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ObjectivesInflammatory myopathy or myositis is a heterogeneous family of immune-mediated diseases including dermatomyositis (DM), antisynthetase syndrome (AS), immune-mediated necrotising myopathy (IMNM) and inclusion body myositis (IBM). Immune checkpoint inhibitors (ICIs) can also cause myositis (ICI-myositis). This study was designed to define gene expression patterns in muscle biopsies from patients with ICI-myositis.MethodsBulk RNA sequencing was performed on 200 muscle biopsies (35 ICI-myositis, 44 DM, 18 AS, 54 IMNM, 16 IBM and 33 normal muscle biopsies) and single nuclei RNA sequencing was performed on 22 muscle biopsies (seven ICI-myositis, four DM, three AS, six IMNM and two IBM).ResultsUnsupervised clustering defined three distinct transcriptomic subsets of ICI-myositis: ICI-DM, ICI-MYO1 and ICI-MYO2. ICI-DM included patients with DM and anti-TIF1γ autoantibodies who, like DM patients, overexpressed type 1 interferon-inducible genes. ICI-MYO1 patients had highly inflammatory muscle biopsies and included all patients that developed coexisting myocarditis. ICI-MYO2 was composed of patients with predominant necrotising pathology and low levels of muscle inflammation. The type 2 interferon pathway was activated both in ICI-DM and ICI-MYO1. Unlike the other types of myositis, all three subsets of ICI-myositis patients overexpressed genes involved in the IL6 pathway.ConclusionsWe identified three distinct types of ICI-myositis based on transcriptomic analyses. The IL6 pathway was overexpressed in all groups, the type I interferon pathway activation was specific for ICI-DM, the type 2 IFN pathway was overexpressed in both ICI-DM and ICI-MYO1 and only ICI-MYO1 patients developed myocarditis.

ObjectivesInflammatory myopathy or myositis is a heterogeneous family of immune-mediated diseases including dermatomyositis (DM), antisynthetase syndrome (AS), immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM). Immune checkpoint inhibitors (ICI) can also cause myositis (ICI-myositis). This study was designed to define gene expression patterns in muscle biopsies from patients with ICI-myositis.MethodsBulk RNA sequencing was performed on 200 muscle biopsies (35 ICI-myositis, 44 DM, 18 AS, 54 IMNM, 16 IBM, and 33 normal muscle biopsies) and single nuclei RNA sequencing was performed on 22 muscle biopsies (7 ICI-myositis, 4 DM, 3 AS, 6 IMNM, and 2 IBM).ResultsUnsupervised clustering defined three distinct transcriptomic subsets of ICI-myositis: ICI-DM, ICI-MYO1, and ICI-MYO2. ICI-DM included patients with DM and anti-TIF1γ autoantibodies who, like DM patients, overexpressed type 1 interferon-inducible genes. ICI-MYO1 patients had highly inflammatory muscle biopsies and included all patients that developed co-existing myocarditis. ICI-MYO2 was composed of patients with predominant necrotizing pathology and low levels of muscle inflammation. The type 2 interferon pathway was activated both in ICI-DM and ICI-MYO1. Unlike the other types of myositis, all three subsets of ICI-myositis patients overexpressed genes involved in the IL6 pathway.ConclusionsWe identified three distinct types of ICI-myositis based on transcriptomic analyses. The IL6 pathway was overexpressed in all groups, the type I interferon pathway activation was specific for ICI-DM, the type 2 IFN pathway was overexpressed in both ICIDM and ICI-MYO1, and only ICI-MYO1 patients developed myocarditis.

ObjectivesMyositis is a heterogeneous family of diseases including dermatomyositis (DM), immune-mediated necrotising myopathy (IMNM), antisynthetase syndrome (AS) and inclusion body myositis (IBM). Myositis-specific autoantibodies define different subtypes of myositis. For example, patients with anti-Mi2 autoantibodies targeting the chromodomain helicase DNA-binding protein 4 (CHD4)/NuRD complex (a transcriptional repressor) have more severe muscle disease than other DM patients. This study aimed to define the transcriptional profile of muscle biopsies from anti-Mi2-positive DM patients.MethodsRNA sequencing was performed on muscle biopsies (n=171) from patients with anti-Mi2-positive DM (n=18), DM without anti-Mi2 autoantibodies (n=32), AS (n=18), IMNM (n=54) and IBM (n=16) as well as 33 normal muscle biopsies. Genes specifically upregulated in anti-Mi2-positive DM were identified. Muscle biopsies were stained for human immunoglobulin and protein products corresponding to genes specifically upregulated in anti-Mi2-positive muscle biopsies.ResultsA set of 135 genes, includingSCRT1andMADCAM1, was specifically overexpressed in anti-Mi2-positive DM muscle. This set was enriched for CHD4/NuRD-regulated genes and included genes that are not otherwise expressed in skeletal muscle. The expression levels of these genes correlated with anti-Mi2 autoantibody titres, markers of disease activity and with the other members of the gene set. In anti-Mi2-positive muscle biopsies, immunoglobulin was localised to the myonuclei, MAdCAM-1 protein was present in the cytoplasm of perifascicular fibres, and SCRT1 protein was localised to myofibre nuclei.ConclusionsBased on these findings, we hypothesise that anti-Mi2 autoantibodies could exert a pathogenic effect by entering damaged myofibres, inhibiting the CHD4/NuRD complex, and subsequently derepressing the unique set of genes defined in this study.

Objective Anoctamin 5 (ANO5) is a putative intracellular calcium-activated chloride channel. Recessive mutations in ANO5 may present from asymptomatic hyperCKemia and exercise-induced myalgia to proximal and/or distal muscle weakness. Here we describe the clinical, pathological, and molecular findings of three unrelated patients with ANO5-related muscular dystrophy. Methods In this retrospective study, we analyzed our database which includes 1700 muscle biopsies performed for diagnostic purposes from October 2004 to February 2019. Patients were attended by two myology experts, who performed and analyzed the muscle biopsies. Muscle biopsies were frozen in cooled isopenthane, cryostat sectioned, and routinely stained and reacted (minimum 16 stainings). A custom panel, including 115 genes (Nextera Rapid Capture, Illumina) and whole-exome sequencing analysis, was used for next-generation sequencing in cases without a definite pathological diagnosis. Results Three patients were diagnosed with ANO5-related muscular dystrophy, with all presenting the common exon 5 mutation c.191dup plus a compound heterozygous missense mutation. They showed three different phenotypes (distal myopathy, LGMD2L, and asymptomatic hyperCKemia). Curiously, all three muscle biopsies showed different patterns, but numerous ragged-red fibers with little endomysial inflammation and partial invasion cell by T lymphocytes were observed in one. Conclusion ANO5-related muscular dystrophy is a heterogeneous disease with different clinical phenotypes as well as different histological patterns, which may even mimic a mitochondrial myopathy. The results of this study provide further knowledge of the clinical, histological, and pathological features related to ANO5 mutations.

Aquesta tesi consisteix en un estudi epidemiològic descriptiu de jugadors masculins de futbol en les etapes formatives en clubs no professionals que comprenen les edats dels 10 als 18 anys. En aquesta s'estudien les categories Alevins, Infantils, Cadets i Juvenils, així com el conjunt de totes elles. L'objectiu és descriure la realitat actual de les lesions en el futbol formatiu de la ciutat de Lleida. Després, amb els resultats obtinguts i la seva posterior anàlisi, poder proposar programes d'exercicis preventius específics per a cada categoria, a més, de globals que serveixin per a totes. L'estudi el compon una mostra de 647 esportistes de cinc clubs de futbol de la ciutat de Lleida. El gran valor afegit a la tesis recau en les eines de recollida de dades, les quals han estat provades i validades. Amb l'ús d'aquestes eines s'ha creat un protocol metodològic per tal d'obtenir uns resultats rigorosos i facilitar l'anàlisi posterior tant per a l'investigador, com pel club implicat. Pel tractament de dades i anàlisi dels resultats epidemiològics s'aplicaran procediments d'estadística descriptiva i d'estadística d’inferència. En total s'han registrat 131 lesions, amb una incidència de 14,03 lesions per cada 1.000 hores d'exposició. D'aquestes 131 lesions, 49 lesions s'han registrat en entrenaments, amb una incidència de 6,62 lesions per cada 1.000 hores d'exposició i 82 lesions s'han registrat en situació de partit, amb una incidència de 42,47 lesions per cada 1.000 hores d'exposició. La cuixa va ser la zona més afectada, amb una incidència de 5,79 lesions per 1000 hores d'exposició i una prevalença de 54 lesions (41,2%). El teixit més prevalent ha estat el múscul-tendinós amb 72 lesions registrades (54,9%) i una incidència de 7,72 lesions per 1000 hores d'exposició. A partir del treball realitzat es considera que s’han obert noves i importants línies d'investigació com: crear programes preventius específics, analitzar la seva implementació i efectivitat, finalitzar el prototip de la consola virtual per observar en temps real els registres inscrits a l'instant i la seva posterior anàlisi sense haver d'esperar a l'informe de fi de temporada, millorar l'automatització dels registres, crear un "big data" dels registres capacitat amb fórmules d'avís de risc de lesió i traslladar tot el que s'ha fet amb petites modificacions a altres esports. Es considera que aquesta tesi és l'inici del que pot arribar a ser un gran final. Esta tesis consiste en un estudio epidemiológico descriptivo de jugadores masculinos de fútbol en etapas formativas en clubs no profesionales que comprende las edades de los 10 a los 18 años. En él se estudian las categorías Alevines, Infantiles, Cadetes y Juveniles, así como el conjunto de todas ellas. El objetivo