Search

Abstract Several indices have been devised to quantify a person’s stability from its gait pattern during overground walking. However, clinical interpretation of the indices is difficult because the link between being stable and adopting a mechanically stable gait pattern may not be straightforward. This is particularly true for one of these indices, the margin of stability, for which opposite interpretations are available in the literature. We collected overground walking data in two groups of 20 children, with unilateral cerebral palsy (CP) and typically developing (TD), for two conditions, on flat and on uneven grounds (UG). We postulated that TD children were more stable during gait than children with CP and that both groups were more stable on flat compared to UG. We explored the coherent association between several indices and the two postulates to clarify clinical interpretation. Our results showed that increased margin of stability, increased amplitude of the whole-body angular momentum, decreased duration of single limb support, increased variability (gait kinematics, step length, and step width) were associated with reduced stability for both postulates. However, results for the margin of stability were paradoxical between the sides in the CP group where small margin of stability was indicative of a fall forward strategy on the affected side rather than improved stability. Whole-body angular momentum and duration of single limb support appeared as the most sensitive indices. However, walking speed influenced these and would need to be considered when comparing groups of different walking speed.

Abstract Accelerating text input in augmentative and alternative communication (AAC) is a long-standing area of research with bearings on the quality of life in individuals with profound motor impairments. Recent advances in large language models (LLMs) pose opportunities for re-thinking strategies for enhanced text entry in AAC. In this paper, we present SpeakFaster, consisting of an LLM-powered user interface for text entry in a highly-abbreviated form, saving 57% more motor actions than traditional predictive keyboards in offline simulation. A pilot study on a mobile device with 19 non-AAC participants demonstrated motor savings in line with simulation and relatively small changes in typing speed. Lab and field testing on two eye-gaze AAC users with amyotrophic lateral sclerosis demonstrated text-entry rates 29–60% above baselines, due to significant saving of expensive keystrokes based on LLM predictions. These findings form a foundation for further exploration of LLM-assisted text entry in AAC and other user interfaces.

Abstract Background Rehabilitation plays a crucial role in restoring work ability and facilitating the reintegration of post-COVID patients into the workforce. The impact of rehabilitation on work ability and return to work (RTW) of post-COVID patients remains poorly understood. This study was conducted to assess the work ability and RTW of post-COVID patients before rehabilitation and 12 months after rehabilitation and to identify physical and neuropsychological health factors influencing RTW 12 months after rehabilitation. Methods This longitudinal observational study included 114 post-COVID patients with work-related SARS-CoV-2 infection who underwent inpatient post-COVID rehabilitation with indicative focus on pulmonology and/or psychotraumatology (interval between date of SARS-CoV-2 infection and start of rehabilitation: M = 412.90 days). Employment status, work ability, and the subjective prognosis of employment (SPE) scale were assessed before rehabilitation (T1) and 12 months after rehabilitation (T4). The predictors analysed at T4 were functional exercise capacity, physical activity, subjective physical and mental health status, fatigue, depression, and cognitive function. Longitudinal analyses were performed via the Wilcoxon signed-rank test. Logistic and linear regression analyses identified predictors of work ability and return to work (RTW), whereas mediation analyses examined the relationships between these predictors and work ability. Results At T4, the median of WAI total score indicated poor work ability, which significantly worsened over time (p

Summary Background Minimally invasive surgery is becoming the method of choice for the resection of esophageal cancer worldwide. Methods: Retrospective analysis of prospectively collected clinical data in a tertiary care center with a detailed description of the course of the program. Results A total of 136 transthoracic esophageal resections were performed between 2010 and 2023. The study group included 116 operations, 69 of which were fully minimally invasive and 47 hybrid. 80.0% of the study group underwent surgery using a multimodality approach. The median operation time was 431 min (± 103). The R0 resection rate was 100%. Forty-two patients (36.2%) had no postoperative complications. The postoperative Clavien-Dindo > IIIb morbidity was 27%. The postoperative 90-d mortality rate was 1.7%. The average number of lymph nodes removed in the last quarter of cancer patients was 31. The anastomotic insufficiency rate for reoperation was 4% (Ivor-Lewis 4.2%, McKeown 5%). Conclusions With extensive expertise in high-end minimally invasive abdominal and thoracic surgery, implementation of a minimally invasive esophageal resection program with a clinical and oncologic outcome within generally accepted limits is feasible.

