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Having a clear and stable sense of how one performs in a field is a key contributor to goal pursuit. Performance feedback is often considered a crucial resource for developing this clear and stable self-knowledge but may be less optimally integrated when feedback is considered inaccurate or dishonest. The current paper investigates how such feedback perceptions may limit the development of people's ability self-concept, and how workplace contexts can restrict communication. A 2-week daily diary study among 197 junior researchers working in STEM-fields (N = 1,353 data points) showed that those in more competitive (vs. more collaborative) work environments overall perceived feedback as more inaccurate and dishonest (but not as more positively inflated). These results did not differ for men and women, showing that both face negative consequences of working in a more competitive context in terms of their ability to get high-quality feedback. On the daily level, results showed that days on which people received more inaccurate and dishonest (but not positively inflated) feedback were also days on which they reported higher imposter feelings, and lower ability self-esteem, self-concept clarity, and self-concept stability. In turn, days on which people felt more like an imposter and reported lower ability self-esteem, self-concept clarity, and self-concept stability, were also days on which motivation was lower. Ability self-esteem and self-concept clarity (but not imposter feelings and self-concept stability) were also related to lower daily risk-taking tendencies. Together, these results show that an important contextual factor--the perceived competitiveness of one's work environment--influences feedback inaccuracy and dishonesty, with consequences for the ability to develop a clear, stable and certain ability self-concept.

Understanding the neural underpinning of human gait and balance is one of the most pertinent challenges for 21st-century translational neuroscience due to the profound impact that falls and mobility disturbances have on our aging population. Posture and gait control does not happen automatically, as previously believed, but rather requires continuous involvement of central nervous mechanisms. To effectively exert control over the body, the brain must integrate multiple streams of sensory information, including visual, vestibular, and somatosensory signals. The mechanisms which underpin the integration of these multisensory signals are the principal topic of the present work. Existing multisensory integration theories focus on how failure of cognitive processes thought to be involved in multisensory integration leads to falls in older adults. Insufficient emphasis, however, has been placed on specific contributions of individual sensory modalities to multisensory integration processes and cross-modal interactions that occur between the sensory modalities in relation to gait and balance. In the present work, we review the contributions of somatosensory, visual, and vestibular modalities, along with their multisensory intersections to gait and balance in older adults and patients with Parkinson’s disease. We also review evidence of vestibular contributions to multisensory temporal binding windows, previously shown to be highly pertinent to fall risk in older adults. Lastly, we relate multisensory vestibular mechanisms to potential neural substrates, both at the level of neurobiology (concerning positron emission tomography imaging) and at the level of electrophysiology (concerning electroencephalography). We hope that this integrative review, drawing influence across multiple subdisciplines of neuroscience, paves the way for novel research directions and therapeutic neuromodulatory approaches, to improve the lives of older adults and patients with neurodegenerative diseases.

This study examined the impact of two questionnaire characteristics, scale position and questionnaire length, on the prevalence of random responders in the TIMSS 2015 eighth-grade student questionnaire. While there was no support for an absolute effect of questionnaire length, we did find a positive effect for scale position, with an increase of 5% in random responding over the course of the questionnaire (in both the shorter and the longer version). However, scale character turned out to be an unexpected but more important determinant. Scales about students' confidence in mathematics or science showed an increase of 9% in random responding, which is double the impact of scale position. Potential mechanisms underlying the confidence case and general implications of the results for questionnaire design are discussed.

Questionnaires in educational research assessing students' attitudes and beliefs are low-stakes for the students. As a consequence, students might not always consistently respond to a questionnaire scale but instead provide more random response patterns with no clear link to items' contents. We study inter-individual differences in students' intra-individual random responding profile across 19 questionnaire scales in the TIMSS 2015 eighth-grade student questionnaire in seven countries. A mixture IRT approach was used to assess students' random responder status on a questionnaire scale. A follow-up latent class analysis across the questionnaire revealed four random responding profiles that generalized across countries: A majority of consistent nonrandom responders, intermittent moderate random responders, frequent random responders, and students that were exclusively triggered to respond randomly on the confidence scales in the questionnaire. We discuss the implications of our findings in light of general data-quality concerns and the potential ineffectiveness of early-warning monitoring systems in computer-based surveys.

This article discusses the development of task-based performance tests designed to measure digital skills among children aged between 12 and 17 years old. The tasks reflect authentic everyday situations to evaluate skill levels. The primary objective is to design performance tests that provide a comprehensive understanding of children’s digital skills. The tests cover three distinct skill dimensions: (a) information navigation and processing; (b) communication and interaction; and (c) content creation and production. These include several subdimensions, offering a detailed perspective on children’s digital skills. The development process itself revealed several methodological challenges that needed to be addressed, yielding valuable lessons for future applications. Key lessons from our cross-national experiences include the importance of involving children early in the design process, using a combination of open-ended and closed tasks, and allocating ample time to walk through the coding scheme.

Objective: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a variety of disease symptoms and an unpredictable clinical course. To improve treatment outcome, stratification based on immunological manifestations commonly seen in patients with SLE such as autoantibodies, type I interferon (IFN) signature and neutrophil extracellular trap (NET) release may help. It is assumed that there is an association between these immunological phenomena, since NET release induces IFN production and IFN induces autoantibody formation via B-cell activation. Here we studied the association between autoantibodies, the IFN signature, NET release, and clinical manifestations in patients with SLE. Methods: We performed principal component analysis (PCA) and hierarchical clustering of 57 SLE-related autoantibodies in 25 patients with SLE. We correlated each autoantibody to the IFN signature and NET inducing capacity. Results: We observed two distinct clusters: one cluster contained mostly patients with a high IFN signature. Patients in this cluster often present with cutaneous lupus, and have higher anti-dsDNA concentrations. Another cluster contained a mix of patients with a high and low IFN signature. Patients with high and low NET inducing capacity were equally distributed between the clusters. Variance between the clusters is mainly driven by antibodies against histones, RibP2, RibP0, EphB2, RibP1, PCNA, dsDNA, and nucleosome. In addition, we found a trend towards increased concentrations of autoantibodies against EphB2, RibP1, and RNP70 in patients with an IFN signature. We found a negative correlation of NET inducing capacity with anti-FcER (r = −0.530; p = 0.007) and anti-PmScl100 (r = −0.445; p = 0.03). Conclusion: We identified a subgroup of patients with an IFN signature that express increased concentrations of antibodies against DNA and RNA-binding proteins, which can be useful for further patient stratification and a more targeted therapy. We did not find positive associations between autoantibodies and NET inducing capacity. Our study further strengthens the evidence of a correlation between RNA-binding autoantibodies and the IFN signature.

SUMMARY: Poultry litter amendments are commonly used to mitigate ammonia levels by binding and reducing ammonia volatilization in poultry housing, but there are concerns that litter amendments may impact broiler health. The goal of our study is to characterize the effect of an organic-certified diatomaceous earth litter amendment on the microbial content of the litter, and the gastrointestinal microbiome and leg health of fast-growing broilers. The study was carried out over a 2-yr period involving 5 consecutive flocks housed in a barn, where one half of the barn received the litter amendment while the other half served as a control. Key health indicators such as gastrointestinal microbiome diversity, and leg health were monitored. The findings suggest that the organic litter amendment, while not significantly altering the bacterial counts in the litter, may offer benefits in improving broiler wellbeing. This is evidenced by differences in footpad dermatitis and hock burn scores between the treated and control groups, highlighting the potential of such amendments not only in managing ammonia levels but also in promoting animal health. This study provides valuable insights into the applied implications of using an organic diatomaceous earth amendment in a poultry facility, indicating a positive impact on bird welfare without altering the microbial balance within the litter.

Despite the sensitivity of fit indices to various model and data characteristics in structural equation modeling, these fit indices are used in a rigid binary fashion as a mere rule of thumb threshold value in a search for model adequacy. Here, we address the behavior and interpretation of the popular Comparative Fit Index (CFI) by stressing that its metric for model assessment is the amount of misspecification in a baseline model and by further decomposition into its fundamental components: sample size, number of variables and the degree of multivariate dependence in the data. Simulation results show how these components influence the performance of CFI and its rule of thumb in practice. We discuss the usefulness of additional qualifications when applying the CFI rule of thumb and potential adjustments to its threshold value as a function of data characteristics. In conclusion, we at a minimum recommend a dual reporting strategy to provide the necessary context and base for meaningful interpretation and even more optimal, a move to using CFI as a real incremental fit index intended to evaluate the relative effect size of cumulative theoretically motivated model restrictions in terms of % reduction in misspecification as measured by the baseline model.

Alcohol use disorder (AUD) exacts enormous personal, social and economic costs globally. Return to alcohol use in treatment-seeking patients with AUD is common, engendered by a cycle of repeated abstinence-relapse episodes even with use of currently available pharmacotherapies. Repeated ethanol use induces dopaminergic signaling neuroadaptations in ventral tegmental area (VTA) neurons of the mesolimbic reward pathway, and sustained dysfunction of reward circuitry is associated with return to drinking behavior. We tested this hypothesis by infusing adeno-associated virus serotype 2 vector encoding human glial-derived neurotrophic factor (AAV2-hGDNF), a growth factor that enhances dopaminergic neuron function, into the VTA of four male rhesus monkeys, with another four receiving vehicle, following induction of chronic alcohol drinking. GDNF expression ablated the return to alcohol drinking behavior over a 12-month period of repeated abstinence-alcohol reintroduction challenges. This behavioral change was accompanied by neurophysiological modulations to dopamine signaling in the nucleus accumbens that countered the hypodopaminergic signaling state associated with chronic alcohol use, indicative of a therapeutic modulation of limbic circuits countering the effects of alcohol. These preclinical findings suggest gene therapy targeting relapse prevention may be a potential therapeutic strategy for AUD.

Alina Sigaeva,* Runrun Li,* Jan Jelle van Laar, Leon Wierenga, Romana Schirhagl Department of Biomaterials and Biotechnology, Groningen University, University Medical Center Groningen, Groningen, the Netherlands*These authors contributed equally to this workCorrespondence: Romana Schirhagl, Email romana.schirhagl@gmail.comIntroduction: As nanodiamonds become more and more widely used for intracellular labelling and measurements, the task of delivering these nanoparticles inside cells becomes more and more important. Certain cell types easily take up nanodiamonds, while others require special procedures.Methods: In previous research, we found that HT-29 cells (a colon cancer cell line), which are notoriously difficult in the context of nanodiamond internalization, show increased uptake rates, when pre-treated with trypsin- ethylenediaminetetraacetic acid (trypsin-EDTA). However, the uptake mechanism has not been studied before. This article focuses on a more detailed investigation of the reasons underlying this phenomenon. We start by identifying the timing of fluorescent nanodiamond (FND) uptake in trypsin-EDTA pre-treated cells. We then use a combination of chemical inhibitors and Immunocytochemistry to identify the main pathways employed by HT-29 cells in the internalization process.Results and Discussion: We investigate how these pathways are affected by the trypsin-EDTA pre-treatment and conclude by offering possible explanations for this phenomenon. We found that nanodiamonds are internalized via different pathways. Clathrin-mediated endocytosis proves to be the dominating mechanism. Trypsin-EDTA treatment increases particle uptake and affects the uptake mechanism.Keywords: nanodiamonds, cell uptake, cancer cells, HT29 cells, NV centers, imaging

