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Major histocompatibility complex (MHC) I is an important component of intracellular antigen presentation. However, improper expression of MHC I upon the cell surface has been associated with several autoimmune diseases. Myositis is a rare acquired autoimmune diseases which targets skeletal muscle, and MHC I overexpression on the surface of muscle fibres and immune cell infiltration are clinical hallmarks. MHC I overexpression may have an important pathogenic role, mediated by the activation of the endoplasmic reticulum (ER) stress response. Given the evidence that muscle is a diverse source of cytokines, we aimed to investigate whether MHC I overexpression can modify the profile of muscle-derived cytokines and what role the ER stress pathway may play. Using C2C12 myoblasts we overexpressed MHC I with a H-2kb vector in the presence or absence of salubrinal an ER stress pathway modifying compound. MHC I overexpression induced ER stress pathway activation and elevated cytokine gene expression. MHC I overexpression caused significant release of cytokines and chemokines, which was attenuated in the presence of salubrinal. Conditioned media from MHC I overexpressing cells induced in vitro T-cell chemotaxis, atrophy of healthy myotubes and modified mitochondrial function, features which were attenuated in the presence of salubrinal. Collectively, these data suggest that MHC I overexpression can induce pro-inflammatory cytokine/chemokine release from C2C12 myoblasts, a process which appears to be mediated in-part by the ER stress pathway.

OBJECTIVE: Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of complex autoimmune conditions characterized by inflammation in skeletal muscle and extramuscular compartments, and interferon (IFN) system activation. We undertook this study to examine the contribution of genetic variation to disease susceptibility and to identify novel avenues for research in IIMs.METHODS: Targeted DNA sequencing was used to mine coding and potentially regulatory single nucleotide variants from ~1,900 immune-related genes in a Scandinavian case-control cohort of 454 IIM patients and 1,024 healthy controls. Gene-based aggregate testing, together with rare variant- and gene-level enrichment analyses, was implemented to explore genotype-phenotype relations.RESULTS: Gene-based aggregate tests of all variants, including rare variants, identified IFI35 as a potential genetic risk locus for IIMs, suggesting a genetic signature of type I IFN pathway activation. Functional annotation of the IFI35 locus highlighted a regulatory network linked to the skeletal muscle-specific gene PTGES3L, as a potential candidate for IIM pathogenesis. Aggregate genetic associations with AGER and PSMB8 in the major histocompatibility complex locus were detected in the antisynthetase syndrome subgroup, which also showed a less marked genetic signature of the type I IFN pathway. Enrichment analyses indicated a burden of synonymous and noncoding rare variants in IIM patients, suggesting increased disease predisposition associated with these classes of rare variants.CONCLUSION: Our study suggests the contribution of rare genetic variation to disease susceptibility in IIM and specific patient subgroups, and pinpoints genetic associations consistent with previous findings by gene expression profiling. These features highlight genetic profiles that are potentially relevant to disease pathogenesis.

Overview: While Agile development approaches to physical products have allowed companies to respond more quickly to change and increase R&D productivity, implementing these approaches also poses ne...

Objectives To describe the prevalence and clinical associations of autoantibodies to a novel autoantigen, eukaryotic initiation factor 3 (eIF3), detected in idiopathic inflammatory myositis. Methods Sera or plasma from 678 PM patients were analysed for autoantigen specificity by radio-labelled protein immunoprecipitation (IPP). Samples immunoprecipitating the same novel autoantigens were further analysed by indirect immunofluorescence and IPP using pre-depleted cell extracts. The autoantigen was identified through a combination of IPP and MALDI-TOF mass spectrometry, and confirmed using commercial antibodies and IPP-western blots. Additional samples from patients with DM (668), DM-overlap (80), PM-overlap (191), systemic sclerosis (150), systemic lupus erythematosus (200), Sjogren’s syndrome (40), rheumatoid arthritis (50) and healthy controls (150) were serotyped by IPP as disease or healthy controls. Results IPP revealed a novel pattern in three PM patients (0.44%) that was not found in disease-specific or healthy control sera. Indirect immunofluorescence demonstrated a fine cytoplasmic speckled pattern for all positive patients. Mass spectrometry analysis of the protein complex identified the target autoantigen as eIF3, a cytoplasmic complex with a role in the initiation of translation. Findings were confirmed by IPP-Western blotting. The three anti-eIF3-positive patients had no history of malignancy or interstitial lung disease, and had a favourable response to treatment. Conclusion We report a novel autoantibody in 0.44% of PM patients directed against a cytoplasmic complex of proteins identified as eIF3. Although our findings need further confirmation, anti-eIF3 appears to correlate with a good prognosis and a favourable response to treatment.

Why are some new products so successful and some companies outstanding performers in new-product development? The article identifies success factors from numerous research studies into NPD (new-product development) performance in industry. Three categories of success drivers have been defined. First, success drivers, that explain the success of individual new-product projects, are more tactical: They capture the characteristics of new product projects, such as certain executional best practices (building in voice-of-customer; doing the front-end homework; and adopting a global orientation for the project), and well as the nature of the product itself (a compelling value proposition, for example). A second category is drivers of success at the business level: They include organizational and strategic factors, such as the business's innovation strategy and how the firm makes its RD how it organizes for NPD; climate and culture; and leadership The third category of success divers identified is the systems and methods the firm has in place for managing NPD, for example gating systems, Agile development approaches, and ideation methods. The details of each of these 20 success drivers, along with their managerial implications, are outlined in the article.

The Pandemic taught us that accelerated new‐product development is more important than ever, and provided examples of firms developing breakthrough products in record time. This article outlines five approaches to accelerated development. The first two deal with adequately resourcing new‐product projects, namely the use of focused teams; and effective portfolio management to prioritize projects and reallocate resources. Newer digital tools are outlined that speed new‐products developments. Finally, two development methods are described that move development projects faster: Lean development and Agile development. Accelerated development also has hidden costs: undertaking less innovative projects, and cutting too many corners. Although important, the topic is under‐researched, and the limited research has yielded inconclusive results about acceleration’s expected benefits.

INTRODUCTION: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac condition and the most common cause of sudden cardiac death (SCD) in patients below the age of 35. Genetic testing is a vital part of HCM diagnostics, yet correlation with clinical phenotypes remains complex. Identifying clinical predictors of informative genetic testing may prevent unnecessary investigations and improve cost-effectiveness of services. This article reviews the current literature pertinent to identifying such predictors.METHODS: Five literature databases were screened using a suitably designed search strategy. Studies investigating the correlation between having a positive genetic test for HCM and a range of clinical and radiological parameters were included in the systematic review.RESULTS: Twenty-nine observational studies of a total of 9,486 patients were included. The main predictors of informative genetic testing were younger age, higher septal thickness, reverse septal curvature, family history of HCM and SCD and the absence of hypertension. Two externally validated scoring systems have also been developed: the Mayo and Toronto scores. Novel imaging markers and complex algorithmic models are emerging predictors.CONCLUSION: Using clinical predictors to decide whom to test is a feasible alternative to investigating all comers. Nonetheless, currently there is not enough evidence to unequivocally recommend for or against this strategy. Further validation of current predictors and identification of new ones remain open research avenues.

Dynamo action is studied using numerical simulations of planar Boussinesq convection at rapid rotation, focusing on dynamo action below convective onset. Subcritical dynamo action is successfully sustained in numerous cases, with an extension of the subcritical regime at more rapid rotation. The presence of a subcritical dynamo is dependent on a large-scale mean field with optimum values of the magnetic Prandtl number and magnetic Reynolds number.

Objectives It has been over 10 years since the first report of autoantibodies directed against phenylalanyl tRNA synthetase (anti-Zo) in a patient with features of the anti-synthetase syndrome. In that time no further cases have been published. Here we aim to characterize more fully the clinical phenotype of anti-Zo–associated myositis by describing the clinical features of nine patients. Methods Anti-Zo was identified by protein-immunoprecipitation in patients referred for extended spectrum myositis autoantibody testing at our laboratory. Results were confirmed by immunodepletion using a reference serum. Medical records were retrospectively reviewed to provide detailed information of the associated clinical phenotype for all identified patients. Where possible, HLA genotype was imputed using Illumina protocols. Results Nine patients with anti-Zo were identified. The median age at disease onset was 51 years, and six patients were female. Seven patients had evidence of inflammatory muscle disease, seven of interstitial lung disease and six of arthritis. The reported pattern of interstitial lung disease varied with usual interstitial pneumonia, non-specific interstitial pneumonia and organizing pneumonia all described. Other features of the anti-synthetase syndrome such as RP and mechanics hands were common. HLA data was available for three patients, all of whom had at least one copy of the HLA 8.1 ancestral haplotype. Conclusion Patients with anti-Zo presenting with features of the anti-synthetase syndrome and interstitial lung disease is a common finding. Like other myositis autoantibodies, there is likely to be a genetic association with the HLA 8.1 ancestral haplotype.

The idiopathic inflammatory myopathies (IIM), often referred to collectively but less specifically as “myositis,” have an estimated prevalence of ~14 per 100,000 with an annual incidence of ~8 per 1,000,000 population, which appears to be increasing over time. Any age group can be affected, but myositis commonly presents between 30 and 60 years of age. Differences are seen based on autoantibody subtypes as, for example, anti-signal recognition particle (SRP) seems more common in younger adults. Females are affected about twice as often as males, but again there are important differences when considering specific clinical subtypes as inclusion body myositis (IBM) is more common in males. Current research is focussed on understanding the complex interactions between genetic susceptibility and exposures to environmental triggers. The majority of genetic risk factors identified to date lie within the major histocompatibility complex (MHC), a region which contains genes responsible for antigen presentation, but a small number of genetic risk factors have been found outside this region and implicated in innate and adaptive immune functions. Important environmental associations have been already identified, including exposures to ultraviolet radiation, smoking and certain medications such as statins.

Agile-Stage-Gate is a hybrid product development model that integrates elements of both Agile and Stage-Gate to help companies realize the strengths of both. Recent studies show positive results in manufacturing companies, although SMEs are notably absent despite being the majority. This paper reports results of a test of the model in three deliberately chosen manufacturing SMEs. Results were improved: time to market, overall new product process, higher success rate. Agile required adaptations, and novel solutions were found by the test firms. The positive results suggest that Agile-Stage-Gate must be considered as a recommended product development approach in SME manufacturers.

