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Abstract Introduction Multiple sclerosis (MS) is a disabling disease with unpredictable clinical manifestations. As clinical assessments may not fully capture the impact of MS on quality of life, they can be complemented by patient-reported outcome (PRO) measures to provide a more comprehensive picture of MS disease state and impact. The objectives of this study were to explore the experiences of people with relapsing–remitting MS, including symptoms and impacts on daily life, and to provide a conceptual model of MS outcomes. Methods A literature review of studies that evaluated the experiences of people with MS was completed and combined with semi-structured concept elicitation interviews conducted with 14 people with relapsing–remitting MS in the USA. Results The average age of the 14 participants was 43.9 (range 25–64) years, most were White (78.6%) and female (78.6%), and the mean duration since diagnosis was 6.6 (2–10) years. The most bothersome symptoms identified included fatigue (n = 9), cognitive dysfunction (n = 5), mobility/difficulty with walking (n = 3), and vision problems (n = 3). The most commonly reported impacts on daily life were balance problems/instability (n = 13), work life/productivity (n = 12), difficulty walking (n = 11), daily activities/household chores (n = 11), and leisure activities (n = 10). Conclusion There was a high frequency of concepts associated with physical function, fatigue, and sensory-motor actions. A conceptual model was developed that captures the disease symptoms, impairments, and impacts identified in the interviews as well as known processes and symptoms identified in the literature search. This model underpins the appropriateness of PRO instruments, such as the PROMIS Fatigue (MS) 8a and PROMIS Physical Function (MS) 15a, which evaluate symptoms and impacts that matter most to people with MS.

Abstract Background For a sustainable production of food, research on agricultural soil microbial communities is inevitable. Due to its immense complexity, soil is still some kind of black box. Soil study designs for identifying microbiome members of relevance have various scopes and focus on particular environmental factors. To identify common features of soil microbiomes, data from multiple studies should be compiled and processed. Taxonomic compositions and functional capabilities of microbial communities associated with soils and plants have been identified and characterized in the past few decades. From a fertile Loess–Chernozem-type soil located in Germany, metagenomically assembled genomes (MAGs) classified as members of the phylum Thaumarchaeota/Thermoproteota were obtained. These possibly represent keystone agricultural soil community members encoding functions of relevance for soil fertility and plant health. Their importance for the analyzed microbiomes is corroborated by the fact that they were predicted to contribute to the cycling of nitrogen, feature the genetic potential to fix carbon dioxide and possess genes with predicted functions in plant-growth-promotion (PGP). To expand the knowledge on soil community members belonging to the phylum Thaumarchaeota, we conducted a meta-analysis integrating primary studies on European agricultural soil microbiomes. Results Taxonomic classification of the selected soil metagenomes revealed the shared agricultural soil core microbiome of European soils from 19 locations. Metadata reporting was heterogeneous between the different studies. According to the available metadata, we separated the data into 68 treatments. The phylum Thaumarchaeota is part of the core microbiome and represents a major constituent of the archaeal subcommunities in all European agricultural soils. At a higher taxonomic resolution, 2074 genera constituted the core microbiome. We observed that viral genera strongly contribute to variation in taxonomic profiles. By binning of metagenomically assembled contigs, Thaumarchaeota MAGs could be recovered from several European soil metagenomes. Notably, many of them were classified as members of the family Nitrososphaeraceae, highlighting the importance of this family for agricultural soils. The specific Loess-Chernozem Thaumarchaeota MAGs were most abundant in their original soil, but also seem to be of importance in other agricultural soil microbial communities. Metabolic reconstruction of Switzerland_1_MAG_2 revealed its genetic potential i.a. regarding carbon dioxide (CO $$_2$$ 2 ) fixation, ammonia oxidation, exopolysaccharide production and a beneficial effect on plant growth. Similar genetic features were also present in other reconstructed MAGs. Three Nitrososphaeraceae MAGs are all most likely members of a so far unknown genus. Conclusions On a broad view, European agricultural soil microbiomes are similarly structured. Differences in community structure were observable, although analysis was complicated by heterogeneity in metadata recording. Our study highlights the need for standardized metadata reporting and the benefits of networking open data. Future soil sequencing studies should also consider high sequencing depths in order to enable reconstruction of genome bins. Intriguingly, the family Nitrososphaeraceae commonly seems to be of importance in agricultural microbiomes.

