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The Bulk Metallic Glass (BMG) Vitreloy 105 (Zr52.5Ti5Ni14.6Cu17.9Al10) as well as two crystalline reference materials of the same composition were machined with Pulsed Electrochemical Machining (PECM). One reference material was nano crystalline with an average grain size of 11 nm and the second one was a fine grain crystalline sample with an average grainsize of 110 nm. The goal was to achieve maximum surface quality in terms of roughness by utilizing a readily available industrial process. Samples were characterized by tactile profilometer, atomic force microscopy and electron microscopy methods. The results show superior surface quality of the amorphous samples over the reference materials with an average roughness depth as low as 1 nm. The observed dissolution mechanism of the BMG differs from the reference materials -as in contrast to the crystalline alloys that show a passive layer formation - no such surface layer other than the native oxide could be observed. The PECM procedure is found to be a promising post-processing step for BMGs with a resulting surface that can face even the most challenging surface quality requirements.

Abstract Rates of nitrogen transformations support quantitative descriptions and predictive understanding of the complex nitrogen cycle, but measuring these rates is expensive and not readily available to researchers. Here, we compiled a dataset of gross nitrogen transformation rates (GNTR) of mineralization, nitrification, ammonium immobilization, nitrate immobilization, and dissimilatory nitrate reduction to ammonium in terrestrial ecosystems. Data were extracted from 331 studies published from 1984–2022, covering 581 sites. Globally, 1552 observations were appended with standardized soil, vegetation, and climate data (49 variables in total) potentially contributing to the observed variations of GNTR. We used machine learning-based data imputation to fill in partially missing GNTR, which improved statistical relationships between theoretically correlated processes. The dataset is currently the most comprehensive overview of terrestrial ecosystem GNTR and serves as a global synthesis of the extent and variability of GNTR across a wide range of environmental conditions. Future research can utilize the dataset to identify measurement gaps with respect to climate, soil, and ecosystem types, delineate GNTR for certain ecoregions, and help validate process-based models.

Abstract Proximity effects allow for the adjustment of magnetic properties in a physically elegant way. If two thin ferromagnetic (FM) films are brought into contact, electronic coupling alters their magnetic exchange interaction at their interface. For a low- $$T_C$$ T C rare-earth FM coupled to a 3d transition metal FM, even room temperature magnetism is within reach. In addition, magnetic proximity coupling is particularly promising for increasing the magnetic order of metastable materials such as europium monoxide (EuO) beyond their bulk $$T_C$$ T C , since neither the stoichiometry nor the insulating properties are modified. We investigate the magnetic proximity effect at Fe/EuO and Co/EuO interfaces using hard X-ray photoelectron spectroscopy. By exciting the FM layers with circularly polarized light, magnetic dichroism is observed in angular dependence on the photoemission geometry. In this way, the depth-dependence of the magnetic signal is determined element-specifically for the EuO and 3d FM parts of the bilayers. In connection with atomistic spin dynamics simulations, the thickness of the EuO layer is found to be crucial, indicating that the observed antiferromagnetic proximity coupling is a short-ranged and genuine interface phenomenon. This fact turns the bilayer into a strong synthetic ferrimagnet. The increase in magnetic order in EuO occurs in a finite spatial range and is therefore particularly strong in the 2D limit—a counterintuitive but very useful phenomenon for spin-based device applications.

Abstract Background Multiple Sclerosis (MS) is a chronic inflammatory neurodegenerative disease with diverse symptomatology, significantly impacting patients’ quality of life (QoL). While pharmacological therapies focus primarily on reducing inflammation and relapse rates, non-pharmacological interventions, including digital health applications, have shown promise in improving QoL among persons with MS (PwMS). Pilot studies had shown the feasibility and acceptability of levidex, a digital health application based on cognitive behavioral therapy (CBT) principles, a broad set of behavior change techniques, and relevant lifestyle-change advice. This randomized controlled trial aimed to examine the effects of levidex on MS-related QoL over 6 months. Methods Participants who were diagnosed with MS for at least one year were recruited via the internet in Germany, using a secure survey software platform, and were randomly assigned to the intervention group (IG), in which they received standard care + levidex, or an active control group (CG), in which they received standard care and were offered web-adapted material on the topic of lifestyle change from the German Multiple Sclerosis Society (DMSG). The primary outcome was MS-related QoL after 6 months, measured by the Hamburg Quality of Life Questionnaire in MS (HAQUAMS); secondary outcomes included QoL subscales, sick days, and health behavior, among others. Analyses of Covariance (ANCOVA) were used to examine intervention effects at 6 months. Participants were recruited between November 2020 and February 2022. Results A total of 421 adult participants (mean age: 47.5, 78.1% women) were included and randomized (IG, n = 195, CG, n = 226). After 6 months, the IG exhibited significantly higher MS-related QoL, compared to the CG (total score HAQUAMS, adjusted group mean difference = -0.14, 95% CI: [-0.22, -0.06], p = 0.001; Cohen’s d = 0.23), with significant effects also observed on the cognitive and mood subscales. At 6 months, IG participants also reported significantly fewer sick days (median = 2 days in IG vs. 6 days in CG; W = 3939, p = 0.012) and significantly higher levels of daily activities, as measured by the Frenchay Activity Index, adjusted group mean difference = 1.37, 95% CI = [0.33, 2.40], p = 0.010; Cohen’s d = 0.16. Safety analyses showed no adverse events and good satisfaction. Conclusions Compared to the control group, levidex facilitated clinically relevant improvements in MS-related QoL, reduced sick days, and enhanced activity in PwMS over 6 months. These findings suggest that levidex can serve as an effective non-pharmacological adjunctive treatment element to standard care and could help improve QoL among PwMS. Trial registration Registered on 22.09.2020 at the German Clinical Trials Register DRKS00023023.

Abstract Lithium dendrite growth in inorganic solid-state electrolytes acts as a main stumbling block for the commercial development of all-solid-state lithium batteries. Indeed, Li dendrites often lead to solid-state electrolyte fractures, undermining device integrity and safety. Despite the significance of these issues, the mechanisms driving the solid-state electrolyte fracture process at the microscopic level remain poorly understood. Here, via operando optical and ex situ dark field X-ray microscopy measurements of LiSn∣single-crystal Li6.5La3Zr1.5Ta0.5O12∣LiSn symmetric cells, we provide insights into solid-state electrolyte strain patterns and lattice orientation changes associated with dendrite growth. We report the observation of dislocations in the immediate vicinity of dendrite tips, including one instance where a dislocation is anchored directly to a tip. This latter occurrence in single-crystalline ceramics suggests an interplay between dendrite proliferation and dislocation formation. We speculate that the mechanical stress induced by dendrite expansion triggers dislocation generation. These dislocations seem to influence the fracture process, potentially affecting the directional growth and branching observed in lithium dendrites.

