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Background: Regarding the analysis of RCT data there is a debate going on whether an adjustment for the baseline value of the outcome variable should be made. When an adjustment is made, there is a lot of misunderstanding regarding the way this should be done. Therefore, the aims of this educational paper are: 1) to explain different methods used to estimate treatment effects in RCTs, 2) to illustrate the different methods with a real life example and 3) to give an advise on how to analyse RCT data. Methods: Longitudinal analysis of covariance, repeated measures analysis in which also the baseline value is used as outcome and the analysis of changes were theoretically explained and applied to an example dataset investigating a systolic blood pressure lowering treatment. Results: It was shown that differences at baseline should be taken into account and that regular repeated measures analysis and regular analysis of changes did not adjust for the baseline differences between the groups and therefore lead to biased estimates of the treatment effect. In the real life example, due to the differences at baseline between the treatment and control group, the different methods lead to different estimates of the treatment effect. Conclusion: Regarding the analysis of RCT data, it is advised to use longitudinal analysis of covariance or a repeated measures analysis without the treatment variable, but with the interaction between treatment and time in the model. Keywords: Randomised controlled trials, Longitudinal of covariance, Repeated measures, Analysis of changes, Regression to the mean

Studies evaluating the benefits and risks of green spaces on children's health are scarce. The present study aimed to examine the associations between exposure to green spaces during pregnancy and early childhood with respiratory, cardiometabolic, and neurodevelopmental outcomes in school-age children. We performed an Individual-Participant Data (IPD) meta-analysis involving 35,000 children from ten European birth cohorts across eight countries. For each participant, we calculated residential Normalized Difference Vegetation Index (NDVI) within a 300 m buffer and the linear distance to green spaces (meters) during prenatal life and childhood. Multiple harmonized health outcomes were selected: asthma and wheezing, lung function, body mass index, diastolic and systolic blood pressure, non-verbal intelligence, internalizing and externalizing problems, and ADHD symptoms. We conducted a two-stage IPD meta-analysis and evaluated effect modification by socioeconomic status (SES) and sex. Between-study heterogeneity was assessed via random-effects meta-regression. Residential surrounding green spaces in childhood, not pregnancy, was associated with improved lung function, particularly higher FEV 1 (β = 0.06; 95 %CI: 0.03, 0.09 I 2  = 4.03 %, p < 0.001) and FVC (β = 0.07; 95 %CI: 0.04, 0.09 I 2  = 0 %, p < 0.001) with a stronger association observed in females (p < 0.001). This association remained robust after multiple testing correction and did not change notably after adjusting for ambient air pollution. Increased distance to green spaces showed an association with lower FVC (β = -0.04; 95 %CI: -0.07, -0.02, I 2  = 4.8, p = 0.001), with a stronger effect in children from higher SES backgrounds (p < 0.001). No consistent associations were found between green spaces and asthma, wheezing, cardiometabolic, or neurodevelopmental outcomes, with direction of effect varying across cohorts. Wheezing and neurodevelopmental outcomes showed high between-study heterogeneity, and the age at outcome assessment was only associated with heterogeneity in internalizing problems.. This large European meta-analysis suggests that childhood exposure to green spaces may lead to better lung function. Associations with other respiratory outcomes and selected cardiometabolic and neurodevelopmental outcomes remain inconclusive., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

