ORCID Profile
0000-0001-6591-1444
Current Organisations
Perron Institute for Neurological and Translational Science
,
Murdoch University
,
Fiona Stanley Hospital
,
University of Notre Dame Australia
,
South Metropolitan Health Service
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Publisher: The Journal of Rheumatology
Date: 15-11-2015
Abstract: Currently there are no evidence-based recommendations regarding fitness and strength tests for patients with childhood or adult idiopathic inflammatory myopathies (IIM). This hinders clinicians and researchers in choosing the appropriate fitness- or muscle strength-related outcome measures for these patients. Through a Delphi survey, we aimed to identify a candidate core set of fitness and strength tests for children and adults with IIM. Fifteen experts participated in a Delphi survey that consisted of 5 stages to achieve a consensus. Using an extensive search of published literature and through the work of experts, a candidate core set based on expert opinion and clinimetrics properties was developed. Members of the International Myositis Assessment and Clinical Studies Group were invited to review this candidate core set during the final stage, which led to a final candidate core set. A core set of fitness- and strength-related outcome measures was identified for children and adults with IIM. For both children and adults, different tests were identified and selected for maximal aerobic fitness, submaximal aerobic fitness, anaerobic fitness, muscle strength tests, and muscle function tests. The core set of fitness- and strength-related outcome measures provided by this expert consensus process will assist practitioners and researchers in deciding which tests to use in patients with IIM. This will improve the uniformity of fitness and strength tests across studies, thereby facilitating the comparison of study results and therapeutic exercise program outcomes among patients with IIM.
Publisher: Elsevier BV
Date: 06-2011
DOI: 10.1016/J.JNEUROIM.2011.02.011
Abstract: Susceptibility to sporadic inclusion body myositis (sIBM) in Caucasians has been consistently associated with alleles of the major histocompatibility complex (MHC) 8.1 ancestral haplotype (AH) (defined by HLA-B*0801 and HLA-DRB1*0301). In this study recombination mapping was utilised to further refine the known 8.1AH susceptibility region near HLA-DRB1*0301. Caucasian sIBM patients carrying part of the 8.1AH were genotyped for a selection of 8.1AH-haplotypic polymorphisms. A common 8.1AH-specific susceptibility region was defined, spanning 172 kb and encompassing three genes--HLA-DRB3, HLA-DRA and BTNL2. It is thus likely that 8.1AH-derived susceptibility to sIBM originates from at least one of these genes.
Publisher: Elsevier BV
Date: 02-2007
DOI: 10.1016/J.NMD.2006.10.007
Abstract: Statins can cause a necrotizing myopathy and hyperCKaemia which is reversible on cessation of the drug. What is less well known is a phenomenon whereby statins may induce a myopathy, which persists or may progress after stopping the drug. We investigated the muscle pathology in 8 such cases. All had myofibre necrosis but only 3 had an inflammatory infiltrate. In all cases there was diffuse or multifocal up-regulation of MHC-I expression even in non-necrotic fibres. Progressive improvement occurred in 7 cases after commencement of prednisolone and methotrexate, and in one case spontaneously. These observations suggest that statins may initiate an immune-mediated myopathy that persists after withdrawal of the drug and responds to immunosuppressive therapy. The mechanism of this myopathy is uncertain but may involve the induction by statins of an endoplasmic reticulum stress response with associated up-regulation of MHC-I expression and antigen presentation by muscle fibres.
Publisher: Elsevier BV
Date: 06-2022
DOI: 10.1016/J.BERH.2022.101761
Abstract: Inclusion body myositis (IBM) is a slowly progressive muscle disease affecting ageing in iduals. IBM presents with a distinctive pattern of weakness involving the quadriceps and finger flexor muscles, although other muscles including pharyngeal muscles become affected over time. Pathological hallmarks of IBM include autoimmune features, including endomysial infiltration by highly differentiated T cells, as well as degenerative features marked by intramyofibre protein aggregates organised into inclusion bodies. Despite some progress in understanding the cellular pathways involved in IBM, it remains untreatable, and the progression of the disease leads to progressive weakness, disability, wheelchair dependency and loss of independence. Therefore, there is an urgent need to improve our understanding of the underlying mechanisms and pathways involved in this disease to identify new treatment targets. Here, we discuss the current understanding of aetiopathogenesis, the interrelationship between autoimmunity and degeneration, and how ageing is a major influencer of both these features.
Publisher: Elsevier BV
Date: 09-2012
DOI: 10.1016/J.JNEUROIM.2012.04.021
Abstract: The NOTCH4 gene, located within the MHC region, is involved in cellular differentiation and has varying effects dependent on tissue type. Coding region polymorphisms haplotypic of the sIBM-associated 8.1 ancestral haplotype were identified in NOTCH4 and genotyped in two different Caucasian sIBM cohorts. In both cohorts the frequency of the minor allele of rs422951 and the 12-repeat variation for rs72555375 was increased and was higher than the frequency of the sIBM-associated allele HLA-DRB1*0301. These NOTCH4 polymorphisms can be considered to be markers for sIBM susceptibility, but require further investigation to determine whether they are directly involved in the disease pathogenesis.
Publisher: Springer Science and Business Media LLC
Date: 27-02-2020
DOI: 10.1038/S41525-020-0118-3
Abstract: We conducted DNA methylation association analyses using Illumina 450K data from whole blood for an Australian amyotrophic lateral sclerosis (ALS) case–control cohort (782 cases and 613 controls). Analyses used mixed linear models as implemented in the OSCA software. We found a significantly higher proportion of neutrophils in cases compared to controls which replicated in an independent cohort from the Netherlands (1159 cases and 637 controls). The OSCA MOMENT linear mixed model has been shown in simulations to best account for confounders. When combined in a methylation profile score, the 25 most-associated probes identified by MOMENT significantly classified case–control status in the Netherlands s le (area under the curve, AUC = 0.65, CI 95% = [0.62–0.68], p = 8.3 × 10 −22 ). The maximum AUC achieved was 0.69 (CI 95% = [0.66–0.71], p = 4.3 × 10 −34 ) when cell-type proportion was included in the predictor.
