Search

Navigating social situations is complex due to others' hidden intentions and evolving strategies, requiring learning from past experiences. Anxiety complicates adaptation to uncertainty, especially in non-social settings. However, research on the anxiety's impact on learning within social uncertainty remains scarce. In a preregistered study (N = 190), we investigated whether individuals with higher trait anxiety struggled to adjust learning rates in a social context with stable or volatile outcomes utilizing various learning models (e.g., additive, multiplicative, betrayal). Participants engaged in a modified trust game with stable and volatile players, alongside a non-social task with slot machines. Participants showed higher learning rates in social than non-social contexts, with notably elevated social learning rates in individuals with heightened fear of negative evaluation (FNE)—a crucial trait linked to anxiety, especially social anxiety. This suggests individuals with increased FNE might be more sensitive to learning under social uncertainty.

Abstract In global impact modeling, there is a need to address the heterogeneous characteristics of households and individuals that drive different behavioral responses to, for example, environmental risk, socio-economic policy changes and spread of diseases. In this research, we present GLOPOP-S, the first global synthetic population dataset with 1,999,227,130 households and 7,335,881,094 individuals for the year 2015, consistent with population statistics at an administrative unit 1 level. GLOPOS-S contains the following attributes: age, education, gender, income/wealth, settlement type (urban/rural), household size, household type, and for selected countries in the Global South, ownership of agricultural land and dwelling characteristics. To generate GLOPOP-S, we use microdata from the Luxembourg Income Study (LIS) and Demographic and Health Surveys (DHS) and apply synthetic reconstruction techniques to fit national survey data to regional statistics, thereby accounting for spatial differences within and across countries. Additionally, we have developed methods to generate data for countries without available microdata. The dataset can be downloaded per region or country. GLOPOP-S is open source and can be extended with other attributes.

Accurate hydrologic modeling is vital to characterizing how the terrestrial water cycle responds to climate change. Pure deep learning (DL) models have been shown to outperform process-based ones while remaining difficult to interpret. More recently, differentiable physics-informed machine learning models with a physical backbone can systematically integrate physical equations and DL, predicting untrained variables and processes with high performance. However, it is unclear if such models are competitive for global-scale applications with a simple backbone. Therefore, we use – for the first time at this scale – differentiable hydrologic models (full name δHBV-globe1.0-hydroDL, shortened to δHBV here) to simulate the rainfall–runoff processes for 3753 basins around the world. Moreover, we compare the δHBV models to a purely data-driven long short-term memory (LSTM) model to examine their strengths and limitations. Both LSTM and the δHBV models provide competitive daily hydrologic simulation capabilities in global basins, with median Kling–Gupta efficiency values close to or higher than 0.7 (and 0.78 with LSTM for a subset of 1675 basins with long-term discharge records), significantly outperforming traditional models. Moreover, regionalized differentiable models demonstrated stronger spatial generalization ability (median KGE 0.64) than a traditional parameter regionalization approach (median KGE 0.46) and even LSTM for ungauged region tests across continents. Nevertheless, relative to LSTM, the differentiable model was hampered by structural deficiencies for cold or polar regions, highly arid regions, and basins with significant human impacts. This study also sets the benchmark for hydrologic estimates around the world and builds a foundation for improving global hydrologic simulations.

One aim of vocational education is educating students for occupations by fostering the development of students' capacities to become successful practitioners. During their education students are usually afforded work experience. When this is the case, students learn both at school and at the workplace. Learning at the workplace requires assessment, but this differs from assessment at school because of where (at the workplace), how (through participation) and what students learn (a process of belonging, becoming and being). At the workplace, students are usually assigned an educator who takes on the dual role of educator and assessor. This review takes a sociocultural perspective on learning at the workplace and from this perspective brings together what is already known about how workplace educators assess student performance through a qualitative systematic review. Our analysis aimed for narrative synthesis using iterative thematic analysis. The results depict workplace assessment as manifested in day-to-day work and shaped by relationships. Workplace educators are engaged in a continuous process of assessment-related interactions. They prefer using criteria that are embedded in the norms and values of their vocational community, rather than criteria prescribed by school. Workplace assessment requires negotiated criteria and truly collaborative assessment practices. These practices can be purposefully co-designed and require close communication between school and work. This review shows that assessment of workplace performance in vocational education can be conceptualised as a practice that is shaped by the specific workplace in which it is embedded. From this perspective assessment can be explicated and acknowledged, and as a consequence be further conceptualised and researched in both assessment research and vocational education research.

