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Abstract How stress affects functional hemispheric asymmetries is relevant because stress represents a risk factor for the development of mental disorders and various mental disorders are associated with atypical lateralization. Using three lateralization tasks, we investigated whether functional hemispheric asymmetries in the form of hemispheric dominance for language (verbal dichotic listening task), emotion processing (emotional dichotic listening task), and visuo-spatial attention (line bisection task) were affected by acute stress in healthy adults. One hundred twenty right-handed men and women performed these lateralization tasks in randomized order after exposure to a mild online stressor (i.e., an online variant of the Trier Social Stress Test (TSST), TSST-OL) and a non-stressful online control task (friendly TSST-OL, fTSST-OL) in a within-subjects design. Importantly, the verbal and the emotional dichotic listening tasks were presented online whereas the line bisection task was completed in paper–pencil form. During these tasks, we found the expected hemispheric asymmetries, indicating that online versions of both the verbal and the emotional dichotic listening task can be used to measure functional hemispheric asymmetries in language and emotion processing remotely. Even though subjective and physiological markers confirmed the success of the online stress manipulation, replicating previous studies, we found no stress-induced effect on functional hemispheric asymmetries. Thus, in healthy participants, functional hemispheric asymmetries do not seem to change flexibly in response to acute stress.

We question the validity of standard measures of gender ideology. When asked about “men” and "women" in general, respondents may imagine women (men) with lower (higher) labor market resources. Therefore, standard measures may conflate gender ideologies (injunctive norms) with stereotypical beliefs (descriptive norms). We test this hypothesis with an experiment in the German family panel pairfam: ∼1,200 respondents rated the appropriate division of housework in ∼3,700 hypothetical couples. By gradually adding information about labor market resources, we were able to override respondents' stereotypical beliefs. We find that with more information, even "traditional" respondents support egalitarian housework arrangements. The main difference between "traditional" and "egalitarian" respondents is not in their ideologies (as previously thought), but in their interpretation of vague items. This leads us to conclude that standard measures overestimate traditional gender ideologies. Our study also illustrates how varying the amount of information can help identify respondents' implicit beliefs.

For a long time, the family of receptor tyrosine kinases, including epidermal growth factor receptor and insulin-like growth factor 1 receptor, was regarded as the main players stimulating cell proliferative signaling. Today, it is increasingly clear that many G protein-coupled receptors (GPCRs) are also involved in controlling the hallmarks of cancer by activating diverse intracellular signaling networks. GPCRs can therefore be considered as promising drug targets for fighting against diverse types of human malignancies. Although plant polyphenols, flavonoids, are well known for their diverse anticancer effects inhibiting the growth, proliferation, migration, and invasion of malignant cells, involvement of GPCRs in these activities has still remained largely unelucidated. Therefore, in this review article, the current knowledge about the role of GPCRs in anticancer action of structurally varied flavonoids is compiled, highlighting the ability of these natural polyphenols to modulate the expression levels of GPCRs but also suppress the action of endogenous ligands and downstream tumor-promoting events. These data show that targeting the respective GPCRs by specific flavonoids may open new perspectives in the therapeutic intervention in human malignancies.

Abstract Background We evaluated the role of dual-energy computed tomography (DECT)-based collagen maps in assessing thoracic disc degeneration. Methods We performed a retrospective analysis of patients who underwent DECT and magnetic resonance imaging (MRI) of the thoracic spine within a 2-week period from July 2019 to October 2022. Thoracic disc degeneration was classified by three blinded radiologists into three Pfirrmann categories: no/mild (grade 1–2), moderate (grade 3–4), and severe (grade 5). The DECT performance was determined using MRI as a reference standard. Interreader reliability was assessed using intraclass correlation coefficient (ICC). Five-point Likert scales were used to assess diagnostic confidence and image quality. Results In total, 612 intervertebral discs across 51 patients aged 68 ± 16 years (mean ± standard deviation), 28 males and 23 females, were assessed. MRI revealed 135 no/mildly degenerated discs (22.1%), 470 moderately degenerated discs (76.8%), and 7 severely degenerated discs (1.1%). DECT collagen maps achieved an overall accuracy of 1,483/1,838 (80.8%) for thoracic disc degeneration. Overall recall (sensitivity) was 331/405 (81.7%) for detecting no/mild degeneration, 1,134/1,410 (80.4%) for moderate degeneration, and 18/21 (85.7%) for severe degeneration. Interrater agreement was good (ICC = 0.89). Assessment of DECT-based collagen maps demonstrated high diagnostic confidence (median 4; interquartile range 3–4) and good image quality (median 4; interquartile range 4–4). Conclusion DECT showed an overall 81% accuracy for disc degeneration by visualizing differences in the collagen content of thoracic discs. Relevance statement Utilizing DECT-based collagen maps to distinguish various stages of thoracic disc degeneration could be clinically relevant for early detection of disc-related conditions. This approach may be particularly beneficial when MRI is contraindicated. Key Points A total of 612 intervertebral discs across 51 patients were retrospectively assessed with DECT, using MRI as a reference standard. DECT-based collagen maps allowed thoracic disc degeneration assessment achieving an overall 81% accuracy with good interrater agreement (ICC = 0.89). DECT-based collagen maps could be a good alternative in the case of contraindications to MRI. Graphical Abstract

Abstract In this article the authors offer their perspective on the changes in the Dutch harm reduction field. From the 1970s to the 1990s, the Netherlands emerged as a leader in harm reduction services, driven by grassroots movements like the Medisch-sociale Dienst Heroïne Gebruikers (MDHG) (Medisch-sociale Dienst Heroïne Gebruikers (MDHG) translates to Medical-Social Service Heroin Users in English) in Amsterdam and Junkiebond in Rotterdam. These organisations advocated for health-centred policies, initiated needle exchange programmes, and created safe consumption spaces. Their efforts led to significant public health improvements and policy shifts towards harm reduction, reducing HIV and hepatitis rates among people who use drugs. By the 1980s, harm reduction became institutionalised within local health and social care systems, leading to notable declines in drug-related harm and crime. However, from the 2000s, a shift towards security and crime prevention emerged, influenced by socio-political changes. Increased criminal justice measures and budget cuts for harm reduction services strained the system, making it harder to address emerging drug trends and the complex needs of people who use drugs. Despite challenges, there is renewed momentum for reform, particularly at the local level, advocating for the responsible regulation of psychoactive substances. Amsterdam Mayor Femke Halsema's 2024 conference on drug regulation exemplifies this shift, calling for policies that address prohibition failures and centre harm reduction. International bodies like the UN High Commissioner for Human Rights support this approach, emphasising a health and rights-based framework. As the Netherlands navigates these evolving dynamics, there is a pressing need to reinvest in harm reduction infrastructure, ensuring it meets diverse community needs and reaffirms its foundational rights-affirming principles.

Abstract The significant advances in the differentiation of human pluripotent stem (hPS) cells into pancreatic endocrine cells, including functional β-cells, have been based on a detailed understanding of the underlying developmental mechanisms. However, the final differentiation steps, leading from endocrine progenitors to mono-hormonal and mature pancreatic endocrine cells, remain to be fully understood and this is reflected in the remaining shortcomings of the hPS cell-derived islet cells (SC-islet cells), which include a lack of β-cell maturation and variability among different cell lines. Additional signals and modifications of the final differentiation steps will have to be assessed in a combinatorial manner to address the remaining issues and appropriate reporter lines would be useful in this undertaking. Here we report the generation and functional validation of hPS cell reporter lines that can monitor the generation of INS+ and GCG+ cells and their resolution into mono-hormonal cells (INS eGFP , INS eGFP /GCG mCHERRY ) as well as β-cell maturation (INS eGFP /MAFA mCHERRY ) and function (INS GCaMP6 ). The reporter hPS cell lines maintained strong and widespread expression of pluripotency markers and differentiated efficiently into definitive endoderm and pancreatic progenitor (PP) cells. PP cells from all lines differentiated efficiently into islet cell clusters that robustly expressed the corresponding reporters and contained glucose-responsive, insulin-producing cells. To demonstrate the applicability of these hPS cell reporter lines in a high-content live imaging approach for the identification of optimal differentiation conditions, we adapted our differentiation procedure to generate SC-islet clusters in microwells. This allowed the live confocal imaging of multiple SC-islets for a single condition and, using this approach, we found that the use of the N21 supplement in the last stage of the differentiation increased the number of monohormonal β-cells without affecting the number of α-cells in the SC-islets. The hPS cell reporter lines and the high-content live imaging approach described here will enable the efficient assessment of multiple conditions for the optimal differentiation and maturation of SC-islets.

