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News Article | October 28, 2015
Site: www.nature.com

An ambitious study that planned to collect information on 80,000 British babies throughout their lives has ended just 8 months after its official launch because not enough prospective parents signed up. The closure comes less than a year after the US National Institutes of Health (NIH) cancelled a similar effort to trace 100,000 children from birth, prompting fears that researchers will now shy away from proposing similar studies. “I am afraid that the scientific community may not dare to embark on similarly ambitious cohort studies in the near future,” says Camilla Stoltenberg, who heads the Norwegian Institute of Public Health in Oslo. She is responsible for a major birth-cohort study in Norway and chaired the inter­national scientific-advisory committee to the UK project, called Life Study. Prized by both medical researchers and social scientists, birth-cohort studies reveal associations between factors early in life, such as poverty or a mother’s diet in pregnancy, and outcomes later on, ranging from diseases to cognition and earnings. Various efforts already exist around the world, but Life Study was to be one of the biggest and most ambitious yet. It got the green light in 2011 when government funding bodies, including the Economic and Social Research Council (ESRC) and the Medical Research Council, agreed to support the study with £38.4 million (US$58.9 million) until 2019. In January 2015, a team led by Carol Dezateux, a paediatric epidemiologist at University College London’s Institute of Child Health, opened the study’s first dedicated recruitment centre, on the outskirts of London. The researchers hoped to sign up as many as 16,000 prospective mothers — of a total target of 60,000 — by July 2016. Another 20,000 babies were to be recruited nationwide after birth. But between January and early September this year, just 249 women signed up, according to the ESRC, which oversaw the study. A review of the project in July identified recruitment as a major concern, and on 10 July, the ESRC decided that the study should close. The cancellation was publicly announced on 22 October. Dezateux and some of her colleagues say that the closure was premature, and that they were not sufficiently consulted on the decision. They accept that recruitment was difficult, a challenge intensified by the study’s remit to include a substantial proportion of families from ethnic-minority and disadvantaged groups, who have historically been particularly hard to recruit. But the researchers say that they intended to test and refine recruitment methods during the first phase of the study — for example, the team had planned to make the study less burdensome for women by collecting information during a routine ultrasound scan rather than asking for a separate visit — and that the review process did not take such plans fully into account. Fiona Armstrong, who was responsible for Life Study at the ESRC, says that the research council did indeed consider the researchers’ plans to adjust the recruitment process — and consulted the research team as part of that process — but ultimately, it still concluded that “whatever might be done wasn’t enough”. “We couldn’t take the risk of putting more and more money into it,” she says. The study consumed around £9 million ($13.8 million), a sliver of the more than $1.2 billion — over 15 years — that was sunk into the US National Children’s Study (NCS). Epidemiologists are drawing parallels between Life Study’s demise and that of the NCS. “It’s déjà vu all over again,” says Mark Klebanoff, a paediatric epidemiologist at Nationwide Children’s Hospital in Columbus, Ohio. Clinical epidemiologist George Davey Smith, who co-directs a separate birth-cohort study at the University of Bristol, UK, notes that a huge challenge for both efforts was that they were trying to provide answers to extremely diverse questions, which put constraints on the studies’ designs. For example, assessing inequalities between socio-economic groups requires data from a large, representative population sample that includes disadvantaged and minority groups — whereas answering questions relating to the origin of disease requires the collection of extensive biological samples such as blood and tissues. “It’s incredibly sad,” he adds of Life Study’s end. Those involved in both studies hope to salvage something from the wreckage. After the NCS ended, plans emerged for a more modest study of influences on child health; Dezateux says that she and her colleagues are “determined to take forward key elements” of Life Study. Whether and how such studies can be conducted in future is unclear. Response rates are falling in many surveys and population studies compared with those in decades past, say researchers — perhaps because there are more demands on people’s attention. “We have to be mindful of the fact that people’s lives are busier than ever,” says Klebanoff. “We have to find ways of doing this that pose the least burden possible to participants.” Scientists need to exploit existing data sources more, says Stoltenberg. Extensive databases of health, educational and income data exist in many countries and provide vast amounts of information on the cheap — as long as people consent to their use. In Norway, such databases have been crucial to the success of its national birth-cohort study, which is following more than 100,000 children, she says. But it is important to create systems through which information can be more easily extracted from such databases for use in cohort and other types of research, she adds. “We don’t have the infrastructure,” she says. “We’re trying to drive sophisticated vehicles like birth-cohort studies where there are no real roads.”


News Article | December 13, 2016
Site: www.eurekalert.org

An exciting X-ray imaging technology has been successfully developed to the point where it is now ready for translation into all kinds of beneficial applications, including potentially life-saving uses in security and healthcare. Funded by the Engineering and Physical Sciences Research Council (EPSRC), a major five-year project led by UCL (University College London) has achieved this breakthrough. The work also involved dozens of industrial, academic and research partners in the UK and worldwide. Compared with conventional X-rays, the technology can, for example, identify tumours in living tissue earlier and spot smaller cracks and defects in materials. This is because it excels at determining different shapes and different types of matter - a capability that conventional X-rays could only match by using prohibitively high doses of radiation. The technique at the heart of the advance is called phase-contrast X-ray imaging. Instead of measuring the extent to which tissue or materials absorb radiation - as in conventional X-ray imaging - it measures the physical effect that passing through different types of tissue or material has on the speed of the X-ray itself. Professor Alessandro Olivo, who led the project team, says: "The technique has been around for decades but it's been limited to large-scale synchrotron facilities such as Oxfordshire's Diamond Light Source. We've now advanced this embryonic technology to make it viable for day-to-day use in medicine, security applications, industrial production lines, materials science, non-destructive testing, the archaeology and heritage sector, and a whole range of other fields." This vast potential is already beginning to be explored. For example: Professor Olivo says: "This has the potential to be incredibly versatile, game-changing technology. We're currently negotiating with a number of companies to explore how it could be put to practical use. There's really no limit to the benefits this technique could deliver." For media enquiries contact: Alessandro Olivo, Professor of Applied Physics, UCL, tel: 0207 679 2444, e-mail: a.olivo@ucl.ac.uk; or the EPSRC Press Office, tel: 01793 444 404, e-mail: pressoffice@epsrc.ac.uk The 5-year project Transforming the Use of X-rays in Science and Society ran from November 2011 to October 2016 and received £1.05 million in EPSRC funding under the Challenging Engineering programme. The project created 28 new collaborations and produced around 75 journal papers. Partners and collaborators included: Academia: Imperial College London; Queen Mary University of London; University of Oxford; Ludwig-Maximillian University, Munich; University of Washington in St Louis, Missouri; Kyoto University; Heriot-Watt University; University of Bristol; University of Dundee; University of Glasgow; University of Strathclyde; University of Saskatchewan; University of Trieste; University of Pisa. Research Institutes/Facilities: Diamond Light Source; ELETTRA Sincrotrone Trieste ScpA; European Synchrotron Radiation Facility; Research Complex at Harwell; CNR Institute of Crystallography - Italy; EMPA Switzerland; Barts Health NHS Trust; INFN Istituto Nazionale di Fisica Nucleare, Pisa and Trieste Sections. Within UCL: Department of Mechanical Engineering; Department of Chemical Engineering; Department of Physics and Astronomy; London Centre for Nanotechnology (a joint UCL-Imperial College establishment); Institute of Child Health; Great Ormond Street Hospital. The Engineering and Physical Sciences Research Council (EPSRC): As the main funding agency for engineering and physical sciences research, our vision is for the UK to be the best place in the world to Research, Discover and Innovate. By investing £800 million a year in research and postgraduate training, we are building the knowledge and skills base needed to address the scientific and technological challenges facing the nation. Our portfolio covers a vast range of fields from healthcare technologies to structural engineering, manufacturing to mathematics, advanced materials to chemistry. The research we fund has impact across all sectors. It provides a platform for future economic development in the UK and improvements for everyone's health, lifestyle and culture. We work collectively with our partners and other Research Councils on issues of common concern via Research Councils UK. http://www. UCL (University College London): UCL was founded in 1826. We were the first English university established after Oxford and Cambridge, the first to open up university education to those previously excluded from it, and the first to provide systematic teaching of law, architecture and medicine. We are among the world's top universities, as reflected by performance in a range of international rankings and tables. UCL currently has over 38,000 students from 150 countries and over 12,000 staff. Our annual income is more than £1 billion. Wellcome Trust: Wellcome exists to improve health for everyone by helping great ideas to thrive. We're a global charitable foundation, both politically and financially independent. We support scientists and researchers, take on big problems, fuel imaginations and spark debate.


