Background Idiopathic mast cell activation syndrome (MCAS) is characterized by three diagnostic criteria: (1) episodic mast cell (MC)-driven signs/symptoms of at least two organ systems in the absence of clonal MC expansion and definite triggers, (2) episodic increase in tryptase, and (3) response to MC-targeted treatment. Many patients believe they have MCAS, but how often this is the case remains unknown.

Methods We prospectively investigated patients with suspected MCAS (n = 100) for the diagnostic criteria including baseline tryptase, KIT D816V mutation, and patient-reported outcome measures (PROMs) over the course of 12 weeks. Comorbid depression and anxiety were explored with the Hospital Anxiety and Depression Scale (HADS).

Results In 53% of our patients (80% females), suspicion of MCAS was based on self-evaluation. In total, patients reported 87 different symptoms, mostly fatigue (n = 57), musculoskeletal pain/weakness (n = 49), and abdominal pain (n = 43), with overall high disease activity and impact. Two of 79 patients had increased tryptase (by >20% +2 ng/ml) following an episode. Only 5%, with any of the PROMs used, showed complete response to MC-targeted treatment. Depression and anxiety disorders were frequent comorbidities (n = 23 each), and 65 patients had pathological HADS values, which were linked to high disease impact and poor symptom control.

Conclusion Mast cell activation syndrome was confirmed in only 2% of patients, which implies that it is not MC activation that drives signs and symptoms in most patients with suspected MCAS. There is a high need for comprehensive research efforts aimed at the identification of the true underlying pathomechanism(s) in patients with suspected MCAS.

Background Co-medication is common among patients with allergic rhinitis (AR), but its dimension and patterns are unknown. This is particularly relevant since AR is understood differently across European countries, as reflected by rhinitis-related search patterns in Google Trends. This study aims to assess AR co-medication and its regional patterns in Europe, using real-world data.

Methods We analysed 2015–2020 MASK-air® European data. We compared days under no medication, monotherapy and co-medication using the visual analogue scale (VAS) levels for overall allergic symptoms (‘VAS Global Symptoms’) and impact of AR on work. We assessed the monthly use of different medication schemes, performing separate analyses by region (defined geographically or by Google Trends patterns). We estimated the average number of different drugs reported per patient within 1 year.

Results We analysed 222,024 days (13,122 users), including 63,887 days (28.8%) under monotherapy and 38,315 (17.3%) under co-medication. The median ‘VAS Global Symptoms’ was 7 for no medication days, 14 for monotherapy and 21 for co-medication (p < .001). Medication use peaked during the spring, with similar patterns across different European regions (defined geographically or by Google Trends). Oral H1-antihistamines were the most common medication in single and co-medication. Each patient reported using an annual average of 2.7 drugs, with 80% reporting two or more.

Conclusions Allergic rhinitis medication patterns are similar across European regions. One third of treatment days involved co-medication. These findings suggest that patients treat themselves according to their symptoms (irrespective of how they understand AR) and that co-medication use is driven by symptom severity.

Helicobacter pylori is a pathogen that colonizes the stomach and causes chronic gastritis. Helicobacter pylori can colonize deep inside gastric glands, triggering increased R-spondin 3 (Rspo3) signaling. This causes an expansion of the "gland base module," which consists of self-renewing stem cells and antimicrobial secretory cells and results in gland hyperplasia. The contribution of Rspo3 receptors Lgr4 and Lgr5 is not well explored. Here, we identified that Lgr4 regulates Lgr5 expression and is required for H. pylori-induced hyperplasia and inflammation, while Lgr5 alone is not. Using conditional knockout mice, we reveal that R-spondin signaling via Lgr4 drives proliferation of stem cells and also induces NF-kappa B activity in the proliferative stem cells. Upon exposure to H. pylori, the Lgr4-driven NF-kappa B activation is responsible for the expansion of the gland base module and simultaneously enables chemokine expression in stem cells, resulting in gland hyperplasia and neutrophil recruitment. This demonstrates a connection between R-spondin-Lgr and NF-kappa B signaling that links epithelial stem cell behavior and inflammatory responses to gland-invading H. pylori.

