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Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease.

Is it tautological to call an action “wrongful discrimination?” Some philosophers and political theorists answer this question in the affirmative and claim that the term “discrimination” is intrinsically evaluative. Others agree that “discrimination” usually conveys the action's moral wrongness but claim that the term can be used in a purely descriptive way. In this paper, we present two corpus studies and two experiments designed to test whether the folk concept of discrimination is evaluative. We demonstrate that the term has undergone a historical development and is nowadays no longer used purely descriptively. Further, we show that this evaluation cannot be cancelled without yielding a contradiction. We conclude that the descriptive use of “discriminatory” is a thing of the past.

Giant viruses (Nucleocytoviricota) are significant lethality agents of various eukaryotic hosts. Although metagenomics indicates their ubiquitous distribution, available giant virus isolates are restricted to a very small number of protist and algal hosts. Here we report on the first viral isolate that replicates in the amoeboflagellate Naegleria. This genus comprises the notorious human pathogen Naegleria fowleri, the causative agent of the rare but fatal primary amoebic meningoencephalitis. We have elucidated the structure and infection cycle of this giant virus, Catovirus naegleriensis (a.k.a. Naegleriavirus, NiV), and show its unique adaptations to its Naegleria host using fluorescence in situ hybridization, electron microscopy, genomics, and proteomics. Naegleriavirus is only the fourth isolate of the highly diverse subfamily Klosneuvirinae, and like its relatives the NiV genome contains a large number of translation genes, but lacks transfer RNAs (tRNAs). NiV has acquired genes from its Naegleria host, which code for heat shock proteins and apoptosis inhibiting factors, presumably for host interactions. Notably, NiV infection was lethal to all Naegleria species tested, including the human pathogen N. fowleri. This study expands our experimental framework for investigating giant viruses and may help to better understand the basic biology of the human pathogen N. fowleri.

Abstract Background Longitudinal cohort studies are pivotal to understand how socioeconomic, environmental, biological, and lifestyle factors influence health and disease. The added value of cohort studies increases as they accumulate life course data and expand across generations. Ensuring that participants stay motivated to contribute over decades of follow-up is, however, challenging. Participant engagement and involvement (PEI) aims to secure the long-term commitment of participants and promote researcher-participant interaction. This study explored PEI practices in a selection of pregnancy and birth, twin, and family-based population cohort studies. Methods Purposive sampling was used to identify cohorts in Europe, Australia and New Zealand. Fourteen semi-structured digital interviews were conducted with cohort study representatives to explore strategies for participant recruitment, informed consent, communication of general and individual information to participants, data collection, and participant involvement. Experiences, resources allocated to PEI, and reflections on future PEI, were discussed. The interview data were analyzed using a content analysis approach and summary results were reviewed and discussed by the representatives. Results The cohort studies used various strategies to recruit participants including support from health professionals and organizations combined with information on the studies’ web sites and social media. New approaches such as intra-cohort recruitment, were being investigated. Most cohorts transitioned from paper-based to digital solutions to collect the participants’ consent and data. While digital solutions increased efficiency, they also brought new challenges. The studies experimented with the use of participant advisory panels and focus groups to involve participants in making decisions, although their success varied across age and socio-economic background. Most representatives reported PEI resources to be limited and called for more human, technical, educational and financial resources to maximize the positive effects of PEI. Conclusions This study of PEI among well-established cohort studies underscores the importance of PEI for project sustainability and highlights key factors to consider in developing PEI. Our analysis shows that knowledge gaps exist regarding which approaches have highest impact on retention rates and are best suited for different participant groups. Research is needed to support the development of best practices for PEI as well as knowledge exchange between cohorts through network building.

Abstract Background The allo-octoploid Fragaria x ananassa follows disomic inheritance, yet the high sequence similarity among its subgenomes can lead to misalignment of short sequencing reads (150 bp). This misalignment results in an increased number of erroneous variants during variant calling. To accurately associate traits with the appropriate subgenome, it is essential to filter out these erroneous variants. By classifying variants into correct (type 1) and erroneous types (homoeologous variants—type 2, and multi-locus variants—type 3), we can improve the reliability of downstream analyses. Results Our analysis reveals that while erroneous variant types often display skewed average allele balances (AAB) for heterozygous calls, this measure alone is insufficient. To mitigate the erroneous variants further, we employed a Linkage Disequilibrium (LD) based filtering method that correlates highly (99%) with an approach that utilizes a genetic map from a biparental population. This combined filtering strategy—using both LD-based and average allele balance methods—resulted in the lowest switch error rate (0.037). Notably, our best filtering approach decreased phasing switch error rates by 44% and preserved 72% of the original dataset. Conclusions The results indicate that identifying erroneous variants due to subgenome similarity can be effectively achieved without extensive genotyping of mapping populations. By implementing the LD-based filtering method, the phasing accuracy improved which improves the tracability of important alleles in the germplasm, paving the way for better understanding of trait associations in F. x ananassa.

