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Marella CE van Ruissen,1,2 Sebastiaan JW van Kraaij,1,2 Pim Gal,1,2 Wouter A Bakker,1,2 Hemme J Hijma,1,2 Geert Jan Groeneveld,1,2 Marieke L de Kam,1 Jacobus Burggraaf,1,2 Matthijs Moerland1,2 1Center for Human Drug Research, Leiden, The Netherlands; 2Leiden University Medical Center, Leiden, The NetherlandsCorrespondence: Matthijs Moerland, Center for Human Drug Research, Zernikedreef 8, Leiden, 2333CL, The Netherlands, Tel +31 71 524 6400, Fax +31 71 5246 499, Email mmoerland@chdr.nlAbstract: Dermal allyl isothiocyanate (AITC) administration and whole-body heat stress (WBHS) are two challenge models that are used to evaluate physiological mechanisms of vasodilation and pharmacological activity in humans. Their exact vasodilatory mechanisms in humans are not fully elucidated but are likely to be nitric oxide (NO)-mediated. This study aimed to evaluate whether there is overlap in the vasodilatory pathways of dermal AITC application and WBHS by combining the challenges. In this open-label interventional study, healthy volunteers underwent dermal administration of AITC twice: under basal conditions and during WBHS. Dermal blood flow (DBF) was non-invasively measured using laser speckle contrast imaging four times, once in each of the following situations: baseline, WBHS only, AITC only, and WBHS combined with AITC. A total of 12 male volunteers, aged 18– 61 years, participated in the study. Compared to baseline, following AITC application, their DBF increased by 63.43 AU (baseline: 32.55, 95% CI [17.78, 47.31] AU, AITC only: 95.97, 95% CI [81.21, 110.7] AU, p < 0.0001). During WBHS, the increase in DBF after AITC was 42.76 AU (WBHS only: 87.25, 95% CI [72.49, 102.0] AU, WBHS+AITC: 130.0, 95% CI [115.2, 144.8] AU, p < 0.0001). The combination of WBHS and AITC resulted in a lower DBF than the sum of the DBF responses to AITC and WBHS when applied separately (ED 20.67, 95% CI [− 3.532, 44.88], p = 0.0916). This might point towards the presence of an interaction in the vasodilatory mechanism of AITC application and WBHS, possibly indicating overlap in their NOS-driven vasodilatory pathways.Keywords: clinical study, vasodilatory pathways, laser speckle contrast imaging, pharmacological challenge models

DNA metabarcoding requires only a single DNA fragment to detect a species in mixed zooplankton samples, compared to morphology-based methods that rely on the presence of intact specimens. However, metabarcoding protocols have not yet been fully standardised, thus hindering data comparability between studies. To converge on standardised metabarcoding protocols, we used an experimental field-sampling approach to compare the effects of sampling gear (ring-, Manta- and WP2 nets), day and night (DN) sampling and tow duration (5-, 10- and 15-minute tows) on marine zooplankton composition. High-throughput sequencing of the cytochrome c oxidase subunit I (COI) gene region with different primers and taxonomic assignment of amplicon sequence variants at 97% similarity to barcode records were used to identify species. Metabarcoding detected a total of 224 species, of which 92% matched prior occurrence records from the region. Malacostraca (crabs, hermit crabs, lobsters, prawns and shrimps) was the best-represented class (49%), followed by Copepoda (21%), Actinopterygii (ray-finned fishes; 21%), and Gastropoda (9%). Species counts ranged from 9–61 species per tow, with high proportions of unique species in replicate tows. Mean species counts did not differ significantly between net types, DN samples or tow durations, respectively. Proportionate representation amongst taxonomic classes remained within a narrow range, except when sampling deeper habitats with a smaller mesh size. DN samples showed no evidence of daily vertical migration of zooplankton. Consistent inferred species composition across net types, tow duration and DN sampling treatments reflects high detection sensitivity of individual-based sampling, allowing for greater flexibility in planning of zooplankton sampling regimes.

Honey bees are vital to human well-being and are under multiple stresses. We need to be able to assess the viability and productivity of honey bee colonies in different landscapes and under different management and climate-change scenarios. We have developed a prototype digital twin, HONEYBEE-pDT, based on the BEEHAVE model, which simulates foraging, population dynamics and Varroa mite infestation of a single honey bee colony. The main input data are land-cover maps and daily weather data. We have developed the pDT for simulating large areas and have tested it for the whole of Germany. We have also developed a web-based GUI that users can use to run the pDT for specific sites. Hive weight data from hundreds of hives will be used for calibration and validation.

Abstract Background First generation Bruton tyrosine kinase inhibitors (BTKi) such as ibrutinib have been associated with cardiovascular toxicities. Newer generation BTKi (e.g.,acalabrutinib and zanabrutinib) have been associated with lower incidence of cardiotoxicity in clinical trials. Objective Given paucity in real-world data on the overall cardiac risk factor profile, especially with the newer BTKi, our study evaluated the incidence of cardiotoxicity with various BTKi among a large, commercially insured population of patients. Methods We performed a retrospective cohort analysis of all adults with a diagnosis of B-cell malignancy undergoing treatment with BTKi acalabrutinib and ibrutinib between January 2018 and June 2020 using Optum’s de-identified Clinformatics® Data Mart Database. We then identified patients who had pre-existing cardiac disease one year prior to starting BTKi. New incidence of atrial fibrillation/flutter, hypertension, bleeding, ventricular tachycardia/fibrillation and sudden cardiac death from the time of index presciption were compared with standard Chi Square or Student t-test where appropriate. Multivariate logistic regression models were also estimated to evaluate for confounding. Results A total of 1691 patients were included in the final analysis. 1595 (94%, median age 75 (19–90) years, 61% male gender) patients received ibrutinib, and 96 (6%, median age 73.5 (32–90) years, 62.5% male gender) patients received acalabrutinib. The median duration of drug exposure of ibrutinib was 238 (2-1084) days vs. 150 (30–870) days for acalabrutinib. There was lower new incidence of atrial fibrillation/flutter (4.6%-vs-17%, p = 0.013), hypertension (6.3%-vs-25%, p = NS), sudden cardiac arrest/death (0% vs. 1.5%, p = NS) in the acalabrutinib group compared to ibrutinib, of which only the lower incidence of atrial fibrillation/flutter was statistically significant. This was despite the finding of a higher prevalence of atrial fibrillation/flutter at baseline in patients receiving acalabrutinib. Conclusions There was lower incidence of new atrial fibrillation/flutter with acalabrutinib when compared to ibrutinib in a real-world cohort of patients.

Abstract C–C Motif Chemokine Ligand 17 (CCL17) is a chemokine that binds and signals through the G‐protein coupled CC‐chemokine receptor 4 and has been implicated in the development of inflammatory and arthritic pain. GSK3858279 is a high‐affinity, first‐in‐class, monoclonal antibody, binding specifically to CCL17 and inhibiting downstream signaling. In this phase I, randomized, single‐center, double‐blind, placebo‐controlled, three‐period, incomplete‐block crossover study (NCT04114656), the analgesic effects and safety of intravenous GSK3858279 were assessed in a battery of evoked acute pain assessments on healthy, adult (aged ≥18 years), male participants. Participants were randomized 1:1 to receive either one placebo (0.9% w/v NaCl) dose followed by two GSK3858279 doses (PAA treatment sequence), or one GSK3858279 dose followed by two placebo doses (APP treatment sequence). The co‐primary end points were ultraviolet B heat pain detection threshold (°C), cold pressor time to pain tolerance threshold (PTT, sec), and electrical PTT (mA, single stimulus). Twenty‐one participants were enrolled (PAA = 11; APP = 10). Mean age (standard deviation) was 29.3 (7.9) years for PAA, 31.1 (7.7) years for APP. No significant differences were observed in the analgesic effect between GSK3858279 and placebo for any end point. Exposure to GSK3858279 was similar between Period 1 (APP sequence), and Periods 2 and 3 (PAA sequence), with some GSK3858279 carry‐over. Changes in serum CCL17 levels were consistent with the expected GSK3858279 activity. All drug‐related adverse events were mild in intensity and caused no discontinuations. The absence of an efficacy signal in this acute pain model does not preclude efficacy in chronic pain states.

Wedgefishes (Rhinidae) are threatened by unsustainable fishing globally, and especially in the Southwest Indian Ocean (SWIO), due to their high-value fins in the shark trade. The whitespotted wedgefish Rhynchobatus djiddensis and the bottlenose wedgefish R. australiae are both classified as Critically Endangered on the IUCN Red List of Threatened Species, yet a lack of species-specific knowledge and taxonomic uncertainty still exists within this genus. Genetic approaches aid in taxonomic classification and identifying distinct populations for targeted conservation. Morphological specimen identification of samples (n = 189) collected across the SWIO was confirmed based on the cytochrome oxidase c subunit I (COI) and/or nicotinamide adenine dehydrogenase subunit 2 (ND2) gene regions. The genetic diversity and population structure within and between species and sampling locations were investigated using a dual marker approach: (1) 2 concatenated mitochondrial gene regions, namely COI and the control region (n = 117), and (2) 9 nuclear microsatellite markers (n = 146). The overall genetic diversity was moderate, with an indication that different evolutionary forces are at play on a mitochondrial versus nuclear level. The 2 species were delineated based on both marker types, and for R. djiddensis, the sampling locations of South Africa and Mozambique were genetically homogeneous. For R. australiae, significant differentiation was found between sampling locations, with Madagascar and Tanzania being genetically the most similar. This information provides critical insights into the distribution range and population structure of the whitespotted wedgefish species complex that can support the sustainable management of wedgefishes.

IntroductionThe spatial distribution of white matter hyperintensities (WMH) on MRI is often considered in the diagnostic evaluation of patients with cognitive problems. In some patients, clinicians may classify WMH patterns as "unusual", but this is largely based on expert opinion, because detailed quantitative information about WMH distribution frequencies in a memory clinic setting is lacking. Here we report voxel wise 3D WMH distribution frequencies in a large multicenter dataset and also aimed to identify individuals with unusual WMH patterns.MethodsIndividual participant data (N = 3525, including 777 participants with subjective cognitive decline, 1389 participants with mild cognitive impairment and 1359 patients with dementia) from eleven memory clinic cohorts, recruited through the Meta VCI Map Consortium, were used. WMH segmentations were provided by participating centers or performed in Utrecht and registered to the Montreal Neurological Institute (MNI)-152 brain template for spatial normalization. To determine WMH distribution frequencies, we calculated WMH probability maps at voxel level. To identify individuals with unusual WMH patterns, region-of-interest (ROI) based WMH probability maps, rule-based scores, and a machine learning method (Local Outlier Factor (LOF)), were implemented.ResultsWMH occurred in 82% of voxels from the white matter template with large variation between subjects. Only a small proportion of the white matter (1.7%), mainly in the periventricular areas, was affected by WMH in at least 20% of participants. A large portion of the total white matter was affected infrequently. Nevertheless, 93.8% of individual participants had lesions in voxels that were affected in less than 2% of the population, mainly located in subcortical areas. Only the machine learning method effectively identified individuals with unusual patterns, in particular subjects with asymmetric WMH distribution or with WMH at relatively rarely affected locations despite common locations not being affected.DiscussionAggregating data from several memory clinic cohorts, we provide a detailed 3D map of WMH lesion distribution frequencies, that informs on common as well as rare localizations. The use of data-driven analysis with LOF can be used to identify unusual patterns, which might serve as an alert that rare causes of WMH should be considered.

This study applies a "within-family, age-snapshot design" to investigate differences between siblings in the development of compliance during the preschool years by disaggregating situational, within-family, and between-family effects. The aim of the study was to investigate the relation between sibling differences in compliance and the within-family factors birth order and differential parenting, as well as interactions between these factors. Using observational data of 311 Dutch families (self-identified as culturally Dutch) with 2 children when each child was 3 and 4 years old (firstborns: 36.2 months old; SD = 3.6; 48% girls, second-borns (2 years later): 36.67 months old; SD = 0.62; 47% girls) and both parents. Three-level cross-classified multilevel models showed main effects of observed sibling noncompliance and differential verbal discipline on noncompliance. In addition, second-born children were more compliant than their firstborn siblings, but only when the firstborn was disciplined physically more often than his/her younger sibling. The results provide evidence that birth-order effects may partially be explained by differential parenting and suggest that differences between siblings cannot be fully understood without taking into account the influence of both direct and indirect sibling effects.

Objectives Diagnostic prediction models exist to assess the probability of bacterial meningitis (BM) in paediatric patients with suspected meningitis. To evaluate the diagnostic accuracy of these models in a broad population of children suspected of a central nervous system (CNS) infection, we performed external validation.Methods We performed a systematic literature review in Medline to identify articles on the development, refinement or validation of a prediction model for BM, and validated these models in a prospective cohort of children aged 0–18 years old suspected of a CNS infection.Primary and secondary outcome measures We calculated sensitivity, specificity, predictive values, the area under the receiver operating characteristic curve (AUC) and evaluated calibration of the models for diagnosis of BM.Results In total, 23 prediction models were validated in a cohort of 450 patients suspected of a CNS infection included between 2012 and 2015. In 75 patients (17%), the final diagnosis was a CNS infection including 30 with BM (7%). AUCs ranged from 0.69 to 0.94 (median 0.83, interquartile range [IQR] 0.79–0.87) overall, from 0.74 to 0.96 (median 0.89, IQR 0.82–0.92) in children aged ≥28 days and from 0.58 to 0.91 (median 0.79, IQR 0.75–0.82) in neonates.Conclusions Prediction models show good to excellent test characteristics for excluding BM in children and can be of help in the diagnostic workup of paediatric patients with a suspected CNS infection, but cannot replace a thorough history, physical examination and ancillary testing.

Abstract Dynamic balance assessments such as walking adaptability may yield a more realistic prediction of drug‐induced falls compared with postural stability measurements, as falls often result from limited gait adjustments when walking. The Interactive Walkway (IWW) measures walking adaptability but sensitivity to medication effects is unknown. If proven sensitive and specific, IWW could serve as a biomarker for targeted fall‐risk assessments in early clinical drug development. In this three‐way crossover study, 18 healthy elderly (age: 65–80 years) subjects received 5 mg zolpidem, 10 mg suvorexant, or placebo in the morning. Assessments were performed pre‐dose and approximately hourly until 9 h post‐dose. IWW assessments included an 8‐meter walking test, goal‐directed stepping, obstacle‐avoidance, and tandem‐walking. Other pharmacodynamic measurements were the Timed‐Up‐and‐Go (TUG) test at a comfortable and fast pace, adaptive tracking, and body sway. A decline in performance was observed for zolpidem compared with placebo for 3 h post‐dose in IWW walking adaptability outcome measures, TUG, adaptive tracking, and body sway. For the IWW tasks, a decrease in walking speed (among others) was observed. IWW parameters were not affected by suvorexant compared with placebo at any timepoint. However, an increase of 9.8% (95%CI: 1.8%, 18.5%) in body sway was observed for suvorexant compared with placebo up to 3 h post‐dose. The IWW successfully quantified drug effects of two hypnotic drugs and distinguished between zolpidem and suvorexant regarding their effects on walking. As a biomarker, the IWW demonstrated sensitivity in assessing dynamic balance and potential fall risk in early phase clinical drug development.

Abstract Climate change, with warming and drying weather conditions, is reducing the growth, seed production, and survival of fire‐adapted plants in fire‐prone regions such as Mediterranean‐type ecosystems. These effects of climate change on local plant demographics have recently been shown to reduce the persistence time of local populations of the fire‐killed shrub Banksia hookeriana dramatically. In principle, extinctions of local populations may be partly compensated by recolonization events through long‐distance dispersal mechanisms of seeds, such as post‐fire wind and bird‐mediated dispersal, facilitating persistence in spatially structured metapopulations. However, to what degree and under which assumptions metapopulation dynamics might compensate for the drastically increased local extinction risk remains to be explored. Given the long timespans involved and the complexity of interwoven local and regional processes, mechanistic, process‐based models are one of the most suitable approaches to systematically explore the potential role of metapopulation dynamics and its underlying ecological assumptions for fire‐prone ecosystems. Here we extend a recent mechanistic, process‐based, spatially implicit population model for the well‐studied fire‐killed and serotinous shrub species B. hookeriana to a spatially explicit metapopulation model. We systematically tested the effects of different ecological processes and assumptions on metapopulation dynamics under past (1988–2002) and current (2003–2017) climatic conditions, including (i) effects of different spatio‐temporal fires, (ii) effects of (likely) reduced intraspecific plant competition under current conditions and (iii) effects of variation in plant performance among and within patches. In general, metapopulation dynamics had the potential to increase the overall regional persistence of B. hookeriana. However, increased population persistence only occurred under specific optimistic assumptions. In both climate scenarios, the highest persistence occurred with larger fires and intermediate to long inter‐fire intervals. The assumption of lower intraspecific plant competition caused by lower densities under current conditions alone was not sufficient to increase persistence significantly. To achieve long‐term persistence (defined as >400 years) it was necessary to additionally consider empirically observed variation in plant performance among and within patches, that is, improved habitat quality in some large habitat patches (≥7) that could function as source patches and a higher survival rate and seed production for a subset of plants, specifically the top 25% of flower producers based on current climate conditions monitoring data. Our model results demonstrate that the impacts of ongoing climate change on plant demographics are so severe that even under optimistic assumptions, the existing metapopulation dynamics shift to an unstable source‐sink dynamic state. Based on our findings, we recommend increased research efforts to understand the consequences of intraspecific trait variation on plant demographics, emphasizing the variation of individual traits both among and within populations. From a conservation perspective, we encourage fire and land managers to revise their prescribed fire plans, which are typically short interval, small fires, as they conflict with the ecologically appropriate spatio‐temporal fire regime for B. hookeriana, and likely as well for many other fire‐killed species.

Background: There is a lack of evidence associating intraoperative transoesophageal echocardiography (TOE) use with improved outcomes among coronary artery bypass graft (CABG) surgery subpopulations. Methods: This matched retrospective cohort study used a US private claims dataset to compare outcomes among different CABG surgery patient populations with vs without TOE. Statistical analyses involved exact matching on pre-selected subgroups (congestive heart failure, single vessel, and multivessel CABG) and used fine and propensity-score balanced techniques to conduct multiple matched comparisons and sensitivity analyses. Results: Of 42 249 patients undergoing isolated CABG surgery, 24 919 (59.0%) received and 17 330 (41.0%) did not receive TOE. After matching, intraoperative TOE was significantly associated with a lower, 30-day mortality: 2.63% vs 3.20% (odds ratio [OR]: 0.81; 95% confidence interval [CI]: 0.71–0.92; P=0.002). In the subgroup matched comparisons, intraoperative TOE was significantly associated with a lower, 30-day mortality rate among those with congestive heart failure: 4.20% vs 5.26% (OR: 0.78; 95% CI: 0.66–0.94; P=0.007) and among those undergoing multivessel CABG with congestive heart failure: 4.23% vs 5.24% (OR: 0.80; 95% CI: 0.65–0.97; P=0.025), but not among those undergoing multivessel CABG without congestive heart failure: 1.83% vs 2.15% (OR: 0.85; 95% CI: 0.70–1.02; P=0.089, nor any of the remaining three subgroups. Conclusions: Among US adults undergoing isolated CABG surgery, intraoperative TOE was associated with improved outcomes in patients with congestive heart failure (vs without) and among patients undergoing multivessel (vs single vessel) CABG. These findings support prioritised TOE allocation to these patient populations at centres with limited TOE capabilities.

Background: With the increasing prevalence of pregnant women adhering to a vegan diet, gaining insight into their nutritional intake and its association with maternal and fetal outcomes is essential to providing recommendations and developing guidelines for general practice. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic review of the available scientific literature in Medline, Embase, and Cochrane was conducted in January 2024. Results: The titles and abstracts of 2211 unique articles were screened. Only six studies were eligible for inclusion and assessed for methodological quality using the (National Institutes of Health Study Quality (NIHSQ) Assessment Tool. The intake of protein and various micronutrients was significantly lower among vegan pregnant women compared to omnivorous women. Vitamin B12 supplements seemed sufficient in optimizing maternal and umbilical cord vitamin B12 levels amongst vegan mothers. Further, women on a vegan diet less often showed excessive pregnancy weight gain. However, children from women on a vegan diet had a significantly lower birth weight than those from women on an omnivorous diet. Conclusion: So far, only a few studies, with a large diversity of (assessment of) outcomes and insufficient power, have been published on this topic, limiting our ability to make firm conclusions about the effects of a vegan diet during pregnancy on maternal and fetal outcomes.

In this study, we examined gender and sexuality representation in language and math textbooks for Dutch secondary education. We analyzed all male and female characters in 13 language textbooks (N = 7,347) and 12 math textbooks (N = 4,591). Our results confirmed our expectations based on the theory of the hidden curriculum: female characters were underrepresented in all textbooks (40% in language, 44% in math textbooks), but overrepresented in household tasks and EHW (Education, Health, and Welfare) professions. Male characters were overrepresented in occupational roles, especially in STEM (Science, Technology, Engineering, and Math) professions and technical tasks. Further, female characters in language textbooks were overrepresented in parental roles, and male characters were overrepresented among characters with disharmonious traits and behaviors. We found no characters from sexual minorities in any of the textbooks. In conclusion, in line with theories of the hidden curriculum, Dutch textbooks include gender stereotypic messages and are heteronormative. These findings are relevant in light of previous studies demonstrating the negative impact of these biases on children. Publishers and schools that want to be more inclusive are recommended to be more critical in their selection of stories and role models in their books.