Background: Limited treatment options with a rapid onset of action are available to treat off episodes in Parkinson’s disease (PD) patients. Therefore, the development of rapid onset formulations, for instance with levodopa, is warranted, which was the reason to investigate an inhalable formulation of levodopa. Objectives: The primary objective was to determine the duration until maximum effect is reached of inhaled levodopa on the improvement of motor function of PD patients. The secondary objective was to compare the time until maximal effect and the maximal effect of inhaled levodopa versus oral levodopa. Design: Open-label randomized two-way one-period crossover trial. Methods: Nine PD patients in the ‘off state’ received one dose of inhaled levodopa (90 mg) from Cyclops® and one dose of levodopa orodispersible tablet (100 mg) on two consecutive days in a randomized order. A timed tapping test, Timed Up and Go test (TUG test) and Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) III score were performed pre-dose and on set time points up to 90 min post-dose as measure for motor function. In addition, blood samples were taken for a pharmacokinetic evaluation ( T max , C max and area under the concentration time curve (AUC) 0–3 h). Results: The maximal effect of inhaled levodopa was reached at 30 min (tapping test), at 75 min (TUG test) and at 60 min (UPDRS III). The positive effect on the UPDRS was statistically significant within 20 min after inhalation. After oral administration, C max and AUC 0–3 h were found to be significant higher ( p = 0.028 and p = 0.028, respectively) than after pulmonary administration. T max was achieved significantly ( p = 0.028) faster after inhalation. The motor function examinations showed a similar maximum clinical improvement after pulmonary and oral administration and although not significant, inhaled levodopa results in a shorter median duration to maximum clinical effect for the TUG and timed finger-tapping test compared with oral administration (TUG: inhalation 55.0 and oral 67.5 min, timed finger-tapping test: inhalation 35.0 and oral 57.5 min). After the levodopa inhalation, there were no adverse events observed and no significant differences found in long-function parameters. Conclusion: Inhaled levodopa from Cyclops ® shows promising data as a rescue therapy for PD patients with off episodes, not responsive to the current oral therapies. Trial registration: The study protocol was approved by the local ethics board ‘Regionale toetsingscommissie patiëntgebonden onderzoek’ (RTPO) in Leeuwarden, The Netherlands (approval number RTPO1019). The study was registered in in the Dutch trial register (LTR) with identification number NL6876. From 5 March 2024 on, the research data on onderzoekmetmensen.nl are known as ‘Overview of Medical Research in the Netherlands’ (OMON). This means the use of the name LTR has thus been dropped. Now, it is registered in the OMON with the same identification number (NL6876, Effectiveness of inhaled levodopa in PD | Research with human participants (onderzoekmetmensen.nl)). All patients provided written informed consent.

Introduction In rheumatoid arthritis (RA), immunosuppressive therapies may achieve symptomatic relief, but do not induce long-term, drug-free remission. Meanwhile, the lifelong use of immunosuppressive drugs confers increased risk for malignancy and infections. As such, there is an unmet need for novel treatments that selectively target the pathogenic immune response in RA by inducing tolerance to autoantigens. Autologous cell therapy using antigen-loaded tolerogenic dendritic cells (tolDCs) aims to reinstate autoantigen-specific immunological tolerance in RA and could potentially meet this need.Methods and analysis We report here the design of the phase I/II, investigator-initiated, open-label, dose-escalation trial TOLERANT. In this study, we will evaluate the intranodal administration of tolDCs in patients with RA that are in remission under immunosuppressive therapy. The tolDCs in this trial are loaded with the heat shock protein 70-derived peptide mB29a, which is an effective surrogate autoantigen in animal models of arthritis. Within this study, three dose-escalation cohorts (two intranodal injections of 5×106, 10×106 and 15×106 tolDCs), each consisting of three patients, are evaluated to identify the highest safe dose (recommended dose), and an extension cohort of nine patients will be treated with the recommended dose. The (co-)primary endpoints of this study are safety and feasibility, which we assess by the number of AEs and the successful production of tolDCs. The secondary endpoints include the immunological effects of the treatment, which we assess with a variety of high-dimensional and antigen-specific immunological assays. Clinical effects are exploratory outcomes.Ethics and dissemination Ethical approval for this study has been obtained from the Netherlands Central Committee on Research Involving Human Subjects. The outcomes of the trial will be disseminated through publications in open-access, peer-reviewed scientific journals, scientific conferences and to patient associations.Trial registration numbers NCT05251870; 2019-003620-20 (EudraCT); NL71296.000.20 (CCMO register).

Objectives: In this study, we measured serum interferon (IFN) levels and activity in patients with sarcoidosis and tuberculosis (TB) with and without uveitis. We aimed to understand the role of IFN in the pathophysiology of both conditions and explore its potential as a discriminating marker for these clinically similar diseases. Methods: Sera from an Indonesian TB and a Dutch sarcoidosis cohort were used in the analysis. IFNα2 and IFNγ concentrations were measured using Simoa® and Luminex assays, respectively. Serum IFN activity was assessed by incubating THP-1 cells with patient serum and measuring IFN-stimulated gene transcription using qPCR. Anti-IFNα2 and IFNγ autoantibodies were detected via Luminex assay and tested for neutralizing capacity using a flow cytometry-based signal transducer and activator of transcription (STAT) 1 phosphorylation inhibition assay. Results: IFNα2 was detected in 74 % and 64 % of patients with sarcoidosis and pulmonary TB, respectively, while IFNγ was found in 78 % and 23 % of patients with sarcoidosis and TB, respectively. For uveitis cases specifically, IFNα2 was detected in 85 % of sarcoid uveitis (SU) and 33 % of tubercular uveitis (TBU) cases. Similarly, IFNγ was detected in 69 % of SU and 17 % of TBU cases. IFNγ serum concentrations were higher in sarcoidosis than that in TB patients (p