Analysis by a Great Ormond Street Hospital (GOSH) led team looking at the effectiveness of different elements of the post mortem process shows that, despite full standard investigation, in the majority of cases of stillbirth the cause remains unknown. The papers highlight the need for further research to improve post mortem techniques to better detect a cause of death. The findings from the research, funded by the stillbirth and neonatal death charity Sands, are highlighted in a collection of six papers published in the journal Ultrasound in Obstetrics and Gynecology. The series of articles are significant as they challenge the accepted thinking on the diagnosis and causes of stillbirth and earlier deaths in the womb from 12 to 24 weeks, and the value of specific elements of the traditional post mortem process. Post mortem examinations are traditionally considered the best way of working out how a person has died. The examination involves several different elements, and developments in scanning techniques over recent years means that more information can now be gathered by less invasive approaches. GOSH consultant paediatric pathologist Professor Neil Sebire and colleagues have now carried out a detailed analysis of findings from a large number of post mortem examinations investigating stillbirth and earlier deaths in the womb to see which aspects of the examinations provide the most information about why the baby had died. The team reviewed the value of the autopsy and examination of tissue samples under the microscope, as well as the effectiveness of analysing the placenta and reviewing case notes for determining cause of stillbirths and earlier intrauterine deaths in over 1,000 cases. They found that clinical review identified the cause of death in about 20% of cases, with placental examination providing a cause in about another 20%, whilst carrying out invasive post mortem examination identified the cause of death in only a small percentage of cases. Professor Neil Sebire, GOSH consultant paediatric pathologist and lead researcher, said: "Overall, post mortem examination remains the most effective way of determining how a person has died. However, this research highlights that, in the case of stillbirths, analysing information such as the clinical circumstances and examination of the placenta, without the use of invasive techniques, allows us to get almost as much information. The problem is that using current methods, even including full autopsy, we are still often not able to find out why the baby has died. It's therefore vitally important that we advance better ways of properly investigating these cases by developing new, more refined techniques. This will ensure we can support families in the best possible way." In addition to this finding, the papers also suggest that the importance of having an apparently small baby as a risk factor for stillbirth may have been overestimated. In many cases, the stillbirth may have actually occurred when the baby was normal in size but weight loss occurs after death. While having a small baby in utero is certainly linked to increased stillbirth risk, this finding challenges the likely impact of identifying small babies to prevent stillbirth. Professor Basky Thilaganathan, Editor in Chief of Ultrasound in Obstetrics & Gynecology (UOG), said: "Sebire and colleagues produce convincing data to demonstrate that fetal body weight decreases substantially between intrauterine demise and postnatal weight assessment. This suggests that the majority of stillbirths considered to be small for gestation by birth weight, were likely to have been appropriately sized at the time of death. This finding questions the fundamental rationale and potential effectiveness of current health policy that is solely focused on the detection and elective birth of small fetuses to reduce the risk of stillbirth." Clea Harmer, Chief Executive of Sands, said: "When a baby dies before birth, the most pressing question for parents is why? This study reveals how much we can expect to learn from the way post mortems are done today and highlights just how many gaps there are in our knowledge. These gaps won't close without continued and expanded funding for research, and access to good-quality pathology services for all parents when their baby dies. "We are pleased to have been able to fund such an important study with money raised from bereaved parents themselves who remain determined that other families should not suffer as they have done." Professor Neil Sebire's work is supported by Great Ormond Street Hospital Children's Charity. The project is one of over 1000 being carried out at Great Ormond Street Hospital and the UCL Great Ormond Street Institute of Child Health as part of their research programme. For further information please contact Andrew Willard in the GOSH-ICH Press Office at andrew.willard@gosh.nhs.uk or on 020 7239 3043. For out-of-hours media enquiries call the GOSH switchboard on 020 7405 9200. Great Ormond Street Hospital is one of the world's leading children's hospitals with the broadest range of dedicated, children's healthcare specialists under one roof in the UK. The hospital's pioneering research and treatment gives hope to children from across the UK with the rarest, most complex and often life-threatening conditions. Our patients and families are central to everything we do - from the moment they come through the door and for as long as they need us. Great Ormond Street Hospital, with its academic partner, the UCL GOS Institute of Child Health, has a world leading research portfolio. Its programme is made possible through many different funding sources, such as government and charitable funding, including from Great Ormond Street Hospital Children's Charity. You can help us to provide world class care for our patients and families. For more information visit http://www. Ultrasound in Obstetrics and Gynecology (UOG), published by Wiley, is the official journal of the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) and is recognised as the leading peer-reviewed journal on imaging within the field of obstetrics and gynecology, publishing important research from all parts of the world. ISUOG is a charity and membership association encouraging exceptional research and education in ultrasound and related imaging within the field of obstetrics and gynecology. ISUOG has been in existence since 1991 and, with over 13300 members in 128 countries, is the leading international society representing professionals in ultrasound for obstetrics and gynecology. Wiley, a global company, helps people and organizations develop the skills and knowledge they need to succeed. Our online scientific, technical, medical, and scholarly journals, combined with our digital learning, assessment and certification solutions help universities, learned societies, businesses, governments and individuals increase the academic and professional impact of their work. For more than 200 years, we have delivered consistent performance to our stakeholders. Sands, the stillbirth and neonatal death charity, was founded in 1978 by a small group of bereaved parents who were devastated by the death of their babies, and by the total lack of acknowledgement and understanding of the significance and impact of their loss. Since that time, they have supported many thousands of families whose babies have died, offering emotional support, comfort and information. Today Sands operates through the UK with three aims: to support anyone affected by the death of a baby; to work in partnership with health professionals to try to ensure that bereaved parents and families receive the best possible care; and to promote and fund research that could help reduce the loss of babies' lives. Sands website can be found at http://www. For further information or to speak to parents who have experienced the stillbirth of their baby, please contact the Sands press office on 0203 598 1959 or communications@uk-sands.org