International sharing of cohort data for research is important and challenging. We explored the feasibility of multicohort federated analyses by examining associations between 3 pregnancy exposures (maternal education, exposure to green vegetation, and gestational diabetes) and offspring body mass index (BMI) from infancy to age 17 years. We used data from 18 cohorts (n = 206,180 mother-child pairs) from the EU Child Cohort Network and derived BMI at ages 0-1, 2-3, 4-7, 8-13, and 14-17 years. Associations were estimated using linear regression via 1-stage individual participant data meta-analysis using DataSHIELD. Associations between lower maternal education and higher child BMI emerged from age 4 and increased with age (difference in BMI z score comparing low with high education, at age 2-3 years = 0.03 (95% confidence interval (CI): 0.00, 0.05), at 4-7 years = 0.16 (95% CI: 0.14, 0.17), and at 8-13 years = 0.24 (95% CI: 0.22, 0.26)). Gestational diabetes was positively associated with BMI from age 8 years (BMI z score difference = 0.18, 95% CI: 0.12, 0.25) but not at younger ages; however, associations attenuated towards the null when restricted to cohorts that measured gestational diabetes via universal screening. Exposure to green vegetation was weakly associated with higher BMI up to age 1 year but not at older ages. Opportunities of cross-cohort federated analyses are discussed., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Objective: Research on adults has identified an immigrant health advantage, known as the 'immigrant health paradox', by which migrants exhibit better health outcomes than natives. Is this health advantage transferred from parents to children in the form of higher birth weight relative to children of natives?, Setting: Western Europe and Australia., Participants: We use data from nine birth cohorts participating in the LifeCycle Project, including five studies with large samples of immigrants' children: Etude Longitudinale Française depuis l'Enfance-France (N=12 494), the Raine Study-Australia (N=2283), Born in Bradford-UK (N=4132), Amsterdam Born Children and their Development study-Netherlands (N=4030) and the Generation R study-Netherlands (N=4877). We include male and female babies born to immigrant and native parents., Primary and Secondary Outcome Measures: The primary outcome is birth weight measured in grams. Different specifications were tested: birth weight as a continuous variable including all births (DV1), the same variable but excluding babies born with over 4500 g (DV2), low birth weight as a 0-1 binary variable (1=birth weight below 2500 g) (DV3). Results using these three measures were similar, only results using DV1 are presented. Parental migration status is measured in four categories: both parents natives, both born abroad, only mother born abroad and only father born abroad., Results: Two patterns in children's birth weight by parental migration status emerged: higher birth weight among children of immigrants in France (+12 g, p<0.10) and Australia (+40 g, p<0.10) and lower birth weight among children of immigrants in the UK (-82 g, p<0.05) and the Netherlands (-80 g and -73 g, p<0.001) compared with natives' children. Smoking during pregnancy emerged as a mechanism explaining some of the birth weight gaps between children of immigrants and natives., Conclusion: The immigrant health advantage is not universally transferred to children in the form of higher birth weight in all host countries. Further research should investigate whether this cross-national variation is due to differences in immigrant communities, social and healthcare contexts across host countries., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Background: Preterm birth is the leading cause of perinatal morbidity and mortality and is associated with adverse developmental and long-term health outcomes, including several cardiometabolic risk factors and outcomes. However, evidence about the association of preterm birth with later body size derives mainly from studies using birth weight as a proxy of prematurity rather than an actual length of gestation. We investigated the association of gestational age (GA) at birth with body size from infancy through adolescence., Methods and Findings: We conducted a two-stage individual participant data (IPD) meta-analysis using data from 253,810 mother-child dyads from 16 general population-based cohort studies in Europe (Denmark, Finland, France, Italy, Norway, Portugal, Spain, the Netherlands, United Kingdom), North America (Canada), and Australasia (Australia) to estimate the association of GA with body mass index (BMI) and overweight (including obesity) adjusted for the following maternal characteristics as potential confounders: education, height, prepregnancy BMI, ethnic background, parity, smoking during pregnancy, age at child's birth, gestational diabetes and hypertension, and preeclampsia. Pregnancy and birth cohort studies from the LifeCycle and the EUCAN-Connect projects were invited and were eligible for inclusion if they had information on GA and minimum one measurement of BMI between