This article explores operational challenges in mining, with a focus on energy management amid depleting ore grades and rising costs. The urgent need for innovative energy management systems and strategies is highlighted by analyzing the unexplored landscape of mine energy budgeting and forecasting and identifying gaps in current practices. Drawing from the literature, this paper offers new insights into energy budgeting and the evaluation of energy efficiency initiatives by integrating traditional and advanced measurement and verification (M&V) techniques. M&V practices are crucial for energy management, particularly in deep-level mines, with a focus on practical knowledge and advanced methodologies. Key findings from this study show that integrating advanced M&V techniques with unplanned events is crucial to improve the financial management of mines. By leveraging these key findings, this article proposes a roadmap of the next seven milestones needed in advanced M&V research to aid effective energy management in a mining environment. If executed successfully, a practical method for applying advanced M&V processes to deep-level mining operations can be constructed. Such a generic method will enhance mining companies’ energy efficiency initiatives and improve financial management practices on a global scale.

This study investigated the application of machine learning to optimise the pumping load shift of a complex dewatering system in a deep-level mine, aiming to reduce energy costs associated with the dewatering process, which consumes an average of 14% of the mine’s electricity. Traditional practices, reliant on human control and simulations, often lead to inconsistent savings and occasional losses. The study employed multivariate linear regression (MLR) and extreme gradient boosting (XGBoost) on a mine dewatering system, to identify important parameters influencing the pumping load shift performance. Critical parameters significantly impacting the energy consumption of the dewatering system were identified by the best-performing model, XGBoost. Implementing a pumping schedule based on XGBoost insights resulted in consistent load shifting and enhanced energy cost savings. These findings highlight the potential of machine learning in comprehending and optimising complex systems in deep-level mines, with the case study approach proving effective in quantifying and validating real-world impacts. This approach could offer substantial energy savings through data-driven decision-making.

Aims This study aimed to evaluate the effectiveness of somatostatin analogues (SA) for cystoid maculopathy (CM) in retinitis pigmentosa (RP) patients.Materials and methods In this retrospective case series, clinical and imaging characteristics of 28 RP patients with CM, unresponsive to carbonic anhydrase inhibitors, were collected from medical charts. All patients received SA treatment as an alternative (octreotide long-acting release at 20 mg/month or 30 mg/month, or lanreotide at 90 mg/month or 120 mg/month). Outcome measures were mean reduction in foveal thickness (FT) and foveal volume (FV) and mean increase in best-corrected visual acuity at 3, 6 and 12 months of treatment initiation. Linear mixed models were used to calculate the effectiveness over time.Results 52 eyes of 28 RP patients were included; 39% were male. The median age at the start of treatment was 39 years (IQR 30–53). Median follow-up was 12 months (range 6–12). From baseline to 12 months, the mean FT decreased from 409±136 µm to 334±119 µm and the mean FV decreased from 0.31±0.10 mm3 to 0.25±0.04 mm3. Linear mixed model analyses showed a significant decrease in log FT and log FV at 3, 6 and 12 months after the start of treatment compared with baseline measurements (p

This dataset provides longitudinal survey data from a European project, ySKILLS, which was focused on the role of digital skills in youths’ development. It contains data from 10,821 participants from Grades 6–10 (in Wave 1) in Estonia, Finland, Germany, Italy, Poland, and Portugal. The data was collected between Spring 2021 and Spring 2023, the participants were recruited through schools, where the data collection also took place, except for online data collections due to restrictions caused by COVID-19. The dataset is novel in its multidimensional approach to the construct of digital literacy. It provides insight into the development of digital skills in youth and the role of digital skills and internet usage in youths’ positive and negative online experiences and wellbeing. It also contains data that allows for the analysis of the role of digital skills in class networks. The data are beneficial for researchers interested in the examination of youths’ online skills, internet usage, online experiences, and wellbeing from a longitudinal perspective.