Great Ormond Street Hospital NHS Foundation Trust

London, United Kingdom

Great Ormond Street Hospital NHS Foundation Trust

London, United Kingdom
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Houghton B.C.,University College London | Booth C.,University College London | Booth C.,Great Ormond Street Hospital NHS Foundation Trust | Thrasher A.J.,University College London | Thrasher A.J.,Great Ormond Street Hospital NHS Foundation Trust
Current Opinion in Pharmacology | Year: 2015

Lentiviral vectors (LVV) are important tools for the treatment of immune system disorders. Integration of therapeutic genetic material into the haematopoietic stem cell compartment using LVV can mediate long-term correction of haematopoietic lineages, thereby correcting disease phenotypes. Twenty years of vector development have successfully brought LVV to the clinic, with follow up studies of clinical trials treating primary immunodeficiencies now being reported. Results have demonstrated clear improvements in the quality of life for patients with a number of conditions in the absence of the severe adverse events observed in earlier retroviral gene therapy trials. Growing interest in gene modified adoptive T cell transfer as an alternative strategy has driven further technology innovation, including characterisation of novel viral envelopes. We will also discuss the progression of gene editing technology to preclinical investigations in models of immune deficiency. © 2015 Elsevier Ltd. All rights reserved.

Bockenhauer D.,University College London | Bockenhauer D.,Great Ormond Street Hospital NHS Foundation Trust
Pediatric Nephrology | Year: 2017

Hyponatremia is a common complication in neonatal polycystic kidney disease and is thought to be due to water retention. Aquaretics are drugs that promote free water excretion by blocking the arginine vasopressin receptor type 2 (AVPR2) in the collecting duct and thus impair urinary concentration. AVPR2 is also a key stimulant for cyclic AMP production in the collecting duct and in this way promotes cyst proliferation and pathologic kidney growth in autosomal dominant polycystic kidney disease (ADPKD). Consequently, the aquaretic tolvaptan is now used to slow down progression of ADPKD in adult patients. Whether this beneficial effect on retarding cystic disease progression also extends to recessive forms of polycystic kidney disease (PKD) is currently not known. A recent case report in Pediatric Nephrology touches on the intersecting indications for tolvaptan for both hyponatremia and cyst retardation in neonatal PKD and suggests that use for one indication may have beneficial effects on the other. © 2017 IPNA

Keir L.S.,University of Bristol | Marks S.D.,Great Ormond Street Hospital NHS Foundation Trust | Kim J.J.,Great Ormond Street Hospital NHS Foundation Trust
Drug Design, Development and Therapy | Year: 2012

Hemolytic uremic syndrome is the leading cause of acute kidney injury in childhood. Ninety percent of cases are secondary to gastrointestinal infection with shigatoxin-producing bacteria. In this review, we discuss the molecular mechanisms of shigatoxin leading to hemolytic uremic syndrome and the emerging role of the complement system and vascular endothelial growth factor in its pathogenesis. We also review the evidence for treatment options to date, in particular antibiotics, plasma exchange, and immunoadsorption, and link this to the molecular pathology. Finally, we discuss future avenues of treatment, including shigatoxin-binding agents and complement inhibitors, such as eculizumab. © 2012 Keir et al, publisher and licensee Dove Medical Press Ltd.

Bee N.,Great Ormond Street Hospital NHS Foundation Trust
Pediatric Critical Care Medicine | Year: 2017

OBJECTIVES:: There is increasing interest in hydrogen sulphide as a marker of pathologic conditions or predictors of outcome. We speculate that as hydrogen sulphide is a diffusible molecule, if there is an increase in plasma hydrogen sulphide in sepsis, it may accumulate in the alveolar space and be detected in exhaled gas. “We wished to determine whether we could detect hydrogen sulphide in exhaled gases of ventilated children and neonates and if the levels changed in sepsis.” DESIGN:: Prospective, observational study. SETTING:: The study was conducted across three intensive care units, pediatric, neonatal and cardiac in a large tertiary children’s hospital. PATIENTS:: We studied ventilated children and neonates with sepsis, defined by having two or more systemic inflammatory response syndrome criteria and one organ failure or suspected infection. A control group of ventilated non-septic patients was also included. INTERVENTION:: A portable gas chromatograph (OralChroma; Envin Scientific, Chester, United Kingdom) was used to measure H2S in parts per billion. MEASUREMENTS AND MAIN RESULTS:: A 1-2 mL sample of expired gas was taken from the endotracheal tube and analyzed. A repeat sample was taken after 30 minutes and a further single daily sample up to a maximum of 5 days or until the patient was extubated. WBC and C-reactive protein were measured around the time of gas sampling. Each group contained 20 subjects. Levels of H2S were significantly higher in septic patients (Mann Whitney U-test; p < 0.0001) and trended to control levels over five days. C-reactive protein levels were also significantly raised (p < 0.001) and mirrored the decrease in H2S levels. CONCLUSION:: Hydrogen sulphide can be detected in expired pulmonary gases in very low concentrations of parts per billion. Significantly higher levels are seen in septic patients compared with controls. The pattern of response was similar to that of C-reactive protein. ©2017The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

