Hyde, S. | Search bioRxiv

bioRxiv2023

In vivo expansion of gene-targeted hepatocytes through transient inhibition of an essential gene

Homology Directed Repair (HDR)-based genome editing is an approach that could permanently correct a broad range of genetic diseases. However, its utility is limited by inefficient and imprecise DNA repair mechanisms in terminally differentiated tissues. Here, we tested "Repair Drive", a novel method for improving targeted gene insertion in the liver by selectively expanding correctly repaired hepatocytes in vivo. Our system consists of transient conditioning of the liver by knocking down an essential gene, and delivery of an untargetable version of the essential gene in cis with a therapeutic transgene. We show that Repair Drive dramatically increases the percentage of correctly targeted hepatocytes, up to 25%. This resulted in a five-fold increased expression of a therapeutic transgene. Repair Drive was well-tolerated and did not induce toxicity or tumorigenesis in long term follow up. This approach will broaden the range of liver diseases that can be treated with somatic genome editing.

genetics↗

bioRxiv2022

Evaluation of Postgraduate Educational Environment of Doctors Training in Psychiatry: a mixed method study

IntroductionEducational Environment (EE) is of paramount importance in Medical Education, but can be intangible and hard to clearly determine. Professional satisfaction and patient care improve in a pleasant learning environment; where postgraduate physicians are encouraged, suitably supervised, and fostered. A negative learning environment can be detrimental to trainees and teams morale and can jeopardize the multidisciplinary working relationship. ObjectivesThe objective of this study was to measure the Educational Environment (EE) of Psychiatry postgraduate training in the Midwest of Ireland training Deanery; what aspects of training are working well and what areas are seen as not optimal. MethodsThis study took place between April and June 2021. A mixed methods approach was adopted, using the Postgraduate Hospital Educational Environment Measure (PHEEM) and semi-structured one-to-one interviews. ResultsResponse rate was 88% (n=22). The total PHEEM score was 105.64{+/-}23.52, indicating a postgraduate EE with more positive than negative aspects, but with room for improvement. There were no differences in overall PHEEM and subscale scores between trainees gender, training grades or years of working experience. Three themes were identified that contribute to trainees perception of EE: the commitment of the trainees supervisors to the role they play in trainees overall development, the clinical workload of the trainee, and the day-to-day working conditions of the trainee. Definite disparities between work placements were evident in the collected data across these three themes. ConclusionsAlthough the training program had an overall positive EE, specific answers and interview themes indicated some areas of weakness that may contribute to trainee dissatisfaction and possible burnout. Planned interventions targeting these areas and tracking changes in EE and burnout rates over time may be useful measures going forward. Declaration of InterestNone

scientific communication and education↗