Persons with Parkinson's disease (PD) often show particular problems in seemingly simple routines despite relatively preserved cognitive function. We therefore investigated the processing of everyday events on behavioral and neurophysiological levels in a PD and control group. The participants had to indicate via button press whether three sequentially presented sub-events described a previously defined event (e.g., going grocery shopping). Sub-event sequences were either correct or included an event that did not belong to the event (content violation), or events were chronologically wrong (temporal violation). During task execution event-related potentials (ERPs) were recorded. Generally, the PD group showed less accurate performance independently from task conditions, and reaction times to temporal violations were particularly slow compared to the control group. Regarding ERP results, the control group showed a right lateralized N400 effect in response to content violations, which was absent in the PD group indicating altered content event processing. Concerning the reanalysis of content event violations, the expression of late positive components (LPCs) was similar between both groups. Upon temporal violations, both groups also showed a LPC with a tendentially earlier onset in the PD group, resembling positive components indicative of novelty processing. Together, these findings suggest poor event prediction in PD, which may originate from weak event representation or retrieval and possibly relate to prevalent behavioral dysfunctions in everyday life in PD.

There are multiple reasons why the next generation of biological and medical studies require increasing numbers of samples. Biological systems are dynamic, and the effect of a perturbation depends on the genetic background and environment. As a consequence, many conditions need to be considered to reach generalizable conclusions. Moreover, human population and clinical studies only reach sufficient statistical power if conducted at scale and with precise measurement methods. Finally, many proteins remain without sufficient functional annotations, because they have not been systematically studied under a broad range of conditions. In this review, we discuss the latest technical developments in mass spectrometry (MS)-based proteomics that facilitate large-scale studies by fast and efficient chromatography, fast scanning mass spectrometers, data-independent acquisition (DIA), and new software. We further highlight recent studies which demonstrate how high-throughput (HT) proteomics can be applied to capture biological diversity, to annotate gene functions or to generate predictive and prognostic models for human diseases.

Background Aim of our prospective, multicenter, nonrandomized study was to identify characteristic features and similarities of patients with functional respiratory disorders regarding socio-familial and behavioral aspects, in comparison with controls in a cross-sectional analysis using standardized psychological questionnaires. Furthermore, we investigated the longitudinal outcome of symptoms, effects of primary interventions and the stability of psychological traits 6 months after diagnosis and primary intervention.

Methods Initially, 106 patients (68 females, 27 males) and 58 controls (33 females, 25 males) were recruited for the study. Mean age was 12.6 years in patients and 11.9 years in controls.

Results The child behavior checklist (CBCL) showed significantly increased scores for anxious/depressed (p = 0.002) and schizoid/obsessive (p = 0.001) behavior in patients. A trend was evident for internalizing behavior (p = 0.009) and for a higher total score (p = 0.008). In the self-assessment youth self-report (YSR), there was a trend towards higher values for anxious/depressed behavior in patients (p = 0.06) and towards more externalizing behavior (p = 0.029) in the control group. After 6 months, 31% of the patients were free of symptoms, 42% had improved. For themselves, parents reported a decreased burden from 56% to 23% (p < 0.001) and decreased impairment from 57% to 30% (p < 0.008). For their children, parents reported a decrease from 45% to 16% (p < 0.0001) and from 74% to 37% (p < 0.0001), respectively. A longitudinal comparison from T1 to T2 showed no statistically significant changes in all three psychological questionnaires (CBCL, YSR, and SOMS-KJ).

Conclusions In summary, we show that patients with functional respiratory disorders differ from healthy subjects, with internalizing behavior being a characteristic trait. The outcome in terms of symptoms, perceived psycho-familial burden and impairment after 6 months is encouraging. However, we are aware that our preliminary data offer thought-provoking impulses rather than firm findings.

Background In vitro immunoglobulin E (IgE) tests can be better standardized if based on molecules rather than extracts. However, singleplex screening tests for respiratory or food allergies are still based on extracts only.