infancy and adolescence. Using a federated analytical tool (DataSHIELD), we fitted linear and logistic regression models in each cohort separately with a complete-case approach and combined the regression estimates and standard errors through random-effects study-level meta-analysis providing an overall effect estimate at early infancy (>0.0 to 0.5 years), late infancy (>0.5 to 2.0 years), early childhood (>2.0 to 5.0 years), mid-childhood (>5.0 to 9.0 years), late childhood (>9.0 to 14.0 years), and adolescence (>14.0 to 19.0 years). GA was positively associated with BMI in the first decade of life, with the greatest increase in mean BMI z-score during early infancy (0.02, 95% confidence interval (CI): 0.00; 0.05, p < 0.05) per week of increase in GA, while in adolescence, preterm individuals reached similar levels of BMI (0.00, 95% CI: -0.01; 0.01, p 0.9) as term counterparts. The association between GA and overweight revealed a similar pattern of association with an increase in odds ratio (OR) of overweight from late infancy through mid-childhood (OR 1.01 to 1.02) per week increase in GA. By adolescence, however, GA was slightly negatively associated with the risk of overweight (OR 0.98 [95% CI: 0.97; 1.00], p 0.1) per week of increase in GA. Although based on only four cohorts (n = 32,089) that reached the age of adolescence, data suggest that individuals born very preterm may be at increased odds of overweight (OR 1.46 [95% CI: 1.03; 2.08], p < 0.05) compared with term counterparts. Findings were consistent across cohorts and sensitivity analyses despite considerable heterogeneity in cohort characteristics. However, residual confounding may be a limitation in this study, while findings may be less generalisable to settings in low- and middle-income countries., Conclusions: This study based on data from infancy through adolescence from 16 cohort studies found that GA may be important for body size in infancy, but the strength of association attenuates consistently with age. By adolescence, preterm individuals have on average a similar mean BMI to peers born at term., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: DAL has received support from Roche Diagnostics and Medtronic in relation to biomarker research that is not related to the research presented in this paper. The other authors have declared that no competing interests exist., (Copyright: © 2023 Vinther et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: There is a lack of effective interventions available for Pediatric Physical Therapists (PPTs) to promote a physically active lifestyle in children with physical disabilities. Participatory design methods (co-design) may be helpful in generating insights and developing intervention prototypes for facilitating a physically active lifestyle in children with physical disabilities (6-12 years). Materials and methods: A multidisciplinary development team of designers, developers, and researchers engaged in a co-design process-together with parents, PPTs, and other relevant stakeholders (such as the Dutch Association of PPTs and care sports connectors). In this design process, the team developed prototypes for interventions during three co-creation sessions, four one-week design sprint, living-lab testing and two triangulation sessions. All available co-design data was structured and analyzed by three researchers independently resulting in themes for facilitating physical activity. Results: The data rendered two specific outcomes, (1) knowledge cards containing the insights collected during the co-design process, and (2) eleven intervention prototypes. Based on the generated insights, the following factors seem important when facilitating a physically active lifestyle: a) stimulating self-efficacy; b) stimulating autonomy; c) focusing on possibilities; d) focusing on the needs of the individual child; e) collaborating with stakeholders; f) connecting with a child's environment; and g) meaningful goal setting. Conclusion: This study shows how a co-design process can be successfully applied to generate insights and develop interventions in pediatric rehabilitation. The designed prototypes facilitate the incorporation of behavioral change techniques into pediatric rehabilitation and offer new opportunities to facilitate a physically active lifestyle in children with physical disabilities by PPTs. While promising, further studies should examine the feasibility and effectivity of these prototypes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bolster, Gessel, Welten, Hermsen, Lugt, Kotte, Essen and Bloemen.)

The dry one-seeded fruits ( cypselae ) of the Asteraceae are often crowned with a pappus , an appendage of hairs or scales that assists in dispersal. It is generally assumed, but little investigated, that the pappus represents the outer floral whorl where the sepals are usually located. We analysed pappus-sepal homology in dandelions using micromorphological and floral gene expression analyses. We show that the pappus initiates from a ring primordium at the base of the corolla, heterochronic to the petals. Pappus parts form from this ring, with those in the alternipetalaous position usually being ahead in growth, referring to sepal identity. Tof-APETALLA 1 expression increased during floret development and was highest in mature pappus. Tof-PISTILLATA expression was high and confined to the floral tissues containing the petals and stamens, consistent with expectations for sepals. Apart from the pappus, the dispersal structure of dandelion consists of the upper part of the fruit, the beak , which originates from the inner floral whorl. Thus, our results support the homology of the pappus with the sepals, but show that it is highly derived. Together with our floral stage definitions and verified qPCR reference genes, they provide a basis for evolution and development studies in dandelions and possibly other Asteraceae.

We resolve debate over the evolution of vertebrate hypermineralized tissues through analyses of matrix protein-encoding secretory calcium-binding phosphoprotein (SCPP) genes and phylogenetic inference of hypermineralized tissues. Among these genes, AMBN and ENAM are found in both sarcopterygians and actinopterygians, whereas AMEL and SCPP5 are found only in sarcopterygians and actinopterygians, respectively. Actinopterygian AMBN , ENAM , and SCPP5 are expressed during the formation of hypermineralized tissues on scales and teeth: ganoin, acrodin, and collar enamel in gar, and acrodin and collar enameloid in zebrafish. Our phylogenetic analyses indicate the emergence of an ancestral enamel in stem-osteichthyans, whereas ganoin emerged in stem-actinopterygians and true enamel in stem-sarcopterygians. Thus, AMBN and ENAM originated in concert with ancestral enamel, SCPP5 evolved in association with ganoin, and AMEL evolved with true enamel. Shifts in gene expression domain and timing explain the evolution of different hypermineralized tissues. We propose that hypermineralized tissues in osteichthyans coevolved with matrix SCPP genes., Competing Interests: The authors declare no competing interests., (© 2020 The Author(s).)

Background: Primary prevention of overweight is to be preferred above secondary prevention, which has shown moderate effectiveness., Objective: To develop and internally validate a dynamic prediction model to identify young children in the general population, applicable at every age between birth and age 6, at high risk of future overweight (age 8)., Methods: Data were used from the Prevention and Incidence of Asthma and Mite Allergy birth cohort, born in 1996 to 1997, in the Netherlands. Participants for whom data on the outcome overweight at age 8 and at least three body mass index SD scores (BMI SDS) at the age of ≥3 months and ≤6 years were available, were included (N = 2265). The outcome of the prediction model is overweight (yes/no) at age 8 (range 7.4-10.5 years), defined according to the sex- and age-specific BMI cut-offs of the International Obesity Task Force., Results: After backward selection in a Generalized Estimating Equations analysis, the prediction model included the baseline predictors maternal BMI, paternal BMI, paternal education, birthweight, sex, ethnicity and indoor smoke exposure; and the longitudinal predictors BMI SDS, and the linear and quadratic terms of the growth curve describing a child's BMI SDS development over time, as well as the longitudinal predictors' interactions with age. The area under the curve of the model after internal validation was 0.845 and Nagelkerke R 2 was 0.351., Conclusions: A dynamic prediction model for overweight was developed with a good predictive ability using easily obtainable predictor information. External validation is needed to confirm that the model has potential for use in practice., (© 2020 The Authors. Pediatric Obesity published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Background: Variation in shape and size of many floral organs is related to pollinators. Evolution of such organs is driven by duplication and modification of MADS-box and MYB transcription factors. We applied a combination of micro-morphological (SEM and micro 3D-CT scanning) and molecular techniques (transcriptome and RT-PCR analysis) to understand the evolution and development of the callus, stelidia and mentum, three highly specialized floral structures of orchids involved in pollination. Early stage and mature tissues were collected from flowers of the bee-pollinated Phalaenopsis equestris and Phalaenopsis pulcherrima , two species that differ in floral morphology: P. equestris has a large callus but short stelidia and no mentum, whereas P. pulcherrima has a small callus, but long stelidia and a pronounced mentum., Results: Our results show the stelidia develop from early primordial stages, whereas the callus and mentum develop later. In combination, the micro 3D-CT scan analysis and gene expression analyses show that the callus is of mixed petaloid-staminodial origin, the stelidia of staminodial origin, and the mentum of mixed sepaloid-petaloid-staminodial origin. SEP clade 1 copies are expressed in the larger callus of P. equestris , whereas AP3 clade 1 and AGL6 clade 1 copies are expressed in the pronounced mentum and long stelidia of P. pulcherrima. AP3 clade 4, PI -, AGL6 clade 2 and PCF clade 1 copies might have a balancing role in callus and gynostemium development. There appears to be a trade-off between DIV clade 2 expression with SEP clade 1 expression in the callus, on the one hand, and with AP3 clade 1 and AGL6 clade 1 expression in the stelidia and mentum on the other., Conclusions: We detected differential growth and expression of MADS box AP3/PI -like, AGL 6-like and SEP -like, and MYB DIV -like gene copies in the callus, stelidia and mentum of two species of Phalaenopsis, of which these floral structures are very differently shaped and sized. Our study provides a first glimpse of the evolutionary developmental mechanisms driving adaptation of Phalaenopsis flowers to different pollinators by providing combined micro-morphological and molecular evidence for a possible sepaloid-petaloid-staminodial origin of the orchid mentum., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Targeted screening for childhood high blood pressure may be more feasible than routine blood pressure measurement in all children to avoid unnecessary harms, overdiagnosis or costs. Targeting maybe based e.g. on being overweight, but information on other predictors may also be useful. Therefore, we aimed to develop a multivariable diagnostic prediction model to select children aged 9-10 years for blood pressure measurement. Data from 5359 children in a population-based prospective cohort study were used. High blood pressure was defined as systolic or diastolic blood pressure ≥ 95th percentile for gender, age, and height. Logistic regression with backward selection was used to identify the strongest predictors related to pregnancy, child, and parent characteristics. Internal validation was performed using bootstrapping. 227 children (4.2%) had high blood pressure. The diagnostic model included maternal hypertensive disease during pregnancy, maternal BMI, maternal educational level, parental hypertension, parental smoking, child birth weight standard deviation score (SDS), child BMI SDS, and child ethnicity. The area under the ROC curve was 0.73, compared to 0.65 when using only child overweight. Using the model and a cut-off of 5% for predicted risk, sensitivity and specificity were 59% and 76%; using child overweight only, sensitivity and specificity were 47% and 84%. In conclusion, our diagnostic prediction model uses easily obtainable information to identify children at increased risk of high blood pressure, offering an opportunity for targeted screening. This model enables to detect a higher proportion of children with high blood pressure than a strategy based on child overweight only., (Copyright © 2020. Published by Elsevier Inc.)

Aims: The TElemonitoring in the MAnagement of Heart Failure (TEMA-HF) 1 long-term follow-up study assessed whether an initial six-month telemonitoring (TM) programme compared with usual care (UC) would result in reduced all-cause mortality, heart failure admissions and healthcare costs in chronic heart failure (CHF) patients at long-term follow-up., Methods: Of the 160 patients included in the multi-centre, randomised controlled telemonitoring trial (TEMA-HF 1, time point t 0 ); 142 CHF patients (65% male; age: 76 ± 10 years; EF: 36 ± 15%) were alive and entered the follow-up study (time point: t 1 ) with a final evaluation at 79 months (time point: t 2 ). Both TM and UC group patients received standard heart failure care during the follow-up study (time points: t 1 - t 2 ). The primary endpoint was all-cause mortality. Secondary outcomes included days lost due to heart failure readmissions and readmission/patient follow-up related healthcare costs., Results: Compared with usual care, the initial six-month TM programme had no significant effect on all-cause mortality (hazard ratio: 0.83; 95% confidence interval, 0.57 to 1.20; p = 0.32). The number of days lost due to heart failure readmissions was significantly lower in the TM group ( p = 0.04). Healthcare costs did not differ significantly between the TM (€ 9140 ± 10580) and UC group (€ 12495 ± 22433) ( p = 0.87)., Discussion: An initial six-month telemonitoring programme was not associated with reduced all-cause mortality in CHF patients at long-term follow-up but resulted in a reduction in the number of days lost due to heart failure readmissions. This study is registered in the ClinicalTrials.gov registry (NCT03171038) (URL: https://clinicaltrials.gov/ct2/show/NCT03171038 ).

Background: Hypertension, even during childhood, increases the risk of developing atherosclerosis and cardiovascular disease. Therefore, starting prevention of hypertension early in the life course could be beneficial. Prediction models might be useful for identifying children at increased risk of developing hypertension, which may enable targeted primordial prevention of cardiovascular disease., Objective: To provide an overview of childhood prediction models for future hypertension., Methods: Embase and Medline were systematically searched. Studies were included that were performed in the general population, and that reported on development or validation of a multivariable model for children to predict future high blood pressure, prehypertension or hypertension. Data were extracted using the CHARMS checklist for prediction modelling studies., Results: Out of 12 780 reviewed records, six studies were included in which 18 models were presented. Five studies predicted adulthood hypertension, and one predicted adolescent prehypertension/hypertension. BMI and current blood pressure were most commonly included as predictors in the final models. Considerable heterogeneity existed in timing of prediction (from early childhood to late adolescence) and outcome measurement. Important methodological information was often missing, and in four studies information to apply the model in new individuals was insufficient. Reported area under the ROC curves ranged from 0.51 to 0.74. As none of the models were validated, generalizability could not be confirmed., Conclusion: Several childhood prediction models for future hypertension were identified, but their value for practice remains unclear because of suboptimal methods, limited information on performance, or the lack of external validation. Further validation studies are indicated.

Background: In literature, not much emphasis has been placed on methods for analyzing repeatedly measured independent variables, even less so for the use in prediction modeling specifically. However, repeated measurements could especially be interesting for the construction of prediction models. Therefore, our objective was to evaluate different methods to model a repeatedly measured independent variable and a long-term fixed outcome variable into a prediction model., Methods: Six methods to handle a repeatedly measured predictor were applied to develop prediction models. Methods were evaluated with respect to the models' predictive quality (explained variance R 2 and the area under the curve (AUC)) and their properties were discussed. The models included overweight and BMI-standard deviation score (BMI-SDS) at age 10 years as outcome and seven BMI-SDS measurements between 0 and 5.5 years as longitudinal predictor. Methods for comparison encompassed developing models including: all measurements; a single (here: the last) measurement; a mean or maximum value of all measurements; changes between subsequent measurements; conditional measurements; and growth curve parameters., Results: All methods, except for using the maximum or mean, resulted in prediction models for overweight of similar predictive quality, with adjusted Nagelkerke R 2 ranging between 0.230 and 0.244 and AUC ranging between 0.799 and 0.807. Continuous BMI-SDS prediction showed similar results., Conclusions: The choice of method depends on hypothesized predictor-outcome associations, available data, and requirements of the prediction model. Overall, the growth curve method seems to be the most flexible method capable of incorporating longitudinal predictor information without loss in predictive quality., Competing Interests: The study protocol was approved by the Medical Ethics Committee of the VU University Medical Centre Amsterdam, and written informed consent was obtained from all participants.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Objective: To assess the associations of maternal prepregnancy body mass index (BMI) and rates of early-pregnancy, mid-pregnancy and total gestational weight gain with adolescent body fat distribution and cardio-metabolic outcomes., Design: Population-based prospective cohort study., Setting: Western Australia., Population: Thousand three hundred and ninety-two mothers and their children., Methods: Maternal prepregnancy weight was assessed by questionnaire. Maternal weights at a mean of 16.5 ± 2.2 SD and 34.1 ± 1.5 SD weeks of gestation were obtained from medical records. Offspring adiposity and cardio-metabolic outcomes were assessed at a median age 17.0 years [95% confidence interval (CI) range: 16.7, 17.7]., Main Outcome Measures: Adolescent BMI, waist circumference (WC), waist-to-hip