Report on care home costs for older people in Scotland

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Data from: A systematic review and meta-analysis of gene therapy in animal models of cerebral glioma: why did promise not translate to human therapy?

Background: The development of therapeutics is often characterized by promising animal research that fails to translate into clinical efficacy; this holds for the development of gene therapy in glioma. We tested the hypothesis that this is because of limitations in the internal and external validity of studies reporting the use of gene therapy in experimental glioma. Method: We systematically identified studies testing gene therapy in rodent glioma models by searching three online databases. The number of animals treated and median survival were extracted and studies graded using a quality checklist. We calculated median survival ratios and used random effects meta-analysis to estimate efficacy. We explored effects of study design and quality and searched for evidence of publication bias. Results: We identified 193 publications using gene therapy in experimental glioma, including 6,366 animals. Overall, gene therapy improved median survival by a factor of 1.60 (95% CI 1.53–1.67). Study quality was low and the type of gene therapy did not account for differences in outcome. Study design characteristics accounted for a significant proportion of between-study heterogeneity. We observed similar findings in a data subset limited to the most common gene therapy. Conclusion: As the dysregulation of key molecular pathways is characteristic of gliomas, gene therapy remains a promising treatment for glioma. Nevertheless, we have identified areas for improvement in conduct and reporting of studies, and we provide a basis for sample size calculations. Further work should focus on genes of interest in paradigms recapitulating human disease. This might improve the translation of such therapies into the clinic.Hirst, Theodore C. (2016), Data from: A systematic review and meta-analysis of gene therapy in animal models of cerebral glioma: why did promise not translate to human therapy?, Dryad, Dataset, 10.5061/dryad.bs8c

Timing of SMN replacement therapies in models of spinal muscular atrophy: a systematic review and meta-analysis

Background: Mutations in the Survival of Motor Neuron 1 (SMN1) gene lead to a loss of SMN protein in patients with spinal muscular atrophy (SMA). Revolutionary advances in gene therapy have led to SMN-replacement therapies that significantly prolong life expectancy and improve neuromuscular function. However, accumulating evidence suggests that the timing of SMN-replacement therapies is a critical determinant of success. Methods: We performed a systematic review and meta-analysis of all pre-clinical studies testing SMN replacement therapies in mouse models of SMA to assess the impact of timing of delivery on therapeutic effectiveness. We incorporated four databases in this pre-registered study (PROSPERO 2020 CRD42020200180): EMBASE, PubMed, Scopus and Web of Science. Inclusion criteria were; primary research article, a measure of survival analysis, use of an SMA mouse model, and evaluation of an SMN-targeting therapy. Exclusion criteria included; use of therapies not known to directly target SMN, genetic manipulations, and/or lack of appropriate controls. We screened papers using the SyRF platform. The main outcome we assessed was survival in treated groups compared to untreated groups. We performed meta-analysis of survival using median survival ratio and the random effects model and measured heterogeneity using the I2 statistic. Findings: 3,278 studies were initially identified, with 67 ultimately included. SMN-replacement therapies significantly affected survival in favour of treatment by a factor of 1.17 (95% CI 1.06-1.27, p<0.001) with high heterogeneity (I2=95%). Timing of treatment was a significant source of heterogeneity (p<0.01), with earlier treatment having a greater impact on survival. When stratified by type of treatment, earlier treatment continued to have the strongest effect with viral vector replacement therapy and antisense oligonucleotide therapy. Secondary outcome measures of body weight and motor neuron counts were also positively associated with early treatment. Interpretation: Earlier delivery of SMN replacement therapies is a key determinant of treatment efficacy in SMA. Funding: Support for this study was provided by grant funding from SMA Europe and LifeArc/CSO Scotland (awards to THG). The Dataset related to an upcoming publication 'The effect of timing of SMN replacement on survival in mouse models of Spinal Muscular Atrophy: a systematic review and meta-analysis' by H. Chaytow, A. Motyl, N. Huang, G. Currie, Z. Bahor, E. Sena and T. Gillingwate