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Axel Hage *, Mathis de Vries *, Andreas Leffler, Carsten Stoetzer Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hanover, Germany*These authors contributed equally to this workCorrespondence: Axel Hage, Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Carl-Neuberg-Strasse 1, Hanover, 30625, Germany, Tel +49 176 1532 2775, Fax +49 511 532 163498, Email hage.axel@mh-hannover.deIntroduction: Chloroquine (CQ) and its derivate hydroxychloroquine (HCQ) are successfully deployed for different diseases beyond the prophylaxis and treatment of malaria. Both substances exhibit antiviral properties and have been proposed for prophylaxis and treatment of COVID-19 caused by SARS-CoV-2. CQ and HCQ cause similar adverse events including life-threatening cardiac arrhythmia generally based on QT-prolongation, which is one of the most reported adverse events for both agents associated with the treatment of COVID-19. Various drugs known to induce QT-prolongation have been proven to exert local anesthetic (LA)-like properties regarding their impact on the cardiac Na+ channel Nav1.5. Inhibition of Nav1.5 is considered as the primary mechanism of cardiotoxicity caused by LAs. However, the mechanism of the arrhythmogenic effects of CQ and HCQ related to Nav1.5 has not yet been fully investigated. Therefore, the exact mechanism of how CQ and HCQ affect the sodium currents generated by Nav1.5 need to be further elucidated.Objective: This in vitro study aims to investigate the effects of CQ and HCQ on Nav1.5-generated sodium currents to identify possible LA-like mechanisms that might contribute to their arrhythmogenic properties.Methods: The effects of CQ and HCQ on Nav1.5-generated sodium currents by HEK-293 cells expressing either wild-type human Nav1.5 or mutant Nav1.5 F1760A are measured using the whole-cell patch-clamp technique.Results: Both agents induce a state-dependent inhibition of Nav1.5. Furthermore, CQ and HCQ produce a use-dependent block of Nav1.5 and a shift of fast and slow inactivation. Results of experiments investigating the effect on the LA-insensitive mutant Nav1.5-F1760A indicate that both agents at least in part employ the proposed LA-binding site of Nav1.5 to induce inhibition.Conclusion: This study demonstrated that CQ and HCQ exert LA-typical effects on Nav1.5 involving the proposed LA binding site, thus contributing to their arrhythmogenic properties.Keywords: chloroquine, hydroxychloroquine, patch-clamp, cardiac sodium channel, Nav1.5

Laura JGM van Weerdenburg,1 Christina Brock,2,3 Asbjørn Mohr Drewes,2 Harry van Goor,1 Marjan de Vries,1 Oliver HG Wilder-Smith4 1Department of Surgery, Radboud University Medical Centre, Nijmegen, the Netherlands; 2Mech-Sense, Department of Gastroenterology, Aalborg University Hospital, Aalborg, 3Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark; 4Department of Anesthesiology, Pain and Palliative Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands Background and objectives: Contradictory results have been found about the effect of different exercise modalities on pain. The aim of this study was to investigate the early effects of aerobic and isometric exercise on different types of experimental pain, including visceral pain, compared to an active control condition. Methods: Fifteen healthy subjects (6 women, mean [standard deviation] age 25 [6.5] years) completed 3 interventions consisting of 20 minutes of aerobic cycling, 12 minutes of isometric knee extension and a deep breathing procedure as active control. At baseline and after each intervention, psychophysical tests were performed, including electrical stimulation of the esophagus, pressure pain thresholds and the cold pressor test as a measure for conditioned pain modulation. Participants completed the Medical Outcome Study Short-Form 36 and State-Trait Anxiety Inventory prior to the experiments. Data were analyzed using two-way repeated measures analysis of variance. Results: No significant differences were found for the psychophysical tests after the interventions, compared to baseline pain tests and the control condition. Conclusion: No hypoalgesic effect of aerobic and isometric exercise was found. The evidence for exercise-induced hypoalgesia appears to be not as consistent as initially thought, and caution is recommended when interpreting the effects of exercise on pain. Keywords: motor activity, breathing exercises, pain measurement, pain perception

Marjan de Vries,1 Oliver HG Wilder-Smith,2 Marijtje LA Jongsma,3 Emanuel N van den Broeke,1 Martijn Arns,5,6 Harry van Goor,1 Clementina M van Rijn4 1Department of Surgery, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; 2Department of Anesthesiology, Pain and Palliative Care, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; 3Behavioral Science Institute, Radboud University Nijmegen, Nijmegen, The Netherlands; 4Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen, Nijmegen, The Netherlands; 5Research Institute Brainclinics Nijmegen, Nijmegen, The Netherlands; 6Department of Experimental Psychology, Utrecht University, Utrecht, The Netherlands Objectives: Electroencephalography (EEG) may be a promising source of physiological biomarkers accompanying chronic pain. Several studies in patients with chronic neuropathic pain have reported alterations in central pain processing, manifested as slowed EEG rhythmicity and increased EEG power in the brain's resting state. We aimed to investigate novel potential markers of chronic pain in the resting state EEG of patients with chronic pancreatitis. Participants: Resting state EEG data from 16 patients with persistent abdominal pain due to chronic pancreatitis (CP) were compared to data from healthy controls matched for age, sex and education. Methods: The peak alpha frequency (PAF) and power amplitude in the alpha band (7.5–13 Hz) were compared between groups in four regions of interest (frontal, central, parietal, and occipital) and were correlated with pain duration. Results: The average PAF was lowered in CP patients compared with that in healthy controls, observed as a statistically significant between-group effect (mean 9.9 versus 9.5 Hz; P=0.049). Exploratory post hoc analysis of average PAF per region of interest revealed a significant difference, particularly in the parietal and occipital regions. In addition, we observed a significant correlation between pain duration and PAF and showed increased shifts in PAF with longer pain durations. No significant group differences were found in peak power amplitudes. Conclusion: CP pain is associated with alterations in spontaneous brain activity, observed as a shift toward lower PAF. This shift correlates with the duration of pain, which demonstrates that PAF has the potential to be a clinically feasible biomarker for chronic pain. These findings could be helpful for assisting diagnosis, establishing optimal treatment, and studying efficacy of new therapeutic agents in chronic pain patients. Keywords: chronic pain, neuropathic pain, chronic pancreatitis, electroencephalography, EEG, alpha oscillations, peak frequency

Emanuel N van den Broeke,1 Marjan de Vries,1 Harry van Goor,3 Kris CP Vissers,1 Clementina M van Rijn,2 Oliver HG Wilder-Smith11Department of Anesthesiology, Pain and Palliative Medicine, Pain and Nociception Neuroscience Research Group, 2Donders Institute for Brain, Cognition and Behavior, 3Department of Surgery, Radboud University Nijmegen Medical Centre, HB Nijmegen, The NetherlandsBackground: Women who undergo breast cancer surgery have a high risk of developing persistent pain. We investigated brain processing of painful stimuli using electroencephalograms (EEG) to identify event-related potentials (ERPs) in patients with persistent pain after breast cancer treatment.Methods: Nineteen patients (eight women with persistent pain, eleven without persistent pain), who were surgically treated more than 1 year previously for breast cancer (mastectomy, lumpectomy, and axillary lymph node dissection) and/or had chemoradiotherapy, were recruited and compared with eleven healthy female volunteers. A block of 20 painful electrical stimuli was applied to the calf, somatopically remote from the initially injured or painful area. Simultaneously an EEG was recorded, and a visual analog scale (VAS) pain rating obtained.Results: In comparison with healthy volunteers, breast cancer treatment without persistent pain is associated with accelerated stimulus processing (reduced P260 latency) and shows a tendency to be less intense (lower P260 amplitude). In comparison to patients without persistent pain, persistent pain after breast cancer treatment is associated with stimulus processing that is both delayed (ie, increased latency of the ERP positivity between 250–310 ms [P260]), and enhanced (ie, enhanced P260 amplitude).Conclusion: These results show that treatment and persistent pain have opposite effects on cortical responsiveness.Keywords: breast cancer surgery, persistent pain, nerve injury, event-related potentials, pain processing

Secondary school students often only use the rules for doing scientific inquiry when prompted, as if they fail to see the point of doing so. This qualitative design study explores conditions to address this problem in school science inquiry. Dutch students (N = 22, aged 14-15) repeatedly consider the quality of their work: in a conventional, guided inquiry approach; by evaluating their conclusion in terms of the contextual purpose of the investigation; as consumers of knowledge facing the (hypothetical) risk of applying the findings in the real world. By gauging students' confidence in the inquiry's trustworthiness, we established that, while each confrontation instigated some students to (re)consider the quality of their inquiry, the final stage had the greatest impact. Students came to see that finding trustworthy results is essential, requiring scientific standards. The scientific quality of their inquiries was described, weaknesses identified and compared with the improvements students themselves proposed for their inquiries. While the improvements were expressed in non-specific terms these align with a scientific perspective. Students now "wanted" to find trustworthy answers by exploiting scientific standards. In enabling students to engage successfully in basic scientific inquiry, finding ways to establish students' mental readiness for attending to the quality of their scientific claims, and of personalised scientific criteria for their assessment, is indispensable.

Physics inquiry can be interpreted as the construction of a cogent argument in which students apply inquiry knowledge and knowledge of physics to the systematic collection of relevant, valid, and reliable data, creating optimal scientific support for a conclusion that answers the research question. In learning how to devise, conduct and evaluate a rigorous physics inquiry, students should learn to choose and apply suitable techniques and adhere to scientific conventions that guarantee the collection of such data. However, they also need to acquire and apply an understanding of how to justify their choices and present an optimally convincing argument in support of their conclusion. In this modified and augmented Delphi study we present a view of inquiry knowledge and a way to assess it that acknowledges both of these components. Using our own expertise with teaching physics inquiry and using curriculum documents on physics inquiry, "inquiry knowledge" is deconstructed as a set of "understandings of evidence" (UOE)-- insights and views that an experimental researcher relies on in constructing and evaluating scientific evidence. While insights cannot be observed directly, we argue that their presence can be inferred from a student's actions and decisions in inquiry, inferred with more definitude as a more explicit and adequate justification is provided. This set of UOE is presented and validated as an adequate, coherent, partially overlapping set of learning goals for introductory inquiry learning. We specify conceivable types of actions and decisions expected in inquiry as descriptors of five attainment levels, providing an approach to assessing the presence and application of inquiry knowledge. The resulting construct, the assessment rubric for physics inquiry, is validated in this study. It distinguishes nineteen UOE divided over six phases of inquiry. Preliminary results suggesting a high degree of ecological validity are presented and evaluated. Several directions for future research are proposed.

Research and design activities are important focus points in international policies for secondary Science, Technology, Engineering and Mathematics (STEM) education. It is up to school teachers to implement and supervise these activities in the STEM classroom. However, not much is known about the attitudes teachers hold towards supervising research projects or design projects. In this study, a questionnaire to measure teacher attitudes towards supervising research activities and design activities in secondary school was completed by 130 Dutch teachers who taught the relatively new Dutch STEM subjects O&O (research and design) and NLT (nature, life, and technology). These integrated STEM subjects are project and context based and are taught in a limited number of schools. Important differences between these integrated STEM subjects are their student and teacher populations: NLT is taught in grades 10-12 by teachers with a qualification in a science subject, while O&O is taught in grades 7-12 and can be given by any teacher in secondary school. The results showed that on average, both O&O and NLT teachers had high self-efficacy scores on supervising research and design projects even when they had received no special education in doing so. Furthermore, the teachers in general viewed supervising research projects as a more relevant activity than supervising design. Since research and design activities are becoming more important in (inter)national curriculum standards, STEM teacher education and subsequent professional development should not only familiarize teachers with supervising research projects, but with design projects as well.

This paper explores students' ability to analyse and interpret empirical data as inadequate data analysis skills and understandings may contribute to the renowned disappointing outcomes of practical work in secondary school physics. Selected competences, derived from a collection of leading curricula, are explored through interviews and practical tasks, each consisting of three probes. The 51 students, aged 15 and commencing post-compulsory science education in the Netherlands, were able to carry out basic skills such as collecting data and representing these. In interpreting the data in terms of the investigated phenomenon or situation however, performance was weak. Students often appeared to be unable to identify the crucial features of a given graph. Conclusions based on the data were often tautological or superficial, lacking salient features. Students failed to infer implications from the data, to interpret data at a higher level of abstraction, or to specify limitations to the validity of the analysis or conclusions. The findings imply that the students' understanding of data-analysis should be developed further before they can engage successfully in more 'open' practical work. The study offers a collection of activities that may help to address the situation, suggesting a baseline for guided development of data analysis abilities.

