​BackgroundThe clinical severity of disease in neurofibromatosis type 2 (NF2) is variable. Patients affected with a constitutional truncating NF2 mutation have severe disease, while missense mutations or mosaic mutations present with a milder attenuated phenotype. Genotype-derived natural history data are important to inform discussions on prognosis and management.MethodsWe have assessed NF2 clinical phenotype in 142 patients in relation to the UK NF2 Genetic Severity Score to validate its use as a clinical and research tool.ResultsThe Genetic Severity Score showed significant correlations across 10 measures, including mean age at diagnosis, proportion of patients with bilateral vestibular schwannomas, presence of intracranial meningioma, spinal meningioma and spinal schwannoma, NF2 eye features, hearing grade, age at first radiotherapy, age at first surgery and age starting bevacizumab. In addition there was moderate but significant correlation with age at loss of useful hearing, and weak but significant correlations for mean age at death, quality of life, last optimum Speech Discrimination Score and total number of major interventions. Patients with severe disease presented at a younger age had a higher disease burden and greater requirement of intervention than patients with mild and moderate disease.ConclusionsThis study validates the UK NF2 Genetic Severity Score to stratify patients with NF2 for both clinical use and natural history studies.

The interactions of transmembrane (TM) α-helices with the phospholipid membrane and with one another are central to understanding the structure and stability of integral membrane proteins. These interactions may be analyzed via coarse grained molecular dynamics (CGMD) simulations. To obtain statistically meaningful analysis of TM helix interactions, large (N ca. 100) ensembles of CGMD simulations are needed. To facilitate the running and analysis of such ensembles of simulations, we have developed Sidekick, an automated pipeline software for performing high throughput CGMD simulations of α-helical peptides in lipid bilayer membranes. Through an end-to-end approach, which takes as input a helix sequence and outputs analytical metrics derived from CGMD simulations, we are able to predict the orientation and likelihood of insertion into a lipid bilayer of a given helix of a family of helix sequences. We illustrate this software via analyses of insertion into a membrane of short hydrophobic TM helices containing a single cationic arginine residue positioned at different positions along the length of the helix. From analyses of these ensembles of simulations, we estimate apparent energy barriers to insertion which are comparable to experimentally determined values. In a second application, we use CGMD simulations to examine the self-assembly of dimers of TM helices from the ErbB1 receptor tyrosine kinase and analyze the numbers of simulation repeats necessary to obtain convergence of simple descriptors of the mode of packing of the two helices within a dimer. Our approach offers a proof-of-principle platform for the further employment of automation in large ensemble CGMD simulations of membrane proteins.

Childhood onset neurofibromatosis type 2 can be severe and genotype dependent.We present a retrospective phenotypic analysis of all ascertained children in England 1.0). Focal cortical dysplasia occurred in 26% group 3 and 4% 2A. A total of 48% of group 3 underwent ≥1 major intervention (intracranial/spinal surgery/Bevacizumab/ radiotherapy) compared to 35% of 2A; with 23% group 3 undergoing spinal surgery (schwannoma/ependymoma/meningioma resection) compared to 4% of 2A. Mean age starting Bevacizumab was 12.7 in group 3 and 14.9 years in 2A. In conclusion, group 3 phenotype manifests earlier with greater tumour load, poorer visual outcomes and more intervention.childhood NF2, NF2, NF2 genetic severity score, paediatric NF2 genotype phenotype D Gareth Evans and Allyson Parry joint contributed for this study.

Mutations associated with severe systemic disease result in greater visual morbidity at an earlier age. Those with tissue mosaicism are unlikely to have visually debilitating pathology secondary to NF2. Potentially treatable sources of damage to vision, however, affect all groups and must be identified early and treated effectively to retain useful vision throughout life.

