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Background: Creativity requires both divergent and convergent thinking. Previous research established that "divergent" thinking relates to mathematics performance, but generally ignored the role of "convergent" thinking and, hence, leaves it unclear how both might interact when children work on mathematical tasks. This study addressed this paucity in the research literature, with the goal of improving our understanding of the role of creative thinking in primary school mathematics. Aims: This study examined how divergent and convergent thinking contribute to mathematics performance, both directly and jointly, on single- and multiple-solution tasks. Sample: The study was conducted with 229 Dutch fifth graders of 12 primary schools. Method: Divergent and convergent thinking were measured with a visual and verbal task. Path analysis was used including verbal and visual divergent and convergent thinking tasks in relation to single- and multiple-solution mathematics task performance. Working memory was included as a covariate. Results: Verbal convergent thinking positively predicted single- and multiple-solution task performance. Verbal divergent and convergent thinking interacted in relation to single-solution task performance, while visual divergent and convergent thinking interacted in relation to multiple-solution task performance. Conclusions: Children's mathematics performance mainly relies on convergent thinking. The role of divergent thinking is twofold: it complements convergent thinking on multiple-solution tasks and compensates convergent thinking on single-solution tasks.

Abstract Background The Ask-Advise-Connect approach can help primary care providers to increase the number of smokers that attempt to quit smoking and enrol into cessation counselling. The approach has not yet been implemented in general practice in the Netherlands. The aim of this study was to investigate the influence of a comprehensive implementation strategy on the delivery of Ask-Advise-Connect for smoking cessation within Dutch general practice during the COVID-19 pandemic. Methods A pre-post study was conducted between late 2020 and early 2022, and included 106 Dutch primary care providers (GPs, practice nurses and doctor’s assistants). Participation lasted nine months: during the first three months participants delivered smoking cessation care as usual (pre-intervention); the implementation strategy came into effect after three months and participants were followed up for another six months (post-intervention). The implementation strategy consisted of two meetings in which participants were educated about Ask-Advise-Connect, made agreements on the implementation of Ask-Advise-Connect and reflected on these agreements. Participants also received online educational materials and a desk card as reminder. The changes in the proportions of ‘Ask’ and ‘Advise’ over time were modelled using linear mixed effects models. A descriptive analysis was conducted with regard to referrals to cessation counselling. Results Participants provided consultations to 29,112 patients (both smokers and non-smokers). Results of the linear mixed effects model show that the proportion of patients that were asked about smoking (‘Ask’) significantly decreased in the first three months (pre-intervention), but slightly increased again after the implementation strategy came into effect (post-intervention). No significant change over time was found with regard to the proportion of patients advised to quit smoking (‘Advise’). Descriptive statistics suggested that more participants proactively (vs. passively) referred patients to cessation counselling post-intervention (‘Connect’). Conclusions The findings indicate that a comprehensive implementation strategy can support primary care providers in offering smoking cessation care to patients, even under stressful COVID-19 conditions. Additional implementation efforts are needed to increase the proportion of patients that receive a quit advice and proactive referral.

Abstract Facioscapulohumeral muscular dystrophy (FSHD) is caused by the epigenetic derepression of the 4q-linked D4Z4 macrosatellite repeat resulting in inappropriate expression of the D4Z4 repeat-encoded DUX4 gene in skeletal muscle. In 5% of FSHD cases, D4Z4 chromatin relaxation is due to germline mutations in one of the chromatin modifiers SMCHD1, DNMT3B or LRIF1. The mechanism of SMCHD1- and LRIF1-mediated D4Z4 repression is not clear. We show that somatic loss-of-function of either SMCHD1 or LRIF1 does not result in D4Z4 chromatin changes and that SMCHD1 and LRIF1 form an auxiliary layer of D4Z4 repressive mechanisms. We uncover that SMCHD1, together with the long isoform of LRIF1, binds to the LRIF1 promoter and silences LRIF1 expression. The interdependency of SMCHD1 and LRIF1 binding differs between D4Z4 and the LRIF1 promoter, and both loci show different transcriptional responses to either early developmentally or somatically perturbed chromatin function of SMCHD1 and LRIF1.