Jones L.,Institute of Child Health
Cochrane database of systematic reviews (Online) | Year: 2010

BACKGROUND: Malnutrition can often be a consequence of cancer itself or a result of chemotherapy. Nutritional support aims to reverse malnutrition seen at diagnosis, prevent malnutrition associated with treatment and promote weight gain and growth. The most effective and safe forms of nutritional support in children and young people with cancer are unclear. OBJECTIVES: To determine the effects of any form of parenteral (PN) or enteral (EN) nutritional support in children and young people with cancer undergoing chemotherapy. SEARCH STRATEGY: We searched the following databases: CENTRAL (The Cochrane Library 2009, Issue 2), MEDLINE (1950 to 2006), EMBASE (1974 to 2006), CINAHL (1982 to 2006), the National Research Register (2007) and Dissertations & Theses (2007). We scrutinised reference lists of articles to identify additional trials. We also contacted experts in the field for information on relevant trials. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials comparing any form of nutritional support with another, or control, in children or young people with cancer undergoing chemotherapy. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials. Three authors independently assessed quality and extracted data. We contacted trialists for missing information. MAIN RESULTS: We included eight trials which randomised 159 participants (< 21 years) with leukaemias or solid tumours undergoing chemotherapy. The trials were all of low quality. One small trial found that compared to EN, PN significantly increased weight (mean difference (MD) 4.12; 95% CI 1.91 to 6.33), serum albumin levels (MD 0.70; 95% CI 0.14 to 1.26), calorie intake (MD 22.00; 95% CI 5.12 to 38.88) and protein intake (MD 0.80; 95% CI 0.45 to 1.15). One trial comparing peripheral PN and EN with central PN found that mean daily weight gain (MD -27.00; 95% CI -43.32 to -10.68) and energy intakes (MD -15.00; 95% CI -26.81 to -3.19) were significantly less for the peripheral PN and EN group, whereas mean change in serum albumin was significantly greater for that group(MD 0.47; 95% CI 0.13 to 0.81, P = 0.008). AUTHORS' CONCLUSIONS: There is limited evidence from individual trials to suggest that parenteral nutrition is more effective than enteral nutrition in well-nourished children and young people with cancer undergoing chemotherapy. The evidence for other methods of nutritional support remains unclear. No studies were identified comparing the nutritional content in the PN or EN groups of studies. Further research, incorporating larger sample sizes and rigorous methodology utilising valid and reliable outcome measures, is essential.


Solebo A.L.,Institute of Child Health
Cochrane database of systematic reviews (Online) | Year: 2011

Macular holes cause significant loss of central vision. With the aim of improving the outcome of surgery, a variable period of face-down positioning may be advised. To evaluate the evidence of the impact of postoperative face-down positioning on the outcome of surgery for macular hole. We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2011, Issue 8), MEDLINE (January 1950 to August 2011), EMBASE (January 1980 to August 2011), the International Standard Randomised Controlled Trial Number Register (ISRCTN Register) (http://www.controlled-trials.com), the WHO International Clinical Trials Registry Platform (ICTRP) (http://www.who.int/ictrp/search/en) and ClinicalTrials.gov (http://clinicaltrials.gov). There were no date or language restrictions in the electronic searches for trials. The electronic databases were last searched on 29 August 2011. We included randomised controlled trials (RCTs) in which postoperative face-down positioning was compared to no face-down positioning following surgery for macular holes. Data were collected and analysed independently by two authors. Three RCTs were identified, A, B and C; one of which was unpublished data. We were unable to conduct a meta-analysis due to study heterogeneity regarding duration of face-down positioning and surgical methods (use of inner limiting peel). All three studies suggested an overall beneficial effect of posturing in terms of closure of holes: (A: risk ratio (RR) 1.10; 95% confidence interval (CI) 1.00 to 1.20, P = 0.05); B: RR 1.58, CI 1.0 to 2.5, P = 0.01; C: RR 1.03, CI 0.9 to 1.17, P = 0.67). For holes which were smaller than 400 microns in size, all three studies reported that there was no significant effect of face-down positioning on successful hole closure (A: RR 1.03, CI 0.95 to 1.12; B: RR 1.0, CI 0.68 to 1.46; C: RR 1.03, CI 0.9 to 1.17). However, for holes which were larger than 400 microns in size, both of the studies which examined macular holes of this size agreed on the effectiveness of face-down positioning on hole closure following surgery (A: RR 1.2, CI 1.01 to 1.42, P = 0.04; B: RR 2.27, CI 1.04 to 4.97, P = 0.04). There is currently insufficient evidence from which to draw firm conclusions about the impact of postoperative face-down positioning on the outcome of surgery for macular hole. Of three RCTs, two suggested a benefit in larger holes but none demonstrated evidence of a benefit in smaller holes.CONSORT adherent RCTs and large scale, well designed non-randomised observational studies are needed to determine with confidence the value of this intervention.


Saldana L.J.,Institute of Child Health
Journal of laparoendoscopic & advanced surgical techniques. Part A | Year: 2013

Single-incision pediatric endosurgery (SIPES) is defined as minimally invasive surgery performed through a unique incision in the abdomen, chest, or retroperitoneum. Several publications exist, but no previous systematic review has been made to evaluate the real benefits of this approach in terms of feasibility and clinical outcomes. We performed an electronic search in PubMed up to March 2012 with the terms "single AND incision OR site OR port OR trocar AND children" including related articles and obtained 197 articles. After applying our inclusion criteria, 78 articles were reviewed. We identified prospective controlled trials (n=1), case-control studies (n=12), case series (n=49), and case reports (n=16). In total, 4212 patients had been operated on by SIPES and were separated by systems: gastrointestinal (n=2888), urologic (n=390), gynecologic (n=27), other abdominal (n=874), and thoracic (n=33) procedures. The most common procedure was SIPES appendectomy, and a unique prospective controlled trial supports its safety and effectiveness. Technically demanding surgeries such as hepatojejunostomy and colonic surgeries were described. Multichannel ports and multiple ports, standard and articulated instruments, transparietal instruments, retraction sutures, and magnets were used. Operative times, length of stay, and complications similar to standard laparoscopic surgery were described. A low conversion rate (to a reduced port, standard laparoscopy and open procedures) was also mentioned. No comparable measure for pain and cosmesis assessment was used. A wide experience in SIPES and feasibility has already been described with good clinical outcomes and low rate of conversion. Appendectomy is the unique procedure in which SIPES has been demonstrated to be safe and effective. It is pending the execution of prospective controlled trials for other operations to demonstrate, with objective evidence, the real benefits of this less invasive approach.


