Evaluation of children's centres in England (ECCE) : strand 1: first survey of children's centre leaders in the most deprived areas

This report is the first output from the Evaluation of Children's Centres in England (ECCE), a six year study commissioned by the Department for Education and undertaken by NatCen Social Research, the University of Oxford and Frontier Economics. The aim of ECCE is to provide an in-depth understanding of children's centre services, including their effectiveness in relation to different management and delivery approaches and the cost of delivering different types of services. The aim of Strand 1 is to profile children’s centres in the most disadvantaged areas, providing estimates on different aspects of provision with which to select centres for subsequent stages of the evaluation and to explore different models of provision. The findings below relate to 500 children's centres that are representative of all phase 1 and 2 centres (i.e. those in the 30percent most deprived areas).</p

British Society for Rheumatology guideline on prescribing drugs in pregnancy and breastfeeding: immunomodulatory anti-rheumatic drugs and corticosteroids

BackgroundThe rationale behind this update of the 2016 BSR guidelines on prescribing anti-rheumatic drugs in pregnancy and breastfeeding (1, 2) was described in detail in the guideline scope (3). In brief, despite the existence of additional evidence-based guidelines on prescribing/managing rheumatic disease in pregnancy (4-7), the information contained within them requires continual review to include emerging information on the safety of new and existing drugs in pregnancy. Chronic disease adversely affects pregnancy. Data from Mothers and Babies: Reducing Risk through Audits and Confidential Enquiries across the UK (MBRRACE-UK), reports regularly from a national programme of work conducting surveillance and investigating the causes of maternal deaths, stillbirths and infant deaths (8). Data from 2017-19, found that 8.8 women per 100,000 died during pregnancy or up to six weeks after childbirth or the end of pregnancy, and most women who died had multiple health problems or other vulnerabilities (8). In all decisions regarding medication choices and changes, it is important to consider the potential for deterioration in the mother's wellbeing through side effects or reduced disease control (and its adverse impact on the baby). As such, the potential benefit to the fetus from any drug changes in the mother must be balanced against the possible risks to the fetus from loss of disease control in the mother (9).Need for guidelineThere has been an appreciable increase in the number of published pregnancy exposures to biologic disease modifying anti-rheumatic drugs (bDMARDs), and two of these drugs are now licenced for use in pregnancy. In addition, therapeutic advances in management of various inflammatory rheumatic diseases (IRDs) have led to an expansion of bDMARDs and biosimilars with different modes of action, as well as a new class of targeted synthetic DMARDs (tsDMARDs).The continuing expansion of existing and novel DMARDs means that uncertainty remains around use of many of these drugs in pregnancy. This uncertainty may still lead to withdrawal of treatment from pregnant women unnecessarily (10). Discontinuation of treatment in preparation for or during early pregnancy can increase the risk of disease activity and flares during pregnancy, and are reported following discontinuation of biologics in patients with IRDs (11). The compatibility of various immunosuppressive and disease-modifying medications relevant to rheumatic disease will be covered in this update. This updated information will provide advice for healthcare professionals and patients, to ensure more confident prescribing in these scenarios, and