Abstract Background The development of clinical guidelines aimed at GPs is a key strategy to improving the management of chronic kidney disease (CKD). In 2019, the first CKD guideline aimed specifically at GPs practicing in Germany was published by the German College of General Practitioners and Family Physicians (DEGAM.) Aims The aim of this study is to identify the barriers and enablers for the implementation of this guideline. The results of this project, together with quantitative evaluation against quality indicators for CKD in primary care will inform an update to the guideline. Methods We performed 17 semi-structured interviews with GPs practicing in Berlin and Brandenburg. Transcripts were analysed using qualitative content analysis as described by Mayring. Results We found that the perception of low clinical priority of CKD compared to other chronic diseases, opportunity cost of using guidelines, as well as poor patient understanding were significant barriers. GPs expressed that improved graphic design or integration of guideline recommendations in clinical decision support systems were enabling factors. Clinical problems concerning CKD were mostly solved by recourse to informal communication with specialists. GPs reported that they rarely consulted CKD guidelines as an aide to clinical decision making. Conclusion The most significant barrier to use was that guidelines were not used as step-by-step decision aide in consultations with patients. Our analysis suggests that informal contact between primary and secondary care is significant conduit for evidence-based information on CKD in German primary care. Implementation projects should support the development of these relationships.

Abstract E-mental health (EMH) interventions gain increasing importance in the treatment of mental health disorders. Their outpatient efficacy is well-established. However, research on EMH in inpatient settings remains sparse and lacks a meta-analytic synthesis. This paper presents a meta-analysis on the efficacy of EMH in inpatient settings. Searching multiple databases (PubMed, ScienceGov, PsycInfo, CENTRAL, references), 26 randomized controlled trial (RCT) EMH inpatient studies (n = 6112) with low or medium assessed risk of bias were included. A small significant total effect of EMH treatment was found (g = 0.3). The effect was significant both for blended interventions (g = 0.42) and post-treatment EMH-based aftercare (g = 0.29). EMH treatment yielded significant effects across different patient groups and types of therapy, and the effects remained stable post-treatment. The results show the efficacy of EMH treatment in inpatient settings. The meta-analysis is limited by the small number of included studies.

Abstract Background The German multicenter research consortium BipoLife aims to investigate the mechanisms underlying bipolar disorders. It focuses in particular on people at high risk of developing the disorder and young patients in the early stages of the disease. Functional and structural magnetic resonance imaging (MRI) data was collected in all participating centers. The collection of neuroimaging data in a longitudinal, multicenter study requires the implementation of a comprehensive quality assurance (QA) protocol. Here, we outline this protocol and illustrate its application within the BipoLife consortium. Methods The QA protocol consisted of (1) a training of participating research staff, (2) regular phantom measurements to evaluate the MR scanner performance and its temporal stability across the course of the study, and (3) the assessment of the quality of human MRI data by evaluating a variety of image metrics (e.g., signal-to-noise ratio, ghosting level). In this article, we will provide an overview on these QA procedures and show exemplarily the influence of its application on the results of standard neuroimaging analysis pipelines. Discussion The QA protocol helped to characterize the various MR scanners, to record their performance over the course of the study and to detect possible malfunctions at an early stage. It also assessed the quality of the human MRI data systematically to characterize its influence on various analyses. Furthermore, by setting up and publishing this protocol, we define standards that must be considered when analyzing data from the BipoLife consortium. It further promotes a systematic evaluation of data quality and a definition of subject inclusion criteria. In the long term, it will help to increase the chance of achieving clinically relevant results.

Abstract Background Sex differences exist not only in the efficacy but also in adverse event rates of many vaccines. Here we compared the safety of BNT162b2 vaccine administered off-label in female and male children younger than 5 years in Germany. Methods This is a retrospective cohort study, in which we performed a post-hoc analysis of a dataset collected through an authentication-based survey of individuals having registered children aged 0-

Abstract We give an interpretation of holography in the form of the AdS/CFT correspondence in terms of homotopy algebras. A field theory such as a bulk gravity theory can be viewed as a homotopy Lie or L ∞ algebra. We extend this dictionary to theories defined on manifolds with a boundary, including the conformal boundary of AdS, taking into account the cyclic structure needed to define an action with the correct boundary terms. Projecting fields to their boundary values then defines a homotopy retract, which in turn implies that the cyclic L ∞ algebra of the bulk theory is equivalent, up to homotopy, to a cyclic L ∞ algebra on the boundary. The resulting action is the ‘on-shell action’ conventionally computed via Witten diagrams that, according to AdS/CFT, yields the generating functional for the correlation functions of the dual CFT. These results are established with the help of new techniques regarding the homotopy transfer of cyclic L ∞ algebras.

Abstract Background Biliary tract cancer (BTC) is one of the most aggressive malignancies and surgery represents the only curative treatment approach. However, even in patients with complete tumor resection 5-year survival rates are below 30%. So far, prognostic markers to assess the outcome of these patients are lacking. We therefore evaluated bone mineral density (BMD) as a prognostic tool in patients receiving surgery for BTC. methods 76 BTC patients undergoing tumor resection in our clinic (Duesseldorf cohort) as well as an external validation cohort of 34 BTC patients (Cologne cohort) were included. BMD was analyzed at the first lumbar vertebra, using routine CT scans which has been proven comparable to DXA. Results Median overall survival (OS) of the Duesseldorf cohort after surgery was 527 days, one- and five-year survival probabilities were 62 and 18%. Patients with BMD above 156.5 HU had significantly improved OS (1435 days vs. 459 days; p = 0.002). The prognostic value for BMD was confirmed using Cox-regression analysis, as well as an external validation cohort. In subgroup analysis the prognostic effect of BMD was only present in female patients, suggesting sex specific differences. Conclusion BMD is a valuable, easily accessible and independent prognostic marker in patients receiving liver surgery for BTC.

Abstract The digitization of medicine will play an increasingly significant role in future years. In particular, telemedicine, Virtual Reality (VR) and innovative Artificial Intelligence (AI) systems offer tremendous potential in imaging diagnostics and are expected to shape ultrasound diagnostics and teaching significantly. However, it is crucial to consider the advantages and disadvantages of employing these new technologies and how best to teach and manage their use. This paper provides an overview of telemedicine, VR and AI in student ultrasound education, presenting current perspectives and controversies.

Abstract Chronic heart failure (CHF) is one of the most common diseases with a prevalence of 1–2% in adults, disproportionately affecting the elderly. Despite consistent drug therapy, physical activity (PA) is an integral part of current guidelines. Yet adherence to regular PA and exercise interventions is poor and potential predictors and barriers to PA remain elusive. We examined the effects of a telemonitoring-based exercise intervention in 699 CHF patients in a prospective, randomized-controlled (1:1), multicenter trial. The study was registered in the German Clinical Trials Register under DRKS00019022 on 28.05.2020. For both, the exercise and control group, self-reported PA (MET*h/week) increased and sedentary behavior declined during the 12-month intervention period. In the exercise group, daily step count as analyzed via activity trackers remained stable (pre: 6459 [4016] steps/day, post: 6532 [3858] steps/day; p = 0.621). The average number of completed exercise instruction videos provided via an online application was 1.50 [1.44] videos/week at the beginning and gradually decreased to 1.00 [1.50] videos/week; p

Abstract Certifying quantum entanglement is a critical step toward realizing quantum-coherent applications. In this work, we show that entanglement of spins can be unambiguously evidenced in a scanning tunneling microscope with electron spin resonance by exploiting the fact that entangled states undergo a free time evolution with a distinct characteristic time constant that clearly distinguishes it from the time evolution of non-entangled states. By implementing a phase control scheme, the phase of this time evolution can be mapped back onto the population of one entangled spin, which can then be read out reliably using a weakly coupled sensor spin in the junction of the scanning tunneling microscope. We demonstrate through open quantum system simulations with currently available spin coherence times of T 2 ≈ 300 ns, that a signal directly correlated with the degree of entanglement can be measured at temperatures of 100–400 mK accessible in sub-Kelvin scanning tunneling microscopes.

