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Purpose: In the UK, there are over 40,000 childhood cancer survivors (CCS); this figure grows approximately 1300 annually. Two-thirds are at risk of developing serious disabling or life-threatening conditions due to adverse late effects of the cancer or treatment received in childhood. Life-long, follow-up care for the surveillance and management of late effects is recommended. This study explored CCS' views and experiences of long-term follow-up (LTFU) care within a cancer centre., Methods: Paper questionnaires (n = 113) and qualitative interviews (n = 13)., Results: The majority (n = 83, 80%) of CCS reported being satisfied with their LTFU care and felt that it was important to attend long-term survivorship follow-up (n = 97, 86%). However, some were not well informed about their cancer treatment history, purpose for attending the clinic or the potential for late effects. Barriers associated with LTFU included; provision of information, lack of interpersonal relationships, practical and logistic challenges., Conclusions: Barriers identified can be addressed through strategies including provision of verbal and written information and care plans to increase CCS' knowledge of their cancer history, risk of late effects and the purpose of LTFU care, both at transition and throughout their survivorship journey; patient-centred services that enhance patient choice and flexibility of access to multiple specialities; and use of risk stratified pathways to encourage supported self-management based on cancer type, co-morbidity, and level of professional involvement required. Improving regular provision of information at critical time-points, and exploring a flexible, patient-centred delivery of LFTU care based on risk, could increase attendance and self-management in CCS., Competing Interests: Declaration of competing interest The authors declare there are no conflicts of interest for this study., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Over the past few years, a large number of smokers in the UK have stopped smoking with the help of e-cigarettes. So far, UK Stop Smoking Services (SSSs) have been reluctant to include e-cigarettes among their treatment options because data on their efficacy compared with the licensed medications are lacking., Objective: The objective was to compare the efficacy of refillable e-cigarettes and nicotine replacement therapy (NRT) products, when accompanied by weekly behavioural support., Design: A randomised controlled trial comparing e-cigarettes and NRT., Setting: Three sites that provide local SSSs., Participants: The participants were 886 smokers seeking help to quit smoking, aged ≥ 18 years, not pregnant or breastfeeding, with no strong preference to use or not to use NRT or e-cigarettes in their quit attempt, and currently not using NRT or e-cigarettes. A total of 886 participants were randomised but two died during the study (one in each study arm) and were not included in the analysis., Interventions: The NRT arm ( n  = 446) received NRT of their choice (single or combination), provided for up to 12 weeks. The e-cigarette arm ( n  = 438) received an e-cigarette starter pack and were encouraged to buy addtional e-liquids and e-cigarette products of their choice. Both arms received the same standard behavioural support. Participants attended weekly sessions at their SSS and provided outcome data at 4 weeks. They were then followed up by telephone at 6 and 12 months. Participants reporting abstinence or at least 50% reduction in cigarette consumption at 12 months were invited to attend for carbon monoxide (CO) validation. Participants/researchers could not be blinded to the intervention., Main Outcome Measures: The primary outcome was CO-validated sustained abstinence rates at 52 weeks. Participants lost to follow-up or not providing biochemical validation were included as non-abstainers. Secondary outcomes included abstinence at other time points, reduction in smoke intake, treatment adherence and ratings, elicited adverse reactions, and changes in self-reported respiratory health. A cost-efficacy analysis of the intervention was also conducted., Results: The 1-year quit rate was 9.9% in the NRT arm and 18.0% in the e-cigarette arm (risk ratio 1.83, 95% confidence interval 1.30 to 2.58; p  < 0.001). The e-cigarette arm had significantly higher validated quit rates at all time points. Participants in the e-cigarette arm showed significantly better adherence and experienced fewer urges to smoke throughout the initial 4 weeks of their quit attempt than those in the NRT arm, and gave their allocated product more favourable ratings. They were also more likely to be still using their allocated product at 1 year (39.5% vs. 4.3%, χ 2  = 161.4; p  < 0.001). Participants assigned to e-cigarettes reported significantly less coughing and phlegm at 1 year than those assigned to NRT (controlling for smoking status). A detailed economic analysis confirmed that, because e-cigarettes incur lower NHS costs than NRT and generate a higher quit rate, e-cigarette use is more cost-effective., Limitations: The results may not be generalisable to other types of smokers or settings, or to cartridge-based e-cigarettes., Conclusions: Within the context of multisession treatment for smokers seeking help, e-cigarettes were significantly more effective than NRT. If SSSs provide e-cigarette starter packs, it is likely to boost their success rates and improve their cost-efficacy., Future Work: The efficacy of e-cigarettes provided with different levels of support will show whether smokers should be encouraged to switch to vaping within support services or whether e-cigarettes can be recommended with less intensive or no support., Trial Registration: Current Controlled Trials ISRCTN60477608., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 23, No. 43. See the NIHR Journals Library website for further project information. The trial was supported by the Cancer Research UK Prevention Trials Unit (grant A16893)., Competing Interests: Peter Hajek received research funding from, and provided consultancy to, manufacturers of stop smoking medications (Pfizer Inc., New York City, NY, USA). Hayden J McRobbie received a grant from the National Institute for Health Research Health Technology Assessment programme; he also received honoraria for speaking at smoking cessation meetings and attended advisory board meetings organised by Pfizer Inc. and Johnson & Johnson (New Brunswick, NJ, USA). Dunja Przulj received a research grant from Pfizer Inc. Maciej Goniewicz provided consultancy to Johnson & Johnson. Lynne Dawkins reports personal fees from attorneys at law outside the submitted work. Jinshuo Li reports grants from the National Coordinating Centre for Health Technology Assessment (NCCHTA) during the conduct of the study.

Background: Wilms tumour is the most common childhood renal cancer and is genetically heterogeneous. While several Wilms tumour predisposition genes have been identified, there is strong evidence that further predisposition genes are likely to exist. Our study aim was to identify new predisposition genes for Wilms tumour., Methods: In this exome sequencing study, we analysed lymphocyte DNA from 890 individuals with Wilms tumour, including 91 affected individuals from 49 familial Wilms tumour pedigrees. We used the protein-truncating variant prioritisation method to prioritise potential disease-associated genes for further assessment. We evaluated new predisposition genes in exome sequencing data that we generated in 334 individuals with 27 other childhood cancers and in exome data from The Cancer Genome Atlas obtained from 7632 individuals with 28 adult cancers., Findings: We identified constitutional cancer-predisposing mutations in 33 individuals with childhood cancer. The three identified genes with the strongest signal in the protein-truncating variant prioritisation analyses were TRIM28, FBXW7, and NYNRIN. 21 of 33 individuals had a mutation in TRIM28; there was a strong parent-of-origin effect, with all ten inherited mutations being maternally transmitted (p=0·00098). We also found a strong association with the rare epithelial subtype of Wilms tumour, with 14 of 16 tumours being epithelial or epithelial predominant. There were no TRIM28 mutations in individuals with other childhood or adult cancers. We identified truncating FBXW7 mutations in four individuals with Wilms tumour and a de-novo non-synonymous FBXW7 mutation in a child with a rhabdoid tumour. Biallelic truncating mutations in NYNRIN were identified in three individuals with Wilms tumour, which is highly unlikely to have occurred by chance (p<0·0001). Finally, we identified two de-novo KDM3B mutations, supporting the role of KDM3B as a childhood cancer predisposition gene., Interpretation: The four new Wilms tumour predisposition genes identified-TRIM28, FBXW7, NYNRIN, and KDM3B-are involved in diverse biological processes and, together with the other 17 known Wilms tumour predisposition genes, account for about 10% of Wilms tumour cases. The overlap between these 21 constitutionally mutated predisposition genes and 20 genes somatically mutated in Wilms tumour is limited, consisting of only four genes. We recommend that all individuals with Wilms tumour should be offered genetic testing and particularly, those with epithelial Wilms tumour should be offered TRIM28 genetic testing. Only a third of the familial Wilms tumour clusters we analysed were attributable to known genes, indicating that further Wilms tumour predisposition factors await discovery., Funding: Wellcome Trust., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Nicotine preloading means using nicotine replacement therapy prior to a quit date while smoking normally. The aim is to reduce the drive to smoke, thereby reducing cravings for smoking after quit day, which are the main cause of early relapse. A prior systematic review showed inconclusive and heterogeneous evidence that preloading was effective and little evidence of the mechanism of action, with no cost-effectiveness data., Objectives: To assess (1) the effectiveness, safety and tolerability of nicotine preloading in a routine NHS setting relative to usual care, (2) the mechanisms of the action of preloading and (3) the cost-effectiveness of preloading., Design: Open-label randomised controlled trial with examination of mediation and a cost-effectiveness analysis., Setting: NHS smoking cessation clinics., Participants: People seeking help to stop smoking., Interventions: Nicotine preloading comprised wearing a 21 mg/24 hour nicotine patch for 4 weeks prior to quit date. In addition, minimal behavioural support was provided to explain the intervention rationale and to support adherence. In the comparator group, participants received equivalent behavioural support. Randomisation was stratified by centre and concealed from investigators., Main Outcome Measures: The primary outcome was 6-month prolonged abstinence assessed using the Russell Standard. The secondary outcomes were 4-week and 12-month abstinence. Adverse events (AEs) were assessed from baseline to 1 week after quit day. In a planned analysis, we adjusted for the use of varenicline (Champix ® ; Pfizer Inc., New York, NY, USA) as post-cessation medication. Cost-effectiveness analysis took a health-service perspective. The within-trial analysis assessed health-service costs during the 13 months of trial enrolment relative to the previous 6 months comparing trial arms. The base case was based on multiple imputation for missing cost data. We modelled long-term health outcomes of smoking-related diseases using the European-study on Quantifying Utility of Investment in Protection from Tobacco (EQUIPT) model., Results: In total, 1792 people were eligible and were enrolled in the study, with 893 randomised to the control group and 899 randomised to the intervention group. In the intervention group, 49 (5.5%) people discontinued preloading prematurely and most others used it daily. The primary outcome, biochemically validated 6-month abstinence, was achieved by 157 (17.5%) people in the intervention group and 129 (14.4%) people in the control group, a difference of 3.02 percentage points [95% confidence interval (CI) -0.37 to 6.41 percentage points; odds ratio (OR) 1.25, 95% CI 0.97 to 1.62; p  = 0.081]. Adjusted for use of post-quit day varenicline, the OR was 1.34 (95% CI 1.03 to 1.73; p  = 0.028). Secondary abstinence outcomes were similar. The OR for the occurrence of serious AEs was 1.12 (95% CI 0.42 to 3.03). Moderate-severity nausea occurred in an additional 4% of the preloading group compared with the control group. There was evidence that reduced urges to smoke and reduced smoke inhalation mediated the effect of preloading on abstinence. The incremental cost-effectiveness ratio at the 6-month follow-up for preloading relative to control was £710 (95% CI -£13,674 to £23,205), but preloading was dominant at 12 months and in the long term, with an 80% probability that it is cost saving., Limitations: The open-label design could partially account for the mediation results. Outcome assessment could not be blinded but was biochemically verified., Conclusions: Use of nicotine-patch preloading for 4 weeks prior to attempting to stop smoking can increase the proportion of people who stop successfully, but its benefit is undermined because it reduces the use of varenicline after preloading. If this latter effect could be overcome, then nicotine preloading appears to improve health and reduce health-service costs in the long term. Future work should determine how to ensure that people using nicotine preloading opt to use varenicline as cessation medication., Trial Registration: Current Controlled Trials ISRCTN33031001., Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 22, No. 41. See the NIHR Journals Library website for further project information., Competing Interests: All contributors participated in this trial, to which GlaxoSmithKline plc donated free patches. Paul Aveyard is funded by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre and CLAHRC. Peter Hajek and Hayden J McRobbie have provided research and consultancy to several manufacturers of smoking cessation treatments and have been paid for doing so. Tim Coleman is a member of the NIHR Health Technology Assessment Clinical Evaluation and Trials Board. Sarah Lewis is a member of the NIHR Health Services and Delivery Research funding board. Peter Hajek reports a research grant to Queen Mary University of London from Pfizer and personal consultancy fees from Pfizer. Andy McEwen reports grants from Pfizer and hospitality from North 51. Hayden J McRobbie reports a grant and honorarium from Pfizer for speaking at education meetings and an honorarium from Johnson & Johnson for speaking at education meetings and an advisory board meeting.

Objectives: To develop, implement and evaluate a novel patient safety training programme for junior doctors across a Foundation School-'Lessons Learnt: Building a Safer Foundation'., Design, Setting and Participants: Prospective preintervention /postintervention study across 16 Foundation Programmes in North West England, UK. 1169 participants including all Foundation Programme Directors, Administrators, Foundation trainees and senior faculty., Interventions: Half-day stakeholder engagement event and faculty development through recruitment and training of local senior doctors. Foundation trainee-led monthly 60-min sessions integrated into compulsory Foundation teaching from January to July 2011 comprising case-based discussion and analysis of patient safety incidents encountered in practice, facilitated by trained faculty., Main Outcome Measures: Participants' satisfaction and Foundation trainees' patient safety knowledge, skills, attitudes and behavioural change., Results: Participants reported high levels of satisfaction with 'Lessons Learnt'. There was a significant improvement in trainees' objective patient safety knowledge scores (Meanpreintervention=51.1%, SD=17.3%; Meanpostintervention=57.6%, SD=20.1%, p<0.001); subjective knowledge ratings and patient safety skills. Trainees' perceived control and behavioural intentions regarding safety improved significantly postintervention. Feelings and personal beliefs about safety did not shift significantly. Trainees reported significantly more patient safety incidents in the 6 months following introduction of 'Lessons Learnt' (Meanpreintervention=0.67, SD=1.11; Meanpostintervention=1.18, SD=1.46, p<0.001). 32 quality improvement projects were initiated by trainees, spanning the development of novel clinical protocols; implementation of user-informed teaching and improved rota design, Conclusions: Patient safety training can be implemented and sustained to deliver significant improvements in patient safety knowledge, skills and behaviours of junior doctors-with potential for wider positive organisational impact. Medical education commissioners and providers could adopt and build upon the 'Lessons Learnt' approach as a springboard to promote medical engagement in quality and safety improvement.