es describir la realidad actual de las lesiones en el fútbol formativo de la ciudad de Lleida. Tras los resultados obtenidos y su posterior análisis, se podrán proponer programas de ejercicios preventivos específicos para cada categoría, además, de globales que sirvan para todos. El estudio lo compone una muestra de 647 deportistas de cinco clubs de fútbol de la ciudad de Lleida. El gran valor añadido a la tesis recae en las herramientas de recogida de datos, las cuales han sido probadas y validadas. Con el uso de estas herramientas se ha creado un protocolo metodológico con el fin de obtener unos resultados rigurosos y facilitar el análisis posterior tanto para el investigador, como para el club implicado. Para el tratamiento de datos y análisis de los resultados epidemiológicos se aplicaron procedimientos de estadística descriptiva y de estadística inferencial. En total se han registrado 131 lesiones, con una incidencia de 14,03 lesiones por cada 1000 horas de exposición. De estas 131 lesiones, 49 lesiones se han registrado en entrenamientos, con una incidencia de 6,62 lesiones por cada 1000 horas de exposición y 82 lesiones se han registrado en situación de partido, con una incidencia de 42,47 lesiones por cada 1000 horas de exposición. El muslo fue la zona más afectada, con una incidencia de 5,79 lesiones por 1000 horas de exposición y una prevalencia de 54 lesiones (41,2%). El tejido más prevalente ha sido el músculo-tendinoso con 72 lesiones registradas (54,9%) y una incidencia de 7,72 lesiones por 1000 horas de exposición. A partir del trabajo realizado se considera que se han abierto nuevas e importantes líneas de investigación como: crear programas preventivos específicos, analizar su implementación y efectividad, finalizar el prototipo de la consola virtual para observar en tiempo real los registros inscritos al instante y su posterior análisis sin tener que esperar al informe de fin de temporada, mejorar la automatización de los registros, crear un “big data” de los registros capacitado con fórmulas de aviso de riesgo de lesión y trasladar todo lo realizado con pequeñas modificaciones a otros deportes. This thesis consists of a descriptive epidemiological study of male soccer players in formative stages in non-professional clubs that includes the ages of 10 to 18 years. In it, the categories U11-12, U13-14, U15-16 and U17-18, as well as all of them are studied. The goal is to describe the current reality of injuries in the formative soccer of the city of Lleida. After the results obtained and their subsequent analysis, we can propose specific programs of preventive exercises for each category, in addition to the global ones that work for everyone. The study is made up of a sample of 647 athletes from five football clubs in the city of Lleida. The great added value of this thesis are the data collection tools, which have been tested and validated. With the use of these tools, a methodological protocol has been created in order to obtain rigorous results and facilitate subsequent analysis for both the researcher and the club involved. For the treatment of data and analysis of epidemiological results, descriptive statistics and inferential statistics procedures will be applied. In total, 131 injuries have been recorded, with an incidence of 14.03 injuries per 1000 hours of exposure. Of these 131 injuries, 49 injuries have been recorded in training, with an incidence of 6.62 injuries per 1000 hours of exposure and 82 injuries have been recorded in a match situation, with an incidence of 42.47 injuries per 1000 hours of exposure. The thigh was the most affected area, with an incidence of 5.79 injuries per 1000 hours of exposure and a prevalence of 54 injuries (41.2%). The most prevalent tissue has been the muscle-tendon with 72 recorded injuries (54.9%) and an incidence of 7.72 injuries per 1000 hours of exposure. Based on the work carried out, it is considered that new and important research lines have been opened, such as: creating specific preventive programs, analyzing their implementation and effectiveness, finalizing the prototype of the virtual console to observe the registered records in real time and their subsequent analysis without having to wait for the end of the season report, improve the automation of the records, create a "big data" of the records trained with injury risk warning formulas and transfer everything done with minor modifications to other sports. It is considered that this thesis is the beginning of what can become a great end.