Publisher: Elsevier BV
Date: 05-2020
Publisher: American Medical Association (AMA)
Date: 12-2015
DOI: 10.1001/JAMANEUROL.2015.2274
Abstract: To our knowledge, the efficacy of transferring next-generation sequencing from a research setting to neuromuscular clinics has never been evaluated. To translate whole-exome sequencing (WES) to clinical practice for the genetic diagnosis of a large cohort of patients with limb-girdle muscular dystrophy (LGMD) for whom protein-based analyses and targeted Sanger sequencing failed to identify the genetic cause of their disorder. We performed WES on 60 families with LGMDs (100 exomes). Data analysis was performed between January 6 and December 19, 2014, using the xBrowse bioinformatics interface (Broad Institute). Patients with LGMD were ascertained retrospectively through the Institute for Neuroscience and Muscle Research Biospecimen Bank between 2006 and 2014. Enrolled patients had been extensively investigated via protein studies and candidate gene sequencing and remained undiagnosed. Patients presented with more than 2 years of muscle weakness and with dystrophic or myopathic changes present in muscle biopsy specimens. The diagnostic rate of LGMD in Australia and the relative frequencies of the different LGMD subtypes. Our central goals were to improve the genetic diagnosis of LGMD, investigate whether the WES platform provides adequate coverage of known LGMD-related genes, and identify new LGMD-related genes. With WES, we identified likely pathogenic mutations in known myopathy genes for 27 of 60 families. Twelve families had mutations in known LGMD-related genes. However, 15 families had variants in disease-related genes not typically associated with LGMD, highlighting the clinical overlap between LGMD and other myopathies. Common causes of phenotypic overlap were due to mutations in congenital muscular dystrophy-related genes (4 families) and collagen myopathy-related genes (4 families). Less common myopathies included metabolic myopathy (2 families), congenital myasthenic syndrome (DOK7), congenital myopathy (ACTA1), tubular aggregate myopathy (STIM1), myofibrillar myopathy (FLNC), and mutation of CHD7, usually associated with the CHARGE syndrome. Inclusion of family members increased the diagnostic efficacy of WES, with a diagnostic rate of 60% for "trios" (an affected proband with both parents) vs 40% for single probands. A follow-up screening of patients whose conditions were undiagnosed on a targeted neuromuscular disease-related gene panel did not improve our diagnostic yield. With WES, we achieved a diagnostic success rate of 45.0% in our difficult-to-diagnose cohort of patients with LGMD. We expand the clinical phenotypes associated with known myopathy genes, and we stress the importance of accurate clinical examination and histopathological results for interpretation of WES, with many diagnoses requiring follow-up review and ancillary investigations of biopsy specimens or serum s les.
Publisher: Informa UK Limited
Date: 02-2019
DOI: 10.1080/14737175.2019.1572507
Abstract: Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of muscle diseases that carry a significant morbidity and mortality risk. The utilization of imaging in the diagnostic pathway of IIM is therefore important to obtain early diagnosis and even monitor patients over time. Areas covered: Magnetic resonance imaging (MRI) has been the main imaging modality used to detect myositis but limitations include cost and accessibility, leading to delays in time to scan, and patient contraindications. This has led to the exploration of other imaging techniques to diagnose and monitor response to therapy. This article is based primarily on a literature search via PubMed using Boolean terms 'myositis' and the various imaging modalities. Expert opinion: Imaging is sensitive to pathology in IIM and may contribute to the diagnostic process. Learning how specific imaging features can distinguish different forms of IIM may allow more rapid diagnosis of myositis subtype and treatment planning, and to monitor disease activity particularly in patients who respond poorly to treatment. However, more work is needed to investigate the validity and relative utility of these imaging modalities.
Publisher: Wiley
Date: 22-04-2016
Publisher: The American Association of Immunologists
Date: 12-2008
DOI: 10.4049/JIMMUNOL.181.11.7458
Abstract: Studies in experimental cerebral malaria (ECM) in mice have identified T cells and TNF family members as critical mediators of pathology. In this study we report a role for LIGHT-lymphotoxin β Receptor (LTβR) signaling in the development of ECM and control of parasite growth. Specific blockade of LIGHT-LTβR, but not LIGHT-herpesvirus entry mediator interactions, abrogated the accumulation of parasites and the recruitment of pathogenic CD8+ T cells and monocytes to the brain during infection without affecting early activation of CD4+ T cells, CD8+ T cells, or NK cells. Importantly, blockade of LIGHT-LTβR signaling caused the expansion of splenic monocytes and an overall enhanced capacity to remove and process Ag during infection, as well as reduced systemic cytokine levels when control mice displayed severe ECM symptoms. In summary, we have discovered a novel pathogenic role for LIGHT and LTβR in ECM, identifying this TNF family receptor-ligand interaction as an important immune regulator during experimental malaria.
Publisher: Wiley
Date: 2022
DOI: 10.1002/CTI2.1416
Abstract: Sporadic Inclusion Body Myositis (IBM) is an inflammatory muscle disease affecting in iduals over the age of 45, leading to progressive muscle wasting, disability and loss of independence. Histologically, IBM is characterised by immune changes including myofibres expressing major histocompatibility complex molecules and invaded by CD8 + T cells and macrophages, and by degenerative changes including protein aggregates organised in inclusion bodies, rimmed vacuoles and mitochondrial abnormalities. There is currently no cure, and regular exercise is currently the only recognised treatment effective at limiting muscle weakening, atrophy and loss of function. Testosterone exerts anti‐inflammatory effects, inhibiting effector T‐cell differentiation and pro‐inflammatory cytokine production. We conducted a double‐blind, placebo‐controlled, cross‐over trial in men with IBM, to assess whether a personalised progressive exercise training combined with application of testosterone, reduced the inflammatory immune response associated with this disease over and above exercise alone. To assess intervention efficacy, we immunophenotyped blood immune cells by flow cytometry, and measured serum cytokines and chemokines by Luminex immunoassay. Testosterone supplementation resulted in modest yet significant count reduction in the classical monocyte subset as well as eosinophils. Testosterone‐independent immunoregulatory effects attributed to exercise included altered proportions of some monocyte, T‐ and B‐cell subsets, and reduced IL‐12, IL‐17, TNF‐α, MIP‐1β and sICAM‐1 in spite of interin idual variability. Overall, our findings indicate anti‐inflammatory effects of exercise training in IBM patients, whilst concomitant testosterone supplementation provides some additional changes. Further studies combining testosterone and exercise would be worthwhile in larger cohorts and longer testosterone administration periods.
Publisher: Springer Science and Business Media LLC
Date: 30-08-2022
Publisher: Wiley
Date: 07-04-2023
DOI: 10.1002/ACN3.51760
Abstract: 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.
Publisher: Public Library of Science (PLoS)
Date: 21-05-2013
Publisher: The Journal of Rheumatology
Date: 15-02-2019
Abstract: To present and vote on a myositis modified patient-reported outcome core domain set in the life impact area at the Outcome Measures in Rheumatology (OMERACT) 2018. Based on results from international focus groups and Delphi surveys, a draft core set was developed. Domains muscle symptoms, fatigue, level of physical activity, and pain reached ≥ 70% consensus and were mandatory to assess in all trials. Domains lung, joint, and skin symptoms were mandatory in specific circumstances. This core set was endorsed by 85% at OMERACT 2018. We propose a life impact core set for patients with idiopathic inflammatory myopathies and will proceed with instrument selections.
Publisher: Elsevier BV
Date: 2014
DOI: 10.1016/J.NMD.2013.09.011
Abstract: The 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors (statins) are among the most common medications prescribed worldwide, but their efficacy and toxicity vary between in iduals. One of the major factors contributing to intolerance and non-compliance are the muscle side-effects, which range from mild myalgia through to severe life-threatening rhabdomyolysis. One way to address this is pharmacogenomic screening, which aims to in idualize therapy to maximize efficacy whilst avoiding toxicity. Genes encoding proteins involved in the metabolism of statins as well as genes known to cause inherited muscle disorders have been investigated. To-date only polymorphisms in the SLCO1B1 gene, which encodes the protein responsible for hepatic uptake of statins, and the COQ2 gene, important in the synthesis of coenzyme Q10, have been validated as being strongly associated with statin-induced myopathy. The aim of this review is to summarize studies investigating genetic factors predisposing to statin myopathy and myalgia, as the first step towards pharmacogenomic screening to identify at risk in iduals.
Publisher: Oxford University Press (OUP)
Date: 03-08-2022
DOI: 10.1093/RHEUMATOLOGY/KEAC441
Abstract: The assessment of physical function is fundamental in the management of patients with idiopathic inflammatory myopathies (IIMs). We aimed to investigate the physical function of patients with IIMs compared with those with non-IIM autoimmune rheumatic diseases (AIRDs) utilizing Patient-Reported Outcome Measurement Information System (PROMIS) Physical Function (PF) data obtained in the COVAD study, an international self-reported e-survey assessing the safety of COVID-19 vaccines in AIRDs. Demographics, AIRD diagnosis, disease activity, and PROMIS PF short form-10a data were extracted from the COVAD database. PROMIS PF-10a scores were compared between disease categories and stratified by disease activity. Factors affecting PROMIS PF-10a scores other than disease activity were identified by multivariable regression analysis in patients with inactive disease. A total of 1057 IIM patients, 3635 non-IIM AIRD patients and 3981 healthy controls (HCs) responded to the COVAD e-survey from April to August 2021. Using a binomial regression model, the predicted mean of PROMIS PF-10a scores was significantly lower in IIM patients compared with non-IIM AIRD patients or HCs [36.3 (95% CI 35.5, 37.1) vs 41.3 (95% CI 40.2, 42.5) vs 46.2 (95% CI 45.8, 46.6), P & 0.001], irrespective of disease activity. The independent factors for lower PROMIS PF-10a scores in patients with inactive disease were older age, female, longer disease duration, and a diagnosis of inclusion body myositis or polymyositis. Physical function is significantly impaired in IIMs compared with non-IIM AIRDs or HCs, even in patients with inactive disease. Our study highlights a critical need for better strategies to minimize functional disability in patients with IIMs.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2011
Publisher: Springer Science and Business Media LLC
Date: 12-2021
DOI: 10.1038/S41588-021-00973-1
Abstract: 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 in iduals 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.
Publisher: Wiley
Date: 12-04-2022
DOI: 10.1002/RCR2.915
Abstract: Acute onset, atraumatic, bilateral diaphragm paralysis due to isolated bilateral phrenic neuropathy is uncommon. Respiratory physicians should be alert to this disorder because it is associated with considerable morbidity and diagnosis is often delayed. These case reports highlight important aspects of the presentation, investigations and management of this disorder.
Publisher: Oxford University Press (OUP)
Date: 18-10-2013
DOI: 10.1093/BRAIN/AWT281
Abstract: The aim of this work was to evaluate sex differences in the incidence of multiple sclerosis relapses assess the relationship between sex and primary progressive disease course and compare effects of age and disease duration on relapse incidence. Annualized relapse rates were calculated using the MSBase registry. Patients with incomplete data or <1 year of follow-up were excluded. Patients with primary progressive multiple sclerosis were only included in the sex ratio analysis. Relapse incidences over 40 years of multiple sclerosis or 70 years of age were compared between females and males with Andersen-Gill and Tweedie models. Female-to-male ratios stratified by annual relapse count were evaluated across disease duration and patient age and compared between relapse-onset and primary progressive multiple sclerosis. The study cohort consisted of 11 570 eligible patients with relapse-onset and 881 patients with primary progressive multiple sclerosis. Among the relapse-onset patients (82 552 patient-years), 48,362 relapses were recorded. Relapse frequency was 17.7% higher in females compared with males. Within the initial 5 years, the female-to-male ratio increased from 2.3:1 to 3.3:1 in patients with 0 versus ≥4 relapses per year, respectively. The magnitude of this sex effect increased at longer disease duration and older age (P < 10(-12)). However, the female-to-male ratio in patients with relapse-onset multiple sclerosis and zero relapses in any given year was double that of the patients with primary progressive multiple sclerosis. Patient age was a more important determinant of decline in relapse incidence than disease duration (P < 10(-12)). Females are predisposed to higher relapse activity than males. However, this difference does not explain the markedly lower female-to-male sex ratio in primary progressive multiple sclerosis. Decline in relapse activity over time is more closely related to patient age than disease duration.
Publisher: Oxford University Press
Date: 05-2014
DOI: 10.1093/MED/9780199698073.001.0001
Abstract: Part of the Oxford Textbooks in Clinical Neurology series, the Oxford Textbook of Neuromuscular Disorders covers the scientific basis, clinical diagnosis, and treatment of neuromuscular disorders with a particular focus on the most clinically relevant disorders. The resource is organized into seven sections, starting with the general approach to the patient with neuromuscular disorders and then focusing on specific neuromuscular conditions affecting the peripheral nervous system from its origins at the spinal cord anterior horn on its outward course to their effector muscles and the inbound sensory pathways. Chapters on specific neuromuscular conditions are illustrated with typical case histories and their presenting features, allowing readers to put rarer conditions into their clinical context more easily.
Publisher: Springer Science and Business Media LLC
Date: 08-08-2022
DOI: 10.1186/S41927-022-00276-W
Abstract: 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. 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. 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. 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.
Publisher: Informa UK Limited
Date: 05-07-2022
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 30-12-2016
Publisher: Elsevier BV
Date: 12-2013
DOI: 10.1016/J.NMD.2013.09.008
Abstract: A polyT repeat in an intronic polymorphism (rs10524523) in the TOMM40 gene, which encodes an outer mitochondrial membrane translocase involved in the transport of amyloid-β and other proteins into mitochondria, has been implicated in Alzheimer's disease and APOE-TOMM40 genotypes have been shown to modify disease risk and age at onset of symptoms. Because of the similarities between Alzheimer's disease and sporadic inclusion body myositis (s-IBM), and the importance of amyloid-β and mitochondrial changes in s-IBM, we investigated whether variation in poly-T repeat lengths in rs10524523 also influence susceptibility and age at onset in a cohort of 90 Caucasian s-IBM patients (55 males age 69.1 ± 9.6). In carriers of APOE ε3/ε3 or ε3/ε4, genotypes with a very long (VL) poly-T repeat were under-represented in s-IBM compared to controls and were associated with a later age at symptom onset, suggesting that these genotypes may be protective. Our study is the first to suggest that polymorphisms in genes controlling mitochondrial function can influence susceptibility to s-IBM and have disease modifying effects. However, further studies in other s-IBM populations are needed to confirm these findings, as well as expression studies of different TOMM40 alleles in muscle tissue.
Publisher: Elsevier BV
Date: 2013
DOI: 10.1016/J.JNEUROIM.2012.09.003
Abstract: We compared the carriage frequencies of HLA-DRB3 and its major alleles and of HLA-DRB4 and HLA-DRB5 in an Australian sIBM cohort and a population control group who had previously been genotyped for the HLA-DRB1*03:01 risk allele. There was a strong disease association with the carriage of the DRB3*01:01 allele which was accounted for by its linkage disequilibrium with DRB1*03:01. The carriage of HLA-DRB4 was found to be strongly protective and abrogated the risk effect of HLA-DRB1*03:01. The findings indicate that haplotypic combinations of alleles at the HLA-DRB1 and secondary HLA-DRB loci have important risk modifying effects in sIBM.
Publisher: Springer Science and Business Media LLC
Date: 26-04-2018
Publisher: Diving and Hyperbaric Medicine Journal
Date: 20-12-2020
Abstract: (Ashton C, Banham N, Needham M. Acute spontaneous spinal cord infarction: Utilisation of hyperbaric oxygen treatment, cerebrospinal fluid drainage and pentoxifylline. Diving and Hyperbaric Medicine. 2020 December 20 (4):325–331. doi: 10.28920/dhm50.4.325-331. PMID: 33325011.) Introduction: Spinal cord infarction (SCI) is a potentially devastating disorder presenting with an acute anterior spinal artery syndrome, accounting for an estimated 1% of stroke presentations. Aetiologies include aortic surgical complications, systemic hypotension, fibrocartilaginous embolism and vascular malformations. Diagnosis is clinical combined with restriction on diffusion-weighted magnetic resonance imaging (MRI). There are no treatment guidelines for non-perioperative cases although there is limited literature regarding potential therapies, including hyperbaric oxygen treatment (HBOT) and cerebrospinal fluid (CSF) drainage. We describe 13 cases of acute SCI, five receiving HBOT, and three also receiving pentoxifylline and drainage of lumbar CSF. Methods: Data for all patients with MRI-proven SCI at Fiona Stanley Hospital from 2014–2019 were reviewed. Results: Thirteen patients, median age 57 years (31–74), 54% female, were identified. Aetiologies: two fibrocartilaginous emboli seven likely atherosclerotic two thromboembolic two cryptogenic. All presented with flaccid paraplegia except one with Brown-Sequard syndrome. Levels ranged from C4 to T11. Five patients received HBOT within a median time of 40 hours from symptom onset, with an average 15 treatments (10−20). Three of these received triple therapy (HBOT, pentoxifylline, CSF drainage) and had median Medical Research Council manual muscle testing power of 5, median modified Rankin Score (mRS) of 1 and American Spinal Injury Association (ASIA) score of D on discharge, compared with 2 power, mRS 3.5 and ASIA B in those who did not. Conclusions: SCI can be severely disabling. Triple therapy with pentoxifylline, CSF drainage and HBOT may reduce disability and further prospective trials are required.
Publisher: Informa UK Limited
Date: 24-09-2021
Publisher: BMJ
Date: 09-2016
Publisher: Elsevier BV
Date: 09-2019
Publisher: Frontiers Media SA
Date: 30-03-2023
DOI: 10.3389/FIMMU.2023.1153789
Abstract: 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). 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. 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 s les donated by three patients indicated a consistent pattern of more pronounced alterations in muscles, although not significant due to small s le 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 in iduals. 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. Altogether, these results suggest that T-LGL expansion occurring in IBM patients is correlated with exacerbated immune dysregulation and increased disease burden.
Publisher: Oxford University Press (OUP)
Date: 31-10-2022
DOI: 10.1093/RHEUMATOLOGY/KEAC624
Abstract: The COVID-19 vaccination in autoimmune diseases (COVAD) study aimed to assess short-term COVID-19 vaccination-related adverse events (AEs) in RA patients. An online self-reported questionnaire (March–December 2021) was used to capture data related to COVID-19 vaccination-related AEs in RA, other autoimmune rheumatic diseases (AIRDs) (excluding RA and inflammatory myositis), non-rheumatic autoimmune diseases (nrAIDs) and healthy controls (HCs). Descriptive and multivariable regression analyses were performed. Of the 9462 complete respondents, 14.2% (n = 1347) had been diagnosed with RA they had a mean (s.d.) age of 50.7 (13.7) years, 74.2% were women and 49.3% were Caucasian. In total, 76.9% and 4.2% of patients with RA reported minor and major AEs, respectively. Patients with active and inactive RA had similar AE and hospitalization frequencies. Overall, AEs were reported more frequently by BNT162b2 and mRNA-1273 recipients and less frequently by BBV152 recipients compared with the rest. Major AE and hospitalization frequencies were similar across recipients of different vaccines. Patients receiving methotrexate and hydroxychloroquine reported fewer minor AEs than those patients not on them. Compared with HCs and patients with other AIRDs, patients with RA reported similar total AEs, overall minor AEs, and hospitalizations. Compared with nrAIDs, patients with RA reported lower frequencies of overall AEs, minor AEs (both odds ratio [OR] = 0.7 95% CI: 0.5, 0.9), and injection site pain (OR = 0.6 95% CI: 0.5, 0.8) with similar major AE and hospitalization frequencies. Despite the differences in AE frequency across different COVID-19 vaccines, all were well tolerated in patients with RA and were comparable to HCs, providing reassurance as to the safety of COVID-19 vaccination.
Publisher: Hindawi Limited
Date: 10-07-2022
DOI: 10.1111/HSC.13498
Abstract: 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 atient/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 s les and multiple sites.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2020
Publisher: Wiley
Date: 31-10-2013
DOI: 10.1111/IEP.12048
Publisher: Elsevier BV
Date: 10-2020
Publisher: Springer Science and Business Media LLC
Date: 29-01-2022
DOI: 10.1186/S13023-022-02172-5
Abstract: Valosin-containing protein (VCP) associated multisystem proteinopathy (MSP) is a rare inherited disorder that may result in multisystem involvement of varying phenotypes including inclusion body myopathy, Paget’s disease of bone (PDB), frontotemporal dementia (FTD), parkinsonism, and amyotrophic lateral sclerosis (ALS), among others. An international multidisciplinary consortium of 40+ experts in neuromuscular disease, dementia, movement disorders, psychology, cardiology, pulmonology, physical therapy, occupational therapy, speech and language pathology, nutrition, genetics, integrative medicine, and endocrinology were convened by the patient advocacy organization, Cure VCP Disease, in December 2020 to develop a standard of care for this heterogeneous and under-diagnosed disease. To achieve this goal, working groups collaborated to generate expert consensus recommendations in 10 key areas: genetic diagnosis, myopathy, FTD, PDB, ALS, Charcot Marie Tooth disease (CMT), parkinsonism, cardiomyopathy, pulmonology, supportive therapies, nutrition and supplements, and mental health. In April 2021, facilitated discussion of each working group’s conclusions with consensus building techniques enabled final agreement on the proposed standard of care for VCP patients. Timely referral to a specialty neuromuscular center is recommended to aid in efficient diagnosis of VCP MSP via single-gene testing in the case of a known familial VCP variant, or multi-gene panel sequencing in undifferentiated cases. Additionally, regular and ongoing multidisciplinary team follow up is essential for proactive screening and management of secondary complications. The goal of our consortium is to raise awareness of VCP MSP, expedite the time to accurate diagnosis, define gaps and inequities in patient care, initiate appropriate pharmacotherapies and supportive therapies for optimal management, and elevate the recommended best practices guidelines for multidisciplinary care internationally.
Publisher: Elsevier BV
Date: 10-2020
Publisher: Springer Science and Business Media LLC
Date: 04-10-2012
DOI: 10.1007/S11910-011-0232-9
Abstract: The toxic myopathies are a clinically and pathologically erse group of disorders that can be caused by a variety of therapeutic agents used in clinical practice, as well as various venoms and other biological toxins. The most important iatrogenic causes are the statin and fibrate cholesterol-lowering agents that can cause a severe necrotizing myopathy and acute rhabdomyolysis and myoglobinuria. The current update focuses on the mechanisms of statin myotoxicity and the importance of genetic predisposing factors for statin myopathy, as well as the recently described form of necrotizing autoimmune myopathy, which is associated with antibodies to the 3-hydroxy-3-methylglutaryl-coenzyme A reductase enzyme and is responsive to aggressive immunotherapy. Mitochondrial myopathies associated with antiretroviral agents and the pyrimidine nucleoside analogue clevudine, and recent reports of myopathies caused by ingestion of red yeast rice and toxic species of mushrooms are also discussed.
