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Fraser J.,Bristol Royal Hospital for Children | Sidebotham P.,University of Warwick | Frederick J.,Monash University | Covington T.,Review Centre | Mitchell E.A.,University of Auckland
The Lancet | Year: 2014

Despite pronounced reductions in child mortality in industrialised countries, variations exist within and between countries. Many child deaths are preventable, and much could be done to further reduce mortality. For the family, their community, and professionals caring for them, every child's death is a tragedy. Systematic review of all child deaths is grounded in respect for the rights of children and their families, and aimed towards the prevention of future child deaths. In a Series of three papers, we discuss child death in high-income countries in the context of evolving child death review processes. This paper outlines the background to and development of child death review in the USA, England, Australia, and New Zealand. We consider the purpose, process, and outputs of child death review, and discuss how these factors can contribute to a greater understanding of children's deaths and to knowledge for the prevention of future child deaths.


The term epigenetics was coined in 1942 by C.H. Waddington in the context of studies on development. Since then, the meaning of epigenetics changed over time. In the beginning, epigenetics was viewed as a phenomenon above and beyond genetics. Epigenetic explanations were invoked when genetics could not explain a phenomenon. From the mid-seventies, the state of understanding started changing. Epigenetics has now morphed from a phenomenon to a branch of science whose molecular underpinnings are well understood. The current state of knowledge of epigenetics has evolved as our understanding of DNA methylation, chromatin modifications, and noncoding RNA, and their effects on gene expression increased. At this time in the annals of epigentics research, it is appropriate to revisit some of the important discoveries that have helped advance the field to its current state. This is a very brief review of some early discoveries, and by no means is a complete account of the history of epigenetics. In this review, the early history has also been emphasized in order to underscore the transformation of the science of epigenetics from a phenomenon to a modern field of intense research. © 2011 Informa Healthcare USA, Inc.


Mahmood I.,Review Centre
Drug Metabolism and Drug Interactions | Year: 2012

Background: Interspecies differences in biliary excretion and the differences in bile flow rates make scaling across species difficult for drugs that are excreted in the bile. The objective of this study is to predict clearance (CL) and volume of distribution (V) for humans from animals for drugs that are excreted in the bile. Methods: Clearance values of 10 drugs known to be excreted in the bile were selected from the literature. Scaling of CL was performed using at least three animal species. Using simple allometry and the rule of exponents (ROE), clearances of studied drugs were predicted in humans. Besides using the ROE, a ' correction factor ' was applied adjusting bile flow rate based on the species body weight (bile flow mL/day/kg body weight) or liver weight (bile flow mL/day/kg liver weight). Using the ROE and combining it with the ' correction factor ' , the clearances of biliary excreted drugs were predicted for humans. V for 15 drugs (without any correction factor) that are excreted in the bile was also predicted for humans. Results: The results of the study indicated that the ROE in association with the correction factors developed for the biliary excreted drugs substantially improved the prediction of human clearance for drugs that are excreted in the bile. In this study, there was no indication (unlike clearance) that the prediction of volume of drug distribution was affected (systematically under- or over-prediction) because of biliary excretion. Conclusions: The clearance of drugs that are excreted in the bile can be predicted with reasonable accuracy using ROE and a correction factor.


Palusci V.J.,New York University | Covington T.M.,Review Centre
Child Abuse and Neglect | Year: 2014

Comprehensive reviews of child death are increasingly conducted throughout the world, although limited information is available about how this information is systematically used to prevent future deaths. To address this need, we used cases from 2005 to 2009 in the U.S. National Child Death Review Case Reporting System to compare child and offender characteristics and to link that information with actions taken or recommended by review teams. Child, caretaker, and offender characteristics, and outcomes were compared to team responses, and findings were compared to published case series. Among 49,947 child deaths from 23 states entered into the Case Reporting System during the study period, there were 2,285 cases in which child maltreatment caused or contributed to fatality. Over one-half had neglect identified as the maltreatment, and 30% had abusive head trauma. Several child and offender characteristics were associated with specific maltreatment subtypes, and child death review teams recommended and/or planned several activities in their communities. Case characteristics were similar to those published in other reports of child maltreatment deaths. Teams implemented 109 actions or strategies after their review, and we found that aggregating information from child death reviews offers important insights into understanding and preventing future deaths. The National Child Death Review Case Reporting System contains information about a large population which confirms and expands our knowledge about child maltreatment deaths and which can be used by communities for future action. © 2013 Elsevier Ltd.