Background The close temporal association between onset of some connective tissue diseases and cancer suggests a paraneoplastic association. Adult patients with scleroderma with anti-RNA polymerase III autoantibodies and adult patients with dermatomyositis with anti-transcriptional intermediary factor 1 (anti-TIF1) or anti-nuclear matrix protein 2 (anti-NXP2) autoantibodies have a significantly increased risk of developing cancer. Autoantibodies may serve as biomarkers for early detection of cancer and also could be relevant for prediction of responses to immune therapies. We aimed to test whether myositis and scleroderma specific or associated autoantibodies are detectable in individuals with lung cancer. Methods Serum from 60 Caucasian patients with lung cancer (30 with small cell lung cancer, 30 with non-small cell lung cancer) was screened for myositis and scleroderma specific and associated autoantibodies by radiolabelled immunoprecipitation. Results Anti-TIF1, anti-NXP2 or anti-RNA polymerase III autoantibodies were not detected in any of the 60 patients with lung cancer. Anti-glycyl-transfer RNA (tRNA) synthetase (anti-EJ) autoantibodies were detected in one patient with non-small cell lung cancer. No other known myositis or scleroderma autoantibodies were identified. Conclusions Myositis and scleroderma specific autoantibodies, including anti-TIF1, anti-NXP2 and anti-RNA polymerase III, are rare in patients with lung cancer without an autoimmune disease. We report here the first case of anti-EJ autoantibodies being detected in a patient with lung cancer without clinical or radiographic evidence of the anti-synthetase syndrome. Electronic supplementary material The online version of this article (10.1186/s13075-018-1678-9) contains supplementary material, which is available to authorized users.

This article considers how the global "academic pipeline problem" constrains immigrant, low-income, and ethnic minority students' pathways to higher education, and how some students build pathways to college and career identities. After aligning theories of social capital, alienation/belonging, and challenge and their integration in Bridging Multiple Worlds Theory, we summarize six longitudinal studies based on this theory from a 23-year university-community partnership serving low-income, primarily U.S. Mexican immigrant youth. Spanning from childhood to early adulthood, the studies revealed two overarching findings: First, students built pathways to college and career identities while experiencing capital, alienation/belonging, and challenges across their evolving cultural worlds. Second, by "giving back" to families, peers, schools, and communities, students became cultural brokers and later, institutional agents, transforming institutional cultures. Findings highlight the value of integrating interdisciplinary theories, research evidence, and educational systems serving diverse communities to open individual pathways and academic pipelines in multicultural societies.

ObjectivesIdiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare autoimmune diseases in which both genetic and environmental factors play important roles. To identify genetic factors of IIM including polymyositis, dermatomyositis (DM) and clinically amyopathic DM (CADM), we performed the first genome-wide association study for IIM in an Asian population.MethodsWe genotyped and tested 496 819 single nucleotide polymorphism for association using 576 patients with IIM and 6270 control subjects. We also examined the causal mechanism of disease-associated variants by in silico analyses using publicly available data sets as well as by in in vitro analyses using reporter assays and apoptosis assays.ResultsWe identified a variant in WDFY4 that was significantly associated with CADM (rs7919656; OR=3.87; P=1.5×10−8). This variant had a cis-splicing quantitative trait locus (QTL) effect for a truncated WDFY4isoform (tr-WDFY4), with higher expression in the risk allele. Transexpression QTL analysis of this variant showed a positive correlation with the expression of NF-κB associated genes. Furthermore, we demonstrated that both WDFY4 and tr-WDFY4 interacted with pattern recognition receptors such as TLR3, TLR4, TLR9 and MDA5 and augmented the NF-κB activation by these receptors. WDFY4 isoforms also enhanced MDA5-induced apoptosis to a greater extent in the tr-WDFY4-transfected cells.ConclusionsAs CADM is characterised by the appearance of anti-MDA5 autoantibodies and severe lung inflammation, the WDFY4 variant may play a critical role in the pathogenesis of CADM.

The original Stage-Gate process was created in the late 1980s to meet the need to build best practices into new-product projects in a more systematic and disciplined fashion (Cooper 1990). Indeed, ...

ObjectiveTo develop and validate new classification criteria for adult and juvenile idiopathic inflammatory myopathies (IIM) and their major subgroups.MethodsCandidate variables were assembled from published criteria and expert opinion using consensus methodology. Data were collected from 47 rheumatology, dermatology, neurology and paediatric clinics worldwide. Several statistical methods were used to derive the classification criteria.ResultsBased on data from 976 IIM patients (74% adults; 26% children) and 624 non-IIM patients with mimicking conditions (82% adults; 18% children), new criteria were derived. Each item is assigned a weighted score. The total score corresponds to a probability of having IIM. Subclassification is performed using a classification tree. A probability cut-off of 55%, corresponding to a score of 5.5 (6.7 with muscle biopsy) ‘probable IIM’, had best sensitivity/specificity (87%/82% without biopsies, 93%/88% with biopsies) and is recommended as a minimum to classify a patient as having IIM. A probability of ≥90%, corresponding to a score of ≥7.5 (≥8.7 with muscle biopsy), corresponds to ‘definite IIM’. A probability of ConclusionsThe European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria for IIM have been endorsed by international rheumatology, dermatology, neurology and paediatric groups. They employ easily accessible and operationally defined elements, and have been partially validated. They allow classification of ‘definite’, ‘probable’ and ‘possible’ IIM, in addition to the major subgroups of IIM, including juvenile IIM. They generally perform better than existing criteria.

Objectives To characterise the 10 year relationship between anti-transcriptional intermediary factor 1 antibody (anti-TIF1-Ab) positivity and cancer onset in a large UK-based adult dermatomyositis (DM) cohort. Methods Data from anti-TIF1-Ab positive/negative adults with verified diagnoses of DM from UKMYONET were analysed. Each patient was followed up until they developed cancer. Kaplan-Meier methods and Cox-proportional hazard modelling were employed to estimate cumulative cancer incidence. Results Data from 263 DM cases were analysed, with a total of 3,252 person-years and a median 11 years follow-up; 55 (21%) of DM cases were anti-TIF1-Ab positive. After 10 years of follow up, a higher proportion of anti-TIF1-Ab positive cases developed cancer, compared with anti-TIF1-Ab negative cases: 38% vs 15% (hazard ratio 3.4 [95% CI 2.2, 5.4]). All the detected malignancy cases in the anti-TIF1-Ab positive cohort occurred between 3 years prior to and 2.5 years after DM onset. No cancer cases were detected within the following 7.5 years in this group, whereas cancers were detected during this period in the anti-TIF1-Ab negative cases. Ovarian cancer was more common in the anti-TIF1-Ab positive vs negative cohort – 19% versus 2% respectively (p-value

ObjectivesIdiopathic inflammatory myopathies (IIM) are a spectrum of rare autoimmune diseases characterised clinically by muscle weakness and heterogeneous systemic organ involvement. The strongest genetic risk is within the major histocompatibility complex (MHC). Since autoantibody presence defines specific clinical subgroups of IIM, we aimed to correlate serotype and genotype, to identify novel risk variants in the MHC region that co-occur with IIM autoantibodies.MethodsWe collected available autoantibody data in our cohort of 2582 Caucasian patients with IIM. High resolution human leucocyte antigen (HLA) alleles and corresponding amino acid sequences were imputed using SNP2HLA from existing genotyping data and tested for association with 12 autoantibody subgroups.ResultsWe report associations with eight autoantibodies reaching our study-wide significance level of p–5. Associations with the 8.1 ancestral haplotype were found with anti-Jo-1 (HLA-B*08:01, p=2.28×10–53 and HLA-DRB1*03:01, p=3.25×10–9), anti-PM/Scl (HLA-DQB1*02:01, p=1.47×10–26) and anti-cN1A autoantibodies (HLA-DRB1*03:01, p=1.40×10–11). Associations independent of this haplotype were found with anti-Mi-2 (HLA-DRB1*07:01, p=4.92×10–13) and anti-HMGCR autoantibodies (HLA-DRB1*11, p=5.09×10–6). Amino acid positions may be more strongly associated than classical HLA associations; for example with anti-Jo-1 autoantibodies and position 74 of HLA-DRB1 (p=3.47×10–64) and position 9 of HLA-B (p=7.03×10–11). We report novel genetic associations with HLA-DQB1 anti-TIF1 autoantibodies and identify haplotypes that may differ between adult-onset and juvenile-onset patients with these autoantibodies.ConclusionsThese findings provide new insights regarding the functional consequences of genetic polymorphisms within the MHC. As autoantibodies in IIM correlate with specific clinical features of disease, understanding genetic risk underlying development of autoantibody profiles has implications for future research.

Objectives To determine prevalence and co-existence of myositis specific autoantibodies (MSAs) and myositis associated autoantibodies (MAAs) and associated clinical characteristics in a large cohort of idiopathic inflammatory myopathy (IIM) patients. Methods Adult patients with confirmed IIM recruited to the EuroMyositis registry (n = 1637) from four centres were investigated for the presence of MSAs/MAAs by radiolabelled-immunoprecipitation, with confirmation of anti-MDA5 and anti-NXP2 by ELISA. Clinical associations for each autoantibody were calculated for 1483 patients with a single or no known autoantibody by global linear regression modelling. Results MSAs/MAAs were found in 61.5% of patients, with 84.7% of autoantibody positive patients having a sole specificity, and only three cases (0.2%) having more than one MSA. The most frequently detected autoantibody was anti-Jo-1 (18.7%), with a further 21 specificities each found in 0.2–7.9% of patients. Autoantibodies to Mi-2, SAE, TIF1, NXP2, MDA5, PMScl and the non-Jo-1 tRNA-synthetases were strongly associated (p, Highlights • Myositis specific autoantibodies very rarely coexist in the one individual allowing endotypes to be more precisely defined. • The association of anti-TIF1 and cancer-associated myositis is confirmed with a cut-off age of over 58 years. • In a large combined European myositis cohort associations of anti-SRP with carditis and anti-Mi-2 with cancer have emerged. • Myositis associated autoantibodies are strongly associated with having myositis in association with another connective tissue disease.

Introduction ILD represents a heterogeneous spectrum of subgroups, the biggest being IPF and connective tissue disease ILD (CTD-ILD). In IPF, a lack of biomarkers and the dangers of lung biopsy make the diagnosis dependant on HRCT. Usual Interstitial Pneumonia changes are typical of IPF, but can also occur in CTD-ILD, making misdiagnosis a possibility. While CTD-ILDs can respond to immunosuppression with corticosteroids and disease modifying drugs, these agents are ineffective and harmful in IPF, and therefore contraindicated (Raghu et al. N Eng J Med 2012; 366: 1968). Where possible, it is thus important to exclude a covert CTD-ILD in IPF patients. Previous studies have detected autoantibodies in 6%–38% of patients with idiopathic interstitial pneumonias (Song et al. Yonsei Med J 2015; 56: 676, Watanabe et al. Respir Med 2011; 105: 1238), but wide-ranging CTD serotyping has not been undertaken in a large UK IPF cohort. Methods The gold standard for autoantibody detection is immunoprecipitation (IP), which very occasionally detects anti-Ro, but no other, autoantibodies in normal subjects. IP of radio-labelled K562 cells was used to serotype 250 IPF patients recruited via UK-BILD. All satisfied the 2011 ATS/ERS diagnostic guidelines and had IPF-specific HRCT changes (Raghu et al. Am J Respir Crit Care Med 2011; 183: 788). Proteins recognised by autoantibodies from patients’ serum were fractionated by 9% SDS-PAGE gel, and identified by autoradiography. Known autoantigens were identified by direct comparison with antibody positive controls on the same gel. Results Four of 250 IPF patients (1.6%) were IP-positive for recognised CTD-specific autoantibodies, including one with an anti-synthetase (anti-OJ) and three with scleroderma or scleromyositis overlap-associated antibodies (anti-RNA Polymerase II, anti-PM-Scl and anti-Ku respectively). There were no clinical or radiographic characteristics which distinguished antibody positive from antibody negative cases. Conclusion Although CTD-specific autoantibodies were detected in only a tiny proportion of IPF patients, to suggest a possible misdiagnosis, this could have potentially serious therapeutic implications for individual patients. We recommend that, while IPF is clearly a robust diagnosis when made by multidisciplinary teams in tertiary centres, clinicians should endeavour to undertake comprehensive autoantibody testing in all IPF cases.

Background Differentiating CTD-ILD from IPF can be very difficult, because of overlapping HRCT and lung biopsy patterns, and subtle CTD clinical features. Autoantibody testing can raise awareness of the presence of a covert CTD. CTD-ILD associated with amyopathic myositis is a particularly difficult group to diagnose. Anti-Jo-1 antibody testing is commonplace in ILD, but other myositis–associated antibodies, which also associate with CTD-ILD, are not routinely tested for.1 Immunoprecipitation is the gold standard for autoantibody testing, but is expensive and of very limited availability. The EUROLINE testing system is a commercially available system that tests for 16 myositis-associated antibodies, 8 of which are also ILD-associated. Following introduction of EUROLINE testing into our clinical practice, we assess here its utility to exclude covert CTD-ILDs in an IPF cohort from our clinic. Methods We analysed data from 151 consecutive patients to November 2016, diagnosed with IPF by ILD MDT consensus at a UK ILD specialist center. Patient serology included the EUROLINE: Autoimmune Inflammatory Myopathies 16 Ag test (EUROIMMUN). All cases with positive EUROLINE results were also reviewed by a rheumatologist expert in EUROLINE interpretation. Results A positive EUROLINE test was found in 35/151 (23%) of patients, table 1. Only 14/35 (40%) of the positive results were autoantibodies known to be associated with CTD-ILD. Following rheumatology review, all 35 positive results were deemed to be clearly false positives. Conclusions EUROLINE identified false positives in a significant number of IPF cases, so, clinicians need to be cautious regarding the interpretation of this type of CTD-ILD screening. However, with care, myositis-ILD screening may have an important role to play in the evaluation of ILD/IPF cases. Many chest physicians will be unfamiliar with the use of this antibody panel for myositis-ILD screening, and we suggest that an expert rheumatology opinion is sought where positive results are obtained. This methodology could potentially lead to more accurate diagnoses and easier treatment choices. Only some of the EUROLINE antibody specificities are known to be ILD-associated, making it easier to identify many of the false positives as erroneous. Reference Cotton CV, Spencer LG, New RP, Cooper RG. The utility of comprehensive autoantibody testing to differentiate connective tissue disease associated and idiopathic interstitial lung disease subgroup cases. Rheumatology2017;56:1264–71

This article updates on the concept that muscle-derived cytokines (myokines) play important roles in muscle health and disease.Interleukin-6 (IL-6) is released from normal skeletal muscle in response to exercise, mediating both anti-inflammatory responses and metabolic adaptations, actions contradictory to the prevailing view that IL-6 is a proinflammatory cytokine that is inducing and propagating disease. The anti-inflammatory effects of IL-6 result from its trans-membrane signalling capability, via membrane-bound receptors, whereas its proinflammatory effects result instead from signalling via the soluble IL-6 receptor and gp130. IL-15 is elevated following exercise, promoting muscle fibre hypertrophy in some circumstances, while inducing fibre apoptosis in others. This functional divergence appears because of variations in expression of IL-15 receptor isoforms. Decorin, a recently described myokine, is also elevated following exercise in normal muscle, and promotes muscle fibre hypertrophy by competitively binding to, and thus inhibiting, myostatin, a negative regulator of muscle protein synthesis. Exercise-induced myostatin downregulation thus promotes muscle fibre growth, prompting recent trials of a biological myostatin inhibitor in inclusion body myositis.Myokines appear to exert diverse beneficial effects, though their mechanistic roles in myositis and other myopathologies remain poorly understood.

New evidence reveals that Agile methods, until now used primarily for IT developments, can be integrated with traditional gating approaches to yield significant potential benefits for manufacturers of B2B physical products. Indeed, this new Agile-Stage-Gate hybrid approach represents a significant change to our thinking about how new-product development should be done since the introduction of today's popular gating systems thirty years ago! The article shows how Agile emerged in the IT industry and early attempts to integrate it with gating models, also in the IT world. The article moves on to the recent use of this hybrid model by manufacturers, and the results achieved by early adopters when implementing this new system in industries from food to heavy equipment. In terms of implementation, the details of the new Agile-Stage-Gate system are presented, including the “Power of Nine” – the three key artefacts (such as sprints and scrums); three important tools (such as sprint backlogs and burndown charts), and the three vital roles (such as the product owner and the scrum master) needed to make it work. Agile from the IT world cannot be directly integrated into Stage-Gate for physical products without some important modifications, however. These needed adjustments – such as redefining a “done sprint” and how to present versions of the product or “protocepts” for continuous customer feedback – are outlined, complete with a case study from an equipment manufacturer. Additionally, the article identifies and deals with ten important issues and apparent inconsistencies that arise when implementing this new system for B2B products.

The idiopathic inflammatory myopathies (IIM) are a rare and heterogeneous group of acquired autoimmune muscle disorders, often referred to as ‘myositis’. Clinical assessment, together with muscle biopsy findings and autoantibody status are key factors to consider when making a diagnosis of IIM, and in stratification of the ‘IIM spectrum’ into disease subgroups. Treatment stratified according to serotype (and in the future, likely also genotype) is increasingly being used to take account of the heterogeneity within the IIM spectrum. Subgroup classification is also important in terms of monitoring for complications, such as malignancy and interstitial lung disease. Disease monitoring should include the use of standardized tools such as the IMACS disease activity outcome measures. Other tools such as muscle MRI can be useful in identifying areas of active muscle inflammation. Treatment outcomes in IIM remain unsatisfactory. The evidence base to guide treatment decisions is remarkably limited. In addition to muscle inflammation, a number of noninflammatory cell-mediated mechanisms may contribute to weakness and disability, and for which no specific treatments are currently available.

Agile development methodologies have been widely employed in the software industry, where they have been found to yield positive results. But can these new methods, with their new tools such as sprints, scrums, burndown charts, and backlogs, really be integrated with the traditional and popular Stage-Gate approach and then applied to physical products? Initial but limited evidence suggests yes: Larger IT firms have already integrated Agile and Stage-Gate and gained the benefits of both approaches; and most recently, a handful of manufacturing firms have employed this Agile–Stage-Gate hybrid model for physical new products. And if recent evidence can be trusted, this new approach promises to be the most significant change to our thinking about how new-product development should be done since the introduction of today's popular gating systems 30 years ago. The benefits of this hybrid model are a faster and more adaptive response to changing customer needs, better integration of voice-of-customer, better team communication, improved development productivity, and faster to market. A case example from a toy company, LEGO, is provided as an illustration. But there are negatives as well, and additionally, manufacturers must make modifications to Agile in order to adopt it successfully. Although initial results appear promising, much research is needed to explore this new Agile–Stage-Gate hybrid model, and many research challenges remain.

Maladaptive endoplasmic reticulum (ER) stress is associated with modified reactive oxygen species (ROS) generation and mitochondrial abnormalities, and is postulated as a potential mechanism involved in muscle weakness in myositis, an acquired autoimmune neuromuscular disease. This study investigates the impact of ROS generation in an in vitro model of ER stress in skeletal muscle, using the ER stress inducer tunicamycin (24 h) in the presence or absence of a superoxide dismutase/catalase mimetic Eukarion (EUK)-134. Tunicamycin induced maladaptive ER stress, which was mitigated by EUK-134 at the transcriptional level. ER stress promoted mitochondrial dysfunction, described by substantial loss of mitochondrial membrane potential, as well as a reduction in respiratory control ratio, reserve capacity, phosphorylating respiration, and coupling efficiency, which was ameliorated by EUK-134. Tunicamycin induced ROS-mediated biogenesis and fusion of mitochondria, which, however, had high propensity of fragmentation, accompanied by upregulated mRNA levels of fission-related markers. Increased cellular ROS generation was observed under ER stress that was prevented by EUK-134, even though no changes in mitochondrial superoxide were noticeable. These findings suggest that targeting ROS generation using EUK-134 can amend aspects of ER stress-induced changes in mitochondrial dynamics and function, and therefore, in instances of chronic ER stress, such as in myositis, quenching ROS generation may be a promising therapy for muscle weakness and dysfunction.

In patients with myositis, persistent skeletal muscle weakness in the absence of significant inflammatory cell infiltrates is a well-recognised, but poorly understood, cause of morbidity. This has led researchers to investigate cellular mechanisms independent of immune cells, which may contribute to this underlying muscle weakness. Chronic ER stress pathway activation is evident in the muscle of myositis patients, and is now a potential mediator of muscle weakness in the absence of inflammation. Abnormal ER stress pathway activation is associated with mitochondrial dysfunction, resulting in bioenergetic deficits and reactive oxygen species (ROS) generation, which in this context may potentially damage muscle proteins and thus impair contractile performance. This study examined whether treatment with the HSP90 inhibitor 17-N-allylamino-17-demethoxygeldanamycin (17AAG) could mitigate these ER stress-induced changes. C2C12 myotubes were treated with the ER stress-inducing compound Tunicamycin, in the presence or absence of 17AAG. Myotubes were examined for changes relating to ER stress pathway activation, mitochondrial function, markers of oxidative damage and in myotubular dimensions. ER stress pathway activation caused mitochondrial dysfunction, as evidenced by reduced oxygen consumption and ATP generation and by increased gene expression levels of the bio-energetic regulator, uncoupling protein 3 (UCP-3), the latter indicative of electron transport chain uncoupling. ER stress pathway activation also caused increased gene expression of superoxide dismutase (SOD) 2 and peroxiredoxin (PRDX) 3, elevated H2O2 levels, and reduced total thiol pool levels and a significant diminution of myotubular dimensions. Exposure to 17AAG ameliorated these ER stress-induced changes. These findings, which suggest that 17AAG can reduce ER stress-induced mitochondrial dysfunction, oxidative damage and myotubular atrophy, have potential implications in the context of human myositis.

Background The recently published 2017 European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) classification criteria for adult and juvenile idiopathic inflammatory myopathies (IIM) and their major subgroups reflect a long-appreciated need for more accurate case definition in ongoing research in these complex and heterogenous diseases.1 However a number of issues remain unresolved. There was a high frequency of missing data in both the derivation and validation samples, only one of the now numerous myositis specific autoantibodies is included, and certain well recognised IIM subtypes are not specifically classified despite their well phenotyped and differing natural histories, clinical features and treatment modalities.2 3 Objectives To perform an external validation of the EULAR/ACR classification criteria in an incident IIM cohort and examine how classification criteria-assigned IIM subtype correlates with expert opinion. Methods Adults with newly diagnosed IIM attending Salford Royal NHS Foundation Trust Neuromuscular services were identified. A retrospective review of all putative cases was performed, and cases fulfilling a consensus expert-opinion diagnosis of definite IIM included. A broad range of clinical, serological and histological data were collected and each case assigned a single IIM subtype by expert opinion. The EULAR/ACR classification criteria were applied and sensitivity, specificity, positive and negative predictive value calculated, presented with 95% confidence intervals (CI). Results A total of 922 cases were screened with 255 expert opinion definite IIM identified. The sensitivity to diagnose an IIM was 99.6% (97.2–100) and 80.9% (76.0–85.8) for the classification criteria cut-points of ‘probable’ and ‘definite’ respectively. The sensitivity for ‘definite’ IIM improved to 90.2% (86.5–93.8) when biopsy data for 24/34 initially missed cases were excluded. In 94/255 cases the IIM subtype differed between expert opinion and classification criteria, most strikingly in the group subtyped ‘polymyositis’ using the EULAR/ACR criteria, where there was discrepancy in the majority (87/161). Conclusions The criteria performed with high sensitivity in identifying IIM in an external cohort of IIM patients. However, substantial disagreement exists in subtype assignment, especially resulting in a larger proportion of cases of ‘polymyositis’ with heterogeneous features, important to consider in the application of these criteria to subsequent research. References [1] Lundberg IE, Tjarnlund A, Bottai M, Werth VP, Pilkington C, Visser M De, et al. EULAR/ACR classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups. Ann Rheum Dis2017;76:1955–64. [2] Betteridge Z, McHugh N. Myositis-specific autoantibodies: An important tool to support diagnosis of myositis. J Intern Med2016;280:8–23. [3] Longo DL, Dalakas MC. Inflammatory muscle diseases. N Engl J Med2015;372:1734–47. Disclosure of Interest None declared

Background Studying the epidemiology of rare conditions such as the idiopathic inflammatory myopathies (IIM) can assist in the identification of risk factors, disease associations and temporal trends. Interrogation of differing geographically and genetically diverse populations can help to construct a more complete picture of underlying disease patterns. A number of UK centres have contributed to national and international IIM research collaborations, but to date there has been no published report detailing the incidence or prevalence of adult IIM in the UK, or to establish the relative proportion of the varying clinical subtypes. Moreover, previous international studies have focussed on specific IIM subtypes, such as inclusion body myositis (IBM) or immune-mediated necrotising myopathy (IMNM), are historic, were undertaken before recent developments in our understanding of the range of IIM subtypes, and utilised widely varying methodologies and case acquisition strategies. The recently published combined European League Against Rheumatism and American College of Rheumatology (EULAR/ACR) classification criteria for adult and juvenile IIM represent potential progress in identifying IIM, as well as various disease subtypes 1 . We present here the first epidemiological study to utilise these new criteria as part of disease verification. Objectives Identify and characterise all incident adult cases of IIM between Jan 1 st 2007 and Dec 31 st 2016 in the City of Salford, UK. Methods Adults first diagnosed with IIM within the study period were identified by: i) a Salford Royal NHS Foundation Trust (SRFT)inpatient episode IIM-specific ICD-10 coding search; ii) all new patient appointments to SRFT neuromuscular outpatient clinics; iii) all Salford residents enrolled within the UKMYONET study. All patients with ‘definite’ IIM by the 2017 EULAR/ACR classification criteria were included, as were ‘probable’ cases if expert opinion agreed. Cases were excluded if Results The case ascertainment procedures identified 1156 cases which, after review and application of exclusion criteria, resulted in 32 incident cases during the study period. 23/32 were female with a mean age of 58.1 years. The mean incidence of adult IIM was 17.6/1,000,000 person years (py), higher for females than for males (25.2 versus 10.0/1,000,000py respectively). A significant incidence increase over time was apparent (13.6 versus 21.4/1,000,000py; p=0.032). Using EULAR/ACR classification criteria, the largest IIM subtype (21/32) was polymyositis, followed by dermatomyositis (8/32), inclusion body myositis (2/32) and amyopathic dermatomyositis (1/32). Expert opinion subtype differed from EULAR/ACR Classification criteria in 19/32 cases. Conclusions The incidence of adult IIM in Salford is 17.6/1,000,000py, higher in females and is increasing over time. Disagreement exists between EULAR/ACR-derived and expert opinion-derived IIM subtype assignments. References [1] Lundberg IE, Tjarnlund A, Bottai M, et al. EULAR/ACR Classification Criteria for Adult and Juvenile Idiopathic Inflammatory Myopathies and their Major Subgroups. Ann Rheum Dis. 2017;76:1955–64. Disclosure of Interest None declared

Background Quantitative muscle ultrasound (QMUS) imaging has proven to be a useful, non-invasive technique to visualise normal and pathological skeletal muscle tissue.1 Electromyography (EMG) findings are not always disease specific in patients suspected of idopathic inflammatory myopathies (IIM). Objectives To assess diagnostic value of QMUS in patients suspected for an IIM and to compare results with EMG. Methods In 57 patients, suspected for IIM, panel diagnosis blinded for QMUS was used as reference standard. QMUS results were used to classify patients according an ultrasound neuromuscular disorder (NMD) algorithm (normal/borderline/abnormal). The predictive value of QMUS and EMG was assessed in a two by two table and a multivariate logistic regression model. Results Twenty-two patients (39%) were diagnosed with IIM; 8 polymyositis, 4 dermatomyositis, 4 necrotizing myopathy, 3 inclusion body myositis and 3 non-specific myositis. Sixteen patients were classified with other NMD. We found an increased echointensity of the sternocleidomastoid, biceps, forearm flexor and tibialis anterior in the IIM group. Sensitivity, specificity, positive and negative predictive values (PPV/NPV) were 82%, 51%, 51%, 82% for ultrasound NMD algorithm and 63%, 64%, 50%, 75% for EMG. Multivariate analyses showed area under the curve (AUC) (0.81) (0.69–0.92) for ultrasound NMD algorithm, EMG (0.79) (0.67–0.92) and ultrasound NMD algorithm plus EMG (0.82) (0.70–0.93). Conclusions QMUS with NMD algorithm provides a fair diagnostic value for patients suspected for an IIM and is similar to EMG results. A sizeable NPV indicates a low rate of false negative QMUS results. In addition to the relevant PPV for the presence for NMD, QMUS could serve as a potential screening tool for clinicians to detect possible myopathies and to rule out the presence of IIM. References [1] Zaidman CM, van Alfen N. Ultrasound in the Assessment of Myopathic Disorders. J Clin Neurophysiol. 2016;33(2):103–1 Disclosure of Interest None declared

This article considers how the global "academic pipeline problem" constrains immigrant, low-income, and ethnic minority students' pathways to higher education, and how some students build pathways to college and career identities. After aligning theories of social capital, alienation/belonging, and challenge and their integration in Bridging Multiple Worlds Theory, we summarize six longitudinal studies based on this theory from a 23-year university-community partnership serving low-income, primarily U.S. Mexican immigrant youth. Spanning from childhood to early adulthood, the studies revealed two overarching findings: First, students built pathways to college and career identities while experiencing capital, alienation/belonging, and challenges across their evolving cultural worlds. Second, by "giving back" to families, peers, schools, and communities, students became cultural brokers and later, institutional agents, transforming institutional cultures. Findings highlight the value of integrating interdisciplinary theories, research evidence, and educational systems serving diverse communities to open individual pathways and academic pipelines in multicultural societies.