Objectives/Hypothesis This study set out to describe the progression of hearing loss in patients with neurofibromatosis type 2 (NF2), treated in a quaternary multidisciplinary clinic. It also aimed to compare hearing loss across patients grouped according to a known genetic severity score to explore its utility for prognostication. Study Design Retrospective cohort study. Methods We conducted a study of 147 patients with confirmed NF2 diagnosis for a mean observational period of 10 years. Pure‐tone average (PTA), optimum discriminations scores (ODS), and genotype data were collected. Patients were classified according to hearing class (American Academy of Otolaryngology), their candidacy for auditory implantation (UK National NF2 consensus) and grouped by genetic severity as: 1 = tissue mosaic, 2A = mild classic, 2B = moderate classic, and 3 = severe. Survival analysis investigated the effect of genetic severity on the age of loss of serviceable hearing. Results Genetic severity was a significant predictor of hearing outcomes such as ODS, hearing classification, and maximum annual PTA deterioration. Although the overall median age of loss of serviceable hearing was 78 years, there was significant variation according to the genetic severity; the median for severe patients was 32 years compared to a median of 80 for tissue mosaic patients. Conclusions This is the first description of long‐term hearing outcomes in a clinical setting across a large heterogeneous cohort of patients with NF2. The results highlight the potential importance and benefit of considering the genetic severity score of patients when undertaking treatment decisions, as well as planning future natural history studies. Level of Evidence 2c Laryngoscope, 129:974–980, 2019

BackgroundIt is important to inform medical educators and workforce planners in Anaesthesia about early career choices for the specialty, factors that influence them and to elucidate how recent choices of men and women doctors relate to the overall historical trends in the specialty’s popularity.MethodsWe analysed longitudinal data on career choice, based on self-completed questionnaires, from national year-of-qualification cohorts of UK-trained doctors from 1974 to 2012 surveyed one, three and 5 years post-qualification. Career destination data 10 years post-qualification were used for qualifiers between 1993 and 2002, to investigate the association between early choice and later destinations.ResultsIn years 1, 3 and 5 post-qualification, respectively, 59.9% (37,385), 64.6% (31,473), and 67.2% (24,971) of contactable doctors responded. There was an overall increase, from the early to the later cohorts, in the percentage of medical graduates who wished to enter anaesthesia: for instance year 1 choices rose from 4.6 to 9.4%, comparing the 1974 and 2012 cohorts. Men were more likely than women to express an early preference for a career in anaesthesia: for example, at year 3 after qualification anaesthesia was the choice of 10.1% of men and 7.9% of women. There was a striking increase in the certainty with which women chose anaesthesia as their future career specialty in recent compared to earlier cohorts, not reflected in any trends observed in men choosing anaesthesia.Sixty percent of doctors who were anaesthetists, 10 years after qualifying, had specified anaesthesia as their preferred specialty when surveyed in year 1, 80% in year 3, and 92% in year 5.Doctors working as anaesthetists were less likely than those working in other hospital specialties to have specified, as strong influences on specialty choice, ‘experience of the subject’ as students, ‘inclinations before medical school’, and ‘what I really want to do’. Men anaesthetists were more influenced in their specialty choice than men in other hospital specialties by ‘wanting a career with acceptable hours’; the corresponding difference among women was not significant.ConclusionsWe suggest a focus on inspirational teaching of anaesthesia in medical school and on greater exposure to the specialty in the foundation programme. Factors which may discourage women from entering anaesthesia should be explored and addressed.Electronic supplementary materialThe online version of this article (doi:10.1186/s12871-017-0392-5) contains supplementary material, which is available to authorized users.

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Genetic testing and management of individuals at risk for NF2‐related schwannomatosis is complicated by the high rate of mosaicism resulting in a milder, later onset, more asymmetrical disease and the phenotypic overlap with the related schwannomatosis conditions. This updated protocol has been devised for the English NF2‐related schwannomatosis service. It provides those affected with mosaic NF2‐related schwannomatosis estimated risks of having an affected child; and management guidelines both for individuals at risk of NF2‐related schwannomatosis, or with potential disease, due to having features that fall short of consensus diagnostic criteria. Risks of mosaicism and inferred transmission risks were derived from genetic testing of over 1000 individuals through the Manchester NF2 genetic testing service. This updated protocol, reflects the lower transmission risks now inferred in mosaic NF2‐related schwannomatosis, informed by the greater sensitivity of Next Generation Sequencing in detecting low levels of mosaicism in blood, along with improved ability to analyse tumour DNA. Screening for features of NF2‐related schwannomatosis is proposed until the risk of having the condition falls below a pragmatic threshold of 1%. Using these revised transmission figures, this threshold can now be reached at a younger age in many of those at risk, with earlier reassurance and discharge.