Abstract Background Physical therapy interventions play a crucial role in the daily care of patients recovering from severe stroke. However, the efficacy of these interventions and associated modalities, including duration, intensity, and frequency, have not been fully elucidated. In 2020, a systematic review reported the beneficial effects of physical therapy for patients with severe stroke but did not assess therapeutic modalities. We aim to update the current evidence on the effects of physical therapy interventions and their modalities in relation to the recovery phase in people with severe stroke in a hospital or inpatient rehabilitation facility. Methods We searched CENTRAL, MEDLINE, Web of Science, and three other relevant databases between December 2018 and March 2021 and updated the search between April 2021 and March 2023. ClinicalTrials.gov and ICTRP for searching trial registries helped to identify ongoing RCTs since 2023. We included individual and cluster randomized controlled trials in the English and German languages that compared physical therapy interventions to similar or other interventions, usual care, or no intervention in a hospital or rehabilitation inpatient setting. We screened the studies from this recent review for eligibility criteria, especially according to the setting. Critical appraisal was performed according to the Cochrane risk-of-bias tool 2.0. The data were synthesized narratively. Results The update identified 15 new studies, cumulating in a total of 30 studies (n = 2545 participants) meeting the eligibility criteria. These studies reported 54 outcomes and 20 physical therapy interventions. Two studies included participants during the hyperacute phase, 4 during the acute phase,18 during the early subacute phase, and 3 in the late subacute phase. Three studies started in the chronic phase. Summarised evidence has revealed an uncertain effect of physical therapy on patient outcomes (with moderate to low-quality evidence). Most studies showed a high risk of bias and did not reach the optimal sample size. Little was stated about the standard care and their therapy modalities. Discussion There is conflicting evidence for the effectiveness of physical therapy interventions in patients with severe stroke. There is a need for additional high-quality studies that also systematically report therapeutic modalities from a multidimensional perspective in motor stroke recovery. Due to the high risk of bias and the generally small sample size of the included studies, the generalizability of the findings to large and heterogeneous volumes of outcome data is limited. Systematic review registration PROSPERO CRD42021244285.

Abstract Anthropogenic emissions alter atmospheric composition and therefore the climate, with implications for air pollution- and climate-related human health. Mortality attributable to air pollution and non-optimal temperature is a major concern, expected to shift under future climate change and socioeconomic scenarios. In this work, results from numerical simulations are used to assess future changes in mortality attributable to long-term exposure to both non-optimal temperature and air pollution simultaneously. Here we show that under a realistic scenario, end-of-century mortality could quadruple from present-day values to around 30 (95% confidence level:12-53) million people/year. While pollution-related mortality is projected to increase five-fold, temperature-related mortality will experience a seven-fold rise, making it a more important health risk factor than air pollution for at least 20% of the world’s population. These findings highlight the urgent need to implement stronger climate policies to prevent future loss of life, outweighing the benefits of air quality improvements alone.

Abstract Background Periodontitis, a prevalent chronic inflammatory disease, offers insights into the broader landscape of chronic inflammatory conditions. The progression and treatment outcomes of periodontitis are closely related to the oral microbiota’s composition. Adjunctive systemic Amoxicillin 500 mg and Metronidazole 400 mg, often prescribed thrice daily for 7 days to enhance periodontal therapy’s efficacy, have lasting effects on the oral microbiome. However, the precise mechanism through which the oral microbiome influences clinical outcomes in periodontitis patients remains debated. This investigation explores the pivotal role of the oral microbiome's composition in mediating the outcomes of adjunctive systemic antibiotic treatment. Methods Subgingival plaque samples from 10 periodontally healthy and 163 periodontitis patients from a randomized clinical trial on periodontal therapy were analyzed. Patients received either adjunctive amoxicillin/metronidazole or a placebo after mechanical periodontal treatment. Microbial samples were collected at various intervals up to 26 months post-therapy. Using topic models, we identified microbial communities associated with normobiotic and dysbiotic states, validated with 86 external and 40 internal samples. Logistic regression models evaluated the association between these microbial communities and clinical periodontitis parameters. A Directed Acyclic Graph (DAG) determined the mediating role of oral microbiota in the causal path of antibiotic treatment effects on clinical outcomes. Results We identified clear distinctions between dysbiotic and normobiotic microbial communities, differentiating healthy from periodontitis subjects. Dysbiotic states consistently associated with below median %Pocket Probing Depth ≥ 5 mm (OR = 1.26, 95% CI [1.14–1.42]) and %Bleeding on Probing (OR = 1.09, 95% CI [1.00–1.18]). Factors like microbial response to treatment, smoking, and age were predictors of clinical attachment loss progression, whereas sex and antibiotic treatment were not. Further, we showed that the oral microbial treatment response plays a crucial role in the causal effect of antibiotic treatment on clinical treatment outcomes. Conclusions The shift towards a normobiotic subgingival microbiome, primarily induced by adjunctive antibiotics, underscores the potential for microbiome-targeted interventions to enhance therapeutic efficacy in chronic inflammatory conditions. This study reaffirms the importance of understanding the oral microbiome's role in periodontal health and paves the way for future research exploring personalized treatment strategies based on individual microbiome profiles. Video Abstract

Abstract Background We conducted a prospective, randomized, controlled, two-group parallel trial investigating the effectiveness of a care management program employing cardiac care navigators providing post-discharge support to patients compared to standard care. Methods The intervention commenced in 2019/2020 for 2862 patients hospitalized with heart failure, coronary heart disease, or cardiac arrhythmias in departments of cardiology across eight participating sites of a hospital group in Berlin, Germany. We analyzed the results using an intention-to-treat approach. The primary outcome was the all-cause rehospitalization rate after 12 months. Secondary outcomes included rehospitalizations due to one of the qualifying cardiac diagnoses, duration of rehospitalization, mortality, health-related quality of life, and several process indicators. Trial data were collected from a combination of face-to-face and phone interviews conducted by hospital staff throughout the 12-month follow-up period using standardized questionnaires. Administrative claims data were provided by a large statutory health insurer. Outcomes for the intervention and control groups were compared using logistic regression, generalized linear models (GLMs) with a negative binomial distribution, ordinary least squares, and Cox proportional hazards regression. Results Compared to the control group (N = 1294), the intervention group (N = 1256) had a lower rate of all-cause rehospitalizations (62.6% vs. 66.4%, p = 0.05) and shorter lengths of stay (14.49 vs. 16.89 days, p = 0.02) during the 12-month follow-up period. These differences were also present for rehospitalizations due to the cardiac diseases qualifying for study recruitment, with rehospitalization rates for the intervention and control groups being 58.0% vs. 61.4% (p = 0.08) and particularly pronounced for lengths of rehospitalization stay of 12.97 vs. 15.40 days (p = 0.01), respectively. Subgroup analyses indicated positive effects of the intervention for patients 70 years and older (p = 0.05), females (p = 0.06), and those with little or no German language proficiency (p = 0.03). Furthermore, we found positive effects on patients’ adherence to health-related behavioral recommendations (81.91% vs. 73.95%, p = 0.000). Conclusions This study adds to the body of evidence indicating that care management interventions supporting patients as they transition from the inpatient to the outpatient sector can lower rehospitalizations, decrease length of rehospitalization stays, and improve adherence to post-discharge recommendations. Trial registration German Clinical Trial Register, DRKS00020424 . Registered 2020-06-18. (retrospectively registered).

Abstract Background Focal epilepsy is common in children and adults with mitochondrial disease. Seizures are often refractory to pharmacological treatment and, in this patient group, frequently evolve to refractory focal status epilepticus (also known as epilepsia partialis continua). Where this occurs, the long-term prognosis is poor. Transcranial DC stimulation (tDCS) is a promising, non-invasive, adjunctive treatment alternative to common surgical procedures. Limited recruitment of study participants with this rare disease and the ethical challenges of administering a treatment to one group and not another, while maintaining strict methodological rigour can pose challenges to the design of a clinical study. Method We designed the first delayed start, double-blinded, sham-controlled study to evaluate the efficacy of tDCS as an adjunctive treatment for focal epilepsy. We will include participants with a genetically confirmed diagnosis of mitochondrial disease with drug-resistant focal epilepsy aged ≥ 2 years, aiming to collect 30 episodes of focal status epilepticus, each treated for a maximum period of 14 days. The early start intervention arm will receive tDCS from day 1. The delayed start intervention arm will receive sham stimulation until crossover on day 3. Our primary endpoint is a greater than 50% reduction from baseline (on day 0) in seizure frequency assessed by 3x daily reporting, accelerometery, and video monitoring. Changes in the underlying epileptogenic focus within the brain related to the tDCS intervention will be assessed by magnetic resonance imaging (MRI) and/or electroencephalography (EEG). Discussion Study results in favour of treatment efficacy would support development of tDCS into a mainstream treatment option for focal epileptic seizures related to mitochondrial disease. Trials registration ISRCTN: 18,241,112; registered on 16/11/2021.

Abstract The authors present continuous wave (CW) high‐power broad area and ridge waveguide lasers with laser emission at 626 nm at room temperature. For this, the authors employ GaAs‐based diode lasers in the AlGaInP system for laser emission at 626 nm at room temperature. The laser structure is grown on three‐inch wafers by metal organic vapour phase epitaxy. Broad area and ridge waveguide lasers are fabricated. Pulsed broad area laser characterisation on bar level shows laser operation at 20 C heat sink temperature. The authors measured peak lasing wavelengths as short as 625 nm and total maximum output power of both facets up to 1.4 W at an injection current of 2 A. Both, broad area and ridge waveguide lasers show laser operation and CW excitation at room temperature. The ridge waveguide lasers emit output powers of over 90 mW at 626 nm at a maximum injection current of 200 mA with a nearly diffraction‐limited beam profile.

Abstract Background Directional vibrotactile biofeedback for balance control can be instructed in the form of Repulsive (to move in the opposite direction of vibrations) or Attractive (to move in the direction of vibrations) stimulus encodings. However, which of these encodings is less cognitively demanding and poses less interference with high-level cognitive processes of conflict resolution remains unresolved. Methods In two between-subject studies with 30 (16 females) and 35 (23 females) healthy young adults, respectively, we investigated the cognitive load of Attractive and Repulsive vibrotactile biofeedback on 1) working memory (Study I) and 2) cognitive conflict resolution (Study II). Both studies also examined the effectiveness of both feedback stimulus encodings on balance control during quiet standing with eyes closed. Results Both Attractive and Repulsive vibrotactile biofeedback increased balance stability (reduced trunk sway variability) in both the working memory and the conflict resolution study (Study I and II, respectively) with a greater increase of stability for the Repulsive encoding during multitasking demanding cognitive conflict resolution (Study II). Cognitive costs, measured in terms of the Linear Integrated Speed-Accuracy Score (LISAS), were greater for the Attractive encoding during multitasking with working memory demands. When cognitive conflict resolution was required as a secondary cognitive task, both stimulus encodings increased cognitive costs equally. Conclusions The effects of instructed Repulsive and Attractive stimulus encodings for the response-related interpretation of vibrotactile biofeedback of body sway were contrasted with respect to cognitive processing demands and balance stabilisation benefits. Both encodings improved balance stability but at certain cognitive costs. Regarding interference with specific high-level cognitive processes, however, a distinction has to be made between both encodings. Repulsive feedback encoding seems to cause less cognitive costs on working memory load and slightly greater stabilisation when cognitive conflict resolution is required. These results are discussed in the context of the known benefits of avoidance actions on cognitive control.

Abstract Background Diagnosis of dementia with Lewy bodies (DLB) is challenging, especially in the earlier stages of the disease, owing to the clinical overlap with other neurodegenerative diseases such as Alzheimer’s (AD) and Parkinson’s disease (PD). We aimed to identify the transcranial sonography (TCS) parameters that can help us to detect early DLB patients. Methods In this cross-sectional study, we prospectively recruited newly diagnosed DLB patients with less than 3 years from the onset of cognitive symptoms. For comparison purposes, we also included AD and PD patients, with a disease duration of less than 3 years, and a control group. TCS was performed to assess the substantia nigra (SN) echogenicity, the width of the third ventricle, and the frontal horns of the lateral ventricles. Subsequently, TCS images were analyzed with the medical image viewer Horos in order to quantify the intensity of the echogenicity of the SN. Univariate analysis and a logistic regression model were used to identify which variables can predict the diagnosis of DLB. Results One hundred and seven participants were included (23 DLB, 26 AD, 27 PD and 31 controls). The median age of DLB patients was 75(72–77) years, with a disease duration of 2 years. DLB and PD patients showed higher SN hyperechogenicity rates (72.73% and 81.82%, respectively) and a greater area of the SN compared to AD patients and controls (p

Abstract Taking the perspective of career choice as a lifelong, iterative, constructive, and agentic process, the present study focuses on the development of vocational aspirations of nursing trainees; that is, thoughts about a long-term perspective in nursing (i.e., persistence), ideas of finishing the training but changing into another profession after some time (i.e., withdrawal), and decisions to terminate the training before completing the programme through a final examination (i.e., dropout). In order to generate detailed insights about the dynamics behind the development of such aspirations during the initial training phase, a qualitative, longitudinal, within-subject study design based on grounded theory was employed. The results mainly show that social interactions with more experienced nurses, practical work experiences, encounters with environments that are either conducive to learning or not, the satisfaction of different needs (e.g., autonomy, competence, belonging, sense of meaningfulness), as well as the associated feelings of well-being affect how vocational aspirations develop over the first year of training. In addition, the study identifies four different patterns of how trainees typically oscillate between thoughts of staying in nursing and leaving the profession in the short or long run: (a) arriving and wanting to stay, (b) staying as a transitional passage, (c) seeking to stay, and (d) exiting as a knee-jerk reaction. The patterns present evidence of a variety of approaches regarding how trainees deal with certain experiences during their training and how the combination of experiences might affect young professionals’ subsequent career choices.

Abstract Calabi-Yau compactifications have typically a large number of complex structure and/or Kähler moduli that have to be stabilised in phenomenologically-relevant vacua. The former can in principle be done by fluxes in type IIB solutions. However, the tadpole conjecture proposes that the number of stabilised moduli can at most grow linearly with the tadpole charge of the fluxes required for stabilisation. We scrutinise this conjecture in the 26 Gepner model: a non-geometric background mirror dual to a rigid Calabi-Yau manifold, in the deep interior of moduli space. By constructing an extensive set of supersymmetric Minkowski flux solutions, we spectacularly confirm the linear growth, while achieving a slightly higher ratio of stabilised moduli to flux charge than the conjectured upper bound. As a byproduct, we obtain for the first time a set of solutions within the tadpole bound where all complex structure moduli are massive. Since the 26 model has no Kähler moduli, these show that the massless Minkowski conjecture does not hold beyond supergravity.

Abstract The intensive nutrient requirements needed to sustain T cell activation and proliferation, combined with competition for nutrients within the tumor microenvironment, raise the prospect that glucose availability may limit CAR-T cell function. Here, we seek to test the hypothesis that stable overexpression (OE) of the glucose transporter GLUT1 in primary human CAR-T cells would improve their function and antitumor potency. We observe that GLUT1OE in CAR-T cells increases glucose consumption, glycolysis, glycolytic reserve, and oxidative phosphorylation, and these effects are associated with decreased T cell exhaustion and increased Th17 differentiation. GLUT1OE also induces broad metabolic reprogramming associated with increased glutathione-mediated resistance to reactive oxygen species, and increased inosine accumulation. When challenged with tumors, GLUT1OE CAR-T cells secrete more proinflammatory cytokines and show enhanced cytotoxicity in vitro, and demonstrate superior tumor control and persistence in mouse models. Our collective findings support a paradigm wherein glucose availability is rate limiting for effector CAR-T cell function and demonstrate that enhancing glucose availability via GLUT1OE could augment antitumor immune function.

Abstract TRIM25 is an RNA-binding ubiquitin E3 ligase with central but poorly understood roles in the innate immune response to RNA viruses. The link between TRIM25’s RNA binding and its role in innate immunity has not been established. Thus, we utilized a multitude of biophysical techniques to identify key RNA-binding residues of TRIM25 and developed an RNA-binding deficient mutant (TRIM25-m9). Using iCLIP2 in virus-infected and uninfected cells, we identified TRIM25’s RNA sequence and structure specificity, that it binds specifically to viral RNA, and that the interaction with RNA is critical for its antiviral activity.

Abstract Background Emotional disorders such as depression and anxiety disorders share substantial similarities in their etiology and treatment. In recent decades, these commonalities have been increasingly recognized in classification systems and treatment programs crossing diagnostic boundaries. Methods To examine the prospective effects of different transdiagnostic markers on relevant treatment outcomes, we plan to track a minimum of N = 200 patients with emotional disorders during their routine course of cognitive behavioral therapy at two German outpatient clinics. We will collect a wide range of transdiagnostic markers, ranging from basic perceptual processes and self-report measures to complex behavioral and neurobiological indicators, before entering therapy. Symptoms and psychopathological processes will be recorded before entering therapy, between the 20th and 24th therapy session, and at the end of therapy. Discussion Our results could help to identify transdiagnostic markers with high predictive power, but also provide deeper insights into which patient groups with which symptom clusters are less likely to benefit from therapy, and for what reasons. Trial Registration The trial was preregistered at the German Clinical Trial Register (DRKS-ID: DRKS00031206; 2023–05-09).