Publisher: BMJ
Date: 10-06-2018
Publisher: Wiley
Date: 27-01-2023
DOI: 10.1111/IMJ.16004
Abstract: Anti–3‐hydroxy‐3‐methylglutaryl CoA reductase (HMGCR) antibodies are associated with a subtype of immune‐mediated necrotising myopathy (IMNM). 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. 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. 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. 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.
Publisher: Springer Science and Business Media LLC
Date: 27-04-2022
Publisher: Elsevier BV
Date: 12-2008
DOI: 10.1016/J.JOCN.2008.01.011
Abstract: The prevalence of sporadic inclusion body myositis (sIBM) is variable in different populations and ethnic groups. A previous survey in Western Australia in 2000 found a prevalence of 9.3 per million population. We have now performed a follow-up survey to determine whether there has since been any change in prevalence. The current prevalence was found to be 14.9 per million population, with a prevalence of 51.3 per million population in people over 50 years of age. This is the highest reported prevalence of sIBM and correlates with a high frequency of HLA-DR3 and the 8.1 major histocompatibility complex ancestral haplotype in this population. Review of a combined cohort of 57 sIBM cases from three Australian centres revealed a high rate of initial misdiagnosis and a mean time to diagnosis of 5.2 years, which suggests that even the latest prevalence figure may be an underestimate, and emphasising the need to increase the level of awareness of the condition among the medical community.
Publisher: Springer Science and Business Media LLC
Date: 26-03-2021
DOI: 10.1186/S13059-021-02275-5
Abstract: People with neurodegenerative disorders show erse clinical syndromes, genetic heterogeneity, and distinct brain pathological changes, but studies report overlap between these features. DNA methylation (DNAm) provides a way to explore this overlap and heterogeneity as it is determined by the combined effects of genetic variation and the environment. In this study, we aim to identify shared blood DNAm differences between controls and people with Alzheimer’s disease, amyotrophic lateral sclerosis, and Parkinson’s disease. We use a mixed-linear model method (MOMENT) that accounts for the effect of (un)known confounders, to test for the association of each DNAm site with each disorder. While only three probes are found to be genome-wide significant in each MOMENT association analysis of amyotrophic lateral sclerosis and Parkinson’s disease (and none with Alzheimer’s disease), a fixed-effects meta-analysis of the three disorders results in 12 genome-wide significant differentially methylated positions. Predicted immune cell-type proportions are disrupted across all neurodegenerative disorders. Protein inflammatory markers are correlated with profile sum-scores derived from disease-associated immune cell-type proportions in a healthy aging cohort. In contrast, they are not correlated with MOMENT DNAm-derived profile sum-scores, calculated using effect sizes of the 12 differentially methylated positions as weights. We identify shared differentially methylated positions in whole blood between neurodegenerative disorders that point to shared pathogenic mechanisms. These shared differentially methylated positions may reflect causes or consequences of disease, but they are unlikely to reflect cell-type proportion differences.
Publisher: Springer Science and Business Media LLC
Date: 02-04-2018
Publisher: Elsevier BV
Date: 02-2008
DOI: 10.1016/J.NMD.2007.09.005
Abstract: Previous studies have differed as to whether APOE epsilon4 is a susceptibility factor for developing sporadic inclusion body myositis (sIBM), with a positive association being found only in an Australian cohort of cases. We have now re-examined this in a larger cohort of 57 sIBM cases and have also carried out a meta-analysis of all the published studies looking for evidence of a risk association or effect of APOE alleles on disease expression. Our findings argue against a specific role for any APOE alleles in conferring susceptibility to sIBM but have demonstrated a non-significant trend towards an earlier age-of-onset in patients with the epsilon2 allele.
Publisher: Wiley
Date: 09-2013
DOI: 10.1111/IMJ.12234
Abstract: Patients with muscle disorders can present a diagnostic challenge to physicians because of the different ways they can present and the large number of different underlying causes. Recognition of the 'myopathic phenotype' coupled with investigations usually including electrodiagnostic and histological investigations have been essential for diagnosing the underlying cause of a myopathy. Despite these standard investigations, some patients can remain undiagnosed. New tests including more specific antibody tests for immune-mediated myopathies and the introduction of next-generation sequencing promise to revolutionise diagnostic approaches for immune and inherited myopathies, but clinical expertise remains essential to choose the most appropriate tests and interpret the results. The aim of this review is to provide an overview of the different presentations to the neuromuscular clinic and the latest investigations that can be helpful in the diagnosis of muscle disorders.
Publisher: Springer Science and Business Media LLC
Date: 12-01-2018
Publisher: Springer Science and Business Media LLC
Date: 19-01-2022
DOI: 10.1186/S13073-021-01006-6
Abstract: 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. 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 ( N cases = 20,806, N controls = 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 N total = 942, protein N total = 300) and gene knockdown (KD) studies of human neuronal iPSC cells and zebrafish-morpholinos (MO). 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 R 2 = 0.042, B effect = 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. 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 ex les of in-depth investigations of risk loci in ALS exist and a similar approach could be applied to investigate future expected GWAS findings.
Publisher: BMJ
Date: 19-08-2013
Publisher: Wiley
Date: 19-11-2021
DOI: 10.1111/IMJ.15505
Abstract: This document provides consensus‐based recommendations for general physicians and primary care physicians who diagnose and manage patients with mitochondrial diseases (MD). It builds on previous international guidelines, with particular emphasis on clinical management in the Australian setting. This statement was prepared by a working group of medical practitioners, nurses and allied health professionals with clinical expertise and experience in managing Australian patients with MD. As new treatments and management plans emerge, these consensus‐based recommendations will continue to evolve, but current standards of care are summarised in this document.
Publisher: Elsevier BV
Date: 04-2015
Publisher: American Association for the Advancement of Science (AAAS)
Date: 23-02-2022
DOI: 10.1126/SCITRANSLMED.ABJ0264
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study meta-analysis in 9706 s les passing stringent quality control (6763 patients, 2943 controls). We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We then tested 39 DNA methylation-based proxies of putative ALS risk factors and found that high-density lipoprotein cholesterol, body mass index, white blood cell proportions, and alcohol intake were independently associated with ALS. Integration of these results with our latest genome-wide association study showed that cholesterol biosynthesis was potentially causally related to ALS. Last, DNA methylation at several DMPs and blood cell proportion estimates derived from DNA methylation data were associated with survival rate in patients, suggesting that they might represent indicators of underlying disease processes potentially amenable to therapeutic interventions.
Publisher: Wiley
Date: 03-09-2021
DOI: 10.1002/ACN3.51446
Abstract: Neuroinflammation is an important pathogenic mechanism in amyotrophic lateral sclerosis (ALS), with regulatory T cells (Tregs) mediating a slower rate of disease progression. Dimethyl fumarate enhances Treg levels and suppresses pro‐inflammatory T cells. The present study assessed the safety and efficacy of dimethyl fumarate in ALS. Phase‐2, double‐blind, placebo‐controlled randomised clinical trial recruited participants from May 1, 2018 to September 25, 2019, across six Australian sites. Participants were randomised (2:1 ratio) to dimethyl fumarate (480 mg/day) or matching placebo, completing visits at screening, baseline, weeks 12, 24 and 36. The primary efficacy endpoint was a change in Amyotrophic Lateral Sclerosis Functional Rating Scale‐Revised (ALSFRS‐R) at week 36. Secondary outcome measures included survival, neurophysiological index (NI), respiratory function, urinary neurotrophin‐receptor p75 and quality of life. A total of 107 participants were randomised to dimethyl fumarate ( n = 72) or placebo ( n = 35). ALSFRS‐R score was not significantly different at week 36 (−1.12 [−3.75 to 1.52, p = 0.41]). Dimethyl fumarate was associated with a reduced NI decline week 36 (differences in the least‐squares mean: (0.84 [−0.51 to 2.22, p = 0.22]). There were no significant differences in other secondary outcome measures. Safety profiles were comparable between groups. Dimethyl fumarate, in combination with riluzole, was safe and well‐tolerated in ALS. There was no significant improvement in the primary endpoint. The trial provides class I evidence for safety and lack of efficacy of dimethyl fumarate in ALS.
Publisher: Elsevier BV
Date: 12-2013
Publisher: Springer Science and Business Media LLC
Date: 12-02-2016
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.NMD.2014.08.003
Abstract: Relatively little is known about frequency and extent of respiratory problems in sporadic inclusion body myositis (IBM). To address this issue a study of peripheral muscle and respiratory function and related symptoms was performed in a cohort with biopsy-proven IBM. Dyspnoea, daytime sleepiness, dysphagia, spirometry, respiratory muscle strength, arterial blood gas tensions and ventilation during sleep were assessed. Sixteen patients were studied (10 males age 68.1±9.9years disease duration 11.9±5.0years body mass index 28.5±4.0kg/m(2)). Four reported excessive daytime sleepiness 8 had at least mild dysphagia forced vital capacity was <80% predicted normal in 7 sniff nasal inspiratory pressure was reduced in 3 daytime hypoxemia was present in 9 and hypercapnia in one. Sleep study was performed in 15 and revealed sleep disordered breathing (apnoea-hypopnoea index 23.4±12.8 (range 7-50.3)events/h) in all. There were no consistent relationships between respiratory function impairment, occurrence of sleep disordered breathing, and severity of peripheral muscle weakness. Thus, asymptomatic impairment of respiratory function was common and sleep disordered breathing observed in all patients tested, irrespective of daytime respiratory function. This suggests respiratory function testing, including sleep study, should be performed routinely in IBM, irrespective of peripheral muscle function or other disease severity parameters.
Publisher: Elsevier BV
Date: 11-2016
DOI: 10.1016/J.NMD.2016.08.013
Abstract: 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.
Publisher: Elsevier BV
Date: 2008
DOI: 10.1016/J.NMD.2007.11.001
Abstract: There is now compelling evidence that sporadic inclusion body myositis (sIBM) is a muscle-specific autoimmune disease in which both T and B-cells play a part and in which both cytotoxic muscle fibre necrosis and degeneration occur. However the factors responsible for breakdown of immune tolerance and the nature of the target antigens expressed by muscle fibres remain unknown. Genetic factors are known to contribute to susceptibility, in particular MHC haplotyes which may influence antigenic presentation, and could also operate through genetic variations in muscle fibre constituents or immune effector mechanisms. Viral infection may act as a trigger mechanism, as in cases of HIV-associated sIBM. Our understanding of the mechanisms leading to the degenerative changes in muscle fibres is still incomplete. Protein misfolding and proteasomal dysfunction rather than defective transcriptional control is likely to underlie the abnormal accumulation of multiple proteins in the muscle fibre inclusions. However, aberrant transcription is thought to be the basis for the accumulation of potentially toxic mutant protein forms (e.g. UBB(+1)). The origin of the multiple clonally expanded somatic mtDNA mutations in COX-negative segments of muscle fibres remains uncertain but may be linked to the effects of oxidative stress. It is proposed that the disproportionate involvement of certain muscles in sIBM may be due to the existence of muscle group-specific transcriptomes which are differentially affected by the disease process and that the male predominance of the disease may indicate the influence of genes preferentially expressed in males. There is a need to develop better animal models of sIBM in which the relationship between the inflammatory and degenerative components of the disease as well as the gender difference in susceptibility and differential vulnerability of different muscle groups can be more critically investigated.
Publisher: Informa UK Limited
Date: 30-09-2022
DOI: 10.1080/21678421.2021.1980889
Abstract: 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.
Publisher: International Union Against Tuberculosis and Lung Disease
Date: 21-03-2022
DOI: 10.5588/PHA.21.0071
Abstract: BACKGROUND: The level of antibiotic resistance of pathogens causing uncomplicated urinary tract infections (UTIs) is increasing. The 2017–2018 GLASS (Global Antimicrobial Resistance and Use Surveillance System) report indicated % resistance to ceftriaxone and ciprofloxacin in Escherichia coli in Pakistan. METHODS: A prospective study was conducted in the Médecins Sans Frontières (MSF) supported Timurgara District Hospital, Timurgara, Pakistan, from September 2017 to December 2018. Women aged 18–65 years presenting to the Emergency Department with symptoms of uncomplicated UTI (cystitis yelonephritis) were invited to participate. We conducted microbiological culture and sensitivity testing for s les with positive dipstick or nitrite test. RESULTS: Of the 200 patients who participated, 109 (54.5%) were diagnosed with pyelonephritis and 91 (45.5%) with cystitis. Forty-three s les (21.5%) were culture-positive: E. coli was isolated in 27 s les, Enterococcus spp. in 7 and Klebsiella pneumoniae in 6. Overall resistance to ciprofloxacin was observed in 51.8% of E. coli isolates, and ceftriaxone resistance in 66.7% of E. coli isolates and in 33.3% of K. pneumoniae . Resistance to fosfomycin was low (one E. coli isolate). CONCLUSIONS: This study found resistance to first- and second-line antibiotics for treating UTIs as per the MSF protocol. Heightened awareness and potential changes to local prescription practices are necessary to curb the spread of antimicrobial resistance pathogens causing UTIs.
Publisher: Oxford University Press (OUP)
Date: 12-11-2022
Publisher: Whitehouse Publishing
Date: 04-2020
DOI: 10.47795/AYYZ8676
Publisher: Oxford University Press (OUP)
Date: 03-02-2023
DOI: 10.1093/RHEUMATOLOGY/KEAD057
Abstract: COVID-19 vaccines have a favorable safety profile in patients with autoimmune rheumatic diseases (AIRDs) such as idiopathic inflammatory myopathies (IIMs) however, hesitancy continues to persist among these patients. Therefore, we studied the prevalence, predictors and reasons for hesitancy in patients with IIMs, other AIRDs, non-rheumatic autoimmune diseases (nrAIDs) and healthy controls (HCs), using data from the two international COVID-19 Vaccination in Autoimmune Diseases (COVAD) e-surveys. The first and second COVAD patient self-reported e-surveys were circulated from March to December 2021, and February to June 2022 (ongoing). We collected data on demographics, comorbidities, COVID-19 infection and vaccination history, reasons for hesitancy, and patient reported outcomes. Predictors of hesitancy were analysed using regression models in different groups. We analysed data from 18 882 (COVAD-1) and 7666 (COVAD-2) respondents. Reassuringly, hesitancy decreased from 2021 (16.5%) to 2022 (5.1%) (OR: 0.26 95% CI: 0.24, 0.30, P & 0.001). However, concerns/fear over long-term safety had increased (OR: 3.6 95% CI: 2.9, 4.6, P & 0.01). We noted with concern greater skepticism over vaccine science among patients with IIMs than AIRDs (OR: 1.8 95% CI: 1.08, 3.2, P = 0.023) and HCs (OR: 4 95% CI: 1.9, 8.1, P & 0.001), as well as more long-term safety concerns/fear (IIMs vs AIRDs – OR: 1.9 95% CI: 1.2, 2.9, P = 0.001 IIMs vs HCs – OR: 5.4 95% CI: 3, 9.6, P & 0.001). Caucasians [OR 4.2 (1.7–10.3)] were likely to be more hesitant, while those with better PROMIS physical health score were less hesitant [OR 0.9 (0.8–0.97)]. Vaccine hesitancy has decreased from 2021 to 2022, long-term safety concerns remain among patients with IIMs, particularly in Caucasians and those with poor physical function.
Publisher: Springer Science and Business Media LLC
Date: 15-05-2020
DOI: 10.1186/S13075-020-02210-2
Abstract: A myositis-specific autoantibody can now be identified in the majority of patients with myositis. They identify homogeneous patient subgroups and are key tools in developing a personalized approach to disease management. There is substantial clinical interest in exploiting myositis autoantibodies as biomarkers, and consequently, a large number of commercial assays have been developed for their detection. These assays are already in widespread clinical use. In order to better understand perceived concerns from the international myositis community in relation to the reliability of these assays and how they are being used, we conducted a survey of international myositis experts, all of whom were members of the International Myositis Assessment and Clinical Studies group. We collected data on the types of assay used, manufacturers, and the nature of the report provided by different laboratories and received 111 complete responses. Respondents also provided information on how they used the different assays, their confidence in the results, and how this influenced their clinical practice. Enzyme immunoassay/ELISA was the most popular assay method used worldwide followed by line blot. Line blot was the most popular method used in Europe. Despite concerns from over 80% of respondents regarding false-positive and false-negative results with the assay used by their laboratory, over 80% reported that the identification of a myositis autoantibody influenced their diagnostic confidence, the information they provided to a patient, and their recommended treatment. In spite of ongoing concerns from the majority of users regarding the reliability of the results, myositis-specific autoantibody testing, using commercial immunoassays, is being used globally to inform clinical decision-making. These findings highlight the need for urgent guidance on the use of myositis autoantibody testing and on the interpretation of results. Knowledge of the reliability of currently available assays is essential given the importance already placed on myositis-specific autoantibodies as clinical decision-making tools.
Publisher: Elsevier BV
Date: 10-2021
Publisher: Springer Science and Business Media LLC
Date: 14-08-2022
DOI: 10.1007/S00296-022-05157-6
Abstract: Vaccine hesitancy is considered a major barrier to achieving herd immunity against COVID-19. While multiple alternative and synergistic approaches including heterologous vaccination, booster doses, and antiviral drugs have been developed, equitable vaccine uptake remains the foremost strategy to manage pandemic. Although none of the currently approved vaccines are live-attenuated, several reports of disease flares, waning protection, and acute-onset syndromes have emerged as short-term adverse events after vaccination. Hence, scientific literature falls short when discussing potential long-term effects in vulnerable cohorts. The COVAD-2 survey follows on from the baseline COVAD-1 survey with the aim to collect patient-reported data on the long-term safety and tolerability of COVID-19 vaccines in immune modulation. The e-survey has been extensively pilot-tested and validated with translations into multiple languages. Anticipated results will help improve vaccination efforts and reduce the imminent risks of COVID-19 infection, especially in understudied vulnerable groups.
Publisher: Springer Science and Business Media LLC
Date: 31-01-2022
Publisher: SAGE Publications
Date: 03-2022
DOI: 10.1177/17449871221077076
Abstract: There is a global call for more inclusive clinical research that is representative of all populations, particularly those historically under-represented or under-served. A lack of broad representation results in disproportionate health outcomes and limits the applicability and translation of research findings. Identify and describe barriers to participation across the research lifecycle and consider the role of the Clinical Research Nurse (CRN) in promoting inclusivity, including for Aboriginal and Torres Strait Islander Peoples within Australia. Review of recent literature and best practice identified barriers to research participation across the research process at system, participant and practitioner levels. This discussion paper explores the role of the CRN acting as enablers, facilitators and navigators, to mitigate participation barriers. With their comprehensive understanding of the research process, clinical care pathways, reflective practices and participant-centred approaches, CRNs are uniquely positioned to advocate for greater equity in access to clinical research and to motivate stakeholders across the research enterprise to embed inclusive approaches in the design, conduct and dissemination of research. An in-depth understanding of the research process, self, and cultural norms of the populations they serve is essential for CRNs to effectively advocate for equity in access to research.
Publisher: BMJ
Date: 07-2019
DOI: 10.1136/JNNP-2019-ANZAN.66
Abstract: Electrodiagnostic evaluation is crucial in establishing the diagnosis of motor neuron disease (MND) and excluding other pathologies. It is recommended that sensory nerve conduction studies (NCS) include the ulnar and sural nerves, and generally accepted that sensory nerves are normal in MND. There are however previous reports in the literature documenting variable sensory abnormalities in patients with MND. We sought to determine the frequency of unexplained sensory abnormalities seen on NCS in patients with MND. Medical records of patients attending our tertiary MND clinic over a 2 year period were reviewed. We identified 92 patients with a clinical diagnosis of MND for whom electrodiagnostic studies were available to review. Sensory abnormalities in patients without a clear underlying aetiology (eg. compressive neuropathies, diabetes) were considered unexplained. Unexplained sensory abnormalities were detected in at least one nerve in 18/92 (20%) patients. In 17 of those 18 patients, the ulnar sensory response was abnormal. 12 of 18 patients demonstrated abnormalities in 2 or more sensory nerves. Sensory abnormalities were present in 4 of 37 (10.8%) patients with bulbar onset MND and 14 of 55 (25.4%) patients with limb onset MND. Sensory symptoms were infrequently reported and did not correlate with abnormalities found on NCS. Unexplained sensory nerve action potential abnormalities are not uncommon in MND, with ulnar sensory responses the most frequently affected. These findings raise the possibility of sensory nerve pathology in patients with MND and suggest that the presence of unexplained sensory abnormalities should not exclude a diagnosis of MND.
Publisher: Informa UK Limited
Date: 26-04-2017
Publisher: Elsevier BV
Date: 10-2006
DOI: 10.1016/J.JOCN.2005.09.017
Abstract: Herein, we present a case of a parkinsonism-hyperpyrexia syndrome (PHS) in a 58-year-old man with a 10-year history of Parkinson's disease. The patient presented with a 2-week history of fever and increasing confusion, in the context of a number of changes to his medication regimen. On presentation, he was noted to be febrile with autonomic instability, diaphoresis and marked rigidity. He was disoriented and responding to visual hallucinations. Investigations revealed an elevated creatine kinase and a provisional diagnosis of PHS was made. After the patient failed to respond during a 2-week period to supportive measures, electroconvulsive therapy (ECT) treatment was commenced. A good response to eight bilateral ECT treatments was achieved, with resolution of his confusional state and associated psychotic phenomena. We discuss the nosological and management issues associated with this case and discuss the role of ECT as a treatment modality in this condition.