Worth A.J.J.,Great Ormond Street Hospital NHS Foundation Trust | Booth C.,University College London | Veys P.,Great Ormond Street Hospital NHS Foundation Trust
Current Opinion in Hematology | Year: 2013

PURPOSE OF REVIEW: In this article, we summarize the recent advances in treating primary immune deficiency (PID) disorders by stem cell transplantation (SCT); we have focused on articles published in the past 2 years since the last major review of SCT for PID. RECENT FINDINGS: Analyses of the outcomes of SCT for PID by specific molecular defect have clarified which conditions are receptive to unconditioned transplants and which require more myeloablative conditioning. Improved outcomes for 'difficult' conditions [adenosine deaminase-severe combined immunodeficiency (ADA-SCID), major histocompatibility complex class II deficiency] and potential advantages of using cord blood as a stem cell source have also been described. Newborn screening for SCID identifies well babies with SCID: the optimal SCT protocol for such young infants remains to be determined. Reduced toxicity conditioning has been successfully used to treat conditions such as Wiskott-Aldrich syndrome and chronic granulomatous disease, offering curative engraftment with reduced transplant-related mortality. Similarly, treating children with familial hemophagocytic lymphohistiocytosis using reduced intensity conditioning SCT results in much improved outcomes. Advances in next generation sequencing have identified new diseases amenable to SCT, such as DOCK8 deficiency, resulting in improved quality of life and protection from malignancy. SUMMARY: Recent studies suggest that further improvements in treating PID with SCT are possible with a greater understanding of the genetics and immunobiology of these diseases, facilitating the matching of donor type and conditioning regimens, or indeed alternative therapies (such as gene therapy) to specific PID disorders.© 2013 Wolters Kluwer Health Lippincott Williams & Wilkins.

Harris K.A.,Great Ormond Street Hospital NHS Foundation Trust | Kenna D.T.D.,Public Health England
Journal of Medical Microbiology | Year: 2014

Mycobacterium abscessusis a significant pathogen in the cystic fibrosis patient population. PCR amplification and sequencing can provide accurate subspecies identification, and can predict macrolide susceptibility, which is becoming increasingly important for patient management. Molecular techniques for further typing of isolates provide tools for the ongoing investigations into the clinical impact of particular M. abscessusstrains. Whole-genome sequencing is likely to be the only technique that provides sufficient resolution for investigating transmission events between patients. © 2014 The Authors.

Smith P.,Great Ormond Street Hospital NHS Foundation Trust | Bailey C.R.,Guys And St Thomas Nhs Foundation Trust
Anaesthesia | Year: 2015

We performed a review of published literature comparing the i-gel™ with other supraglottic airway devices in children. Sixty-two articles were identified following a literature search; we included data from 14 randomised controlled trials and eight observational studies that compared i-gel sizes 1-2.5 with other commonly used, equivalently-sized, devices. The primary outcome in most studies was oropharyngeal leak pressure. In the 14 randomised trials the i-gel performed the same as the comparator device in five trials, significantly better in eight studies (p < 0.05) and significantly worse in one (p < 0.01). Seven studies assessed fibreoptic views of the larynx through the device; two found significantly better views through the i-gel. Three studies reported a shorter insertion time for the i-gel, whereas two reported a longer time. Insertion success rate, gastric tube placement and complications were similar for all the devices. Seven of the eight observational studies measured average oropharyngeal leak pressures of 20-27 cmH2O and all had first-time insertion success rates exceeding 90%. We conclude that the i-gel is at least equivalent to other supraglottic airway devices currently available for use in children, and may enable a higher oropharyngeal leak pressure and an improved fibreoptic view of the glottis. © 2014 The Association of Anaesthetists of Great Britain and Ireland.

Walker I.A.,Great Ormond Street Hospital NHS Foundation Trust | Reshamwalla S.,Lifebox Foundation | Wilson I.H.,Royal Devon and Exeter NHS Foundation Trust
British Journal of Anaesthesia | Year: 2012

Summary The concept of using a checklist in surgical and anaesthetic practice was energized by publication of the WHO Surgical Safety Checklist in 2008. It was believed that by routinely checking common safety issues, and by better team communication and dynamics, perioperative morbidity and mortality could be improved. The magnitude of improvement demonstrated by the WHO pilot studies was surprising. These initial results have been confirmed by further detailed work demonstrating that surgical checklists, when properly implemented, can make a substantial difference to patient safety. However, introducing surgical checklists is not as straightforward as it seems, and requires leadership, flexibility, and teamwork in a different way to that which is currently practiced. Future work should be aimed at ensuring effective implementation of the WHO Surgical Safety Checklist, which will benefit our patients on a global scale. © The Author [2012].

Buckland K.F.,University College London | Buckland K.F.,Great Ormond Street Hospital NHS Foundation Trust | Bobby Gaspar H.,University College London | Bobby Gaspar H.,Great Ormond Street Hospital NHS Foundation Trust
Advanced Drug Delivery Reviews | Year: 2014

The range of possible gene and cell therapy applications is expanding at an extremely rapid rate and advanced therapy medicinal products (ATMPs) are currently the hottest topic in novel medicines, particularly for inherited diseases. Paediatric patients stand to gain enormously from these novel therapies as it now seems plausible to develop a gene or cell therapy for a vast number of inherited diseases.There are a wide variety of potential gene and cell therapies in various stages of development. Patients who received first gene therapy treatments for primary immune deficiencies (PIDs) are reaching 10 and 15. years post-treatment, with robust and sustained immune recovery. Cell therapy clinical trials are underway for a variety of tissues including corneal, retinal and muscle repair and islet cell transplantation. Various cell therapy approaches are also being trialled to enhance the safety of bone marrow transplants, which should improve survival rates in childhood cancers and PIDs. Progress in genetic engineering of lymphocyte populations to target and kill cancerous cells is also described. If successful these ATMPs may enhance or replace the existing chemo-ablative therapy for several paediatric cancers. Emerging applications of gene therapy now include skin and neurological disorders such as epidermolysis bullosa, epilepsy and leukodystrophy. Gene therapy trials for haemophilia, muscular dystrophy and a range of metabolic disorders are underway. There is a vast array of potential advanced therapy medicinal products (ATMPs), and these are likely to be more cost effective than existing medicines. However, the first clinical trials have not been without setbacks and some of the key adverse events are discussed. Furthermore, the arrival of this novel class of therapies brings many new challenges for the healthcare industry. We present a summary of the key non-clinical factors required for successful delivery of these potential treatments. Technological advances are needed in vector design, raw material manufacture, cell culture and transduction methodology, and particularly in making all these technologies readily scalable. © 2014.

Van't Hoff W.,Great Ormond Street Hospital NHS Foundation Trust | Offringa M.,University of Toronto
Archives of Disease in Childhood | Year: 2015

There has been a huge upsurge in clinical research in children in the last decade, stimulated in England by dedicated research infrastructure and support through the National Institute for Health Research. This infrastructure offering research design, expert review, trial management, research nurse, data support and dedicated facilities enables paediatricians to conduct more and better research. The challenge is how to design and conduct trials that will make a real difference to children's health. Standards for Research (StaR) in Child Health was founded in 2009 to address the paucity and shortcomings of paediatric clinical trials. This global initiative involves methodologists, clinicians, patient advocacy groups and policy makers dedicated to developing practical, evidence-based standards for enhancing the reliability and relevance of paediatric clinical research. In this overview, we highlight the contribution of StaR to this agenda, describe the international context, and suggest how StaR 's future plans could be integrated with new and existing support for research. © 2015, BMJ Publishing Group. All rights reserved.

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