Abstract Custom-made triflange acetabular implants are increasingly used in complex revision surgery where supporting bone stock is diminished. In most cases these triflange cups induce stress-shielding. A new concept for the triflange is introduced that uses deformable porous titanium to redirect forces from the acetabular rim to the bone stock behind the implant and thereby reduces further stress-shielding. This concept is tested for deformability and primary stability. Three different designs of highly porous titanium cylinders were tested under compression to determine their mechanical properties. The most promising design was used to design five acetabular implants either by incorporating a deformable layer at the back of the implant or by adding a separate generic deformable mesh behind the implant. All implants were inserted into sawbones with acetabular defects followed by a cyclic compression test of 1800N for 1000 cycles. The design with a cell size of 4 mm and 0.2 mm strut thickness performed the best and was applied for the design of the acetabular implants. An immediate primary fixation was realized in all three implants with an incorporated deformable layer. One of the two implants with a separate deformable mesh needed fixation with screws. Cyclic tests revealed an average additional implant subsidence of 0.25 mm that occurred in the first 1000 cycles with minimal further subsidence thereafter. It is possible to realize primary implant fixation and stability in simulated large acetabular revision surgery using a deformable titanium layer behind the cup. Additional research is needed for further implementation of such implants in the clinic.

Abstract Background The Ask-Advise-Connect (AAC) approach can help primary care providers to increase the number of people who attempt to quit smoking and enrol into cessation counselling. We implemented AAC in Dutch general practice during the COVID-19 pandemic. In this study we describe how AAC was received in Dutch general practice and assess which factors played a role in the implementation. Methods A mixed-methods approach was used to evaluate the implementation of AAC. Implementation took place between late 2020 and early 2022 among 106 Dutch primary care providers (general practitioners (GPs), practice nurses and doctor’s assistants). Quantitative and qualitative data were collected through four online questionnaires. A descriptive analysis was conducted on the quantitative data. The qualitative data (consisting of answers to open-ended questions) were inductively analysed using axial codes. The Consolidated Framework for Implementation Research was used to structure and interpret findings. Results During the study, most participants felt motivated (84–92%) and able (80–94%) to apply AAC. At the end of the study, most participants reported that the AAC approach is easy to apply (89%) and provides advantages (74%). Routine implementation of the approach was, however, experienced to be difficult. More GPs (30–48%) experienced barriers in the implementation compared to practice nurses and doctor’s assistants (7–9%). The qualitative analysis showed that especially external factors, such as a lack of time or priority to discuss smoking due to the COVID-19 pandemic, negatively influenced implementation of AAC. Conclusions Although AAC was mostly positively received in Dutch general practice, implementation turned out to be challenging, especially for GPs. Lack of time to discuss smoking was a major barrier in the implementation. Future efforts should focus on providing additional implementation support to GPs, for example with the use of e-health.

Abstract Background Response rates of immune checkpoint inhibitor (ICI) therapy for recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) are low. Patients and Methods This retrospective multicentre cohort study evaluates the predictive and prognostic value of weight loss and changes in body composition prior and during therapy. Patient, tumor, and treatment characteristics of 98 patients were retrieved, including neutrophil and platelet‐lymphocyte‐ratio (NLR and PLR). Programmed death‐ligand 1 (PD‐L1) expression was determined on residual material. Cachexia was defined according to Fearon et al. (2011). Skeletal muscle (SM), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) were evaluated on computed tomography scans at the third lumbar vertebrae level. Univariable and multivariable regression analyses were performed for 6 months progression free survival (PFS6m) and overall survival (OS). Results Significant early weight loss (>2%) during the first 6 weeks of therapy was shown in 34 patients (35%). This patient subgroup had a significantly higher NLR and PLR at baseline. NLR and PLR were inversely correlated with SM and VAT index. Independent predictors of PFS6m were lower World Health Organization performance status (HR 0.16 [0.04–0.54] p = 0.003), higher baseline SAT index (HR 1.045 [1.02–1.08] p = 0.003), and weight loss 2% early weight loss remained a predictor of OS, independent of PD‐L1 expression (HR 2.09 [1.11–3.92] p = 0.02, HR 2.18 [1.13–4.21] p = 0.02). Conclusion We conclude that the combination of cachexia at baseline and weight loss during ICI therapy is associated with worse OS in R/M HNSCC patients, independent of PD‐L1 expression.

