Ancestry, race and ethnicity: the role and relevance of language in clinical genetics practice.

BACKGROUND: The terms ancestry, race and ethnicity are used variably within the medical literature and within society and clinical care. Biological lineage can provide an important context for the interpretation of genomic data, but the language used, and practices around when to ascertain this, vary. METHODS: Using a fictional case scenario we explore the relevance of questions around ancestry, race and ethnicity in clinical genetic practice. RESULTS: In the UK, data on 'ethnicity' are routinely collected by those using genomic medicine, as well as within the wider UK National Health Service, although the reasons for this are not always clear to practitioners and patients. Sometimes it is requested as a proxy for biological lineage to aid variant interpretation, refine estimations of carrier frequency and guide decisions around the need for pharmacogenetic testing. CONCLUSION: There are many challenges around the use and utility of these terms. Currently, genomic databases are populated primarily with data from people of European descent, and this can lead to health disparities and poorer service for minoritised or underserved populations. Sensitivity and consideration are needed when communicating with patients around these areas. We explore the role and relevance of language around biological lineage in clinical genetics practice.

Monoallelic loss-of-function BMP2 variants result in BMP2-related skeletal dysplasia spectrum.

PURPOSE: Bone morphogenic proteins (BMPs) regulate gene expression that is related to many critical developmental processes, including osteogenesis for which they are named. In addition, BMP2 is widely expressed in cells of mesenchymal origin, including bone, cartilage, skeletal and cardiac muscle, and adipose tissue. It also participates in neurodevelopment by inducing differentiation of neural stem cells. In humans, BMP2 variants result in a multiple congenital anomaly syndrome through a haploinsufficiency mechanism. We sought to expand the phenotypic spectrum and highlight phenotypes of patients harboring monoallelic missense variants in BMP2. METHODS: We used retrospective chart review to examine phenotypes from an international cohort of 18 individuals and compared these with published cases. Patient-derived missense variants were modeled in zebrafish to examine their effect on the ability of bmp2b to promote embryonic ventralization. RESULTS: The presented cases recapitulated existing descriptions of BMP2-related disorders, including craniofacial, cardiac, and skeletal anomalies and exhibit a wide phenotypic spectrum. We also identified patients with neural tube defects, structural brain anomalies, and endocrinopathies. Missense variants modeled in zebrafish resulted in loss of protein function. CONCLUSION: We use this expansion of reported phenotypes to suggest multidisciplinary medical monitoring and management of patients with BMP2-related skeletal dysplasia spectrum.

Biallelic PRMT7 pathogenic variants are associated with a recognizable syndromic neurodevelopmental disorder with short stature, obesity, and craniofacial and digital abnormalities.

PURPOSE: Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyzes the methylation of arginine residues on several protein substrates. Biallelic pathogenic PRMT7 variants have previously been associated with a syndromic neurodevelopmental disorder characterized by short stature, brachydactyly, intellectual developmental disability, and seizures. To our knowledge, no comprehensive study describes the detailed clinical characteristics of this syndrome. Thus, we aim to delineate the phenotypic spectrum of PRMT7-related disorder. METHODS: We assembled a cohort of 51 affected individuals from 39 different families, gathering clinical information from 36 newly described affected individuals and reviewing data of 15 individuals from the literature. RESULTS: The main clinical characteristics of the PRMT7-related syndrome are short stature, mild to severe developmental delay/intellectual disability, hypotonia, brachydactyly, and distinct facial morphology, including bifrontal narrowing, prominent supraorbital ridges, sparse eyebrows, short nose with full/broad nasal tip, thin upper lip, full and everted lower lip, and a prominent or squared-off jaw. Additional variable findings include seizures, obesity, nonspecific magnetic resonance imaging abnormalities, eye abnormalities (i.e., strabismus or nystagmus), and hearing loss. CONCLUSION: This study further delineates and expands the molecular, phenotypic spectrum and natural history of PRMT7-related syndrome characterized by a neurodevelopmental disorder with skeletal, growth, and endocrine abnormalities.

Expanding SPTAN1 monoallelic variant associated disorders: From epileptic encephalopathy to pure spastic paraplegia and ataxia.