Abstract Streptococcus suis (S. suis) is one of the most important porcine pathogens, causing severe pathologies such as meningitis or polyarthritis. It is also a very successful colonizer of mucosal surfaces. The IgM-degrading enzyme of S. suis (Ide Ssuis ) specifically cleaves porcine IgM, which results in complement evasion. On the basis of our previous finding that Ide Ssuis also cleaves the IgM B cell receptor in vitro, we verified IgM B cell receptor cleavage ex vivo in whole regional lymph nodes and investigated the working hypothesis that this IgM B cell receptor cleavage results in a long-lasting impaired B cell function. The number of IgM-secreting cells was determined via ELISpot analysis after porcine peripheral blood mononuclear cells had initially been treated with different recombinant S. suis proteins and subsequently stimulated with interleukin-2 and the toll-like receptor 7/8 ligand R848. Compared with treatment with medium or recombinant muramidase-released protein, treatment with rIde Ssuis but also with a cleavage-deficient variant led to a reduction in the number of IgM-secreting cells as well as the level of secreted IgM. Flow cytometry analysis confirmed that the IgM B cell receptor was cleaved only by rIde Ssuis, and the receptor recovered to pretreatment levels on day 2 after treatment. Flow cytometry analysis of B and T cells incubated with fluorescein-labelled recombinant proteins revealed that different rIde Ssuis variants bind specifically to B cells, most prominently the cleavage-deficient variant. Our results indicate that in vitro interference of rIde Ssuis with the IgM B cell receptor results in long-lasting impaired IgM secretion by B cells after toll-like receptor activation. Further studies are warranted to prove that the modulation of B cell function by Ide Ssuis could play a role in vivo.

Abstract Nitrous oxide is a potent greenhouse gas. Anthropogenically enhanced nitrogen deposition causes natural forest soils to release more nitrous oxide, exacerbating global warming. We used data from nitrogen addition experiments conducted in forests worldwide to quantify the spatially varying sensitivity of soil nitrous oxide emission to nitrogen deposition, thereby inferring soil nitrous oxide emission dynamics from nitrogen deposition data. From 1985 to 2015, nitrous oxide emitted from global forest soils increased from 3.55 to 3.85 teragrams of nitrogen per year. Nitrogen deposition contributed directly to 9.0% of global forest soil nitrous oxide emissions. The derived country-specific sensitivities of soil nitrous oxide emission to nitrogen deposition could be employed as localized emission factors for forestland nitrous oxide emission inventories. This study sheds light on a process-augmented data-driven approach to estimating global nitrous oxide emissions by synthesizing experimental and observational data.

Abstract Crystalline whispering gallery mode resonators (WGMRs) have been shown to facilitate versatile sources of quantum states that can efficiently interact with atomic systems. These features make WGMRs an efficient platform for quantum information processing. Here, we experimentally show that it is possible to generate polarization entanglement from WGMRs by using an interferometric scheme. Our scheme gives us the flexibility to control the phase of the generated entangled state by changing the relative phase of the interferometer. The S value of Clauser–Horne–Shimony–Holt’s inequality in the system is 2.45 ± 0.07, which violates the inequality by more than six standard deviations.

Abstract Background Traumatic injuries, defined as physical injuries with sudden onset, are a major cause of distress and disability, with far-reaching societal consequences. A significant proportion of trauma survivors report persistent symptoms and difficulties after the injury, and studies show unmet health care needs. Self-management programs delivered in the sub-acute phase after traumatic injuries are scarcely evaluated. The aim of the present study is to evaluate the effectiveness of a self-management program (SEMPO), delivered 3–4 months after moderate-to-severe traumatic injury. Methods This study protocol describes a pragmatic randomized controlled trial (RCT) with two classical RCT arms (intervention and control) and an explorative self-selection arm. 220 patients will be recruited from Oslo University Hospital, the largest Trauma Referral Centre in Norway. Patients aged 18–72 years residing in the south-east region of Norway, admitted to the Trauma Centre directly or within 72 h after having sustained a moderate to severe traumatic injury, defined as a New Injury Severity Score > 9, having at least 2 days hospital stay, and reporting injury-related symptoms and impairment at discharge from the acute hospital will be included. Patients will be randomly assigned to either a classical RCT randomization arm (intervention or control arm) or to a self-selection arm. In the randomization arm, participants are further randomized into intervention or control group. Participants allocated to the self-selection arm will choose to partake either in the intervention or control arm. The primary outcome is the level of self-efficacy in trauma coping assessed 6 months after completion of the intervention, with a similar time point for the control group. Secondary outcomes include symptom burden, physical functioning and disability, return to work and health care utilization, health-related quality of life, and communication competency. In addition, patients will be asked to nominate one domain-related measurement as their preferred outcome measure. Discussion This RCT will determine the effect of a self-management program tailored to patients with moderate to severe physical trauma, and the self-selection arm incorporates the potential influence of patient treatment preferences on intervention results. If the intervention proves effective, cost-effectiveness and cost-utility analyses will be performed and thereby provide important information for clinicians and policy makers. Trial registration The study is registered in Clinical Trials with the identifier: NCT06305819. Registered on March 05, 2004.

Abstract Philips Visual Patient Avatar is an innovative approach to patient monitoring. Computer-based simulation studies have shown that it can improve diagnostic accuracy and confidence while reducing perceived workload. Following its integration into clinical practice, we conducted a single-centre qualitative study at the University Hospital Zurich to explore the views of anaesthesia, post-anaesthesia and intensive care providers on their experience with the technology. We used an online survey to assess its contributions in different clinical situations. We analysed the data thematically to identify key themes. Of the 510 healthcare providers contacted, 131 (25.7%) completed the survey and 154 comments were collected. Key themes included the detection of specific vital sign changes, focusing on temperature and oxygen saturation (41.9%, 34/81 comments in the operating room; 38.6%, 17/44 comments in the intensive care unit; 10.3%, 3/29 comments in the post-anaesthesia care unit). Additionally, the technology was perceived to support daily routines and situational awareness (28.4%, 23/81 comments in the OR; 9.1%, 4/44 comments in the ICU; 10.3%, 3/29 comments in the PACU). The study provides early, but strong evidence that the Philips Visual Patient Avatar assists healthcare providers in specific clinical situations in the perioperative and critical care settings.

Abstract A genomic database of all Earth’s eukaryotic species could contribute to many scientific discoveries; however, only a tiny fraction of species have genomic information available. In 2018, scientists across the world united under the Earth BioGenome Project (EBP), aiming to produce a database of high-quality reference genomes containing all ~1.5 million recognized eukaryotic species. As the European node of the EBP, the European Reference Genome Atlas (ERGA) sought to implement a new decentralised, equitable and inclusive model for producing reference genomes. For this, ERGA launched a Pilot Project establishing the first distributed reference genome production infrastructure and testing it on 98 eukaryotic species from 33 European countries. Here we outline the infrastructure and explore its effectiveness for scaling high-quality reference genome production, whilst considering equity and inclusion. The outcomes and lessons learned provide a solid foundation for ERGA while offering key learnings to other transnational, national genomic resource projects and the EBP.

Abstract The market coupling of adjacent market zones is a key element in terms of coping with rising levels of uncertainty in the European energy system due to the adoption of more volatile renewable energy sources. An adequate analysis of this issue yet requires an appropriate consideration of uncertainty along with a detailed modelling of market coupling. Thus, we present a novel approach combining a comprehensive unit commitment and dispatch model with a sophisticated methodology to reflect the uncertainty of wind power generation by considering forecast updates for the German market region in the market clearing process. Subsequently, we investigate the impact of uncertainty on cross‐border electricity flows in a European case study. Our results show that all adjacent market zones and all relevant technologies significantly contribute to balancing forecast updates in Germany, underlining the benefits of intraday market coupling. Further, we observe that a joint and unrestricted intraday market is the most cost‐efficient market solution. Finally, our analyses show that more extensive market coupling is indispensable for the further integration of renewable energy sources in the future.

A Europe-wide outbreak of invasive pediatric group A streptococcal infections (iGAS) began in fall 2022. Here, we report the evolution of GAS hospitalizations in children and adolescents during the second outbreak year in 2023–2024 at a tertiary center in Switzerland. Using prospective monitoring of all in-patient GAS cases below 16 years of age, including those with iGAS, we compared case frequencies and clinical characteristics in three time periods (2013–2020; 2022–2023; 2023–2024). Annual GAS hospitalizations increased from a median of 25 cases (range 11–28) in 2013–2020 to 89 and 63 cases, respectively, in 2022–2023 and 2023–2024. iGAS cases evolved similarly (2013–2020, 4 cases (3–8); 2022–2023, 32 cases; 2023–2024, 21 cases). The decline in cases from 2022–2023 to 2023–2024 included all types of GAS organ involvement, except suppurative infections in the head area, which remained largely unchanged (48 vs. 45 cases). Pleural empyema declined from 13 to 7 cases, possibly explained by a poor overlap of the GAS and influenza curves, respectively, in 2023–2024 compared to 2022–2023. These data document the prolongation of the GAS outbreak into its second winter season in 2023–2024.

Abstract Objective The first international consensus criteria for optic neuritis (ICON) were published in 2022. We applied these criteria to a prospective, global observational study of acute optic neuritis (ON). Methods We included 160 patients with a first‐ever acute ON suggestive of a demyelinating CNS disease from the Acute Optic Neuritis Network (ACON). We applied the 2022 ICON to all participants and subsequently adjusted the ICON by replacing a missing relative afferent pupillary defect (RAPD) or dyschromatopsia if magnetic resonance imaging pathology of the optical nerve plus optical coherence tomography abnormalities or certain biomarkers are present. Results According to the 2022 ICON, 80 (50%) patients were classified as definite ON, 12 (7%) patients were classified as possible ON, and 68 (43%) as not ON (NON). The main reasons for classification as NON were absent RAPD (52 patients, 76%) or dyschromatopsia (49 patients, 72%). Distribution of underlying ON etiologies was as follows: 78 (49%) patients had a single isolated ON, 41 (26%) patients were diagnosed with multiple sclerosis, 25 (16%) patients with myelin oligodendrocyte glycoprotein antibody‐associated disease, and 15 (9%) with neuromyelitis optica spectrum disorder. The application of the adjusted ON criteria yielded a higher proportion of patients classified as ON (126 patients, 79%). Interpretation According to the 2022 ICON, almost half of the included patients in ACON did not fulfill the requirements for classification of definite or possible ON, particularly due to missing RAPD and dyschromatopsia. Thorough RAPD examination and formal color vision testing are critical to the application of the 2022 ICON.

Summary: Although dogs exhibit remarkable capabilities for interacting with humans, the underlying cognitive mechanisms remain insufficiently understood. Here, we investigated canine perspective taking by challenging dogs to decide whether and where to steal food in the absence of a human who had prohibited them from doing so. The dogs could only infer the experimenter’s presence through a sound (carrot chopping) they had perceived during a prior exploration phase, in which they also had the opportunity to observe from which locations in the room the human was visible. In the test, the majority of dogs preferred to steal from a plate that was not visible from the location where the human had chopped carrots before when they heard a playback of the chopping sound but not when they heard a control sound (street noise). These findings provide evidence that dogs anticipate the behavior of humans without relying on observable visual cues.

The role of a topologically close-packed (TCP) phase (μ phase) on the plastic deformation of a Ni-based superalloy was investigated employing a combination of in situ scanning electron microscope micropillar compression and atomic-scale characterization using atom probe tomography and transmission electron microscopy. Micropillar tests revealed two distinct slip behaviors: TCP-free pillars deformed via multiple slip systems, whereas TCP-containing pillars deformed by single slip. Notably, while previous studies have reported fracture at the TCP/γ' interface, our findings revealed that in the TCP-containing pillars, deformation was rarely observed at the interface. Instead, slip predominantly occurred in regions approximately 50–100 nm away from the interface. Chemical analysis near the TCP/γ' interface via APT showed an excess Ta content near the interface increasing the antiphase boundary energy and enhancing local order strengthening. Moreover, an approximate 8% lattice misfit at the TCP/γ' interface, coupled with the elastic mismatch between the two phases, provided additional slip resistance in the vicinity of the interface. This study sheds light on the intricate interplay between TCP phase formation, microstructural evolution, and mechanical properties in Ni-based superalloys offering valuable insights into the role of the TCP phases.

In this study, an advanced nanofiber breast cancer in vitro model was developed and systematically characterized including physico-chemical, cell-biological and biophysical parameters. Using electrospinning, the architecture of tumor-associated collagen signatures (TACS5 and TACS6) was mimicked. By employing a rotating cylinder or static plate collector set-up, aligned fibers (TACS5-like structures) and randomly orientated fibers (TACS6-like structures) fibers were produced, respectively. The biocompatibility of these fibers was enhanced by collagen coating, ensuring minimal toxicity and improved cell attachment. Various breast cancer cell lines (MCF7, HCC1954, MDA-MB-468, and MDA-MB-231) were cultured on these fibers to assess epithelial-to-mesenchymal transition (EMT) markers, cellular morphology, and migration.Aligned fibers (TACS5) significantly influenced EMT-related changes, promoting cellular alignment, spindle-shaped morphology and a highly migratory phenotype in mesenchymal and hybrid EMT cells (MDA-MB-468, MDA-MB-231). Conversely, epithelial cells (MCF7, HCC1954) showed limited response, but - under growth factor treatment - started to infiltrate the fibrous scaffold and underwent EMT-like changes, particularly on TACS5-mimicks, emphasizing the interplay of topographical cues and EMT induction.The biophysical analysis revealed a clear correlation between cellular EMT status and cell mechanics, with increased EMT correlating to decreased total cellular stiffness. Cancer cell mechanics, however, were found to be dynamic during biochemical and topographical EMT-induction, exceeding initial stiffness by up to 2-fold. These findings highlight the potential of TACS5-like nanofiber scaffolds in modeling the tumor microenvironment and studying cancer cell behavior and mechanics.

The Satisfaction With Life Scale (SWLS) is a widely used self-report measure of subjective well-being, but studies of its measurement invariance across a large number of nations remain limited. Here, we utilised the Body Image in Nature (BINS) dataset-with data collected between 2020 and 2022 -to assess measurement invariance of the SWLS across 65 nations, 40 languages, gender identities, and age groups (N = 56,968). All participants completed the SWLS under largely uniform conditions. Multi-group confirmatory factor analysis indicated that configural and metric invariance was upheld across all nations, languages, gender identities, and age groups, suggesting that the unidimensional SWLS model has universal applicability. Full scalar invariance was achieved across gender identities and age groups. Based on alignment optimisation methods, partial scalar invariance was achieved across all but three national groups and across all languages represented in the BINS. There were large differences in latent SWLS means across nations and languages, but negligible-to-small differences across gender identities and age groups. Across nations, greater life satisfaction was significantly associated with greater financial security and being in a committed relationship or married. The results of this study suggest that the SWLS largely assesses a common unidimensional construct of life satisfaction irrespective of respondent characteristics (i.e., national group, gender identities, and age group) or survey presentation (i.e., survey language). This has important implications for the assessment of life satisfaction across nations and provides information that will be useful for practitioners aiming to promote subjective well-being internationally.

ABSTRACT Background Malignant tumors release growth factors, promoting lymphangiogenesis in primary tumors and draining sentinel lymph nodes, ultimately facilitating lymph node metastasis. As a malignant lymphatic tumor entity, lymphangiosarcomas are characterized by low survival rates and limited treatment options. The transcription factor SOX18 plays a crucial role in both lymphatic endothelial cell differentiation and cancer‐induced lymphangiogenesis. Aims In this in vitro study, we investigated the potential therapeutic effect of a small molecule called Sm4, which inhibits SOX18, on lymphatic endothelial and lymphangiosarcoma cells in vitro. Methods and Results Human dermal lymphatic endothelial cells (HDLECs), lymphangiosarcoma cells (MO‐LAS), and other endothelial cell lines were cultured. We found that Sox18 exhibited high mRNA expression levels in both HDLEC and MO‐LAS. Sm4 treatment decreased the Sox18 expression level at the mRNA and protein levels in both HDLEC and MO‐LAS significantly, a phenomenon confirmed through immunofluorescence images. Additionally, Sm4 treatment suppressed the expression of key lymphatic phenotype markers (Prox1, Flt4, and Lyve1) and hindered migration in both HDLEC and MO‐LAS, all while maintaining cell viability. Conclusion These findings suggest that targeting SOX18 with Sm4 may hold potential as a therapeutic strategy for lymphangiosarcoma and cancer‐induced lymphatic metastasis. Further in vitro studies are warranted to investigate the mechanisms and conduct dose–response analyses to evaluate Sm4's potential as a targeted therapy for lymphangiosarcoma and cancer‐induced lymphangiogenesis in the future.

Objective The objective of this study was to evaluate the preliminary effectiveness of an electronic pill bottle with automated reminders on hydroxychloroquine (HCQ) adherence in children with pediatric systemic lupus erythematosus (pSLE). Methods This was a self‐controlled, open label, direct‐to‐family pilot trial. Children with pSLE treated with HCQ were recruited from the Childhood Arthritis and Rheumatology Research Alliance Registry. All participants received a pill bottle with a sensor in the cap to record openings and provide automated reminders, which were activated after a two‐week run‐in. The primary outcome was a change in adherence measured using the pill bottle over six months. Secondary outcomes included plasma HCQ concentrations and Medication Adherence Self‐Report Inventory (MASRI) scores, collected during four home visits. An exploratory post hoc analysis examined adherence patterns over time. Results Overall adherence was high and did not change over six months (mean ± SD proportion of recorded out of expected pill bottle openings, 0.86 ± 0.20 and 0.89 ± 0.16, P = 0.590). A post hoc analysis grouped participants by adherence pattern. The group with variable adherence, compared with the group with persistent high adherence, had lower dose‐adjusted HCQ concentrations at baseline (0.387 vs 0.627 ng/mL/mg, P = 0.04) and trended toward lower MASRI scores (77.1 vs 93.4, P = 0.09). After six months, there were no differences in HCQ concentrations or MASRI by group. Conclusion Automated reminders did not improve adherence to HCQ for children with pSLE, although the ability to detect effect was limited by a high baseline adherence and small sample size. Post hoc analyses identified different adherence patterns and a subgroup of patients with low HCQ concentrations who could be targeted for future adherence interventions.

Rationale: Treatment monitoring of tuberculosis patients is complicated by a slow growth rate of Mycobacterium tuberculosis. Recently, host RNA signatures have been used to monitor the response to tuberculosis treatment. Objective: Identifying and validating a whole blood-based RNA signature model to predict microbiological treatment responses in patients on tuberculosis therapy. Methods: Using a multi-step machine learning algorithm to identify an RNA-based algorithm to predict the remaining time to culture conversion at flexible time points during anti-tuberculosis therapy. Results: The identification cohort included 149 patients split into a training and a test cohort, to develop a multistep algorithm consisting of 27 genes (TB27) for predicting the remaining time to culture conversion (TCC) at any given time. In the test dataset, predicted TCC and observed TCC achieved a correlation coefficient of r=0.98. An external validation cohort of 34 patients shows a correlation between predicted and observed days to TCC also of r=0.98. Conclusion: We identified and validated a whole blood-based RNA signature (TB27) that demonstrates an excellent agreement between predicted and observed times to M. tuberculosis culture conversion during tuberculosis therapy. TB27 is a potential useful biomarker for anti-tuberculosis drug development and for prediction of treatment responses in clinical practice.

ABSTRACT Stream periphyton is an ideal study system for explaining how dispersal shapes community patterns. Few studies have tried to investigate periphyton metacommunities at the reach scale, and studies comparing local versus upstream periphyton propagule sources are lacking. We aimed to address these knowledge gaps by disentangling environmental constraints and dispersal sources, including dispersal hypotheses related to periphyton functional guilds. We covered 25‐m sections of streambed with plastic silage cover sheets in three streams in Southern New Zealand, allowing river water to flow over the sheets. Samples on top of these sheets allowed periphyton colonisation only by drifting upstream propagules, while ‘control’ samples placed directly upstream of the plastic sheets were colonised by local and upstream propagules. We collected samples after 7, 14, and 25 days of colonisation. Response variables included periphyton biomass, community structure, and relative abundances of functional guilds. Control samples showed 1.5–6 times higher cell densities than plastic‐cover samples, suggesting that local colonisation is very important for biomass accrual. Periphyton communities on both tile types became more similar to each other with time, indicating that environmental filters overcame effects of colonisation sources. While motile and flagellated taxa showed the ability to reach their preferred microhabitats in all streams, the responses of the remaining functional guilds did not follow the expected patterns. We conclude that periphyton community assembly strongly depends on reach‐scale connectivity, which results in higher biomass accrual and community structure. These findings suggest that the mass effect paradigm is likely to be the principal metacommunity process shaping stream periphyton communities at the reach scale.

[This corrects the article DOI: 10.1371/journal.pone.0262877.].

Aim In the clinical setting of acute myocarditis, existing guidelines recommend refraining from moderate-intensity to high-intensity sports for 3–6 months, yet the extent to which these recommendations are implemented by clinicians and followed by patients remains unclear.Methods From January 2020 to December 2023, consecutive patients with myocarditis according to European Society of Cardiology criteria were prospectively enrolled. Myocarditis was categorised into acute, subacute and non-acute myocarditis. Patients completed a sports questionnaire and sports behaviour was categorised into no sports (NSP), recreational (REC) or competitive sports (COMP).Results A total of 165 patients with myocarditis (mean age 50±17 years, 35% women) completed the questionnaire. Overall 73 (44%) patients received sports counselling. A total of 44 (72%) patients engaged in sports (REC+COMP) with acute or subacute myocarditis, received sports counselling with 38 (87%) adhering. Overall COMP patients (all male) received more counselling (11/11; 100%) compared with REC (53/105; 50%) and NSP (9/49; 18%). Of 39 women in the REC group, 14 (36%) received recommendations, whereas of 66 men 39 (59%) received recommendations (p

Abstract Therapies against hematological malignancies using chimeric antigen receptors (CAR)‐T cells have shown great potential; however, therapeutic success in solid tumors has been constrained due to limited tumor trafficking and infiltration, as well as the scarcity of cancer‐specific solid tumor antigens. Therefore, the enrichment of tumor‐antigen specific CAR‐T cells in the desired region is critical for improving therapy efficacy and reducing systemic on‐target/off‐tumor side effects. Here, we functionalized human CAR‐T cells with superparamagnetic iron oxide nanoparticles (SPIONs), making them magnetically controllable for site‐directed targeting. SPION‐loaded CAR‐T cells maintained their specific cytolytic capacity against melanoma cells expressing the CAR‐specific antigen chondroitin sulfate proteoglycan (CSPG4). Importantly, SPIONs suppressed cytokine release in the loaded CAR‐T cells, shifting the cell death phenotype in the tumor cells from pyroptosis to apoptosis. Furthermore, SPION‐loaded CAR‐T cells could be enriched in a dynamic flow model through an external magnetic field and be detected in MRI. These results demonstrate that lytic cytotoxicity is retained after SPION‐functionalization and provides a basis for future site‐specific immunotherapies against solid tumors with reduced systemic adverse side effects.

Abstract Background Estimating the risk of developing bipolar disorder (BD) in children and adolescents (C&A) with depressive disorders is important to optimize prevention and early intervention efforts. We aimed to quantitatively examine the risk of developing BD from depressive disorders and identify factors which moderate this development. Methods In this systematic review and meta-analysis (PROSPERO:CRD42023431301), PubMed and Web-of-Science databases were searched for longitudinal studies reporting the percentage of C&A with ICD/DSM-defined depressive disorders who developed BD during follow-up. Data extraction, random-effects meta-analysis, between-study heterogeneity analysis, quality assessment, sub-group analyses, and meta-regressions were conducted. Results Thirty-nine studies were included, including 72,371 individuals (mean age=13.9 years, 57.1% females); 14.7% of C&A with a depressive disorder developed BD after 20.4–288 months: 9.5% developed BD-I (95% CI=4.7 to 18.1); 7.7% developed BD-II (95% CI=3.2% to 17.3%); 19.8% (95% CI=9.9% to 35.6%) of C&A admitted into the hospital with a depressive disorder developed BD. Studies using the DSM (21.6%, 95% CI=20.2% to 23.1%) and studies evaluating C&A with a major depressive disorder only (19.8%, 95% CI=16.8% to 23.1%) found higher rates of development of BD. Younger age at baseline, a history of hospitalization and recruitment from specialized clinics were associated with an increased risk of developing BD at follow-up. Quality of included studies was good in 76.9% of studies. Conclusions There is a substantial risk of developing BD in C&A with depressive disorders. This is particularly the case for C&A with MDD, DSM-diagnosed depressive disorders, and C&A admitted into the hospital. Research exploring additional predictors and preventive interventions is crucial.

The intestinal epithelium forms the boundary between the intestinal immune system in the lamina propria and the outside world, the intestinal lumen, which contains a diverse array of microbial and environmental antigens. Composed of specialized cells, this epithelial monolayer has an exceptional turnover rate. Differentiated epithelial cells are released into the intestinal lumen within a few days, at the villus tip, a process that requires strict regulation. Dysfunction of the epithelial barrier increases the intestinal permeability and paves the way for luminal antigens to pass into the intestinal serosa. Stem cells at the bottom of Lieberkühn crypts provide a constant supply of mature epithelial cells. Differentiated intestinal epithelial cells exhibit a diverse array of mechanisms that enable communication with surrounding cells, fortification against microorganisms, and orchestration of nutrient absorption and hormonal balance. Furthermore, tight junctions regulate paracellular permeability properties, and their disruption can lead to an impairment of the intestinal barrier, allowing inflammation to develop or further progress. Intestinal epithelial cells provide a communication platform through which they maintain homeostasis with a spectrum of entities including immune cells, neuronal cells, and connective tissue cells. This homeostasis can be disrupted in disease, such as inflammatory bowel disease. Patients suffering from inflammatory bowel disease show an impaired gut barrier, dysregulated cellular communication, and aberrant proliferation and demise of cells. This review summarizes the individual cellular and molecular mechanisms pivotal for upholding the integrity of the intestinal epithelial barrier and shows how these can be disrupted in diseases, such as inflammatory bowel disease.

Background and aims Hypertrophic cardiomyopathy (HCM) has various aetiologies, including genetic conditions like Fabry disease (FD), a lysosomal storage disorder. FD prevalence in high-risk HCM populations ranges from 0.3% to 11.8%. Early diagnosis of FD is crucial due to available treatments, but its rarity and diverse symptoms complicate identification. Heart-specific FD variants often lead to late diagnoses due to the absence of typical FD symptoms. This prospective study (NCT04943991) was conducted to identify patients with undiagnosed FD using electronic health records (EHR) at a German tertiary-care hospital.Methods Over 20 years (2000–2020), 2824 patients with ‘left ventricular hypertrophy (LVH)’ or ‘hypertrophic cardiomyopathy (HCM)’ were identified by full-text search. Exclusion criteria were age over 85, other diagnosed cardiomyopathies, significant valvular heart disease, death, active malignancy and prior FD testing. The remaining patients received an invitation for FD genetic testing.Results Of the 2824 identified patients, 2626 (93%) fulfilled the exclusion criteria. Among the 198 included patients, 96 responded, and 55 underwent genetic testing, yielding a response rate of 48% and a testing rate of 28%. In one patient (1.8% of tested), FD was diagnosed with the p.N215S variant. Subsequent family screening revealed six additional FD cases, with four initiating FD-specific therapies. Comprehensive clinical evaluations were conducted in five of the seven identified patients.Conclusions Genetic testing of patients with unexplained LVH/HCM using EHR is effective for identifying FD. Subsequent family screening further identified at-risk individuals, promoting regular follow-ups and if needed FD-specific therapies. This approach highlights the potential for broader application in high-risk populations to uncover treatable genetic conditions. The next phase should focus on automating the executed search process.Trial registration number NCT04943991.

Chimeric antigen receptor (CAR) T cell therapy of solid cancer remains below expectations; adding cytokine help through IL-18 has shown remarkable efficacy in first clinical trials. As IL-18 is also a powerful driver of hyperinflammatory conditions, we discuss to what extent unleashing IL-18 is a double-edged sword in CAR T cell therapies.

AimThis study analyzes the prevalence and predictive factors of testosterone-induced erythrocytosis (TIE) in patients receiving testosterone replacement therapy (TRT).MethodsRetrospective single-center observational study.Results247 patients were included; median age was 47.0 years (interquartile range (IQR) 32-60) and median follow-up years 2.9 (1.0-5.5). The most common indication for TRT was central hypogonadism (51%) followed by primary hypogonadism (26%). TRT was carried out with testosterone undecanoate (TU) n=194, testosterone enanthate (TE) n=18 and testosterone gel (n=35). Compared to baseline, hematocrit (HCT) values at last follow-up (LFU) increased significantly by +0.04 (95% confidence interval (CI) [0.027, 0.050], p=0.46, 23% >0.5 and 5%>0.54. 46% of the patients who have reached an HCT value >0.46 have had their highest HCT measurement within the first year of TRT application. Logistic regression analysis indicated that body mass index (BMI) was significantly associated with the development of an HCT ≥0.5 (p=0.013) and HCT ≥0.46 (p=0.008). There was an association between the baseline HCT measurement and the outcome of a HCT measurement ≥0.46 (p=0.025), patients with high starting values were more likely to develop TIE.ConclusionsTIE appears to be frequent and does not only present within the first year of therapy which indicates a close follow-up of laboratory values within the first year followed by annual controls. Baseline BMI and baseline HCT measurement should be considered in risk stratification of TIE development.

IntroductionThe severity of spinal cord injury (SCI) is closely tied to pulmonary function, especially in cases of higher SCI levels. Despite this connection, the underlying pathological mechanisms in the lungs post-SCI are not well understood. Previous research has established a connection between disrupted sympathetic regulation and splenocyte apoptosis in high thoracic SCI, leading to pulmonary dysfunction. The aim of this study was to investigate whether mice with low-level SCI exhibit increased susceptibility to acute lung injury by eliciting systemic inflammatory responses that operate independently of the sympathetic nervous system. MethodsHere, we employed T9 contusion SCI and exposed mice to aerosolized lipopolysaccharide (LPS) to simulate lung inflammation associated with acute respiratory distress syndrome (ARDS). Twenty-four hours post-LPS exposure, lung tissues and bronchoalveolar lavage (BAL) fluid were analyzed. ResultsLPS markedly induced proinflammatory gene expression (SAA3, IRG1, NLRP3, IL-1beta, MCP-1) and cytokine release (IL-1beta, IL-6, MCP-1) in SCI mice compared to controls, indicating an exaggerated inflammatory response. Infiltration of Ly6G/C positive neutrophils and macrophages was significantly higher in SCI mice lungs post-LPS exposure. Interestingly, spleen size and weight did not differ between control and SCI mice, suggesting that T9 SCI alone does not cause spleen atrophy. Notably, bone-marrow-derived macrophages (BMDMs) from SCI mice exhibited hyper-responsiveness to LPS. DiscussionsThis study demonstrated an increase in lung inflammation and immune responses subsequent to low-level T9 SCI, underscoring the widespread influence of systemic inflammation post-SCI, especially pronounced in specific organs like the lungs.

IntroductionTranscranial alternating current stimulation (tACS) is a promising tool for modulating brain oscillations. This study investigated whether 5 Hz tACS could modulate neural oscillations in the prefrontal cortex and how this modulation impacts performance in working memory (WM) tasks.MethodIn two sessions, 28 healthy participants received 5 Hz tACS or sham stimulation over the left dorsolateral prefrontal cortex (DLPFC) while performing tasks with high and low WM loads. Resting-state EEG was recorded before and after stimulations for 5 minutes. EEG power was measured at electrodes surrounding the stimulation site.ResultsThe results showed that tACS significantly improved reaction time (RT) compared to sham stimulation. This effect was task-specific, as tACS improved RT for hit responses only in high WM load trials, with no impact on low-load trials. Moreover, tACS significantly increased EEG power at 5 Hz and in the theta band compared to pre-stimulation levels.DiscussionThese findings demonstrate that tACS applied over left DLPFC modulates post-stimulation brain oscillations at the stimulation sites – known as tACS after-effects. Furthermore, the results suggest that 5 Hz tACS enhances response speed by elevating task-related activity in the prefrontal cortex to an optimal level for task performance.ConclusionIn summary, the findings highlight the potential of tACS as a technique for modulating specific brain oscillations, with implications for research and therapeutic interventions.

IntroductionGenerating physician letters is a time-consuming task in daily clinical practice.MethodsThis study investigates local fine-tuning of large language models (LLMs), specifically LLaMA models, for physician letter generation in a privacy-preserving manner within the field of radiation oncology.ResultsOur findings demonstrate that base LLaMA models, without fine-tuning, are inadequate for effectively generating physician letters. The QLoRA algorithm provides an efficient method for local intra-institutional fine-tuning of LLMs with limited computational resources (i.e., a single 48 GB GPU workstation within the hospital). The fine-tuned LLM successfully learns radiation oncology-specific information and generates physician letters in an institution-specific style. ROUGE scores of the generated summary reports highlight the superiority of the 8B LLaMA-3 model over the 13B LLaMA-2 model. Further multidimensional physician evaluations of 10 cases reveal that, although the fine-tuned LLaMA-3 model has limited capacity to generate content beyond the provided input data, it successfully generates salutations, diagnoses and treatment histories, recommendations for further treatment, and planned schedules. Overall, clinical benefit was rated highly by the clinical experts (average score of 3.4 on a 4-point scale).DiscussionWith careful physician review and correction, automated LLM-based physician letter generation has significant practical value.

Summary: We hypothesized that the heterogeneous architecture of biological neural networks provides a substrate to regulate the well-known tradeoff between robustness and efficiency, thereby allowing different subpopulations of the same network to optimize for different objectives. To distinguish between subpopulations, we developed a metric based on the mathematical theory of simplicial complexes that captures the complexity of their connectivity by contrasting its higher-order structure to a random control and confirmed its relevance in several openly available connectomes. Using a biologically detailed cortical model and an electron microscopic dataset, we showed that subpopulations with low simplicial complexity exhibit efficient activity. Conversely, subpopulations of high simplicial complexity play a supporting role in boosting the reliability of the network as a whole, softening the robustness-efficiency tradeoff. Crucially, we found that both types of subpopulations can and do coexist within a single connectome in biological neural networks, due to the heterogeneity of their connectivity.

Here, we retrospectively evaluated the informational yield of 338 post-reperfusion kidney transplant biopsies (including 95 living donations) assessed according to BANFF for the histological characteristics interstitial fibrosis and tubular atrophy (IF/TA), glomerulosclerosis, arteriosclerosis, and acute tubular injury (ATI). Associations with delayed graft function (DGF) and death-censored graft survival were explored through Cox-regression analyses. The maximum follow-up time was 11.4 years, with DGF observed in 108 (32%) cases. After deceased donation there was no association between DGF and histologic parameters. Univariable Cox-regression unveiled an association of IF/TA and glomerulosclerosis with long-term death-censored graft survival (HR per 10% increase: IF/TA 1.63; 95% CI 1.17–2.28; p = 0.003; glomerulosclerosis 1.19; 95% CI 1.01–1.39; p = 0.031). In multivariable Cox regression analyses, adjusted for recognized clinical risk variables like expanded criteria donor-status, donor age, history of diabetes, and HLA-mismatches, only IF/TA maintained association over the total observation period in deceased donations and in the total cohort. Arteriosclerosis and ATI were not associated with clinical outcome after deceased donation. Especially ATI did not affect delayed graft function if only deceased donations were considered. Our data underlines the role of organ quality for transplant outcome prior to acute lesions such as ATI during the transplantation process.

Objective Secondary sclerosing cholangitis (SSC) represents a disease with a poor prognosis increasingly diagnosed in clinical settings. Notably, SSC in critically ill patients (SSC-CIP) is the most frequent cause. Variables associated with worse prognosis remain unclear. The primary aim of this study was to identify factors associated with transplant-free survival in SSC-CIP patients using readily available data.Methods A cohort of 47 patients diagnosed with SSC-CIP was retrospectively analysed for clinical, biochemical and endoscopic variables. Kaplan-Meier survival curves, log-rank tests and univariate Cox proportional hazards models were used to assess associations with transplant-free survival. A multivariable Cox regression model was constructed using Lasso regularisation and validated with Bootstrap resampling. Model performance was assessed using the C-statistic for discrimination.Results Kaplan-Meier analysis identified bile duct obstruction requiring stent placement, and cholangitis episodes, as significant prognostic factors. In univariable analysis, age over 47 years (HR 2.61 (95% CI 1.02, 7.06), p=0.04), at least one cholangitis episode (HR 2.46 (95% CI 1.005, 6.06), p=0.04), stent placement (HR 2.89 (95% CI 1.13, 7.38), p=0.03), lower albumin levels (HR 0.52 (95% CI 0.28, 0.97), p=0.04) and higher international normalised ratio (INR) (HR 3.22 (95% CI 1.09, 9.53), p=0.03) were significant. Multivariable analysis showed that age at diagnosis, albumin and INR were significant independent predictors. The C-index was 0.78 (95% CI 0.65, 0.91), surpassing the model of end-stage liver disease score’s prognostic accuracy (Concordance Index at 3 years: 66.2% vs 74.9%).Conclusion These findings provide valuable insights for establishing standard exception criteria for this rare liver disease, which could lead to improved organ allocation. Further prospective multicentre studies are necessary to validate our findings.

IntroductionSerum levels of interleukin-6 (IL-6) are increased in COVID-19 patients. IL-6 is an effective therapeutic target in inflammatory diseases and tocilizumab, a monoclonal antibody that blocks signaling via the IL-6 receptor (IL-6R), is used to treat patients with severe COVID-19. However, the IL-6R exists in membrane-bound and soluble forms (sIL-6R), and the sIL-6R in combination with soluble glycoprotein 130 (sgp130) forms an IL-6-neutralizing buffer system capable of neutralizing small amounts of IL-6.MethodsIn this study, we analyzed serum levels of IL-6, sIL-6R and sgp130 in the serum of COVID-19 convalescent individuals with a history of mild COVID-19 disease and in acute severely ill COVID-19 patients compared to uninfected control subjects. Furthermore, we used single cell RNA sequencing data in order to determine which immune cell types are sources and targets of the individual cytokines and whether their expression is altered in severe COVID-19 patients.ResultsWe find that sIL-6R levels are not only increased in acute severely ill patients, but also in convalescents after a mild COVID-19 infection. We show that this increase in sIL-6R results in an enhanced capacity of the sIL-6R/sgp130 buffer system, but that significantly enhanced free IL-6 is still present due to an overload of the buffer. Further, we identify IL-6 serum levels, age and the number of known pre-existing medical conditions as crucial determinants of disease outcome for the patients. We also show that IL-11 has no major systemic role in COVID-19 patients and that sCD25 is only increased in acute severely ill COVID-19 patients, but not in mild convalescent individuals.DiscussionIn conclusion, our study shows long-lasting alterations of the IL-6 system after COVID-19 disease, which might be relevant when applying anti-IL-6 or anti-IL-6R therapy.

The risk of national food supply disruptions is linked to both domestic production and food imports. But assessments of climate change risks for food systems typically focus on the impacts on domestic production, ignoring climate impacts in supplying regions. Here, we use global crop modeling data in combination with current trade flows to evaluate potential climate change impacts on national food supply, comparing impacts on domestic production alone (domestic production impacts) to impacts considering how climate change impacts production in all source regions (consumption impact). Under 2°C additional global mean warming over present day, our analysis highlights that climate impacts on national supply are aggravated for 53% high income and 56% upper medium income countries and mitigated for 60% low- and 71% low-medium income countries under consumption-based impacts compared to domestic impacts alone. We find that many countries are reliant on a few mega-exporters who mediate these climate impacts. Managing the risk of climate change for national food security requires a global perspective, considering not only how national production is affected, but also how climate change affects trading partners.

BackgroundWith the help of superparamagnetic iron oxide nanoparticles (SPIONs), cells can be magnetically directed so that they can be accumulated at target sites. This principle can be used to make monocytes magnetically steerable in order to improve tumor accumulation, e.g., for immunotherapy with chimeric antigen receptor (CAR) monocytes. Here, we investigated the loading of monocytic THP-1 cells with SPIONs, analyzed their impact on the viability and cellular reactive oxygen species (ROS) generation and their magnetic enrichment. Finally, we compared and confirmed the experimentally generated magnetic enrichment data with computational simulations.Methods and resultsWhen THP-1 cells were incubated with citrate-coated SPIONs (SPIONCitrate) or citrate-stabilized gold-coated SPIONs (SPIONGold), cells ingested the particles, as determined via transmission electron microscopy and atomic emission spectroscopy. Flow cytometry showed that the particles were biocompatible and produced hardly any ROS. With SPION-loading, cells accumulated in Ibidi flow slides at the edge of a Neodym magnet, where the magnetic field and force were maximal, as calculated by our computational model.ConclusionTHP-1 cells were successfully loaded with SPIONs, which exhibited excellent biocompatibility and provided the cells with magnetic steerability. The computational model predicted the actual magnetic accumulation of the SPION-loaded cells, enabling a more systematic and faster exploration of the design space in the future.

This study integrates political socialization theory and behavioral genetics to disentangle the mechanisms underlying differences in the intergenerational transmission of voter turnout in majority and immigrant families. The pathways shaping the intergenerational transmission of electoral participation are examined through variations in political exposure within families, offspring’s social engagement in the host country, and the socioeconomic status of the family. We base our analysis on data from the German TwinLife study, comparing majority adolescents with first-generation, second-generation and 2.5th generation immigrants using a genetically sensitive multilevel research design. Focusing on electoral participation, we find that within-family transmission is disrupted for second-generation and 2.5-generation immigrants, whereas there is no difference between native citizens and first-generation immigrants. Taken together, within-family political exposure, social engagement and socioeconomic status only weakly explain the observed gap in intergenerational transmission.