The assessment of workplace learning by educators at the workplace is a complex and inherently social process, as the workplace is a participatory learning environment. We therefore propose seeing assessment as a process of judgment embedded in a community of practice and to this purpose use the philosophy of inferentialism to unravel the judgment process of workplace educators by seeing it as an interrelated system of judgments, actions and reasons. Focussing on the unfolding of a process, we applied a longitudinal holistic case study design. Results show that educators are engaged in a constant judgment process during which they use multiple and adaptive frames of reference when forming their judgment about students. They construct an overarching image of students that develops throughout the placement, and their judgments about students go hand in hand with their actions relating to fostering independent practice.

The inadequate disposal of tires poses a significant threat to human health and requires effective recycling solutions. The crosslinked structure of rubber, formed through sulfur bridges during vulcanization, presents a major challenge for recycling because it prevents the rubber scraps from being reshaped thermoplastically. Reclaiming or devulcanization aims to reverse this crosslinking, allowing waste rubber to be transformed into products that can be reprocessed and revulcanized, thereby saving costs and preserving resources. Microwave technology shows promise for devulcanization due to its ability to break sulfur crosslinks. In this study, we investigate the devulcanization of ground tire rubber (GTR) through a combined process applied to samples from both car and truck tires subjected to varying periods of microwave irradiation (0, 3, 5 and 10 min). The devulcanized GTR was then blended with natural rubber (NR) and underwent a new vulcanization process, simulating recycling for novel applications. The GTR was mixed with NR in proportions of 0, 10, 30 and 50 parts per hundred rubber (phr). This study also examines the differences between the GTR from car tires and GTR from truck tires. The results showed that the treatment effectively breaks the crosslinks in the GTR, creating double bonds (C=C) and improving the mechanical properties of the revulcanized samples. The crosslinking density and related properties of the samples increased with treatment time, reaching a maximum at 5 min of microwave treatment, followed by a decrease at 10 min. Additionally, the incorporation of GTR enhanced the thermal stability of the resulting materials.

Background Blockade of the programmed cell death protein 1 (PD-1) immune checkpoint (ICB) is revolutionizing cancer therapy, but little is known about the mechanisms governing its expression on CD8 T cells. Because PD-1 is induced during activation of T cells, we set out to uncover regulators whose inhibition suppresses PD-1 abundance without adversely impacting on T cell activation.Methods To identify PD-1 regulators in an unbiased fashion, we performed a whole-genome, fluorescence-activated cell sorting (FACS)-based CRISPR-Cas9 screen in primary murine CD8 T cells. A dual-readout design using the activation marker CD137 allowed us to uncouple genes involved in PD-1 regulation from those governing general T cell activation.Results We found that the inactivation of one of several members of the TMED/EMP24/GP25L/p24 family of transport proteins, most prominently TMED10, reduced PD-1 cell surface abundance, thereby augmenting T cell activity. Another client protein was cytotoxic T lymphocyte-associated protein 4 (CTLA-4), which was also suppressed by TMED inactivation. Treatment with TMED inhibitor AGN192403 led to lysosomal degradation of the TMED-PD-1 complex and reduced PD-1 abundance in tumor-infiltrating CD8 T cells (TIL) in mice, thus reversing T cell dysfunction. Clinically corroborating these findings, single-cell RNA analyses revealed a positive correlation between TMED expression in CD8 TIL, and both a T cell dysfunction signature and lack of ICB response. Similarly, patients receiving a TIL product with high TMED expression had a shorter overall survival.Conclusion Our results uncover a novel mechanism of PD-1 regulation, and identify a pharmacologically tractable target whose inhibition suppresses PD-1 abundance and T cell dysfunction.

IntroductionAutosomal dominant retinitis pigmentosa type 17 (adRP, type RP17) is caused by complex structural variants (SVs) affecting a locus on chromosome 17 (chr17q22). The SVs disrupt the 3D regulatory landscape by altering the topologically associating domain (TAD) structure of the locus, creating novel TAD structures (neo-TADs) and ectopic enhancer-gene contacts. Currently, screening for RP17-associated SVs is not included in routine diagnostics given the complexity of the variants and a lack of cost-effective detection methods. The aim of this study was to accurately detect novel RP17-SVs by establishing a systematic and efficient workflow.MethodsGenetically unexplained probands diagnosed with adRP (n = 509) from an international cohort were screened using a smMIPs or genomic qPCR-based approach tailored for the RP17 locus. Suspected copy number changes were validated using high-density SNP-array genotyping, and SV breakpoint characterization was performed by mutation-specific breakpoint PCR, genome sequencing and, if required, optical genome mapping. In silico modeling of novel SVs was performed to predict the formation of neo-TADs and whether ectopic contacts between the retinal enhancers and the GDPD1-promoter could be formed.ResultsUsing this workflow, potential RP17-SVs were detected in eight probands of which seven were confirmed. Two novel SVs were identified that are predicted to cause TAD rearrangement and retinal enhancer-GDPD1 contact, one from Germany (DE-SV9) and three with the same SV from the United States (US-SV10). Previously reported RP17-SVs were also identified in three Australian probands, one with UK-SV2 and two with SA-SV3.DiscussionIn summary, we describe a validated multi-step pipeline for reliable and efficient RP17-SV discovery and expand the range of disease-associated SVs. Based on these data, RP17-SVs can be considered a frequent cause of adRP which warrants the inclusion of RP17-screening as a standard diagnostic test for this disease.

The human neural retina is a complex tissue with abundant alternative splicing and more than 10% of genetic variants linked to inherited retinal diseases (IRDs) alter splicing. Traditional short-read RNA-sequencing methods have been used for understanding retina-specific splicing but have limitations in detailing transcript isoforms. To address this, we generated a proteogenomic atlas that combines PacBio long-read RNA-sequencing data with mass spectrometry and whole genome sequencing data of three healthy human neural retina samples. We identified nearly 60,000 transcript isoforms, of which approximately one-third are novel. Additionally, ten novel peptides confirmed novel transcript isoforms. For instance, we identified a novel IMPDH1 isoform with a novel combination of known exons that is supported by peptide evidence. Our research underscores the potential of in-depth tissue-specific transcriptomic analysis to enhance our grasp of tissue-specific alternative splicing. The data underlying the proteogenomic atlas are available via EGA with identifier EGAD50000000101, via ProteomeXchange with identifier PXD045187, and accessible through the UCSC genome browser.

Objective To investigate whether six combined computer- and mobile-based physical activity interventions differ regarding use, attrition, usability and appreciation among adults aged 50 years and older. Methods The interventions were studied in a randomized controlled trial. Participants were allocated to the computer-based Active Plus or I Move program including a mobile-based activity tracker, or ecological momentary intervention (EMI), or chatbot, or to a waiting list control group. Use and attrition were investigated via log data gathered within the intervention software. Appreciation was assessed via online evaluation questionnaires. ANOVAs and Chi-squares were performed to test for intervention differences on use, attrition and appreciation ( p ≤ .05). Results A total of 954 participants aged 50 years and older with varying health conditions were included. Attrition differed between interventions ( χ 2 = 27.121, p

To understand the question why people obey or break rules, different approaches have focused on different theories and subsets of variables. The present research develops a cross-theoretical approach that integrates these perspectives. We apply this in a survey of compliance with COVID-19 pandemic mitigation rules in Israel. The data reveal that compliance in this setting was shaped by a combination of variables originating from legitimacy, capacity, and opportunity theories (but not rational choice or social theories). This demonstrates the importance of moving beyond narrow theoretical perspectives of compliance, to a cross-theoretical understanding-in which different theoretical approaches are systematically integrated.

Abstract Histone H2AX plays a key role in DNA damage signalling in the surrounding regions of DNA double-strand breaks (DSBs). In response to DNA damage, H2AX becomes phosphorylated on serine residue 139 (known as γH2AX), resulting in the recruitment of the DNA repair effectors 53BP1 and BRCA1. Here, by studying resistance to poly(ADP-ribose) polymerase (PARP) inhibitors in BRCA1/2-deficient mammary tumours, we identify a function for γH2AX in orchestrating drug-induced replication fork degradation. Mechanistically, γH2AX-driven replication fork degradation is elicited by suppressing CtIP-mediated fork protection. As a result, H2AX loss restores replication fork stability and increases chemoresistance in BRCA1/2-deficient tumour cells without restoring homology-directed DNA repair, as highlighted by the lack of DNA damage-induced RAD51 foci. Furthermore, in the attempt to discover acquired genetic vulnerabilities, we find that ATM but not ATR inhibition overcomes PARP inhibitor (PARPi) resistance in H2AX-deficient tumours by interfering with CtIP-mediated fork protection. In summary, our results demonstrate a role for H2AX in replication fork biology in BRCA-deficient tumours and establish a function of H2AX separable from its classical role in DNA damage signalling and DSB repair.

Abstract Background Antimicrobial resistance is a major global health threat. Therefore, promising new antibacterial technologies that could minimize our dependence on antibiotics should be widely adopted. This study aims to identify the barriers and facilitators of the adoption of new antibacterial technologies in hospital patient care. Methods Semi-structured interviews, based on the Consolidated Framework for Implementation Research, were conducted with healthcare professionals related to the orthopedics department of an academic hospital in The Netherlands. Results In total, 11 healthcare professionals were interviewed. Scientific evidence for the effectiveness of the technology was the most explicitly mentioned facilitator of adoption, but other (often contextual) factors were also considered to be important. At the level of the inner and outer setting, high costs and lacking coverage, competition from other firms, and problems with ordering and availability were the most explicit perceived barriers to adoption. Participants did not collectively feel the need for new antibacterial technologies. Conclusions Barriers and facilitators of the adoption of new antibacterial technologies were identified related to the technology, the hospital, and external factors. The implementation climate might have an indirect influence on adoption. New antibacterial technologies that are scientifically proven effective, affordable, and easily obtainable will most likely be adopted.

UNLABELLED: To understand how compliance develops both in everyday and corporate environments, it is crucial to understand how different mechanisms work together to shape individuals (non)compliant behavior. Existing compliance studies typically focus on a subset of theories (i.e., rational choice theories, social theories, legitimacy theories, capacity theories, and opportunity theories) to understand how key variables from one or several of these theories shape individual compliance. The present study provides a first integrated understanding of compliance, rooted in complexity science, in which key elements from these theories are considered simultaneously, and their relations to compliance and each other are explored using network analysis. This approach is developed by analyzing online survey data (N = 562) about compliance with COVID-19 mitigation measures. Traditional regression analysis shows that elements from nearly all major compliance theories (except for social theories) are associated with compliance. The network analysis revealed groupings and interconnections of variables that did not track the existing compliance theories and point to a complexity overlooked in existing compliance research. These findings demonstrate a fundamentally different perspective on compliance, which moves away from traditional narrow, non-network approaches. Instead, they showcase a complexity science understanding of compliance, in which compliance is understood as a network of interacting variables derived from different theories that interact with compliance. This points to a new research agenda that is oriented on mapping compliance networks, and testing and modelling how regulatory and management interventions interact with each other and compliance within such networks. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10551-022-05128-8.