Abstract Background The cost of tobacco is one of the most reported reasons for smoking cessation. Rather than quitting, smokers can use also strategies to reduce tobacco expenditure while continuing smoking, such as smoking less or using price-minimising strategies. The Netherlands announced to increase the price of a pack cigarettes from seven (2018) to ten euros (2023), to reduce tobacco prevalence and consumption. This study explores the self-reported strategies to reduce tobacco spending among Dutch smokers, and whether this differed per age, income, and education. Additionally, we analysed among quitters in these subgroups whether price played a role in their decision to quit. Methods Cross-sectional survey data from the International Tobacco Control (ITC) Netherlands Wave 2 (September–November 2020, N = 1915) was used. Strategies to reduce spending among smokers (N = 1790) were: reducing consumption, bulk buying, switching to cheaper products or buying from low-taxed sources. These were collapsed into: reducing consumption (solely or in combination with other behaviours), solely price-minimising behaviours (such as buying cheaper brands), or no strategies to reduce spending. Associations between strategies and characteristics were analysed through multinomial and binary logistic regression models. Second, we explored which subgroups were more likely to report that price played a role in their decision to quit among quitters (N = 125). Results The majority of smokers used strategies to reduce tobacco spending: 35.6% reduced consumption and 19.3% used solely price-minimising strategies. 82.1% of quitters reported that price played a role in their decision to quit. Low-income individuals were more likely to report price as a reason for quitting and reduce consumption, but also to buy cheaper products. Highly nicotine dependent smokers were more likely to use price-minimising behaviours, and less likely to reduce consumption. Conclusions The majority reported using strategies to reduce spending or that price played a role in their decision to quit. Reducing consumption was the most reported strategy. Low-income smokers were more likely to reportedly reduce consumption, buy cheaper products, or quit. Price policies have the potential to reduce socioeconomic inequalities in smoking. To discourage price-minimising behaviours, such as switching to cheaper products, reducing price differences between products should be prioritized.

To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P

Carriers of the fragile X premutation (PM) can develop a variety of early neurological symptoms, including depression, anxiety and cognitive impairment as well as being at risk for developing the late-onset fragile X-associated tremor/ataxia syndrome (FXTAS). The absence of effective treatments for FXTAS underscores the importance of developing efficacious therapies to reduce the neurological symptoms in elderly PM carriers and FXTAS patients. A recent preliminary study reported that weekly infusions of Allopregnanolone (Allop) may improve deficits in executive function, learning and memory in FXTAS patients. Based on this study we examined whether Allop would improve neurological function in the aged CGG knock-in (CGG KI) dutch mouse, B6.129P2(Cg)-Fmr1tm2Cgr/Cgr, that models much of the symptomatology in PM carriers and FXTAS patients. Wild type and CGG KI mice received 10 weekly injections of Allop (10 mg/kg, s.c.), followed by a battery of behavioral tests of motor function, anxiety, and repetitive behavior, and 5-bromo-2'-deoxyuridine (BrdU) labeling to examine adult neurogenesis. The results provided evidence that Allop in CGG KI mice normalized motor performance and reduced thigmotaxis in the open field, normalized repetitive digging behavior in the marble burying test, but did not appear to increase adult neurogenesis in the hippocampus. Considered together, these results support further examination of Allop as a therapeutic strategy in patients with FXTAS.

In this conversation analytic study, we investigate requests for assistance in the third-age (65+) language classroom. Seven Dutch seniors participated in a one-month course of English as a foreign language. We found that these seniors asked many language-related questions which fell into one of three categories: (1) production-oriented questions, (2) comprehension-oriented questions and (3) wonderment questions. These questions differ in the ways the sequences are shaped: (a) what precedes the request for assistance, (b) the person who is recruited to provide the assistance, (c) the person who offers the assistance, and (d) the response to the provided assistance and the subsequent interaction. We found wonderment questions to be the most prevalent category. Our findings suggest that the senior learners in our data show clear ownership and agency over their own learning process, demonstrated by their active participation and frequent (wonderment) questions in the classroom.

BackgroundEarly life provides a window of opportunity to prevent allergic diseases. With a prevalence of 0.5–2% in infants, hen’s egg allergy is one of the most common food allergies. The immunomodulatory effects of human milk oligosaccharides (HMOs), 2′-fucosyllactose (2’FL), and 3-fucosyllactose (3FL) were studied in an in vitro mucosal immune model and an in vivo murine model for hen’s egg (ovalbumin) allergy.MethodsIntestinal epithelial cell (IEC)/dendritic cell (DC) and DC/T cell cocultures were used to expose IECs to ovalbumin (OVA) in an in vitro mucosal immune model. The effects of epithelial pre-incubation with 0.1% 2’FL or 3FL and/or 0.5 mM butyrate were studied. Three- to four-weeks-old female C3H/HeOuJ mice were fed AIN93G diets containing 0.1–0.5% 2’FL or 3FL 2 weeks before and during OVA sensitization and challenge. Allergic symptoms and systemic and local immune parameters were assessed.ResultsExposing IECs to butyrate in vitro left the IEC/DC/T cell cross-talk unaffected, while 2’FL and 3FL showed differential immunomodulatory effects. In 3FL exposed IEC-DC-T cells, the secretion of IFNγ and IL10 was enhanced. This was observed upon pre-incubation of IECs with 2’FL and butyrate as well, but not 2’FL alone. The presence of butyrate did not affect OVA activation, but when combined with 3FL, an increase in IL6 release from DCs was observed (p

Early math skills lay the foundation for children’s long-term academic success. An increasing number of randomized controlled math interventions have been carried out across educational settings. The aim of the present systematic review was to identify the distribution of the randomized controlled math interventions conducted between 2001 and 2021 in educational settings across Early Childhood Education (ECE) up to high school among various sample types, and to describe their central features at each educational setting separately. Based on the knowledge gaps exposed through the systematic review, we aimed to discuss where and how future math interventions are still needed in order to optimize all children’s math skill development across educational settings and sample types from early on. A total of n = 75 math interventions meeting the inclusion criteria using the PRISMA-guidelines were identified, of which the majority of them were executed in the elementary school, mostly targeting at-risk children. It is proposed that there is still a large potential of promoting children’s math skills from early on in the ECE settings, utilizing both teachers and parents, among at-risk and non-at-risk samples.

Objective To study associations between the first-trimester maternal determinants of renin-angiotensin-aldosterone system (RAAS) activation and telomere length (TL) in pregnancies conceived natural and after IVF/ICSI. Methods In 145 pregnancies of the Rotterdam Periconception cohort renin, prorenin and aldosterone concentrations were measured in maternal blood at 9 weeks gestational age (GA). TL was measured by qPCR at 20 weeks GA. Results A significantly negative correlation was found between renin and TL, which was attenuated for prorenin but not observed for aldosterone. Maternal TL was significantly shorter in pregnancies conceived after in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) compared to natural pregnancies. Conclusion The negative association between first-trimester maternal renin and maternal TL, and the shorter maternal TL in women after IVF/ICSI treatment compared to natural pregnancies, substantiates the role of excessive RAAS activation.

Background: Respiratory syncytial virus (RSV) is a leading cause of childhood mortality in infants below 6 months of age. In low-income and middle-income countries (LMICs), the public health burden is substantial and resources are limited. It is critical to inform decision makers about effectiveness of new interventions. Methods: We developed a mathematical model where individual RSV subtype A (RSV-A) and B (RSV-B) maternally derived neutralizing titers were predicted at time of birth after maternal vaccination with the RSV prefusion F protein-based vaccine. We estimated the subsequent duration of vaccine-induced immunity and compared this to the age at time of death distribution in the RSV GOLD Mortality Database to predict the potential impact of maternal vaccination on RSV-related childhood mortality. We used country-specific timing of antenatal care visits distributions and mortality estimates to make country-specific predictions for number of cases averted. Findings: The model predicts that on average a neonate born at 40 weeks gestational age will be protected between 6 and 7 months from RSV-A and approximately 5 months from RSV-B related mortality. We estimated the potential impact of RSV-related mortality for in-hospital and out-of-hospital cases in LMICs and predicted that in 51 GAVI-eligible countries maternal vaccination could avert between 55% and 63% of the RSV-related in-hospital mortality cases below 6 months of age. Interpretation: We show that maternal vaccination could substantially decrease RSV-A and RSV-B related in-hospital and out-of-hospital mortality in LMICs in the first 6 months of life.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid tumors and is resistant to immunotherapy. B cells play an essential role in PDAC progression and immune responses, both locally and systemically. Moreover, increasing evidence suggests that microbial compositions inside the tumor, as well as in the oral cavity and the gut, are important factors in shaping the PDAC immune landscape. However, the gut-associated lymphoid tissue (GALT) has not previously been explored in PDAC patients. In this study, we analyzed healthy vermiform appendix (VA) from 20 patients with PDAC and 32 patients with colon diseases by gene expression immune profiling, flow cytometry analysis, and microbiome sequencing. We show that the VA GALT of PDAC patients exhibits markers of increased inflammation and cytotoxic cell activity. In contrast, B cell function is decreased in PDAC VA GALT based on gene expression profiling; B cells express significantly fewer MHC class II surface receptors, whereas plasma cells express the immune checkpoint molecule HLA-G. Additionally, the vermiform appendix microbiome of PDAC patients is enriched with Klebsiella pneumoniae, Bifidobacterium animalis, and Adlercreutzia equolifaciens, while certain commensals are depleted. Our findings may suggest impaired B cell function within the GALT of PDAC patients, which could potentially be linked to microbial dysbiosis. Additional investigations are imperative to validate our observations and explore these potential targets of future therapies.

Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients' primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy.

Thick terms and concepts, such as honesty and cruelty, are atthe heart of a variety of debates in linguistics, philosophy oflanguage, and metaethics. Central to these debates is thequestion of how the descriptive and evaluative components ofthick concepts are related and whether they can be separatedfrom each other. So far, no empirical data on how thick termsare used in ordinary language has been collected to informthese debates. In this paper, we present the first empiricalstudy, designed to investigate whether the evaluativecomponent of thick concepts can be separated. Our study mightbe considered to falsify the view that evaluation isconversationally implicated. However, our study also revealsan effect of valence, indicating that people reason differentlyabout positive and negative thick terms. While evaluationscannot be cancelled for negative thick terms, they can be forpositive ones. Three follow-up studies were conducted toexplain this effect. We conclude that the effect of valence isbest accounted for by a difference in the social norms guidingevaluative language.

Genetic factors explain a major proportion of human height variation, but differences in mean stature have also been found between socio-economic categories suggesting a possible effect of environment. By utilizing a classical twin design which allows decomposing the variation of height into genetic and environmental components, we tested the hypothesis that environmental variation in height is greater in offspring of lower educated parents. Twin data from 29 cohorts including 65,978 complete twin pairs with information on height at ages 1 to 69 years and on parental education were pooled allowing the analyses at different ages and in three geographic-cultural regions (Europe, North America and Australia, and East Asia). Parental education mostly showed a positive association with offspring height, with significant associations in mid-childhood and from adolescence onwards. In variance decomposition modeling, the genetic and environmental variance components of height did not show a consistent relation to parental education. A random-effects meta-regression analysis of the aggregate-level data showed a trend towards greater shared environmental variation of height in low parental education families. In conclusion, in our very large dataset from twin cohorts around the globe, these results provide only weak evidence for the study hypothesis.

Abstract Genome-wide association studies (GWAS) have dissected numerous genetic factors underlying refractive errors (RE) such as myopia. Despite significant insights into understanding the genetic architecture of RE, few studies have validated and explored the functional role of candidate genes within these loci. To functionally follow-up on GWAS and characterize the potential role of candidate genes on the development of RE, we prioritized nine genes (TJP2, PDE11A, SHISA6, LAMA2, LRRC4C, KCNQ5, GNB3, RBFOX1, and GRIA4) based on biological and statistical evidence; and used CRISPR/cas9 to generate knock-out zebrafish mutants. These mutant fish were screened for abnormalities in axial length by spectral-domain optical coherence tomography and refractive status by eccentric photorefraction at the juvenile (2 months) and adult (4 months) developmental stage. We found a significantly increased axial length and myopic shift in refractive status in three of our studied mutants, indicating a potential involvement of the human orthologs (LAMA2, LRRC4C, and KCNQ5) in myopia development. Further, in-situ hybridization studies showed that all three genes are expressed throughout the zebrafish retina. Our zebrafish models provide evidence of a functional role of these three genes in refractive error development and offer opportunities to elucidate pathways driving the retina-to-sclera signaling cascade that leads to myopia.