Abstract A previously published genome-wide association study (GWAS) meta-analysis across eight neuropsychiatric disorders identified antagonistic single-nucleotide polymorphisms (SNPs) at eleven genomic loci where the same allele was protective against one neuropsychiatric disorder and increased the risk for another. Until now, these antagonistic SNPs have not been further investigated regarding their link to brain structural phenotypes. Here, we explored their associations with cortical surface area and cortical thickness (in 34 brain regions and one global measure each) as well as the volumes of eight subcortical structures using summary statistics of large-scale GWAS of brain structural phenotypes. We assessed if significantly associated brain structural phenotypes were previously reported to be associated with major neuropsychiatric disorders in large-scale case-control imaging studies by the ENIGMA consortium. We further characterized the effects of the antagonistic SNPs on gene expression in brain tissue and their association with additional cognitive and behavioral phenotypes, and performed an exploratory voxel-based whole-brain analysis in the FOR2107 study (n = 754 patients with major depressive disorder and n = 847 controls). We found that eight antagonistic SNPs were significantly associated with brain structural phenotypes in regions such as anterior parts of the cingulate cortex, the insula, and the superior temporal gyrus. Case-control differences in implicated brain structural phenotypes have previously been reported for bipolar disorder, major depressive disorder, and schizophrenia. In addition, antagonistic SNPs were associated with gene expression changes in brain tissue and linked to several cognitive-behavioral traits. In our exploratory whole-brain analysis, we observed significant associations of gray matter volume in the left superior temporal pole and left superior parietal region with the variants rs301805 and rs1933802, respectively. Our results suggest that multiple antagonistic SNPs for neuropsychiatric disorders are linked to brain structural phenotypes. However, to further elucidate these findings, future case-control genomic imaging studies are required.

Abstract The neurotrophic growth factor brain‐derived neurotrophic factor (BDNF) plays a crucial role in various neurodegenerative and psychiatric diseases, such as Alzheimer's disease, schizophrenia and depression. BDNF has been proposed as a potential biomarker for diagnosis, prognosis and monitoring therapy. Understanding the factors influencing BDNF levels and whether they follow a circadian rhythm is essential for interpreting fluctuations in BDNF measurements. We aimed to investigate the circadian rhythm of BDNF by collecting multiple peripheral venous blood samples from young, healthy male participants at 12 different time points over 24 h. In addition, vital parameters, cortisol and insulin like growth factor 1 (IGF1) were measured to explore potential regulatory mechanisms, interfering variables and their correlations with BDNF concentration. The findings revealed that plasma BDNF did not exhibit any significant fluctuations over 24 h, suggesting the absence of a circadian rhythm. However, serum BDNF levels decreased during sleep. Furthermore, serum BDNF showed a positive correlation with heart rate but a negative correlation with IGF1. No significant correlation was observed between cortisol and BDNF or IGF1. Although plasma BDNF suggests steady‐state conditions, the decline of serum BDNF during the nocturnal period could be attributed to physical inactivity and associated with reduced haemodynamic blood flow (heart rate reduction during sleep). The type of sample collection (peripheral venous cannula vs. blood sampling using a butterfly system) does not significantly affect the measured BDNF levels. The sample collection during the day did not significantly affect BDNF analysis, emphasizing the importance of considering activity levels rather than timing when designing standardized protocols for BDNF assessments.

Young people use digital media for various purposes, such as communication, entertainment, and information. As they grow up, their media repertoires become more complex and diverse. This article examines these media repertoires in more detail, considering the dynamic changes in individual development, social circumstances, and deep mediatization. Using semi-structured interviews with young people and one parent each, as well as a media-actor mapping, the study reveals significant changes in the composition and function of media repertoires from late childhood to early and middle adolescence. Drawing on the theoretical background of communicative figurations, it highlights changes in media ensembles, actor constellations, frames of relevance, and communicative practices. Besides changes in media repertoires for coping with developmental tasks and individual transitions in life, social factors such as the role of family and peers are considered. The empirical findings also point to the added value of qualitative longitudinal data which allows for a comprehensive examination of the complexity of changing media repertoires within a deeply mediatized society and a rapidly evolving media environment.

