The impact of early-years provision in Children's Centres (EPICC) on child cognitive and socio-emotional development: study protocol for a randomised controlled trial.

BACKGROUND: There are marked disparities between pre-school children in key skills affecting school readiness, disparities that commonly persist and influence children's later academic achievements, employment, and adjustment. Much of this disparity is linked to socio-economic disadvantage and its impact on the home learning environment. Children's Centres are an ideal context in which to implement and evaluate programmes to address this problem. They principally serve the 30% worst areas on the Indices of Deprivation Affecting Children, providing for families from the antenatal period up to age 5 years, aiming to promote parenting skills and provide care for children. METHODS: We are conducting a randomised controlled trial, based in Children Centres, to evaluate a parenting intervention for caregivers of children between 28 and 45 months of age. The intervention provides training to parents in dialogic book-sharing. The training is run by a facilitator who sees parents in small groups, on a weekly basis over 7 weeks. The study is a cluster randomised controlled trial. Twelve of the Children's Centres in the town of Reading in the UK have been randomly assigned to an index or control condition. The primary outcome is child cognition (language, attention, and executive function); and secondary outcomes are child social development, behaviour problems, and emotion regulation, parenting during book-sharing and problem solving and parental child behaviour management strategies. Data are collected at baseline, post-intervention and 4-6 months post-intervention. DISCUSSION: The Impact of Early-years Provision in Children's Centres trial (EPICC) aims to evaluate the impact of an early parenting intervention on several key risk factors for compromised child development, including aspects of parenting and child cognition, social development, behaviour problems and emotion regulation. The study is being carried out in Children's Centres, which largely serve the most disadvantaged families in the UK. Since the intervention is brief and, with modest levels of training, readily deliverable within Children's Centres and similar early childcare provision centres, demonstration that it is of benefit to child cognition, socio-emotional development and behaviour would be important. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN28513611 . Registered on 28 March 2017. This is version 1 of the protocol for the EPICC trial

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

The impact of early-years provision in Children\u27s Centres (EPICC) on child cognitive and socio-emotional development: Study protocol for a randomised controlled trial

Background: There are marked disparities between pre-school children in key skills affecting school readiness, disparities that commonly persist and influence children\u27s later academic achievements, employment, and adjustment. Much of this disparity is linked to socio-economic disadvantage and its impact on the home learning environment. Children\u27s Centres are an ideal context in which to implement and evaluate programmes to address this problem. They principally serve the 30% worst areas on the Indices of Deprivation Affecting Children, providing for families from the antenatal period up to age 5 years, aiming to promote parenting skills and provide care for children. Methods: We are conducting a randomised controlled trial, based in Children Centres, to evaluate a parenting intervention for caregivers of children between 28 and 45 months of age. The intervention provides training to parents in dialogic book-sharing. The training is run by a facilitator who sees parents in small groups, on a weekly basis over 7 weeks. The study is a cluster randomised controlled trial. Twelve of the Children\u27s Centres in the town of Reading in the UK have been randomly assigned to an index or control condition. The primary outcome is child cognition (language, attention, and executive function); and secondary outcomes are child social development, behaviour problems, and emotion regulation, parenting during book-sharing and problem solving and parental child behaviour management strategies. Data are collected at baseline, post-intervention and 4-6 months post-intervention. Discussion: The Impact of Early-years Provision in Children\u27s Centres trial (EPICC) aims to evaluate the impact of an early parenting intervention on several key risk factors for compromised child development, including aspects of parenting and child cognition, social development, behaviour problems and emotion regulation. The study is being carried out in Children\u27s Centres, which largely serve the most disadvantaged families in the UK. Since the intervention is brief and, with modest levels of training, readily deliverable within Children\u27s Centres and similar early childcare provision centres, demonstration that it is of benefit to child cognition, socio-emotional development and behaviour would be important

Whole-genome sequencing reveals host factors underlying critical COVID-19

Altres ajuts: Department of Health and Social Care (DHSC); Illumina; LifeArc; Medical Research Council (MRC); UKRI; Sepsis Research (the Fiona Elizabeth Agnew Trust); the Intensive Care Society, Wellcome Trust Senior Research Fellowship (223164/Z/21/Z); BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070, BBS/E/D/30002275); UKRI grants (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1); UK Research and Innovation (MC_PC_20029); the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z); the Edinburgh Clinical Academic Track (ECAT) programme; the National Institute for Health Research, the Wellcome Trust; the MRC; Cancer Research UK; the DHSC; NHS England; the Smilow family; the National Center for Advancing Translational Sciences of the National Institutes of Health (CTSA award number UL1TR001878); the Perelman School of Medicine at the University of Pennsylvania; National Institute on Aging (NIA U01AG009740); the National Institute on Aging (RC2 AG036495, RC4 AG039029); the Common Fund of the Office of the Director of the National Institutes of Health; NCI; NHGRI; NHLBI; NIDA; NIMH; NINDS.Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care or hospitalization after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease