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The aim of this study is to determine whether primary over-expression of Aβ PP in skeletal muscle results in the development of features of inclusion body myositis ( IBM) in a new lineage of the MCK-Aβ PP transgenic mouse. Quantitative histological, immunohistochemical and western blotting studies were performed on muscles from 3 to 18 month old transgenic and wild-type C57 BL6/ SJL mice. Electron microscopy was also performed on muscle sections from selected animals. Although western blotting confirmed that there was over-expression of full length Aβ PP in transgenic mouse muscles, deposition of amyloid-β and fibrillar amyloid could not be demonstrated histochemically or with electron microscopy. Additionally, other changes typical of IBM such as rimmed vacuoles, cytochrome C oxidase-deficient fibres, upregulation of MHC antigens, lymphocytic inflammatory infiltration and T cell fibre invasion were absent. The most prominent finding in both transgenic and wild-type animals was the presence of tubular aggregates which was age-related and largely restricted to male animals. Expression of full length Aβ PP in this MCK-Aβ PP mouse lineage did not reach the levels required for immunodetection or deposition of amyloid-β as in the original transgenic strains, and was not associated with the development of pathological features of IBM. These negative results emphasise the potential pitfalls of re-deriving transgenic mouse strains in different laboratories. [ABSTRACT FROM AUTHOR]

Background Aims Methods Results Conclusions Idiopathic inflammatory myopathies (IIMs) are a group of autoimmune diseases characterised by inflammation of skeletal muscle and other organ systems. They have high morbidity and mortality but, in part because of their rarity and heterogeneity, improving understanding and outcomes remains challenging. To address these problems, numerous IIM registries exist globally, but no national registry yet exists in Australia.The Australian Myositis Registry (AMR) is a national prospective cohort database designed to record clinical, laboratory and patient‐experience data of Australian IIM patients with the potential for wide‐reaching research impact.The AMR was built on the Research Electronic Data Capture secure database system. An extensive set of data fields informed by a contemporary understanding of IIM pathogenesis and clinically relevant features are available to help capture the full breadth of disease phenotype and treatment. Data fields include current classification criteria, all currently available autoantibodies and the internationally accepted core set measures. After an extended period of design, collaboration and review, the AMR launched in 2023 across two sites in New South Wales and Western Australia. The AMR is seeking to expand with more sites across Australia.As of August 2024, 170 participants are enrolled.The AMR is the first nationwide registry in Australia for patients with IIMs and one of the very few national registries for IIMs globally. It aims to provide valuable insight into the epidemiology and clinical experience of IIMs in Australia to help address multiple research agendas. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Motor neuron disease (MND) is a progressive neurodegenerative condition with a limited life expectancy. There is very little data on mortality and its associated factors beyond 30 days following gastrostomy. We explored the demographic, clinical, and nutritional predictors for early mortality at 30, 90, and 180 days following gastrostomy in these patients. Methods: This was a retrospective study involving 94 MND patients in Western Australia who underwent gastrostomy between 2015 and 2021. Patients were divided into two groups based on mortality at 30, 90, and 180 days post‐gastrostomy. T‐test (or Mann–Whitney), chi‐square test and Fisher's exact test were used for detecting between‐group differences in various factors. Multivariable logistic regression was used to identify factors associated with post‐gastrostomy mortality at 90 and 180 days. Results: No mortality was attributable to gastrostomy‐related complications. Lower forced vital capacity (FVC) (p =.039) and greater weight loss (%) (p =.022) from diagnosis to gastrostomy were observed in those who died within 30 days post‐gastrostomy. Older age (p =.022), male sex (p =.041), lower FVC (p =.04), requiring but not tolerating noninvasive ventilation (p =.035), and greater weight loss (%) (p =.012) were independent predictors of 90‐day post‐gastrostomy mortality. However, only older age (p =.01) and greater weight loss (p =.009) were predictors of mortality at 180 days post‐gastrostomy. Discussion: Our data indicated that mortality at 90 and 180 days was influenced by the weight loss (%) from diagnosis to gastrostomy, highlighting the importance of nutritional care in the MND population. Gastrostomy placement prior to substantial weight loss may reduce the risk of weight loss‐associated mortality and warrants further investigation. [ABSTRACT FROM AUTHOR]

Background and purpose Methods Results Discussion Given the accepted multistep process of disease causation in amyotrophic lateral sclerosis (ALS), the present study was undertaken to determine the number of steps required for disease onset across each of the ALS phenotypes.Clinical and demographic data were prospectively accumulated using the Australian Motor Neurone Disease Registry (2005–2016), and age‐specific incidence rates were calculated. Poisson regression was utilized to assess the relationship between log age‐specific incidence and log age of onset, with McFadden's R2 used to assess the goodness of fit of the model.In total, 2647 ALS patients were included, with mean disease‐onset age being 62.2 ± 12.1 years. A linear relationship between log incidence and log age was established across ALS phenotypes, with variable slope estimates: bulbar 5.1 (95% confidence interval [CI] 4.6–5.6); cervical 2.7 (95% CI 2.3–3.0); lumbar 3.5 (95% CI 3.2–3.9); flail arm 4.7 (95% CI 3.9–5.5); flail leg 3.6 (95% CI 2.6–4.5); primary lateral sclerosis 2.7 (95% CI 1.8–3.7). Slope estimates were significantly higher in the bulbar compared to the cervical, lumbar and primary lateral sclerosis phenotypes. McFadden's R2 values were >0.4 for all phenotypes indicating excellent model fit.A multistep process has been established across all ALS phenotypes with variable slope estimates, suggesting that the number of steps to develop disease is different across clinical presentations. Identification of mechanisms underlying slope estimate variability could exert pathophysiological significance. [ABSTRACT FROM AUTHOR]

Introduction: Idiopathic inflammatory myopathies (known as 'myositis') are a group of rare sporadic inflammatory muscle disorders that significantly impact function and quality of life. There are no standardised approaches in the use of assistive technologies in myositis. This study was initiated to investigate current use and perceived value of assistive technology (AT) by people with myositis. Methods: A cross‐sectional online questionnaire (Qualtrics) was designed to capture information regarding AT use and perceived value and demographic information from people with myositis across Australia. The questionnaire was distributed via the Myositis Association of Australia and specialist myositis clinics. Participants were asked to identify which AT items they owned and how frequently the item was used and to rate the 'usefulness' of those items. Information was also collected on participants' engagement with health professionals regarding assistive technologies. Consumer and community involvement: Consumer involvement via the Myositis Research Consumer Panel identified a knowledge gap regarding AT. The questionnaire was designed with consumer input and review. Results: One hundred two people (102) with myositis completed the questionnaire. One hundred (100) participants owned at least one AT device, with a median of 12.5 items and a maximum of 65 items. The most used devices were associated with toileting, personal care and mobility. Participants rated AT devices relating to environmental support, sleeping, seating and body support as most useful. There was a positive correlation between disease duration and number of devices used (r2 = 0.248, p = 0.012). Majority of participants (75.5%) were interested in talking to health professionals about AT; however, only 50% had done so. Conclusion: AT device usage is high among people with myositis, with most items deemed to be useful. Greater occupational therapy input into recommendations and potential funding options may improve knowledge and access to AT. [ABSTRACT FROM AUTHOR]

Neurological disorders are a leading cause of disease burden worldwide, placing a heavy demand on health systems. This study evaluated the impacts and cost savings of a community‐based nursing service providing supported discharge for neurological patients deemed high‐risk for unplanned emergency department presentations and/or hospital readmissions. It focused on adult patients with stroke, epilepsy, migraine/headache or functional neurological disorders discharged from a Western Australian tertiary hospital. An observational design was used comprising prospective enrolment of patients receiving nurse‐led supported discharge and follow‐up (Neurocare), 21 August 2018 to 6 December 2019 (N = 81), and hospital administrative data, 1 February 2016 to 31 January 2018, for patients in previous care model (N = 740). Healthcare utilisation and annualised cost savings from reduced rehospitalisation and/or emergency department presentations within 28 days post discharge were compared. Neurocare patients' postdischarge functional and health‐related quality of life outcomes, and perceived involvement in self‐management and integrated care were surveyed. The hospital's total cost savings are A$101,639 per annum and A$275/patient/year with a return on investment of 2.01. There was no significant difference in hospital length of stay (LOS) between models, but older age was associated with longer length of hospital stay and a predictor for non‐neurological readmissions. Neurocare patients showed improved functional status, less equipment and/or service needs, improved health‐related quality of life. They felt involved in self‐managing their condition with well‐integrated postdischarge care. This nurse‐led model of transitional care for neurology patients discharged from hospital produced cost savings and a positive return on investment compared with usual care. With service maturity, earlier supported hospital discharge and reduced LOS may follow. Patients' reduced service needs and improved functional status and health‐related quality of life may positively impact healthcare utilisation. Future research should include larger patient samples and multiple sites. [ABSTRACT FROM AUTHOR]

• Early evidence that IMT is highly effective in people with IBM. • No complications from IMT were observed in this small population. • No change was seen in quality of life, sleep or breathlessness over the eight weeks. • Further research is required to determine if it reduces morbidity due to complications of respiratory muscle weakness*. Inclusion body myositis is the most common acquired myositis in adults, predominantly weakening forearm flexor and knee extensor muscles. Subclinical respiratory muscle weakness has recently been recognised in people with inclusion body myositis, increasing their risk of respiratory complications. Inspiratory muscle training, a technique which demonstrates efficacy and safety in improving respiratory function in people with neuromuscular disorders, has never been explored in those with inclusion body myositis. In this pilot study, six adults with inclusion body myositis (age range 53 to 81 years) completed eight weeks of inspiratory muscle training. Measures of respiratory function, quality of life, sleep quality and a two-minute walk test were performed pre and post-intervention. All participants improved their respiratory function, with maximal inspiratory pressure, sniff nasal inspiratory pressure and forced vital capacity increasing by an average of 50 % (p =.002), 43 % (p =.018) and 13 % (p =.003) respectively. No significant change was observed in quality of life, sleep quality or two-minute walk test performance. No complications occurred due to inspiratory muscle training This pilot study provides the first evidence that inspiratory muscle training may be safe and effective in people with Inclusion Body Myositis, potentially mitigating the complications of poor respiratory function. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Enteral feeding via gastrostomy is a key intervention to prevent significant weight loss in Motor Neuron Disease (MND). The aim of this study was to explore demographic, clinical, and nutritional factors associated with survival time in MND patients with gastrostomy. Methods: The retrospective study analyzed 94 MND patients (n = 58 bulbar‐onset and n = 36 limb‐onset) who underwent gastrostomy between 2015 and 2021. The primary outcome was the survival time from gastrostomy insertion to death. Independent variables of interest explored were: age at gastrostomy insertion, disease onset type, known genetic cause, use of riluzole, non‐invasive ventilation (NIV) use, forced vital capacity prior to gastrostomy, weight loss from diagnosis to gastrostomy insertion, and body mass index (BMI) at the time of gastrostomy insertion. Results: The median survival time from gastrostomy to death was 357 days (± 29.3, 95%CI: 299.5, 414.5). Kaplan–Meier method and log‐rank test revealed patients with lower body mass index <18.5 kg/m2 at the time of gastrostomy insertion (p =.023) had shorter survival. Cox proportional hazards model with multivariable adjustment revealed that older age (p =.008), and greater weight loss from diagnosis to gastrostomy (p =.003) were associated with shorter survival time post gastrostomy. Limb onset (p =.023), NIV use not being required (p =.008) and daily NIV use when required and tolerated (p =.033) were associated with longer survival. Discussion: Preventing or minimizing weight loss from MND diagnosis and encouraging NIV use when clinically indicated are modifiable factors that may prolong the survival of MND patients with gastrostomy. [ABSTRACT FROM AUTHOR]

Objective: Inclusion body myositis (IBM) is a progressive late‐onset muscle disease characterised by preferential weakness of quadriceps femoris and finger flexors, with elusive causes involving immune, degenerative, genetic and age‐related factors. Overlapping with normal muscle ageing makes diagnosis and prognosis problematic. Methods: We characterised peripheral blood leucocytes in 81 IBM patients and 45 healthy controls using flow cytometry. Using a random forest classifier, we identified immune changes in IBM compared to HC. K‐means clustering and the random forest one‐versus‐rest model classified patients into three immunophenotypic clusters. Functional outcome measures including mTUG, 2MWT, IBM‐FRS, EAT‐10, knee extension and grip strength were assessed across clusters. Results: The random forest model achieved a 94% AUC ROC with 82.76% specificity and 100% sensitivity. Significant differences were found in IBM patients, including increased CD8+ T‐bet+ cells, CD4+ T cells skewed towards a Th1 phenotype and altered γδ T cell repertoire with a reduced proportion of Vγ9+Vδ2+ cells. IBM patients formed three clusters: (i) activated and inflammatory CD8+ and CD4+ T‐cell profile and the highest proportion of anti‐cN1A‐positive patients in cluster 1; (ii) limited inflammation in cluster 2; (iii) highly differentiated, pro‐inflammatory T‐cell profile in cluster 3. Additionally, no significant differences in patients' age and gender were detected between immunophenotype clusters; however, worsening trends were detected with several functional outcomes. Conclusion: These findings unveil distinct immune profiles in IBM, shedding light on underlying pathological mechanisms for potential immunoregulatory therapeutic development. [ABSTRACT FROM AUTHOR]

Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of muscle disorders including adult and juvenile dermatomyositis, polymyositis, immune-mediated necrotising myopathy and sporadic inclusion body myositis, all of which present with variable symptoms and disease progression. The identification of effective biomarkers for IIMs has been challenging due to the heterogeneity between IIMs and within IIM subgroups, but recent advances in machine learning (ML) techniques have shown promises in identifying novel biomarkers. This paper reviews recent studies on potential biomarkers for IIM and evaluates their clinical utility. We also explore how data analytic tools and ML algorithms have been used to identify biomarkers, highlighting their potential to advance our understanding and diagnosis of IIM and improve patient outcomes. Overall, ML techniques have great potential to revolutionize biomarker discovery in IIMs and lead to more effective diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Background: Anti–3‐hydroxy‐3‐methylglutaryl CoA reductase (HMGCR) antibodies are associated with a subtype of immune‐mediated necrotising myopathy (IMNM). Aims: To determine clinical associations of anti‐HMGCR antibodies for anti‐HMGCR–associated IMNM (HMGCR‐IMNM) among a cohort of patients in Western Australia and to determine whether serial HMGCR antibody levels parallel disease activity. Methods: Adult patients with positive anti‐HMGCR antibodies detected by enzyme‐linked immunosorbent assay between January 2015 and November 2019 were included. Symptoms, examination findings, imaging findings and blood test results were reviewed retrospectively using patient records and laboratory database results. Results: Among 26 patients with positive anti‐HMGCR antibodies, 23 were diagnosed with HMGCR‐IMNM representing a positive predictive value (PPV) of 88%. Myopathy was frequently severe at diagnosis with limb weakness graded as Medical Research Council score 3 or below in 78% of patients, bulbar muscle weakness in 39% and an average creatine kinase (CK) at diagnosis of 7986 U/L. The majority (83%) required at least two therapies to maintain remission, 48% had at least one flare of disease and 57% did not achieve CK normalisation. Correlation between CK and anti‐HMGCR antibody level at diagnosis was low (r = 0.04). Anti‐HMGCR antibodies fell with treatment in 10 of 12 patients, but remained persistently positive in 83% of patients. Conclusions: The PPV of anti‐HMGCR antibodies for HMGCR‐IMNM in this Western Australian cohort is 88%. Patients typically present with proximal limb weakness, dysphagia and markedly elevated CK, and, despite multiagent immunosuppression, a significant number of patients have evidence of persistent biochemical myositis. Anti‐HMGCR antibodies did not correlate with CK levels at diagnosis. [ABSTRACT FROM AUTHOR]

Valosin‐containing protein (VCP)‐associated multisystem proteinopathy (MSP) is a rare genetic disorder with abnormalities in the autophagy pathway leading to various combinations of myopathy, bone diseases, and neurodegeneration. Ninety percent of patients with VCP‐associated MSP have myopathy, but there is no consensus‐based guideline. The goal of this working group was to develop a best practice set of provisional recommendations for VCP myopathy which can be easily implemented across the globe. As an initiative by Cure VCP Disease Inc., a patient advocacy organization, an online survey was initially conducted to identify the practice gaps in VCP myopathy. All prior published literature on VCP myopathy was reviewed to better understand the different aspects of management of VCP myopathy, and several working group sessions were conducted involving international experts to develop this provisional recommendation. VCP myopathy has a heterogeneous clinical phenotype and should be considered in patients with limb‐girdle muscular dystrophy phenotype, or any myopathy with an autosomal dominant pattern of inheritance. Genetic testing is the only definitive way to diagnose VCP myopathy, and single‐variant testing in the case of a known familial VCP variant, or multi‐gene panel sequencing in undifferentiated cases can be considered. Muscle biopsy is important in cases of diagnostic uncertainty or lack of a definitive pathogenic genetic variant since rimmed vacuoles (present in ~40% cases) are considered a hallmark of VCP myopathy. Electrodiagnostic studies and magnetic resonance imaging can also help rule out disease mimics. Standardized management of VCP myopathy will optimize patient care and help future research initiatives. [ABSTRACT FROM AUTHOR]

Introduction: Inclusion body myositis (IBM) is the most commonly acquired skeletal muscle disease of older adults involving both autoimmune attack and muscle degeneration. As exercise training can improve outcomes in IBM, this study assessed whether a combination of testosterone supplementation and exercise training would improve muscle strength, physical function and quality of life in men affected by IBM, more than exercise alone. Methods: This pilot study was a single site randomised, double-blind, placebo-controlled, crossover study. Testosterone (exercise and testosterone cream) and placebo (exercise and placebo cream) were each delivered for 12 weeks, with a two-week wash-out between the two periods. The primary outcome measure was improvement in quadriceps isokinetic muscle strength. Secondary outcomes included assessment of isokinetic peak flexion force, walk capacity and patient reported outcomes, and other tests, comparing results between the placebo and testosterone arms. A 12-month Open Label Extension (OLE) was offered using the same outcome measures collected at 6 and 12-months. Results: 14 men completed the trial. There were no significant improvements in quadriceps extension strength or lean body mass, nor any of the secondary outcomes. Improvement in the RAND Short Form 36 patient reported outcome questionnaire 'emotional wellbeing' sub-category was reported during the testosterone arm compared to the placebo arm (mean difference [95% CI]: 6.0 points, [95% CI 1.7,10.3]). The OLE demonstrated relative disease stability over the 12-month period but with a higher number of testosterone-related adverse events. Conclusions: Adding testosterone supplementation to exercise training did not significantly improve muscle strength or physical function over a 12-week intervention period, compared to exercise alone. However, the combination improved emotional well-being over this period, and relative stabilisation of disease was found during the 12-month OLE. A longer duration trial involving a larger group of participants is warranted. [ABSTRACT FROM AUTHOR]

An innovative approach to patient management, evidence-based policy development, and clinical drug trials is required to provide personalized care and to improve the likelihood of finding an effective treatment for Motor Neurone Disease (MND). The MiNDAus Partnership builds on and extends existing national collaborations in a targeted approach to improve the standard and coordination of care for people living with MND in Australia, and to enhance the prospects of discovering a cure or treatment. Relationships have been developed between leading clinical and research groups as well as patient-centered organizations, care providers, and philanthropy with a shared vision. MiNDAus has established a corporate structure and meets at least biannually to decide on how best to progress research, drug development, and patient management. The key themes are; (i) empowering patients and their family carers to engage in self-management and ensure personalized service provision, treatment, and policy development, (ii) integration of data collection so as to better inform policy development, (iii) unifying patients and carers with advocacy groups, funding bodies, clinicians and academic institutions so as to inform policy development and research, (iv) coordination of research efforts and development of standardized national infrastructure for conducting innovative clinical MND trials that can be harmonized within Australia and with international trials consortia. Such a collaborative approach is required across stakeholders in order to develop innovative management guidelines, underpinned by necessary and evidence-based policy change recommendations, which, will ensure the best patient care until a cure is discovered. [ABSTRACT FROM AUTHOR]

