Developing a core outcome set for the health outcomes for children and adults with congenital oesophageal atresia and/or tracheo-oesophageal fistula:OCELOT task group study protocol

Introduction Heterogeneity in reported outcomes of infants with oesophageal atresia (OA) with or without tracheo-oesophageal fistula (TOF) prevents effective data pooling. Core outcome sets (COS) have been developed for many conditions to standardise outcome reporting, facilitate meta-analysis and improve the relevance of research for patients and families. Our aim is to develop an internationally-agreed, comprehensive COS for OA-TOF, relevant from birth through to transition and adulthood. Methods and analysis A long list of outcomes will be generated using (1) a systematic review of existing studies on OA-TOF and (2) qualitative research with children (patients), adults (patients) and families involving focus groups, semistructured interviews and self-reported outcome activity packs. A two-phase Delphi survey will then be completed by four key stakeholder groups: (1) patients (paediatric and adult); (2) families; (3) healthcare professionals; and (4) researchers. Phase I will include stakeholders individually rating the importance and relevance of each long-listed outcome using a 9-point Likert scale, with the option to suggest additional outcomes not already included. During phase II, stakeholders will review summarised results from phase I relative to their own initial score and then will be asked to rescore the outcome based on this information. Responses from phase II will be summarised using descriptive statistics and a predefined definition of consensus for inclusion or exclusion of outcomes. Following the Delphi process, stakeholder experts will be invited to review data at a consensus meeting and agree on a COS for OA-TOF. Ethics and dissemination Ethical approval was sought through the Health Research Authority via the Integrated Research Application System, registration no. 297026. However, approval was deemed not to be required, so study sponsorship and oversight were provided by Alder Hey Children’s NHS Foundation Trust. The study has been prospectively registered with the COMET Initiative. The study will be published in an open access forum.</p

Developing a core outcome set for the health outcomes for children and adults with congenital oesophageal atresia and/or tracheo-oesophageal fistula: OCELOT task group study protocol

Introduction: Heterogeneity in reported outcomes of infants with oesophageal atresia (OA) with or without tracheo-oesophageal fistula (TOF) prevents effective data pooling. Core outcome sets (COS) have been developed for many conditions to standardise outcome reporting, facilitate meta-analysis and improve the relevance of research for patients and families. Our aim is to develop an internationally-agreed, comprehensive COS for OA-TOF, relevant from birth through to transition and adulthood. Methods and analysis: A long list of outcomes will be generated using (1) a systematic review of existing studies on OA-TOF and (2) qualitative research with children (patients), adults (patients) and families involving focus groups, semistructured interviews and self-reported outcome activity packs. A two-phase Delphi survey will then be completed by four key stakeholder groups: (1) patients (paediatric and adult); (2) families; (3) healthcare professionals; and (4) researchers. Phase I will include stakeholders individually rating the importance and relevance of each long-listed outcome using a 9-point Likert scale, with the option to suggest additional outcomes not already included. During phase II, stakeholders will review summarised results from phase I relative to their own initial score and then will be asked to rescore the outcome based on this information. Responses from phase II will be summarised using descriptive statistics and a predefined definition of consensus for inclusion or exclusion of outcomes. Following the Delphi process, stakeholder experts will be invited to review data at a consensus meeting and agree on a COS for OA-TOF. Ethics and dissemination: Ethical approval was sought through the Health Research Authority via the Integrated Research Application System, registration no. 297026. However, approval was deemed not to be required, so study sponsorship and oversight were provided by Alder Hey Children’s NHS Foundation Trust. The study has been prospectively registered with the COMET Initiative. The study will be published in an open access forum

Developing a core outcome set for the health outcomes for children and adults with congenital oesophageal atresia and/or tracheo-oesophageal fistula:OCELOT task group study protocol

Introduction Heterogeneity in reported outcomes of infants with oesophageal atresia (OA) with or without tracheo-oesophageal fistula (TOF) prevents effective data pooling. Core outcome sets (COS) have been developed for many conditions to standardise outcome reporting, facilitate meta-analysis and improve the relevance of research for patients and families. Our aim is to develop an internationally-agreed, comprehensive COS for OA-TOF, relevant from birth through to transition and adulthood. Methods and analysis A long list of outcomes will be generated using (1) a systematic review of existing studies on OA-TOF and (2) qualitative research with children (patients), adults (patients) and families involving focus groups, semistructured interviews and self-reported outcome activity packs. A two-phase Delphi survey will then be completed by four key stakeholder groups: (1) patients (paediatric and adult); (2) families; (3) healthcare professionals; and (4) researchers. Phase I will include stakeholders individually rating the importance and relevance of each long-listed outcome using a 9-point Likert scale, with the option to suggest additional outcomes not already included. During phase II, stakeholders will review summarised results from phase I relative to their own initial score and then will be asked to rescore the outcome based on this information. Responses from phase II will be summarised using descriptive statistics and a predefined definition of consensus for inclusion or exclusion of outcomes. Following the Delphi process, stakeholder experts will be invited to review data at a consensus meeting and agree on a COS for OA-TOF. Ethics and dissemination Ethical approval was sought through the Health Research Authority via the Integrated Research Application System, registration no. 297026. However, approval was deemed not to be required, so study sponsorship and oversight were provided by Alder Hey Children’s NHS Foundation Trust. The study has been prospectively registered with the COMET Initiative. The study will be published in an open access forum.</p

A novel 33-Gene targeted resequencing panel provides accurate, clinical-grade diagnosis and improves patient management for rare inherited anaemias

Accurate diagnosis of rare inherited anaemias is challenging, requiring a series of complex and expensive laboratory tests. Targeted next-generation-sequencing (NGS) has been used to investigate these disorders, but the selection of genes on individual panels has been narrow and the validation strategies used have fallen short of the standards required for clinical use. Clinical-grade validation of negative results requires the test to distinguish between lack of adequate sequencing reads at the locations of known mutations and a real absence of mutations. To achieve a clinically-reliable diagnostic test and minimize false-negative results we developed an open-source tool (CoverMi) to accurately determine base-coverage and the ‘discoverability’ of known mutations for every sample. We validated our 33-gene panel using Sanger sequencing and microarray. Our panel demonstrated 100% specificity and 99·7% sensitivity. We then analysed 57 clinical samples: molecular diagnoses were made in 22/57 (38·6%), corresponding to 32 mutations of which 16 were new. In all cases, accurate molecular diagnosis had a positive impact on clinical management. Using a validated NGS-based platform for routine molecular diagnosis of previously undiagnosed congenital anaemias is feasible in a clinical diagnostic setting, improves precise diagnosis and enhances management and counselling of the patient and their family

Neglecting legumes has compromised human health and sustainable food production

The United Nations declared 2016 as the International Year of Pulses (grain legumes) under the banner 'nutritious seeds for a sustainable future'. A second green revolution is required to ensure food and nutritional security in the face of global climate change. Grain legumes provide an unparalleled solution to this problem because of their inherent capacity for symbiotic atmospheric nitrogen fixation, which provides economically sustainable advantages for farming. In addition, a legume-rich diet has health benefits for humans and livestock alike. However, grain legumes form only a minor part of most current human diets, and legume crops are greatly under-used. Food security and soil fertility could be significantly improved by greater grain legume usage and increased improvement of a range of grain legumes. The current lack of coordinated focus on grain legumes has compromised human health, nutritional security and sustainable food production.We thank World University Network (WUN) and research collaboration awards (UWA and the University of Leeds) for financial support. CHF thanks the Biotechnology and Biological Sciences Research Council (BBSRC UK (BB/M009130/1) and the European Union (KBBE-2012-6-311840; ECOSEED) for financial support. JWC thanks BBSRC (UK) and Wherry and Sons, (UK) for an industrial CASE studentship (BB/K501839/1). H-ML was supported by the Hong Kong RGC Collaborative Research Fund (CUHK3/CRF/11G), the Lo Kwee-Seong Biomedical Research Fund and Lee Hysan Foundation. Ka-Ming Fung, Qianwen Wang, Lydia Kit-Wah Siu, and Yihan Jiang of The Chinese University of Hong Kong assisted in the production of Fig. 2, Table 1 and the associated webpage, highlight and cover design. We thank Hari Upadhyaya for the images shown in Fig. 4. TAM and JMH thank the Western Australian Government, Department of Industry and Resources for financial support. The authors thank Bodhi‟s Bakery, Fremantle, Western Australia, for baking the bread and biscuits and Belmar Foods, Balcatta, Western Australia, for manufacturing and providing the pasta. BNK and HB are supported by Australian Research Council (ARC), ITRH – Legumes for Sustainable Agriculture (IH140100013). MJC and CHF thank the ARC (DP150103211) for financial support. AJM is supported by grant funding (BB/JJ004553/1 and BB/L010305/1) from the BBSRC and the John Innes Foundation.http://www.nature.com/nplantshb2017Plant Production and Soil Scienc

Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin with gemtuzumab ozogamicin improves event-free survival in younger patients with newly diagnosed aml and overall survival in patients with npm1 and flt3 mutations

Purpose To determine the optimal induction chemotherapy regimen for younger adults with newly diagnosed AML without known adverse risk cytogenetics. Patients and Methods One thousand thirty-three patients were randomly assigned to intensified (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin [FLAG-Ida]) or standard (daunorubicin and Ara-C [DA]) induction chemotherapy, with one or two doses of gemtuzumab ozogamicin (GO). The primary end point was overall survival (OS). Results There was no difference in remission rate after two courses between FLAG-Ida + GO and DA + GO (complete remission [CR] + CR with incomplete hematologic recovery 93% v 91%) or in day 60 mortality (4.3% v 4.6%). There was no difference in OS (66% v 63%; P = .41); however, the risk of relapse was lower with FLAG-Ida + GO (24% v 41%; P < .001) and 3-year event-free survival was higher (57% v 45%; P < .001). In patients with an NPM1 mutation (30%), 3-year OS was significantly higher with FLAG-Ida + GO (82% v 64%; P = .005). NPM1 measurable residual disease (MRD) clearance was also greater, with 88% versus 77% becoming MRD-negative in peripheral blood after cycle 2 (P = .02). Three-year OS was also higher in patients with a FLT3 mutation (64% v 54%; P = .047). Fewer transplants were performed in patients receiving FLAG-Ida + GO (238 v 278; P = .02). There was no difference in outcome according to the number of GO doses, although NPM1 MRD clearance was higher with two doses in the DA arm. Patients with core binding factor AML treated with DA and one dose of GO had a 3-year OS of 96% with no survival benefit from FLAG-Ida + GO. Conclusion Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with NPM1 and FLT3 mutations had substantial improvements in OS. By contrast, in patients with core binding factor AML, outcomes were excellent with DA + GO with no FLAG-Ida benefit

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries