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Background Myotonic dystrophy type 1 (DM1) is an incurable multisystem disease caused by a CTG-repeat expansion in the DM1 protein kinase (DMPK) gene. The OPTIMISTIC clinical trial demonstrated positive and heterogenous effects of cognitive behavioral therapy (CBT) on the capacity for activity and social participations in DM1 patients. Through a process of reverse engineering, this study aims to identify druggable molecular biomarkers associated with the clinical improvement in the OPTIMISTIC cohort. Methods Based on full blood samples collected during OPTIMISTIC, we performed paired mRNA sequencing for 27 patients before and after the CBT intervention. Linear mixed effect models were used to identify biomarkers associated with the disease-causing CTG expansion and the mean clinical improvement across all clinical outcome measures. Results We identified 608 genes for which their expression was significantly associated with the CTG-repeat expansion, as well as 1176 genes significantly associated with the average clinical response towards the intervention. Remarkably, all 97 genes associated with both returned to more normal levels in patients who benefited the most from CBT. This main finding has been replicated based on an external dataset of mRNA data of DM1 patients and controls, singling these genes out as candidate biomarkers for therapy response. Among these candidate genes were DNAJB12, HDAC5, and TRIM8, each belonging to a protein family that is being studied in the context of neurological disorders or muscular dystrophies. Across the different gene sets, gene pathway enrichment analysis revealed disease-relevant impaired signaling in, among others, insulin-, metabolism-, and immune-related pathways. Furthermore, evidence for shared dysregulations with another neuromuscular disease, Duchenne muscular dystrophy, was found, suggesting a partial overlap in blood-based gene dysregulation. Conclusions DM1-relevant disease signatures can be identified on a molecular level in peripheral blood, opening new avenues for drug discovery and therapy efficacy assessments.

Muscular dystrophies are a group of rare and severe inherited disorders mainly affecting the muscle tissue. Duchene Muscular Dystrophy, Myotonic Dystrophy types 1 and 2, Limb Girdle Muscular Dystrophy and Facioscapulohumeral Muscular Dystrophy are some of the members of this family of disorders. In addition to the current diagnostic tools, there is an increasing interest for the development of novel non-invasive biomarkers for the diagnosis and monitoring of these diseases. miRNAs are small RNA molecules characterized by high stability in blood thus making them ideal biomarker candidates for various diseases. In this study, we present the first genome-wide next-generation small RNA sequencing in serum samples of five different types of muscular dystrophy patients and healthy individuals. We identified many small RNAs including miRNAs, lncRNAs, tRNAs, snoRNAs and snRNAs, that differentially discriminate the muscular dystrophy patients from the healthy individuals. Further analysis of the identified miRNAs showed that some miRNAs can distinguish the muscular dystrophy patients from controls and other miRNAs are specific to the type of muscular dystrophy. Bioinformatics analysis of the target genes for the most significant miRNAs and the biological role of these genes revealed different pathways that the dysregulated miRNAs are involved in each type of muscular dystrophy investigated. In conclusion, this study shows unique signatures of small RNAs circulating in five types of muscular dystrophy patients and provides a useful resource for future studies for the development of miRNA biomarkers in muscular dystrophies and for their involvement in the pathogenesis of the disorders. © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

Background The Health Service Executive in Ireland aims to facilitate the translation of research and innovation into policy and practice and increase dissemination of research. Previous HSE surveys showed that a high volume of research was undertaken but the impact on practice and policy was unclear. Researchers reported sharing their research in publications, conferences, and through education and training but identified problems in engaging with practice and policy stakeholders. Survey respondents requested help with dissemination and getting research into practice. An organisation-wide project to identify frameworks to support knowledge translation (KT), dissemination, and impact identified a recommended methodology, created guidance, and training for knowledge creators and users. Objectives Provide a series of six guides, tools and templates, to support knowledge creators and users across the organisation Provide online training to support translation and dissemination of research knowledge Underline the importance of planning KT and impact at research commencement and identify the planned outcomes Develop user-friendly training to explain the elements of KT and dissemination. Results Two pilot studies were undertaken to test the guidance which, although positively received, resulted in changes to the format, design, and language to increase useability. An explainer video and six online training modules were developed, based on the guidance and pilot feedback to be rolled out from July 2021. Learning was enhanced through transfer of complex information and models into short training modules to be accessed by researchers with a range of experience and understanding. Conclusions KT is a complex area and developing education and training for it requires understanding the different learning needs of knowledge creators and users. Education and training should focus on the need for KT and impact from the start of a project. Key messages Practical guidance to assist researchers in translation of their research findings into practice and improving dissemination enhances service user impact. Education and training should focus on the need to plan for KT from the start of a project.

Importance: Mutations in the mitochondrial MT-ATP6 gene are an important cause of mitochondrial disease. Phenotypes related to these mutations include Leigh syndrome (LS), and the syndrome of neuropathy, ataxia, and retinitis pigmentosa (NARP); however, there are also reports of other and intermediate phenotypes. Objective: To characterise the phenotypic and genotypic spectrum of the MT-ATP6 related mitochondrial disease in a large and well-defined mitochondrial disease cohort. Design: A retrospective, observational cohort study. Setting: Three national diagnostic and clinical centres for mitochondrial disorders in Newcastle upon Tyne, Oxford and London; patients were recruited to the Mitochondrial Disease Patient Cohort, UK. Participants: Eighty-eight patients with clinically and genetically defined mitochondrial disease due to mutations in the MT-ATP6 gene that were included in this study. Data from 36 clinically unaffected carriers of MT-ATP6 mutations were also analysed. Main Outcomes and Measures: All patients were interviewed and examined. All available medical notes and clinical, radiological, and genetic investigations were reviewed. Results: We identified 88 clinically affected individuals and 36 asymptomatic family members from 60 pedigrees. Among the patients of whom the respective data were available, 57 of 69 (83%) had cerebellar ataxia, 42 of 57 (74%) had peripheral neuropathy, and 40 of 59 (68%) had some degree of cognitive dysfunction or learning disability. Thirty-two patients (36%) had a presentation compatible with LS, whereas just seven patients (8%) had the complete neuropathy, ataxia, and retinitis pigmentosa phenotype without LS. We observed meaningful differences between the clinical features associated with the common MT-ATP6 mutations. Of interest, four adult patients developed unexpected, subacute brainstem dysfunction akin to Leigh-like crisis, one patient had a stroke-like episode, and three patients exhibited symptoms similar to episodic ataxia. Conclusions and Relevance: The majority of patients with genetic defects of MT-ATP6 have cerebellar ataxia and peripheral neuropathy, and some degree of cognitive dysfunction seems relatively common among these patients. Moreover, some patients experience sudden exacerbations that are suggestive of a mitochondrial energy crisis and mandate active supportive treatment. These findings may be useful in the diagnostics and care of patients with MT-ATP6 related mitochondrial disease.

[Devito] is an open-source Python project based on domain-specific language and compiler technology. Driven by the requirements of rapid HPC applications development in exploration seismology, the language and compiler have evolved significantly since inception. Sophisticated boundary conditions, tensor contractions, sparse operations and features such as staggered grids and sub-domains are all supported; operators of essentially arbitrary complexity can be generated. To accommodate this flexibility whilst ensuring performance, data dependency analysis is utilized to schedule loops and detect computational-properties such as parallelism. In this article, the generation and simulation of MPI-parallel propagators (along with their adjoints) for the pseudo-acoustic wave-equation in tilted transverse isotropic media and the elastic wave-equation are presented. Simulations are carried out on industry scale synthetic models in a HPC Cloud system and reach a performance of 28TFLOP/s, hence demonstrating Devito's suitability for production-grade seismic inversion problems.

Introduction: The loss of mitochondrial function and content have been implicated in sarcopenia although they have been little studied in the very old, the group in which sarcopenia is most common. In this pilot study, our aim was to determine if mitochondrial respiratory chain function and content are preserved among healthy 85-year-olds. Methods: We recruited 19 participants (11 female) through their general practitioner and assessed their medical history, functional status and self-reported physical activity. We identified sarcopenia using grip strength, Timed Up-and-Go and bioimpedance analysis. We assessed mitochondrial respiratory chain function using phosphorous magnetic resonance spectroscopy, estimating τ1/2 PCr, the recovery half-time of phosphocreatine in the calf muscles following a bout of aerobic exercise. We performed a biopsy of the vastus lateralis muscle and assessed mitochondrial respiratory chain content by measuring levels of subunits of complex I and IV of the respiratory chain, expressed as Z-scores relative to that in young controls. Results: Participants had a median (IQR) of 2 (1,3) long-term conditions, reported regular aerobic physical activity, and one participant (5.3%) had sarcopenia. Sixteen participants completed the magnetic resonance protocol and the mean (SD) τ1/2 PCr of 35.6 (11.3) seconds was in keeping with preserved mitochondrial function. Seven participants underwent muscle biopsy and the mean fibre Z-scores were −0.7 (0.7) and −0.2 (0.4) for complexes I and IV, respectively, suggesting preserved content of mitochondrial respiratory chain enzymes. Conclusion: Muscle mitochondrial respiratory chain function and content are preserved in a sample of active, well-functioning 85-year-olds, among whom sarcopenia was uncommon. The results from this study will help inform future work examining the association between muscle mitochondrial deficiency and sarcopenia.