage. In contrast, PRN was susceptible to QCCJB and HKHJC at the seedling stage and TTKSK at the adult stage. Interestingly, PRN’s susceptibility to QCCJB and HKHJC showed that RMRL was non-functional in the Pinnacle background but its presence also suppressed Rpg1-mediated resistance. Thus, in the absence of a gene/s found in the Q21861 background, Rpg1 becomes non-functional if RMRL is present, suggesting that another polymorphic gene, that we designated Rrr1 (required for rpg4-mediated resistance 1), is required for RMRL resistance and Rpg1-mediated resistance in the presence of RMRL. Utilizing a PRN/Q21861 derived recombinant inbred line (RIL) population, Rrr1 was delimited to a ∼0.5 MB physical region, slightly proximal (∼1.8 MB) of RMRL on barley chromosome 5H. A second gene, designated required for Rpg1-mediated resistance 2 (Rrr2), with duplicate gene action to Rrr1 in Rpg1-mediated resistance function, was genetically delimited to a physical region of ∼0.7 MB, slightly distal (∼3.1 MB) to Rpg1 on the short arm of barley chromosome 7H. Thus, Rrr1 is required for RMRL resistance and Rrr1 or Rrr2 is required for functional Rpg1-mediated resistance in the presence of the RMRL introgression. Candidate Rrr1 and Rrr2 genes were identified that need to be considered when pyramiding Rpg1 and RMRL in barley.

One of the crucial steps in the life cycle of angiosperms is the development of carpels. They are the most complex plant organs, harbor the seeds, and, after fertilization, develop into fruits and are thus an important ecological and economic trait. CRABS CLAW (CRC), a YABBY protein and putative transcription factor, is one of the major carpel developmental regulators in A. thaliana that includes a C2C2 zinc finger and a domain with similarities to an HMG box. CRC is involved in the regulation of processes such as carpel fusion and growth, floral meristem termination, and nectary formation. While its genetic interactions with other carpel development regulators are well described, its biochemical properties and molecular way of action remain unclear. We combined Bimolecular Fluorescence Complementation, Yeast Two-Hybrid, and Yeast One-Hybrid analyzes to shed light on the molecular biology of CRC. Our results showed that CRC dimerizes, also with other YABBY proteins, via the YABBY domain, and that its DNA binding is mainly cooperative and is mediated by the YABBY domain. Further, we identified that CRC is involved in floral meristem termination via transcriptional repression while it acts as a transcriptional activator in nectary development and carpel fusion and growth control. This work increases our understanding on how YABBY transcription factors interact with other proteins and how they regulate their targets.

Past and recent attempts at devising objective biomarkers for traumatic brain injury (TBI) in both blood and cerebrospinal fluid have focused on abundance measures of time-dependent proteins. Similar independent determinants would be most welcome in diagnosing the most common form of TBI, mild TBI (mTBI), which remains difficult to define and confirm based solely on clinical criteria. There are currently no consensus diagnostic measures that objectively define individuals as having sustained an acute mTBI. Plasma metabolomic analyses have recently evolved to offer an alternative to proteomic analyses, offering an orthogonal diagnostic measure to what is currently available. The purpose of this study was to determine whether a developed set of metabolomic biomarkers is able to objectively classify college athletes sustaining mTBI from non-injured teammates, within 6 hours of trauma and whether such a biomarker panel could be effectively applied to an independent cohort of TBI and control subjects. A 6-metabolite panel was developed from biomarkers that had their identities confirmed using tandem mass spectrometry (MS/MS) in our Athlete cohort. These biomarkers were defined at ≤6 hours following mTBI and objectively classified mTBI athletes from teammate controls, and provided similar classification of these groups at the 2, 3, and 7 days post-mTBI. The same 6-metabolite panel, when applied to a separate, independent cohort provided statistically similar results despite major differences between the two cohorts. Our confirmed plasma biomarker panel objectively classifies acute mTBI cases from controls within 6 hours of injury in our two independent cohorts. While encouraged by our initial results, we expect future studies to expand on these initial observations.

In this work we address the main issues of Information Technology (IT) consumerization that are related to security risks, and vulnerabilities of devices used within Bring Your Own Device (BYOD) strategy in particular. We propose a ‘soft’ mitigation strategy for user actions based on nudging, widely applied to health and social behavior influence. In particular, we propose a complementary, less strict, more flexible Information Security policies, based on risk assessment of device vulnerabilities and threats to corporate data and devices, combined with a strategy of influencing security behavior by nudging. We argue that nudging, by taking into account the context of the decision-making environment, and the fact that the employee may be in better position to make a more appropriate decision, may be more suitable than strict policies in situations of uncertainty of security-related decisions. Several examples of nudging are considered for different tested and potential scenarios in security context.