Introduction: The COVID‐19 pandemic was a public health emergency (PHE) of unprecedented magnitude and impact. It provided the possibility to investigate the Dutch citizens' understanding and perception of the actors involved in the Dutch pandemic response as a PHE unfolded. Methods: Three focus groups (FGs) were held with 16 Dutch citizens in June 2020. Citizens were recruited using the Dutch Health Care Consumer Panel. During the FGs, participants were asked to fill in a table with actors they thought were involved in the management of the COVID‐19 pandemic. They also received information on actors involved in Dutch outbreak responses. Then, the actors named and omitted by the participants were discussed. Results: An analysis of the FGs suggests that the Dutch citizens participating in the study were not fully aware of the scope of actors involved in the Dutch COVID‐19 pandemic response. Some participants would have appreciated more information on the actors involved. This would help them have an informed opinion of the actors involved in the decision‐making process, and accept non‐pharmaceutical interventions implemented. Lastly, most participants recognised that they played a role in limiting the spread of the COVID‐19 pandemic. Yet, very few spontaneously mentioned themselves as actors within the COVID‐19 pandemic response. Conclusion: This study suggests that early in the COVID‐19 pandemic, the Dutch citizens participating in this study's FG did not have a complete understanding of the scope of actors involved in the Dutch COVID‐19 pandemic response, or the potential role of the citizen. Future research can build on these results to explore the citizen's perception of their role during PHEs of another origin, as well as other geographical and historical contexts. Patient or Public Contribution: The public participated in the focus groups and received a non‐expert report summarising the outcomes of the focus groups. [ABSTRACT FROM AUTHOR]

Hoe legitiem is de breukdelengemeenschap voor de legitimaris?: In deze bijdrage bespreekt de auteur de civielrechtelijke gevolgen voor de legitimaris van het arrest van de Hoge Raad d.d. 16 februari 2024 over de breukdelengemeenschap. Bezien wordt of het aangaan van een breukdelengemeenschap – al dan niet gecombineerd met een finaal verrekenbeding bij echtscheiding – een quasi-legaat oplevert. Daarnaast wordt uitgebreid stilgestaan bij de vraag of deze handelwijze paulianeus is ten opzichte van de legitimaris. De zorgplicht van de notaris bij het opmaken van dergelijke huwelijkse voorwaarden komt ook nog kort ter sprake. [ABSTRACT FROM AUTHOR]

Technological design is a core activity in Science, Technology, Engineering and Mathematics (STEM) education. During the design process, students often employ research activities to enhance the quality of their design decisions and to rise above a mere trial-and-error approach to designing. There are many functions of research within the design process, for example theoretical research, user research, or testing a prototype. In this study, we aimed to examine student and teacher perceptions of the functions of research in the context of a design-oriented STEM module in Dutch secondary education. To do so, we first examined in what ways students and teachers who conducted or respectively taught the STEM module recognized functions of research within design. We also looked at the value students attributed to these functions, and how teachers described their facilitation of the functions of research within design. During the STEM module, students conducted a design project related to an authentic problem in biomedical technology, while using research activities to support their design decisions. Results from student focus groups and teacher interviews showed that they recognized several ways in which research activities contribute to a design process. Students valued the functions of research within design as important for the end product, although some students preferred to skip research and start building their design right away. Some teachers employed strategies to ensure students learned to do research steps, for example by a reverse design exercise. The results from this study raise the question whether all students should apply research activities in the same order during a design process, since different students seem to prefer different ways of designing. A design-oriented STEM module like this one is an appropriate way to start showing students the functions of research within design, however differentiation between different students' preferences could possibly enhance this learning process.

Research and design activities are becoming more important in Science, Technology, Engineering and Mathematics (STEM) and D&T (design and technology) education. Research and design are often taught separately from each other, while in professional STEM practices, many projects are neither 'research only' or 'design only'--they are both. In this study, we aimed to provide insights in teachers' personal and shared knowledge on how research and design can be connected. To this end, we examined the development of pedagogical content knowledge (PCK) and beliefs of six teachers of the Dutch STEM subject O&O (research and design), who participated in a professional learning community (PLC) aimed at connecting research and design within this subject. Results of pre and post-PLC interviews showed that teachers' personal PCK was very diverse, probably due to their different beliefs, backgrounds and teaching contexts. Through jointly designing instructional strategies for connecting research and design, teachers contributed to a collective knowledge base. The results of this study indicate that a professional learning community in which teachers with varying backgrounds construct knowledge and instructional strategies together, can be a powerful method to enhance personal PCK and collective knowledge. These are promising outcomes in the light of shaping professional development activities for STEM and D&T teachers, which in turn aims to provide students with a holistic and realistic view on current professional STEM fields.