Background: Amyotrophic lateral sclerosis (ALS) is a complex, late-onset, neurodegenerative disease with a genetic contribution to disease liability. Genome-wide association studies (GWAS) have identified ten risk loci to date, including the TNIP1/GPX3 locus on chromosome five. Given association analysis data alone cannot determine the most plausible risk gene for this locus, we undertook a comprehensive suite of in silico, in vivo and in vitro studies to address this. Methods: The Functional Mapping and Annotation (FUMA) pipeline and five tools (conditional and joint analysis (GCTA-COJO), Stratified Linkage Disequilibrium Score Regression (S-LDSC), Polygenic Priority Scoring (PoPS), Summary-based Mendelian Randomisation (SMR-HEIDI) and transcriptome-wide association study (TWAS) analyses) were used to perform bioinformatic integration of GWAS data (Ncases = 20,806, Ncontrols = 59,804) with 'omics reference datasets including the blood (eQTLgen consortium N = 31,684) and brain (N = 2581). This was followed up by specific expression studies in ALS case-control cohorts (microarray Ntotal = 942, protein Ntotal = 300) and gene knockdown (KD) studies of human neuronal iPSC cells and zebrafish-morpholinos (MO). Results: SMR analyses implicated both TNIP1 and GPX3 (p < 1.15 × 10−6), but there was no simple SNP/expression relationship. Integrating multiple datasets using PoPS supported GPX3 but not TNIP1. In vivo expression analyses from blood in ALS cases identified that lower GPX3 expression correlated with a more progressed disease (ALS functional rating score, p = 5.5 × 10−3, adjusted R2 = 0.042, Beffect = 27.4 ± 13.3 ng/ml/ALSFRS unit) with microarray and protein data suggesting lower expression with risk allele (recessive model p = 0.06, p = 0.02 respectively). Validation in vivo indicated gpx3 KD caused significant motor deficits in zebrafish-MO (mean difference vs. control ± 95% CI, vs. control, swim distance = 112 ± 28 mm, time = 1.29 ± 0.59 s, speed = 32.0 ± 2.53 mm/s, respectively, p for all < 0.0001), which were rescued with gpx3 expression, with no phenotype identified with tnip1 KD or gpx3 overexpression. Conclusions: These results support GPX3 as a lead ALS risk gene in this locus, with more data needed to confirm/reject a role for TNIP1. This has implications for understanding disease mechanisms (GPX3 acts in the same pathway as SOD1, a well-established ALS-associated gene) and identifying new therapeutic approaches. Few previous examples of in-depth investigations of risk loci in ALS exist and a similar approach could be applied to investigate future expected GWAS findings. [ABSTRACT FROM AUTHOR]

Inclusion body myositis (IBM) is a progressive inflammatory-degenerative muscle disease of older individuals, with some patients producing anti-cytosolic 5′-nucleotidase 1A (NT5C1A, aka cN1A) antibodies. Human Leukocyte Antigens (HLA) is the highest genetic risk factor for developing IBM. In this study, we aimed to further define the contribution of HLA alleles to IBM and the production of anti-cN1A antibodies. We HLA haplotyped a Western Australian cohort of 113 Caucasian IBM patients and 112 ethnically matched controls using Illumina next-generation sequencing. Allele frequency analysis and amino acid alignments were performed using the Genentech/MiDAS bioinformatics package. Allele frequencies were compared using Fisher's exact test. Age at onset analysis was performed using the ggstatsplot package. All analysis was carried out in RStudio version 1.4.1717. Our findings validated the independent association of HLA-DRB1*03:01:01 with IBM and attributed the risk to an arginine residue in position 74 within the DRβ1 protein. Conversely, DRB4*01:01:01 and DQA1*01:02:01 were found to have protective effects; the carriers of DRB1*03:01:01 that did not possess these alleles had a fourteenfold increased risk of developing IBM over the general Caucasian population. Furthermore, patients with the abovementioned genotype developed symptoms on average five years earlier than patients without. We did not find any HLA associations with anti-cN1A antibody production. High-resolution HLA sequencing more precisely characterised the alleles associated with IBM and defined a haplotype linked to earlier disease onset. Identification of the critical amino acid residue by advanced biostatistical analysis of immunogenetics data offers mechanistic insights and future directions into uncovering IBM aetiopathogenesis. • HLA-DRB1*03:01:01 of the 8.1 ancestral haplotype is a genetic risk factor for Inclusion Body Myositis (IBM) in Caucasians. • HLA-DRB4*01:01:01 and DQA1*01:02:01 are found at lower frequencies in Caucasian IBM patients and therefore are protective. • Carriers of DRB1*03:01:01 but not DRB4*01:01:01 or DQA1*01:02:01 are 14x more at risk of IBM, with a 5 years earlier onset. • An arginine in position 74 of the DRβ1 protein confers the allelic risk, while a glutamine at this position is protective. • We found no HLA association with the production of anti-cN1A antibodies in IBM. [ABSTRACT FROM AUTHOR]

Background: Inclusion body myositis is an idiopathic inflammatory myopathy and the most common myopathy affecting people older than 50 years. To date, there are no effective drug treatments. We aimed to assess the safety, efficacy, and tolerability of bimagrumab-a fully human monoclonal antibody-in individuals with inclusion body myositis.Methods: We did a multicentre, double-blind, placebo-controlled study (RESILIENT) at 38 academic clinical sites in Australia, Europe, Japan, and the USA. Individuals (aged 36-85 years) were eligible for the study if they met modified 2010 Medical Research Council criteria for inclusion body myositis. We randomly assigned participants (1:1:1:1) using a blocked randomisation schedule (block size of four) to either bimagrumab (10 mg/kg, 3 mg/kg, or 1 mg/kg) or placebo matched in appearance to bimagrumab, administered as intravenous infusions every 4 weeks for at least 48 weeks. All study participants, the funder, investigators, site personnel, and people doing assessments were masked to treatment assignment. The primary outcome measure was 6-min walking distance (6MWD), which was assessed at week 52 in the primary analysis population and analysed by intention-to-treat principles. We used a multivariate normal repeated measures model to analyse data for 6MWD. Safety was assessed by recording adverse events and by electrocardiography, echocardiography, haematological testing, urinalysis, and blood chemistry. This trial is registered with ClinicalTrials.gov, number NCT01925209; this report represents the final analysis.Findings: Between Sept 26, 2013, and Jan 6, 2016, 251 participants were enrolled to the study, of whom 63 were assigned to each bimagrumab group and 62 were allocated to the placebo group. At week 52, 6MWD change from baseline did not differ between any bimagrumab dose and placebo (least squares mean treatment difference for bimagrumab 10 mg/kg group, 17·6 m, SE 14·3, 99% CI -19·6 to 54·8; p=0·22; for 3 mg/kg group, 18·6 m, 14·2, -18·2 to 55·4; p=0·19; and for 1 mg/kg group, -1·3 m, 14·1, -38·0 to 35·4; p=0·93). 63 (100%) participants in each bimagrumab group and 61 (98%) of 62 in the placebo group had at least one adverse event. Falls were the most frequent adverse event (48 [76%] in the bimagrumab 10 mg/kg group, 55 [87%] in the 3 mg/kg group, 54 [86%] in the 1 mg/kg group, and 52 [84%] in the placebo group). The most frequently reported adverse events with bimagrumab were muscle spasms (32 [51%] in the bimagrumab 10 mg/kg group, 43 [68%] in the 3 mg/kg group, 25 [40%] in the 1 mg/kg group, and 13 [21%] in the placebo group) and diarrhoea (33 [52%], 28 [44%], 20 [32%], and 11 [18%], respectively). Adverse events leading to discontinuation were reported in four (6%) participants in each bimagrumab group compared with one (2%) participant in the placebo group. At least one serious adverse event was reported by 21 (33%) participants in the 10 mg/kg group, 11 (17%) in the 3 mg/kg group, 20 (32%) in the 1 mg/kg group, and 20 (32%) in the placebo group. No significant adverse cardiac effects were recorded on electrocardiography or echocardiography. Two deaths were reported during the study, one attributable to subendocardial myocardial infarction (secondary to gastrointestinal bleeding after an intentional overdose of concomitant sedatives and antidepressants) and one attributable to lung adenocarcinoma. Neither death was considered by the investigator to be related to bimagrumab.Interpretation: Bimagrumab showed a good safety profile, relative to placebo, in individuals with inclusion body myositis but did not improve 6MWD. The strengths of our study are that, to the best of our knowledge, it is the largest randomised controlled trial done in people with inclusion body myositis, and it provides important natural history data over 12 months.Funding: Novartis Pharma. [ABSTRACT FROM AUTHOR]