Students' health profession education includes learning at the workplace through placements. For students, participating in daily work activities in interaction with supervisors, co-workers and peers is a valuable practice to learn the expertise that is needed to become a health care professional. To contribute to the understanding of HPE-students' workplace learning, the focus of this study is to identify affordances and characterise student's participation during placements. We applied a research design based on observations. Three student-physiotherapists and four student-nurses were shadowed during two of their placement days. A categorisation of affordances is provided, in terms of students' participation in activities, direct interactions and indirect interactions. Students' daily participation in placements is discussed through unique combinations and sequences of the identified affordances reflecting changing patterns over time, and differences in the degree of presence or absence of supervisors, co-workers and peers.

IntroductionGenetic predisposition to autoimmune encephalitis with antibodies against N-methyl-D-aspartate receptor (NMDAR) is poorly understood. Given the diversity of associated environmental factors (tumors, infections), we hypothesized that human leukocyte antigen (HLA) and killer-cell immunoglobulin-like receptors (KIR), two extremely polymorphic gene complexes key to the immune system, might be relevant for the genetic predisposition to anti-NMDAR encephalitis. Notably, KIR are chiefly expressed by Natural Killer (NK) cells, recognize distinct HLA class I allotypes and play a major role in anti-tumor and anti-infection responses.MethodsWe conducted a Genome Wide Association Study (GWAS) with subsequent control-matching using Principal Component Analysis (PCA) and HLA imputation, in a multi-ethnic cohort of anti-NMDAR encephalitis (n=479); KIR and HLA were further sequenced in a large subsample (n=323). PCA-controlled logistic regression was then conducted for carrier frequencies (HLA and KIR) and copy number variation (KIR). HLA-KIR interaction associations were also modeled. Additionally, single cell sequencing was conducted in peripheral blood mononuclear cells from 16 cases and 16 controls, NK cells were sorted and phenotyped.ResultsAnti-NMDAR encephalitis showed a weak HLA association with DRB1*01:01~DQA1*01:01~DQB1*05:01 (OR=1.57, 1.51, 1.45; respectively), and DRB1*11:01 (OR=1.60); these effects were stronger in European descendants and in patients without an underlying ovarian teratoma. More interestingly, we found increased copy number variation of KIR2DL5B (OR=1.72), principally due to an overrepresentation of KIR2DL5B*00201. Further, we identified two allele associations in framework genes, KIR2DL4*00103 (25.4% vs. 12.5% in controls, OR=1.98) and KIR3DL3*00302 (5.3% vs. 1.3%, OR=4.44). Notably, the ligands of these KIR2DL4 and KIR3DL3, respectively, HLA-G and HHLA2, are known to act as immune checkpoint with immunosuppressive functions. However, we did not find differences in specific KIR-HLA ligand interactions or HLA-G polymorphisms between cases and controls. Similarly, gene expression of CD56dim or CD56bright NK cells did not differ between cases and controls.DiscussionOur observations for the first time suggest that the HLA-KIR axis might be involved in anti-NMDAR encephalitis. While the genetic risk conferred by the identified polymorphisms appears small, a role of this axis in the pathophysiology of this disease appears highly plausible and should be analyzed in future studies.

Summary: Inherited retinal diseases (IRDs) are a group of rare monogenic diseases with high genetic heterogeneity (pathogenic variants identified in over 280 causative genes). The genetic diagnostic rate for IRDs is around 60%, mainly thanks to the routine application of next-generation sequencing (NGS) approaches such as extensive gene panels or whole exome analyses. Whole-genome sequencing (WGS) has been reported to improve this diagnostic rate by revealing elusive variants, such as structural variants (SVs) and deep intronic variants (DIVs).We performed WGS on 33 unsolved cases with suspected autosomal recessive IRD, aiming to identify causative genetic variants in non-coding regions or to detect SVs that were unexplored in the initial screening. Most of the selected cases (30 of 33, 90.9%) carried monoallelic pathogenic variants in genes associated with their clinical presentation, hence we first analyzed the non-coding regions of these candidate genes. Whenever additional pathogenic variants were not identified with this approach, we extended the search for SVs and DIVs to all IRD-associated genes.Overall, we identified the missing causative variants in 11 patients (11 of 33, 33.3%). These included three DIVs in ABCA4, CEP290 and RPGRIP1; one non-canonical splice site (NCSS) variant in PROM1 and three SVs (large deletions) in EYS, PCDH15 and USH2A. For the previously unreported DIV in CEP290 and for the NCCS variant in PROM1, we confirmed the effect on splicing by reverse transcription (RT)-PCR on patient-derived RNA.This study demonstrates the power and clinical utility of WGS as an all-in-one test to identify disease-causing variants missed by standard NGS diagnostic methodologies.