Incremental nonlinear dynamic inversion (INDI) is a widely used approach to controlling UAVs with highly nonlinear dynamics. One key element of INDI-based controllers is the control allocation realizing pseudo controls using available actuators. However, the tracking of commanded pseudo controls is not the only objective considered during control allocation. Since the approach only works locally due to linearization and the solution is often ambiguous, additional aspects like control efforts or penalizing the deviation of certain states must be considered. Conducting the control allocation by solving a quadratic program this results in a considerable number of weighting parameters, which must be tuned during control design. Currently, this is conducted manually and is therefore time consuming. An automated approach for tuning these parameters is therefore highly beneficial. Thus, this paper presents and evaluates a model-based approach automatically tuning the control allocation parameters of a tiltrotor VTOL using an optimization algorithm. This optimization algorithm searches for optimal parameters minimizing a cost functional that reflects the design target. This cost functional is calculated based on a test mission for the VTOL which is conducted within a simulation environment. The test mission represents the common operating range of the VTOL. The simulation environment consists of an aircraft model as well as a model of the INDI-based controller which is dependent on the control allocation parameters. On this basis, model-based optimization is conducted and the optimal parameters are identified. Finally, successful real-world tests on a 4-degrees-of-freedom testbench using the identified parameters are presented. Since the control allocation parameters can significantly influence the aircraft’s stability, the 4-DOF testbench for the aircraft is required for rapid validation of the parameters at a minimum amount of risk.

Introduction: The menoci web portal addresses the needs of FAIR representation of biomedical basic research data and has been successfully implemented for several large consortia at Göttingen Campus. The operation of multiple menoci instances requires efficient measures to reduce administrative resource efforts. This manuscript describes our approach to automatize server operation and software updating procedures. Methods: The menoci instances are hosted on virtual machines (VM) using IT infrastructure of the local academic IT-service provider. Source code and process documentation is hosted in the Göttingen Campus GitLab service. Continuous Integration/Continuous Delivery (CI/CD) pipelines were developed to routinely build updated Docker images from latest source code revisions and the upstream Drupal Docker image. GitLab functionality for code reviews is employed, using protected branches and the “approval” feature for merge requests. Results: At the beginning, menoci development was mainly driven by the implementation of additional modules, features and optimization of user experience to fulfill the researchers’ requirements. Since the roll out of menoci to an increasing list of research consortia, we additionally focused on improving performance, software quality and enhanced automation processes. Our developed automation pipelines include updates for web server and database components, as well as the Drupal content management system and other components that together form the menoci platform. Furthermore, all menoci code enhancements are automatically distributed to all instances. Success or failing of update processes is monitored systematically to facilitate error handling. All processes are extensively documented to easily integrate new team members into administrative tasks. Discussion: Our experience indicated that automation processes are key to reduce resource efforts for technical administrative tasks. However, a high degree of automation and dependencies invoke the potential of small errors possibly leading to large effects. Therefore, tight quality control by testing and monitoring processes is necessary.

In a punch-bending machine, wire products are manufactured for a wide range of industrial sectors, such as the electronics industry. The raw material for this process is flat wire made of high-strength steel. During the manufacturing process of the flat wire, residual stresses and plastic deformations are induced into the wire. These residual stresses and deformations fluctuate over the length of the semi-finished product and have a negative effect on the final product quality. Straightening machines are used to reduce this influence to a minimum. So far, the adjustment of a straightening machine has been performed manually, which is a lengthy and complex task even for an experienced worker. This inevitably leads to the use of inefficient straightening strategies and causes high rejection rates in the entire production process. Due to a lack of sensor information from the straightening operation, application of modern feedback control methods has not been practicable. This paper presents a novel design for a straightening machine with an integrated, precise straightening force measurement. By simultaneously monitoring the position of the straightening rollers, state variables of the straightening operation can be derived. Additionally, a tension control for feeding the flat wire is introduced. This is implemented to mitigate the disturbing effects caused by irregularities in the wire-feeding process. In the results of this article, the high precision of the developed force measurement design and its possible applications are shown.

The current focus on renewable energy in global policy highlights the importance of methane production from biomass through anaerobic digestion (AD). To improve biomass digestion while ensuring overall process stability, microbiome-based management strategies become more important. In this study, metagenomes and metaproteomes were used for metagenomically assembled genome (MAG)-centric analyses to investigate a full-scale biogas plant consisting of three differentially operated digesters. Microbial communities were analyzed regarding their taxonomic composition, functional potential, as well as functions expressed on the proteome level. Different abundances of genes and enzymes related to the biogas process could be mostly attributed to different process parameters. Individual MAGs exhibiting different abundances in the digesters were studied in detail, and their roles in the hydrolysis, acidogenesis and acetogenesis steps of anaerobic digestion could be assigned. Methanoculleus thermohydrogenotrophicum was an active hydrogenotrophic methanogen in all three digesters, whereas Methanothermobacter wolfeii was more prevalent at higher process temperatures. Further analysis focused on MAGs, which were abundant in all digesters, indicating their potential to ensure biogas process stability. The most prevalent MAG belonged to the class Limnochordia; this MAG was ubiquitous in all three digesters and exhibited activity in numerous pathways related to different steps of AD.

