The Children and Young People's Health Partnership Evelina London Model of Care: process evaluation protocol

Introduction Children and young people (CYP) in the UK have poor health outcomes, and there is increasing emergency department and hospital outpatient use. To address these problems in Lambeth and Southwark (two boroughs of London, UK), the local Clinical Commissioning Groups, Local Authorities and Healthcare Providers formed The Children and Young People’s Health Partnership (CYPHP), a clinical-academic programme for improving child health. The Partnership has developed the CYPHP Evelina London model, an integrated healthcare model that aims to deliver effective, coordinated care in primary and community settings and promote better self-management to over approximately 90 000 CYP in Lambeth and Southwark. This protocol is for the process evaluation of this model of care. Methods and analysis Alongside an impact evaluation, an in-depth, mixed-methods process evaluation will be used to understand the barriers and facilitators to implementing the model of care. The data collected mapped onto a logic model of how CYPHP is expected to improve child health outcomes. Data collection and analysis include qualitative interviews and focus groups with stakeholders, a policy review and a quantitative analysis of routine clinical and administrative data and questionnaire data. Information relating to the context of the trial that may affect implementation and/or outcomes of the CYPHP model of care will be documented. Ethics and dissemination The study has been reviewed by NHS REC Cornwall & Plymouth (17/SW/0275). The findings of this process evaluation will guide the scaling up and implementation of the CYPHP Evelina London Model of Care across the UK. Findings will be disseminated through publications and conferences, and implementation manuals and guidance for others working to improve child health through strengthening health systems. Trial registration number NCT03461848

Uterine selection of human embryos at implantation

Human embryos frequently harbor large-scale complex chromosomal errors that impede normal development. Affected embryos may fail to implant although many first breach the endometrial epithelium and embed in the decidualizing stroma before being rejected via mechanisms that are poorly understood. Here we show that developmentally impaired human embryos elicit an endoplasmic stress response in human decidual cells. A stress response was also evident upon in vivo exposure of mouse uteri to culture medium conditioned by low-quality human embryos. By contrast, signals emanating from developmentally competent embryos activated a focused gene network enriched in metabolic enzymes and implantation factors. We further show that trypsin, a serine protease released by pre-implantation embryos, elicits Ca2+ signaling in endometrial epithelial cells. Competent human embryos triggered short-lived oscillatory Ca2+ fluxes whereas low-quality embryos caused a heightened and prolonged Ca2+ response. Thus, distinct positive and negative mechanisms contribute to active selection of human embryos at implantation

The Effects of Cocaine on Different Redox Forms of Cysteine and Homocysteine, and on Labile, Reduced Sulfur in the Rat Plasma Following Active versus Passive Drug Injections

Received: 28 November 2012 / Revised: 19 April 2013 / Accepted: 6 May 2013 / Published online: 16 May 2013 The Author(s) 2013. This article is published with open access at Springerlink.comThe aim of the present studies was to evaluate cocaine-induced changes in the concentrations of different redox forms of cysteine (Cys) and homocysteine (Hcy), and products of anaerobic Cys metabolism, i.e., labile, reduced sulfur (LS) in the rat plasma. The above-mentioned parameters were determined after i.p. acute and subchronic cocaine treatment as well as following i.v. cocaine self-administration using the yoked procedure. Additionally, Cys, Hcy, and LS levels were measured during the 10-day extinction training in rats that underwent i.v. cocaine administration. Acute i.p. cocaine treatment increased the total and protein-bound Hcy contents, decreased LS, and did not change the concentrations of Cys fractions in the rat plasma. In turn, subchronic i.p. cocaine administration significantly increased free Hcy and lowered the total and protein-bound Cys concentrations while LS level was unchanged. Cocaine self-administration enhanced the total and protein-bound Hcy levels, decreased LS content, and did not affect the Cys fractions. On the other hand, yoked cocaine infusions did not alter the concentration of Hcy fractions while decreased the total and protein-bound Cys and LS content. This extinction training resulted in the lack of changes in the examined parameters in rats with a history of cocaine self-administration while in the yoked cocaine group an increase in the plasma free Cys fraction and LS was seen. Our results demonstrate for the first time that cocaine does evoke significant changes in homeostasis of thiol amino acids Cys and Hcy, and in some products of anaerobic Cys metabolism, which are dependent on the way of cocaine administration

