Functional correlates of clinical phenotype and severity in recurrent SCN2A variants

In SCN2A-related disorders, there is an urgent demand to establish efficient methods for determining the gain- (GoF) or loss-of-function (LoF) character of variants, to identify suitable candidates for precision therapies. Here we classify clinical phenotypes of 179 individuals with 38 recurrent SCN2A variants as early-infantile or later-onset epilepsy, or intellectual disability/autism spectrum disorder (ID/ASD) and assess the functional impact of 13 variants using dynamic action potential clamp (DAPC) and voltage clamp. Results show that 36/38 variants are associated with only one phenotypic group (30 early-infantile, 5 later-onset, 1 ID/ASD). Unexpectedly, we revealed major differences in outcome severity between individuals with the same variant for 40% of early-infantile variants studied. DAPC was superior to voltage clamp in predicting the impact of mutations on neuronal excitability and confirmed GoF produces early-infantile phenotypes and LoF later-onset phenotypes. For one early-infantile variant, the co-expression of the alpha(1) and beta(2) subunits of the Na(v)1.2 channel was needed to unveil functional impact, confirming the prediction of 3D molecular modeling. Neither DAPC nor voltage clamp reliably predicted phenotypic severity of early-infantile variants. Genotype, phenotypic group and DAPC are accurate predictors of the biophysical impact of SCN2A variants, but other approaches are needed to predict severity. A comprehensive biophysical analysis of disease-associated mutations in the voltage-gated sodium channel gene, SCN2A, suggests that dynamic action potential clamp may be a better predictor than voltage clamp of how these mutations alter neuronal excitability, though other approaches are needed to predict severity

Exploring patient acceptability of a short‐stay care pathway in hospital post arthroplasty: A theory‐informed qualitative study

Abstract Introduction Arthroplasty is an effective, yet costly, surgical procedure for end‐stage osteoarthritis. Shorter stays in hospital are being piloted in Australia. In some countries, short stay is established practice, associated with improving perioperative care and enhanced recovery after surgery practices. Exploring the acceptability to patients of a short stay care pathway in hospital postarthroplasty is important for informing health policy, adoption and potential scalability of this model of care. Methods Consecutive patients at one site, at least 3 months post total joint arthroplasty, were invited to participate in theory‐informed semi‐structured qualitative interviews. The Theoretical Framework of Acceptability (TFA) informed development of the interview guide. Interview data were analysed using the Framework Method. Results Eighteen patients were invited. Fifteen consented to be contacted and were interviewed. Short‐stay post arthroplasty was highly acceptable to patients who had the supports necessary to recover safely at home. Key findings were as follows: flexibility of short‐stay care pathway was essential and valued; prior beliefs and expectations informed acceptability; and the absence of out‐of‐pocket expenses had an incentivizing effect, but was not the primary reason for patients choosing this care pathway. Further themes analysed within the TFA constructs highlighted nuances of acceptability relating to this model of care. Conclusions A short stay in hospital post arthroplasty appeared to be acceptable to patients who had experienced this care pathway. Our thematic findings identified aspects of the short‐stay care pathway that enhanced acceptability and some aspects that limited acceptability. These findings can inform refinement of the short‐stay care pathway. Patient or Public Contribution Patients/people with lived experience were not involved in the study design or conduct of this preliminary work; as this short‐stay model of care was recently introduced, only a small group of patients was eligible to participate in this study. This study is the first step towards understanding the experiences of patients about a short‐stay model of care post arthroplasty. The findings will help inform future patient and public involvement in expanding the programme