Abstract Bacteria occupy all major ecosystems and maintain an intensive relationship to the eukaryotes, developing together into complex biomes (i.e., phycosphere and rhizosphere). Interactions between eukaryotes and bacteria range from cooperative to competitive, with the associated microorganisms affecting their host`s development, growth and health. Since the advent of non-culture dependent analytical techniques such as metagenome sequencing, consortia have been described at the phylogenetic level but rarely functionally. Multifaceted analysis of the microbial consortium of the ancient phytoplankton Botryococcus as an attractive model food web revealed that its all abundant bacterial members belong to a niche of biotin auxotrophs, essentially depending on the microalga. In addition, hydrocarbonoclastic bacteria without vitamin auxotrophies seem adversely to affect the algal cell morphology. Synthetic rearrangement of a minimal community consisting of an alga, a mutualistic and a parasitic bacteria underpins the model of a eukaryote that maintains its own mutualistic microbial community to control its surrounding biosphere. This model of coexistence, potentially useful for defense against invaders by a eukaryotic host could represent ecologically relevant interactions that cross species boundaries. Metabolic and system reconstruction is an opportunity to unravel the relationships within the consortia and provide a blueprint for the construction of mutually beneficial synthetic ecosystems.

Abstract Background Anaerobic digestion (AD) of protein-rich grass silage was performed in experimental two-stage two-phase biogas reactor systems at low vs. increased organic loading rates (OLRs) under mesophilic (37 °C) and thermophilic (55 °C) temperatures. To follow the adaptive response of the biomass-attached cellulolytic/hydrolytic biofilms at increasing ammonium/ammonia contents, genome-centered metagenomics and transcriptional profiling based on metagenome assembled genomes (MAGs) were conducted. Results In total, 78 bacterial and archaeal MAGs representing the most abundant members of the communities, and featuring defined quality criteria were selected and characterized in detail. Determination of MAG abundances under the tested conditions by mapping of the obtained metagenome sequence reads to the MAGs revealed that MAG abundance profiles were mainly shaped by the temperature but also by the OLR. However, the OLR effect was more pronounced for the mesophilic systems as compared to the thermophilic ones. In contrast, metatranscriptome mapping to MAGs subsequently normalized to MAG abundances showed that under thermophilic conditions, MAGs respond to increased OLRs by shifting their transcriptional activities mainly without adjusting their proliferation rates. This is a clear difference compared to the behavior of the microbiome under mesophilic conditions. Here, the response to increased OLRs involved adjusting of proliferation rates and corresponding transcriptional activities. The analysis led to the identification of MAGs positively responding to increased OLRs. The most outstanding MAGs in this regard, obviously well adapted to higher OLRs and/or associated conditions, were assigned to the order Clostridiales (Acetivibrio sp.) for the mesophilic biofilm and the orders Bacteroidales (Prevotella sp. and an unknown species), Lachnospirales (Herbinix sp. and Kineothrix sp.) and Clostridiales (Clostridium sp.) for the thermophilic biofilm. Genome-based metabolic reconstruction and transcriptional profiling revealed that positively responding MAGs mainly are involved in hydrolysis of grass silage, acidogenesis and / or acetogenesis. Conclusions An integrated -omics approach enabled the identification of new AD biofilm keystone species featuring outstanding performance under stress conditions such as increased OLRs. Genome-based knowledge on the metabolic potential and transcriptional activity of responsive microbiome members will contribute to the development of improved microbiological AD management strategies for biomethanation of renewable biomass.

Abstract This paper deals with the cancellation mechanism, which identifies the energy density of space-time expansion in an empty universe with the zero-point energy density and avoids the scale discrepancy with the observed energy density (cosmological constant problem). Using an intrinsic degree of freedom which describes the coupling of a variable cosmological term $$\varLambda $$ Λ with non-relativistic matter and radiation, the following consequences are demonstrated by coupling only a small contribution of $$\varLambda $$ Λ with non-relativistic matter. First, the standard model of cosmology with a positive cosmological constant can be generalised such that the missing mass problem of dark matter is solved by an overall negative variable cosmological term. Second, the model under consideration is compatible with constraints from the standard model of particle physics. Third, an equation of state parameter of dark matter is derived which agrees with observations of rotational curves of galaxies. Moreover, the creation and annihilation process of dark matter is presented.