Lepton Acceleration in Pulsar Wind Nebulae

Pulsar Wind Nebulae (PWNe) act as calorimeters for the relativistic pair winds emanating from within the pulsar light cylinder. Their radiative dissipation in various wavebands is significantly different from that of their pulsar central engines: the broadband spectra of PWNe possess characteristics distinct from those of pulsars, thereby demanding a site of lepton acceleration remote from the pulsar magnetosphere. A principal candidate for this locale is the pulsar wind termination shock, a putatively highly-oblique, ultra-relativistic MHD discontinuity. This paper summarizes key characteristics of relativistic shock acceleration germane to PWNe, using predominantly Monte Carlo simulation techniques that compare well with semi-analytic solutions of the diffusion-convection equation. The array of potential spectral indices for the pair distribution function is explored, defining how these depend critically on the parameters of the turbulent plasma in the shock environs. Injection efficiencies into the acceleration process are also addressed. Informative constraints on the frequency of particle scattering and the level of field turbulence are identified using the multiwavelength observations of selected PWNe. These suggest that the termination shock can be comfortably invoked as a principal injector of energetic leptons into PWNe without resorting to unrealistic properties for the shock layer turbulence or MHD structure.Comment: 19 pages, 5 figures, invited review to appear in Proc. of the inaugural ICREA Workshop on "The High-Energy Emission from Pulsars and their Systems" (2010), eds. N. Rea and D. Torres, (Springer Astrophysics and Space Science series

The Impact of miRNA Target Sites in Coding Sequences and in 3′UTRs

Animal miRNAs are a large class of small regulatory RNAs that are known to directly and negatively regulate the expression of a large fraction of all protein encoding genes. The identification and characterization of miRNA targets is thus a fundamental problem in biology. miRNAs regulate target genes by binding to 3′ untranslated regions (3′UTRs) of target mRNAs, and multiple binding sites for the same miRNA in 3′UTRs can strongly enhance the degree of regulation. Recent experiments have demonstrated that a large fraction of miRNA binding sites reside in coding sequences. Overall, miRNA binding sites in coding regions were shown to mediate smaller regulation than 3′UTR binding. However, possible interactions between target sites in coding sequences and 3′UTRs have not been studied. Using transcriptomics and proteomics data of ten miRNA mis-expression experiments as well as transcriptome-wide experimentally identified miRNA target sites, we found that mRNA and protein expression of genes containing target sites both in coding regions and 3′UTRs were in general mildly but significantly more regulated than those containing target sites in 3′UTRs only. These effects were stronger for conserved target sites of length 7–8 nt in coding regions compared to non-conserved sites. Combined with our other finding that miRNA target sites in coding regions are under negative selection, our results shed light on the functional importance of miRNA targeting in coding regions

Predictions for the X-ray circumgalactic medium of edge-on discs and spheroids

We investigate how the X-ray circumgalactic medium (CGM) of present-day galaxies depends on galaxy morphology and azimuthal angle using mock observations generated from the EAGLE cosmological hydrodynamic simulation. By creating mock stacks of eROSITA-observed galaxies oriented to be edge-on, we make several observationally-testable predictions for galaxies in the stellar mass range M⋆ = 1010.7 − 11.2 M⊙. The soft X-ray CGM of disc galaxies is between 60 and 100% brighter along the semi-major axis compared to the semi-minor axis, between 10-30 kpc. This azimuthal dependence is a consequence of the hot (T > 106 K) CGM being non-spherical: specifically it is flattened along the minor axis such that denser and more luminous gas resides in the disc plane and co-rotates with the galaxy. Outflows enrich and heat the CGM preferentially perpendicular to the disc, but we do not find an observationally-detectable signature along the semi-minor axis. Spheroidal galaxies have hotter CGMs than disc galaxies related to spheroids residing at higher halos masses, which may be measurable through hardness ratios spanning the 0.2 − 1.5 keV band. While spheroids appear to have brighter CGMs than discs for the selected fixed M⋆ bin, this owes to spheroids having higher stellar and halo masses within that M⋆ bin, and obscures the fact that both simulated populations have similar total CGM luminosities at the exact same M⋆. Discs have brighter emission inside 20 kpc and more steeply declining profiles with radius than spheroids. We predict that the eROSITA 4-year all-sky survey should detect many of the signatures we predict here, although targeted follow-up observations of highly inclined nearby discs after the survey may be necessary to observe some of our azimuthally-dependent predictions

A novel class of microRNA-recognition elements that function only within open reading frames.

MicroRNAs (miRNAs) are well known to target 3' untranslated regions (3' UTRs) in mRNAs, thereby silencing gene expression at the post-transcriptional level. Multiple reports have also indicated the ability of miRNAs to target protein-coding sequences (CDS); however, miRNAs have been generally believed to function through similar mechanisms regardless of the locations of their sites of action. Here, we report a class of miRNA-recognition elements (MREs) that function exclusively in CDS regions. Through functional and mechanistic characterization of these 'unusual' MREs, we demonstrate that CDS-targeted miRNAs require extensive base-pairing at the 3' side rather than the 5' seed; cause gene silencing in an Argonaute-dependent but GW182-independent manner; and repress translation by inducing transient ribosome stalling instead of mRNA destabilization. These findings reveal distinct mechanisms and functional consequences of miRNAs that target CDS versus the 3' UTR and suggest that CDS-targeted miRNAs may use a translational quality-control-related mechanism to regulate translation in mammalian cells

EAGLE and Illustris-TNG Predictions for Resolved eROSITA X-Ray Observations of the Circumgalactic Medium around Normal Galaxies

We simulate stacked observations of nearby hot X-ray coronae associated with galaxies in the EAGLE and Illustris-TNG hydrodynamic simulations. A forward modeling pipeline is developed to predict 4-year eROSITA observations and stacked image analysis, including the effects of instrumental and astrophysical backgrounds. We propose an experiment to stack z~0.01 galaxies separated by specific star-formation rate (sSFR) to examine how the hot (T>=10^6 K) circumgalactic medium (CGM) differs for high- and low-sSFR galaxies. The simulations indicate that the hot CGM of low-mass (M_*~10^{10.5} Msol), high-sSFR (defined as the top one-third ranked by sSFR) central galaxies will be detectable to a galactocentric radius r~30-50 kpc. Both simulations predict lower luminosities at fixed stellar mass for the low-sSFR galaxies (the lower third of sSFR) with Illustris-TNG predicting 3x brighter coronae around high-sSFR galaxies than EAGLE. Both simulations predict detectable emission out to r~150-200 kpc for stacks centered on high-mass (M_*~10^{11.0} Msol) galaxies, with EAGLE predicting brighter X-ray halos. The extended soft X-ray luminosity correlates strongly and positively with the mass of circumgalactic gas within the virial radius (f_{CGM}). Prior analyses of both simulations have established that f_{CGM} is reduced by expulsive feedback driven mainly by black hole growth, which quenches galaxy growth by inhibiting replenishment of the ISM. Both simulations predict that eROSITA stacks should not only conclusively detect and resolve the hot CGM around L^* galaxies for the first time, but provide a powerful probe of how the baryon cycle operates, for which there remains an absence of consensus between state-of-the-art simulations

Developing self-regulation for dietary temptations: intervention effects on physical, self-regulatory and psychological outcomes

We aimed to investigate whether a self-regulatory skills intervention can improve weight loss-related outcomes. Fifty-five participants (M BMI = 32.60 ± 4.86) were randomized into self-regulation training and advice groups and received two training workshops and weekly practice tasks. The self-regulation training group was trained to use six self-regulatory skills: Delayed gratification, thought control, goal setting, self-monitoring, mindfulness, and coping. The advice group received dietary and physical activity advice for weight loss. Physical, self-regulatory, and psychological measures were taken at baseline, end of intervention (week 8) and at follow-up (week 12). Using intention-to-treat analysis, weight, waist circumference, body fat and body mass index (BMI) were significantly reduced at follow-up for both groups. There were significant increases in all six self-regulatory skills and the psychological measures of self-efficacy, self-regulatory success, and physical self-worth for both groups. Results indicate that self-regulatory skills training might be as effective as dietary and physical activity advice in terms of weight loss and related outcomes

Vitamin D supplementation and breast cancer prevention : a systematic review and meta-analysis of randomized clinical trials

In recent years, the scientific evidence linking vitamin D status or supplementation to breast cancer has grown notably. To investigate the role of vitamin D supplementation on breast cancer incidence, we conducted a systematic review and meta-analysis of randomized controlled trials comparing vitamin D with placebo or no treatment. We used OVID to search MEDLINE (R), EMBASE and CENTRAL until April 2012. We screened the reference lists of included studies and used the “Related Article” feature in PubMed to identify additional articles. No language restrictions were applied. Two reviewers independently extracted data on methodological quality, participants, intervention, comparison and outcomes. Risk Ratios and 95% Confident Intervals for breast cancer were pooled using a random-effects model. Heterogeneity was assessed using the I2 test. In sensitivity analysis, we assessed the impact of vitamin D dosage and mode of administration on treatment effects. Only two randomized controlled trials fulfilled the pre-set inclusion criteria. The pooled analysis included 5372 postmenopausal women. Overall, Risk Ratios and 95% Confident Intervals were 1.11 and 0.74–1.68. We found no evidence of heterogeneity. Neither vitamin D dosage nor mode of administration significantly affected breast cancer risk. However, treatment efficacy was somewhat greater when vitamin D was administered at the highest dosage and in combination with calcium (Risk Ratio 0.58, 95% Confident Interval 0.23–1.47 and Risk Ratio 0.93, 95% Confident Interval 0.54–1.60, respectively). In conclusions, vitamin D use seems not to be associated with a reduced risk of breast cancer development in postmenopausal women. However, the available evidence is still limited and inadequate to draw firm conclusions. Study protocol code: FARM8L2B5L