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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.

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.

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.

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, ...

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.

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.

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.

Objectives The aim was to identify and characterize all incident adult cases of idiopathic inflammatory myopathies (IIM) between 1 January 2007 and 31 December 2016 in the City of Salford, UK. Methods Adults first diagnosed with IIM within the study period were identified by: a Salford Royal NHS Foundation Trust (SRFT) inpatient episode IIM-specific ICD-10 coding search; all new patient appointments to SRFT neuromuscular outpatient clinics; and 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 consensus expert opinion agreed. Cases were excluded if

Idiopathic 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.We 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.We identified a variant inAs 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.

Background The idiopathic inflammatory myopathies (IIM) represent a rare and heterogeneous group of multisystem autoimmune diseases. The rarity of IIM has hampered research efforts, resulting in remarkably limited therapeutic evidence. The EuroMyositis Registry was created to pool resources and expertise across the international IIM research community. Objectives To describe the phenotypic characteristics of different IIM subtypes. Associations with malignancy, interstitial lung disease (ILD), cardiac involvement and dysphagia were assessed. Methods Pooled data from the EuroMyositis Registry (from Belgium, China, Czech Republic, Hungary, Italy, Mexico, Norway, Sweden, Switzerland, UK, Vietnam) were obtained. Associations were assessed using logistic regression and multinomial logistic regression with polymyositis (PM) as the reference group. Results Data regarding 3,196 patients were analysed. The UK was the largest contributor (n=1,307). The most common diagnoses were dermatomyositis (34%), PM (32%) and connective tissue disease (CTD)-overlap myositis (15%). In those with anti-synthetase syndrome (7%), 85% had muscle weakness, 86% ILD and 58% arthritis. Overall, 43% had a myositis specific antibody, most commonly anti-Jo1 autoantibodies (20%). Glucocorticoid usage was noted in 98%. Most commonly used disease modifying agents were methotrexate (71%) and azathioprine (50%). Malignancy occurred in 9% and was associated with a diagnosis of dermatomyositis (Relative Risk Ratio [RRR] 1.68, 95% CI 1.09–2.56, p=0.018). Cardiac involvement occurred in 9%, most commonly in those with CTD-overlap myositis (13%), and was associated with a higher Health Assessment Questionnaire disability index (1 versus 0.75, OR 1.40, 95% CI 1.03–1.91, p=0.031). Dysphagia occurred in 39% and was associated with a diagnosis of CTD-overlap myositis (RRR 2.25, 95% CI 1.61–3.15, p Conclusions This large international cohort demonstrates the heterogeneity of IIM and the burden of associated malignancy, ILD, cardiac and gastrointestinal involvement. The EuroMyositis Registry facilitates international collaborative research outputs, underlining the benefits of harmonised data collection methodology between centres. Acknowledgements This work was supported by researchers at the National Institute for Health Research (NIHR) Biomedical Research Unit. The views expressed are those of the authors and not necessarily those of the UK National Health Service, the NIHR or the UK Department of Health Disclosure of Interest J. Lilleker: None declared, J. Vencovsky: None declared, G. Wang: None declared, L. Wedderburn Grant/research support from: The UK JDM Cohort and Biomarker study is supported by grants from the NIHR and Myositis UK, L. Diederichsen: None declared, J. Schmidt: None declared, P. Jordan: None declared, O. Benveniste: None declared, M. G. Danieli: None declared, K. Dankό: None declared, N. T. P. Thuy: None declared, M. Vazquez-Del Mercado: None declared, O. Molberg: None declared, B. De Paepe: None declared, J. De Bleecker: None declared, B. Maurer Grant/research support from: AbbVie, Protagen, EMDO, Novartis, Roche, Actelion, N. Pipitone Speakers bureau: GRAPPA Workshop, Alfa-Wassermann, N. McHugh: None declared, Z. Betteridge: None declared, P. New: None declared, R. Cooper: None declared, W. Ollier: None declared, J. Lamb Grant/research support from: MedImmune, N. S. Krogh: None declared, I. Lundberg Grant/research support from: Astra-Zeneca, Bristol-Myers Squibb, Consultant for: Bristol-Myers Squibb, Idera, H. Chinoy Grant/research support from: MedImmune, Novartis

OVERVIEW:As the creator of the Stage-Gate® process, I am often asked, “What's next after stage-gate?” For years, I've not had an answer. Now, we're seeing new approaches emerging from progressive companies that represent a new generation of idea-to-launch processes. In some cases, it's an evolution of Stage-Gate to a better, faster model; in other firms, its closer to a revolution, moving to a very different system. But there is anything but unanimity as to what the next generation idea-to-launch system should be. This article looks at what leading firms are doing to move beyond their current idea-to-launch methodology and tries to integrate these practices into a next-generation system.

Objective. To identify new genetic associations with juvenile and adult dermatomyositis (DM). Methods. We performed a genome-wide association study (GWAS) of adult and juvenile DM patients of European ancestry (n = 1178) and controls (n = 4724). To assess genetic overlap with other autoimmune disorders, we examined whether 141 single nucleotide polymorphisms (SNPs) outside the major histocompatibility complex (MHC) locus, and previously associated with autoimmune diseases, predispose to DM. Results. Compared to controls, patients with DM had a strong signal in the MHC region consisting of GWAS-level significance (P < 5x10(-8) ) at 80 genotyped SNPs. An analysis of 141 non-MHC SNPs previously associated with autoimmune diseases showed that three SNPs linked with three genes were associated with DM, with a false discovery rate (FDR) < 0.05. These genes were phospholipase C like 1 (PLCL1, rs6738825, FDR=0.00089), B lymphoid tyrosine kinase (BLK, rs2736340, FDR=0.00031), and chemokine (C-C motif) ligand 21 (CCL21, rs951005, FDR=0.0076). None of these genes was previously reported to be associated with DM. Conclusion. Our findings confirm the MHC as the major genetic region associated with DM and indicate that DM shares non-MHC genetic features with other autoimmune diseases, suggesting the presence of additional novel risk loci. This first identification of autoimmune disease genetic predispositions shared with DM may lead to enhanced understanding of pathogenesis and novel diagnostic and therapeutic approaches. � 2013 American College of Rheumatology.

PURPOSE OF REVIEW: To review the progress that has been made in understanding the genetics of the idiopathic inflammatory myopathies (IIMs) in the past 2 years, with particular focus on polymyositis, dermatomyositis and inclusion body myositis. RECENT FINDINGS: Candidate gene studies in the Japanese population have implicated signal transducer and activator of transcription 4 as a risk locus for IIM, and HLA-DRB1 as a risk locus for anti-melanoma differentiation-associated gene 5-positive dermatomyositis. Evidence for gene-environment interactions has been found between HLA-DRB1*03 and smoking as a risk factor for the development of anti-histidyl tRNA synthetase antibodies, and HLA-DRB1*11:01 and statins for the development of anti-hydroxymethyl glutaryl-coenzyme A reductase-positive statin-induced myopathy. The HLA-DRB1*03:01/*01:01 genotype confers the highest disease risk in inclusion body myositis. A recent genome-wide association study has been performed in dermatomyositis. The most significant signals were in the major histocompatibility complex region, with other loci suggesting evidence of genetic overlap with different autoimmune diseases. SUMMARY: Recent association and gene-environment interaction studies have increased our knowledge of genetic risk factors for the IIMs. Ongoing international collaborations will facilitate larger and more meaningful genetic studies revealing much about the genetic architecture of these complex diseases.

OVERVIEW:There is a real shortage of breakthrough initiatives in businesses' development portfolios. A major challenge in developing these high-risk projects is portfolio management—how executives make R&D investment decisions. Financial approaches, such as net present value and the productivity index, are traditionally recommended to lend rigor to go/kill decisions. An overreliance on financial tools favors incremental projects whose financial forecasts are reliable, however, producing an abundance of small, low-hanging-fruit projects and a failure to allocate resources to strategic projects. Different toolsets must be used to assess high-risk breakthrough initiatives, including strategic buckets, expected commercial value, and spiral development processes. All of these must be supported by a climate and culture that provide the appetite to take on risky projects.

Limb girdle muscular dystrophy type 2L or anoctaminopathy is a condition mainly characterized by adult onset proximal lower limb muscular weakness and raised CK values, due to recessive ANO5 gene mutations. An exon 5 founder mutation (c.191dupA) has been identified in most of the British and German LGMD2L patients so far reported. We aimed to further investigate the prevalence and spectrum of ANO5 gene mutations and related clinical phenotypes, by screening 205 undiagnosed patients referred to our molecular service with a clinical suspicion of anoctaminopathy. A total of 42 unrelated patients had two ANO5 mutations (21%), whereas 14 carried a single change. We identified 34 pathogenic changes, 15 of which are novel. The c.191dupA mutation represents 61% of mutated alleles and appears to be less prevalent in non-Northern European populations. Retrospective clinical analysis corroborates the prevalently proximal lower limb phenotype, the male predominance and absence of major cardiac or respiratory involvement. Identification of cases with isolated hyperCKaemia and very late symptomatic male and female subjects confirms the extension of the phenotypic spectrum of the disease. Anoctaminopathy appears to be one of the most common adult muscular dystrophies in Northern Europe, with a prevalence of about 20%-25% in unselected undiagnosed cases. © 2013 WILEY PERIODICALS, INC.

Summary Background While the chronic inflammation related to autoimmune diseases is known to be associated with an increased cardiovascular risk, much less is known about cerebrovascular risks. Objectives The present population-based, age- and sex-matched follow-up study was undertaken to investigate the risks of acute myocardial infarction (AMI) and ischaemic stroke in patients with dermatomyositis (DMS). Methods In total 907 patients with DMS were enrolled and compared with a non-DMS control group consisting of 4535 age- and sex-matched, randomly sampled subjects without DMS. The AMI-free and ischaemic stroke-free survival curves were generated using the Kaplan–Meier method. Cox proportional hazard regression was used to estimate the DMS-associated risks of AMI and ischaemic stroke. Results During the 2-year follow-up period, 14 patients with DMS (1·5%) and 18 patients in the non-DMS control group (0·4%) suffered AMIs. The crude hazard ratio (HR) for suffering an AMI in patients with DMS compared with subjects in the non-DMS group was 3·96 [95% confidence interval (CI) 1·97–7·96, P = 0·0001], while the adjusted HR was 3·37 (95% CI 1·67–6·80, P = 0·0007), after taking into account demographic characteristics and cardiovascular comorbidities. During the same follow-up period, 46 patients (5·1%) and 133 subjects in the control group (2·9%) developed ischaemic strokes. The crude HR for developing an ischaemic stroke in patients with DMS compared with subjects in the non-DMS group was 1·78 (95% CI 1·27–2·49, P = 0·0007), and the adjusted HR was 1·67 (95% CI, 1·19–2·34, P = 0·0028). Conclusions These findings suggest that DMS is associated with an increased risk of cardiovascular and cerebrovascular events.