Rare disease genomic testing in the UK and Ireland: promoting timely and equitable access.

PURPOSE AND SCOPE: The aim of this position statement is to provide recommendations regarding the delivery of genomic testing to patients with rare disease in the UK and Ireland. The statement has been developed to facilitate timely and equitable access to genomic testing with reporting of results within commissioned turnaround times. METHODS OF STATEMENT DEVELOPMENT: A 1-day workshop was convened by the UK Association for Clinical Genomic Science and attended by key stakeholders within the NHS Genomic Medicine Service, including clinical scientists, clinical geneticists and patient support group representatives. The aim was to identify best practice and innovations for streamlined, geographically consistent services delivering timely results. Attendees and senior responsible officers for genomic testing services in the UK nations and Ireland were invited to contribute. RESULTS AND CONCLUSIONS: We identified eight fundamental requirements and describe these together with key enablers in the form of specific recommendations. These relate to laboratory practice (proportionate variant analysis, bioinformatics pipelines, multidisciplinary team working model and test request monitoring), compliance with national guidance (variant classification, incidental findings, reporting and reanalysis), service development and improvement (multimodal testing and innovation through research, informed by patient experience), service demand, capacity management, workforce (recruitment, retention and development), and education and training for service users. This position statement was developed to provide best practice guidance for the specialist genomics workforce within the UK and Ireland but is relevant to any publicly funded healthcare system seeking to deliver timely rare disease genomic testing in the context of high demand and limited resources.

Efficacy and safety of ciclosporin versus methotrexate in the treatment of severe atopic dermatitis in children and young people (TREAT): a multicentre parallel group assessor-blinded clinical trial.

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.

British Society for Paediatric and Adolescent Dermatology assessment and support of mental health in children and young people with skin conditions: a multidisciplinary expert consensus statement and recommendations.

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.

Protocol of a cluster randomised trial of BodyKind: a school-based body image programme for adolescents.

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 (4th 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 .

A cluster analysis of health behaviours and their relationship to mental health difficulties, life satisfaction and functioning in adolescents.

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.

Postprandial vascular-inflammatory and thrombotic responses to high-fat feeding are augmented by manipulating the lipid droplet size distribution.

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/m2) 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.

Effect of a Primary Care Walking Intervention with and without Nurse Support on Physical Activity Levels in 45- to 75-Year-Olds: The Pedometer And Consultation Evaluation (PACE-UP) Cluster Randomised Clinical Trial.

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.

The impact of explaining vegetarian meal requests on the affective responses and perceptions of meat eaters.

Social situations can present challenges for those looking to reduce or avoid eating meat. In an experimental vignette study with a large representative sample of 1,117 UK-based meat eaters, we explore affective responses to requests for vegetarian meals and perceptions of those making the request across four social situations: a BBQ, a pub, a restaurant dinner, and a dinner party. We examine moderators of these perceptions including whether the requester presents themselves as vegetarian or a meat restrictor and whether they cite health, environmental or no motives for their request. Overall, we find that these moderators have a greater impact on meat eaters' perceptions of the requester than on their affective responses to the request. We also find that these outcomes are more impacted by the mention of motives than they are diet type. Standout findings include evidence that people citing environmental motives for their vegetarian meal request are perceived more negatively, while those with health motives are perceived more positively. We also identify substantial heterogeneity across the respondents' levels of meat attachment: those who are more attached to meat have more negative perceptions of vegetarian meal requesters and experience higher negative affect and lower positive affect in response to the request.

Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes.

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.

Data collection and outcome measurement in student counseling services in Irish higher education institutions: Counselors' views on challenges and facilitators.

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).

BRCA1, BRCA2 and CHEK2 c.1100 delC mutations in patients with double primaries of the breasts and/or ovaries.

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.

Developing a national database for higher education student counselling services: the importance of collaborations.

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.

Prevalence of cardiac pathology and relation to mortality in a multiethnic population hospitalised with COVID-19.

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.

Radiological Features of Giant Cell Tumours of Bone.

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.

Comorbidities and Pregnancy Do Not Affect Local Recurrence in Patients With Giant Cell Tumour of Bone.

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.

Prediction of pathological fracture in patients with metastatic disease of the lower limb.

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.

Ligand cleavage enables formation of 1,2-ethanedithiol capped colloidal quantum dot solids.

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.

Mutations in GDF6 are associated with vertebral segmentation defects in Klippel-Feil syndrome.

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.

BRCA1/2 mutation analysis in male breast cancer families from North West England.

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.