Novel truncating mutations in CTNND1 cause a dominant craniofacial and cardiac syndrome.

CTNND1 encodes the p120-catenin (p120) protein, which has a wide range of functions, including the maintenance of cell-cell junctions, regulation of the epithelial-mesenchymal transition and transcriptional signalling. Due to advances in next-generation sequencing, CTNND1 has been implicated in human diseases including cleft palate and blepharocheilodontic (BCD) syndrome albeit only recently. In this study, we identify eight novel protein-truncating variants, six de novo, in 13 participants from nine families presenting with craniofacial dysmorphisms including cleft palate and hypodontia, as well as congenital cardiac anomalies, limb dysmorphologies and neurodevelopmental disorders. Using conditional deletions in mice as well as CRISPR/Cas9 approaches to target CTNND1 in Xenopus, we identified a subset of phenotypes that can be linked to p120-catenin in epithelial integrity and turnover, and additional phenotypes that suggest mesenchymal roles of CTNND1. We propose that CTNND1 variants have a wider developmental role than previously described and that variations in this gene underlie not only cleft palate and BCD but may be expanded to a broader velocardiofacial-like syndrome

Lessons learned on recruitment and retention in hard-to-reach families in a phase III randomised controlled trial of preparatory information for children undergoing general anaesthesia

Abstract Background Recruitment and retention are documented as two of the most difficult elements of conducting clinical trials. These issues are even more challenging in paediatric trials, particularly when the families being recruited and retained are deemed ‘hard to reach’. Methods Through the authors’ own reflection on the conduct of the trial this paper examines recruitment and retention with hard to reach families from the perspective of a recently completed clinical trial on preparatory information for children undergoing general anaesthesia for tooth extractions in which approximately 83% of those approached and eligible agreed to participate. Results The lessons learned for recruitment include: the importance of children’s assent; maximising limited resources when screening and approaching potential participants; valuing families’ time; and developing effective professional relationships. The retention rate was 83-85.5% at follow up time points up to 3.5 weeks following recruitment, insights into how this was accomplished include: ensuring continuity of care; determination to connect via telephone; valuing families’ time; and close monitoring of appointment date changes. Conclusions Implications for future paediatric trials with hard to reach families are discussed. Trial registration ISRCTN18265148 ; NIHR Portfolio 10,006. Date of Registration: 29 November 2013. The trial was registered after commencement but before completion of data collection

How families prepare their children for tooth extraction under general anaesthesia: Family and clinical predictors of non-compliance with a ‘serious game’

Objective: To explore family and clinical factors for usage of an online serious game designed to prepare children with ECC for dental treatment under general anaesthesia. Design: Observational study. Secondary data of 60 children, aged 5-to-7, randomised to the intervention group in a phase-III randomised controlled trial [NIHR Portfolio 10006, ISRCTN: 18265148] testing the efficacy of the serious game http://www.scottga.org (available online). Usage was captured automatically, with each click, in real time. The total number of replays and total number of missing slides per game-run performed by the child, were recorded and used to monitor usage. Compliance outcomes were: total time running the game and number of completely missed slides. Results: 57/60 played the game. Median age of parent/carer was 32. For 74% of the families, fathers resided at home and for 65% the parent/carer had A-levels-to-university education. At recruitment, 70% of the children were reported as anxious/highly-fearful and 37% as “significantly psychologically disturbed”. Conclusions: Factors for non-compliance were absence of a father at home (P = 0.01) and higher child-anxiety (P = 0.01) and, to a lesser extent, a low parent/carer education level (P = 0.09). Interactive cartoons featuring dental assessment, oral health messages and modelling featured in the more popular slides.</p

Improving access to preparatory information for children undergoing general anaesthesia for tooth extraction and their families: study protocol for a Phase III randomized controlled trial.

Children can find anaesthesia induction especially distressing and postoperative psychological and physical morbidity are common. Preparation programmes for general anaesthesia (GA) are highly effective in reducing this distress. A Phase II study has already verified the effectiveness of a prototype preoperative GA-coping computer game to help children cope with induction in a dental GA setting. The biggest patient users of pediatric GA services in the UK are children who need to have teeth removed (estimated to be 100,000 yearly). Tooth decay is the most common disease in children worldwide. This study is a Phase III randomized controlled trial (RCT) and will evaluate the effectiveness of the new internet version of this game. Methods/designThe Phase III RCT will use a double-blind three-armed design. The clinical trial will recruit up to 210 children and will compare the web-based game against standard care and another non-medical game. At least 53 patients in each group will be required for 90% statistical power. Distress will be assessed through an evaluation of the child’s behaviour during the visit and later parental reports of physical and psychological morbidity. The satisfaction of parents and children will be measured; the mode of usage of the web-based game will be automatically recorded and the impact on the service (for example, recovery time and throughput) will be reported. The Phase III study primary outcome will measure: (1) patient experience: acceptance of anaesthetic induction, child cooperation and distress, reduction of peri- and postoperative morbidity, child and family satisfaction, and (2) service improvement: anaesthetic time and improvement in throughput. Measures will be administered at baseline, at the time of the GA treatment visit, and at 48 hours and one week postoperatively. DiscussionThis study aims to determine the effectiveness of an online GA-coping game for children and families undergoing tooth extraction under GA. <br/

Lessons learned on recruitment and retention in hard-to-reach families in a phase III randomised controlled trial of preparatory information for children undergoing general anaesthesia

BackgroundRecruitment and retention are documented as two of the most difficult elements of conducting clinical trials. These issues are even more challenging in paediatric trials, particularly when the families being recruited and retained are deemed ‘hard to reach’.MethodsThrough the authors’ own reflection on the conduct of the trial this paper examines recruitment and retention with hard to reach families from the perspective of a recently completed clinical trial on preparatory information for children undergoing general anaesthesia for tooth extractions in which approximately 83% of those approached and eligible agreed to participate.ResultsThe lessons learned for recruitment include: the importance of children’s assent; maximising limited resources when screening and approaching potential participants; valuing families’ time; and developing effective professional relationships. The retention rate was 83-85.5% at follow up time points up to 3.5 weeks following recruitment, insights into how this was accomplished include: ensuring continuity of care; determination to connect via telephone; valuing families’ time; and close monitoring of appointment date changes.ConclusionsImplications for future paediatric trials with hard to reach families are discussed.Trial registrationISRCTN18265148; NIHR Portfolio 10,006. Date of Registration: 29 November 2013. The trial was registered after commencement but before completion of data collection.</p