AIMS OF THE STUDY According to current evidence, one out of ten fracture patients with osteoporosis does not sustain another fracture if he or she is on adequate medication. However, epidemiological surveys show that only about 15 to 30% of affected patients avail themselves of the treatments. This cohort study investigated how many fracture patients with a recommendation for antiosteoporotic therapy effectively received treatment and the possible reasons why the treatment was not implemented. METHODS As part of a quality improvement programme in a Swiss trauma centre, fracture patients were actively checked for osteoporosis in accordance with a standardised outpatient programme. The results, together with detailed therapy recommendations, were transmitted to each patient’s general practitioner (GP). A prospective questionnaire survey evaluated all patients with a diagnosis of osteoporosis for subsequent realisation of therapy 1 year after the fracture (mean ± standard deviation; chi-square; analysis of variance; significance level p

In diesem Jahr war die Deutsche Zentralbibliothek für Wirtschaftswissenschaften mit ihrem Standort in Hamburg Ausrichter der alle zwei Jahre durchgeführten Fortbildungsveranstaltung für die Fachreferentinnen und Fachreferenten der Wirtschaftswissenschaften. An zwei Tagen wurde den Kolleginnen und Kollegen ein interessantes Programm aus Vorträgen, Workshops und Gruppenarbeit geboten. Im Mittelpunkt der Tagung standen die aktuellen und zukünftigen Herausforderungen und Rahmenbedingungen für wissenschaftliche Bibliotheken sowie die sich daraus ergebenden Veränderungen und Anpassungsoptionen für das Fachreferat. Der folgende Tagungsbericht gibt einen gerafften Überblick zu den einzelnen Themenbereichen.

This project was initiated with the goal of investigating the malt quality of winter rye cultivars and hybrids grown in the United States in 2014 and 2015, but high levels of deoxynivalenol (DON) were subsequently found in many of the malt samples. DON levels in 75% of the investigated rye samples (n = 117) were actually below 1.0 mg/kg, as quantified by a gas chromatography combined with electron capture detector (GC-ECD). However, 83% of the samples had DON in excess of 1.0 mg/kg following malting, and the average DON level in malted rye was 10.6 mg/kg. In addition, relatively high levels of 3-acetate DON (3-ADON), 15-acetate DON (15-ADON), nivalenol (NIV), and DON-3-glucoside (D3G) were observed in some rye malts. Our results show that rye grain DON is likely a poor predicator of type B trichothecenes in malt in practice, because high levels of malt DON, 15-ADONm and D3G were produced, even when the rye samples with DON levels below 0.50 mg/kg were processed. Fusarium Tri5 DNA content in rye was highly associated with malt DON levels (r = 0.83) in a small subset of samples (n = 55). The impact of Fusarium infection on malt quality was demonstrated by the significant correlations between malt DON levels and wort viscosity, β-glucan content, wort color, wort p-coumaric acid content, and total phenolic content. Additional correlations of rye Fusarium Tri5 DNA contents with malt diastatic power (DP), wort free amino nitrogen (FAN) content, and arabinoxylan content were observed.

The packaging of DNA into nucleosomes and the organisation into higher order structures of chromatin limits the access of sequence specific DNA binding factors to DNA. In cells, DNA methylation is preferentially occuring in the linker region of nucleosomes, suggesting a structural impact of chromatin on DNA methylation. These observations raise the question whether DNA methyltransferases are capable to recognize the nucleosomal substrates and to modify the packaged DNA. Here, we performed a detailed analysis of nucleosome binding and nucleosomal DNA methylation by the maintenance DNA methyltransferase Dnmt1. Our binding studies show that Dnmt1 has a DNA length sensing activity, binding cooperatively to DNA, and requiring a minimal DNA length of 20 bp. Dnmt1 needs linker DNA to bind to nucleosomes and most efficiently recognizes nucleosomes with symmetric DNA linkers. Footprinting experiments reveal that Dnmt1 binds to both DNA linkers exiting the nucleosome core. The binding pattern correlates with the efficient methylation of DNA linkers. However, the enzyme lacks the ability to methylate nucleosomal CpG sites on mononucleosomes and nucleosomal arrays, unless chromatin remodeling enzymes create a dynamic chromatin state. In addition, our results show that Dnmt1 functionally interacts with specific chromatin remodeling enzymes to enable complete methylation of hemi-methylated DNA in chromatin.