will highlight any medications that should be stopped and/or avoided in the reproductive age group unless highly effective contraception is used, in line with guidance issued by the Medicines and Healthcare Products Regulatory Agency (MHRA) and the Faculty of Sexual and Reproductive Healthcare (12, 13). Objectives of guidelineTo update the previous BSR guidelines on prescribing in pregnancy in rheumatic disease of the following drug categories: antimalarials; corticosteroids; conventional synthetic (cs)DMARDs and immunosuppressive therapies; bDMARDs; and tsDMARDs. The full list of medications is shown in appendix 1. This revised guideline was produced by systematically reviewing all evidence published since the previous guideline, to answer specific questions in relation to each drug, as follows: Should it be stopped pre-conception? Is it compatible with pregnancy? Is it compatible with breastmilk exposure? Where possible, recommendations are made regarding compatibility with paternal exposure.Target audienceThe primary audience consists of health professionals in the UK directly involved in managing patients with rheumatic disease who are (or are planning to become) pregnant and/or breastfeeding, men with rheumatic disease who are planning to conceive, and patients with rheumatic disease who have unintentionally conceived whilst taking these medications. This audience includes rheumatologists, rheumatology nurses/allied health professionals, rheumatology speciality trainees and pharmacists, as well as the patients themselves. The guideline will also be useful to obstetricians, obstetric physicians, midwives, renal physicians, dermatologists, gastroenterologists, respiratory physicians and general practitioners who prescribe these medications in pregnancy. This guideline uses the terms “woman”, “maternal” or “mother” throughout. These should be taken to include people who do not identify as women but are pregnant or have given birth (14). Where the term “breastfeeding” is used in this guideline it also refers to infant breastmilk exposure via other methods (e.g. expressed breastmilk, administered via a bottle). The areas the guideline does not coverThis guideline does not cover the management of infertility or the indications for these drugs in specific rheumatic diseases in pregnancy. Other drug categories (pain management; non-steroidal anti-inflammatory drugs (NSAIDs) and low dose aspirin; anticoagulants; bisphosphonates; anti-hypertensives; and pulmonary vasodilators) are considered in the BSR guideline on prescribing drugs in pregnancy and breastfeeding: comorbidity medications used in rheumatology practice (reference to be inserted once published). All recommendations in this guideline were formulated by the working group on the basis of published evidence at the time of the systematic literature search, and do not necessarily refer to licencing information or Summary of Product Characteristics for individual medications.Stakeholder involvementThis guideline was commissioned by the BSR Standards, Guidelines and Audit Working Group. A Guideline Working group (GWG) was created, consisting of a chair (IG), alongside representatives from relevant stakeholders shown in appendix 2. In accordance with BSR policy, all members of the GWG made declarations of interest, available on the BSR website.Involvement and affiliations of stakeholder groups involved in guideline developmentThe GWG consisted of rheumatologists from a range of clinical backgrounds, various allied health professionals, other specialists in women’s health, lay members and representatives from the United Kingdom Tetralogy Information Service (UKTIS). All members of the working group contributed to the process for agreeing key questions, guideline content, recommendations and strength of agreement. <br/

British Society for Rheumatology guideline on prescribing drugs in pregnancy and breastfeeding:comorbidity medications used in rheumatology practice

BackgroundThe rationale behind this update on the 2016 BSR guidelines on prescribing anti-rheumatic drugs in pregnancy and breastfeeding [1, 2] was described in detail in the guideline scope [3]. In brief, despite the existence of additional evidence-based guidelines on prescribing/managing rheumatic disease in pregnancy [4-7] the information contained within them requires continual review to include emerging information on the safety of new and existing drugs in pregnancy.Chronic disease adversely affects pregnancy. Data from Mothers and Babies: Reducing Risk through Audits and Confidential Enquiries across the UK (MBRRACE-UK), reports regularly from a national programme of work conducting surveillance and investigating the causes of maternal deaths, stillbirths and infant deaths [8]. Data from 2017-19, found that 8.8 women per 100,000 died during pregnancy or up to six weeks after childbirth or the end of pregnancy, and most women who died had multiple health problems or other vulnerabilities[8]. In all decisions regarding medication choices and changes, it is also important to consider the potential for deterioration in the mother's wellbeing through side effects or reduced disease control (and its adverse impact on the baby). Therefore, the exposure of the fetus to different drugs when switches are made must be balanced against possible fetal gains, and understanding the potential impact of reduced control of the medical disorder on a pregnancy is vital [9].Need for guidelinePatients with inflammatory rheumatic disease (IRD) should be counselled to achieve and then maintain remission or low disease activity before/during pregnancy to reduce the risk of adverse pregnancy outcomes [10]. This goal is primarily achieved through adjustment of therapy to ensure disease control with disease modifying anti-rheumatic drugs (DMARDs) and/or immunosuppressive drugs that are compatible with pregnancy. These medications are reviewed in the BSR &amp; BHPR guideline on prescribing drugs in pregnancy and breastfeeding: immunomodulatory anti-rheumatic drugs and corticosteroids [11]. Many patients with IRD however, have an additional burden of pain and comorbid illness [12] that require treatment with other medications. The compatibility of various comorbidity medications relevant to rheumatic disease will be covered in this update. This updated information will provide advice for healthcare professionals and patients to ensure more confident prescribing in these scenarios and will highlight any medications that should be stopped and/or avoided in the reproductive age group unless highly effective contraception is used, in line with guidance issued by the Medicines and Healthcare Products Regulatory Agency (MHRA) and Faculty of Sexual and Reproductive Healthcare [13, 14]. Objectives of guidelineTo update the previous BSR guidelines on prescribing in pregnancy in rheumatic disease for the following drug categories: pain management; Non-steroidal anti-inflammatory drugs (NSAIDs) and low dose aspirin; anticoagulants; colchicine; dapsone; bisphosphonates; anti-hypertensives; and pulmonary vasodilators. This revised guideline was produced by consensus review of current evidence to answer specific questions in relation to each drug as follows. Should it be stopped pre-conception? Is it compatible with pregnancy? Is it compatible with breastmilk exposure? Where possible recommendations are made regarding compatibility with paternal exposure.Target audienceThe primary audience consists of health professionals in the UK directly involved in managing patients with rheumatic disease who are (or are planning to become) pregnant and/or breastfeeding, men planning to conceive, and patients who have unintentionally conceived whilst taking these medications. This audience includes rheumatologists, rheumatology nurses/allied health professionals, rheumatology speciality trainees and pharmacists, as well as the patients themselves. The guideline will also be useful to obstetricians, obstetric physicians, renal physicians, dermatologists and general practitioners who may prescribe these medications to patients in pregnancy. This guideline uses the terms “woman”, “maternal” or “mother” throughout. These should be taken to include people who do not identify as women but are pregnant or have given birth [15]. Where the term “breastfeeding” is used in this guideline it also refers to infant breastmilk exposure via other methods (e.g. expressed breastmilk, administered via a bottle).The areas the guideline does not coverThis guideline does not cover the management of infertility or acute pain relief during labour, hence morphine was excluded. Other drug categories: antimalarials; corticosteroids; disease modifying anti-rheumatic and immunosuppressive therapies; and biologic drugs are considered in another guideline (REF for part I). All recommendations in this guideline were formulated by the working group on the basis of published evidence at the time of the systematic literature search, and do not necessarily refer to licensing information or Summary of Product Characteristics for individual medications.Stakeholder InvolvementThis guideline was commissioned by the BSR Standards, Guidelines and Audit Working Group. A Guideline Working group (GWG) was created, consisting of a chair (IG), alongside representatives from relevant stakeholders (Table 1). In accordance with BSR policy, all members of the GWG made declarations of interest, available on the BSR website.Involvement and affiliations of stakeholder groups involved in guideline developmentThe GWG consisted of rheumatologists from a range of clinical backgrounds, various allied health professionals, other specialists in women’s health, lay members and representatives from the United Kingdom Tetralogy Information Service (UKTIS). All members of the working group contributed to the process for agreeing key questions, guideline content, recommendations and strength of agreement. <br/

A Copine family member, Cpne8, is a candidate quantitative trait gene for prion disease incubation time in mouse

Prion disease incubation time in mice is determined by many factors including genetic background. The prion gene itself plays a major role in incubation time; however, other genes are also known to be important. Whilst quantitative trait loci (QTL) studies have identified multiple loci across the genome, these regions are often large, and with the exception of Hectd2 on Mmu19, no quantitative trait genes or nucleotides for prion disease incubation time have been demonstrated. In this study, we use the Northport heterogeneous stock of mice to reduce the size of a previously identified QTL on Mmu15 from approximately 25 to 1.2 cM. We further characterised the genes in this region and identify Cpne8, a member of the copine family, as the most promising candidate gene. We also show that Cpne8 mRNA is upregulated at the terminal stage of disease, supporting a role in prion disease. Applying these techniques to other loci will facilitate the identification of key pathways in prion disease pathogenesis