Abstract Purpose Childhood Cancer Survivors (CCSs) have an increased risk for treatment-related chronic health conditions, but the adherence to long-term follow-up (LTFU) care decreases over time. We therefore assessed the CCSs’ development of cancer knowledge, cancer worries, self-management skills, and expectations for LTFU care in a structured, cancer center-based transition model—a crucial part for maintaining adherence. Methods Using questionnaire-based surveys, we compared the CCSs’ cancer knowledge with medical record data and assessed cancer worries (6 questions), self-management skills (15 questions), and expectations (12 questions) longitudinally by validated scales. We used descriptive statistics for presenting our results. Results We analyzed 17 CCSs, 71% were female, had a median age of 8 years at diagnosis and 21 years at study enrollment. The knowledge about late effects increased during the transition process, except for the risk of secondary malignancies. Leukemia survivors had a decrease in cancer worries. At least 75% of the CCSs agreed to 11 of 15 self-management questions before and after transition, with the highest increase over time in less parental involvement. The CCSs expected the most, that physicians know the CCSs’ cancer history, that the visit starts on time, and that physicians can always be called in case of questions. Conclusions Our transition model improved cancer knowledge, especially the risk for late effects, decreased cancer worries, and identified expectations for LTFU care which should be considered in the future. A structured transition process with evidence-based tools further increases the knowledge of CCS for LTFU through empowerment.

Abstract Background Prostate-specific membrane antigen positron emission tomography (PSMA-PET) is an essential tool for patient selection before radioligand therapy (RLT). Interim-staging with PSMA-PET during RLT allows for therapy monitoring. However, its added value over post-treatment imaging is poorly elucidated. The aim of this study was to compare early treatment response assessed by post-therapeutic whole-body scans (WBS) with interim-staging by PSMA-PET after 2 cycles in order to prognosticate OS. Methods Men with metastasized castration-resistant PC (mCRPC) who had received at least two cycles of RLT, and interim PSMA-PET were evaluated retrospectively. PROMISE V2 framework was used to categorize PSMA expression and assess response to treatment. Response was defined as either disease control rate (DCR) for responders or progression for non-responders. Results A total of 188 men with mCRPC who underwent RLT between February 2015 and December 2021 were included. The comparison of different imaging modalities revealed a strong and significant correlation with Cramer V test: e.g. response on WBS during second cycle compared to interim PET after two cycles of RLT (cφ = 0.888, P

Abstract Switching to a diet lower in red meat has the potential to reduce greenhouse gas emissions. Using a unique time series of daily sales data from three German university canteens from 2017 to 2019, we analyse the effects of a monthly Veggie Day in a food-away-from-home context. We find that the temporary ban on meat dishes did not lead to a widespread boycott – as the heated public debates might have suggested. In our setting, a Veggie Day could reduce greenhouse gas emissions by up to 66%. However, especially at the site with a higher share of meat eaters on regular days, up to 22% of customers bypassed the meat-free main dishes on Veggie Days and ate at other on-site alternatives where meat was available. However, total on-site sales did not decrease significantly. Students were less likely to switch to alternatives than staff and guests. A less stringent implementation of a Veggie Day where only beef dishes were removed from the menu, did not result in a significant shift to alternatives but could reduce emissions by up to 51%.

Biocatalysis has established itself as a successful tool in organic synthesis. A particularly fast technique for screening enzymes is the in vitro expression or cell-free protein synthesis (CFPS). The system is based on the transcription and translation machinery of an extract-donating organism to which substrates such as nucleotides and amino acids, as well as energy molecules, salts, buffer, etc., are added. After successful protein synthesis, further substrates can be added for an enzyme activity assay. Although mimicking of cell-like conditions is an approach for optimization, the physical and chemical properties of CFPS are not well described yet. To date, standard conditions have mainly been used for CFPS, with little systematic testing of whether conditions closer to intracellular conditions in terms of viscosity, macromolecules, inorganic ions, osmolarity, or water content are advantageous. Also, very few non-physiological conditions have been tested to date that would expand the parameter space in which CFPS can be performed. In this study, the properties of an Escherichia coli extract-based CFPS system are evaluated, and the parameter space is extended to high viscosities, concentrations of inorganic ion and osmolarity using ten different technical additives including organic solvents, polymers, and salts. It is shown that the synthesis of two model proteins, namely superfolder GFP (sfGFP) and the enzyme truncated human cyclic GMP-AMP synthase fused to sfGFP (thscGAS-sfGFP), is very robust against most of the tested additives.

In these proceedings the growing and reflective community of Citizen Science actors give insights into their findings which were presented at the joint conference of Österreich forscht and the European Citizen Science Association (ECSA) in Vienna 2024. The conference key topic was change, since we face changes in various aspects, in nature and society as well in the way Citizen Science is executed and perceived. Enjoy reading and get guidance and inspiration for your further work in the field of Citizen Science.

Abstract Background The Ryan White Medical Case Management System, which serves more than half of people living with HIV (PLWH) in the USA, is an opportune setting for identifying and addressing depression among PLWH. A growing body of research suggests that interventions that promote positive emotion may lessen symptoms of depression and improve physical and psychological well-being among people experiencing a variety of health-related stress, including living with HIV. Research on how best to integrate standardized mental health screening and referral to evidence-based interventions in Ryan White Medical Case Management settings has the potential to improve the health and wellbeing of PLWH. Methods This mixed-methods study will enroll up to N = 300 Ryan White clients who screen positive for depressive symptoms in ORCHID (Optimizing Resilience and Coping with HIV through Internet Delivery), a web-based, self-guided positive emotion regulation intervention. The study will be conducted in 16 Ryan White Medical Case Management clinics in Chicago, IL. Following pre-implementation surveys and interviews with Medical Case Managers (MCMs) and Supervisors to develop an implementation facilitation strategy, we will conduct a hybrid type 2 implementation-effectiveness stepped wedge cluster randomized trial to iteratively improve the screening and referral process via interviews with MCMs in each wedge. We will test the effectiveness of ORCHID on depression and HIV care outcomes for PLWH enrolled in the program. RE-AIM is the implementation outcomes framework and the Consolidated Framework for Implementation Research is the implementation determinants framework. Discussion Study findings have the potential to improve mental health and substance use screening of Ryan White clients, decrease depression and improve HIV care outcomes, and inform the implementation of other evidence-based interventions in the Ryan White Medical Case Management System. Trial registration ClinicalTrials.gov NCT05123144. Trial registered 6/24/2021

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.

Wastewater treatment plants (WWTPs) have been identified as important point sources for microplastics (MPs) in the environment; monitoring MP emissions in the WWTP effluent is therefore essential for contamination control. The aim of this study is to acquire a large number of samples (320) over a period of two years and three months to determine the temporal variations in microplastic contamination in the outlet of the municipal WWTP Landau-Mörlheim. The effluent of the third cleaning stage is sampled with a 10 µm filter cartridge, processed in the laboratory using a hydrogen peroxide treatment, and MPs are then detected by fluorescence staining. The results show high temporal variations in the microplastic concentrations in the effluent of the WWTP. This indicates that high numbers of samples are necessary to obtain a representative assessment of the microplastic emissions; single samples are not representative. The average microplastic concentration in the effluent was 27.8 ± 29.8 MP/L, ranging from 0.6 MP/L to 194.0 MP/L. This leads to a yearly emission of 1.5 × 1011 MP for the WWTP Landau-Mörlheim, corresponding to an emission of 2.8 × 106 MP/inhabitant and year. Statistically significant seasonal variations could not be observed, although there is a trend towards lower MP concentrations in summer. Further, no correlations with other wastewater or weather parameters could be found.

The environmental impacts of the postindustrial era, which rely on fossil fuels, have compelled a reconsideration of the future of energy and chemical industries. Fungi are a valuable resource for improving a circular economy through the enhanced valorization of biomass and plant waste. They harbor a great diversity of oxidative enzymes, especially in their secretome. Enzymatic breakdown of the plant cell wall complex and lignocellulosic biomass yields sugars for fermentation and biofuel production, as well as aromatic compounds from lignin that can serve as raw materials for the chemical industry. To harness the biocatalytic potential, it is essential to identify and explore wild-type fungi and their secretomes. This study successfully combined genome mining and activity screening to uncover the oxidative potential of a collection of underexploited ascomycetes and basidiomycetes. The heme peroxidase and laccase activities of four promising candidates, Bipolaris victoriae, Colletotrichum sublineola, Neofusicoccum parvum and Moesziomyces antarcticus, were investigated to gain a deeper insight into their enzyme secretion. Furthermore, a plant-based medium screening with the phytopathogen C. sublineola revealed that soybean meal is a beneficial component to trigger the production and secretion of enzymes that catalyze H2O2-dependent oxidations. These results demonstrate that understanding fungal secretomes and their enzymatic potential opens exciting avenues for sustainable biotechnological applications across various industries.

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.