MRI biomarker assessment of neuromuscular disease progression: a prospective observational cohort study

BACKGROUND: A substantial impediment to progress in trials of new therapies in neuromuscular disorders is the absence of responsive outcome measures that correlate with patient functional deficits and are sensitive to early disease processes. Irrespective of the primary molecular defect, neuromuscular disorder pathological processes include disturbance of intramuscular water distribution followed by intramuscular fat accumulation, both quantifiable by MRI. In pathologically distinct neuromuscular disorders, we aimed to determine the comparative responsiveness of MRI outcome measures over 1 year, the validity of MRI outcome measures by cross-sectional correlation against functionally relevant clinical measures, and the sensitivity of specific MRI indices to early muscle water changes before intramuscular fat accumulation beyond the healthy control range. METHODS: We did a prospective observational cohort study of patients with either Charcot-Marie-Tooth disease 1A or inclusion body myositis who were attending the inherited neuropathy or muscle clinics at the Medical Research Council (MRC) Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, London, UK. Genetic confirmation of the chromosome 17p11·2 duplication was required for Charcot-Marie-Tooth disease 1A, and classification as pathologically or clinically definite by MRC criteria was required for inclusion body myositis. Exclusion criteria were concomitant diseases and safety-related MRI contraindications. Healthy age-matched and sex-matched controls were also recruited. Assessments were done at baseline and 1 year. The MRI outcomes-fat fraction, transverse relaxation time (T2), and magnetisation transfer ratio (MTR)-were analysed during the 12-month follow-up, by measuring correlation with functionally relevant clinical measures, and for T2 and MTR, sensitivity in muscles with fat fraction less than the 95th percentile of the control group. FINDINGS: Between Jan 19, 2010, and July 7, 2011, we recruited 20 patients with Charcot-Marie-Tooth disease 1A, 20 patients with inclusion body myositis, and 29 healthy controls (allocated to one or both of the 20-participant matched-control subgroups). Whole muscle fat fraction increased significantly during the 12-month follow-up at calf level (mean absolute change 1·2%, 95% CI 0·5-1·9, p=0·002) but not thigh level (0·2%, -0·2 to 0·6, p=0·38) in patients with Charcot-Marie-Tooth disease 1A, and at calf level (2·6%, 1·3-4·0, p=0·002) and thigh level (3·3%, 1·8-4·9, p=0·0007) in patients with inclusion body myositis. Fat fraction correlated with the lower limb components of the inclusion body myositis functional rating score (ρ=-0·64, p=0·002) and the Charcot-Marie-Tooth examination score (ρ=0·63, p=0·003). Longitudinal T2 and MTR changed consistently with fat fraction but more variably. In muscles with a fat fraction lower than the control group 95th percentile, T2 was increased in patients compared with controls (regression coefficients: inclusion body myositis thigh 4·0 ms [SE 0·5], calf 3·5 ms [0·6]; Charcot-Marie-Tooth 1A thigh 1·0 ms [0·3], calf 2·0 ms [0·3]) and MTR reduced compared with controls (inclusion body myositis thigh -1·5 percentage units [pu; 0·2], calf -1·1 pu [0·2]; Charcot-Marie-Tooth 1A thigh -0·3 pu [0·1], calf -0·7 pu [0·1]). INTERPRETATION: MRI outcome measures can monitor intramuscular fat accumulation with high responsiveness, show validity by correlation with conventional functional measures, and detect muscle water changes preceding marked intramuscular fat accumulation. Confirmation of our results in further cohorts with these and other muscle-wasting disorders would suggest that MRI biomarkers might prove valuable in experimental trials. FUNDING: Medical Research Council UK

Visual art inspired by the collective feeding behavior of sand-bubbler crabs

Sand--bubblers are crabs of the genera Dotilla and Scopimera which are known to produce remarkable patterns and structures at tropical beaches. From these pattern-making abilities, we may draw inspiration for digital visual art. A simple mathematical model is proposed and an algorithm is designed that may create such sand-bubbler patterns artificially. In addition, design parameters to modify the patterns are identified and analyzed by computational aesthetic measures. Finally, an extension of the algorithm is discussed that may enable controlling and guiding generative evolution of the art-making process

Effect of certolizumab pegol over 96 weeks of treatment on inflammation of the spine and sacroiliac joints, as measured by MRI, and the association between clinical and MRI outcomes in patients with axial spondyloarthritis.

OBJECTIVE: To report MRI outcomes and explore the relationship between clinical remission and MRI inflammation in patients with axial spondyloarthritis (axSpA) from the RAPID-axSpA trial, including radiographic (r-)axSpA and non-radiographic (nr-)axSpA. METHODS: RAPID-axSpA (NCT01087762) was double-blind and placebo-controlled to week 24, dose-blind to week 48 and open-label to week 204. Patients were randomised to certolizumab pegol (CZP) or placebo. Placebo patients entering dose-blind were rerandomised to CZP. MRIs performed at baseline, weeks 12, 48 and 96 were scored by 2 reviewers independently: Spondyloarthritis Research Consortium of Canada (SPARCC) for sacroiliac (SI) joints; Berlin modification of the Ankylosing Spondylitis spine MRI scoring system for disease activity (Berlin) for spine. Inflammation thresholds: SPARCC≥2; Berlin>2. Remission thresholds: SPARCC<2 (SI joints); Berlin≤2 (spine); Ankylosing Spondylitis Disease Activity Score (ASDAS) inactive disease (<1.3, clinical). RESULTS: Across 163 patients in the MRI set (109 CZP; 54 placebo), week 12 mean changes from baseline in MRI scores were greater for CZP versus placebo: SPARCC: -4.8 (SD 8.6) vs -1.6 (7.8; p<0.001); Berlin: -2.9 (4.2) vs 0.2 (4.8; p<0.001). Improvements were maintained to week 96. Week 12 MRI remission was achieved by 52.6% of patients with baseline MRI inflammation in SI joints, 62.0% in the spine and 37.9% of patients with both. MRI remission rates were sustained to week 96, with similar trends in r-axSpA and nr-axSpA. At week 96, 57.5% vs 65.9% of patients achieving versus not achieving clinical remission had MRI remission. CONCLUSIONS: CZP reduced inflammation in the spine and SI joints in patients with r-axSpA and nr-axSpA, with improvements maintained over 96 weeks. Substantial proportions of patients achieved MRI remission. Concordance between clinical remission and current definitions of absence of MRI inflammation was limited. TRIAL REGISTRATION NUMBER: NCT01087762; Post-results

Rheumatic disease and COVID-19: epidemiology and outcomes

Patients with rheumatoid arthritis, systemic lupus erythematosus or psoriasis, when analysed as a combined group, might have a slightly increased risk of death from COVID-19 compared to those without these diseases, although the role of disease activity and treatment in this risk estimation was not taken into account2. Treatment with cytokine inhibitors could reduce the risk of SARS-SoV-2 infection (as measured by development of SARS-CoV-2 antibodies), although the mechanisms of this protective effect are not clear3. Chronic use of glucocorticoids at moderate or high doses (≥10 mg per day prednisolone or equivalent) is associated with hospitalization for severe COVID-194

Global research collaboration in a pandemic-challenges and opportunities: the COVID-19 Global Rheumatology Alliance

PURPOSE OF REVIEW: This review discusses the coronavirus disease-2019 (COVID-19) Global Rheumatology Alliance (GRA), the reason for its formation, the challenges with running the registry, and future opportunities for global collaborative research in rheumatology. RECENT FINDINGS: The GRA has been successful in collecting and publishing a large volume of case data on patients with rheumatic disease with COVID-19. In addition, the GRA has published reviews, opinion pieces, and patient-directed summaries of research to further assist in disseminating timely and accurate information about COVID-19 in rheumatic diseases. There have been numerous challenges in the journey but they have been addressed through a collaborative problem-solving approach. SUMMARY: The initial objectives of the GRA to describe the outcomes in patients with rheumatic disease who developed COVID-19 have been achieved. There has been extensive use of the data in the clinic and also to try and understand the mechanisms of disease and opportunities for drug repurposing. There remain numerous important areas for research which the GRA will continue to pursue as the pandemic evolves

Understanding and managing anti-MDA 5 dermatomyositis, including potential COVID-19 mimicry

Anti-Melanoma Differentiation-Associated gene 5 (MDA-5) Dermatomyositis (MDA5, DM) is a recently identified subtype of myositis characteristically associated with Rapidly Progressive Interstitial Lung Disease (RP-ILD) and unique cutaneous features. We reviewed PubMed, SCOPUS and Web of Science databases and selected 87 relevant articles after screening 1485 search results, aiming to gain a better understanding of the pathophysiology, clinical features, diagnosis, and treatment approaches of anti-MDA-5 DM described in the literature. The etiopathogenesis is speculatively linked to an unidentified viral trigger on the background of genetic predisposition culminating in an acquired type I interferonopathy. The clinical phenotype is highly varied in different ethnicities, with new clinical features having been recently described, expanding the spectrum of cases that should raise the suspicion of anti-MDA-5 DM. Unfortunately, the diagnosis is frequently missed despite excessive mortality, calling for wider awareness of suspect symptoms. RP ILD is the major determinant of survival, treatment being largely based on observational studies with recent insights into aggressive combined immunosuppression at the outset

Novel coronavirus disease-2019 (COVID-19) in people with rheumatic disease: Epidemiology and outcomes

There is concern that people with rheumatic disease, often treated with immunosuppressive or immunomodulatory medication, may be at an increased risk of poor outcomes of novel coronavirus disease-2019 (COVID-19). However, hyperinflammation is a major cause of morbidity and mortality in COVID-19 and treatment with glucocorticoids has been shown to improve outcomes in patients with severe COVID-19. Therefore, uncertainty exists about continuing or withholding immune therapies with the risk of infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This review covers the current knowledge with respect to the risk of infection and outcomes and risk factors for poor outcomes in patients with rheumatic disease. We also discuss data from other immune-mediated diseases and its relevance to patients with rheumatic disease. In addition, we cover the limitations of the research efforts to date and how the current knowledge translates into practice guidance. Finally, we discuss our vision of the future research agenda

A study of a couple with type 2 diabetes: dyadic adjustment and psychological morbidity

Objective: this study assessed dyadic adjustment and psychological morbidity in type 2 diabetic patients and their partners, focusing on the role of gender. Methods: 214 diabetic patients and their partners participated in the cross-sectional study and were assessed on psychological morbidity (HADS) and marital adjustment (RDAS). Data was analyzed using dyadic analysis, a statistical process that studies the patient/partner dyads simultaneously. Results: results revealed that the negative relationship between dyadic adjustment and psychological morbidity in female patients was stronger than in male diabetic patients or in partners of male diabetic patients. On the other hand, the relationship between dyadic adjustment and psychological morbidity in partners of diabetic men was stronger than the same relationship in partners of diabetic women. Conclusion: since gender is a moderator, it is important to attend to the different needs of female and male patients and the education of diabetic patients should be centered on the patient/partner dyad.Fundação para a Ciência e a Tecnologia (FCT

Localisation of RNAs into the germ plasm of vitellogenic xenopus oocytes

We have studied the localisation of mRNAs in full-grown Xenopus laevis oocytes by injecting fluorescent RNAs, followed by confocal microscopy of the oocyte cortex. Concentrating on RNA encoding the Xenopus Nanos homologue, nanos1 (formerly Xcat2), we find that it consistently localised into aggregated germ plasm ribonucleoprotein (RNP) particles, independently of cytoskeletal integrity. This implies that a diffusion/entrapment-mediated mechanism is active, as previously reported for previtellogenic oocytes. Sometimes this was accompanied by localisation into scattered particles of the “late”, Vg1/VegT pathway; occasionally only late pathway localisation was seen. The Xpat RNA behaved in an identical fashion and for neither RNA was the localisation changed by any culture conditions tested. The identity of the labelled RNP aggregates as definitive germ plasm was confirmed by their inclusion of abundant mitochondria and co-localisation with the germ plasm protein Hermes. Further, the nanos1/Hermes RNP particles are interspersed with those containing the germ plasm protein Xpat. These aggregates may be followed into the germ plasm of unfertilized eggs, but with a notable reduction in its quantity, both in terms of injected molecules and endogenous structures. Our results conflict with previous reports that there is no RNA localisation in large oocytes, and that during mid-oogenesis even germ plasm RNAs localise exclusively by the late pathway. We find that in mid oogenesis nanos1 RNA also localises to germ plasm but also by the late pathway. Late pathway RNAs, Vg1 and VegT, also may localise into germ plasm. Our results support the view that mechanistically the two modes of localisation are extremely similar, and that in an injection experiment RNAs might utilise either pathway, the distinction in fates being very subtle and subject to variation. We discuss these results in relation to their biological significance and the results of others