Abstract Plants have an amazing ability to adapt to their environment, and this extends beyond biochemical responses and includes developmental changes that help them better exploit resources and survive. The plasticity observed in individual plant morphology is associated with robust developmental pathways that are influenced by environmental factors. However, there is still much to learn about the mechanisms behind the formation of the root system. In Arabidopsis thaliana, the root system displays a hierarchical structure with primary and secondary roots. The process of lateral root (LR) organogenesis involves multiple steps, including LR pre-patterning, LR initiation, LR outgrowth, and LR emergence. The study of root developmental plasticity in Arabidopsis has led to significant progress in understanding the mechanisms governing lateral root formation. The importance of root system architecture lies in its ability to shape the distribution of roots in the soil, which affects the plant's ability to acquire nutrients and water. In Arabidopsis, lateral roots originate from pericycle cells adjacent to the xylem poles known as the xylem-pole-pericycle (XPP). The positioning of LRs along the primary root is underpinned by a repetitive pre-patterning mechanism that establishes primed sites for future lateral root formation. In a subset of primed cells, the memory of a transient priming stimulus leads to the formation of stable pre-branch sites and the establishment of founder cell identity. These founder cells undergo a series of highly organized periclinal and anticlinal cell divisions and expansion to form lateral root primordia. Subsequently, LRP emerges through three overlying cell layers of the primary root, giving rise to fully developed LRs. In addition to LRs Arabidopsis can also develop adventitious lateral roots from the primary root in response to specific stress signals such as wounding or environmental cues. Overall, this review creates an overview of the mechanisms governing root lateral root formation which can be a stepping stone to improved crop yields and a better understanding of plant adaptation to changing environments.

Data from whole-class discussions in Dutch upper primary school show that teachers occasionally explicitly take downgraded epistemic stances through epistemic disclaimers such as 'ik weet het niet' (English: "I don't know (it)"), which contrasts with their institutionally assigned epistemic authority. In the current study, we have collected turns in which such epistemic disclaimers occur, and analysed them using conversation analysis. In our analyses, we focused on the positions of the turns in which epistemic disclaimers occur, and on the varying ways in which these turns influence the subsequent course of interaction. We have found that teachers' epistemic disclaimers occur in initiating turns, facilitating student participation, but also in responsive turns. The latter vary in the extent to which they facilitate participation, ranging from facilitating student participation in a similar way to the initiating turns, to blocking further student contributions altogether. This study furthermore demonstrates that teachers employ epistemic disclaimers to navigate two teacher roles, namely those of a teacher with epistemic authority, and of a facilitator of whole class-discussions.

This intervention study examined the effectiveness of instructional support tailored toward two techniques (i.e., random associations and constraint identification) to strengthen children's creative problem-solving skills within upper-elementary science education. Five inquiry-based science lessons with ample opportunity for creative problem-solving (i.e., divergent and convergent thinking) were provided. Children were assigned to a condition with instructional support (n = 107) or without (n = 134). Domain-general and specific measures of divergent and convergent thinking were included, and reading comprehension as well as mathematical ability were taken into account. Repeated measures multivariate analyses of covariance revealed how all children improved in terms of domain-general convergent thinking, with a larger increase for children who performed better in mathematics. This shows a promising premise for future research focusing on the domain generality of convergent thinking and for the potential of transfer across domains. No additional improvement based on instructional support was found and children did not improve in terms of divergent thinking. The constraint identification and random associations technique might not be suitable for elementary school children, yet future research is necessary to validate such claims. Meanwhile, teachers could possibly support convergent thinking by simply providing exercises for divergent and convergent thinking.

BACKGROUND: Overweight and obesity impose a considerable individual and social burden, and the urban environments might encompass factors that contribute to obesity. Nevertheless, there is a scarcity of research that takes into account the simultaneous interaction of multiple environmental factors. OBJECTIVES: Our objective was to perform an exposome-wide association study of body mass index (BMI) in a multicohort setting of 15 studies. METHODS: Studies were affiliated with the Dutch Geoscience and Health Cohort Consortium (GECCO), had different population sizes (688-141,825), and covered the entire Netherlands. Ten studies contained general population samples, others focused on specific populations including people with diabetes or impaired hearing. BMI was calculated from self-reported or measured height and weight. Associations with 69 residential neighborhood environmental factors (air pollution, noise, temperature, neighborhood socioeconomic and demographic factors, food environment, drivability, and walkability) were explored. Random forest (RF) regression addressed potential nonlinear and nonadditive associations. In the absence of formal methods for multimodel inference for RF, a rank aggregation-based meta-analytic strategy was used to summarize the results across the studies. RESULTS: Six exposures were associated with BMI: five indicating neighborhood economic or social environments (average home values, percentage of high-income residents, average income, livability score, share of single residents) and one indicating the physical activity environment (walkability in 5-km buffer area). Living in high-income neighborhoods and neighborhoods with higher livability scores was associated with lower BMI. Nonlinear associations were observed with neighborhood home values in all studies. Lower neighborhood home values were associated with higher BMI scores but only for values up to [euro]300,000. The directions of associations were less consistent for walkability and share of single residents. DISCUSSION: Rank aggregation made it possible to flexibly combine the results from various studies, although between-study heterogeneity could not be estimated quantitatively based on RF models. Neighborhood social, economic, and physical environments had the strongest associations with BMI. https://doi.org/10.1289/EHP13393, Introduction Overweight and obesity impose a considerable individual and social burden, with global rates that have nearly tripled since 1975. (1) This striking rise could be attributed to changes in [...]

Abstract Creativity and mental disorders are sometimes seen as intertwined, but research is still unclear on whether, how much, and why. Here we explore the potential role of shared genetic factors behind creativity and symptoms of borderline personality disorder (BPD, characterized by mood swings and randomness of thoughts). Data were collected from 6745 twins (2378 complete pairs) by the Netherlands Twin Register on BPD scores (PAI-BOR questionnaire) and working in a creative profession (proxy for creativity). First, we tested whether there is an association between BPD symptoms and creative professions. Results confirmed that individuals scoring higher on the BPD spectrum are more likely to have a creative profession (Cohen’s d = 0.16). Next, we modeled how much of this association reflects underlying genetic and/or environmental correlations—by using a bivariate classical twin design. We found that creativity and BPD were each influenced by genetic factors (heritability = 0.45 for BPD and 0.67 for creativity) and that these traits are genetically correlated rG = 0.17. Environmental influences were not correlated. This is evidence for a common genetic mechanism between borderline personality scores and creativity which may reflect causal effects and shed light on mechanisms.

Abstract Background The cost of tobacco is one of the most reported reasons to quit smoking. The Netherlands increased tobacco taxes twice in the span of nine months: a €1 increase per pack in April 2020, and a €0.12 increase per pack in January 2021. This study examines to what extent people report to think about quitting due to the upcoming tax increase(s), as well as how it relates to their age, income or educational level. Additionally, we examined whether thinking about quitting was associated with quit intention and quit behaviour, and whether these associations were different for the two tax increases. Methods Longitudinal data from the International Tobacco Control (ITC) Netherlands Surveys, Cohort 2 were used (N = 5919 observations; wave 1 (February – March 2020): n = 2051; wave 2 (September – November 2020): n = 1919; wave 3 (June – July 2021): n = 1949). Generalised Estimating Equation (GEE) regressions were fit to test the associations between thinking about quitting due to the tax increase and post-tax increases in quit intention, serious quit attempts, and quitting smoking (≤ 1 cigarette a month), as well as sociodemographic variables. Results Circa half of the people who smoke reported thinking about quitting smoking due to the upcoming tax increase (Wave 1 = 51.3% (n = 1052); Wave 2 = 47.3% (n = 849)). Individuals who reported thinking about quitting smoking due to upcoming tax increase(s) were more likely to have increased their quit intention (aOR: 2.00, p ≤ .001) or have carried out a serious quit attempt (aOR:1.48, p ≤ .001) post-tax increase. More people attempted to quit smoking between wave 2 and 3 (post 2021 increase) than between wave 1 and 2 (post 2020 increase). We did not find an interaction effect between wave and thinking about quitting for quit intention, quit attempts, and quitting smoking. Conclusions Tax increases stimulate people to think about quitting. Thinking about quitting due to an upcoming tax increase was associated with more positive quit intention and serious quit attempts.

Background: Tumor heterogeneity is a hurdle to effective therapy, as illustrated by the ‘mixed responses’ frequently seen in immunotherapy-treated patients. Previously, AXL+ tumor cells were identified to be highly resistant to targeted therapy, whereas more differentiated MITF+ tumor cells do respond to RAF and MEK inhibitors. Patients and methods: In this study, we analyzed tumor heterogeneity and explored the presence of the previously described AXL+ or MITF+ melanoma subpopulations in metastatic tissues by NanoString gene expression analysis, single-cell RNA sequencing and in situ multiplex immunofluorescence. Furthermore, we analyzed how these subpopulations correlate with immunological pressure and response to immunotherapy by immunomodulating antibodies or autologous tumor lysate-loaded dendritic cell vaccination. Results: Our data demonstrate large interpatient variability and variable therapy-induced changes independent of the type of therapy. We identify the presence of previously described AXL+ and MITF+ subpopulations in metastatic tissues both at the mRNA level and in situ at the protein level, and demonstrate that MITF+ melanoma cells are significantly decreased upon immunotherapy, while AXL+ melanoma cell numbers are stable. MITF+ tumor cells showed the most significant inverse correlation with CD8+ T cells. Our patient cohort also shows that immunotherapy-induced changes in the abundance of AXL+ or MITF+ tumor cells did not correlate with improved survival. Conclusions: Overall, this study suggests that more differentiated MITF+ tumors are efficiently targeted by immunotherapy, while AXL+ tumor cells may be more resistant, analogous to their response to targeted therapy.

Background Operational research (OR) is a process to improve health system capacity by evaluating interventions to improve health delivery and outcomes. The World Health Organization (WHO) Structured Operational Research Training Initiative (SORT-IT) programme promotes how OR contributes to improved health care delivery and health outcomes. A partnership project between the International Institute of Primary Health Care (IPHCE) in Ethiopia and The University of Queensland (UQ) in Australia modified the SORT-IT programme to deliver a hybrid Training of Trainers programme and improve OR capacity. Objective This study was performed to develop and evaluate the effectiveness of Train-the Trainers approach in building capability to expand the capacity of the IPHCE to deliver the SORT-IT programme. Methods Recruitment of participants and training were aligned with the principles of the SORT-IT programme. Training was face-to-face for the first session with subsequent training sessions delivered via Zoom over a 13-week period. Participants were required to complete all activities in line with SORT-IT deliverables. Slide decks supporting the SORT-IT training videos were developed and adapted to the Ethiopian context. Results Participants had diverse experience from programme directors to research officers. All training sessions were recorded and available for participants to watch and review when required. All participants completed OR protocols to the draft stage. Course evaluation revealed participants found the content and format of the training useful, pertinent, and interesting. Conclusion A hybrid model (face-to-face and video platform) for OR training was implemented. Managing contextual challenges such as information technology were managed easily by programme staff. Translating course requirements at a management level proved challenging with data collection for the protocols but provided insight into potential future challenges. This OR Training of Trainers course demonstrated that sharing of skills and knowledge can occur through a hybrid delivery model and contribute to developing capacity.

BackgroundManaging risk effectively within small animal veterinary practice is integral for staff, patient and client safety. Veterinary personnel are exposed to many risks, including bites, scratches, sharps injuries and exposure to zoonotic diseases and multi-resistant organisms. Patients may also be exposed to healthcare-associated infections, including multi-resistant organisms. While veterinary owners/managers have a duty of care under legislated Workplace Health and Safety requirements, all staff have a responsibility to contribute to assessing and minimizing risk. The application of standard and transmission precautions will help with risk minimization. This study aimed to determine how small animal veterinary staff understand and perceive infection prevention and control risk and to provide recommendations to assist with risk mitigation.MethodsA mixed methods design was used. A digital questionnaire was administered to small animal veterinary staff in Australia to identify knowledge, attitudes and practices of risk related behaviors. Follow up focus groups were conducted with small animal practitioners to explore factors supporting and preventing veterinary staff from implementing recommended practices identified in the questionnaire.ResultsSmall animal veterinary staff acknowledged they participated in many high-risk activities, including recapping needles and eating and drinking in patient care areas. Injuries were common, with 77% of staff receiving a bite or scratch, and 22% receiving a sharps injury in the preceding six months. Less than one in five of these incidents was reported. Staff agreed effective infection prevention and control was the responsibility of all staff, but a designated staff member should take responsibility for managing it. The practice owner/manager was integral to supporting and promoting recommended strategies, contributing to a positive workplace culture and improving safety for staff and patients.ConclusionSmall animal veterinary staff have some understanding of how to identify, report, manage and mitigate risk but were limited by their knowledge of infection prevention and control principles.

Objective To explore associations between general health-related problems and subclinical coronary artery disease (CAD), determined by CT coronary calcium score (CT-CCS), in a general population.Design A cross-sectional design.Setting This study was performed in a prospective population-based cohort, examining the health and health-related behaviour of individuals living in the Northern Netherlands.Participants The initial cohort comprised 6763 participants ≥45 years of age who underwent CT-scanning. Participants were included for the current analysis if they filled in three validated questionnaires (Symptomatic Checklist-90, Research and Development Survey-36 and Reviving the Early Diagnosis of CardioVascular Diseases questionnaire (RED-CVD)) and did not have a history of cardiovascular disease. The final analysis included 6530 participants.Primary outcome measure Backward-stepwise and forward-stepwise logistic regression analyses were performed to determine associations between general health-related problems and subclinical CAD (CCS≥100 and ≥300).Results The median age was 53 years (25th, 75th percentile: 48, 58); 57% were women. CRCS≥100 was found in 1236 (19%) participants, 437 (12%) in women and 799 (29%) men and CCS≥300 in 643 (9.9%) participants of which 180 (4.8%) were women and 463 (16.6%) men. In univariate analysis, in women the expectation of health to worsen (OR=1.13, 95% CI: 1.05 to 1.21), and in men reduced exercise intolerance (OR=1.14, 95% CI: 1.06 to 1.23) were associated with CCS≥100. The total RED-CVD score in women (OR=1.06, (95% CI: 1.05 to 1.08) and men (OR=1.07, 95% CI: 1.06 to 1.09), and in men also reduced exercise intolerance (OR=1.15, 95% CI: 1.06 to 1.25) and headache (OR=0.55, 95% CI: 0.38 to 0.79) were associated with CCS≥300. In multivariate analyses, only general health expectation in women was still significantly associated with subclinical CAD (CCS≥300) (OR=1.92, 95% CI: 1.56 to 2.37).Conclusion Only a few general health-related problems were associated with the presence of subclinical CAD in the general population, however, these problems showed no strong association. Therefore, using health-related symptoms does not seem useful to pre-select for CT-CCS.Trial registration number CCMO Register, NL17981.042.07 and NL58592.042.16.

The current understanding of the RSV-related mortality age distribution in low- and lower-middle-income countries (LMICs) relies on a limited number of disease incidence studies reporting wide age bands, and lacking specificity to Gavi-eligible countries. Understanding the age distribution of RSV-related deaths is crucial for the implementation of RSV interventions in LMICs that rely on support from Gavi. This study aims to provide the age profile of RSV mortality specifically in Gavi-eligible countries.Utilizing data from the RSV GOLD project, an ongoing global online mortality registry focusing on children under the age of 5 with laboratory-confirmed RSV infection, we employed two models (Complete Data Model and Prospective Data Model) to estimate the age profiles. To mitigate biases related to age group representation, we applied post-stratification weighting in our analysis.We included 423 pediatric deaths, including 145 from the community, under 2 years of age from 15 Gavi-eligible countries. Both models identified a peak age at 1 month and found that the majority of RSV-related mortality cases (59–77 %) from Gavi-eligible countries occur before 6 months of life. However, the models exhibited disparities in other age-related metrics. We present fitted age-at-time-of-death probability distributions to aid impact and cost-effectiveness studies.We expect that implementing infant RSV immunization strategies, such as maternal vaccination or infant immunoprophylaxis, will have high impact on RSV-related mortality in Gavi-eligible countries. The divergent results from the two models underscore the importance of carefully considering potential biases in retrospective and surveillance data when interpreting the age profile of RSV mortality cases in future research.