Target To validate a novel singleplex IgE screening test for respiratory allergies, based on a mix of major allergenic molecules Der p 1, Der p 2, Fel d 1, Can f 1, Can f 2, Can f 3, Can f 5, Bet v 1, Phl p 1, and Art v 1 (Molecular SX01, NOVEOS, HYCOR, USA), and requiring only four microliters (μl) of serum.

Methods We examined six subsets of sera from participants of the German Multicenter Allergy Study (MAS) birth cohort enrolling 1314 newborns during 1990: (1) monosensitized (n = 58); (2) polysensitized (n = 24); (3) nonsensitized, with total IgE levels above (n = 24) or (4) below (n = 24) 300 kU/L; (5) sensitized to milk and/or egg but not to airborne allergens (n = 24); and (6) sera of children aged ≤5 years at their earliest IgE monosensitization to airborne allergens (n = 41). Sera were analyzed with the novel molecular SX01 test (NOVEOS) and with three categories of comparators: ImmunoCAP Phadiatop SX01, extracts, and molecules of D. pteronyssinus, cat, dog, grass, and birch. Sensitivity, specificity, positive and negative predictive values were calculated. Quantitative interrelationships were determined using Spearman's rank-order correlation coefficient and Bland–Altmann plots.

Results The molecular SX01 test predicted the outcome of IgE tests based on molecules, extracts, or Phadiatop in 188 (96.4%), 171 (87.7%), and 171 (87.7%) of the 195 sera, respectively. Accordingly, sensitivity was 93.5%, 89.0%, and 82.4%, whereas specificity was 100%, 97.6%, and 96.1% when compared with molecular, extract, and Phadiatop tests, respectively. Inconsistent outcomes were largely confined to sera with IgE-Ab levels around the cutoff value of 0.35 kU/L, except for 5/195 (2.5%) sera, containing high levels of IgE to Phl p 5 and/or Alt a 1 only. IgE levels measured by the molecular SX01 test and with IgE tests to molecules, extracts, and Phadiatop were highly correlated (rho 0.90; p < .001), (rho 0.87, p < .001), (rho 0.84, p < .001), respectively. The novel molecular SX01 test detected IgE-Ab in 27/28 (sensitivity 96.4%) of the sera of preschool children at their earliest IgE sensitization to the same molecules.

Discussion Our study validates the prototype of a novel category of IgE test, based on molecular mixes. The test's rather good precision and accuracy in early screening IgE sensitization to airborne allergens in German children may be further improved by adding a few other molecules, such as Phl p 5 and Alt a 1.

Background The Dermatophagoides pteronyssinus molecule Der p 23 is a major allergen whose clinical relevance has been shown in cross-sectional studies. We longitudinally analysed the trajectory of Der p 23-specific IgE antibody (sIgE) levels throughout childhood and youth, their early-life determinants and their clinical relevance for allergic rhinitis and asthma.

Methods We obtained sera and clinical data of 191 participants of the German Multicentre Allergy Study, a prospective birth cohort. Serum samples from birth to 20 years of age with sIgE reactivity to Der p 23 in a customised semiquantitative microarray were newly analysed with a singleplex quantitative assay. Early mite exposure was assessed by measuring the average content of Der p 1 in house dust at 6 and 18 months.

Results Der p 23-sIgE levels were detected at least once in 97/191 participants (51%). Prevalence of Der p 23 sensitisation and mean sIgE levels increased until age 10 years, plateaued until age 13 years and were lowest at age 20 years. Asthma, allergic rhinitis (AR) and atopic dermatitis (AD) were more prevalent in Der p 23-sensitised children, including those with monomolecular but persistent sensitisation (11/97, 11%). A higher exposure to mites in infancy and occurrence of AD before 5 years of age preceded the onset of Der p 23 sensitisation, which in turn preceded a higher incidence of asthma.

Conclusions Der p 23 sensitisation peaks in late childhood and then decreases. It is preceded by early mite exposure and AD. Asthma and AR can occur in patients persistently sensitised to Der p 23 as the only mite allergen, suggesting the inclusion of molecular testing of Der p 23-sIgE for subjects with clinical suspicion of HDM allergy but without sIgE to other major D.pt. allergens.

Background Peanut and tree nut allergies are common in childhood and often severe in nature. The clinical picture shows a wide variety of symptoms.

Objective To analyze the distribution of clinical symptoms and severity during oral food challenges (OFC) in children.

Methods Analysis of 1.013 prospectively recorded, positive OFCs with peanut (n = 607), hazelnut (n = 266), walnut (n = 97), and cashew (n = 43). Symptoms were categorized as immediate-type skin, gastrointestinal, upper and lower respiratory, cardiovascular symptoms, and eczema exacerbation. Symptom severity and treatment were recorded.

Results Skin symptoms presented in 78%, followed by gastrointestinal (47%), upper (42%), and lower respiratory symptoms (32%). Cardiovascular symptoms presented in 6%. In three-quarter of the reactions, more than one organ was involved. Importantly, severe reactions occurred at every dose level. Peanut- and cashew-allergic patients had a higher relative risk of gastrointestinal symptoms compared with hazelnut- and walnut-allergic patients. Patients without vomiting had a 1.7 times higher risk developing immediate-type skin and/or lower respiratory symptoms. Three-quarter of the patients ever had eczema but worsening presented in only 10.5% of the OFCs. In patients with multiple food allergies, organs involved, eliciting dose and severity differed between allergens.

Conclusion Although comparisons between allergen groups with different clinical history, severity, comorbidities and laboratory data are difficult and might contain bias, our data confirm the high allergenic potential of peanut and tree nuts. The rare occurrence of eczema worsening emphasizes that avoidance diets of peanuts and tree nuts to cure eczema seem to be unnecessary and may hamper tolerance maintenance.

Despite the prominence of person-centred care (PCC) in nursing, there is no general agreement on the assumptions and the meaning of PCC. We sympathize with the work of others who rethink PCC towards relational, embedded, and temporal selfhood rather than individual personhood. Our perspective addresses criticism of humanist assumptions in PCC using critical posthumanism as a diffraction from dominant values We highlight the problematic realities that might be produced in healthcare, leading to some people being more likely to be disenfranchised from healthcare than others. We point to the colonial, homo- and transphobic, racist, ableist, and ageist consequences of humanist traditions that have influenced the development of PCC. We describe the deep rooted conditions that structurally uphold inequality and undermine nursing practice that PCC reproduces. We advocate for the self-determination of patients and emphasize that we support the fundamental mechanisms of PCC enabling patients' choice; however, without critical introspection, these are limited to a portion of humans. Last, we present limitations of our perspective based on our white*-cisheteropatriarchy** positionality. We point to the fact that any reimagining of models such as PCC should be carefully done by listening, following, and ceding power to people with diversity dimensions*** and the lived experience or expertise that exists from diverse perspectives. We point towards Black, queer feminism, and critical disabilities studies to contextualize our point of critique with humanism and PCC to amplify equity for all people and communities. Theory and philosophy are useful to understand restrictive factors in healthcare delivery and to inform systematic strategies to improve the quality of care so as not to perpetuate the oppression of groups of people with diversity dimensions. *We purposely capitalize Black and use lower case for white to decentre whiteness and as an intentional act of antiracism (see White Homework a podcast series by Tori W. Douglas). *Cisheteropatriarchy describes people with intersecting identities of dominant social groups; cisgender is the gender identity that aligns with the gender you were assigned at birth, hetero means heterosexual, and patriarchy refers to structural systems of power based on maleness where women are often excluded and hold less power. *With diversity dimensions, we refer to subjective lived experience and material realities of people that exist outside the 'dominant minorities' of white-cisheteropatriarchy, meaning groups of people in society who historically and currently hold more power and through this, structurally dominate the norms and possibilities of living for other people.

Das Workbook "Politisches Weiterdenken" bietet einen innovativen Ansatz zur politischen Bildung im digitalen Zeitalter. Es verknüpft theoretische Grundlagen mit praxisorientierten Methoden und stellt generative KI als Werkzeug für die Förderung von Zukunftskompetenzen und demokratischer Teilhabe vor. Zentrale Themen sind Futures Literacy, Truth Literacy, Complexity Literacy und der reflektierte Einsatz von KI in Bildungskontexten. Angesichts populistischer Herausforderungen und gesellschaftlicher Transformationen unterstützt das Workbook Lehrende und Lernende dabei, kritisches Denken und Selbstwirksamkeit zu stärken. Neben theoretischen Impulsen enthält es konkrete Szenarien, Mega-Prompts und Anleitungen, um politische Entwicklungen auf verschiedenen gesellschaftlichen Ebenen zu reflektieren und praxisnah zu bearbeiten.

Efficient crew scheduling is essential for cost-effective and reliable public transportation operations. This paper presents a mathematical model for an extensive duty network and introduces an advanced scheduling approach that integrates column generation and dynamic network generation to iteratively construct and refine duty schedules. The column generation method is used to compute an upper bound and generate an initial duty schedule, while dynamic network generation iteratively improves the schedule, ensuring feasibility and enabling cost reductions. The proposed approach balances computational efficiency with solution quality, allowing for early termination with near-optimal results.

Both the extensive and dynamic approaches face challenges in computing optimal solutions within a practical runtime. The extensive duty network model benefits significantly from preprocessing, which reduces the complexity of the problem and improves solvability. However, its applicability remains limited for medium to large-scale instances. The dynamic network generation approach, in contrast, efficiently computes high-quality duty schedules in comparably short computational time. It can be used flexibly—either to generate initial feasible solutions, refine existing schedules, or continue iterating until optimality is proven if required.

Despite the challenges in proving optimality, the structured nature of the dynamic network generation approach makes it highly promising for integration with other planning steps, such as timetabling and vehicle scheduling. Future research should further evaluate the integration of dynamic network generation into broader transportation planning frameworks and explore enhancements to improve convergence speed. Overall, while not necessarily the most efficient standalone method for optimizing crew schedules, the dynamic network generation approach offers a powerful and flexible tool for integrated public transportation planning, enabling both efficiency gains and operational adaptability.

Organized domestic workers have recently been at the forefront of political campaigns in Peru to promote legislative reforms concerning forced labor. This empirical case study investigates how the international labor norm concerning forced labor is disseminated, appropriated and politically mobilized at the national level. It thereby examines the dynamics and cultural embedding of the appropriation process and its implications for labor regulation, policy responses and trade union actions. The research delves into the ways and spaces in which international and national actors, the International Labour Organisation and national domestic workers’ trade unions, translate the international norms into their local context, adapt and negotiate them. I argue that the mobilization against forced domestic labor is embedded in the period of reconfiguration of the domestic work sector in Peru and that it is oriented toward internationally institutionalized categorizations and indicators. By employing the theoretical lens of vernacularization, a contextualizing examination of the labor policy actors, their positions and knowledge bases, as well as an analysis of decisive moments, spaces, technologies and developments of communicative actions, enables a sociological understanding of the emergence and manifestation of the mobilization against forced domestic work. The process of vernacularization creates a localized version of international norms that retains elements of the original while incorporating local specificities in the implementation. It creates a space where different forms of knowledge interact – local knowledge and transnational technicized knowledge. This research adds a nuanced understanding of the intersection between internationalization of ‘universal’ labor standards, knowledge production, and trade union mobilization within a feminized and racialized sector.

This open access textbook offers science education researchers a hands-on guide for learning, critically examining, and integrating machine learning (ML) methods into their science education research projects. These methods power many artificial intelligence (AI)-based technologies and are widely adopted in science education research. ML can expand the methodological toolkit of science education researchers and provide novel opportunities to gain insights on science-related learning and teaching processes, however, applying ML poses novel challenges and is not suitable for every research context.

The volume first introduces the theoretical underpinnings of ML methods and their connections to methodological commitments in science education research. It then presents exemplar case studies of ML uses in both formal and informal science education settings. These case studies include open-source data, executable programming code, and explanations of the methodological criteria and commitments guiding ML use in each case. The textbook concludes with a discussion of opportunities and potential future directions for ML in science education.

This textbook is a valuable resource for science education lecturers, researchers, under-graduate, graduate and postgraduate students seeking new ways to apply ML in their work.