Mahmood I.,Review Centre
Expert Opinion on Drug Metabolism and Toxicology | Year: 2015

Introduction: Children are not small adults because the differences between adults and children are not simply due to body weight, but also due to physiological and biochemical differences. Hence, dosing in children should not be a 'small adult dose'. During pediatric drug development, selection of a suitable dose for the first-in-children clinical study (Pharmacokinetic [PK], safety and efficacy) is of utmost importance. Considering the importance of clearance in dose selection, a lot of approaches have been suggested for the prediction of drug clearance in children. This review examines many proposed methods for the prediction of drug clearance in the pediatric population and highlights the application and limitations of these proposed methods.Areas covered: In this review, different methods for the prediction of drug clearance in the pediatric population are discussed. These methods include allometric models, population-based pharmacometric models and physiologically based PK models.Expert opinion: All models discussed here have uncertainties in their predictive power and should be only used as exploratory tools during pediatric drug development. Allometric models, if used with knowledge and understanding, is a powerful tool for the prediction of drug clearance in pediatric population. © 2015 Informa UK, Ltd.


Roberts J.N.,Review Centre | Gruber M.F.,Review Centre
Vaccine | Year: 2015

Despite supportive public health policies (e.g., ACIP recommendations), the potential for providing clinical benefit through maternal immunization has yet to be fully realized. For vaccines already licensed and approved for use in adults, specific FDA approval for use during pregnancy to prevent disease in the mother and/or infant may have a significant impact on uptake and usage in pregnant women. In addition, for either a licensed vaccine or a novel vaccine, FDA approval for use during pregnancy would result in labeling that would serve as a resource for practitioners and would facilitate the safe and effective use of the vaccine during pregnancy. In the U.S., while many vaccines are approved for use in adults and most are not contraindicated for use in pregnant women, no vaccine is licensed for use specifically during pregnancy. Among the perceived obstacles hindering the clinical development of vaccines for use in pregnancy, regulatory issues are frequently cited. One aim of this article is to address the perceived regulatory obstacles. General concepts and regulatory considerations for clinical safety and effectiveness evaluations for vaccines indicated for use during pregnancy will be discussed. This discussion is not intended to establish data requirements or to articulate agency policy or guidance regarding specific vaccine products. © 2015.


Eccleston C.,Review Centre
Cochrane database of systematic reviews (Online) | Year: 2012

Psychological therapies have been developed for parents of children and adolescents with a chronic illness. Such therapies include parent only or parent and child/adolescent, and are designed to treat parent behaviour, parent mental health, child behaviour/disability, child mental health, child symptoms and/or family functioning. No comprehensive, meta-analytic reviews have been published in this area. To evaluate the effectiveness of psychological therapies that include coping strategies for parents of children/adolescents with chronic illnesses (painful conditions, cancer, diabetes mellitus, asthma, traumatic brain injury, inflammatory bowel diseases, skin diseases or gynaecological disorders). The therapy will aim to improve parent behaviour, parent mental health, child behaviour/disability, child mental health, child symptoms and family functioning. We searched CENTRAL, MEDLINE, EMBASE and PsycINFO for randomised controlled trials (RCTs) of psychological interventions that included parents of children and adolescents with a chronic illness. The initial search was from inception of these databases to June 2011 and we conducted a follow-up search from June 2011 to March 2012. We identified additional studies from the reference list of retrieved papers and from discussion with investigators. Included studies were RCTs of psychological interventions that delivered treatment to parents of children and adolescents (under 19 years of age) with a chronic illness compared to active control, wait list control or treatment as usual. We excluded studies if the parent component was a coaching intervention, the aim of the intervention was health prevention/promotion, the comparator was a pharmacological treatment, the child/adolescent had an illness not listed above or the study included children with more than one type of chronic illness. Further to this, we excluded studies when the sample size of either comparator group was fewer than 10 at post-treatment. We included 35 RCTs involving a total of 2723 primary trial participants. Two review authors extracted data from 26 studies. We analysed data using two categories. First, we analysed data by each medical condition across all treatment classes at two time points (immediately post-treatment and the first available follow-up). Second, we analysed data by each treatment class (cognitive behavioural therapy (CBT), family therapy (FT), problem solving therapy (PST) and multisystemic therapy (MST)) across all medical conditions at two time points (immediately post-treatment and the first available follow-up). We assessed treatment effectiveness on six possible outcomes: parent behaviour, parent mental health, child behaviour/disability, child mental health, child symptoms and family functioning. Across all treatment types, psychological therapies that included parents significantly improved child symptoms for painful conditions immediately post-treatment. Across all medical conditions, cognitive behavioural therapy (CBT) significantly improved child symptoms and problem solving therapy significantly improved parent behaviour and parent mental health immediately post-treatment. There were no other effects at post-treatment or follow-up. The risk of bias of included studies is described. There is no evidence on the effectiveness of psychological therapies that include parents in most outcome domains of functioning, for a large number of common chronic illnesses in children. There is good evidence for the effectiveness of including parents in psychological therapies that reduce pain in children with painful conditions. There is also good evidence for the effectiveness of CBT that includes parents for improving the primary symptom complaints when available data were included from chronic illness conditions. Finally, there is good evidence for the effectiveness of problem solving therapy delivered to parents on improving parent problem solving skills and parent mental health. All effects are immediately post-treatment. There are no significant findings for any treatment effects in any condition at follow-up.


