Childhood obesity: Evidence for distinct early and late environmental determinants a 12-year longitudinal cohort study (EarlyBird 62)

Background/objective:The prevalence of childhood obesity continues to rise in most countries, but the exposures responsible remain unclear. The shape of the body mass index (BMI) distribution curve defines how a population responds, and can be described by its three parameters-skew (L), median (M) and variance (S). We used LMS analysis to explore differences in the BMI trajectories of contemporary UK children with those of 25 years ago, and to draw inferences on the exposures responsible.Subjects/methods:We applied Cole's LMS method to compare the BMI trajectories of 307 UK children (EarlyBird cohort) measured annually from 5-16 years (2000-2012) with those of the BMI data set used to construct the UK 1990 growth centiles, and used group-based trajectory modelling (GBTM) to establish whether categorical trajectories emerged.Results:Gender-specific birth weights were normally distributed and similar between both data sets. The skew and variance established by 5 years in the 1990 children remained stable during the remainder of their childhood, but the pattern was different for children 25 years on. The skew at 5 years among the EarlyBird children was greatly exaggerated, and involved selectively the offspring of obese parents, but returned to 1990 levels by puberty. As the skew diminished, so the variance in BMI rose sharply. The median BMI of the EarlyBird children differed little from that of 1990 before puberty, but diverged from it as the variance rose. GBTM uncovered four groups with distinct trajectories, which were related to parental obesity.Conclusions:There appear to be two distinct environmental interactions with body mass among contemporary children, the one operating selectively according to parental BMI during early childhood, the second more generally in puberty.Bright Future TrustBUPA FoundationPeninsula FoundationKirby Laing TrustEarlyBird Diabetes Trus

Exploring the Adolescent Fall in Physical Activity: A 10-yr Cohort Study (EarlyBird 41)

This is a non-final version of an article published in final form in Medicine & Science in Sports & Exercise Vol. 47 (10), pp. 2084–2092 (2015)INTRODUCTION: Contemporary adolescents are deemed inactive, especially girls, but whether for biological reasons associated with their maturation, changes in their behavior or because of environmental constraints, is uncertain. We examined the trends in physical activity (PA) in relation to both biological and environmental factors in an attempt to establish what drives activity patterns from childhood through adolescence. METHODS: Physical activity (7-d Actigraph accelerometry) was measured annually from 5 to 15 yr in a single cohort of some 300 UK children. Total PA (TPA; in-school and out-of-school separately and combined as whole day) and intensity-specific PA (sedentary, light, and moderate-and-vigorous [MVPA]) were analyzed. Biological age (years before/after measured peak height velocity) and pubertal stage (self-reported pubic hair development-Tanner staging) were also measured as was socioeconomic status (postcode-derived index of multiple deprivation [IMD]). RESULTS: Total PA was stable from 5 to 8 yr (trend P = 0.10) but fell progressively from 9 to 15 yr (by approximately 30% in girls and approximately 20% in boys, both P < 0.001; sex interaction, P < 0.01). Half of this fall was attributable to light intensity PA and only a quarter to MVPA. The decline in PA was related similarly to chronological and biological age, whereas pubertal stage explained the more rapid PA decline in girls (puberty-adjusted sex interaction, P = 0.51). Total PA fell to the same extent for in-school and out-of-school settings (both P < 0.001), and for lower and higher IMD areas (both P < 0.001). Total PA tracked moderately to strongly from childhood into adolescence (r = 0.58; P < 0.001). CONCLUSIONS: The adolescent decline in PA is consistent across different environmental settings, attributable to falls in light-intensity/habitual activity and influenced by puberty, suggesting that the inactivity of adolescence may, in part, be under biological control.Bright Future TrustKirby Laing FoundationPeninsula FoundationEarlyBird Diabetes TrustNational Institute for Health Research (NIHR) Collaborations for Leadership in Applied Health Research and Care (CLAHRC

Objectively Measured Physical Activity and Its Association With Adiponectin and Other Novel Metabolic Markers: A longitudinal study in children (EarlyBird 38)

OBJECTIVE—Recent evidence suggests that, in children, traditional markers of metabolic disturbance are related only weakly to physical activity. We therefore sought to establish the corresponding relationships with newer metabolic markers

Physical activity attenuates the mid-adolescent peak in insulin resistance but by late adolescence the effect is lost: a longitudinal study with annual measures from 9-16 years (EarlyBird 66)