Abstract Within the brain, the connections between neurons are constantly changing in response to environmental stimuli. A prime environmental regulator of neuronal activity is diet, and previous work has highlighted changes in hypothalamic connections in response to diets high in dietary fat and elevated sucrose. We sought to determine if the change in hypothalamic neuronal connections was driven primarily by an elevation in dietary fat alone. Analysis was performed in both male and female animals. We measured Agouti-related peptide (AgRP) neuropeptide and Synaptophysin markers in the paraventricular nucleus of the hypothalamus (PVH) in response to an acute 48 h high fat diet challenge. Using two image analysis methods described in previous studies, an effect of a high fat diet on AgRP neuronal projections in the PVH of male or female mice was not identified. These results suggest that it may not be dietary fat alone that is responsible for the previously published alterations in hypothalamic connections. Future work should focus on deciphering the role of individual macronutrients on neuroanatomical and functional changes.

Abstract Background Medical text, as part of an electronic health record, is an essential information source in healthcare. Although natural language processing (NLP) techniques for medical text are developing fast, successful transfer into clinical practice has been rare. Especially the hospital domain offers great potential while facing several challenges including many documents per patient, multiple departments and complex interrelated processes. Methods In this work, we survey relevant literature to identify and classify approaches which exploit NLP in the clinical context. Our contribution involves a systematic mapping of related research onto a prototypical patient journey in the hospital, along which medical documents are created, processed and consumed by hospital staff and patients themselves. Specifically, we reviewed which dataset types, dataset languages, model architectures and tasks are researched in current clinical NLP research. Additionally, we extract and analyze major obstacles during development and implementation. We discuss options to address them and argue for a focus on bias mitigation and model explainability. Results While a patient’s hospital journey produces a significant amount of structured and unstructured documents, certain steps and documents receive more research attention than others. Diagnosis, Admission and Discharge are clinical patient steps that are researched often across the surveyed paper. In contrast, our findings reveal significant under-researched areas such as Treatment, Billing, After Care, and Smart Home. Leveraging NLP in these stages can greatly enhance clinical decision-making and patient outcomes. Additionally, clinical NLP models are mostly based on radiology reports, discharge letters and admission notes, even though we have shown that many other documents are produced throughout the patient journey. There is a significant opportunity in analyzing a wider range of medical documents produced throughout the patient journey to improve the applicability and impact of NLP in healthcare. Conclusions Our findings suggest that there is a significant opportunity to leverage NLP approaches to advance clinical decision-making systems, as there remains a considerable understudied potential for the analysis of patient journey data.

In Deutschland stellt Mehrsprachigkeit keine Ausnahme dar. Dennoch bestehen hartnäckige Vorurteile, beispielsweise, dass mehrsprachige Kinder keine ihrer Sprachen „richtig“ beherrschen (doppelte Halbsprachigkeit) und dass die mit dem Migrationshintergrund vermeintlich verbundenen schlechten Deutschkenntnisse zu schlechten Schulleistungen führen. So werden Schü–ler:innen mit Migrationshintergrund ohne weitere Differenzierung in den PISA-Studien stygmatisiert. In diesem Beitrag wird belegt, dass Mehr–sprachigkeit Vorteile für den Schriftspracherwerb mit sich bringt und dass die Gleichsetzung von Mehrsprachigkeit und Migrationshintergrund nicht haltbar ist. Es wird für einen aktiven und wertschätzenden Gebrauch sowie Förderung der Mehrsprachigkeit in der schulischen Vermittlung von Lese- und Schreibkompetenzen plädiert.

Abstract Theories of embodied cognition suggest that a shared environment and ongoing sensorimotor interaction are central for interpersonal learning and engagement. To investigate the embodied, distributed and hence dynamically unfolding nature of social cognitive capacities, we present a novel laboratory-based coordination task: the BallGame. Our paradigm requires continuous sensing and acting between two players who jointly steer a virtual ball around obstacles towards as many targets as possible. By analysing highly resolved measures of movement coordination and gaming behaviour, game-concurrent experience ratings, semi-structured interviews, and personality questionnaires, we reveal contributions from different levels of observation on social experience. In particular, successful coordination (number of targets collected) and intermittent periods of high versus low movement coordination (variability of relation) emerged as prominent predictors of social experience. Importantly, having the same (but incomplete) view on the game environment strengthened interpersonal coordination, whereas complementary views enhanced engagement and tended to generate more complex interactive behaviour. Overall, we find evidence for a critical balance between similarity and synchrony on the one hand, and variability and difference on the other, for successful engagement in social interactions. Finally, following participant reports, we highlight how interpersonal experience emerges from specific histories of coordination that are closely related to the interaction context in both space and time.

Abstract Background Physiologically based kinetic models facilitate the safety assessment of inhaled engineered nanomaterials (ENMs). To develop these models, high quality datasets on well-characterized ENMs are needed. However, there are at present, several data gaps in the systemic availability of poorly soluble particles after inhalation. The aim of the present study was therefore to acquire two comparable datasets to parametrize a physiologically-based kinetic model. Method Rats were exposed to cerium dioxide (CeO2, 28.4 ± 10.4 nm) and titanium dioxide (TiO2, 21.6 ± 1.5 nm) ENMs in a single nose-only exposure to 20 mg/m3 or a repeated exposure of 2 × 5 days to 5 mg/m3. Different dose levels were obtained by varying the exposure time for 30 min, 2 or 6 h per day. The content of cerium or titanium in three compartments of the lung (tissue, epithelial lining fluid and freely moving cells), mediastinal lymph nodes, liver, spleen, kidney, blood and excreta was measured by Inductively Coupled Plasma-Mass Spectrometry (ICP-MS) at various time points post-exposure. As biodistribution is best studied at sub-toxic dose levels, lactate dehydrogenase (LDH), total protein, total cell numbers and differential cell counts were determined in bronchoalveolar lavage fluid (BALF). Results Although similar lung deposited doses were obtained for both materials, exposure to CeO2 induced persistent inflammation indicated by neutrophil granulocytes influx and exhibited an increased lung elimination half-time, while exposure to TiO2 did not. The lavaged lung tissue contained the highest metal concentration compared to the lavage fluid and cells in the lavage fluid for both materials. Increased cerium concentrations above control levels in secondary organs such as lymph nodes, liver, spleen, kidney, urine and faeces were detected, while for titanium this was found in lymph nodes and liver after repeated exposure and in blood and faeces after a single exposure. Conclusion: We have provided insight in the distribution kinetics of these two ENMs based on experimental data and modelling. The study design allows extrapolation at different dose-levels and study durations. Despite equal dose levels of both ENMs, we observed different distribution patterns, that, in part may be explained by subtle differences in biological responses in the lung.

Abstract Background Ethical competence is a key competence in nursing and the development of the competence is a central part in nursing education. During clinical studies, nursing students face ethical problems that require them to apply and develop their ethical knowledge and skills. Little is known about how ethical competence evolves during students’ initial clinical placements. This study explored the development of ethical competence in first-year nursing students during their first clinical placements in nursing homes. Methods This exploratory-descriptive qualitative study used focus group interviews to collect data and a phenomenological hermeneutical method for analysis. Twenty-eight first-year nursing students participated in six focus groups. The data were collected between March and April 2024 at Oslo Metropolitan University in Norway. Results The naïve reading of the data involved an awareness of the students applying their prior knowledge, modifying their prior knowledge and developing skills that allowed them to manoeuvre ethical practices that, in some cases, appeared excellent and, in other cases, grim. The structural analysis identified three themes: (i) ethical competence forges in practice, (ii) ethical competence evolves at the intersection of knowledge and skills and (iii) ethical competence unfolds through meaningful discussions. A comprehensive understanding of the data was formulated as ‘Being on a journey towards ethical competence’. This presents a metaphor illustrating that nursing students embark on a journey towards ethical competence; from their point of departure, their clinical experiences forge the essential waypoints along their path, knowledge and skills fuelling their navigation in rugged terrain towards their destination. Conclusions Nursing students’ ethical competence evolved in intricate ways during their initial clinical period. Being informed bystanders or participants in the care of nursing home residents in situations of ethical tension may be a unique position enabling students to evaluate care options differently from those immersed in the ward culture. The findings indicate that organised professional development in nursing homes needs to focus on more reflexively driven ways of supervising students in their first clinical study period. Educational institutions need to continue and further develop reflection-based learning activities and meeting points with students and their peers during their clinical placement periods.

Abstract Background Meta-analyses indicate a high prevalence of burnout among medical students. Although studies have investigated different coping strategies and health interventions to prevent burnout, professional experience’s influence on burnout resilience as seldom been explored. Therefore, in our study we aimed to examine the self-efficacy’s mediating role in the relationship between past vocational training and burnout resilience. In the process, we also analysed the associations between study-related variables and burnout resilience. Methods In our cross-sectional study, we analysed the data of 2217 medical students at different stages of their university education (i.e. 1st, 3rd, 6th, 10th semester, and final year) at five medical faculties in Germany. The questionnaire included items addressing variables related to medical school, previous professional and academic qualifications, and validated instruments for measuring burnout and self-efficacy. Results The overall prevalence of burnout was 19.7%, as defined by high scores for emotional exhaustion and notable values in at least one of the other two dimensions (cynicism or academic efficacy). Higher levels for self-efficacy (p

Abstract Recent work on flux compactifications suggests that the tadpole constraint generically allows only a limited number of complex structure moduli to become massive, i.e., be stabilized at quadratic order in the spacetime superpotential. We study the effects of higher-order terms systematically around the Fermat point in the 19 Landau-Ginzburg model. This model lives at strong coupling and features no Kähler moduli. We show that indeed massless fields can be stabilized in this fashion. We observe that, depending on the flux, this mechanism is more effective when the number of initially massless fields is large. These findings are compatible with both the tadpole conjecture and the massless Minkowski conjecture. Along the way, we complete the classification of integral flux vectors with small tadpole contribution. Thereby we are closing in on a future complete understanding of all possible flux configurations in the 19 Landau-Ginzburg model.

The cellular response to oxidants or xenobiotics comprises two key pathways, resulting in modulation of NRF2 and FOXO transcription factors, respectively. Both mount a cytoprotective response, and their activation relies on crucial protein thiol moieties. Using fumaric acid esters (FAEs), known thiol‐reactive compounds, we tested for activation of NRF2 and FOXO pathways in cultured human hepatoma cells by dimethyl/diethyl as well as monomethyl/monoethyl fumarate. Whereas only the diesters caused acute glutathione depletion and activation of the stress kinase p38MAPK, all four FAEs stimulated NRF2 stabilization and upregulation of NRF2 target genes. However, no significant FAE‐induced activation of FOXO‐dependent target gene expression was observed. Therefore, while both NRF2 and FOXO pathways are responsive to oxidants and xenobiotics, FAEs selectively activate NRF2 signaling.

Abstract Objective Perineuronal nets (PNN) are specialized extracellular matrix (ECM) components of the central nervous system, frequently accumulating at the surface of inhibitory GABAergic interneurons. While an altered distribution of PNN has been observed in neurological disorders including Alzheimer's disease, schizophrenia and epilepsy, their anatomical distribution also changes during physiological brain maturation and aging. Such an age‐dependent shift was experimentally associated also with hippocampal engram formation during brain maturation. Our aim was to histopathologically assess PNN in the hippocampus of adult and pediatric patients with temporal lobe epilepsy (TLE) compared to age‐matched post‐mortem control subjects and to compare PNN‐related changes with memory impairment observed in our patient cohort. Methods Sixty‐six formalin‐fixed and paraffin‐embedded tissue specimens of the human hippocampus were retrieved from the European Epilepsy Brain Bank. Twenty‐nine patients had histopathologically confirmed hippocampal sclerosis (HS), and eleven patients suffered from TLE without HS. PNN were immunohistochemically visualized using an antibody directed against aggrecan and manually counted from hippocampus subfields and the subiculum. Results PNN density increased with age in both human controls and TLE patients. However, their density was significantly higher in all HS patients compared to age‐matched controls. Intriguingly, TLE patients presented presurgically with better memory when their hippocampal PNN density was higher (p

Abstract Background Imprinting disorders are rare diseases resulting from altered expression of imprinted genes, which exhibit parent-of-origin-specific expression patterns regulated through differential DNA methylation. A subgroup of patients with imprinting disorders have DNA methylation changes at multiple imprinted loci, a condition referred to as multi-locus imprinting disturbance (MLID). MLID is recognised in most but not all imprinting disorders and is also found in individuals with atypical clinical features; the presence of MLID often alters the management or prognosis of the affected person. Some cases of MLID are caused by trans-acting genetic variants, frequently not in the patients but their mothers, which have counselling implications. There is currently no consensus on the definition of MLID, clinical indications prompting testing, molecular procedures and methods for epigenetic and genetic diagnosis, recommendations for laboratory reporting, considerations for counselling, and implications for prognosis and management. The purpose of this study is thus to cover this unmet need. Methods A comprehensive literature search was conducted resulting in identification of more than 100 articles which formed the basis of discussions by two working groups focusing on clinical diagnosis (n = 12 members) and molecular testing (n = 19 members). Following eight months of preparations and regular online discussions, the experts from 11 countries compiled the preliminary documentation and determined the questions to be addressed during a face-to-face meeting which was held with the attendance of the experts together with four representatives of patient advocacy organisations. Results In light of available evidence and expert consensus, we formulated 16 propositions and 8 recommendations as interim guidance for the clinical and molecular diagnosis of MLID. Conclusions MLID is a molecular designation, and for patients with MLID and atypical phenotypes, we propose the alternative term multi-locus imprinting syndrome. Due to the intrinsic variability of MLID, the guidelines underscore the importance of involving experts from various fields to ensure a confident approach to diagnosis, counselling, and care. The authors advocate for global, collaborative efforts in both basic and translational research to tackle numerous crucial questions that currently lack answers, and suggest reconvening within the next 3–5 years to evaluate the research advancements and update this guidance as needed.

Abstract Evolutionary transitions in individuality are events in the history of life leading to the emergence of new levels of individuality. Recent studies have described an ecological scaffolding scenario of such transitions focused on the evolutionary consequences of an externally imposed renewing meta-population structure with limited dispersal. One difficulty for such a scenario has been explaining the stability of collective-level traits when scaffolding conditions no longer apply. Here, we show that the stability of scaffolded traits can rely on evolutionary hysteresis: even if the environment is reverted to an ancestral state, collectives do not return to ancestral phenotypes. We describe this phenomenon using a stochastic meta-population model and adaptive dynamics. Further, we show that ecological scaffolding may be limited to Goldilocks zones of the environment. We conjecture that Goldilocks zones—even if they might be rare—could act as initiators of evolutionary transitions and help to explain the near ubiquity of collective-level individuality.

Abstract Background Self-reported health is a widely used health indicator in surveys and questionnaires. The measure gained attention when research identified its association with mortality in the 1970s and 1980s. The measure is also associated with morbidity and other health outcomes such as the utilisation of health services. Self-reported health is a particularly useful measure for young people because this age group is generally clinically healthy. However, it is known that many chronic conditions have long latency periods that are initiated early in life. Because of its predictive nature, self-reported health can be used to estimate young people’s current and future health. Despite its widespread use, however, self-reported health remains a poorly understood concept. This paper presents the protocol for a systematic review that will identify and synthesise qualitative studies that investigate the factors that are considered by young people when they assess their health, and when they talk about health overall. Methods The population of the review is young people aged 10–24 years, with or without health conditions. We will search the databases of MEDLINE (Ovid®), PsycINFO (APA PsycNet), ProQuest Sociology Collection, and Web of Science Core Collection™. We will also utilise techniques of reference checking and forward citation searching, as this strategy has been shown to result in a higher number of high-quality studies in social science systematic reviews. Google Scholar and Google Search were used during preliminary searches; Google Scholar will be utilised for forward citation searching. We will include studies written in English, German, or Finnish; there will be no lower date limit. One reviewer will screen all citations. A second reviewer will independently screen a sample of 20% of the abstracts. Data will be extracted by one researcher, two other researchers will independently review all data extracted, and quality appraisal will be completed by the first reviewer. We will utilise the Quality Framework for the appraisal of included articles and thematic synthesis of qualitative studies. Discussion The results of this systematic review will improve the understanding of the factors that are considered during the self-assessments of health; this will improve the interpretation of the results of quantitative research. Also, an improved understanding of the conceptualisation of health will inform the development of health policies and interventions that support young people’s health. Systematic review registration PROSPERO CRD42022367519.

Abstract Background Cluster headache is characterized by activation of the trigeminovascular pathway with subsequent pain signalling in the meningeal vessels, and inflammation has been suggested to play a role in the pathophysiology. To further investigate inflammation in cluster headache, inflammatory markers were analysed in patients with cluster headache and controls. Methods We performed a case–control study, collecting cerebrospinal fluid and serum samples from healthy controls, cluster headache patients in remission, active bout, and during an attack to cover the dynamic range of the cluster headache phenotype. Inflammatory markers were quantified using Target 48 OLINK cytokine panels. Results Altered levels of several cytokines were found in patients with cluster headache compared to controls. CCL8, CCL13, CCL11, CXCL10, CXCL11, HGF, MMP1, TNFSF10 and TNFSF12 levels in cerebrospinal fluid were comparable in active bout and remission, though significantly higher than in controls. In serum samples, CCL11 and CXCL11 displayed decreased levels in patients. Only one cytokine, IL-13 was differentially expressed in serum during attacks. Conclusion and interpretation Our data shows signs of possible neuroinflammation occurring in biological samples from cluster headache patients. Increased cerebrospinal fluid cytokine levels are detectable in active bout and during remission, indicating neuroinflammation could be considered a marker for cluster headache and is unrelated to the different phases of the disorder.

Abstract Phenotypic heterogeneity in bacteria can result from stochastic processes or deterministic programs. The deterministic programs often involve the versatile second messenger c-di-GMP, and give rise to daughter cells with different c-di-GMP levels by deploying c-di-GMP metabolizing enzymes asymmetrically during cell division. By contrast, less is known about how phenotypic heterogeneity is kept to a minimum. Here, we identify a deterministic c-di-GMP-dependent program that is hardwired into the cell cycle of Myxococcus xanthus to minimize phenotypic heterogeneity and guarantee the formation of phenotypically similar daughter cells during division. Cells lacking the diguanylate cyclase DmxA have an aberrant motility behaviour. DmxA is recruited to the cell division site and its activity is switched on during cytokinesis, resulting in a transient increase in the c-di-GMP concentration. During cytokinesis, this c-di-GMP burst ensures the symmetric incorporation and allocation of structural motility proteins and motility regulators at the new cell poles of the two daughters, thereby generating phenotypically similar daughters with correct motility behaviours. Thus, our findings suggest a general c-di-GMP-dependent mechanism for minimizing phenotypic heterogeneity, and demonstrate that bacteria can ensure the formation of dissimilar or similar daughter cells by deploying c-di-GMP metabolizing enzymes to distinct subcellular locations.

Global climate change threatens ecosystem functioning worldwide. Forest ecosystems are particularly important for carbon sequestration, thereby buffering climate change and providing socio-economic services. However, recurrent stresses, such as heat waves, droughts and floods can affect forests with potential cascading effects on their carbon sink capacity, drought resilience and sustainability. Knowledge about the stress impact on the multitude of processes driving soil-plant-atmosphere interactions within these complex forest systems is widely lacking and uncertainty about future changes extremely high. Thus, forecasting forest response to climate change will require a dramatically improved process understanding of carbon and water cycling across various temporal (minutes to seasons) and spatial (leaf to ecosystem) scales covering atmosphere, biosphere, pedosphere and hydrosphere components.Many relevant processes controlling carbon and water exchange occur at small scales (e.g. rhizosphere, single leaf) with a high spatial and temporal variability, which is poorly constrained. However, interactions and feedback loops can be key players that amplify or dampen a system’s response to stress. Moreover, spatial and temporal scaling rules for these non-linear processes in structurally and functionally diverse ecosystems are unknown. Legacy effects, for example, altered response after previous stress and retarded recovery of forests after climate extremes, are not captured in state-of-the-art models. Currently, we are lacking the appropriate and interconnected measurement, data assimilation and modelling tools allowing for a comprehensive, real-time quantification of key processes at high spatio-temporal coverage in heterogeneous environments. Moreover, since climate impacts are highly unpredictable with respect to timing and location, future research will require novel mobile, easily deployable and cost-efficient approaches. ECOSENSE, therefore, assembles expertise from environmental and engineering sciences, both being excellently paired at the University of Freiburg.Our interdisciplinary research project will investigate all relevant scales in a next-generation ecosystem research assessment (ECOSENSE). Our vision is to detect and forecast critical changes in ecosystem functioning, based on the understanding of hierarchical process interaction. In the first phase, ECOSENSE will explore these process interactions by investigating pools and fluxes of water and carbon, i.e. CO2 exchange, isotope discrimination and volatile organic compounds (VOC), as well as stress indicators by remotely and in situ sensed chlorophyll fluorescence.To address these research tasks, ECOSENSE will develop, implement and test a distributed, autonomous, intelligent sensor network, based on novel microsensors tailored to the specific needs in remote and harsh forest environments. They will measure the spatio-temporal dynamics of ecosystem pools and fluxes in a naturally complex structured forest system with minimal physiological impact. Measured data will be transferred in real-time into a sophisticated database, which will be explored for process analysis, conducted by Artificial Intelligence and close to real-time process-based ecosystem models for now- and forecasting applications. Thereby, ECOSENSE will: i) break new ground for integrative ecosystem research by identifying hierarchies and interactions of abiotic and physiological processes of forest carbon and water exchange, ii) provide a profound understanding of complex ecosystem responses to environmental stressors and iii) enable the prediction of process-based alterations in ecosystem functioning and sustainability.Our novel ECOSENSE toolkit, tested and validated in controlled climate extreme experiments and our ECOSENSE Forest, will open new horizons for rapid assessment in vast and remote ecosystems. Thereby, ECOSENSE will allow for a unique avenue of data acquisition and, consequently, for unprecedented scale-crossing ecosystem understanding and modelling.

Abstract Background Good timing resolution in medical imaging applications such as TOF-CT or TOF-PET can boost image quality or patient comfort significantly by reducing the influence of background noise. However, the timing resolution of state-of-the-art detectors in CT and PET are limited by their light emission process. Core-valence cross-luminescence is an alternative, but well-known compounds (e.g. BaF2) pose several problems for medical imaging applications, such as their emission wavelength in the deep UV. CsZnCl-based materials show promise to solve this issue, as they provide fast decay times of 1–2 ns and an emission wavelength around 300 nm. Results In this work, we investigated two CsZnCl-compounds: Cs2ZnCl4 and Cs3ZnCl5. We validated the previously published decay times on a time-correlated single-photon counting setup with 1.786 ± 0.016 ns for Cs2ZnCl4 and 1.034 ± 0.013 ns for Cs3ZnCl5. The setup’s high resolution enabled the discovery of an additional prompt emission component with a significant abundance of 98 ± 18 (Cs2ZnCl4) and 86 ± 14 (Cs3ZnCl5) photons/MeV energy deposit. In a PET coincidence experiment, we measured the best coincidence time resolution (CTR) of 62 ps (FWHM) for Cs2ZnCL4 coupled to FBK VUV SiPMs with silicon oil. To assess the CTR for lower energies, we filtered the energy along the Compton continuum and found a deteriorated CTR that seems to be mainly influenced by photon statistics. Furthermore, this study gave us a rough estimate of e.g. 150 ps (FWHM) CTR at 100 keV energy for Cs2ZnCL4. From measurements with high activity of 14 MBq to check for pile-up effects we assume that Cs2ZnCl4 is better suited for high-rate time-of-flight applications than lutetium-based oxides. Simulations demonstrated that the stopping power of Cs2ZnCl4 is lower than for LSO:Ce,Ca, meaning that a high amount of material would be needed for TOF-PET applications. However, the stopping power seems acceptable for applications in TOF-CT. Conclusions The fast decay time, state-of-the-art CTR in benchtop experiments and high-rate suitability make CsZnCl materials a promising candidate for time-of-flight experiments. We consider especially TOF-CT a suitable application due to its relatively low X-ray energies (~ 100 keV) and the thusly acceptable stopping power of Cs2ZnCl4. Currently, further exploration of the prompt emission and its creation mechanism is planned, as well as investigating the light transport of Cs2ZnCl4 in longer crystals.

Abstract Background In addition to several sequelae of post-COVID-19, individuals also experience significant limitations in work ability, resulting in negative consequences for the return-to-work (RTW) process. This systematic review and meta-analysis were conducted to assess the impact of post-COVID-19 on work ability and RTW of individuals previously infected with SARS-CoV-2. Methods Studies on the work ability and RTW of patients with post-COVID-19 (more than 12 weeks after an acute SARS-CoV-2 infection) were regarded eligible for inclusion. Systematic search of literature was performed up to March 2023 using five databases (MEDLINE, EMBASE, CINAHL, CENTRAL and WHO COVID 19). Study selection followed the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) Statement. A meta-analysis estimated the overall success rate of RTW. The risk of bias of the included studies was evaluated with the Newcastle Ottawa Scale (NOS). Results 19 relevant studies, published between 2021 and 2023, were included in the systematic review, involving 21.155 patients from 14 different countries. The findings indicate that a significant proportion of individuals with post-COVID-19 experience persistent symptoms and functional impairments, with fatigue being the most prominent symptom. These persistent symptoms can have a considerable (negative) impact on individuals’ physical and psychological capacity to participate in work-related activities, leading to lower work ability and increased absenteeism. The RTW for post-COVID-19 patients is complex, with approximately 60.9% of patients successfully returning to work after 12 or more weeks following SARS-CoV-2 infection. Among those who successfully returning to work, a considerable number need modifications in their work duties or hours to cope with residual impairments. Factors such as workplace accommodations, supportive policies, and occupational rehabilitation programs play a crucial role in facilitating successful RTW. Conclusions The systematic review underscores the substantial impact of post-COVID-19 on work-related outcomes. The implications of this research highlight the need for healthcare providers, employers, and policymakers to collaborate in creating inclusive work environments and implementing tailored rehabilitation programs to support individuals recovering from post-COVID-19. Further research should focus on long-term follow-up studies with mixed methods to gain a more comprehensive understanding of the long-term consequences of post-COVID-19 on work ability and RTW outcomes. PROSPERO registration number CRD42023385436.