Background: Peritoneal metastases (PM) commonly occur in colorectal cancer patients. Systemic chemotherapy yields poor outcomes for these patients. It is hypothesised that traditional systemic chemotherapy is not very effective for this patient population. This study investigates to what extent systemic anti-cancer therapy crosses the peritoneal barrier. Methods: In a Phase I study, eighteen patients received systemic oxaliplatin, 5-FU, and bevacizumab. Plasma and peritoneal fluid samples were collected to measure drug concentrations. A non-compartmental analysis determined the Area Under the Curve (AUC) for oxaliplatin and 5-FU in both matrices. Intraperitoneal (IP) and intravenous (IV) exposure ratios were calculated, along with the bevacizumab concentration IP/IV ratio. The relationship between tumour load and IP/IV ratios and the correlation between the IP/IV ratios of different treatments were assessed statistically. Results: A total of 438 5-FU samples and 578 oxaliplatin samples were analysed in plasma and peritoneal fluid. Bevacizumab was quantified with 17 measurements in plasma and 15 measurements IP. Median IP/IV ratios were 0.143, 0.352 and 0.085 for 5-FU, oxaliplatin and bevacizumab, respectively. Oxaliplatin exhibited a longer IP half-life than 5-FU. A correlation was found between oxaliplatin and bevacizumab IP/IV ratios (R=0.69, p=0.01). No statistical correlations were found between the other investigated drugs. Conclusions: Our findings indicate that only a small percentage of systemically administered anti-cancer treatment reaches the IP cavity, questioning their efficacy against PM. This strengthens the hypothesis for repeated intraperitoneal chemotherapy to reach adequate anti-cancer drug levels.

Introduction Health inequalities are rooted in inequality in vital resources for health, including financial resources, a supportive informal network, a stable living situation, work or daytime activities or education and literacy. About 25% of Dutch citizens experience deprivation of such resources. Social policy consists of crucial instruments for improving resources in those groups but can also have adverse effects and lead to additional burdens. This project aims to contribute to the reduction of health inequalities through (1) a better understanding of how social policy interventions can contribute to reducing health inequality through the redistribution of burdens and resources and (2) developing anticipatory governance strategies to implement those insights, contributing to a change in social policy systems.Methods and analysis Two systems approaches are combined for establishing a systems change in the Netherlands. First, a realist approach enables insights into what in social policy interventions may impact health outcomes, for whom and under what circumstances. Second, an institutional approach enables scaling up these insights, by acknowledging the crucial role of institutional actors for accomplishing a systems change. Together with stakeholders, we perform a realist review of the literature and identify existing promising social policy interventions. Next, we execute mixed-methods realist evaluations of selected social policy interventions in seven municipalities, ranging from small, mid-size to large, and in both urban and rural settings. Simultaneously, through action research with (national) institutional actors, we facilitate development of anticipatory governance strategies.Ethics and dissemination This study is not liable to the Medical Research Involving Subjects Act (WMO). Informed consent to participate in the study is obtained from participants for the use of all forms of personally identifiable data. Dissemination will be codeveloped with target populations and includes communication materials for citizens, education materials for students, workshops, infographics and decision tools for policy-makers and publications for professionals.