Active and repressed ribosomal RNA (rRNA) genes are characterised by specific epigenetic marks and differentially positioned nucleosomes at their promoters. Repression of the rRNA genes requires a non-coding RNA (pRNA) and the presence of the nucleolar remodeling complex (NoRC). ATP-dependent chromatin remodeling enzymes are essential regulators of DNA-dependent processes, and this regulation occurs via the modulation of DNA accessibility in chromatin. We have studied the targeting of NoRC to the rRNA gene promoter; its mechanism of nucleosome positioning, in which a nucleosome is placed over the transcription initiation site; and the functional role of the pRNA. We demonstrate that NoRC is capable of recognising and binding to the nucleosomal rRNA gene promoter on its own and binds with higher affinity the nucleosomes positioned at non-repressive positions. NoRC recognises the promoter nucleosome within a chromatin array and positions the nucleosomes, as observed in vivo. NoRC uses the release mechanism of positioning, which is characterised by a reduced affinity for the remodeled substrate. The pRNA specifically binds to NoRC and regulates the enzyme by switching off its ATPase activity. Given the known role of pRNA in tethering NoRC to the rDNA, we propose that pRNA is a key factor that links the chromatin modification activity and scaffolding function of NoRC.

Bone is capable of adapting during life in response to stress. Therefore, variation in locomotor and manipulative behaviours across extant hominoids may be reflected in differences in trabecular bone structure. The hand is a promising region for trabecular analysis, as it is the direct contact between the individual and the environment and joint positions at peak loading vary amongst extant hominoids. Building upon traditional volume of interest-based analyses, we apply a whole-epiphysis analytical approach using high-resolution microtomographic scans of the hominoid third metacarpal to investigate whether trabecular structure reflects differences in hand posture and loading in knuckle-walking (Gorilla, Pan), suspensory (Pongo, Hylobates and Symphalangus) and manipulative (Homo) taxa. Additionally, a comparative phylogenetic method was used to analyse rates of evolutionary changes in trabecular parameters. Results demonstrate that trabecular bone volume distribution and regions of greatest stiffness (i.e., Young's modulus) correspond with predicted loading of the hand in each behavioural category. In suspensory and manipulative taxa, regions of high bone volume and greatest stiffness are concentrated on the palmar or distopalmar regions of the metacarpal head, whereas knuckle-walking taxa show greater bone volume and stiffness throughout the head, and particularly in the dorsal region; patterns that correspond with the highest predicted joint reaction forces. Trabecular structure in knuckle-walking taxa is characterised by high bone volume fraction and a high degree of anisotropy in contrast to the suspensory brachiators. Humans, in which the hand is used primarily for manipulation, have a low bone volume fraction and a variable degree of anisotropy. Finally, when trabecular parameters are mapped onto a molecular-based phylogeny, we show that the rates of change in trabecular structure vary across the hominoid clade. Our results support a link between inferred behaviour and trabecular structure in extant hominoids that can be informative for reconstructing behaviour in fossil primates.

Das Bundeskabinett hat am 6. November 2019 den Entwurf des Genehmigungsbeschleunigungsgesetzes beschlossen. Er benennt zwölf Pilotprojekte, die durch Maßnahmengesetze des Bundestages statt durch behördlichen Verwaltungsakt genehmigt werden sollen. Wesentliches Ziel des Gesetzentwurfs ist es, den verwaltungsgerichtlichen Rechtsschutz und insbesondere die Umweltverbandsklage auszuschalten, die gegen einen Gesetzesbeschluss nicht zur Verfügung stehen. Diese Konsequenz ist weder verfassungs- noch europarechtskonform.

Art. 20a GG verlangt, dass der Bundesgesetzgeber zusätzliche Maßnahmen zur schnelleren Reduktion der Emissionen im Verkehrssektor erlässt und nicht das Erreichen dieses Ziels durch eigenes Handeln zusätzlich erschwert. Eine Senkung der Energiesteuer wäre allenfalls dann verfassungskonform, wenn sie gleichzeitig durch andere Maßnahmen flankiert würde, die insgesamt ausreichen, um die notwendige Verringerung der deutschen Gesamtemissionen zu bewirken. Dies ist aber offensichtlich nicht der Fall.

Public prosecutors decide whether a criminal suspect is investigated. Or not. They decide whether a person is indicted and whether there will be a trial. Or not. If you control them, you can make your opponents‘ life miserable and let your friends run free. On the other hand: If prosecutors don’t have to answer to politics at all, who will hold them accountable? This is what we discuss with these distinguished guests in this week’s episode of our Rule of Law podcast.

Die deutsche Staatsanwaltschaft darf wegen fehlender Unabhängigkeit keine Europäischen Haftbefehle ausstellen. So hat es gerade der EuGH entschieden. Das Urteil sollte Anlass für eine allgemeinere Debatte über die Unabhängigkeit der Justiz in Deutschland sein. Denn Entwicklungen wie in Polen oder Ungarn wären auch hierzulande rechtlich möglich. Die Debatte um constitutional resilience muss daher auch die institutionelle Unabhängigkeit der Justiz in den Blick nehmen.