Abstract Background Research on the effects of physical exercise on canine body composition is limited. The aim of this study was to investigate the effects of a physical exercise programme on bodyweight, body condition score (BCS) and chest, abdominal and thigh circumferences in dogs. Twenty-one healthy dogs of different breeds exercised together with their owners during an eight-week programme consisting of jogging and strength exercises. Standardised measurements were performed in triplicates with a measuring tape on standing dogs. Chest circumference was measured at three anatomical locations, abdomen at two and thigh at one. Data on bodyweight, BCS (9-point scale) and circumferences were analysed with mixed model repeated measures analyses to evaluate changes after the programme and effects of target distance. Results Seven dog owners choose a target distance of 2 km and 14 owners choose 5–10 km. Mean BCS decreased (P = 0.007) after the programme (5.1 ± 0.9 vs. 4.7 ± 0.6) but there was no effect of target distance. Almost all chest and abdominal circumference measurements decreased (P ≤ 0.007) with the 2 km group driving the reduction in chest circumference and the 5–10 km group driving the reduction in abdominal circumference. In contrast, thigh circumference (28.8 ± 0.4 vs. 30.2 ± 0.4) increased (P = 0.007) while bodyweight was maintained. There were positive correlations between BCS and abdominal/chest ratios before and after the programme (Pearson correlation; R square ≤ 0.43, P ≤ 0.0012) but the mean ratio remained constant. Conclusions Results indicated a redistribution between total body fat and muscle mass in body composition of normal weight to slightly overweight dogs after the physical exercise programme. The use of bodyweight alone was not a reliable evaluation method to complement the BCS assessment. However, repeated measurements of chest, abdominal and thigh circumference might aid in the assessment of body composition in dogs performing physical exercise. Further research should include a control group and objective evaluations of total body fat and lean mass, in order to investigate the effectiveness of physical exercise as a freestanding method for decreasing BCS and increasing muscle mass in overweight dogs.

Abstract Background The eye is a highly specialized sensory organ which encompasses the retina as a part of the central nervous system, but also non-neural compartments such as the transparent vitreous body ensuring stability of the eye globe and a clear optical axis. Hyalocytes are the tissue-resident macrophages of the vitreous body and are considered to play pivotal roles in health and diseases of the vitreoretinal interface, such as proliferative vitreoretinopathy or diabetic retinopathy. However, in contrast to other ocular macrophages, their embryonic origin as well as the extent to which these myeloid cells might be replenished by circulating monocytes remains elusive. Results In this study, we combine transgenic reporter mice, embryonic and adult fate mapping approaches as well as parabiosis experiments with multicolor immunofluorescence labeling and confocal laser-scanning microscopy to comprehensively characterize the murine hyalocyte population throughout development and in adulthood. We found that murine hyalocytes express numerous well-known myeloid cell markers, but concomitantly display a distinct immunophenotype that sets them apart from retinal microglia. Embryonic pulse labeling revealed a yolk sac-derived origin of murine hyalocytes, whose precursors seed the developing eye prenatally. Finally, postnatal labeling and parabiosis established the longevity of hyalocytes which rely on Colony Stimulating Factor 1 Receptor (CSF1R) signaling for their maintenance, independent of blood-derived monocytes. Conclusion Our study identifies hyalocytes as long-living progeny of the yolk sac hematopoiesis and highlights their role as integral members of the innate immune system of the eye. As a consequence of their longevity, immunosenescence processes may culminate in hyalocyte dysfunction, thereby contributing to the development of vitreoretinal diseases. Therefore, myeloid cell-targeted therapies that convey their effects through the modification of hyalocyte properties may represent an interesting approach to alleviate the burden imposed by diseases of the vitreoretinal interface.

Abstract Background Radiotherapy is essential in the treatment of prostate cancer. An alternative to conventional photon radiotherapy is the application of carbon ions, which provide a superior intratumoral dose distribution and less induced damage to adjacent healthy tissue. A common characteristic of prostate cancer cells is their dependence on androgens which is exploited therapeutically by androgen deprivation therapy in the advanced prostate cancer stage. Here, we aimed to analyze the transcriptomic response of prostate cancer cells to irradiation by photons in comparison to carbon ions, focusing on DNA damage, DNA repair and androgen receptor signaling. Methods Prostate cancer cell lines LNCaP (functional TP53 and androgen receptor signaling) and DU145 (dysfunctional TP53 and androgen receptor signaling) were irradiated by photons or carbon ions and the subsequent DNA damage was assessed by immuno-cytofluorescence. Furthermore, the cells were treated with an androgen-receptor agonist. The effects of irradiation and androgen treatment on the gene regulation and the transcriptome were investigated by RT-qPCR and RNA sequencing, followed by bioinformatic analysis. Results Following photon or carbon ion irradiation, both LNCaP and DU145 cells showed a dose-dependent amount of visible DNA damage that decreased over time, indicating occurring DNA repair. In terms of gene regulation, mRNAs involved in the TP53-dependent DNA damage response were significantly upregulated by photons and carbon ions in LNCaP but not in DU145 cells, which generally showed low levels of gene regulation after irradiation. Both LNCaP and DU145 cells responded to photons and carbon ions by downregulation of genes involved in DNA repair and cell cycle, partially resembling the transcriptome response to the applied androgen receptor agonist. Neither photons nor carbon ions significantly affected canonical androgen receptor-dependent gene regulation. Furthermore, certain genes that were specifically regulated by either photon or carbon ion irradiation were identified. Conclusion Photon and carbon ion irradiation showed a significant congruence in terms of induced signaling pathways and transcriptomic responses. These responses were strongly impacted by the TP53 status. Nevertheless, irradiation mode-dependent distinct gene regulations with undefined implication for radiotherapy outcome were revealed. Androgen receptor signaling and irradiations shared regulation of certain genes with respect to DNA-repair and cell-cycle.

Societal Impact Statement Forest trees tend to be strongly genetically adapted to their local environments, but climate change will probably subject trees to novel combinations of precipitation, temperature, and photoperiod. Local adaptation was investigated in the ecologically and economically important Patagonian tree species Nothofagus pumilio by characterizing its genetic diversity in relation to the varied environmental conditions across its range. These insights are useful for conservation and management decisions, for example by identifying suitable populations to establish seed source plantations for restoration and characterizing relationships with environmental drivers of selection to better understand how this species will respond to climate change. Summary Nothofagus pumilio is a foundation tree species that inhabits a 2000‐km‐long range in the southern Andes, a region with two perpendicular environmental gradients: temperature and photoperiod (North–South), and precipitation (West–East). We investigated local adaptation patterns by searching for relationships between environmental clines and signatures of adaptation in candidate genes related to stress response, growth, and phenology. Using a paired site sampling design within a landscape genome analysis, we analyzed 493 adult N. pumilio trees in 20 sampling sites across the species' latitudinal range. We screened 47,336 single nucleotide polymorphism (SNP) loci in 1632 contigs (i.e., coding regions along the genome). Population structure and genetic diversity analyses preceded four genome scan analyses using genetic and environmental data. Population structure and genetic diversity are mainly oriented along the latitude axis. Genome scans identified 445 outlier SNPs, which are loci showing signatures of selection. Temperature and photoperiod variables were associated with notably more outliers than precipitation. However, the most frequent biological functions among genes were water deprivation response and cold response, suggesting that stress response is comprised of complex and polygenic traits that are affected by many environmental variables. Our findings suggest that N. pumilio shows signatures of local adaptation to extant climate conditions, including temperature, photoperiod, and precipitation. However, climate change is likely to alter existing relationships among environmental conditions to which this species is currently adapted. These changes may have unpredictable consequences for the species' future survival, adaptation potential, and the people who depend upon these forests.

Human CD81 and CD9 are members of the tetraspanin family of proteins characterized by a canonical structure of four transmembrane domains and two extracellular loop domains. Tetraspanins are known as molecular facilitators, which assemble and organize cell surface receptors and partner molecules forming clusters known as tetraspanin-enriched microdomains. They have been implicated to play various biological roles including an involvement in infections with microbial pathogens. Here, we demonstrate an important role of CD81 for the invasion of epithelial cells by Salmonella enterica. We show that overexpression of CD81 in HepG2 cells enhances invasion of various typhoidal and non-typhoidal Salmonella serovars. Deletion of CD81 by CRISPR/Cas9 in intestinal epithelial cells (C2BBe1 and HT29-MTX-E12) reduces S. Typhimurium invasion. In addition, the effect of human CD81 is species-specific as only human but not rat CD81 facilitates Salmonella invasion. Finally, immunofluorescence microscopy and proximity ligation assay revealed that both human tetraspanins CD81 and CD9 are recruited to the entry site of S. Typhimurium during invasion but not during adhesion to the host cell surface. Overall, we demonstrate that the human tetraspanin CD81 facilitates Salmonella invasion into epithelial host cells.

BackgroundDespite the evidence of beneficial effects of physical activity (PA), people with multiple sclerosis (pwMS) are less physically active than the general population. To increase PA in pwMS, we developed a structured individually tailored PA promotion program which is conducted within clinical practice in a university-based outpatient clinic since 2016. This study serves as retrospective quality control of this program.ObjectiveIn a retrospective cohort study, we assessed the physical fitness of pwMS and the impact of the program on short- and long-term PA changes and behavioral determinants.MethodsThe program consisted of four appointments each 2–4 weeks apart. Spiroergometric test results of female pwMS were compared to female non-MS controls who underwent a voluntary physical fitness analysis. The short version of the Freiburger questionnaire, self-developed questions and the modified Physical activity screening questionnaire (PASQ) were sent to all participants assessing the PA levels before the program, 3 months after the program (short-term), and at the time of the survey (long-term). Additionally, established questionnaires assessed behavioral determinants before the program and long-term.ResultsA total of 166 participants [mean age 38.32 (± 10.61 SD), mean EDSS 2.30 (±1.29 SD)] and mostly females (63.3%, n = 105) were included in the study and started the program. A total of 136 participants completed the program. Out of these 63.9% (n = 87) answered the questionnaires in 12.38 (±11.34 SD) months after finishing the program. At baseline female pwMS (n = 100) showed a lower physical fitness in comparison to non-MS controls (n = 26) (maximal workload (Watts): 138.86 ± 37.85 vs. 191.73 ± 45.25, p

Rationale of the trial Although the use of engineered T cells in cancer immunotherapy has greatly advanced the treatment of hematological malignancies, reaching meaningful clinical responses in the treatment of solid tumors is still challenging. We investigated the safety and tolerability of IMA202 in a first-in-human, dose escalation basket trial in human leucocyte antigen A*02:01 positive patients with melanoma-associated antigen A1 (MAGEA1)-positive advanced solid tumors.Trial design The 2+2 trial design was an algorithmic design based on a maximally acceptable dose-limiting toxicity (DLT) rate of 25% and the sample size was driven by the algorithmic design with a maximum of 16 patients. IMA202 consists of autologous genetically modified cytotoxic CD8+ T cells expressing a T cell receptor (TCR), which is specific for a nine amino acid peptide derived from MAGEA1. Eligible patients underwent leukapheresis, T cells were isolated, transduced with lentiviral vector carrying MAGEA1-specific TCR and following lymphodepletion (fludarabine/cyclophosphamide), infused with a median of 1.4×109 specific T cells (range, 0.086×109–2.57×109) followed by interleukin 2.Safety of IMA202 No DLT was observed. The most common grade 3–4 adverse events were cytopenias, that is, neutropenia (81.3%), lymphopenia (75.0%), anemia (50.0%), thrombocytopenia (50.0%) and leukopenia (25.0%). 13 patients experienced cytokine release syndrome, including one grade 3 event. Immune effector cell-associated neurotoxicity syndrome was observed in two patients and was grade 1 in both.Efficacy of IMA202 Of the 16 patients dosed, 11 (68.8%) patients had stable disease (SD) as their best overall response (Response Evaluation Criteria in Solid Tumors V.1.1). Five patients had initial tumor shrinkage in target lesions and one patient with SD experienced continued shrinkage in target lesions for 3 months in total but had to be classified as progressive disease due to progressive non-target lesions. IMA202 T cells were persistent in peripheral blood for several weeks to months and were also detectable in tumor tissue. Peak persistence was higher in patients who received higher doses.Conclusion In conclusion, IMA202 had a manageable safety profile, and it was associated with biological and potential clinical activity of MAGEA1-targeting genetically engineered TCR-T cells in a poor prognosis, multi-indication solid tumor cohort.Trial registration numbers NCT04639245, NCT05430555.

The prevention and management of hypertension through healthy lifestyle modifications is a challenge for public health. The prevalence of hypertension among Indonesians was 34,1%. Lifestyle behaviors such as body mass index, central obesity, and sodium intake are associated with the risk of hypertension. This study aimed to analyze the influence of nutritional status and abdominal circumference on blood pressure in adult men. This cross-sectional research was conducted in Sukajadi Village, Bogor, between 2022-2023. The subjects were 73 purposively selected adult men. Data on subject characteristics were obtained through interviews. Anthropometric data were obtained by measuring abdominal circumference, body weight, and body height to assess the body mass index (BMI). Consumption data were collected using SQ-FFQ. The data analysis was performed using a linear regression test with a significance level of 95%. The results showed that Body mass index (p=0,007) and abdominal circumference (p=0,005) affected systolic blood pressure, while sodium intake (p=0,906) was not related to systolic blood pressure in adult men. Conclusions: Body mass index and abdominal circumference greatly influenced the systolic blood pressure. Further studies are needed to determine the various factors that influence systolic blood pressure and the risk of hypertension.

Abstract Synucleinopathies such as Parkinson’s disease (PD) are defined by the accumulation and aggregation of the α-synuclein protein in neurons, glia and other tissues. We have previously shown that destabilization of α-synuclein tetramers is associated with familial PD due to SNCA mutations and demonstrated brain-region specific alterations of α-synuclein multimers in sporadic PD patients following the classical Braak spreading theory. In this study, we assessed relative levels of disordered and higher-ordered multimeric forms of cytosolic α-synuclein in blood from familial PD with G51D mutations and sporadic PD patients. We used an adapted in vitro-cross-linking protocol for human EDTA-whole blood. The relative levels of higher-ordered α-synuclein tetramers were diminished in blood from familial PD and sporadic PD patients compared to controls. Interestingly, the relative amount of α-synuclein tetramers was already decreased in asymptomatic G51D carriers, supporting the hypothesis that α-synuclein multimer destabilization precedes the development of clinical PD. Our data, therefore suggest that measuring α-synuclein tetramers in blood may have potential as a facile biomarker assay for early detection and quantitative tracking of PD progression.

Abstract Background Soil structure is a key indicator of the functioning of soil processes in grasslands, which is influenced by site conditions and management. Methods In this study, we investigated soil structure and its relationship with root growth in 31 Leptosols under different grassland management intensities using X‐ray microcomputed tomography. A close relationship between land use intensity, soil structure, and root growth was observed. Results Our results show that land use type affects root development and soil structure. Pastures had more developed roots and more structured soils than meadows and mown pastures. However, all pastures were unfertilized, while meadows and mown pastures had both fertilized and unfertilized plots. Although no significant differences were found in the unfertilized plots, sample size was limited. In particular, fertilization negatively affected root growth and soil structure, resulting in significant differences between fertilized and unfertilized grasslands. Mowing frequency also had an effect on soil physics, but to a much lesser extent than fertilization. Conclusions Increased land use intensity, characterized by increased fertilization and more frequent mowing, reduces root growth and adversely affects soil structure. Therefore, X‐ray microcomputed tomography is a suitable method to investigate the relationship between soil structure and roots in the soil.

Gaining housing autonomy in ownership-oriented housing systems has been observed as increasingly difficult for contemporary youth, including university students. This article analyses how students make sense of their experiences in private rentals, which is assumed to shape their dispositions and capacities to act in the housing market in the future. We contribute to the conceptualisation of young people’s housing choices and aspirations by offering evidence from the understudied post-socialist context of Tallinn, Estonia. Inspired by Bourdieu’s theory of practice and combining in-depth interviews with a survey, we show how the student experience in a weakly regulated private rental market supports their selfperception as established ‘players’ in the market, while developing a distinct investmentminded disposition to housing. Furthermore, the high symbolic value of homeownership conveyed by families in a ‘super homeownership’ society has rather strengthened among students, despite restricted opportunities to market entry.

Abstract Background In symptomatic end-stage osteoarthritis of the ankle joint, total ankle replacement and ankle arthrodesis are the two primary surgical options for patients for whom conservative treatment fails. Published revision rates are often biased and difficult to compare. In this study, unplanned reoperation rates and revision rates were determined for both surgical interventions based on a large dataset, and risk factors for unplanned reoperations were identified. Methods German-wide health data of the largest German health-care insurance carrier between 2001 and 2012 were retrospectively analyzed, and unplanned reoperation rates within 10 years were determined for index surgeries conducted in 2001 and 2002. Unplanned reoperation rates within 5 years for index surgeries conducted in 2001/2002 were compared to index surgeries conducted in 2006/2007. Multivariate logistic regression was used to identify risk factors for unplanned reoperations. Results After ankle arthrodesis, 19% (95% confidence interval [CI], 16–22%) of 741 patients needed to undergo an unplanned reoperation within ten years. After total ankle replacement, the unplanned reoperation rate was 38% [95% CI, 29–48%] among 172 patients. For initial surgeries conducted at a later date, unplanned reoperation rates within five years were 21% [95% CI, 19–24%] for 1,168 ankle arthrodesis patients and 23% [95% CI, 19–28%] for 561 total ankle replacement patients. Significant risk factors for unplanned reoperations after ankle arthrodesis in the initial cohort were age

Abstract Research to improve and expand treatment options for motor impairment after stroke remains an important issue in rehabilitation as the reduced ability to move affected limbs is still a limiting factor in the selection of training content for stroke patients. The combination of action observation and peripheral nerve stimulation is a promising method for inducing increased excitability and plasticity in the primary motor cortex of healthy subjects. In addition, as reported in the literature, the use of action observation and motor imagery in conjunction has an advantage over the use of one or the other alone in terms of the activation of motor-related brain regions. The aim of the pilot study was thus to combine these findings into a multimodal approach and to evaluate the potential impact of the concurrent application of the three methods on dexterity in stroke patients. The paradigm developed accordingly was tested with 10 subacute patients, in whom hand dexterity, thumb-index pinch force and thumb tapping speed were measured for a baseline assessment and directly before and after the single intervention. During the 10-min session, patients were instructed to watch a repetitive thumb-index finger tapping movement displayed on a monitor and to imagine the sensations that would arise from physically performing the same motion. They were also repeatedly electrically stimulated at the wrist on the motorically more affected body side and asked to place their hand behind the monitor for the duration of the session to support integration of the displayed hand into their own body schema. The data provide a first indication of a possible immediate effect of a single application of this procedure on the dexterity in patients after stroke.

Abstract Functional impairments contribute to poor quality of life in schizophrenia spectrum disorders (SSD). We sought to (Objective I) define the main functional phenotypes in SSD, then (Objective II) identify key biopsychosocial correlates, emphasizing interpretable data-driven methods. Objective I was tested on independent samples: Dataset I (N = 282) and Dataset II (N = 317), with SSD participants who underwent assessment of multiple functioning areas. Participants were clustered based on functioning. Objective II was evaluated in Dataset I by identifying key features for classifying functional phenotype clusters from among 65 sociodemographic, psychological, clinical, cognitive, and brain volume measures. Findings were replicated across latent discriminant analyses (LDA) and one-vs.-rest binomial regularized regressions to identify key predictors. We identified three clusters of participants in each dataset, demonstrating replicable functional phenotypes: Cluster 1—poor functioning across domains; Cluster 2—impaired Role Functioning, but partially preserved Independent and Social Functioning; Cluster 3—good functioning across domains. Key correlates were Avolition, anhedonia, left hippocampal volume, and measures of emotional intelligence and subjective social experience. Avolition appeared more closely tied to role functioning, and anhedonia to independent and social functioning. Thus, we found three replicable functional phenotypes with evidence that recovery may not be uniform across domains. Avolition and anhedonia were both critical but played different roles for different functional domains. It may be important to identify critical functional areas for individual patients and target interventions accordingly.

Neural radiance fields have emerged as a dominant paradigm for creating complex 3D environments incorporating synthetic novel views. However, 3D object removal applications utilizing neural radiance fields have lagged behind in effectiveness, particularly when open set queries are necessary for determining the relevant objects. One such application area is in architectural heritage preservation, where the automatic removal of non-architectural objects from 3D environments is necessary for many downstream tasks. Furthermore, when modeling occupied buildings, it is crucial for modeling techniques to be privacy preserving by default; this also motivates the removal of non-architectural elements. In this paper, we propose a pipeline for the automatic creation of cleaned, architectural structure only point clouds utilizing a language embedded radiance field (LERF) with a specific application toward generating suitable point clouds for the structural integrity assessment of occupied buildings. We then validated the efficacy of our approach on the rooms of the historic Sion hospital, a national historic monument in Valais, Switzerland. By using our automatic removal pipeline on the point clouds of rooms filled with furniture, we decreased the average earth mover’s distance (EMD) to the ground truth point clouds of the physically emptied rooms by 31 percent. The success of our research points the way toward new paradigms in architectural modeling and cultural preservation.

Abstract Background The SCHUMANN study evaluated the efficacy and safety of the selective P2 × 3 antagonist eliapixant in patients with endometriosis-associated pelvic pain (EAPP). Methods SCHUMANN was a randomized, placebo- and active comparator-controlled, double-blind to placebo and open-label to comparator, parallel-group, multicenter, dose-finding phase 2b study. The participants were women with surgically diagnosed endometriosis who fulfilled defined EAPP criteria. Participants were randomized 1:1:1:1 to twice daily (BID) 25 mg, 75 mg, or 150 mg oral eliapixant or a placebo for 12 weeks. An exploratory once-daily elagolix 150 mg treatment group was also included. The primary endpoint was the absolute change in mean worst EAPP from baseline to the end of intervention (EOI). Results Overall, 215 participants were randomized for treatment (44 to eliapixant 25 mg, 44 to eliapixant 75 mg, 43 to eliapixant 150 mg, 43 to a placebo, and 41 to elagolix 150 mg). For safety reasons, the study was terminated early; both treatment and enrollment stopped immediately, producing less than 50% of the planned number of completers. The study found no significant differences in EAPP reduction from baseline between groups and no significant dose-response model. The elagolix 150 mg group showed better pain reduction than any of the other groups. No new safety signals were observed, relative to the previously known safety profile of eliapixant, which was generally well tolerated. However, one case of moderate and probably drug-induced liver injury in a participant receiving eliapixant 150 mg BID supported the association between eliapixant and a potential increase in liver function values, defined before the start of the phase 2 program. Conclusions This study did not meet its primary objective as no statistically significant or clinically relevant differences in changes of mean worst EAPP from baseline were observed between treatment groups. The single observed case of moderate, probably drug-induced liver injury was the second case in the eliapixant phase 2 program conducted in the following indications: refractory or unexplained chronic cough, diabetic neuropathic pain, overactive bladder, and EAPP. Due to this, the benefit-risk ratio for the study was no longer considered to be positive. Clinical trial registration ClinicalTrials.gov identifier NCT04614246; registered November 3, 2020.

Abstract Background Infection with the Epstein-Barr virus (EBV) elicits a complex T-cell response against a broad range of viral proteins. Hence, identifying potential differences in the cellular immune response of patients with different EBV-associated diseases or different courses of the same disorder requires interrogation of a maximum number of EBV antigens. Here, we tested three novel EBV-derived antigen formulations for their ability to reactivate virus-specific T cells ex vivo in patients with EBV-associated infectious mononucleosis (IM). Methods We comparatively analyzed EBV-specific CD4+ and CD8+ T-cell responses to three EBV-derived antigen formulations in 20 pediatric patients during the early phase of IM: T-activated EBV proteins (BZLF1, EBNA3A) and EBV-like particles (EB-VLP), both able to induce CD4+ and CD8+ T-cell responses ex vivo, as well as an EBV-derived peptide pool (PP) covering 94 well-characterized CD8+ T-cell epitopes. We assessed the specificity, magnitude, kinetics, and functional characteristics of EBV-specific immune responses at two sequential time points (v1 and v2) within the first six weeks after IM symptom onset (Tonset). Results All three tested EBV-derived antigen formulations enabled the detection of EBV-reactive T cells during the early phase of IM without prior T-cell expansion in vitro. EBV-reactive CD4+ and CD8+ T cells were mainly mono-functional (CD4+: mean 64.92%, range 56.15-71.71%; CD8+: mean 58.55%, range 11.79-85.22%) within the first two weeks after symptom onset (v1) with IFN-γ and TNF-secreting cells representing the majority of mono-functional EBV-reactive T cells. By contrast, PP-reactive CD8+ T cells were primarily bi-functional (>60% at v1 and v2), produced IFN-γ and TNF and had more tri-functional than mono-functional components. We observed a moderate correlation between viral load and EBNA3A, EB-VLP, and PP-reactive CD8+ T cells (r s = 0.345, 0.418, and 0.356, respectively) within the first two weeks after Tonset, but no correlation with the number of detectable EBV-reactive CD4+ T cells. Conclusions All three EBV-derived antigen formulations represent innovative and generic recall antigens suitable for monitoring EBV-specific T-cell responses ex vivo. Their combined use facilitates a thorough analysis of EBV-specific T-cell immunity and allows the identification of functional T-cell signatures linked to disease development and severity.

Abstract Background Prioritisation of chemical pollutants is a major challenge for environmental managers and decision-makers alike, which is essential to help focus the limited resources available for monitoring and mitigation actions on the most relevant chemicals. This study extends the original NORMAN prioritisation scheme beyond target chemicals, presenting the integration of semi-quantitative data from retrospective suspect screening and expansion of existing exposure and risk indicators. The scheme utilises data retrieved automatically from the NORMAN Database System (NDS), including candidate substances for prioritisation, target and suspect screening data, ecotoxicological effect data, physico-chemical data and other properties. Two complementary workflows using target and suspect screening monitoring data are applied to first group the substances into six action categories and then rank the substances using exposure, hazard and risk indicators. The results from the ‘target’ and ‘suspect screening’ workflows can then be combined as multiple lines of evidence to support decision-making on regulatory and research actions. Results As a proof-of-concept, the new scheme was applied to a combined dataset of target and suspect screening data. To this end, > 65,000 substances on the NDS, of which 2579 substances supported by target wastewater monitoring data, were retrospectively screened in 84 effluent wastewater samples, totalling > 11 million data points. The final prioritisation results identified 677 substances as high priority for further actions, 7455 as medium priority and 326 with potentially lower priority for actions. Among the remaining substances, ca. 37,000 substances should be considered of medium priority with uncertainty, while it was not possible to conclude for 19,000 substances due to insufficient information from target monitoring and uncertainty in the identification from suspect screening. A high degree of agreement was observed between the categories assigned via target analysis and suspect screening-based prioritisation. Suspect screening was a valuable complementary approach to target analysis, helping to prioritise thousands of substances that are insufficiently investigated in current monitoring programmes. Conclusions This updated prioritisation workflow responds to the increasing use of suspect screening techniques. It can be adapted to different environmental compartments and can support regulatory obligations, including the identification of specific pollutants in river basins and the marine environments, as well as the confirmation of environmental occurrence levels predicted by modelling tools. Graphical Abstract

Abstract Background The COVID-19 pandemic has posed challenges that worsened people’s mental health. We explored the impact of the COVID-19 pandemic on the mental well-being of the population, as indicated by the prevalence rates of benzodiazepine and benzodiazepine-related drug (BDZ) use. Methods This population‐based, time‐series analysis included all prescriptions of BDZs dispensed in Estonia between 2012 and 2021. The monthly prevalence rates of BDZ use were calculated. Autoregressive integrated moving average models with pulse and slope intervention functions tested for temporary and long-term changes in monthly prevalence rates after the onset of the COVID-19 pandemic. Results Throughout the 10-year study period, a total of 5,528,911 BDZ prescriptions were dispensed to 397,436 individuals. A significant temporary increase in the overall prevalence rate of BDZ use in March 2020 (2.698 users per 1000, 95% CI 1.408–3.988) was observed, but there was no statistically significant long-term change. This temporary increase affected all the examined subgroups, except for new users, individuals aged 15–29 years, and prescribing specialists other than general practitioners and psychiatrists. The long-term increase in BDZ use was confined to females aged 15–29 years (0.056 users per 1000 per month, 95% CI 0.033–0.079), while no significant change was observed among males of the same age (0.009 users per 1000 per month, 95% CI – 0.017 to 0.035). Among females aged 15–29 years, a significant long-term increase in BDZ use was observed for anxiety disorders (0.017 users per 1000 per month, 95% CI 0.010–0.023), depressive disorders (0.021 users per 1000 per month, 95% CI 0.012–0.030), and other mental and behavioral disorders (0.020 users per 1000 per month, 95% CI 0.010–0.030), but not for sleep disorders (– 0.008 users per 1000 per month, 95% CI – 0.018–0.002). Conclusion The COVID-19 pandemic led to a short-term increase in BDZ use immediately after the pandemic was declared. In the long term, young females experienced a sustained increase in BDZ use. The prolonged effect on girls and young women suggests their greater vulnerability. These results underscore the need to effectively address the long-term effects of the pandemic among youth.

Abstract Sudden aggravations of chronic inflammatory airway diseases are difficult-to-foresee life-threatening episodes for which advanced prognosis-systems are highly desirable. Here we present an experimental chip-based fluidic system designed for the rapid and sensitive measurement of biomarkers prognostic for potentially imminent asthma or COPD exacerbations. As model biomarkers we chose three cytokines (interleukin-6, interleukin-8, tumor necrosis factor alpha), the bacterial infection marker C-reactive protein and the bacterial pathogen Streptococcus pneumoniae—all relevant factors in exacerbation episodes. Assay protocols established in laboratory environments were adapted to 3D-printed fluidic devices with emphasis on short processing times, low reagent consumption and a low limit of detection in order to enable the fluidic system to be used in point-of-care settings. The final device demonstrator was validated with patient sample material for its capability to detect endogenous as well as exogenous biomarkers in parallel.

Background: Although highly efficacious, immune checkpoint inhibitors induce a multitude of immune-related adverse events including lichenoid skin reactions (irLP) that are often therapy-resistant. Objectives: To compare the clinical, histological, and transcriptional features of irLP with spontaneous lichen planus (LP). Methods: Clinical and histological presentations of irLP and LP, as well as the gene expression profiles of irLP and LP lesional and healthy skin were assessed. Results: irLP differed considerably from LP with regard to the distribution pattern of skin lesions with irLP appearing mostly in an exanthematous form, whereas lesions were more localized in the LP group. Histologically, dermal lymphocyte infiltration was significantly lower in irLP compared with LP, whereas lymphocyte exocytosis and apoptotic keratinocytes were significantly higher in irLP. Gene expression analysis revealed irLP to have a more inflammatory profile with elevated IFNG levels and a possible role of phagosome signaling compared with LP. Limitations: The study is descriptive and necessitates further investigation with larger cohorts and broader analyses. Conclusion: irLP differs from spontaneous LP on the clinical, histopathological, and gene expression level. The inflammatory gene signature in irLP suggests that topical JAK inhibitors could be an effective treatment, targeting local skin inflammation without systemic immunosuppression.

Abstract Introduction Immunocompromised (IC) patients mount poor immune responses to vaccination. Higher-dose coronavirus disease 2019 (COVID-19) vaccines may offer increased immunogenicity. Methods A pairwise meta-analysis of 98 studies reporting comparisons of mRNA-1273 (50 or 100 mcg/dose) and BNT162b2 (30 mcg/dose) in IC adults was performed. Outcomes were seroconversion, total and neutralizing antibody titers, and cellular immune responses. Results mRNA-1273 was associated with a significantly higher seroconversion likelihood [relative risk, 1.11 (95% CI, 1.08, 1.14); P

Microplastic (MP) has emerged as a significant environmental challenge due to increased plastic production and its widespread presence in the environment. This study aimed to assess MP concentrations throughout the treatment process at nine wastewater treatment plants (WWTPs) in Germany, from influent to effluent. A customized sampling technique was employed, followed by field and laboratory preparation and the quantification of polymers (PE, PP, PS, PMMA, and PET) using TED-GCMS. MP concentrations decreased progressively in the WWTPs, with influent concentrations ranging from 2.5 to 13.6 mg/L. Effluent concentrations in the conventional WWTPs ranged from 0.001 to 0.051 mg/L, while advanced treatment via filtration yielded concentrations below the limit of quantification at 0.005 mg/L. All tested of the WWTPs demonstrated an over 99% removal efficiency for microplastics. Despite effective retention by the WWTPs, a critical evaluation of the results is necessary. There is a need to optimize existing technologies and enhance the standardization of sampling, processing, and measurement methods, as well as intensify efforts towards creating preventive measures to reduce plastic emissions.

Hydrological models can benefit from soft calibration, a process by which the proper simulation of hydrological variables is proved while or before addressing hard calibration. Soft calibration reduces the probability of obtaining a statistically accurate but unrealistic model. However, it requires soft data, which is often hard to acquire or unavailable. This work presents HydRoVars, an R tool developed to facilitate the estimation of data which can be implemented in a soft calibration procedure. It allows us to estimate two key hydrological indices (the runoff coefficient and baseflow index) and weather-related variables at the catchment scale for one or numerous basins. The runoff coefficient is calculated automatically from precipitation and streamflow datasets. Groundwater contribution is estimated through a semi-automatic process based on a baseflow filter which considers hydrogeological properties. Modellers would benefit from incorporating soft calibration in their calibration procedures, and this tool might help to estimate these relevant hydrological variables in their modelled area. The tool has been tested in 19 subbasins of the Tagus River basin (Spain) located in different geological regions. In the test cases, we demonstrate the usefulness of this tool to improve the model representation and gain an understanding of the catchments' hydrology. HIGHLIGHTS An R tool has been developed to collect weather and hydrological variables.; It allows estimating the runoff coefficient, and the baseflow index at the catchment scale.; Runoff coefficient can be automatically obtained for multiple basins.; Guidance is provided for a realistic groundwater contribution estimation.; Its usefulness has been tested in the Upper Tagus River basin (Spain).;

Abstract Many targeted cancer therapies rely on biomarkers assessed by scoring of immunohistochemically (IHC)-stained tissue, which is subjective, semiquantitative, and does not account for expression heterogeneity. We describe an image analysis-based method for quantitative continuous scoring (QCS) of digital whole-slide images acquired from baseline human epidermal growth factor receptor 2 (HER2) IHC-stained breast cancer tissue. Candidate signatures for patient stratification using QCS of HER2 expression on subcellular compartments were identified, addressing the spatial distribution of tumor cells and tumor-infiltrating lymphocytes. Using data from trastuzumab deruxtecan-treated patients with HER2-positive and HER2-negative breast cancer from a phase 1 study (NCT02564900; DS8201-A-J101; N = 151), QCS-based patient stratification showed longer progression-free survival (14.8 vs 8.6 months) with higher prevalence of patient selection (76.4 vs 56.9%) and a better cross-validated log-rank p value (0.026 vs 0.26) than manual scoring based on the American Society of Clinical Oncology / College of American Pathologists guidelines. QCS-based features enriched the HER2-negative subgroup by correctly predicting 20 of 26 responders.