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DNA methylation may restrict the activity of gene transfer vectors due to inadvertent silencing. In P19 embryonic carcinoma cells in vitro, we found that transgene expression regulated by the SFFV LTR and EF1α promoter declined rapidly within 16 days, but for A2UCOE derived from the human HNRPA2B1-CBX3 housekeeping gene locus, remained completely stable. Silencing correlated with extensive epigenetic methylation of CpG sites, whereas the A2UCOE was almost completely resistant. Linking of the A2UCOE upstream of the SFFV LTR protected this element from both DNA methylation and silencing. Analysis of engrafted hematopoietic cells in vivo transduced with the same vectors revealed a similar pattern. The A2UCOE displayed little or no methylation in either primary or secondary graft recipients, and gene expression profiles were highly conserved between the two groups. These studies provide convincing evidence that DNA methylation plays a direct role in regulating self-inactivating (SIN) lentiviral transgene expression, and that the stability of expression from the A2UCOE is, at least in part, due to methylation resistance. The A2UCOE therefore has considerable utility for gene therapy applications where reliable and sustained gene expression is desirable.

Background The implementation of the National Genomic Medicine Service in the UK has increased patient access to germline genomic testing. Increased testing leads to more genetic diagnoses but does result in the identification of genomic variants of uncertain significance (VUS). The rigorous process of interpreting these variants requires multi-disciplinary, highly trained healthcare professionals (HCPs). To meet this training need, we designed two Massive Open Online Courses (MOOCs) for HCPs involved in germline genomic testing pathways: Fundamental Principles (FP) and Inherited Cancer Susceptibility (ICS). Methods An evaluation cohort of HCPs involved in genomic testing were recruited, with additional data also available from anonymous self-registered learners to both MOOCs. Pre- and post-course surveys and in-course quizzes were used to assess learner satisfaction, confidence and knowledge gained in variant interpretation. In addition, granular feedback was collected on the complexity of the MOOCs to iteratively improve the resources. Results A cohort of 92 genomics HCPs, including clinical scientists, and non-genomics clinicians (clinicians working in specialties outside of genomics) participated in the evaluation cohort. Between baseline and follow-up, total confidence scores improved by 38% (15.2/40.0) (95% confidence interval [CI] 12.4–18.0) for the FP MOOC and 54% (18.9/34.9) (95%CI 15.5–22.5) for the ICS MOOC ( p  < 0.0001 for both). Of those who completed the knowledge assessment through six summative variant classification quizzes (V1–6), a mean of 79% of respondents classified the variants such that correct clinical management would be undertaken (FP: V1 (73/90) 81% Likely Pathogenic/Pathogenic [LP/P]; V2 (55/78) 70% VUS; V3 (59/75) 79% LP/P; V4 (62/72) 86% LP/LP. ICS: V5 (66/91) 73% VUS; V6 (76/88) 86% LP/P). A non-statistically significant higher attrition rate was seen amongst the non-genomics workforce when compared to genomics specialists for both courses. More participants from the non-genomics workforce rated the material as “Too Complex” (FP n  = 2/7 [29%], ICS n  = 1/5 [20%]) when compared to the specialist genomics workforce (FP n  = 1/43 [2%], ICS n  = 0/35 [0%]). Conclusions After completing one or both MOOCs, self-reported confidence in genomic variant interpretation significantly increased, and most respondents could correctly classify variants such that appropriate clinical management would be instigated. Genomics HCPs reported higher satisfaction with the level of content than the non-genomics clinicians. The MOOCs provided foundational knowledge and improved learner confidence, but should be adapted for different workforces to maximise the benefit for clinicians working in specialties outside of genetics.

Background Powerful new genomic technologies are transforming the way healthcare is delivered, shaping medical practice across all specialties. In this rapidly changing landscape, there is an urgent need to equip the clinical workforce with knowledge and skills to navigate the new healthcare terrain. Co-design of healthcare resources with end users is increasingly gaining traction as a method of ensuring that educational content and delivery are tailored to users’ needs, increasing likelihood of use and resulting in better outcomes for patients. Here we describe the co-design and ongoing co-creation of GeNotes – an NHS England National Genomics Education flagship online resource providing genomics education at the point of patient care. Methods To understand the barriers to implementation of genomic medicine and the training needs of the diverse NHS workforce, we adopted a co-design approach with clinicians from both primary and secondary care who are uniquely placed to understand the context in which they are working and identify their own training needs. Concept design, initial user research and subsequent ‘alpha’ and ‘private beta’ phase user research was conducted in a series of co-design iterations employing a mixed methodology integrating quantitative and qualitative data collection and analysis. Results User evaluation data demonstrated excellent feedback across the tested domains (content, navigation, likelihood of use and recommendation to colleagues). We identified several key themes from user testing that shaped the resource’s development. Conclusions The co-design approach to the development of this point-of-care genomics education resource for clinicians has allowed insight into the education needs, challenges and learning styles of end-users. The utility of this approach was supported by excellent user feedback across the tested domains, and we recommend it to others involved in developing healthcare resources in a fast-paced environment.

IntroductionA national genomics resource ‘GeNotes’ has been developed by NHS England Genomics Education Programme (GEP) to support routine implementation of genomic testing in clinical practice.1 GeNotes provides clinicians with information at the point of need, with opportunities for extended learning. The GeNotes resources consist of ‘In the Clinic’ scenarios (Tier 1), and a ‘Knowledge Hub’ (Tier 2) with resources including genetic conditions, genomic technologies and core concepts. Genomics resources have been launched across multiple specialties including cardiology, oncology and neurology, and now, also in Gastroenterology, and will assist our specialty in the provision of Genomic Service which is now in the ‘mainstreaming’ phase.MethodsIn June 2023 the Gastro-Hep working group (WG) was convened by co-chairs (KM and GPA), consisting of higher specialist resident doctors and specialist consultants with expertise (identified through the BSG and by the co-chairs) supported by a GeNotes Gastro-Hep Liaison (RS), and working with the GEP Education Development Lead (AF), with administrative support from the GEP. T1 and T2 resources were mapped to the NHS National Genomics Testing Directory. Additional resources were developed to support the application of genomics relevant to clinical practice, but which are outside existing testing directory indications, for example non-Mendelian risk for common diseases such as coeliac disease and IBD.ResultsTier 1 articles are centred around the point of patient care and feature a clinical scenario. Tier 2 acts as an encyclopaedia of resources that can be accessed either via links embedded in tier 1 or independently. The Gastro-Hep WG have produced 18 original Tier 1 ‘In the Clinic’ articles on topics including both gastroenterology (e.g. ‘A patient with polyposis’) and hepatology (e.g. ‘A patient with unexplained intrahepatic cholestasis’). We have also produced 7 original Tier 2 ‘Knowledge Hub’ resources, on topics ranging from serrated polyposis syndrome to polycystic liver disease.The WG has also co-produced a further 3 cross-speciality T1s and 10 T2s including oncology, paediatrics, pharmacogenomics and primary care. The Gastro-Hep GeNotes webpage official launch is late February 2025, however the WG will meet regularly to update the resources in future years. User feedback from website users will be collated and analysed to continue to improve user experience.ConclusionsPrevious evidence indicated a lack of confidence in delivery and interpretation of genomics by gastroenterologists.2 The first wave of Gastroenterology & Hepatology GeNotes resources is completed, providing specialty-specific guidance and resources to facilitate mainstreaming of genomic testing. Future iterations and amendments will be facilitated through the Gastroenterology WG.ReferencesGenotes – a ‘just-in-time’ genomics education resource co-designed with clinicians. Frost BMC Med Educ. 2024.Mainstreaming of genomic medicine in gastroenterology, present and future: a nationwide survey of UK gastroenterology trainees - PubMed. Al Bakir BMJ Open. 2019.

Dystroglycan is a protein which binds directly to two proteins defective in muscular dystrophies (dystrophin and laminin α 2) and whose own aberrant post-translational modification is the common aetiological route of neuromuscular diseases associated with mutations in genes encoding at least six other proteins (POMT1, POMT2, POMGnT1, LARGE, FKTN and FKRP). It is surprising, therefore, that to our knowledge no mutations of the human dystroglycan gene itself have yet been reported. In this study, we describe a patient with a heterozygous de novo deletion of a ∼2-Mb region of chromosome 3, which includes the dystroglycan gene ( DAG1 ). The patient is a 16-year-old female with learning difficulties, white matter abnormalities, elevated serum creatine kinase, oral-motor dyspraxia and facial hypotonia but minimal clinically significant involvement of other muscles. As these symptoms are a subset of those observed in disorders of dystroglycan glycosylation (muscle–eye–brain disease and Warker–Warburg syndrome), we assess the likely contribution to her phenotype of her heterogosity for a null mutation of DAG1 . We also show that the transcriptional compensation observed in the Dag1 +/− mouse is not observed in the patient. Although we cannot show that haploinsufficiency of DAG1 is the sole cause of this patient's myopathy and white matter changes, this case serves to constrain our ideas of the severity of the phenotypic consequences of heterozygosity for null DAG1 mutations.

ObjectivesAs mainstreaming of genomic medicine is being implemented rapidly throughout paediatrics, it is critical that healthcare professionals are effectively upskilled in a timely fashion.1 Genomic Notes for Clinicians (GeNotes) is an NHS England National Genomics Education freely accessible online ‘just in time’ educational resource, designed to meet this need. It is aligned to the National Genomic Test Directory and supports clinicians, at the point of care, to identify when and how to request genomic tests and return results (‘In The Clinic’), and provides and extended learning opportunity (‘Knowledge Hub’). Paediatric content was launched on the public beta website in May 2023. We assessed usability, content and real-world use of the paediatric GeNotes resources.MethodsUsability testing took place in March 2022 and comprised user testing sessions in which participants completed a series of tasks using GeNotes by following a relevant clinical scenario. Data were collected via moderated user testing sessions, a feedback questionnaire and follow-up interviews. The sessions and interviews included a System Usability Scale (SUS) assessment.2 Live website analytics were undertaken to identify those pages most frequently accessed. Self-selection bias may affect the results as participants are likely to have a positive attitude towards genomics. We excluded IP addresses from National Genomics Education staff to avoid skewing the data on the pre-launch test site, however this was not possible for the live website.ResultsFive user testing sessions, 31 feedback surveys and 3 follow-up interviews were conducted. 61% of survey respondents were consultants and 39% were trainees working across quaternary, tertiary, secondary and community paediatrics across various UK regions. 91% said they would be likely or very likely to use GeNotes in the future. The mean SUS score was 86, indicating a high usability (the mean score for digital services is 68). Respondents reported that content is easy to navigate and appropriately detailed. Live website analytics identified that, between 14th June and 27th September 2023, there were 2,753 visits by 1,563 users to paediatric ‘In the Clinic’ pages, most frequently developmental delay/intellectual disability, macrocephaly, and suspected autism spectrum disorder.ConclusionUser testing suggests that GeNotes is a well-received, highly-usable educational resource appropriately pitched at paediatricians, which is being frequently accessed. Further work is required to expand the repository of resources in line with this rapidly evolving field, including resources to support Genomics England’s Generation Study, and to improve accessibility by exploring other routes of access, such as a mobile application.ReferencesAccelerating genomic medicine in the NHS, NHS England, 2022.Brooke J. SUS: A quick and dirty usability scale’ in Usability Evaluation in Industry, 1996.

Organizational climate refers to the shared meaning organizational members attach to the events, policies, practices, and procedures they experience as well as to the behaviors they see being rewarded, supported, and expected (Schneider, Ehrhart, & Macey, 2011). Climate scholars have most frequently used referent-shift consensus and dispersion composition models (Chan, 1998) to conceptualize and measure organizational climate. Based on these models, climate emergence has been characterized by low variance or high consensus of individual-level climate perceptions (Chan, 1998; Ehrhart, Schneider, & Macey, 2013; Hazy & Ashley, 2011; Kuenzi & Schminke, 2009) within formally defined organizational groups (e.g., work teams). Climate scholars have begun to acknowledge these approaches may not offer adequate explanations for organizational-level perceptual variance patterns that could result from socially-derived influences such as demographic attribute similarity. Perceptual variance may instead be better explained by a patterned emergence compilation model (Fulmer & Ostroff, 2015), whereby nonuniform patterns of dispersion assume that skewness and/or multiple modes exist within the climate of an organization. Ostroff and Fulmer (2014) and Fulmer and Ostroff (2015) have proposed that configural measurement techniques such as latent class cluster analysis (LCCA; Nylund, Asparouhov, & Muthén, 2007) be used to identify subgroups of employees who perceive the organization similarly (i.e., subclimates). LCCA addresses the problems inherent in identifying subclimates via traditional composition models and measurement approaches, but has yet to be used for this purpose. To address this gap, this exploratory study examined whether an organization may be usefully classified into subclimates, based on similarity of response patterns across safety climate dimensions. Subclimates were conceptualized as latent, unobserved groups characterized by systematic response patterns that exhibit within-group agreement and between-group differentiation, using LCCA to reveal five latent groups. Each distinct subclimate was subsequently examined for meaningful differences between them on profile characteristics and demographic attributes.

Dystroglycan is a protein which binds directly to two proteins defective in muscular dystrophies (dystrophin and laminin α2) and whose own aberrant post-translational modification is the common aetiological route of neuromuscular diseases associated with mutations in genes encoding at least six other proteins (POMT1, POMT2, POMGnT1, LARGE, FKTN, FKRP). It is surprising, therefore, that to our knowledge no mutations of the human dystroglycan gene itself have yet been reported. Here we describe a patient with a heterozygous de novo deletion of a ~2-megabase region of chromosome 3 which includes the dystroglycan gene (DAG1). The patient is a 16-year old female with learning difficulties, white matter abnormalities, elevated serum creatine kinase (CK), oral-motor dyspraxia and facial hypotonia but minimal clinically significant involvement of other muscles. As these symptoms are a subset of those seen in disorders of dystroglycan glycosylation (muscle-eye-brain disease and Warker-Warburg syndrome), we assess the likely contribution to her phenotype of her heterogosity for a null mutation of DAG1. We also show that the transcriptional compensation seen in the Dag1+/- mouse is not seen in the patient. Although we cannot demonstrate that haploinsufficiency of DAG1 is the sole cause of this patient's myopathy and white matter changes, this case serves to constrain our ideas of the severity of the phenotypic consequences of heterozygosity for null DAG1 mutations.

During a forty-five year period the architecture of Henry Edmund Goodridge progressed from Regency Greek Revival, through late Georgian Picturesque towards Victorian Eclecticism. The aim of this study is to show how through such development Goodridge produced a style that fused historical architectural forms with modern advances in technology, in order to create an architecture that was appropriate to the age he inhabited. This work will investigate Goodridge’s built and unrealised projects at each stage of his career, creating a full list of his works, including newly discovered material (Appendix I), and discuss what they illustrate about his architectural aims and ideas. Such analysis will reveal that, rather than the malleable local architect of common perception, Goodridge was a talented and innovative professional who was continuously at the forefront of national developments in aesthetics and architectural style.