HECTD2 Is Associated with Susceptibility to Mouse and Human Prion Disease

Prion diseases are fatal transmissible neurodegenerative disorders, which include Scrapie, Bovine Spongiform Encephalopathy (BSE), Creutzfeldt-Jakob Disease (CJD), and kuru. They are characterised by a prolonged clinically silent incubation period, variation in which is determined by many factors, including genetic background. We have used a heterogeneous stock of mice to identify Hectd2, an E3 ubiquitin ligase, as a quantitative trait gene for prion disease incubation time in mice. Further, we report an association between HECTD2 haplotypes and susceptibility to the acquired human prion diseases, vCJD and kuru. We report a genotype-associated differential expression of Hectd2 mRNA in mouse brains and human lymphocytes and a significant up-regulation of transcript in mice at the terminal stage of prion disease. Although the substrate of HECTD2 is unknown, these data highlight the importance of proteosome-directed protein degradation in neurodegeneration. This is the first demonstration of a mouse quantitative trait gene that also influences susceptibility to human prion diseases. Characterisation of such genes is key to understanding human risk and the molecular basis of incubation periods

Receptor Complementation and Mutagenesis Reveal SR-BI as an Essential HCV Entry Factor and Functionally Imply Its Intra- and Extra-Cellular Domains

HCV entry into cells is a multi-step and slow process. It is believed that the initial capture of HCV particles by glycosaminoglycans and/or lipoprotein receptors is followed by coordinated interactions with the scavenger receptor class B type I (SR-BI), a major receptor of high-density lipoprotein (HDL), the CD81 tetraspanin, and the tight junction protein Claudin-1, ultimately leading to uptake and cellular penetration of HCV via low-pH endosomes. Several reports have indicated that HDL promotes HCV entry through interaction with SR-BI. This pathway remains largely elusive, although it was shown that HDL neither associates with HCV particles nor modulates HCV binding to SR-BI. In contrast to CD81 and Claudin-1, the importance of SR-BI has only been addressed indirectly because of lack of cells in which functional complementation assays with mutant receptors could be performed. Here we identified for the first time two cell types that supported HCVpp and HCVcc entry upon ectopic SR-BI expression. Remarkably, the undetectable expression of SR-BI in rat hepatoma cells allowed unambiguous investigation of human SR-BI functions during HCV entry. By expressing different SR-BI mutants in either cell line, our results revealed features of SR-BI intracellular domains that influence HCV infectivity without affecting receptor binding and stimulation of HCV entry induced by HDL/SR-BI interaction. Conversely, we identified positions of SR-BI ectodomain that, by altering HCV binding, inhibit entry. Finally, we characterized alternative ectodomain determinants that, by reducing SR-BI cholesterol uptake and efflux functions, abolish HDL-mediated infection-enhancement. Altogether, we demonstrate that SR-BI is an essential HCV entry factor. Moreover, our results highlight specific SR-BI determinants required during HCV entry and physiological lipid transfer functions hijacked by HCV to favor infection

Completion of Hepatitis C Virus Replication Cycle in Heterokaryons Excludes Dominant Restrictions in Human Non-liver and Mouse Liver Cell Lines

Hepatitis C virus (HCV) is hepatotropic and only infects humans and chimpanzees. Consequently, an immunocompetent small animal model is lacking. The restricted tropism of HCV likely reflects specific host factor requirements. We investigated if dominant restriction factors expressed in non-liver or non-human cell lines inhibit HCV propagation thus rendering these cells non-permissive. To this end we explored if HCV completes its replication cycle in heterokaryons between human liver cell lines and non-permissive cell lines from human non-liver or mouse liver origin. Despite functional viral pattern recognition pathways and responsiveness to interferon, virus production was observed in all fused cells and was only ablated when cells were treated with exogenous interferon. These results exclude that constitutive or virus-induced expression of dominant restriction factors prevents propagation of HCV in these cell types, which has important implications for HCV tissue and species tropism. In turn, these data strongly advocate transgenic approaches of crucial human HCV cofactors to establish an immunocompetent small animal model

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead