Search

Background: Conventional systemic drugs are used to treat children and young people (CYP) with severe atopic dermatitis (AD) worldwide, but no robust randomized controlled trial (RCT) evidence exists regarding their efficacy and safety in this population. While novel therapies have expanded therapeutic options, their high cost means traditional agents remain important, especially in lower-resource settings., Objectives: To compare the safety and efficacy of ciclosporin (CyA) with methotrexate (MTX) in CYP with severe AD in the TREatment of severe Atopic Eczema Trial (TREAT) trial., Methods: We conducted a parallel group assessor-blinded RCT in 13 UK and Irish centres. Eligible participants aged 2-16 years and unresponsive to potent topical treatment were randomized to either oral CyA (4 mg kg-1 daily) or MTX (0.4 mg kg-1 weekly) for 36 weeks and followed-up for 24 weeks. Co-primary outcomes were change from baseline to 12 weeks in Objective Severity Scoring of Atopic Dermatitis (o-SCORAD) and time to first significant flare (relapse) after treatment cessation. Secondary outcomes included change in quality of life (QoL) from baseline to 60 weeks; number of participant-reported flares following treatment cessation; proportion of participants achieving ≥ 50% improvement in Eczema Area and Severity Index (EASI 50) and ≥ 75% improvement in EASI (EASI 75); and stratification of outcomes by filaggrin status., Results: In total, 103 participants were randomized (May 2016-February 2019): 52 to CyA and 51 to MTX. CyA showed greater improvement in disease severity by 12 weeks [mean difference in o-SCORAD -5.69, 97.5% confidence interval (CI) -10.81 to -0.57 (P = 0.01)]. More participants achieved ≥ 50% improvement in o-SCORAD (o-SCORAD 50) at 12 weeks in the CyA arm vs. the MTX arm [odds ratio (OR) 2.60, 95% CI 1.23-5.49; P = 0.01]. By 60 weeks MTX was superior (OR 0.33, 95% CI 0.13-0.85; P = 0.02), a trend also seen for ≥ 75% improvement in o-SCORAD (o-SCORAD 75), EASI 50 and EASI 75. Participant-reported flares post-treatment were higher in the CyA arm (OR 3.22, 95% CI 0.42-6.01; P = 0.02). QoL improved with both treatments and was sustained after treatment cessation. Filaggrin status did not affect outcomes. The frequency of adverse events (AEs) was comparable between both treatments. Five (10%) participants on CyA and seven (14%) on MTX experienced a serious AE., Conclusions: Both CyA and MTX proved effective in CYP with severe AD over 36 weeks. Participants who received CyA showed a more rapid response to treatment, while MTX induced more sustained disease control after discontinuation., Competing Interests: Conflicts of interest C.F. is Chief Investigator of the UK National Institute for Health Research-funded TREAT (ISRCTN15837754) and SOFTER (ClinicalTrials.gov: NCT03270566) trials, as well as the UK–Irish Atopic eczema Systemic Therapy Register (A-STAR; ISRCTN11210918) and a Principal Investigator in the European Union (EU) Horizon 2020-funded BIOMAP Consortium (http://www.biomap-imi.eu). He also leads the EU Trans-Foods consortium. His department has received investigator-led funding from Sanofi-Genzyme and Pfizer for microbiome work. D.O’K. has received funding for advisory board participation with Sanofi-Genzyme. M.W. is a steering committee member of A-STAR (ISRCTN11210918). T.M. has received funding for advisory boards and teaching from Sanofi-Genzyme, AbbVie and Pfizer. M.J.C. has received investigator-led funding from Hyphens Pharma, Johnson & Johnson, Sanofi, L’Oréal, LEO Pharma, ACO Nordic, Pfizer, Regeneron and Sanofi-Genzyme, as well as funding for advisory board participation with Menlo. He has also received consultant fees from Boots, Eli Lilly and Procter & Gamble. S.J.B. is a medical advisor to the Ichthyosis Support Group and Eczema Outreach Support and has received funding from the Wellcome Trust. A.D.I. has received consulting fees from Area, Almirall, AbbVie, Pfizer, Eli Lilly and Sanofi-Regeneron, and is the Director of the International Eczema Council. A.R.-H., A.P.J., B.R.T., C.S., M.-L.L., E. Hilger, M.D.S., F.A., F.B., D.G., P.B., B.E., J.E.G., S.A., S.B., P.R.W., L.S.T., R.H., T.H.S., E. Howard, J.R. and L.S. declare no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Background: Poor body image is prevalent among adolescents and associated with several negative outcomes for their physical and psychological health. There is a pressing need to address this growing public health concern, yet there are few evidence-informed universal programmes for older adolescents that address contemporary body image concerns (i.e., social media). BodyKind is a four lesson, school-based, teacher led, universal body image programme that incorporates empirically supported principles of cognitive dissonance, self-compassion, compassion for others and social activism, to support positive body image development. Building on previous pilot trials in the USA, this paper outlines the protocol for a cluster randomised control trial (cRCT) and implementation evaluation of the BodyKind programme which was culturally adapted for the Irish cultural context., Methods: We aim to recruit 600 students aged 15-17 years in Transition Year (4 th year) across 26 second-level schools in Ireland. Using minimisation, schools will be randomly assigned to receive BodyKind (intervention condition, n=300) or classes as usual (waitlist control, n=300). Teachers in intervention groups will receive training and deliver the programme to students over four weeks, at a rate of one lesson per week. Primary outcomes of body appreciation, body dissatisfaction and psychological wellbeing and secondary outcomes of self-compassion, compassion for others, body ideal internalisation, social justice motives and appearance-based social media use will be assessed at pre-, post- and 2 month follow up. Mediation and moderation analyses will be conducted to identify how and for whom the intervention works best. An implementation evaluation will assess the quality of programme implementation across schools and how this may influence intervention outcomes. Waitlist control schools will receive the programme after the 2-month follow up., Conclusion: This study will be the first to implement a cRCT and an implementation evaluation to assess the impact of this multicomponent school-based body image programme designed to support healthy body image development. If shown to be effective, BodyKind will have the potential to improve adolescent body image and wellbeing and inform efforts to implement sustainable and scalable programmes in schools., Trial Registration: The trial was retrospectively registered on 10/10/2023 on ClinicalTrials.gov NCT06076993 ., (© 2023. The Author(s).)