Flamm E.G.,Review Centre
Toxicology Mechanisms and Methods | Year: 2013

Due to the ever increasing number of substances added to infant formula, and the fact that the majority of data determining the safety of these substances has been derived from adult animals, a search of the available data was performed to determine if an appropriate neonatal model could be found that could be used for performing toxicological safety studies. This exercise utilized three different forms of media. The first informational source is from a publication from the Institute of Medicine (IOM) of the National Academies. The second form of informational data utilized was from simple YAHOO and Google Scholar searches on the internet. The third source of information was from the U.S. Food and Drug Administration (FDA), more specifically, the Center for Drug Evaluation and Review (CDER) preclinical guidance document. Following the examination of the above informational sources, it became apparent that neonatal rats and pigs have been the most utilized of the neonatal models. Following the evaluation of the papers, the experimental paradigm which appears to be the most appropriate for testing substances new to infant formula, and could be used as a pivotal study was the neonatal pig utilizing the automated feeding device called the Autosow. © 2013 Informa Healthcare USA, Inc.


Background and Objective: Interspecies pharmacokinetic scaling is widely used to predict pharmacokinetic parameters in adult humans but has not been used for the prediction of pharmacokinetic parameters in children. The current study was undertaken to evaluate whether or not drug clearance in children from adult rat, dog and human clearance values could be predicted allometrically. Methods: Four methods (simple allometry, maximum lifespan potential [MLP], MLP with an empirical correction factor and a fixed exponent of 0.75 in association with adult data) were used for the prediction of drug clearance in children. The first three methods included adult animal (rat and dog) data and human data, whereas the fixed exponent of 0.75 included only adult human data. Results: The results of this study indicated that simple allometry would systematically overpredict drug clearance in children, whereas application of MLP would underpredict drug clearance in children. Therefore, an empirical correction factor was introduced into MLP, which substantially improved the prediction of drug clearance in children. Prediction based on a fixed exponent of 0.75 and adult human clearance was highly erratic and inferior to the prediction of drug clearance in children from MLP or MLP with an empirical correction factor. Conclusions: Overall, the results of the study indicated that interspecies scaling using adult rat, dog and human clearance values could be useful to predict drug clearance in children in different age groups. © 2010 Adis Data Information BV. All rights reserved.


News Article | August 5, 2015
Site: www.prnewswire.co.uk

Leading automotive glass repair and replacement provider Auto Windscreens has today (5th August) announced its acquisition of AA AutoWindshields, the AA's automotive glazing business. The deal will see AA AutoWindshields' Preston offices and its 200 staff and technicians integrated with Auto Windscreens and, under a ten year partnership arrangement, the AA will continue to use Auto Windscreens to deliver glass repair and replacement services for AA members; its business-to-business and insurance customers. Chris Thornton, Managing Director of Auto Windscreens commented "There are clear synergies for the two businesses.  We place customer satisfaction at the heart of our business, reflecting the AA's own customer ethos.  We are exceptionally proud to be rated No. 1 by customers on Review Centre for 'car service and repairs' with a score of 4.7 out of 5 and a 97% recommendation rate by customers. "This marks the beginning of a new and exciting chapter for Auto Windscreens and further reinforces our position as a leader in the industry.  Through a continuing collaboration with the AA we will provide a full windscreen repair and replacement service to their customers and insurance policyholders." Auto Windscreens is owned by Trifords Limited, part of the Markerstudy Group of Companies. It is a leading automotive glazing company, serving customers throughout the UK and across all sectors from managed fleet to insurance. With a nationwide network of fleet and mobile service units, Auto Windscreens is an expert in windscreen repair and windscreen replacement. The company head office and dedicated contact centre is based in Chesterfield.

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