ratio (WHR), blood pressure, total and HDL-cholesterol, triglycerides, insulin, glucose and HOMA-IR., Results: Higher prepregnancy BMI was associated with higher adolescent BMI, WC, WHR, systolic blood pressure, insulin, glucose and HOMA-IR levels (P-values <0.05). Adjustment for adolescent current BMI attenuated the associations of prepregnancy BMI with adolescent cardio-metabolic outcomes. Higher weight gain in early-pregnancy, but not mid-pregnancy, was associated with higher adolescent BMI, WC and WHR (P-values <0.05), but not with other cardio-metabolic risk factors. Total gestational weight gain was associated with adolescent BMI and WC (P-values <0.05). Higher prepregnancy BMI and early-pregnancy weight gain were associated with increased risks of the high-metabolic risk cluster in adolescents (OR 1.57, 95% CI 1.33, 1.85 and OR 1.23, 95% CI 1.03, 1.47 per SD increase in prepregnancy BMI and early-pregnancy weight gain, respectively)., Conclusions: Higher maternal prepregnancy BMI and early-pregnancy weight gain rate are associated with an adverse adolescent cardio-metabolic profile. These associations are largely mediated by adolescent BMI., (© 2015 Royal College of Obstetricians and Gynaecologists.)

In classical theory, teeth of vertebrate dentitions evolved from co-option of external skin denticles into the oral cavity. This hypothesis predicts that ordered tooth arrangement and regulated replacement in the oral dentition were also derived from skin denticles. The fossil batoid ray Schizorhiza stromeri (Chondrichthyes; Cretaceous) provides a test of this theory. Schizorhiza preserves an extended cartilaginous rostrum with closely spaced, alternating saw-teeth, different from sawfish and sawsharks today. Multiple replacement teeth reveal unique new data from micro-CT scanning, showing how the 'cone-in-cone' series of ordered saw-teeth sets arrange themselves developmentally, to become enclosed by the roots of pre-existing saw-teeth. At the rostrum tip, newly developing saw-teeth are present, as mineralized crown tips within a vascular, cartilaginous furrow; these reorient via two 90° rotations then relocate laterally between previously formed roots. Saw-tooth replacement slows mid-rostrum where fewer saw-teeth are regenerated. These exceptional developmental data reveal regulated order for serial self-renewal, maintaining the saw edge with ever-increasing saw-tooth size. This mimics tooth replacement in chondrichthyans, but differs in the crown reorientation and their enclosure directly between roots of predecessor saw-teeth. Schizorhiza saw-tooth development is decoupled from the jaw teeth and their replacement, dependent on a dental lamina. This highly specialized rostral saw, derived from diversification of skin denticles, is distinct from the dentition and demonstrates the potential developmental plasticity of skin denticles., (© 2015 The Authors.)

A well-known characteristic of chondrichthyans (e.g. sharks, rays) is their covering of external skin denticles (placoid scales), but less well understood is the wide morphological diversity that these skin denticles can show. Some of the more unusual of these are the tooth-like structures associated with the elongate cartilaginous rostrum 'saw' in three chondrichthyan groups: Pristiophoridae (sawsharks; Selachii), Pristidae (sawfish; Batoidea) and the fossil Sclerorhynchoidea (Batoidea). Comparative topographic and developmental studies of the 'saw-teeth' were undertaken in adults and embryos of these groups, by means of three-dimensional-rendered volumes from X-ray computed tomography. This provided data on development and relative arrangement in embryos, with regenerative replacement in adults. Saw-teeth are morphologically similar on the rostra of the Pristiophoridae and the Sclerorhynchoidea, with the same replacement modes, despite the lack of a close phylogenetic relationship. In both, tooth-like structures develop under the skin of the embryos, aligned with the rostrum surface, before rotating into lateral position and then attaching through a pedicel to the rostrum cartilage. As well, saw-teeth are replaced and added to as space becomes available. By contrast, saw-teeth in Pristidae insert into sockets in the rostrum cartilage, growing continuously and are not replaced. Despite superficial similarity to oral tooth developmental organization, saw-tooth spatial initiation arrangement is associated with rostrum growth. Replacement is space-dependent and more comparable to that of dermal skin denticles. We suggest these saw-teeth represent modified dermal denticles and lack the 'many-for-one' replacement characteristic of elasmobranch oral dentitions.

Objective: To assess whether variations in maternal haemoglobin levels during pregnancy are associated with cardio-metabolic risk factors in school age children., Design: Population-based prospective cohort study., Setting: Rotterdam, The Netherlands, 2002-2012., Population: Mothers and children (n = 5002) participating in the Generation R Study., Methods: We obtained maternal haemoglobin levels during early pregnancy (median gestational age 14.6 weeks [95% range 10.3, 25.3]) from venous blood samples. Maternal anaemia and elevated haemoglobin levels were based on World Health Organization criteria. We measured childhood cardio-metabolic risk factors at age 6 years., Main Outcome Measures: Cardio-metabolic risk factors included body mass index, total fat mass percentage, android/gynoid fat mass ratio, systolic and diastolic blood pressure, left ventricular mass, and blood levels of cholesterol, insulin and C-peptide., Results: Maternal haemoglobin levels were not associated with childhood body mass index, total fat mass percentage, android/gynoid fat mass ratio, systolic blood pressure, cholesterol or insulin levels. Compared with children with normal maternal haemoglobin levels, children from anaemic mothers had slightly higher diastolic blood pressures (difference 0.70 mmHg, 95% CI 0.12, 1.29) and lower C-peptide levels (difference factor 0.93, 95% CI 0.88, 0.98), and children of mothers with elevated haemoglobin levels had lower left ventricular masses (difference -1.08 g, 95% CI -1.88, -0.29). These associations attenuated after adjustment for multiple testing and were not consistent within linear models., Conclusion: These results do not strongly support the hypothesis that variations in maternal haemoglobin levels during pregnancy influence cardio-metabolic risk factors in childhood., (© 2014 Royal College of Obstetricians and Gynaecologists.)

Shark and ray (elasmobranch) dentitions are well known for their multiple generations of teeth, with isolated teeth being common in the fossil record. However, how the diverse dentitions characteristic of elasmobranchs form is still poorly understood. Data on the development and maintenance of the dental patterning in this major vertebrate group will allow comparisons to other morphologically diverse taxa, including the bony fishes, in order to identify shared pattern characters for the vertebrate dentition as a whole. Data is especially lacking from the Batoidea (skates and rays), hence our objective is to compile data on embryonic and adult batoid tooth development contributing to ordering of the dentition, from cleared and stained specimens and micro-CT scans, with 3D rendered models. We selected species (adult and embryonic) spanning phylogenetically significant batoid clades, such that our observations may raise questions about relationships within the batoids, particularly with respect to current molecular-based analyses. We include developmental data from embryos of recent model organisms Leucoraja erinacea and Raja clavata to evaluate the earliest establishment of the dentition. Characters of the batoid dentition investigated include alternate addition of teeth as offset successional tooth rows (versus single separate files), presence of a symphyseal initiator region (symphyseal tooth present, or absent, but with two parasymphyseal teeth) and a restriction to tooth addition along each jaw reducing the number of tooth families, relative to addition of successor teeth within each family. Our ultimate aim is to understand the shared characters of the batoids, and whether or not these dental characters are shared more broadly within elasmobranchs, by comparing these to dentitions in shark outgroups. These developmental morphological analyses will provide a solid basis to better understand dental evolution in these important vertebrate groups as well as the general plesiomorphic vertebrate dental condition.