Necrotising Autoimmune Myopathy (NAM) presents as a subacute proximal myopathy with high creatine kinase levels. It is associated with statin exposure, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) antibody, connective tissue diseases, signal recognition particle (SRP) antibody and malignancy. This case series presents our Western Australian NAM patient cohort: comparing the subgroup presentations, biopsy appearance and treatment outcomes. We retrospectively collected data on patients diagnosed with NAM at the Western Australian Neuroscience Research Institute between the years 2000 and 2015. We identified 20 patients with Necrotising Autoimmune Myopathy: 14 with anti-HMGCR antibodies; two with anti-SRP antibodies; three with connective tissue disease; two as yet unspecified. Median creatine kinase level was 6047units/L (range 1000–17000). The statin naïve patients with HMGCR antibodies and patients with SRP antibodies were the most severely affected subgroups, with higher creatine kinase levels, and were more resistant to immunotherapy. Two or more immunotherapy agents were required in 90%; eight patients required IVIG and rituximab. Steroid weaning commonly precipitated relapses. Four patients had complete remission, and the remaining patients still require immunotherapy. Necrotising Autoimmune Myopathy is a potentially treatable myopathy, which can be precipitated by statin therapy and requires early, aggressive immunotherapy, usually requiring multiple steroid sparing agents for successful steroid weaning. [ABSTRACT FROM AUTHOR]

Background: Validated patient-reported outcome measures to assess disease impact in patients with adult idiopathic inflammatory myopathies (IIMs) are needed. The objective of this study was to assess the construct validity of PROMIS Pain Interference, Fatigue, and Physical Function measures in comparison with core disease activity measures., Methods: Adults with IIM, excluding inclusion body myositis, from OMERACT Myositis Working Group (MWG) clinic sites completed PROMIS Short Form v1.0-Pain Interference 6a, PROMIS Short Form v1.0-Fatigue 7a, and PROMIS Short Form v2.0-Physical Function 8b measures. Core disease activity measures including patient and physician global disease activity assessments, manual muscle testing, serum creatine kinase activity, and Health Assessment Questionnaire Disability Index (HAQ-DI) were simultaneously assessed. To evaluate construct validity, a priori hypotheses for the expected correlations between PROMIS measures, age, and core disease measures were determined by >70 % agreement among MWG members and were compared against observed Pearson's correlations. Internal consistency of items and floor or ceiling effects for the PROMIS measures were also assessed. Subgroup analysis according to IIM subtype (dermatomyositis vs. non-dermatomyositis IIM) was performed., Results: 135 adults with IIM from 5 countries across North America, Europe, Asia, and Australia were included. For construct validity, a priori hypotheses were confirmed for 5 of 6 (83 %) PROMIS Pain Interference, 4 of 5 (80 %) PROMIS Fatigue, and 3 of 4 (75 %) PROMIS Physical Function correlations. Internal consistency was high for each PROMIS measure (Cronbach's alpha >0.9). Ceiling effects were observed only for PROMIS Pain Interference, with low/no pain in 29 % of patients. Subgroup analysis between dermatomyositis (n = 65) and non-dermatomyositis (n = 70) subtypes demonstrated similar correlations between PROMIS measures and disease activity measures., Conclusions: PROMIS Short Form v1.0-Pain Interference 6a, PROMIS Short Form v1.0-Fatigue 7a, and PROMIS Short Form v2.0-Physical Function 8b measures demonstrate strong construct validity when compared to core disease activity measures in IIM, with consistent results across IIM subtypes. These findings support the use of these selected PROMIS measures to assess core domains of interest for measuring life impact in IIMs., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Merrilee Needham has received honorarium for educational talks and advisory boards from CSL, Sanofi-Aventis, and Teva. Ellen Romich received support from NIH Rheumatology Research Training Grant T32-AR076951 which was paid to the institution. Christopher A. Mecoli received support from K23AR075898 Grant., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: International focus groups with patients with idiopathic inflammatory myopathies (IIM) conducted by the OMERACT Myositis Working Group over the years demonstrated the pain as an important symptom experienced by these patients. In this study, we aimed to examine the frequency and degree of pain interference, the aspects of daily life impacted by pain, and the factors associated with pain interference in adults with IIM., Methods: This was a prospective observational study with two visits. The patients who fulfilled the probable/definite IIM (ACR/EULAR Myositis Classification Criteria) were enrolled. Pain interference was assessed with PROMIS pain interference form (6a). Myositis core set measures and PROMIS fatigue (7a) and physical function (8b) were obtained at both visits. Logistic regression and linear mixed models were performed to assess the association between pain interference and other parameters., Results: A total of 129 patients with IIM (60 % females) were recruited from U.S., South Korea, Netherlands, Sweden, and Australia. Approximately 71 % reported pain interference. The patients in the greater pain interference group were more likely to be female, had significantly worse patient/physician global disease activity, fatigue, and physical function than those in the lower pain interference group. The most commonly impacted life aspect was household chores. Manual muscle testing, patient/physician global disease activity, fatigue, and physical function were all significantly associated with pain interference score >60., Conclusion: The majority of the patients with IIM experience the impact of pain on their daily activities, particularly household chores. Myositis disease activity, duration, and subtype could be associated with greater pain interference., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

With improved understanding of disease pathogenesis and availability of outcome measures, there has been a remarkable increase in the number of therapeutic clinical trials in idiopathic inflammatory myopathies (myositis) over the last three years reaching as many as five trials per site. These trials share similar design and inclusion/exclusion criteria resulting in a competitive clinical trial landscape in myositis. While these are exciting times for the myositis field, we have a number of concerns about the design and conduct of the myositis trials. These include competitive landscape, lengthy placebo arms, underrepresentation of minority groups among participants, use of patient reported outcome measures with limited/no data on validity in myositis, antiquated disease classification criteria, and unclear performance of the ACR/EULAR Myositis Response Criteria in skin-predominant patients despite inclusion of these patients in trials. In this viewpoint, we further discuss these concerns and offer potential solutions such as including patient perspectives in the trial design and adoption of innovative frameworks., Competing Interests: Competing interests: DS, JKP, MN, IEL, and LCS are members of the OMERACT Myositis Working Group. JJP received funding from NIAMS (K23AR073927); grants from Pfizer Inc, CORBUS, Kezar, Priovant and EMD Serono; royalty from Uptodate; and consulting fees from Pfizer, Kezar, Alexion, EMD Serono, Priovant and Guidepoint Inc. IEL received support from Swedish Research Council; consulting fees from Corbus Pharmaceutical, EMD Serono, ArgenX, Pfizer, Galapagos, Bristol Myers Squibb and Chugai; honoraria from Boehringer-Ingelheim; and currently holds stock in Roche and Novartis. MN received honorarium from Abcuro, Novartis, Sanofi-Aventis, Genzyme and Teva; participated on Data Safety Monitoring Board or Advisory Board for Abcuro, Teva and Sanofi-Genzyme; and received materials from Sanofi-Aventis. VW received grants from Pfizer, Corbus, CSL Behring, Priovant, Rome, Ventus and Horizon; received consulting fees from Pfizer, Janssen, Neovacs, Octapharma and CSL Behring; and University of Pennsylvania owns the copyright for the Cutaneous Dermatomyositis Disease Area and Severity Index. LCS received grants from Pfizer, Corbus, Kezar; royalties for IP related to anti-HMGCR assay from Inova Diagnostics; consulting fees from Janssen, Boehringer-Ingelheim, Mallincrodt, EMD Serono, ArgenX, Allogene, Pfizer, Horizon Therapeutics, Octopharma and NuVig; received payment for expert testimony from Bendin Sumrall and Ladner LLC, Feldman, Kleidman Coffey & Sappe LLP, Downs Ward Bender Hauptmann & Herzog, PA, Sulloway and Hollis, received support for attending meetings and travel from Octapharma and has patent with Inova Diagnostics/RDL., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: There is growing interest in ultrasound (US) as an outcome measure in IBM. Our study aimed to determine the ability of B mode US and power Doppler (PD) to detect changes in affected muscles over time and if US domains correlate with disease progression., Methods: Participants attended on four occasions over a median follow-up period of 26 months. All completed a patient self-reported health assessment questionnaire (HAQ), patient visual analogue scale (pVAS), manual muscle testing (MMT), and US (fascial thickness-FT, muscle bulk, echogenicity, and PD) on deltoid and vastus lateralis (VL) muscles at each visit., Results: This longitudinal observational study had 35 participants: 21 (60%) males, median age 70 (IQR (64-76), and the majority (85.7%) not on immunosuppression. When analysed for sex differences at baseline, males had lower FT-VL (p=0.018) and higher muscle bulk (p=0.002) than females. Only FT-deltoid (p<0.001) increased significantly over time with follow-up. When participants were stratified into progressors and non-progressors, FT at baseline was lower in progressors (0.06 vs. 0.09, p=0.017), who were predominantly male. There were no significant differences in other US domains., Conclusions: Our study highlights previously unreported sex differences in US findings in IBM. Certain US domains, such as FT, showed measurable changes over time and correlated with disease progression. However, further studies with longer follow-up periods and larger patient cohorts will need to be performed to determine whether B mode US could be a useful disease outcome measure for therapeutic trials.

The 2017 EULAR/ACR classification criteria for adult/juvenile idiopathic inflammatory myopathies (IIM) were established using a data-driven approach by an international group of myositis experts to allow classification of IIM and its major subtypes. Since their publication, the performance of the criteria has been tested in multiple cohorts worldwide and significant limitations have been identified. Moreover, the understanding and classification of IIM have evolved since 2017. This scoping review was undertaken as part of a large international project to revise the EULAR/ACR criteria and aims to i) summarise the evidence from the current literature on the performance characteristics of the 2017 EULAR/ACR classification criteria in various cohorts and IIM subtypes, and ii) delineate the factors that need to be considered in the revision of the classification criteria. A systematic search of Medline (via PubMed), Cumulative Index to Nursing and Allied Health Literature, and conference abstract archives was conducted independently by three investigators for studies on the EULAR/ACR criteria published between October 2017 and January 2023. This scoping review of 19 articles and 13 abstracts revealed overall good performance characteristics of the EULAR/ACR criteria for IIM, yet deficiencies in lack of inclusion of certain IIM subtypes, such as immune mediated necrotising myopathy, amyopathic dermatomyositis, antisynthetase syndrome and overlap myositis. Published modifications that may improve the performance characteristics of the criteria for classification of IIM subtypes were also summarised. The results of this review suggest that a revision of the EULAR/ACR criteria is warranted.

Objectives: We investigated shear wave elastography (SWE), B mode US and power Doppler (PDUS) as imaging biomarkers for longitudinal follow-up in idiopathic inflammatory myopathy (IIM), with a particular focus on immune-mediated necrotizing myopathy (IMNM) and DM., Methods: Participants had serial SWE, PDUS on the deltoid (D) and vastus lateralis (VL) muscles on four occasions at intervals of 3-6 months. Clinical assessments included manual muscle testing, and patient- and physician-reported outcome scales., Results: Thirty-three participants were included: IMNM = 17, DM = 12, overlap myositis = 3, PM = 1. Twenty were in a prevalent clinic group, and 13 were recently treated cases in an incident group. Differential changes in SWS and US domains occurred with time in both the prevalent and incident groups. In the VL-prevalent subgroup, echogenicity increased over time (P = 0.040), while in the incident cases there was a trend for reduction to normal over time (P = 0.097) with treatment. Muscle bulk reduced in the D-prevalent subgroup over time (P = 0.096), suggesting atrophy. SWS also reduced in the VL-incident subgroup over time (P = 0.096), suggesting a trend towards improvement in muscle stiffness with treatment., Conclusion: SWE and US appear promising as imaging biomarkers for patient follow-up in IIM and indicate changes over time, especially with echogenicity, muscle bulk and SWS in the VL. Due to the limitations of the participant numbers, additional studies with a larger cohort are needed to help evaluate these US domains further and outline specific characteristics within the IIM subgroups., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of muscle disorders including adult and juvenile dermatomyositis, polymyositis, immune-mediated necrotising myopathy and sporadic inclusion body myositis, all of which present with variable symptoms and disease progression. The identification of effective biomarkers for IIMs has been challenging due to the heterogeneity between IIMs and within IIM subgroups, but recent advances in machine learning (ML) techniques have shown promises in identifying novel biomarkers. This paper reviews recent studies on potential biomarkers for IIM and evaluates their clinical utility. We also explore how data analytic tools and ML algorithms have been used to identify biomarkers, highlighting their potential to advance our understanding and diagnosis of IIM and improve patient outcomes. Overall, ML techniques have great potential to revolutionize biomarker discovery in IIMs and lead to more effective diagnosis and treatment., (© The Author(s) 2024. Published by Oxford University Press.)

Purpose of Review: This review offers a contemporary clinical approach to the recognition, prevention and management of sarcopenia, and discusses recent clinically relevant advances in the aetiopathogenesis of muscle ageing that may lead to future therapeutic targets., Recent Findings: The key recent directions for sarcopenia are in the diagnosis, understanding molecular mechanisms and management. Regarding the recognition of the condition, it has become increasingly clear that different definitions hamper progress in understanding. Therefore, the Global Leadership in Sarcopenia has been established in 2022 to develop a universally accepted definition. Moreover, substantial work is occurring to understand the various roles and contribution of inflammation, oxidative stress, mitochondrial dysfunction and metabolic dysregulation on skeletal muscle function and ageing. Finally, the role of resistance-based exercise regimes has been continually emphasised. However, the role of protein supplementation and hormone replacement therapy (HRT) are still under debate, and current clinical trials are underway., Summary: With the global ageing of our population, there is increasing emphasis on maintaining good health. Maintenance of skeletal muscle strength and function are key to preventing frailty, morbidity and death., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: In 2015/2016, annual national expenditure on neurological conditions exceeded $A3 billion. However, a comprehensive study of the Australian neurological workforce and supply/demand dynamics has not previously been undertaken., Methods: Current neurological workforce was defined using neurologist survey and other sources. Workforce supply modelling used ordinary differential equations to simulate neurologist influx and attrition. Demand for neurology care was estimated by reference to literature regarding incidence and prevalence of selected conditions. Differences in supply versus demand for neurological workforce were calculated. Potential interventions to increase workforce were simulated and effects on supply versus demand estimated., Results: Modelling of the workforce from 2020 to 2034 predicted an increase in neurologist number from 620 to 89. We estimated a 2034 capacity of 638 024 Initial and 1 269 112 Review encounters annually, and deficits against demand estimated as 197 137 and 881 755, respectively. These deficits were proportionately greater in regional Australia, which has 31% of Australia's population (Australian Bureau of Statistics) but is served by only 4.1% of its neurologists as determined by our 2020 survey of Australia and New Zealand Association of Neurologists members. Nationally, simulated additions to the neurology workforce had some effect on the review encounter supply deficit (37.4%), but in Regional Australia, this impact was only 17.2%., Interpretation: Modelling of the neurologist workforce in Australia for 2020-2034 demonstrates a significant shortfall of supply relative to current and projected demand. Interventions to increase neurologist workforce may attenuate this shortfall but will not eliminate it. Thus, additional interventions are needed, including improved efficiency and additional use of support staff., Competing Interests: Competing interests: CM has received conference travel support and/or speaker fees from Merck, Novartis and Biogen. He has received research support from the National Health and Medical Research Council, Multiple Sclerosis Research Australia, The University of Melbourne, The Royal Melbourne Hospital Neuroscience Foundation, and Dementia Australia. MN: I have received honoraria and consultancy fees from Abcuro, Sanofi-Genyzme, Roche, Biogen and CSL-BehringTomas Kalincik has served on scientific advisory boards for Roche, Sanofi-Genzyme, Novartis, Merck and Biogen, steering committee for Brain Atrophy Initiative by Sanofi-Genzyme, received conference travel support and/or speaker honoraria from WebMD Global, Novartis, Biogen, Sanofi-Genzyme, Teva, BioCSL and Merck and received research support from Biogen. Other authors have no conflicts of interest to report., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Inclusion body myositis (IBM) is a progressive inflammatory myopathy characterised by skeletal muscle infiltration and myofibre invasion by CD8 + T lymphocytes. In some cases, IBM has been reported to be associated with a systemic lymphoproliferative disorder of CD8 + T cells exhibiting a highly differentiated effector phenotype known as T cell Large Granular Lymphocytic Leukemia (T-LGLL)., Methods: We investigated the incidence of a CD8 + T-LGL lymphoproliferative disorder in 85 IBM patients and an aged-matched group of 56 Healthy Controls (HC). Further, we analysed the phenotypical characteristics of the expanded T-LGLs and investigated whether their occurrence was associated with any particular HLA alleles or clinical characteristics., Results: Blood cell analysis by flow cytometry revealed expansion of T-LGLs in 34 of the 85 (40%) IBM patients. The T cell immunophenotype of T-LGL HIGH patients was characterised by increased expression of surface molecules including CD57 and KLRG1, and to a lesser extent of CD94 and CD56 predominantly in CD8 + T cells, although we also observed modest changes in CD4 + T cells and γδ T cells. Analysis of Ki67 in CD57 + KLRG1 + T cells revealed that only a small proportion of these cells was proliferating. Comparative analysis of CD8 + and CD4 + T cells isolated from matched blood and muscle samples donated by three patients indicated a consistent pattern of more pronounced alterations in muscles, although not significant due to small sample size. In the T-LGL HIGH patient group, we found increased frequencies of perforin-producing CD8 + and CD4 + T cells that were moderately correlated to combined CD57 and KLRG1 expression. Investigation of the HLA haplotypes of 75 IBM patients identified that carriage of the HLA-C*14:02:01 allele was significantly higher in T-LGL HIGH compared to T-LGL LOW individuals. Expansion of T-LGL was not significantly associated with seropositivity patient status for anti-cytosolic 5'-nucleotidase 1A autoantibodies. Clinically, the age at disease onset and disease duration were similar in the T-LGL HIGH and T-LGL LOW patient groups. However, metadata analysis of functional alterations indicated that patients with expanded T-LGL more frequently relied on mobility aids than T-LGL LOW patients indicating greater disease severity., Conclusion: Altogether, these results suggest that T-LGL expansion occurring in IBM patients is correlated with exacerbated immune dysregulation and increased disease burden., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 McLeish, Sooda, Slater, Kachigunda, Beer, Paramalingam, Lamont, Chopra, Mastaglia, Needham and Coudert.)

Objective: Pain interference, fatigue, and impaired physical function are common features of idiopathic inflammatory myopathies (IIM). The objective of this study was to evaluate the construct validity and test-retest reliability of the Patient Reported Outcome Information System (PROMIS) Pain Interference 6av1.0, Fatigue 7av1.0, and Physical Function 8bv2.0 instruments., Methods: Patient-Reported Outcome Measures (PROMs) were deployed to adult IIM patients from OMERACT Myositis Working Group (MWG) international clinic sites via two online surveys (2019, 2021). Internal consistency of each PROM was analyzed by Cronbach's α. Construct validity was determined by a priori hypotheses generated by the MWG with >75% agreement for each hypothesis and calculated with Pearson correlations. Test-retest reliability was assessed using intraclass correlation coefficient with PROMIS instruments administered at time zero and 7 days., Results: Surveys were sent to 368 participants in total; participants who completed each questionnaire varied (n=65 to 263). For construct validity, 10 out of 13 a priori hypotheses were met supporting construct validity of PROMIS instruments (Pain Interference 3/4, fatigue 4/4, and Physical Function 3/5). Test-retest reliability was strong for all PROMIS instruments. All PROMIS instruments demonstrated excellent internal consistency. None of the measures demonstrated any ceiling or floor effects except for a ceiling effect in the Pain Interference instrument., Conclusions: This study presents test-retest reliability and construct validity evidence supporting PROMIS Pain Interference (6a v1.0), Fatigue (7a v1.0), and Physical Function (8b v2.0) using a large international cohort of patients with IIM. Internal consistency of these instruments was excellent. A ceiling effect was noted in the Pain Interference instrument., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: B mode ultrasound (US) and shear wave elastography (SWE) are easily accessible imaging tools for idiopathic inflammatory myopathies (IIM) but require further validation against standard diagnostic procedures such as MRI and muscle biopsy., Methods: In this prospective cross-sectional study we compared US findings to MRI and muscle biopsy findings in a group of 18 patients (11 F, 7 M) with active IIM (dermatomyositis 6, necrotising autoimmune myopathy 7, inclusion body myositis 4, overlap myositis 1) who had one or both procedures on the same muscle. US domains (echogenicity, fascial thickness, muscle bulk, shear wave speed and power doppler) in the deltoid and vastus lateralis were compared to MRI domains (muscle oedema, fatty infiltration/atrophy) and muscle biopsy findings (lymphocytic inflammation, myonecrosis, atrophy and fibro-fatty infiltration). A composite index score (1-4) was also used as an arbitrary indicator of overall muscle pathology in biopsies., Results: Increased echogenicity correlated with the presence of fatty infiltration/atrophy on MRI (p = 0.047) in the vastus lateralis, and showed a non-significant association with muscle inflammation, myonecrosis, fibrosis and fatty infiltration/atrophy (p > 0.333) Severe echogenicity also had a non-significant association with higher composite biopsy index score in the vastus lateralis (p = 0.380). SWS and US measures of fascial thickness and muscle bulk showed poor discrimination in differentiating between pathologies on MRI or muscle biopsy. Power Doppler measures of vascularity correlated poorly with the presence of oedema on MRI, or with inflammation or fatty infiltration on biopsy. Overall, US was sensitive in detecting the presence of muscle pathology shown on MRI (67-100%) but showed poorer specificity (13-100%). Increased echogenicity showed good sensitivity when detecting muscle pathology (100%) but lacked specificity in differentiating muscle pathologies (0%). Most study participants rated US as the preferred imaging modality., Conclusions: Our findings show that US, in particular muscle echogenicity, has a high sensitivity, but low specificity, for detecting muscle pathology in IIM. Traditional visual grading scores are not IIM-specific and require further modification and validation. Future studies should continue to focus on developing a feasible scoring system, which is reliable and allows translation to clinical practice., (© 2022. The Author(s).)

Amyotrophic Lateral Sclerosis (ALS) is recognised to be a complex neurodegenerative disease involving both genetic and non-genetic risk factors. The underlying causes and risk factors for the majority of cases remain unknown; however, ever-larger genetic data studies and methodologies promise an enhanced understanding. Recent analyses using published summary statistics from the largest ALS genome-wide association study (GWAS) (20,806 ALS cases and 59,804 healthy controls) identified that schizophrenia (SCZ), cognitive performance (CP) and educational attainment (EA) related traits were genetically correlated with ALS. To provide additional evidence for these correlations, we built single and multi-trait genetic predictors using GWAS summary statistics for ALS and these traits, (SCZ, CP, EA) in an independent Australian cohort (846 ALS cases and 665 healthy controls). We compared methods for generating the risk predictors and found that the combination of traits improved the prediction (Nagelkerke-R 2 ) of the case-control logistic regression. The combination of ALS, SCZ, CP, and EA, using the SBayesR predictor method gave the highest prediction (Nagelkerke-R 2 ) of 0.027 (P value = 4.6 × 10 -8 ), with the odds-ratio for estimated disease risk between the highest and lowest deciles of individuals being 3.15 (95% CI 1.96-5.05). These results support the genetic correlation between ALS, SCZ, CP and EA providing a better understanding of the complexity of ALS., (© 2021. The Author(s), under exclusive licence to European Society of Human Genetics.)

A 38-year-old pregnant woman presented at 30 weeks gestation in respiratory distress with pre-eclampsia. This was on the background of slowly progressive dyspnoea over six years, with generalised weakness and previous surgery for ptosis and prognathia. After successful caesarean delivery at 31 weeks, the patient was found to have a homozygous likely pathogenic variant in the MYOD1 gene. This case presents a milder phenotype for MYOD1 congenital myopathy, usually associated with diaphragmatic defects, respiratory insufficiency and dysmorphic facies. It also highlights the difficulties of managing an undiagnosed patient through pregnancy.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons., (© 2021. The Author(s).)

Background: Before the role of shear wave elastography (SWE) and B mode ultrasound (US) in the diagnosis of different forms of idiopathic inflammatory myopathies (IIM) can be investigated, normative data is required. This study aimed to describe and then compare normative SWE and B mode ultrasound metrics of muscles in healthy controls and patients with IIM., Methods: Twenty nine healthy adult controls and 10 IIM patients (5 with inclusion body myositis and 5 with necrotising autoimmune myopathy) underwent a full clinical examination, laboratory investigations, SWE and US measurements of selected proximal and distal limb muscles. Shear wave speed (SWS) and multiple US domains [echogenicity, fascial thickness, muscle bulk and power Doppler (PD)] were measured in both groups., Results: In healthy controls (n = 29; mean age 46.60 ± 16.10; 44.8 % female), age was inversely correlated with SWS at the deltoid (stretch) (Rs. -0.40, p = 0.030) and PD score at the deltoid (rest) (Rs. -0.40, P = 0.032). Those ≥ 50 years old had a lower SWS at the deltoid (stretch) compared to the < 50 year group (2.92 m/s vs. 2.40 m/s, P = 0.032). Age correlated with increased echogenicity in the flexor digitorum profundus (Rs. 0.38, P = 0.045). Females had a smaller muscle bulk in the deltoid (P = 0.022). Body mass index (BMI) was inversely associated with SWS in the deltoid (stretch) (Rs - 0.45, P = 0.026), and positively correlated with echogenicity in the deltoid (Rs. 0.69, P = 0.026). In patients ≥50 years of age, patients with IIM (mean age 61.00 ± 8.18; females 20.0 %) had a higher proportion of abnormal echogenicity scores at the flexor digitorum profundus (FDP) (40.00 % vs. 14.30 %, P = 0.022) and tibialis anterior (TA) (80.00 % vs. 28.60 %, P = 0.004). Fascial thickness was lower in the FDP (0.63mm vs. 0.50mm, p = 0.012) and TA (0.58mm vs. 0.45mm, P = 0.001)., Conclusions: Our findings suggest there is scope for US techniques to be useful for diagnostic screening of affected muscles in patients with IIM, especially in those with suspected inclusion body myositis or necrotising autoimmune myopathy. We provide normative data for future studies into SWE and US techniques in skeletal muscle. The differences between IIM patients and controls warrant further study in a broader IIM patient cohort.