Abstract The paper deals with the scale discrepancy between the observed vacuum energy in cosmology and the theoretical quantum vacuum energy (cosmological constant problem). Here, we demonstrate that Einstein’s equation and an analogy to particle physics leads to the first physical justification of the so-called fine-tuning problem. This fine-tuning could be automatically satisfied with the variable cosmological term $$\varLambda (a)=\varLambda _0+\varLambda _1 a^{-(4-\epsilon )}$$ Λ(a)=Λ0+Λ1a-(4-ϵ) , $$0 < \epsilon \ll 1,$$ 0

Abstract Background Isolated transient vertigo can be the only symptom of posterior circulation ischemia. Thus, it is important to differentiate isolated vertigo of a cerebrovascular origin from that of more benign origins, as patients with cerebral ischemia have a much higher risk for future stroke than do those with ‘peripheral’ vertigo. The current study aims to identify risk factors for cerebrovascular origin of isolated transient vertigo, and for future cerebrovascular events. Methods From the files of 339 outpatients with isolated transient vertigo we extracted history, clinical and technical findings, diagnosis, and follow-up information on subsequent stroke or transient ischemic attack (TIA). Risk factors were analyzed using multivariate regression models (logistic or Cox) and reconfirmed in univariate analyses. Results On first presentation, 48 (14.2%) patients received the diagnosis ‘probable or definite cerebrovascular vertigo’. During follow-up, 41 patients suffered stroke or TIA (event rate 7.9 per 100 person years, 95% confidence interval (CI) 5.5–10.4), 26 in the posterior circulation (event rate 4.8 per 100 person years, 95% CI 3.0–6.7). The diagnosis was not associated with follow-up cerebrovascular events. In multivariate models testing multiple potential determinants, only the presentation mode was consistently associated with the diagnosis and stroke risk: patients who presented because of vertigo (rather than reporting vertigo when they presented for other reasons) had a significantly higher risk for future stroke or TIA (p = 0.028, event rate 13.4 vs. 5.4 per 100 person years) and for future posterior circulation stroke or TIA (p = 0.044, event rate 7.8 vs. 3.5 per 100 person years). Conclusions We here report for the first time follow-up stroke rates in patients with transient isolated vertigo. In such patients, the identification of those with cerebrovascular origin remains difficult, and presentation mode was found to be the only consistent risk factor. Confirmation in an independent prospective sample is needed.

To meet the requirements imposed by the time-dependency of acute stroke therapies, it is necessary 1) to initiate structural and cultural changes in the breadth of stroke-ready hospitals and 2) to find new ways to train the personnel treating patients with acute stroke. We aimed to implement and validate a composite intervention of a stroke team algorithm and simulation-based stroke team training as an effective quality initiative in our regional interdisciplinary neurovascular network consisting of 7 stroke units.We recorded door-to-needle times of all consecutive stroke patients receiving thrombolysis at seven stroke units for 3 months before and after a 2 month intervention which included setting up a team-based stroke workflow at each stroke unit, a train-the-trainer seminar for stroke team simulation training and a stroke team simulation training session at each hospital as well as a recommendation to take up regular stroke team trainings.The intervention reduced the network-wide median door-to-needle time by 12 minutes from 43,0 (IQR 29,8-60,0, n = 122) to 31,0 (IQR 24,0-42,0, n = 112) minutes (p < 0.001) and substantially increased the share of patients receiving thrombolysis within 30 minutes of hospital arrival from 41.5% to 59.6% (p < 0.001). Stroke team training participants stated a significant increase in knowledge on the topic of acute stroke care and in the perception of patient safety. The overall course concept was regarded as highly useful by most participants from different professional backgrounds.The composite intervention of a binding team-based algorithm and stroke team simulation training showed to be well-transferable in our regional stroke network. We provide suggestions and materials for similar campaigns in other stroke networks.

BackgroundA(δ) and C fibers are the major pain-conducting nerve fibers, activate only partly the same brain areas, and are differently involved in pain syndromes. Whether a stimulus excites predominantly A(δ) or C fibers is a commonly asked question in basic pain research but a quick test was lacking so far.Methodology/principal findingsOf 77 verbal descriptors of pain sensations, "pricking", "dull" and "pressing" distinguished best (95% cases correctly) between A(δ) fiber mediated (punctate pressure produced by means of von Frey hairs) and C fiber mediated (blunt pressure) pain, applied to healthy volunteers in experiment 1. The sensation was assigned to A(δ) fibers when "pricking" but neither "dull" nor "pressing" were chosen, and to C fibers when the sum of the selections of "dull" or "pressing" was greater than that of the selection of "pricking". In experiment 2, with an independent cohort, the three-descriptor questionnaire achieved sensitivity and specificity above 0.95 for distinguishing fiber preferential non-mechanical induced pain (laser heat, exciting A(δ) fibers, and 5-Hz electric stimulation, exciting C fibers).ConclusionA three-item verbal rating test using the words "pricking", "dull", and "pressing" may provide sufficient information to characterize a pain sensation evoked by a physical stimulus as transmitted via A(δ) or via C fibers. It meets the criteria of a screening test by being easy to administer, taking little time, being comfortable in handling, and inexpensive while providing high specificity for relevant information.