The final publication is available at Springer via http://dx.doi.org/10.1007/s00125-015-3714-5There is another ORE record for this publication: http://hdl.handle.net/10871/34546AIMS/HYPOTHESIS: The aim of this work was to test whether the mid-adolescent peak in insulin resistance (IR) and trends in other metabolic markers are influenced by long-term exposure to physical activity. METHODS: Physical activity (7 day ActiGraph accelerometry), HOMA-IR and other metabolic markers (glucose, fasting insulin, HbA1c, lipids and BP) were measured annually from age 9 years to 16 years in 300 children (151 boys) from the EarlyBird study in Plymouth, UK. The activity level of each child was characterised, with 95% reliability, by averaging their eight annual physical activity measures. Age-related trends in IR and metabolic health were analysed by multi-level modelling, with physical activity as the exposure measure (categorical and continuous) and body fat percentage (assessed by dual-energy X-ray absorptiometry) and pubertal status (according to age at peak height velocity and Tanner stage) as covariates. RESULTS: The peak in IR at age 12-13 years was 17% lower (p < 0.001) in the more active adolescents independently of body fat percentage and pubertal status. However, this difference diminished progressively over the next 3 years and had disappeared completely by the age of 16 years (e.g. difference was -14% at 14 years, -8% at 15 years and +1% at 16 years; 'physical activity × age(2)' interaction, p < 0.01). Triacylglycerol levels in girls (-9.7%, p = 0.05) and diastolic blood pressure in boys (-1.20 mmHg, p = 0.03) tended to be lower throughout adolescence in the more active group. CONCLUSIONS/INTERPRETATION: Our finding that physical activity attenuates IR during mid-adolescence may be clinically important. It remains to be established whether the temporary attenuation in IR during this period has implications for the development of diabetes in adolescence and for future metabolic health generally.Bright Future TrustKirby Laing FoundationPeninsula FoundationEarlyBird Diabetes TrustNational Institute for Health Research (NIHR) Collaborations for Leadership in Applied Health Research and Care (CLAHRC

Cell-format-dependent mechanical damage in silicon anodes

It is generally believed that silicon-based anodes for Li-ion batteries would benefit from stronger binders, as cyclic volume changes would not disrupt the cohesion of the composite electrode. Here, we put this belief to the proof by testing electrodes containing SiOx particles and an aromatic polyimide binder. We observe that the electrodes can stretch laterally by as much as 6% during the first cycle, indicating that internal stresses are high enough to induce plastic deformation on the copper current collector. Remarkably, no coating delamination is observed. Additional consequences were size-dependent: while pouch-cell-sized electrodes developed wrinkles, coin-cell-sized ones remained mostly smooth. We demonstrate that wrinkling of the current collector damages the electrode coating, inactivating SiOx domains and accelerating capacity fade. This size-dependent performance decay indicates that, in extreme cases, testing outcomes are highly dependent on scale. Novel battery materials may require testing at larger cell formats for complete validation

Discovery of a potent and selective CDKL5/GSK3 chemical probe that is neuroprotective

Despite mediating several essential processes in the brain, including during development, cyclin-dependent kinase-like 5 (CDKL5) remains a poorly characterized human protein kinase. Accordingly, its substrates, functions, and regulatory mechanisms have not been fully described. We realized that availability of a potent and selective small molecule probe targeting CDKL5 could enable illumination of its roles in normal development as well as in diseases where it has become aberrant due to mutation. We prepared analogs of AT-7519, a compound that has advanced to phase II clinical trials and is a known inhibitor of several cyclin-dependent kinases (CDKs) and cyclin-dependent kinase-like kinases (CDKLs). We identified analog 2 as a highly potent and cell-active chemical probe for CDKL5/GSK3 (glycogen synthase kinase 3). Evaluation of its kinome-wide selectivity confirmed that analog 2 demonstrates excellent selectivity and only retains GSK3α/β affinity. We next demonstrated the inhibition of downstream CDKL5 and GSK3α/β signaling and solved a co-crystal structure of analog 2 bound to human CDKL5. A structurally similar analog (4) proved to lack CDKL5 affinity and maintain potent and selective inhibition of GSK3α/β, making it a suitable negative control. Finally, we used our chemical probe pair (2 and 4) to demonstrate that inhibition of CDKL5 and/or GSK3α/β promotes the survival of human motor neurons exposed to endoplasmic reticulum stress. We have demonstrated a neuroprotective phenotype elicited by our chemical probe pair and exemplified the utility of our compounds to characterize the role of CDKL5/GSK3 in neurons and beyond

Discovery and characterization of a specific inhibitor of serine-threonine kinase cyclin dependent kinase-like 5 (CDKL5) demonstrates role in hippocampal CA1 physiology

Pathological loss-of-function mutations in cyclin-dependent kinase-like 5 (CDKL5) cause CDKL5 deficiency disorder (CDD), a rare and severe neurodevelopmental disorder associated with severe and medically refractory early-life epilepsy, motor, cognitive, visual, and autonomic disturbances in the absence of any structural brain pathology. Analysis of genetic variants in CDD has indicated that CDKL5 kinase function is central to disease pathology. CDKL5 encodes a serine-threonine kinase with significant homology to GSK3β, which has also been linked to synaptic function. Further, Cdkl5 knock-out rodents have increased GSK3β activity and often increased long-term potentiation (LTP). Thus, development of a specific CDKL5 inhibitor must be careful to exclude cross-talk with GSK3β activity. We synthesized and characterized specific, high-affinity inhibitors of CDKL5 that do not have detectable activity for GSK3β. These compounds are very soluble in water but blood–brain barrier penetration is low. In rat hippocampal brain slices, acute inhibition of CDKL5 selectively reduces postsynaptic function of AMPA-type glutamate receptors in a dose-dependent manner. Acute inhibition of CDKL5 reduces hippocampal LTP. These studies provide new tools and insights into the role of CDKL5 as a newly appreciated key kinase necessary for synaptic plasticity. Comparisons to rodent knock-out studies suggest that compensatory changes have limited the understanding of the roles of CDKL5 in synaptic physiology, plasticity, and human neuropathology

Structure and Evolution of Nearby Stars with Planets. I. Short-Period Systems

Using the Yale stellar evolution code, we have calculated theoretical models for nearby stars with planetary-mass companions in short-period nearly circular orbits: 51 Pegasi, Tau Bootis, Upsilon Andromedae, Rho Cancri, and Rho Coronae Borealis. We present tables listing key stellar parameters such as mass, radius, age, and size of the convective envelope as a function of the observable parameters (luminosity, effective temperature, and metallicity), as well as the unknown helium fraction. For each star we construct best models based on recently published spectroscopic data and the present understanding of galactic chemical evolution. We discuss our results in the context of planet formation theory, and, in particular, tidal dissipation effects and stellar metallicity enhancements.Comment: 48 pages including 13 tables and 5 figures, to appear in Ap

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY) : a randomised, controlled, open-label, platform trial

Funding UK Research and Innovation (Medical Research Council) and National Institute for Health and Care Research (Grant ref: MC_PC_19056). Acknowledgements Above all, we would like to thank the patients who participated in this trial. We would also like to thank the many doctors, nurses, pharmacists, other allied health professionals, and research administrators at NHS hospital organisations across the whole of the UK, supported by staff at the National Institute of Health Research (NIHR) Clinical Research Network, NHS DigiTrials, Public Health England, Department of Health & Social Care, the Intensive Care National Audit & Research Centre, Public Health Scotland, National Records Service of Scotland, the Secure Anonymised Information Linkage (SAIL) at University of Swansea, and the NHS in England, Scotland, Wales and Northern Ireland. The RECOVERY trial is supported by grants to the University of Oxford from UK Research and Innovation (UKRI) and NIHR (MC_PC_19056), the Wellcome Trust (Grant Ref: 222406/Z/20/Z) through the COVID-19 Therapeutics Accelerator, and by core funding provided by the NIHR Oxford Biomedical Research Centre, the Wellcome Trust, the Bill and Melinda Gates Foundation, the Foreign, Commonwealth and Development Office, Health Data Research UK, the Medical Research Council Population Health Research Unit, the NIHR Health Protection Unit in Emerging and Zoonotic Infections, and NIHR Clinical Trials Unit Support Funding. TJ is supported by a grant from UK Medical Research Council (MC_UU_0002/14). WSL is supported by core funding provided by NIHR Nottingham Biomedical Research Centre. Tocilizumab was provided free of charge for this trial by Roche Products Limited. Regeneron Pharmaceuticals supported the trial through provision of casirivimab and imdevimab. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR, or the UK Department of Health and Social Care. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. The sponsor was not involved in study design, data collection and analysis or manuscript writing.Peer reviewe