PURPOSE: Nonerythrocytic αII-spectrin (SPTAN1) variants have been previously associated with intellectual disability and epilepsy. We conducted this study to delineate the phenotypic spectrum of SPTAN1 variants. METHODS: We carried out SPTAN1 gene enrichment analysis in the rare disease component of the 100,000 Genomes Project and screened 100,000 Genomes Project, DECIPHER database, and GeneMatcher to identify individuals with SPTAN1 variants. Functional studies were performed on fibroblasts from 2 patients. RESULTS: Statistically significant enrichment of rare (minor allele frequency < 1 × 10-5) probably damaging SPTAN1 variants was identified in families with hereditary ataxia (HA) or hereditary spastic paraplegia (HSP) (12/1142 cases vs 52/23,847 controls, p = 2.8 × 10-5). We identified 31 individuals carrying SPTAN1 heterozygous variants or deletions. A total of 10 patients presented with pure or complex HSP/HA. The remaining 21 patients had developmental delay and seizures. Irregular αII-spectrin aggregation was noted in fibroblasts derived from 2 patients with p.(Arg19Trp) and p.(Glu2207del) variants. CONCLUSION: We found that SPTAN1 is a genetic cause of neurodevelopmental disorder, which we classified into 3 distinct subgroups. The first comprises developmental epileptic encephalopathy. The second group exhibits milder phenotypes of developmental delay with or without seizures. The final group accounts for patients with pure or complex HSP/HA.

Low-level laser therapy for oral mucositis in children with cancer.

OBJECTIVE: To assess the efficacy of oral low-level laser therapy (LLLT) - also known as photobiomodulation - in the reduction of oral mucositis experienced by children and young people with cancer undergoing chemotherapy. DESIGN: A systematic review to evaluate the efficacy of oral LLLT for oral mucositis in children with cancer and the safety of oral LLLT in any age with cancer (International Prospective Register of Systematic Reviews/PROSPERO registration: CRD42018099772). Multiple databases and grey literature were screened. Randomised controlled trials were considered for assessing efficacy, and all studies were considered for assessing safety. Primary outcomes included severity of oral mucositis, oral pain and adverse events. Where results were compatible, meta-analysis was performed using a random-effects model. A narrative synthesis considered other outcome measures. RESULTS: 14 studies (n>416 children) were included in the narrative synthesis of LLLT efficacy. 5 studies (n=380 children and young people) were included in the meta-analyses. Results demonstrate that LLLT may reduce the severity of oral mucositis and the level of oral pain, but further randomised controlled trials are needed to confirm or deny this. There is vast variation in different trial protocols. Insufficient blinding between LLLT or sham therapy/control led to a strong risk of performance bias. 75 studies (encompassing 2712 patients of all ages who had undergone LLLT) demonstrated minor and infrequent adverse reactions, but most studies had significant areas of weakness in quality. CONCLUSION: LLLT appears to be a safe therapy, but further evidence is needed to assess its efficacy as a prevention or treatment tool for oral mucositis in children with cancer.

Rough endoplasmic reticulum expansion: a consistent finding in a patient cohort with vascular Ehlers-Danlos Syndrome and Osteogenesis Imperfecta.

Vascular Ehlers-Danlos Syndrome (vEDS) and Osteogenesis Imperfecta (OI) are two forms of connective tissue disorders. Previously, transmission electron microscopy of skin biopsies was routinely performed on all patients who were clinically suspected to have vEDS. At present, molecular genetics using genomic DNA extracted from a blood sample is the first line investigation for these patients. However, when variants of uncertain clinical significance are identified on genetic testing and individuals do not have the classical features of OI or vEDS, additional phenotypic information obtained from a skin biopsy can be valuable for contributing to the evidence for re-classifying pathogenicity of variants.We present a cohort of six patients with molecularly confirmed vEDS and one patient with a severe form of OI, who each had expanded (or dilated), protein-filled, rough endoplasmic reticulum identified on transmission electron microscopy. The patients were identified through retrospective screening of medical records, and biopsies were taken between 1999-2016. We discuss the potential role for assessing rough endoplasmic reticulum expansion as a useful tool to allow further phenotyping of these individuals.

Searching for the true attrition rate of UK paediatric trainees.

OBJECTIVE: To quantitatively analyse the number of doctors leaving the paediatric specialty training (ST) programme in the UK, to assist with evidence-based workforce planning. DESIGN: Data were sought on those leaving the UK paediatrics training programme between 2014 and 2019 from Heads of Schools of Paediatrics and Freedom of Information Act requests. SETTING: Retrospective data analysis. OUTCOME MEASURES: Overall attrition rate, attrition rate across level of training, attrition rate across geographical area, recorded reason for leaving. RESULTS: All results must be interpreted with caution due to limitations in record keeping and analysis. The annual attrition rate across all ST levels between 2014 and 2019 is estimated at 3.7%-4.2% (ie, 749-845 trainees may have left the paediatric training programme over 2014-2019). No reason for leaving was recorded for three-quarters of individuals, around 630 doctors. Of those leaving paediatrics, significantly more (χ², p=0.015) did so at ST3 (20.3%) versus the next highest training year, ST2 (13.6%). CONCLUSIONS: This project seems to demonstrate worryingly poor record-keeping of the true attrition rate of paediatric trainees by organisations responsible for workforce planning, including Health Education England, the Royal College of Paediatrics and Child Health and individual paediatric schools across the UK. To allow evidence-based workforce planning for the benefit of UK children, it is vital that accurate records on trainees who leave the training programme are kept and shared across the UK.

Completion of paediatric training: trends across 2011-2017 cohorts.

OBJECTIVE: To determine trends in the demographics and destinations of doctors who have recently completed paediatric training in the UK. DESIGN: A survey was sent to all new paediatric certificate holders 1 year on from completing specialty training every year from 2011 to 2017. SETTING: Retrospective survey. OUTCOME MEASURES: Demographics, career destinations, time to complete training, working patterns, subspecialty registration, numbers of job applications, and use of the period of grace are reported. RESULTS: 1262 people who gained their paediatric certificate in the UK between 2011 and 2017 completed the survey (60.6% response rate). 58.5% (n=738) of respondents were female, and 32.4% (n=224) of women work less than full time, compared with 4.6% (n=23) of men. 85.9% (n=1056) of respondents were in a UK consultant post. 7.6% (n=94) were working overseas. 65.1% (n=722) remained in the region they trained in. 64.8% (n=1348) were registered for general paediatrics, whereas 35.2% (n=733) had subspecialised.Respondents who held a non-UK medical degree (47.5%, n=501) made more job applications on average (mean=2.2; 95% CI 2.0 to 2.5) than those with a UK degree (52.5%, n=554) (mean=1.1; 95% CI 1.0 to 1.2) (p<0.001). Average training time increased from 9.8 years (95% CI 9.4 to 10.2) to 11.3 years (95% CI 11.1 to 11.6) (p<0.001). Respondents' use of their grace period reduced from 42.7% (n=47) to 20.6% (n=29) (p<0.001). CONCLUSIONS: The data reflect the diverse paediatric workforce and doctors' working patterns following the completion of paediatric training in the UK. The trends demonstrated are vital to consider for evidence-based workforce planning.

Osteogenesis imperfecta type I: The role of deep phenotyping in a patient with a ruptured uterus.

As molecular diagnosis of Osteogenesis Imperfecta has become more accessible, there is an increasing ability to consider additional techniques to undertake deep phenotyping of the patient. In this report, we present the details of a female patient with type I Osteogenesis Imperfecta caused due to a pathogenic COL1A1 variant, who suffered from uterine rupture during labour in her second pregnancy, at age 33. Her presentation, patient journey, and histological results are described. Collagen flowers were identified with electron microscopy of a skin biopsy, and the significance of these are explored. Two other recorded cases of women with Osteogenesis Imperfecta who developed uterine rupture are discussed. This report demonstrates the potential role for ultrastructural tissue examination and deep phenotyping, to allow further insights into the relationship between genotype and phenotype.

WORKFORCE: Newly graduated doctors' experiences of conducting medical ward rounds alone: A regional cross-sectional study.

Newly graduated doctors may be expected to conduct ward rounds alone, yet studies exploring this are limited. A regional cross-sectional study was undertaken to explore foundation year 1 doctors' (FY1s) experiences of conducting ward rounds alone; all 289 FY1s on medical rotations in Yorkshire and the Humber Foundation School were invited to participate in an online survey in November 2016. Thirty-four percent (n=98) responded. The majority (62%, n=61) of respondents reported conducting the daily ward round alone (without a more senior doctor present) two or more times a week. However, 56% (n=55) reported that they had never received teaching on ward round conduct and only 7% (n=7) reported feeling prepared for conducting ward rounds alone at the start of their medical rotation. FY1-led ward rounds are a regular occurrence yet training is not commonplace; widespread, early training should be considered to prepare future doctors for their role.

How can training in care of the dying be improved?

BACKGROUND: Care of the dying patient is an intrinsic part of the role of Foundation Year doctors (FYs). This study aimed to explore FYs' experiences of training and their perceived training needs for their role in care of the dying. Care of the dying patient is an intrinsic part of the role of Foundation Year doctors METHODS: All FYs in one Foundation school were invited to take part in semi-structured group or individual interviews. A total of 8 group interviews and 21 individual interviews were conducted with 47 participants. Interview recordings were transcribed verbatim and framework analysis was undertaken. FINDINGS: Key themes derived from the interviews included FYs' teaching opportunities regarding care of the dying and their learning methods for this subject matter which included learning from experience, observation, simulation, written guidance and supervision. Areas for further training was another key theme and training needs identified included prescribing, communication, recognising dying, documentation, societal perspective and emotional resilience. DISCUSSION: FYs' training experiences in this area vary. This study identifies training needs that can be used to inform both undergraduate and postgraduate curricula.

Ward rounds: can an aide-memoire help new doctors?

BACKGROUND: Ward rounds are fundamental to the care of medical inpatients, and newly graduated doctors may be expected to conduct them alone. There are no studies exploring the frequency with which this occurs, however, or how prepared they feel for this task. METHODS: Newly graduated (Foundation Year-1, FY1) doctors in Northern Lincolnshire and Goole (NLaG) National Health Service Foundation Trust were surveyed at the end of their FY1 year. An online survey asked: how often they conducted medical ward rounds alone; how prepared they felt to do so; and how often they considered 13 important aspects of care. An aide-memoire outlining aspects to consider on ward rounds was introduced during induction for a second cohort of FY1s, and the survey was repeated. FINDINGS: In the initial survey (2015), 42% (n = 19) of the 45 FY1s in NLaG responded: 84% (n = 16) reported conducting ward rounds alone twice or more each week, with 5% (n = 1) feeling prepared and 89% (n = 17) feeling unprepared to do so. In the second survey (2016), following the introduction of the aide-memoire, 52% (n = 25) of the 48 FY1s responded: 32% (n = 7) reported feeling prepared with the aide-memoire (a 27% increase from 2015). There was also a statistically significant increase in the frequency with which they reported considering three of 13 important aspects of care: nutrition, mobility and discharge planning. There are no studies exploring the frequency with which newly graduated doctors conduct ward rounds alone DISCUSSION: The FY1s were regularly conducting ward rounds alone, and felt unprepared for this. An aide-memoire is a low-cost intervention with some value in improving preparedness, and could be further developed and used elsewhere.

Care of the dying: a qualitative exploration of Foundation Year doctors' experiences.

CONTEXT: Foundation Year doctors (FYs), who are newly qualified, are expected to provide care for dying patients. Experiences at this early mandatory stage of training may form the foundation for future encounters, but little is documented about what these experiences involve. The aim of this research was to explore the experiences of FYs in caring for the dying, using the recently published Priorities for Care of the Dying Person as a conceptual framework, to identify areas for improvement in education and clinical practice. METHODS: Semi-structured group and individual interviews were conducted to explore the experiences of FYs and how these relate to the five aspects of Priorities for Care of the Dying Person: 'recognise', 'communicate', 'involve', 'support' and 'plan and do'. All FYs in the North Yorkshire and East Coast Foundation School (n=335) were invited to participate and 47 FYs were recruited from five sites through convenience sampling and snowballing. Recordings were transcribed verbatim and a framework analysis approach was used with the published Priorities for Care of the Dying Person guidelines as a conceptual framework. RESULTS: Five main themes and 13 subthemes emerged from the data. The five main themes, which mapped to the conceptual framework, were: recognition that the patient is dying; communication with the patient, family and other staff; involvement of the patient and family in their care; support for the dying person and their family; and planning and carrying out good care of the dying. Examples of when things are done poorly or done well were shared, giving context to experience. CONCLUSIONS: Areas for improvement were identified around all five main themes. These will be useful for informing those involved in undergraduate and foundation training on how to improve the experiences of Foundation Year doctors and thereby improve patient care.

Academic poster design at a national conference: a need for standardised guidance?

BACKGROUND: Academic posters are a common means of disseminating information at conferences. Presentation at conferences is frequently given weight in postgraduate training programme recruitment. Some conferences provide guidance for visual presentation of posters. For the Association of the Study of Medical Education (ASME) Annual Scientific Meeting (ASM) 2015, poster abstract guidance was provided; however, the guidance on poster design was limited to size and orientation. The aim of this study was to investigate academic poster quality at a national medical education conference to identify where standards could be promoted and improved. Presentation at conferences is frequently given weight in postgraduate training programme recruitment METHODS: Six auditors assessed all posters displayed at the ASME ASM (15-17 July 2015) using guidelines based upon a modified checklist for academic posters. Ten criteria were agreed as assessment standards for poster design quality. RESULTS: One-hundred-and-eighty posters were assessed: 29 per cent had appropriate copyright for the materials displayed (n = 52); 41 per cent included suitable contact details (n = 73); 48 per cent (n = 87) had a text to graphic ratio of 50 : 50; 72 per cent (n = 130) met ASME guidance for layout and orientation; 76 per cent (n = 137) had appropriate referencing; 78 per cent showed evidence of proofreading for grammar and spelling (n = 140); 79 per cent (n = 142) were readable at a distance of 2 metres; and 87 per cent used appropriate academic logos (n = 156). DISCUSSION: There was variability in design quality as assessed by these criteria. We recommend that detailed guidance should be produced and disseminated by the organising conference. This may improve poster quality and aid in the communication of presented material. We aim to re-audit following the production and dissemination of poster presentation guidance.