Mercuri E.,Catholic University | Mercuri E.,Institute of Child Health | Muntoni F.,Institute of Child Health
Annals of Neurology | Year: 2012

Congenital muscular dystrophies are a highly heterogeneous group of conditions. In the last few years the identification of several new genes encoding for both glycosyltransferases and structural proteins has expanded the spectrum of the known forms. New classifications based on combined clinical, genetic and pathological data include all the recently discovered genes and allow an easier identification of the different forms and insight on pathogenetic mechanisms. The aim of this review is to discuss the most recent advances in this field, providing a conceptual framework to help the understanding of the responsible mechanisms and, when available, an update on the therapeutic perspectives. © 2012 American Neurological Association.


Kristiansen M.,Institute of Child Health | Ham J.,Institute of Child Health
Cell Death and Differentiation | Year: 2014

Developing sympathetic neurons of the superior cervical ganglion are one of the best studied models of neuronal apoptosis. These cells require nerve growth factor (NGF) for survival at the time that they innervate their final target tissues during late embryonic and early postnatal development. In the absence of NGF, developing sympathetic neurons die by apoptosis in a transcription- dependent manner. Molecular studies of sympathetic neuron apoptosis began in the 1980s. We now know that NGF withdrawal activates the mitochondrial (intrinsic) pathway of apoptosis in sympathetic neurons cultured in vitro, and the roles of caspases, Bcl-2 (B-cell CLL/lymphoma 2) family proteins and XIAP (X-linked inhibitor of apoptosis protein) have been extensively studied. Importantly, a considerable amount has also been learned about the intracellular signalling pathways and transcription factors that regulate programmed cell death in sympathetic neurons. In this article, we review the key papers published in the past few years, covering all aspects of apoptosis regulation in sympathetic neurons and focusing, in particular, on how signalling pathways and transcription factors regulate the cell death programme. We make some comparisons with other models of neuronal apoptosis and describe possible future directions for the field. © 2014 Macmillan Publishers Limited All rights reserved.


Wells J.C.K.,Institute of Child Health
Reviews in Endocrine and Metabolic Disorders | Year: 2012

The consequences of fetal growth retardation remain unclear, in part because they appear to vary between industrialized and developing countries. Data on body composition offer a new opportunity to investigate this issue, and may be of particular value in addressing the controversial role of nutrition in infancy, which has been proposed by some to boost survival, and by others to increase long-term risk of chronic diseases. The uncertainty regarding the effects of post-natal nutrition is presenting challenges to nutritional policy as many countries undergo the nutrition transition, whereby the nutritional status of individuals may shift within the life-course. A theoretical model, building on the thrifty phenotype hypothesis, is presented to clarify how body composition data can address this dilemma. Measurements of body composition can now be obtained in infants and children using several different technologies, indicating that large-scale studies can now be conducted to investigate objectively the association between early growth patterns and later health. © Springer Science+Business Media, LLC 2012.


Background: The upper gastrointestinal (UGI) contrast study is used in the assessment of children with gastro-oesophageal reflux (GOR) and for detection of structural anomalies. The pH study is more sensitive than the UGI study for the diagnosis of GOR. The pH study has been replaced by the pH/impedance test, which detects both acid and nonacid reflux. Objective: To compare the UGI contrast study with the pH/impedance test for the diagnosis of GOR in children. Materials and methods: We retrospectively reviewed consecutive records of children investigated for GOR from October 2008 to February 2010, and compared the findings of UGI studies with those of pH/impedance tests. Results: The UGI studies revealed GOR in 116 of 579 children (20%). Of the children undergoing a UGI study, 66 also underwent a pH/impedance test. Using the pH/impedance tests as the reference for GOR, UGI had a sensitivity of 42.8% and a negative predictive value of 24%. There was no significant correlation (P>0.05) between the reflux index and the number of reflux episodes in the pH/impedance tests and height of reflux in the UGI study. There were low incidences of malrotation (0.9%), hiatus hernia (1%) and delayed gastric emptying (0.4%). Conclusion: The UGI study had low sensitivity for the diagnosis of GOR and low yield for the diagnosis of structural anomalies. © Springer-Verlag 2012.

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