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The significant increase of converter interfaced generation, consumption, storage, and transmission in power systems, results in the need to consider converter-driven stability in detail, as well as to study modelling and analysis methods with which such stability effects can be represented and investigated. Due to the multiple causes of converter-driven stability effects, a classification into further categories of fast and slow converter-driven stability is necessary, which is systematically presented in this paper. We further provide a detailed overview on appropriate modelling methods including static, quasi-dynamic and dynamic modelling and their respective applications. Typical analysis methods such as eigenvalue and impedance based analysis are explained and related to the previous modelling approaches. Based on that, a guide to which modelling and analysis method is appropriate for which type of converter-driven stability, is provided. In addition, open and recent research questions with regard to studies on nonlinear analyses of large systems with acceptable computational costs are pointed out.

Abstract Endometriosis is a leading cause of pain and infertility affecting millions of women globally. Herein, we characterize variation in DNA methylation (DNAm) and its association with menstrual cycle phase, endometriosis, and genetic variants through analysis of genotype data and methylation in endometrial samples from 984 deeply-phenotyped participants. We estimate that 15.4% of the variation in endometriosis is captured by DNAm and identify significant differences in DNAm profiles associated with stage III/IV endometriosis, endometriosis sub-phenotypes and menstrual cycle phase, including opening of the window for embryo implantation. Menstrual cycle phase was a major source of DNAm variation suggesting cellular and hormonally-driven changes across the cycle can regulate genes and pathways responsible for endometrial physiology and function. DNAm quantitative trait locus (mQTL) analysis identified 118,185 independent cis-mQTLs including 51 associated with risk of endometriosis, highlighting candidate genes contributing to disease risk. Our work provides functional evidence for epigenetic targets contributing to endometriosis risk and pathogenesis. Data generated serve as a valuable resource for understanding tissue-specific effects of methylation on endometrial biology in health and disease.

Abstract Background Long-read sequencing is increasingly used to uncover structural variants in the human genome, both functionally neutral and deleterious. Structural variants occur more frequently in regions with a high homology or repetitive segments, and one rearrangement may predispose to additional events. Bartter syndrome type 3 (BS 3) is a monogenic tubulopathy caused by deleterious variants in the chloride channel gene CLCNKB, a high proportion of these being large gene deletions. Multiplex ligation-dependent probe amplification, the current diagnostic gold standard for this type of mutation, will indicate a simple homozygous gene deletion in biallelic deletion carriers. However, since the phenotypic spectrum of BS 3 is broad even among biallelic deletion carriers, we undertook a more detailed analysis of precise breakpoint regions and genomic structure. Methods Structural variants in 32 BS 3 patients from 29 families and one BS4b patient with CLCNKB deletions were investigated using long-read and synthetic long-read sequencing, as well as targeted long-read sequencing approaches. Results We report a ~3 kb duplication of 3′-UTR CLCNKB material transposed to the corresponding locus of the neighbouring CLCNKA gene, also found on ~50 % of alleles in healthy control individuals. This previously unknown common haplotype is significantly enriched in our cohort of patients with CLCNKB deletions (45 of 51 alleles with haplotype information, 2.2 kb and 3.0 kb transposition taken together, p=9.16×10−9). Breakpoint coordinates for the CLCNKB deletion were identifiable in 28 patients, with three being compound heterozygous. In total, eight different alleles were found, one of them a complex rearrangement with three breakpoint regions. Two patients had different CLCNKA/CLCNKB hybrid genes encoding a predicted CLCNKA/CLCNKB hybrid protein with likely residual function. Conclusions The presence of multiple different deletion alleles in our cohort suggests that large CLCNKB gene deletions originated from many independently recurring genomic events clustered in a few hot spots. The uncovered associated sequence transposition haplotype apparently predisposes to these additional events. The spectrum of CLCNKB deletion alleles is broader than expected and likely still incomplete, but represents an obvious candidate for future genotype/phenotype association studies. We suggest a sensitive and cost-efficient approach, consisting of indirect sequence capture and long-read sequencing, to analyse disease-relevant structural variant hotspots in general.

Abstract Low‐Voltage (LV) distribution grids are facing a rapid increase of connected Photovoltaic (PV) power plants as well as flexible consumers like Battery‐Electric Vehicle (BEV) chargers and Heat Pumps (HPs). The coordinated operation of these generation, storage and consumption units, referred to as Distributed Energy Resources (DERs), is regarded as a key requirement to maximize the benefits of renewable generation without violating, for example, voltage limits. Therefore, an operation management scheme was proposed in previous work that optimizes the power flows in LV grids in real‐time, where optimality is expressed as a maximization of the utility that DER owners experience from power consumption or injection, respectively. In this contribution, this method is extended by: (1) detailing a time‐varying utility‐model to express customer needs, (2) introducing a distributed implementation enhancing the robustness to failures, (3) developing a testbed using a real‐time digital power grid simulator and a communication network emulator, and (4) integrating a real‐time information flooding protocol. The performance is evaluated in different simulation scenarios, showing that the proposed method is able to cooperatively utilize the flexible units in order to fulfil the DER owners' needs even in the event of controller failures and constrained communication.

Abstract Obesity promotes endothelial dysfunction. Endothelial cells not only respond, but possibly actively promote the development of obesity and metabolic dysfunction. Our aim was to characterize the role of endothelial leptin receptors (LepR) for endothelial and whole body metabolism and diet-induced obesity. Mice with tamoxifen-inducible, Tie2.Cre-ERT2-mediated deletion of LepR in endothelial cells (End.LepR knockout, KO) were fed high-fat diet (HFD) for 16 weeks. Body weight gain, serum leptin levels, visceral adiposity and adipose tissue inflammation were more pronounced in obese End.LepR-KO mice, whereas fasting serum glucose and insulin levels or the extent of hepatic steatosis did not differ. Reduced brain endothelial transcytosis of exogenous leptin, increased food intake and total energy balance were observed in End.LepR-KO mice and accompanied by brain perivascular macrophage accumulation, whereas physical activity, energy expenditure and respiratory exchange rates did not differ. Metabolic flux analysis revealed no changes in the bioenergetic profile of endothelial cells from brain or visceral adipose tissue, but higher glycolysis and mitochondrial respiration rates in those isolated from lungs. Our findings support a role for endothelial LepRs in the transport of leptin into the brain and neuronal control of food intake, and also suggest organ-specific changes in endothelial cell, but not whole-body metabolism.

Abstract The extension of 2D ferromagnetic structures into 3D curved geometry enables to tune its magnetic properties such as uniaxial magnetic anisotropy. Tuning the anisotropy with strain and curvature has become a promising ingredient in modern electronics, such as flexible and stretchable magnetoelectronic devices, impedance-based field sensors, and strain gauges, however, has been limited to extended thin films and to only moderate bending. By applying a self-assembly rolling technique using a polymeric platform, we provide a template that allows homogeneous and controlled bending of a functional layer adhered to it, irrespective of its shape and size. This is an intriguing possibility to tailor the sign and magnitude of the surface strain of integrated, micron-sized devices. In this article, the impact of strain and curvature on the magnetic ground state and anisotropy is quantified for thin-film Permalloy micro-scale structures, fabricated on the surface of the tubular architectures, using solely electrical measurements.

Background and Aims: Numerous endometriosis treatments exist, ranging from surgical to traditional medications to complementary and alternative medicines (CAMs). The ranking of treatments across management categories remains unknown. To address this research gap, this network meta-analysis (NMA) aims to rank endometriosis treatments in terms of efficacy and safety for endometriosis-related pain and quality of life. Method: A systematic literature search and fixed effects NMA was conducted. Eight databases were searched from inception to August 2022. All randomised control trials (RCTs) in women with surgically confirmed endometriosis were considered. Results: After screening 8,668 studies, 165 RCTs were included, consisting of 26,762 participants, investigating 48 medical, 13 CAMs and 16 surgical interventions. Preliminary analysis of the CAMs interventions (9 RCTs, n=522) suggested acupuncture (SMD -1.96; 95%CI: -2.63, -1.29), olive oil (SMD -1.68; 95%CI: -2.69, -0.67), fatty acid supplements (SMD -1.48; 95% CI: -2.15, -0.81), contraception + Chinese medicines (SMD -1.28; 95%CI: -2.39, -0.16), Chinese medicine (SMD -0.91, 95%CI: -1.78, -0.04) and vitamin C&E (SMD -0.38; 95%CI -0.89, 0.13) demonstrated a reduction in pain compared to placebo. There was insufficient evidence to detect a difference in pain using Vitamin D compared to placebo (SMD 0.09 95% CI: -0.55, 0.73). Complete results, including the individual and combined categories within a Bayesian framework and intervention ranking, will be available for ASPIRE 2023. Conclusion: This is the first NMA to compare the evidence of all endometriosis treatments. The findings have the potential to guide treatment decisions and guideline development.

State-of-the-art magnetic skins can only sense in one or two-dimensions, at small spatial resolutions. By combining the ancient art of paper folding, origami, with advanced semiconductor technology, here, authors present cutting edge three-dimensional magnetic sensors.

Abstract Microbial communities in freshwater streams play an essential role in ecosystem functioning via biogeochemical cycling. Yet, the impacts of treated wastewater influx into stream ecosystems on microbial strain diversity remain mostly unexplored. Here, we coupled full‐length 16S ribosomal RNA gene Nanopore sequencing and strain‐resolved metagenomics to investigate the impact of treated wastewater on a mesocosm system (AquaFlow) run with restored river water. Over 10 days, community Bray–Curtis dissimilarities between treated and control mesocosm decreased (0.57 ± 0.058 to 0.26 ± 0.046) based on ribosomal protein S3 gene clustering, finally converging to nearly identical communities. Similarly, strain‐resolved metagenomics revealed a high diversity of bacteria and viruses after the introduction of treated wastewater; these microbes also decreased over time resulting in the same strain clusters in control and treatment at the end of the experiment. Specifically, 39.2% of viral strains detected in all samples were present after the introduction of treated wastewater only. Although bacteria present at low abundance in the treated wastewater introduced additional antibiotic resistance genes, signals of naturally occurring ARG‐encoding organisms resembled the resistome at the endpoint. Our results suggest that the previously stressed freshwater stream and its microbial community are resilient to a substantial introduction of treated wastewater.

Abstract Aims Heart failure (HF) and atrial fibrillation (AF) frequently coexist and are both associated with increased levels of N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP). It is known that AF impairs the diagnostic accuracy of NT‐proBNP for HF. The aim of the present study was to compare the diagnostic and predictive accuracy of NT‐proBNP for HF and AF in stable outpatients with cardiovascular risk factors. Methods and results Data were obtained from the DIAST‐CHF trial, a prospective cohort study that recruited individuals with cardiovascular risk factors and followed them up for 12 years. Data were validated in three independent population‐based cohorts using the same inclusion/exclusion criteria: LIFE‐Adult (n = 2869), SHIP (n = 2013), and SHIP‐TREND (n = 2408). Serum levels of NT‐proBNP were taken once at baseline. The DIAST‐CHF study enrolled 1727 study participants (47.7% female, mean age 66.9 ± 8.1 years). At baseline, patients without AF or HF (n = 1375) had a median NT‐proBNP of 94 pg/mL (interquartile range 51;181). In patients with AF (n = 93), NT‐proBNP amounted to 667 (215;1130) pg/mL. It was significantly higher than in the first group (P 50% [n = 38; 603 (175;1070) pg/mL] and those without HF (P = 1.0). Receiver‐operating characteristic curves of NT‐proBNP showed a similar area under the curve (AUC) for the detection of AF at baseline (0.84, 95% CI [0.79–0.88]) and for HF with EF 50% was significantly lower (0.61 [0.56–0.65]) than for AF (P = 0.001). During follow‐up, AF was newly diagnosed in 157 (9.1%) and HF in 141 (9.6%) study participants. NT‐proBNP was a better predictor of incident AF during the first 2 years (AUC: 0.79 [0.75–0.83]) than of newly diagnosed HF (0.59 [0.55–0.63]; P 50% is very limited.

The acidic tumour microenvironment in melanoma drives immune evasion by cAMP in tumor-infiltrating monocytes. Here, the authors show that the release of an adenylate cyclase inhibitor from micelles restores antitumor immunity and, when combined with regulatory T cell depletion, leads to remission of established B16-F10-OVA tumors.

Abstract Spatial organization and gene expression of mammalian chromosomes are maintained and regulated in conjunction with cell cycle progression. This is perturbed once cells enter senescence and the highly abundant HMGB1 protein is depleted from nuclei to act as an extracellular proinflammatory stimulus. Despite its physiological importance, we know little about the positioning of HMGB1 on chromatin and its nuclear roles. To address this, we mapped HMGB1 binding genome‐wide in two primary cell lines. We integrated ChIP‐seq and Hi‐C with graph theory to uncover clustering of HMGB1‐marked topological domains that harbor genes involved in paracrine senescence. Using simplified Cross‐Linking and Immuno‐Precipitation and functional tests, we show that HMGB1 is also a bona fide RNA‐binding protein (RBP) binding hundreds of mRNAs. It presents an interactome rich in RBPs implicated in senescence regulation. The mRNAs of many of these RBPs are directly bound by HMGB1 and regulate availability of SASP‐relevant transcripts. Our findings reveal a broader than hitherto assumed role for HMGB1 in coordinating chromatin folding and RNA homeostasis as part of a regulatory loop controlling cell‐autonomous and paracrine senescence.

The concept of cellular energy systems of the German Association for Electrical, Electronic & Information Technologies (VDE) proposes sector coupled energy networks for energy transition based on cellular structures. Its decentralized control approach radically differs from that of existing networks. Deeply integrated information and communications technologies (ICT) open opportunities for increased resilience and optimizations. The exploration of this concept requires a comprehensive simulation tool. In this paper, we investigate simulation techniques for cellular energy systems and present a concept based on co-simulation. We combine simulation tools developed for different domains. A classical tool for studying physical aspects of energy systems (Modelica, TransiEnt library) is fused with a state-of-the-art communication networks simulator (OMNeT++) via the standardized functional mock-up interface (FMI). New components, such as cell managers, aggregators, and markets, are integrated via remote procedure calls. A special feature of our concept is that the communication simulator coordinates the co-simulation as a master and integrates other components via a proxy concept. Model consistency across different domains is achieved by a common description of the energy system. Evaluation proves the feasibility of the concept and shows simulation speeds about 20 times faster than real time for a cell with 111 households.

GoalThis paper presents an immersive Virtual Reality (VR) system to analyze and train Executive Functions (EFs) of soccer players. EFs are important cognitive functions for athletes. They are a relevant quality that distinguishes amateurs from professionals.MethodThe system is based on immersive technology, hence, the user interacts naturally and experiences a training session in a virtual world. The proposed system has a modular design supporting the extension of various so-called game modes. Game modes combine selected game mechanics with specific simulation content to target particular training aspects. The system architecture decouples selection/parameterization and analysis of training sessions via a coaching app from an Unity3D-based VR simulation core. Monitoring of user performance and progress is recorded by a database that sends the necessary feedback to the coaching app for analysis.ResultsThe system is tested for VR-critical performance criteria to reveal the usefulness of a new interaction paradigm in the cognitive training and analysis of EFs. Subjective ratings for overall usability show that the design as VR application enhances the user experience compared to a traditional desktop app; whereas the new, unfamiliar interaction paradigm does not negatively impact the effort for using the application.ConclusionThe system can provide immersive training of EF in a fully virtual environment, eliminating potential distraction. It further provides an easy-to-use analyzes tool to compare user but also an automatic, adaptive training mode.

We introduce Single-cell Nanopore Spatial Transcriptomics (scNaST), a software suite to facilitate the analysis of spatial gene expression from second- and third-generation sequencing, allowing to generate a full-length near-single-cell transcriptional landscape of the tissue microenvironment. Taking advantage of the Visium Spatial platform, we adapted a strategy recently developed to assign barcodes to long-read single-cell sequencing data for spatial capture technology. Here, we demonstrate our workflow using four short axis sections of the mouse heart following myocardial infarction. We constructed a de novo transcriptome using long-read data, and successfully assigned 19,794 transcript isoforms in total, including clinically-relevant, but yet uncharacterized modes of transcription, such as intron retention or antisense overlapping transcription. We showed a higher transcriptome complexity in the healthy regions, and identified intron retention as a mode of transcription associated with the infarct area. Our data revealed a clear regional isoform switching among differentially used transcripts for genes involved in cardiac muscle contraction and tissue morphogenesis. Molecular signatures involved in cardiac remodeling integrated with morphological context may support the development of new therapeutics towards the treatment of heart failure and the reduction of cardiac complications.

Dendritic cells (DC) are uniquely capable of initiating and directing immune responses. The range of their activities grounds in the heterogeneity of DC subsets and their functional plasticity. Numerical and functional DC changes influence the development and progression of disease, and correction of such dysregulations has the potential to treat disease causally. In this review, we discuss the major advances in our understanding of the regulation of DC lineage formation, differentiation, and function in the skin. We describe the alteration of DC in disease as well as possibilities for therapeutic reprogramming with a focus on tolerogenic DC. Because regulatory T cells (Treg) are indispensable partners of DC in the induction and control of tolerance, we pay special attention to the interactions with these cells. Above all, we would like to arouse fascination for this cell type and its therapeutic potential in skin diseases.

Due to the energy transition and the distribution of electricity generation, distribution power systems gain a lot of attention as their importance increases and new challenges in operation emerge. The integration of renewables and electric vehicles for instance leads to manifold changes in the system, e.g. participation in provision of ancillary services. To solve these challenges artificial intelligence provides a variety of solutions based on the increase in sensor data and computational capability. This paper provides a systematic overview of some of the most recent studies applying artificial intelligence methods to distribution power system operation published during the last 10 years. Based on that, a general guideline is developed to support the reader in finding a suitable AI technique for a specific operation task. Therefore, four general metrics are proposed to give an orientation of the requirements of each application. Thus, a conclusion can be drawn presenting suitable algorithms for each operation task.

Abstract Background Acute myocardial infarction (AMI), a major source of morbidity and mortality, is also associated with excess costs. Findings from previous studies were divergent regarding the effect on health care expenditure of adherence to guideline-recommended medication. However, gender-specific medication effectiveness, correlating the effectiveness of concomitant medication and variation in adherence over time, has not yet been considered. Methods We aim to measure the effect of adherence on health care expenditures stratified by gender from a third-party payer’s perspective in a sample of statutory insured Disease Management Program participants over a follow-up period of 3-years. In 3627 AMI patients, the proportion of days covered (PDC) for four guideline-recommended medications was calculated. A generalized additive mixed model was used, taking into account inter-individual effects (mean PDC rate) and intra-individual effects (deviation from the mean PDC rate). Results Regarding inter-individual effects, for both sexes only anti-platelet agents had a significant negative influence indicating that higher mean PDC rates lead to higher costs. With respect to intra-individual effects, for females higher deviations from the mean PDC rate for angiotensin-converting enzyme (ACE) inhibitors, anti-platelet agents, and statins were associated with higher costs. Furthermore, for males, an increasing positive deviation from the PDC mean increases costs for β-blockers and a negative deviation decreases costs. For anti-platelet agents, an increasing deviation from the PDC-mean slightly increases costs. Conclusion Positive and negative deviation from the mean PDC rate, independent of how high the mean was, usually negatively affect health care expenditures. Therefore, continuity in intake of guideline-recommended medication is important to save costs.

This work focuses on calculating the amount of control reserve, which can be provided by a pool of renewable power plants on the next day. The power forecast of wind and solar power plants depends on the weather forecast, which always contains errors. A merger of individual plants at different locations is advantageous in order to reduce the overall forecast error. Still, the amount of control reserve needs to be determined with a high level of reliability. For the calculation, a probabilistic approach based on historical and current weather data is chosen. In order to model the spatial dependencies of the forecast errors between individual plants, R‐vine copulas are used. In the copula theory, R‐vine copulas provide high accuracy in modelling the dependency of stochastic variables. The methodology is validated and compared to three alternative approaches with a use case of 32 wind and solar plants. The calculated amount of control reserve provided and the achieved reliability proves to be superior to alternative approaches. Additionally, the required reliability level is varied to investigate the impact on the amount of control reserve, which can be offered with the pool.

Abstract Cell-free DNA (cfDNA) analysis has become essential in cancer diagnostics and prenatal testing. We present cfNOMe, a two-in-one method of measuring cfDNA cytosine methylation and nucleosome occupancy in a single assay using non-disruptive enzymatic cytosine conversion and a custom bioinformatic pipeline. We show that enzymatic cytosine conversion better preserves cfDNA fragmentation information than does bisulfite conversion. Whereas previously separate experiments were required to study either epigenetic marking, cfNOMe delivers reliable results for both, enabling more comprehensive and inexpensive epigenetic cfDNA profiling. cfNOMe has the potential to advance biomarker discovery and diagnostic usage in diseases with systemic perturbations of cfDNA composition.

Background and aimsThe LDL cholesterol (LDL-C) treatment goals recommended by the 2019 ESC/EAS guidelines are only achieved in a minority of patients. The study objective was to estimate the impact of bempedoic acid treatment on LDL-C target attainment, drug costs, and atherosclerotic cardiovascular disease (ASCVD) events. The simulation used a Monte Carlo approach in a representative cohort of German outpatients at high or very-high cardiovascular risk. Additionally to statins, consecutive treatment with ezetimibe, bempedoic acid, and a PCSK9 inhibitor was simulated in patients not achieving their LDL-C goal. Considered were scenarios without and with bempedoic acid (where bempedoic acid was replaced by a PCSK9 inhibitor when LDL-C was not controlled).ResultsThe simulation cohort consisted of 105,577 patients, of whom 76,900 had very-high and 28,677 high cardiovascular risk. At baseline, 11.2% of patients achieved their risk-based LDL-C target. Sequential addition of ezetimibe and bempedoic acid resulted in target LDL-C in 33.1% and 61.9%, respectively. Treatment with bempedoic acid reduced the need for a PCSK9 inhibitor from 66.6% to 37.8% and reduced drug costs by 35.9% per year on stable lipid-lowering medication. Compared to using only statins and ezetimibe, this approach is projected to prevent additional 6,148 ASCVD events annually per 1 million patients, whereas PCSK9 inhibition alone would prevent 7,939 additional ASCVD events annually.ConclusionsA considerably larger proportion of cardiovascular high- and very-high-risk patients can achieve guideline-recommended LDL-C goals with escalated lipid-lowering medication. Bempedoic acid is projected to substantially decrease the need for PCSK9 inhibitor treatment to achieve LDL-C targets, associated with reduced drug costs albeit with fewer prevented events.

Background: Children and youth are affected rather mildly in the acute phase of COVID-19 and thus, SARS-CoV-2 infection infection may easily be overlooked. In the light of current discussions on the vaccinations of children it seems necessary to better identify children who are immune against SARS-CoV-2 due to a previous infection and to better understand COVID-19 related immune reactions in children.Methods: In a cross-sectional design, children aged 1–17 were recruited through primary care pediatricians for the study (a) randomly, if they had an appointment for a regular health check-up or (b) if parents and children volunteered and actively wanted to participate in the study. Symptoms were recorded and two antibody tests were performed in parallel directed against S (in house test) and N (Roche Elecsys) viral proteins. In children with antibody response in either test, neutralization activity was determined.Results: We identified antibodies against SARS-CoV-2 in 162 of 2,832 eligible children (5.7%) between end of May and end of July 2020 in three, in part strongly affected regions of Bavaria in the first wave of the pandemic. Approximately 60% of antibody positive children (n = 97) showed high levels (>97th percentile) of antibodies against N-protein, and for the S-protein, similar results were found. Sufficient neutralizing activity was detected for only 135 antibody positive children (86%), irrespective of age and sex. Initial COVID-19 symptoms were unspecific in children except for the loss of smell and taste and unrelated to antibody responses or neutralization capacity. Approximately 30% of PCR positive children did not show seroconversion in our small subsample in which PCR tests were performed.Conclusions: Symptoms of SARS-CoV-2 infections are unspecific in children and antibody responses show a dichotomous structure with strong responses in many and no detectable antibodies in PCR positive children and missing neutralization activity in a relevant proportion of the young population.

Abstract Background Evaluation of variations in pre- and postoperative patient reported outcomes (PRO) and the association between preoperative patient characteristics and health and satisfaction outcomes after total knee arthroplasty (TKA) may support shared decision-making in Germany. Since previous research on TKA health outcomes indicated valuation differences in longitudinal data, experienced-based population weights were used for the first time as an external valuation system to measure discrepancies between patient and average population valuation of HRQoL. Methods Baseline data (n = 203) included sociodemographic and clinical characteristics and PROs, measured by the EQ-5D-3 L and WOMAC. Six-month follow-up data (n = 161) included medical changes since hospital discharge, PROs and satisfaction. A multivariate linear regression analysis was performed to evaluate the relationship between preoperative patient characteristics and PRO scores. Patient acceptable symptom state (PASS) was calculated to provide a satisfaction threshold. Patient-reported health-related quality of life (HRQoL) valuations were compared with average experienced-based population values to detect changes in valuation. Results One hundred thirty-seven subjects met inclusion criteria. All PRO measures improved significantly. Preoperative WOMAC and EQ-5D VAS, housing situation, marital status, age and asthma were found to be predictors of postoperative outcomes. 73% of study participants valued their preoperative HRQoL higher than the general population valuation, indicating response shift. Preoperatively, patient-reported EQ-5D VAS was substantially higher than average experienced-based population values. Postoperatively, this difference declined sharply. Approximately 61% of the patients reported satisfactory postoperative health, being mainly satisfied with results if postoperative WOMAC was ≥82.49 (change ≥20.25) and postoperative EQ-5D VAS was ≥75 (change ≥6). Conclusion On average, patients benefited from TKA. Preoperative WOMAC and EQ-5D VAS were predictors of postoperative outcomes after TKA. Particularly patients with high absolute preoperative PRO scores were more likely to remain unsatisfied. Therefore, outcome prediction can contribute to shared-decision making. Using general population valuations as a reference, this study underlined a discrepancy between population and patient valuation of HRQoL before, but not after surgery, thus indicating a potential temporary response shift before surgery.

Abstract The future of e-mobility will consist of a large number of connected electric vehicles, smart charging stations and information systems at the intersection of electricity and mobility sector. When engineering and integrating the multitude of systems into even more complex systems-of-systems for e-mobility, interoperability and complexity handling are vital. Model-based system architectures support the engineering process of information systems with the concepts of abstraction, reduction and separation of concerns. In this paper, we contribute to the research body, by extracting requirements for managing complexity and interoperability of these systems. Further, a comparative analysis of the state-of-the-art in existing architecture models and frameworks for e-mobility is conducted. Based on the identified gaps in existing research, we propose the E-Mobility Systems Architecture (EMSA) Model, a three-dimensional systems architecture model for the e-mobility sector. Its structure originates from the well-established Smart Grid Architecture Model. We further allocate all relevant entities from the e-mobility sector to the EMSA dimensions, including a harmonized role model, functional reference architecture, component and systems allocation, as well as a mapping of data standards and communication protocols. The model then is validated qualitatively and quantitatively against the requirements with a case study approach. Our evaluation shows that the EMSA Model fulfills all requirements regarding the management of complexity and ensuring interoperability. From the case study, we further identify gaps in current data model standardization for e-mobility.

The next generation of biomedical tools requires reshapeable electronics to closely interface with biological tissues. This will offer unique mechanical properties and the ability to conform to irregular geometries while being robust and lightweight. Such devices can be achieved with soft materials and thin‐film structures that are able to reshape on demand. However, reshaping at the submillimeter scale remains a challenging task. Herein, shape‐controlled microscale devices are demonstrated that integrate electronic sensors and electroactive polymer actuators. The fast and biocompatible actuators are capable of actively reshaping the device into flat or curved geometries. The curvature and position of the devices are monitored with strain or magnetic sensors. The sensor signals are used in a closed feedback loop to control the actuators. The devices are wafer‐scale microfabricated resulting in multiple functional units capable of grasping, holding, and releasing biological tissues, as demonstrated with a neuronal bundle.

Abstract Background Specialist palliative care in the hospital addresses a heterogeneous patient population with complex care needs. In Germany, palliative care patients are classified based on their primary diagnosis to determine reimbursement despite findings that other factors describe patient needs better. To facilitate adequate resource allocation in this setting, in Australia and in the UK important steps have been undertaken towards identifying drivers of palliative care resource use and classifying patients accordingly. We aimed to pioneer patient classification based on determinants of resource use relevant to specialist palliative care in Germany first, by calculating the patient-level cost of specialist palliative care from the hospital’s perspective, based on the recorded resource use and, subsequently, by analysing influencing factors. Methods Cross-sectional study of consecutive patients who had an episode of specialist palliative care in Munich University Hospital between 20 June and 4 August, 2016. To accurately reflect personnel intensity of specialist palliative care, aside from administrative data, we recorded actual use of all involved health professionals’ labour time at patient level. Factors influencing episode costs were assessed using generalized linear regression and LASSO variable selection. Results The study included 144 patients. Mean costs of specialist palliative care per palliative care unit episode were 6542€ (median: 5789€, SE: 715€) and 823€ (median: 702€, SE: 31€) per consultation episode. Based on multivariate models that considered both variables recorded at beginning and at the end of episode, we identified factors explaining episode cost including phase of illness, Karnofsky performance score, and type of discharge. Conclusions This study is an important step towards patient classification in specialist palliative care in Germany as it provides a feasible patient-level costing method and identifies possible starting points for classification. Application to a larger sample will allow for meaningful classification of palliative patients.

Damaged linearized mtDNA needs to be removed from the cell for mitochondrial genome stability. Here the authors shed light into the identity of the machinery responsible for rapidly degrading linearized DNA, implicating the role of mtDNA replication factors.

The molecular nature of large-cell neuroendocrine lung carcinomas (LCNEC) has remained unclear. Here, the authors show LCNECs represent a distinct transcriptional subgroup among lung cancers and comprise two molecular subgroups, type I (TP53 and STK11/KEAP1 alterations) and type II (TP53 and RB1 inactivation).

The intermittent energy supply from distributed resources and the coupling of different energy and application sectors play an important role for future energy systems. Novel operational concepts require the use of widespread and reliable Information and Communication Technology (ICT). This paper presents the approach of a research project that focuses on the development of an innovative operational concept for a Smart Integrated Energy System (SIES), which consists of a physical architecture, ICT and energy management strategies. The cellular approach provides the architecture of the physical system in combination with Transactive Control (TC) as the system’s energy management framework. Independent dynamic models for each component, the physical and digital system, operational management and market are suggested and combined in a newly introduced co-simulation platform to create a holistic model of the integrated energy system. To verify the effectiveness of the operational concept, energy system scenarios are derived and evaluation criteria are suggested which can be employed to evaluate the future system operations.

Abstract Background Determining what constitutes “good practice” in the measurement of the costs and effects of health promotion and disease prevention measures is of particular importance. The aim of this paper was to gather expert knowledge on (economic) evaluations of health promotion and prevention measures for children and adolescents, especially on the practical importance, the determinants of project success, meaningful parameters for evaluations, and supporting factors, but also on problems in their implementation. This information is targeted at people responsible for the development of primary prevention or health promotion programs. Methods Partially structured open interviews were conducted by two interviewers and transcribed, paraphrased, and summarized for further use. Eight experts took part in the interviews. Results The interviewed experts saw evaluation as a useful tool to establish the effects of prevention programs, to inform program improvement and further development, and to provide arguments to decision making. The respondents’ thought that determinants of a program’s success were effectiveness with evidence of causality, cost benefit relation, target-group reach and sustainability. It was considered important that hard and soft factors were included in an evaluation; costs were mentioned only by one expert. According to the experts, obstacles to evaluation were lacking resources, additional labor requirements, and the evaluators’ unfamiliarity with a program’s contents. It was recommended to consider evaluation design before a program is launched, to co-operate with people involved in a program and to make use of existing structures. Conclusion While in in this study only a partial view of expert knowledge is represented, it could show important points to consider when developing evaluations of prevention programs. By considering these points, researchers could further advance towards a more comprehensive approach of evaluation targeting measures in children and adolescents.

Abstract The rapid development of microelectronics has equally rapidly increased the demand for miniaturized energy storage devices. On‐chip microsupercapacitors (MSCs), as promising power candidates, possess great potential to complement or replace electrolytic capacitors and microbatteries in various applications. However, the areal capacities and energy densities of the planar MSCs are commonly limited by the low voltage window, the thin layer of the electrode materials and complex fabrication processes. Here, a new‐type three‐dimensional (3D) tubular asymmetric MSC with small footprint area, high potential window, ultrahigh areal energy density, and long‐term cycling stability is fabricated with shapeable materials and photolithographic technologies, which are compatible with modern microelectronic fabrication procedures widely used in industry. Benefiting from the novel architecture, the 3D asymmetric MSC displays an ultrahigh areal capacitance of 88.6 mF cm−2 and areal energy density of 28.69 mW h cm−2, superior to most reported interdigitated MSCs. Furthermore, the 3D tubular MSCs demonstrate remarkable cycling stability and the capacitance retention is up to 91.8% over 12 000 cycles. It is believed that the efficient fabrication methodology can be used to construct various integratable microscale tubular energy storage devices with small footprint area and high performance for miniaturized electronics.

Power hardware-in-the-loop (PHiL) simulations provide a powerful environment in the critical process of testing new components and controllers. In this work, we aim to explain the impact of time delays in a PHiL setup and recommend how to consider them in different investigations. The general concept of PHiL, with its necessary components, is explained and the benefits compared to pure simulation and implemented field tests are presented. An example for a flexible PHiL environment is shown in form of the Power Hardware-in-the-Loop Simulation Laboratory (PHiLsLab) at TU Hamburg. In the PHiLsLab, different hardware components are used as the simulator to provide a grid interface via an amplifier system, a real-time simulator by OPAL-RT, a programmable logic controller by Bachmann, and an M-DUINO microcontroller. Benefits and limitations of the different simulators are shown using case examples of conducted investigations. Essentially, all platforms prove to be appropriate and sufficiently powerful simulators, if the time constants and complexity of the investigated case fit the simulator performance. The communication interfaces used between simulator and amplifier system differ in communication speed and delay; therefore, they have to be considered to determine the level of dynamic interactions between the simulated rest of system and the hardware under test.

Interleukin-2 (IL-2) is a T cell growth factor particularly required in regulatory T cell maintenance and memory T cell responses. High-dose IL-2 treatment was the first FDA-approved immunotherapy for cancer, while low-dose IL-2 administration has shown promise in allograft rejection and autoimmune and inflammatory diseases. However, its pleiotropic nature and the existence of IL-2 receptors with different binding affinity limit its therapeutic application. For an improved clinical applicability of the cytokine, a targeted receptor assignment must, therefore, be achieved. Nanoparticles allow controlling the location and dose of immunomodulating compounds and to specifically address specific receptors through targeted drug binding. In this review article we discuss the IL-2 biology and current clinical application with regard to nanoparticle-based IL-2-mediated manipulation of T cell responses in autoimmunity, chronic inflammation, and cancer.

Objective To estimate the effectiveness and safety of laparoscopic surgical excision of rectovaginal endometriosis.Design A multicentre, prospective cohort study.Setting 51 hospitals accredited as specialist endometriosis centres.Participants 5162 women of reproductive age with rectovaginal endometriosis of which 4721 women had planned laparoscopic excision.Interventions Laparoscopic surgical excision of rectovaginal endometriosis requiring dissection of the pararectal space.Main outcome measures Standardised symptom questionnaires enquiring about chronic pelvic pain, bladder and bowel symptoms, analgesia use and quality of life (EuroQol) completed prior to surgery and at 6, 12 and 24 months postoperatively. Serious perioperative and postoperative complications including major haemorrhage, infection and visceral injury were recorded.Results At 6 months postsurgery, there were significant reductions in premenstrual, menstrual and non-cyclical pelvic pain, deep dyspareunia, dyschezia, low back pain and bladder pain. In addition, there were significant reductions in voiding difficulty, bowel frequency, urgency, incomplete emptying, constipation and passing blood. These reductions were maintained at 2 years, with the exception of voiding difficulty. Global quality of life significantly improved from a median pretreatment score of 55/100 to 80/100 at 6 months. There was a significant improvement in quality of life in all measured domains and in quality-adjusted life years. These improvements were sustained at 2 years. All analgesia use was reduced and, in particular, opiate use fell from 28.1% prior to surgery to 16.1% at 6 months. The overall incidence of complications was 6.8% (321/4721). Gastrointestinal complications (enterotomy, anastomotic leak or fistula) occurred in 52 (1.1%) operations and of the urinary tract (ureteric/bladder injury or leak) in 49 (1.0%) procedures.Conclusion Laparoscopic surgical excision of rectovaginal endometriosis appears to be effective in treating pelvic pain and bowel symptoms and improving health-related quality of life and has a low rate of major complications when performed in specialist centres.

Olfactory receptors (ORs) are known to be expressed in a variety of human tissues and act on different physiological processes, such as cell migration, proliferation, or secretion and have been found to function as biomarkers for carcinoma tissues of prostate, lung, and small intestine. In this study, we analyzed the OR expression profiles of several different carcinoma tissues, with a focus on breast cancer. The expression of OR2B6 was detectable in breast carcinoma tissues; here, transcripts of OR2B6 were detected in 73% of all breast carcinoma cell lines and in over 80% of all of the breast carcinoma tissues analyzed. Interestingly, there was no expression of OR2B6 observed in healthy tissues. Immunohistochemical staining of OR2B6 in breast carcinoma tissues revealed a distinct staining pattern of carcinoma cells. Furthermore, we detected a fusion transcript containing part of the coding exon of OR2B6 as a part of a splice variant of the histone HIST1H2BO transcript. In addition, in cancer tissues and cell lines derived from lung, pancreas, and brain, OR expression patterns were compared to that of corresponding healthy tissues. The number of ORs detected in lung carcinoma tissues was significantly reduced in comparison to the surrounding healthy tissues. In pancreatic carcinoma tissues, OR4C6 was considerably more highly expressed in comparison to the respective healthy tissues. We detected OR2B6 as a potential biomarker for breast carcinoma tissues.

Dysfunctional processing of traumatic events may be in particular related to high trait anxiety as a pre-traumatic risk factor for the development of post-traumatic stress disorder (PTSD). However, as this has rarely been investigated in prospective, experimental studies, we aimed to analyse the association between high trait anxiety and affective as well as cognitive processing of stress using a new prospective Virtual Reality analogue trauma paradigm to overcome limitations of retrospective or current analogue designs. Individuals with high and low trait anxiety (N = 80) were exposed to a multi-sensory Virtual Reality emergency scenario while psychophysiological stress response, emotion regulation and intrusive memories were assessed. Our results showed that high trait anxiety individuals display increased (i) subjective stress responses, (ii) emotion dysregulation and (iii) intrusive memories upon VR analogue trauma exposure. In particular, our sample of high trait anxiety individuals displayed limited access to different emotion regulation strategies as well as increased worry and rumination regarding perceived intrusive memories. Considering the complex interplay of multiple risk factors, our findings suggests that peri-traumatic affective processing seems to mediate high trait anxiety and post-traumatic intrusive memories thereby pointing out the central role of peri-traumatic processes for intrusion development. In addition, HA as a modulating pre-traumatic risk factor might further increase the risk of later dysfunctional processing of an analogue trauma by interacting with factors of affective processing during analogue trauma exposure. Implications of these findings which may contribute to a higher risk to develop PTSD are discussed.

The analysis and functional characterization of ectopically expressed human olfactory receptors (ORs) is becoming increasingly important, as many ORs have been identified in several healthy and cancerous tissues. OR activation has been demonstrated to have influence on cancer cell growth and progression. Here, ORs were identified using RNA-Seq analyses and RT-PCR. We demonstrated the OR protein localization in HCT116 cells using immunocytochemistry (IHC). In order to analyze the physiological role of OR51B4, we deorphanized the receptor by the use of CRE-Luciferase assays, conducted calcium imaging experiments as well as scratch- and proliferation assays. Furthermore, western blot analyses revealed the involvement of different protein kinases in the ligand-dependent signaling pathway. Receptor knockdown via shRNA was used to analyze the involvement of OR51B4. We identified OR51B4, which is highly expressed in the colon cancer cell line HCT116 and in native human colon cancer tissues. We deorphanized the receptor and identified Troenan as an effective ligand. Troenan stimulation of HCT116 cells has anti-proliferative, anti-migratory and pro-apoptotic effects, mediated by changes in the intracellular calcium level upon PLC activation. These effects cause changes in the phosphorylation levels of p38, mTor and Akt kinases. Knockdown of the receptor via shRNA confirmed the involvement of OR51B4. This study emphasizes the importance of ectopically expressed ORs in the therapy for several diseases. The findings provide the basis for alternative treatments of colorectal cancer.

The biotrophic basidiomycete fungus Ustilago maydis causes smut disease in maize. Hallmarks of the disease are large tumors that develop on all aerial parts of the host in which dark pigmented teliospores are formed. We have identified a member of the WOPR family of transcription factors, Ros1, as major regulator of spore formation in U. maydis. ros1 expression is induced only late during infection and hence Ros1 is neither involved in plant colonization of dikaryotic fungal hyphae nor in plant tumor formation. However, during late stages of infection Ros1 is essential for fungal karyogamy, massive proliferation of diploid fungal cells and spore formation. Premature expression of ros1 revealed that Ros1 counteracts the b-dependent filamentation program and induces morphological alterations resembling the early steps of sporogenesis. Transcriptional profiling and ChIP-seq analyses uncovered that Ros1 remodels expression of about 30% of all U. maydis genes with 40% of these being direct targets. In total the expression of 80 transcription factor genes is controlled by Ros1. Four of the upregulated transcription factor genes were deleted and two of the mutants were affected in spore development. A large number of b-dependent genes were differentially regulated by Ros1, suggesting substantial changes in this regulatory cascade that controls filamentation and pathogenic development. Interestingly, 128 genes encoding secreted effectors involved in the establishment of biotrophic development were downregulated by Ros1 while a set of 70 "late effectors" was upregulated. These results indicate that Ros1 is a master regulator of late development in U. maydis and show that the biotrophic interaction during sporogenesis involves a drastic shift in expression of the fungal effectome including the downregulation of effectors that are essential during early stages of infection.

By applying first principles density functional theory (DFT) methods, different metal fluorides and their surfaces have been characterized. One of the most investigated metal fluorides is AlF3 in different polymorphs. Its chloride-doped analogon AlClxF3−x (ACF) has recently attracted much attention due to its application in catalysis. After presenting a summary of different first-principle studies on the bulk and surface properties of different main group fluorides, we will revisit the problem of the stability of different α -AlF3 surfaces and extend the investigation to chloride-doped counterparts to simulate the surface properties of amorphous ACF. For each material, we have considered ten different surface cuts with their respective terminations. We found that terminations of ( 01 1 ¯ 0 ) and ( 11 2 ¯ 0 ) yield the most stable surfaces for α -AlF3 and for the chlorine substituted surfaces. A potential equilibrium shape of the crystal for both α -AlF3 and ACF is visualized by a Wulff construction.

The chemosensory capacity of the somatosensory system relies on the appropriate expression of chemoreceptors, which detect chemical stimuli and transduce sensory information into cellular signals. Knowledge of the complete repertoire of the chemoreceptors expressed in human sensory ganglia is lacking. This study employed the next-generation sequencing technique (RNA-Seq) to conduct the first expression analysis of human trigeminal ganglia (TG) and dorsal root ganglia (DRG). We analyzed the data with a focus on G-protein coupled receptors (GPCRs) and ion channels, which are (potentially) involved in chemosensation by somatosensory neurons in the human TG and DRG. For years, transient receptor potential (TRP) channels have been considered the main group of receptors for chemosensation in the trigeminal system. Interestingly, we could show that sensory ganglia also express a panel of different olfactory receptors (ORs) with putative chemosensory function. To characterize OR expression in more detail, we performed microarray, semi-quantitative RT-PCR experiments, and immunohistochemical staining. Additionally, we analyzed the expression data to identify further known or putative classes of chemoreceptors in the human TG and DRG. Our results give an overview of the major classes of chemoreceptors expressed in the human TG and DRG and provide the basis for a broader understanding of the reception of chemical cues.

The ability of animals to sense and differentiate among thousands of odorants relies on a large set of olfactory receptors (OR) and a multitude of accessory proteins within the olfactory epithelium (OE). ORs and related signaling mechanisms have been the subject of intensive studies over the past years, but our knowledge regarding olfactory processing remains limited. The recent development of next generation sequencing (NGS) techniques encouraged us to assess the transcriptome of the murine OE. We analyzed RNA from OEs of female and male adult mice and from fluorescence-activated cell sorting (FACS)-sorted olfactory receptor neurons (ORNs) obtained from transgenic OMP-GFP mice. The Illumina RNA-Seq protocol was utilized to generate up to 86 million reads per transcriptome. In OE samples, nearly all OR and trace amine-associated receptor (TAAR) genes involved in the perception of volatile amines were detectably expressed. Other genes known to participate in olfactory signaling pathways were among the 200 genes with the highest expression levels in the OE. To identify OE-specific genes, we compared olfactory neuron expression profiles with RNA-Seq transcriptome data from different murine tissues. By analyzing different transcript classes, we detected the expression of non-olfactory GPCRs in ORNs and established an expression ranking for GPCRs detected in the OE. We also identified other previously undescribed membrane proteins as potential new players in olfaction. The quantitative and comprehensive transcriptome data provide a virtually complete catalogue of genes expressed in the OE and present a useful tool to uncover candidate genes involved in, for example, olfactory signaling, OR trafficking and recycling, and proliferation.