Background: Psychological and mental health difficulties are common in children and young people (CYP) living with skin conditions and can have a profound impact on wellbeing. There is limited guidance on how best to assess and support the mental health of this population, who are at risk of poor health outcomes., Objectives: To provide consensus-based recommendations on the assessment and monitoring of and support for mental health difficulties in CYP with skin conditions (affecting the skin, hair and nails); to address practical clinical implementation questions relating to consensus guidance; and to provide audit and research recommendations., Methods: This set of recommendations was developed with reference to the AGREE II instrument. A systematic review and literature appraisal was carried out. A multidisciplinary consensus group was convened, with two virtual panel meetings held: an initial meeting to discuss the scope of the study, to review the current evidence and to identify areas for development; and a second meeting to agree on the content and wording of the recommendations. Recommendations were then circulated to stakeholders, following which amendments were made and agreed by email., Results: The expert panel achieved consensus on 11 recommendations for healthcare workers managing CYP with skin conditions. A new patient-completed history-taking aid ('You and Your Skin') was developed and is being piloted., Conclusions: The recommendations focus on improved mental health assessments for CYP presenting with a skin condition, with clinical guidance and suggested screening measures included. Information on accessing psychological support for CYP, when required, is given, and recommendations for staff training in mental health and neurodiversity provided. Embedding a psychosocial approach within services treating CYP with skin disease should ensure that CYP with psychological needs are able to be identified, listened to, supported and treated. This is likely to improve health outcomes., Competing Interests: Conflicts of interest: T.McP. reported personal fees from Sanofi, AbbVie and L’Oreal outside the submitted work and is Trustee of Dipex Charity, being Lead Clinician on the Skins section of their patient experiences site Healthtalk.org and Expert Advisor to NICE and MHRA for matters relating to dermatology. J.R. is Expert Advisor to NICE and MHRA for matters relating to dermatology and Medical Advisor to Nottingham Eczema Support Group. R.A. reported personal fees from Pfizer, AbbVie and Sanofi outside the submitted work. R.B. reported personal fees from UCB outside the submitted work and is Chairperson for Action for XP and Trainee Representative for Psychoderm UK. P.B. reported personal fees from AbbVie, Pfizer, Novartis and L’Oreal outside the submitted work. A.B. reported grants and personal fees from AbbVie, Almirall, Bayer, Bristol Myers Squibb, Galderma, Janssen, LEO Pharma, Lilly, Novartis, Pfizer, Sanofi and UCB outside the submitted work and was Editor of Practical Psychodermatology (Wiley, 2014) and Psychodermatology in Clinical Practice (Springer), and was Chairman of Psychodermatology UK (2008–2020). T.B. is Clinical Director of NHSE for outpatient transformation and past President of British Association of Dermatologists (2020–2022). S.C. reported personal fees from Galderma, LEO and Incyte UK outside the submitted work, and is the Chair of Dermatology Council for England and of Derma and is Trustee for the British Dermatological Nursing Group (2018–current). T.C. is Executive Chair and author of the Primary Care Dermatology Society website and has undertaken work with the MHRA on isotretinoin. E.H. is Trustee of Changing Faces Charity. A.L. is Head of Services of the National Eczema Society. P.M. is Committee Member of Psychodermatology UK. C.M. is on the medical advisory board for National Eczema Society and Ichthyosis Support Group. G.N. is cofounder of Anathem and reported no conflicts of interest related to this work. A.P. is Chief Executive of the National Eczema Society. C.R. is past Chief Executive Officer of Eczema Outreach Support. S.S. reported personal fees from Pfizer outside the submitted work. J.S. is Expert Advisor to NICE on matters relating to paediatric dermatology and Medical Advisor to Nottingham Eczema Support Group. S.B. reported personal fees from AbbVie, Sanofi and Pfizer outside the submitted work and is Expert Advisor to MHRA on Dermatology matters and Co-Chair of Psychodermatology UK. No other disclosures were reported., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

With increasing concerns around student mental health, student counseling services (SCSs) in higher education are being challenged to show evidence of their contribution to the personal and academic development of students through evidence-based approaches including systematic data collection and standardized outcome measurement. This study aims to document data collection and measurement processes in SCSs in higher education institutions (HEIs) in Ireland and to explore the opinions of staff in SCSs on the feasibility and functionality of a standardized national database for SCSs to enhance robust data collection and measurement across the sector. Twenty-three interviews were conducted and thematically analyzed with staff in SCSs in 22 HEIs (85% of publicly funded HEIs). Findings revealed that the process of data collection in SCSs is mainly focused on individual counseling with variations among SCSs in collecting clients' demography, presenting issues, and clinical and educational outcomes. Lack of human and financial resources, no access to an electronic data management system, negative opinions about standardized outcome measures, and concerns over data protection and misuse of data were impeding factors for systematic data collection in SCSs. There is strong support among SCSs for the establishment of a national database which is facilitated by secured funding from the Higher Education Authority, a strong sense of community and trust among student counselors, and a history of data collection through the Psychological Counsellors in Higher Education Ireland association. Findings offer insights into challenges and facilitators for robust data collection and measurement at a national level. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Research has documented relationships between individual health behaviours and mental health, but few studies have examined patterns of health behaviours (i.e., health lifestyles) and mental health outcomes. This study investigated the relationship between health lifestyles and mental health and psychological wellbeing in adolescents. Data from the My World Survey 2 - Second Level (MWS2-SL), a random national sample of 9493 adolescents (44.2% male) aged 12-18 years (M = 14.8, SD = 1.66) in second level education in Ireland were used. TwoStep cluster analysis identified clustering of health behaviours (sleep, alcohol use, cannabis use, social media use, sport and hobby participation). ANOVA and Chi Square tests identified potential differences in demographic characteristics (age, gender, socioeconomic status, ethnicity) and psychological outcomes (anxiety, depression, life satisfaction, daily functioning) across clusters. Three clusters were identified; 1. Low (22.0%), 2. Moderate-high (41.5%) and 3. High (36.5%), health promoting. The 'Low' health-promoting cluster, characterised by high alcohol, cannabis and social media use, moderate sport and hobby participation, and low sleep duration, demonstrated the highest levels of anxiety and depression and the lowest levels of life satisfaction, self-esteem and daily functioning. The 'High' health-promoting cluster reported the most favourable psychological outcomes. Cluster 1 were more likely to be older and male, Cluster 3 were more likely to be younger and female. Findings demonstrate the potential for health promotive lifestyles to mitigate mental health difficulties and promote life satisfaction and daily functioning in adolescents. Health lifestyles represent important indicators of mental health and targets for prevention/promotion efforts., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Student counselling services are at the forefront of providing mental health support to Irish Higher Education students. Since 1996, the Psychological Counsellors in Higher Education in Ireland (PCHEI) association, through their annual survey collection, has collected aggregate data for the sector. However, to identify national trends and effective interventions, a standardised non-aggregate sectoral approach to data collection is required. The Higher Education Authority funded project, 3SET, builds on the PCHEI survey through the development of a national database. In this paper, we outline the steps followed in developing the database, identify the parties involved at each stage and contrast the approach taken to the development of similar databases. Important factors shaping the development have been the autonomy of counselling services, compliance with General Data Protection Regulation, and the involvement of practitioners. This is an ongoing project with the long-term sustainability of the database being a primary objective.

Objective: To determine the prevalence of cardiac abnormalities and their relationship to markers of myocardial injury and mortality in patients admitted to hospital with COVID-19., Methods: A retrospective and prospective observational study of inpatients referred for transthoracic echocardiography for suspected cardiac pathology due to COVID-19 within a London NHS Trust. Echocardiograms were performed to assess left ventricular (LV), right ventricular (RV) and pulmonary variables along with collection of patient demographics, comorbid conditions, blood biomarkers and outcomes., Result: In the predominant non-white (72%) population, RV dysfunction was the primary cardiac abnormality noted in 50% of patients, with RV fractional area change <35% being the most common marker of this RV dysfunction. By comparison, LV systolic dysfunction occurred in 18% of patients. RV dysfunction was associated with LV systolic dysfunction and the presence of a D-shaped LV throughout the cardiac cycle (marker of significant pulmonary artery hypertension). LV systolic dysfunction (p=0.002, HR 3.82, 95% CI 1.624 to 8.982), pulmonary valve acceleration time (p=0.024, HR 0.98, 95% CI 0.964 to 0.997)-marker of increased pulmonary vascular resistance, age (p=0.047, HR 1.027, 95% CI 1.000 to 1.055) and an episode of tachycardia measured from admission to time of echo (p=0.004, HR 6.183, 95% CI 1.772 to 21.575) were independently associated with mortality., Conclusions: In this predominantly non-white population hospitalised with COVID-19, the most common cardiac pathology was RV dysfunction which is associated with both LV systolic dysfunction and elevated pulmonary artery pressure. The latter two, not RV dysfunction, were associated with mortality., Competing Interests: Competing interests: Professor Senior was given speaker fees by Bracco, Milan, Italy, Lantheus Medical Imaging, Boston, Massachusetts and Philips Healthcare, Eindhoven, Holland., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Aims: Postprandial responses are influenced not only by the type and amount of fat ingested, but also lipid droplet size distribution. However, little research has investigated the impact of differential lipid size distributions within a mixed-macronutrient meal context on postprandial vascular health. Therefore, we examined whether manipulating the lipid droplet size distribution within a mixed-macronutrient meal impacts vascular-inflammatory and thrombotic parameters., Methods and Results: In a randomised and counterbalanced fashion, sixteen adults (8 males; age 34 ± 7 years; BMI of 25.3 ± 4.5 kg/m 2 ) completed three separate fasted morning-time feeding challenges, each separated by a minimum washout of 7-days. On each occasion, test-meals matched for carbohydrate and protein content differing only in fat amount and the lipid droplet size distribution were administered, such that participants consumed (1) a low-fat meal (LF) with negligible fat content, (2) an emulsified-high-fat meal with a fine lipid droplet size (FE), or (3) an emulsified-high-fat meal with a coarse lipid droplet size (CE). Periodic blood samples were retrospectively analysed for plasma triglycerides, tumour necrosis factor alpha (TNFα), tissue factor (TF), fibrinogen, and plasminogen activator inhibitor-1 (PAI-1). Triglyceride concentrations increased rapidly overtime under FE (P-time<0.05); this rise was attenuated under CE (P-time>0.05) and was comparable to LF (P-condition>0.05). Similarly, FE induced a significant rise in TNFα, TF, fibrinogen, and PAI-1 (P-time<0.05); these parameters remained unchanged under LF and CE (P-time>0.05)., Conclusion: A high-fat mixed-macronutrient meal with a larger lipid droplet size distribution ameliorates the associated rise in vascular-inflammatory and thrombotic parameters., Trial Registration: ISRCTN88881254., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

This study evaluates the relationship between pregnancy, comorbid conditions and giant cell tumour of bone. Furthermore, it examines if pregnancy and comorbid conditions affect the outcome following treatment for this tumour. A multi-centre retrospective review was conducted of consecutive patients with a confirmed histological diagnosis of giant cell tumour of bone between June 2012 and May 2017. A total of 195 patients were identified from two centres. Of these, 168 patients were treated with curative intent and had more than six months follow-up. Data were collected on pregnancy status, comorbid conditions, site of disease, surgical management and local recurrence rates. Statistical analysis included the Fisher exact test and Kaplan-Meier survival analysis. There were 72 females of childbearing age, of which 15 (21%) were currently pregnant or had been pregnant within the last six months. The pregnancy rate is higher than the highest reported pregnancy rate over the last 10 years (8.4%; Fisher test, p = 0.033). Women were more likely to have a comorbid condition than men (Fisher test, p < 0.002) and had a higher rate of autoimmune disease than the normal population (p = 0.015). Men were older than women (Wilcoxon test, p = 0.046) and had less risk of local recurrence (logrank test, p = 0.014). Pregnancy or comorbid conditions did not increase the local recurrence rate. Predictors for local recurrence included location in the distal radius (logrank test, p < 0.001), intralesional treatment (logrank test, p = 0.008) and age less than 40 (logrank test, p = 0.043). In conclusion, giant cell tumour of bone is more common in pregnant females and patients with immune disease. Comorbidities and pregnancy do not affect the local recurrence rate. Male patients over 40 years of age have a lower risk of local recurrence, and patients with disease in the distal radius have a high risk of recurrence., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Howard et al.)

Introduction The aim of this study was to evaluate radiological measurements to establish the origin of giant cell tumours of bone. Methods A multi-centre retrospective review was conducted of patients with histologically confirmed giant cell tumours of bone. Images were analysed to estimate the centre of the tumour. Measured from the joint line, the ratio between the distance of the centre of the tumour and the physeal scar was calculated. Results Ninety-five patients were included in the study. Two observers found the tumour to be arising from the metaphyseal area in 94% - 97% of the cases. There was good agreement between the measurements of observers (interclass correlation coefficient 0.71). Conclusion  Giant cell tumours of bone appear to be arising from the metaphyseal region., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Howard et al.)

Background: Medical schools differ, particularly in their teaching, but it is unclear whether such differences matter, although influential claims are often made. The Medical School Differences (MedDifs) study brings together a wide range of measures of UK medical schools, including postgraduate performance, fitness to practise issues, specialty choice, preparedness, satisfaction, teaching styles, entry criteria and institutional factors., Method: Aggregated data were collected for 50 measures across 29 UK medical schools. Data include institutional history (e.g. rate of production of hospital and GP specialists in the past), curricular influences (e.g. PBL schools, spend per student, staff-student ratio), selection measures (e.g. entry grades), teaching and assessment (e.g. traditional vs PBL, specialty teaching, self-regulated learning), student satisfaction, Foundation selection scores, Foundation satisfaction, postgraduate examination performance and fitness to practise (postgraduate progression, GMC sanctions). Six specialties (General Practice, Psychiatry, Anaesthetics, Obstetrics and Gynaecology, Internal Medicine, Surgery) were examined in more detail., Results: Medical school differences are stable across time (median alpha = 0.835). The 50 measures were highly correlated, 395 (32.2%) of 1225 correlations being significant with p < 0.05, and 201 (16.4%) reached a Tukey-adjusted criterion of p < 0.0025. Problem-based learning (PBL) schools differ on many measures, including lower performance on postgraduate assessments. While these are in part explained by lower entry grades, a surprising finding is that schools such as PBL schools which reported greater student satisfaction with feedback also showed lower performance at postgraduate examinations. More medical school teaching of psychiatry, surgery and anaesthetics did not result in more specialist trainees. Schools that taught more general practice did have more graduates entering GP training, but those graduates performed less well in MRCGP examinations, the negative correlation resulting from numbers of GP trainees and exam outcomes being affected both by non-traditional teaching and by greater historical production of GPs. Postgraduate exam outcomes were also higher in schools with more self-regulated learning, but lower in larger medical schools. A path model for 29 measures found a complex causal nexus, most measures causing or being caused by other measures. Postgraduate exam performance was influenced by earlier attainment, at entry to Foundation and entry to medical school (the so-called academic backbone), and by self-regulated learning. Foundation measures of satisfaction, including preparedness, had no subsequent influence on outcomes. Fitness to practise issues were more frequent in schools producing more male graduates and more GPs., Conclusions: Medical schools differ in large numbers of ways that are causally interconnected. Differences between schools in postgraduate examination performance, training problems and GMC sanctions have important implications for the quality of patient care and patient safety.

Background: What subjects UK medical schools teach, what ways they teach subjects, and how much they teach those subjects is unclear. Whether teaching differences matter is a separate, important question. This study provides a detailed picture of timetabled undergraduate teaching activity at 25 UK medical schools, particularly in relation to problem-based learning (PBL)., Method: The Analysis of Teaching of Medical Schools (AToMS) survey used detailed timetables provided by 25 schools with standard 5-year courses. Timetabled teaching events were coded in terms of course year, duration, teaching format, and teaching content. Ten schools used PBL. Teaching times from timetables were validated against two other studies that had assessed GP teaching and lecture, seminar, and tutorial times., Results: A total of 47,258 timetabled teaching events in the academic year 2014/2015 were analysed, including SSCs (student-selected components) and elective studies. A typical UK medical student receives 3960 timetabled hours of teaching during their 5-year course. There was a clear difference between the initial 2 years which mostly contained basic medical science content and the later 3 years which mostly consisted of clinical teaching, although some clinical teaching occurs in the first 2 years. Medical schools differed in duration, format, and content of teaching. Two main factors underlay most of the variation between schools, Traditional vs PBL teaching and Structured vs Unstructured teaching. A curriculum map comparing medical schools was constructed using those factors. PBL schools differed on a number of measures, having more PBL teaching time, fewer lectures, more GP teaching, less surgery, less formal teaching of basic science, and more sessions with unspecified content., Discussion: UK medical schools differ in both format and content of teaching. PBL and non-PBL schools clearly differ, albeit with substantial variation within groups, and overlap in the middle. The important question of whether differences in teaching matter in terms of outcomes is analysed in a companion study (MedDifs) which examines how teaching differences relate to university infrastructure, entry requirements, student perceptions, and outcomes in Foundation Programme and postgraduate training.

The aim of this study was to investigate if the risk of pathological fracture can be predicted with the proportion of body weight that can be put through the affected leg in patients with metastatic bone disease of the lower limb. A prospective observational study was conducted in patients with metastatic disease in the lower limb. Receiver Operator Characteristic curves were used to identify the optimum threshold level of single stance weight bearing to predict fracture and compared to the Mirels score. Patients who underwent surgery could weight bear significantly less than those who did not have surgical intervention. The optimum threshold to predict pathological fracture was 85% of total body weight. No patient below the threshold level of 85% single stance body weight sustained a pathological fracture. The use of single stance body weight can be a useful in conjunction with the Mirels score to predict pathological fracture. If less than 85% of total body weight can be put through the affected limb, the risk of fracture increases, and consideration of treatment is suggested.

Colloidal quantum dots have garnered significant interest in optoelectronics, particularly in quantum dot solar cells (QDSCs). Here we report QDSCs fabricated using a ligand that is modified, following film formation, such that it becomes an efficient hole transport layer. The ligand, O-((9H-fluoren-9-yl)methyl) S-(2-mercaptoethyl) carbonothioate (FMT), contains the surface ligand 1,2-ethanedithiol (EDT) protected at one end using fluorenylmethyloxycarbonyl (Fmoc). The strategy enables deprotection following colloidal deposition, producing films containing quantum dots whose surfaces are more thoroughly covered with the remaining EDT molecules. To compare fabrication methods, we deposited CQDs onto the active layer: in one case, the traditional EDT-PbS/EDT-PbS is used, while in the other EDT-PbS/FMT-PbS is used. The devices based on the new EDT/FMT match the PCE values of EDT/EDT controls, and maintain a higher PCE over an 18 day storage interval, a finding we attribute to an increased thiol coverage using the FMT protocol.

Background: Guidelines recommend walking to increase moderate to vigorous physical activity (MVPA) for health benefits., Objectives: To assess the effectiveness, cost-effectiveness and acceptability of a pedometer-based walking intervention in inactive adults, delivered postally or through dedicated practice nurse physical activity (PA) consultations., Design: Parallel three-arm trial, cluster randomised by household., Setting: Seven London-based general practices., Participants: A total of 11,015 people without PA contraindications, aged 45-75 years, randomly selected from practices, were invited. A total of 6399 people were non-responders, and 548 people self-reporting achieving PA guidelines were excluded. A total of 1023 people from 922 households were randomised to usual care ( n  = 338), postal intervention ( n  = 339) or nurse support ( n  = 346). The recruitment rate was 10% (1023/10,467). A total of 956 participants (93%) provided outcome data., Interventions: Intervention groups received pedometers, 12-week walking programmes advising participants to gradually add '3000 steps in 30 minutes' most days weekly and PA diaries. The nurse group was offered three dedicated PA consultations., Main Outcome Measures: The primary and main secondary outcomes were changes from baseline to 12 months in average daily step counts and time in MVPA (in ≥ 10-minute bouts), respectively, from 7-day accelerometry. Individual resource-use data informed the within-trial economic evaluation and the Markov model for simulating long-term cost-effectiveness. Qualitative evaluations assessed nurse and participant views. A 3-year follow-up was conducted., Results: Baseline average daily step count was 7479 [standard deviation (SD) 2671], average minutes per week in MVPA bouts was 94 minutes (SD 102 minutes) for those randomised. PA increased significantly at 12 months in both intervention groups compared with the control group, with no difference between interventions; additional steps per day were 642 steps [95% confidence interval (CI) 329 to 955 steps] for the postal group and 677 steps (95% CI 365 to 989 steps) for nurse support, and additional MVPA in bouts (minutes per week) was 33 minutes per week (95% CI 17 to 49 minutes per week) for the postal group and 35 minutes per week (95% CI 19 to 51 minutes per week) for nurse support. Intervention groups showed no increase in adverse events. Incremental cost per step was 19p and £3.61 per minute in a ≥ 10-minute MVPA bout for nurse support, whereas the postal group took more steps and cost less than the control group. The postal group had a 50% chance of being cost-effective at a £20,000 per quality-adjusted life-year (QALY) threshold within 1 year and had both lower costs [-£11M (95% CI -£12M to -£10M) per 100,000 population] and more QALYs [759 QALYs gained (95% CI 400 to 1247 QALYs)] than the nurse support and control groups in the long term. Participants and nurses found the interventions acceptable and enjoyable. Three-year follow-up data showed persistent intervention effects (nurse support plus postal vs. control) on steps per day [648 steps (95% CI 272 to 1024 steps)] and MVPA bouts [26 minutes per week (95% CI 8 to 44 minutes per week)]., Limitations: The 10% recruitment level, with lower levels in Asian and socioeconomically deprived participants, limits the generalisability of the findings. Assessors were unmasked to the group., Conclusions: A primary care pedometer-based walking intervention in 45- to 75-year-olds increased 12-month step counts by around one-tenth, and time in MVPA bouts by around one-third, with similar effects for the nurse support and postal groups, and persistent 3-year effects. The postal intervention provides cost-effective, long-term quality-of-life benefits. A primary care pedometer intervention delivered by post could help address the public health physical inactivity challenge., Future Work: Exploring different recruitment strategies to increase uptake. Integrating the Pedometer And Consultation Evaluation-UP (PACE-UP) trial with evolving PA monitoring technologies., Trial Registration: Current Controlled Trials ISRCTN98538934., 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. 22, No. 37. See the NIHR Journals Library website for further project information., Competing Interests: Lee David is the director of 10 Minute CBT. She helped to develop Pedometer And Consultation Evaluation-UP (PACE-UP) patient resources and training for the PACE-UP nurses and received personal fees from 10 Minute CBT during the conduct of this study. Tess Harris is a member of the National Institute for Health Research (NIHR) Health Technology Assessment Primary Care and Community Preventative Interventions panel. Julia Fox-Rushby reports grants from the NIHR and membership of the Public Health Research Research Funding Board during the conduct of the study. Katy Morgan’s salary was funded through a NIHR research methods fellowship (reference number MET-12-16), during the conduct of the study.

Humans feel a sense of agency over the effects their motor system causes. This is the case for manual actions such as pushing buttons, kicking footballs, and all acts that affect the physical environment. We ask whether initiating joint attention - causing another person to follow our eye movement - can elicit an implicit sense of agency over this congruent gaze response. Eye movements themselves cannot directly affect the physical environment, but joint attention is an example of how eye movements can indirectly cause social outcomes. Here we show that leading the gaze of an on-screen face induces an underestimation of the temporal gap between action and consequence (Experiments 1 and 2). This underestimation effect, named 'temporal binding,' is thought to be a measure of an implicit sense of agency. Experiment 3 asked whether merely making an eye movement in a non-agentic, non-social context might also affect temporal estimation, and no reliable effects were detected, implying that inconsequential oculomotor acts do not reliably affect temporal estimations under these conditions. Together, these findings suggest that an implicit sense of agency is generated when initiating joint attention interactions. This is important for understanding how humans can efficiently detect and understand the social consequences of their actions., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: The PACE-UP trial demonstrated positive effects of a pedometer-based walking intervention on objective physical activity (PA) outcomes at three and 12 months in 45-75-year-old primary care patients, in postal and nurse-supported trial arms compared with controls. We explored associations between process evaluation measures and change in PA outcomes., Methods: The MRC framework guided process evaluation. Three quantitative measures (nurse session attendance [dose delivered], PA diary completion [fidelity] and pedometer use [fidelity]) were selected as independent variables in multi-level models estimating intervention effectiveness on PA outcomes (changes in step-counts and time in moderate-to-vigorous PA [MVPA] levels in ≥ 10-min bouts)., Results: Dose: attending all three nurse sessions compared with 0-2 sessions was associated with an increase in steps/day at three and 12 months of 1197 (95% confidence interval [CI] = 627-1766) and 605 (95% CI = 74-1137), respectively; and MVPA in bouts (min/week) at three and 12 months by 74 (95% CI = 45-103) and 30 (95% CI = 3-57), respectively. Fidelity: postal and nurse groups showed strong positive associations of diary return with steps/day at three months: postal 1458 (95% CI = 854-2061), nurse 873 (95% CI = 190-1555). MVPA in bouts (min/week): postal 64 (95% CI = 33-94), nurse 50 (95% CI = 15-85). At 12 months, only the postal group effects remained statistically significant: steps/day 1114 (95% CI = 538-1689), MVPA 47 (95% CI = 18-75). Regular pedometer use in the postal group only was associated with higher three-month and 12-month steps/day: 1029 (95% CI = 383-1675) and 606 (95% CI = 22-1190), respectively, and with MVPA in bouts at three months: 40 (95% CI = 6-73)., Conclusion: Process evaluation measures demonstrated significant associations with PA outcomes at three and 12 months. We cannot infer causality, but the associations between the process measures and PA outcomes suggest that they were important in enabling the trial changes observed and should be considered core components of the PACE-UP nurse and postal interventions. We have shown the MRC framework to be a useful tool for process evaluation of intervention implementation., Trial Registration: ISRCTN Registry, ISRCTN98538934 . Registered on 2 March 2012.

Young people often experience worse health outcomes and more dissatisfaction with healthcare compared with other age groups. This survey sought to determine the state of adolescent and young adult health training across medical specialties in the UK. An online questionnaire was distributed to higher specialty trainees in adult medical specialties. Training in adolescent/young adult health/transition was rated as minimal/non-existent by 70/73% of respondents, respectively; 52% reported that they had received no formal training and 61% had never attended a dedicated young person's or transition clinic. The most significant barrier to delivering good adolescent and young adult healthcare was felt to be lack of training to deal with adolescent issues. This survey has identified a 'training gap'; a lack of preparation to meet the specific care needs of the adolescent and young adult population. Improved interventions are required to help drive improvement in care for young people in the UK.

We present the case of a 46-year-old commercial pilot with a history of unilateral leg swelling following a flight to Geneva. Although initial clinical examination suggested a deep vein thrombosis, the swelling only partially resolved with anticoagulation and further imaging suggested the presence of adventitial cystic disease (ACD). The patient underwent initial anticoagulation to allow any thrombus to be lysed, followed by excision of the ACD from the venous wall and venous reconstruction. Following the excision of the ACD, providing the patient remains asymptomatic and further imaging finds normal venous anatomy, we hope the patient will discontinue anticoagulation and return to flying., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Pedometers can increase walking and moderate-to-vigorous physical activity (MVPA) levels, but their effectiveness with or without support has not been rigorously evaluated. We assessed the effectiveness of a pedometer-based walking intervention in predominantly inactive adults, delivered by post or through primary care nurse-supported physical activity (PA) consultations., Methods and Findings: A parallel three-arm cluster randomised trial was randomised by household, with 12-mo follow-up, in seven London, United Kingdom, primary care practices. Eleven thousand fifteen randomly selected patients aged 45-75 y without PA contraindications were invited. Five hundred forty-eight self-reporting achieving PA guidelines were excluded. One thousand twenty-three people from 922 households were randomised between 2012-2013 to one of the following groups: usual care (n = 338); postal pedometer intervention (n = 339); and nurse-supported pedometer intervention (n = 346). Of these, 956 participants (93%) provided outcome data (usual care n = 323, postal n = 312, nurse-supported n = 321). Both intervention groups received pedometers, 12-wk walking programmes, and PA diaries. The nurse group was offered three PA consultations. Primary and main secondary outcomes were changes from baseline to 12 mo in average daily step-counts and time in MVPA (in ≥10-min bouts), respectively, measured objectively by accelerometry. Only statisticians were masked to group. Analysis was by intention-to-treat. Average baseline daily step-count was 7,479 (standard deviation [s.d.] 2,671), and average time in MVPA bouts was 94 (s.d. 102) min/wk. At 12 mo, mean steps/d, with s.d. in parentheses, were as follows: control 7,246 (2,671); postal 8,010 (2,922); and nurse support 8,131 (3,228). PA increased in both intervention groups compared with the control group; additional steps/d were 642 for postal (95% CI 329-955) and 677 for nurse support (95% CI 365-989); additional MVPA in bouts (min/wk) were 33 for postal (95% CI 17-49) and 35 for nurse support (95% CI 19-51). There were no significant differences between the two interventions at 12 mo. The 10% (1,023/10,467) recruitment rate was a study limitation., Conclusions: A primary care pedometer-based walking intervention in predominantly inactive 45- to 75-y-olds increased step-counts by about one-tenth and time in MVPA in bouts by about one-third. Nurse and postal delivery achieved similar 12-mo PA outcomes. A primary care pedometer intervention delivered by post or with minimal support could help address the public health physical inactivity challenge., Clinical Trial Registration: isrctn.com ISRCTN98538934., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: (1) LD reports personal fees from 10-minute CBT (a commercial organisation providing behaviour change training) during the conduct of this study and outside the submitted work; (2) NA reports grants from Department of Health, Sports England, NIHR, Sheffield University, and NICE, outside the submitted work. He is/has been involved as a researcher on the following projects: Age- and lifestyle-related chronic disease and causes of death among adults with cerebral palsy in the United Kingdom. Brunel University, Research Interdisciplinary Award. An examination of the feasibility of an economic evaluation of resistance training for adolescents with cerebral palsy. Brunel University. Research idea Award. (3) JFR reports grants from NIHR, Department of Health, Sports England, MacMillan, and NICE, outside the submitted work. The other authors declare no conflicts of interest. All authors have completed the ICMJE Unified Competing Interest form (available on request from the corresponding author).

We investigated the effect of effort on implicit agency ascription for actions performed under varying levels of physical effort or cognitive load. People are able to estimate the interval between two events accurately, but they underestimate the interval between their own actions and their outcomes. This effect is known as 'intentional binding', and may provide feedback regarding the consequences of our actions. Concurrently with the interval reproduction task, our participants pulled sports resistance bands at high and low resistance levels (Experiments 1 and 2), or performed a working memory task with high and low set-sizes (Experiment 3). Intentional binding was greater under low than high effort. When the effort was task-related (Experiment 1), this effect depended on the individual's explicit appraisal of exertion, while the effect of effort was evident at the group level when the effort was task-unrelated (physical, Experiment 2; mental, Experiment 3). These findings imply that the process of intentional binding is compromised when cognitive resources are depleted, either through physical or mental strain. We discuss this notion in relation to the integration of direct sensorimotor feedback with signals of agency and other instances of cognitive resource depletion and action control during strain., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Most adults do not achieve the 150 minutes weekly of at least moderate intensity activity recommended for health. Adults' most common physical activity (PA) is walking, light intensity if strolling, moderate if brisker. Pedometers can increase walking; however, most trials have been short-term, have combined pedometer and support effects, and have not reported PA intensity. This trial will investigate whether pedometers, with or without nurse support, can help less active 45-75 year olds to increase their PA over 12 months., Design: Primary care-based 3-arm randomized controlled trial with 12-month follow-up and health economic and qualitative evaluations., Participants: Less active 45-75 year olds (n = 993) will be recruited by post from six South West London general practices, maximum of two per household and households randomised into three groups. Step-count and time spent at different PA intensities will be assessed for 7 days at baseline, 3 and 12 months by accelerometer. Questionnaires and anthropometric assessments will be completed., Intervention: The pedometer-alone group will be posted a pedometer (Yamax Digi-Walker SW-200), handbook and diary detailing a 12-week pedometer-based walking programme, using targets from their baseline assessment. The pedometer-plus-support group will additionally receive three practice nurse PA consultations. The handbook, diary and consultations include behaviour change techniques (e.g., self-monitoring, goal-setting, relapse prevention planning). The control group will receive usual care., Outcomes: Changes in average daily step-count (primary outcome), time spent sedentary and in at least moderate intensity PA weekly at 12 months, measured by accelerometry. Other outcomes include change in body mass index, body fat, self-reported PA, quality of life, mood and adverse events. Cost-effectiveness will be assessed by the incremental cost of the intervention to the National Health Service and incremental cost per change in step-count and per quality adjusted life year. Qualitative evaluations will explore reasons for trial non-participation and the interventions' acceptability., Discussion: The PACE-UP trial will determine the effectiveness and cost-effectiveness of a pedometer-based walking intervention delivered by post or practice nurse to less active primary care patients aged 45-75 years old. Approaches to minimise bias and challenges anticipated in delivery will be discussed., Trial Registration: ISRCTN98538934.

EGFR mutation testing of tumor samples is routinely performed to predict sensitivity to treatment with tyrosine kinase inhibitors for patients with non-small cell lung cancer. At least 9 different methodologies are employed in UK laboratories, and the aim of this study was to compare the sensitivity of different methods for the detection of EGFR mutations. Participating laboratories were sent coded samples with varying mutation loads (from 0% to 15%) to be tested for the p.Leu858Arg (p.L858R) missense mutation and c.2235&#95;2249del exon 19 deletion. The p.L858R mutation and deletions within exon 19 of the EGFR gene account for ∼90% of mutation-positive cases. The 11 laboratories used their standard testing method(s) and submitted 15 sets of results for the p.L858R samples and 10 for the exon 19 deletion. The p.Leu858Arg (p.L858R) mutation was detected at levels between 1% and 7.5% by Sanger sequencing, pyrosequencing, real-time polymerase chain reaction (PCR), amplification refractory mutation system, and capillary electrophoresis single-strand conformation analysis. The c.2235&#95;2249del mutation was detected at 1% to 5% by fragment size analysis, Sanger sequencing or real-time PCR. A mutation was detected in 24/25 (96%) of the samples tested which contained 5% mutated DNA. The 1% sensitivity claimed for commercial real-time PCR-targeted EGFR tests was achieved and our results show greater sensitivity for the Sanger sequencing and pyrosequencing screening methods compared to the 10% to 20% detection levels cited on clinical diagnostic reports. We conclude that multiple methodologies are suitable for the detection of acquired EGFR mutations.

Background: Bioelectrical impedance analysis (BIA) is a potentially valuable method for assessing lean mass and body fat levels in children from different ethnic groups. We examined the need for ethnic- and gender-specific equations for estimating fat free mass (FFM) from BIA in children from different ethnic groups and examined their effects on the assessment of ethnic differences in body fat., Methods: Cross-sectional study of children aged 8-10 years in London Primary schools including 325 South Asians, 250 black African-Caribbeans and 289 white Europeans with measurements of height, weight and arm-leg impedance (Z; Bodystat 1500). Total body water was estimated from deuterium dilution and converted to FFM. Multilevel models were used to derive three types of equation {A: FFM = linear combination(height+weight+Z); B: FFM = linear combination(height(2)/Z); C: FFM = linear combination(height(2)/Z+weight)}., Results: Ethnicity and gender were important predictors of FFM and improved model fit in all equations. The models of best fit were ethnicity and gender specific versions of equation A, followed by equation C; these provided accurate assessments of ethnic differences in FFM and FM. In contrast, the use of generic equations led to underestimation of both the negative South Asian-white European FFM difference and the positive black African-Caribbean-white European FFM difference (by 0.53 kg and by 0.73 kg respectively for equation A). The use of generic equations underestimated the positive South Asian-white European difference in fat mass (FM) and overestimated the positive black African-Caribbean-white European difference in FM (by 4.7% and 10.1% respectively for equation A). Consistent results were observed when the equations were applied to a large external data set., Conclusions: Ethnic- and gender-specific equations for predicting FFM from BIA provide better estimates of ethnic differences in FFM and FM in children, while generic equations can misrepresent these ethnic differences.

MLL2 mutations are detected in 55 to 80% of patients with Kabuki syndrome (KS). In 20 to 45% patients with KS, the genetic basis remains unknown, suggesting possible genetic heterogeneity. Here, we present the largest yet reported cohort of 116 patients with KS. We identified MLL2 variants in 74 patients, of which 47 are novel and a majority are truncating. We show that pathogenic missense mutations were commonly located in exon 48. We undertook a systematic facial KS morphology study of patients with KS at our regional dysmorphology meeting. Our data suggest that nearly all patients with typical KS facial features have pathogenic MLL2 mutations, although KS can be phenotypically variable. Furthermore, we show that MLL2 mutation-positive KS patients are more likely to have feeding problems, kidney anomalies, early breast bud development, joint dislocations and palatal malformations in comparison with MLL2 mutation-negative patients. Our work expands the mutation spectrum of MLL2 that may help in better understanding of this molecule, which is important in gene expression, epigenetic control of active chromatin states, embryonic development and cancer. Our analyses of the phenotype indicates that MLL2 mutation-positive and -negative patients differ systematically, and genetic heterogeneity of KS is not as extensive as previously suggested. Moreover, phenotypic variability of KS suggests that MLL2 testing should be considered even in atypical patients.

The 20th and 21st century witnessed the development of many sophisticated vaccinations and other key preventive health interventions, and yet child mortality in sub-Saharan Africa remains unacceptably high. One of the barriers identified to reducing child mortality in rural regions of Africa is distance and lack of transportation. In order to address this, a growing charitable organisation, Riders for Health (http://www.riders.org) has developed a reliable and cost-effective system for managing vehicles used in all types of healthcare delivery. The system intends to ensure that the delivery of health interventions is never undermined by failing vehicles no matter how harsh the terrain. The system provides reliable transport in direct support of partner healthcare goals and, in so doing, maintains a supply of appropriately managed vehicles, particularly motorcycles. Thereby health workers are empowered, their productivity and coverage enhanced and the efficiency of health interventions they promote maximised.

Background: Previous publications and utilisation of risk models for BRCA1 and BRCA2 mutation identification suggests that multiple primary disease in an individual is a strong predictor of a BRCA1/2 mutation and that this is more predictive than the same cancers occurring in close relatives., Methods: This study assessed the pathological mutation detection rates for BRCA1, BRCA2 and the CHEK2c.1100 delC mutation in 2022 women with breast cancer, including 100 with breast/ovary double primary and 255 with bilateral breast cancer., Results and Discussion: Although detection rates for mutations in BRCA1/2 are high at 49% for breast/ovarian double primary and 34% for bilateral breast cancer, the differential effect of multiple primaries in an individual appears to have been overestimated, particularly in those families with only a few malignancies. Nonetheless, bilateral breast cancer does differentially enhance detection rates in strong familial aggregations. CHEK2 1100 DelC mutation rates were lower in bilateral than for unilateral cases at 0.8% compared to 2%. The detected mutation rates for isolated double primary breast and ovarian cancer was 14% (3/22) compared to 17% (17/99) for the same two primaries in two close relatives in families with no other cases of breast/ovarian cancer. Risk models may need to be adjusted if further studies corroborate these findings.

Klippel-Feil syndrome (KFS) is a congenital disorder of spinal segmentation distinguished by the bony fusion of anterior/cervical vertebrae. Scoliosis, mirror movements, otolaryngological, kidney, ocular, cranial, limb, and/or digit anomalies are often associated. Here we report mutations at the GDF6 gene locus in familial and sporadic cases of KFS including the recurrent missense mutation of an extremely conserved residue c.866T>C (p.Leu289Pro) in association with mirror movements and an inversion breakpoint downstream of the gene in association with carpal, tarsal, and vertebral fusions. GDF6 is expressed at the boundaries of the developing carpals, tarsals, and vertebrae and within the adult vertebral disc. GDF6 knockout mice are best distinguished by fusion of carpals and tarsals and GDF6 knockdown in Xenopus results in a high incidence of anterior axial defects consistent with a role for GDF6 in the etiology, diversity, and variability of KFS.

64 families with a history of male breast cancer aged 60 or less or with a family history of male and female breast cancer were screened for the presence of BRCA1 and BRCA2 mutations. Seventeen pathogenic BRCA2 and four BRCA1 mutations were identified (34%) in samples from an affected family member. All but one of the mutations segregated with disease where samples were available and pedigree structure permitted. Despite high sensitivity of mutation testing only 64% of families fulfilling BCLC criteria had an identifiable pathogenic mutation. It is possible that at least some of these families may have mutations in other genes, although we found no involvement of CHEK2 1100delC.

Neurofibromatosis type 2 (NF2) remains a challenging diagnosis in childhood where there may be no neurological involvement. A 12-month-old male in whom NF2 was suspected because of characteristic ophthalmological and cutaneous lesions is reported. Cranial MRI showed no tumours. A pathogenic mutation was identified on NF2 gene analysis. The child developed hypertension due to renal vascular disease. Although renal vascular disease is a recognized complication of neurofibromatosis type 1 (NF1), it has not been reported in NF2.

Interferon regulatory factor 6 (IRF6) belongs to a family of nine transcription factors that share a highly conserved helix-turn-helix DNA-binding domain and a less conserved protein-binding domain. Most IRFs regulate the expression of interferon-alpha and -beta after viral infection, but the function of IRF6 is unknown. The gene encoding IRF6 is located in the critical region for the Van der Woude syndrome (VWS; OMIM 119300) locus at chromosome 1q32-q41 (refs 2,3). The disorder is an autosomal dominant form of cleft lip and palate with lip pits, and is the most common syndromic form of cleft lip or palate. Popliteal pterygium syndrome (PPS; OMIM 119500) is a disorder with a similar orofacial phenotype that also includes skin and genital anomalies. Phenotypic overlap and linkage data suggest that these two disorders are allelic. We found a nonsense mutation in IRF6 in the affected twin of a pair of monozygotic twins who were discordant for VWS. Subsequently, we identified mutations in IRF6 in 45 additional unrelated families affected with VWS and distinct mutations in 13 families affected with PPS. Expression analyses showed high levels of Irf6 mRNA along the medial edge of the fusing palate, tooth buds, hair follicles, genitalia and skin. Our observations demonstrate that haploinsufficiency of IRF6 disrupts orofacial development and are consistent with dominant-negative mutations disturbing development of the skin and genitalia.