The Vitruvian Man is a metaphor for the "ideal man" by feminist posthuman philosopher Rosi Braidotti (2013) as a proxy for eurocentric humanist ideals. The first half of this paper extends Braidotti's concept by thinking about the metaphor of the "ideal nurse" (Vitruvian nurse) and how this metaphor contributes to racism, oppression, and burnout in nursing and might restrict the professionalization of nursing. The Vitruvian nurse is an idealized and perfected form of a nurse with self-sacrificial language (re)producing self-sacrificing expectations. The second half of this paper looks at how regulatory frameworks (using the example of UK's Nursing and Midwifery Council Code of Conduct) institutionalize the conditions of possibility through collective imaginations. The domineering expectations found within the Vitruvian nurse metaphor and further codified by regulatory frameworks give rise to boredom and burnout. The paper ends by suggesting possible ways to diffract regulatory frameworks to practice with affirmative ethics and reduce feelings of self-sacrifice and exhaustion among nurses.

Aim Analysis of cerebrospinal fluid (CSF) is essential for diagnostic workup of patients with neurological diseases and includes differential cell typing. The current gold standard is based on microscopic examination by specialised technicians and neuropathologists, which is time-consuming, labour-intensive and subjective.

Methods We, therefore, developed an image analysis approach based on expert annotations of 123,181 digitised CSF objects from 78 patients corresponding to 15 clinically relevant categories and trained a multiclass convolutional neural network (CNN).

Results The CNN classified the 15 categories with high accuracy (mean AUC 97.3%). By using explainable artificial intelligence (XAI), we demonstrate that the CNN identified meaningful cellular substructures in CSF cells recapitulating human pattern recognition. Based on the evaluation of 511 cells selected from 12 different CSF samples, we validated the CNN by comparing it with seven board-certified neuropathologists blinded for clinical information. Inter-rater agreement between the CNN and the ground truth was non-inferior (Krippendorff's alpha 0.79) compared with the agreement of seven human raters and the ground truth (mean Krippendorff's alpha 0.72, range 0.56–0.81). The CNN assigned the correct diagnostic label (inflammatory, haemorrhagic or neoplastic) in 10 out of 11 clinical samples, compared with 7–11 out of 11 by human raters.

Conclusions Our approach provides the basis to overcome current limitations in automated cell classification for routine diagnostics and demonstrates how a visual explanation framework can connect machine decision-making with cell properties and thus provide a novel versatile and quantitative method for investigating CSF manifestations of various neurological diseases.

Aims Glioblastomas are high-grade brain tumours that are characterised by the accumulation of brain-resident microglia and peripheral macrophages. Recruitment of these myeloid cells can be facilitated by CCR2/CCL2 signalling. Besides the well-known CCR2+ macrophages, we have identified microglia expressing CCR2 in glioma tissues. Thus, we investigated how Ccr2-deficiency of one of the myeloid cell populations affects the other population and tumour biology.

Methods We generated four chimeric groups to analyse single and combined Ccr2-deficiency of microglia and macrophages. On day 21 after tumour cell implantation (GL261), we conducted flow cytometry, immunofluorescence and real-time polymerase chain reaction analyses. Tumour volume and metabolism were determined by magnetic resonance imaging and magnetic resonance spectroscopy. Moreover, in vitro studies were performed with primary microglia and bone marrow-derived macrophages.

Results We demonstrated reduced infiltration of macrophages and microglia depending on the lack of Ccr2. However, the total number of myeloid cells remained constant except for the animals with dual Ccr2-knockout. Both microglia and macrophages with Ccr2-deficiency showed impaired expression of proinflammatory molecules and altered phagocytic activity. Despite the altered immunologic phenotype caused by Ccr2-deficiency, glioma progression and metabolism were hardly affected. Alterations were detected solely in apoptosis and proliferation of tumours from animals with specific Ccr2-deficient microglia, whereas vessel stability was increased in mice with Ccr2-knockout in both cell populations.

Conclusion These results indicate that microglia and macrophages provide a homoeostatic balance within glioma tissue and compensate for the lack of the corresponding counterpart. Moreover, we identified that the CCR2/CCL2 axis is involved in the immunologic function of microglia and macrophages beyond its relevance for migration.