Publisher: Elsevier BV
Date: 2015
DOI: 10.1016/J.JOCN.2014.09.012
Abstract: Inclusion body myositis is the most common myopathy in patients over the age of 40 years encountered in neurological practice. Although it is usually sporadic, there is increasing awareness of the influence of genetic factors on disease susceptibility and clinical phenotype. The diagnosis is based on recognition of the distinctive pattern of muscle involvement and temporal profile of the disease, and the combination of inflammatory and myodegenerative changes and protein deposits in the muscle biopsy. The diagnostic importance of immunohistochemical staining for major histocompatibility complex I and II antigens, for the p62 protein, and of the recently identified anti-cN1A autoantibody in the serum, are discussed. The condition is generally poorly responsive to conventional immune therapies but there have been relatively few randomised controlled trials and most of these have been under-powered and of short duration. There is an urgent need for further well-designed multicentre trials of existing and novel therapies that may alter the natural history of the disease.
Publisher: Wiley
Date: 23-05-2011
DOI: 10.1002/MUS.22020
Abstract: Inclusion-body myopathy, Paget disease of the bone, and frontotemporal dementia (IBMPFD) is an autosomal dominant disorder due to mutations in the valosin-containing protein (VCP) gene. Patients with this disorder may have neuropathic or myopathic features. Peripheral nerve function and axonal excitability were studied in three members from two families with VCP mutations (p.Arg155Leu and p.Leu198Trp). Patients from the first family had neurogenic patterns on needle electromyography (EMG), whereas those in the second family had myopathic EMG changes. In threshold electrotonus for motor axons, the changes to depolarizing and hyperpolarizing conditioning currents were at or outside control limits in all three patients. Superexcitability was increased, and the relative refractory period was reduced. The strength-duration time constant was normal. In sensory axons of all three patients, there were similar changes in threshold electrotonus, but not in superexcitability. These features are best explained by axonal hyperpolarization. The findings provide insight into the pathophysiological mechanisms in these genotypes and, possibly, into all patients with IBMPFD.
Publisher: Elsevier BV
Date: 2020
DOI: 10.2139/SSRN.3741233
Publisher: Frontiers Media SA
Date: 26-03-2021
DOI: 10.3389/FNAGI.2021.658226
Abstract: There is a critical need to establish genetic markers that explain the complex phenotypes and pathogenicity of ALS. This study identified a polymorphism in the Stathmin-2 gene and investigated its association with sporadic ALS (sALS) disease risk, age-of onset and survival duration. The candidate CA repeat was systematically analyzed using PCR, Sanger sequencing and high throughput capillary separation for genotyping. Stathmin-2 expression was investigated using RT-PCR in patient olfactory neurosphere-derived (ONS) cells and RNA sequencing in laser-captured spinal motor neurons. In a case-control analysis of a combined North American sALS cohort ( n = 321) and population control group ( n = 332), long/long CA genotypes were significantly associated with disease risk ( p = 0.042), and most strongly when one allele was a 24 CA repeat ( p = 0.0023). In addition, longer CA allele length was associated with earlier age-of-onset ( p = 0.039), and shorter survival duration in bulbar-onset cases ( p = 0.006). In an Australian longitudinal sALS cohort ( n = 67), ALS functional rating scale scores were significantly lower in carriers of the long/long genotype ( p = 0.034). Stathmin-2 mRNA expression was reduced in sporadic patient ONS cells. Additionally, sALS patients and controls exhibited variable expression of Stathmin-2 mRNA according to CA genotype in laser-captured spinal motor neurons. We report a novel non-coding CA repeat in Stathmin-2 which is associated with sALS disease risk and has disease modifying effects. The potential value of this variant as a disease marker and tool for cohort enrichment in clinical trials warrants further investigation.
Publisher: Springer Science and Business Media LLC
Date: 19-11-2016
Publisher: MDPI AG
Date: 16-10-2021
DOI: 10.3390/MPS4040075
Abstract: In inflammatory myopathies, the self-reactive immune cells involved in muscle aggression have been studied mostly using histological assessment of muscle biopsy sections this methodology provides the advantage of visualizing and identifying cells within the tissue, but it does not allow further investigation. To gain access to live and isolated cells, many studies utilized blood s les however, in the absence of biological tools to discriminate the leukocytes associated with the autoimmune process from those that emerged from responses against pathogens, the information observed on circulating immune cells often lacks in specificity, and thus result interpretation may prove difficult. In order to selectively retrieve self-reactive immune cells, we developed a protocol to isolate live leukocytes from human muscle biopsies, which allows for further analysis using a large range of methodologies. The protocol uses enzymatic digestion to release live leukocytes from freshly collected skeletal muscle s les, followed by filtration and separation of the leukocytes from the myocytes by density gradient centrifugation. The isolated cells can be submitted immediately to various analysis strategies to characterize ex vivo the specific cellular and molecular mechanisms responsible for self-directed immune muscle aggression or may be placed in culture for expansion.
Publisher: AMPCo
Date: 05-2017
DOI: 10.5694/MJA16.01063
Abstract: Major progress has been made over the past decade in the understanding of motor neurone disease (MND), changing the landscape of this complex disease. Through identifying positive prognostic factors, new evidence-based standards of care have been established that improve patient survival, reduce burden of disease for patients and their carers, and enhance quality of life. These factors include early management of respiratory dysfunction with non-invasive ventilation, maintenance of weight and nutritional status, as well as instigation of a multidisciplinary team including neurologists, general practitioners and allied health professionals. Advances in technology have enhanced our understanding of the genetic architecture of MND considerably, with implications for patients, their families and clinicians. Recognition of extra-motor involvement, particularly cognitive dysfunction, has identified a spectrum of disease from MND through to frontotemporal dementia. Although riluzole remains the only disease-modifying medication available in clinical practice in Australia, several new therapies are undergoing clinical trials nationally and globally, representing a shift in treatment paradigms. Successful translation of this clinical research through growth in community funding, awareness and national MND research organisations has laid the foundation for closing the research-practice gap on this debilitating disease. In this review, we highlight these recent developments, which have transformed treatment, augmented novel therapeutic platforms, and established a nexus between research and the MND community. This era of change is of significant relevance to both specialists and general practitioners who remain integral to the care of patients with MND.
Publisher: Elsevier BV
Date: 07-2007
Publisher: Cold Spring Harbor Laboratory
Date: 24-03-2021
DOI: 10.1101/2021.03.12.21253115
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability of around 50%. DNA methylation patterns can serve as biomarkers of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study (EWAS) meta-analysis in 10,462 s les (7,344 ALS patients and 3,118 controls), representing the largest case-control study of DNA methylation for any disease to date. We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We show that DNA-methylation-based proxies for HDL-cholesterol, BMI, white blood cell (WBC) proportions and alcohol intake were independently associated with ALS. Integration of these results with our latest GWAS showed that cholesterol biosynthesis was causally related to ALS. Finally, we found that DNA methylation levels at several DMPs and blood cell proportion estimates derived from DNA methylation data, are associated with survival rate in patients, and could represent indicators of underlying disease processes.
Publisher: BMJ
Date: 2007
Publisher: Elsevier BV
Date: 09-2012
DOI: 10.1016/J.JNEUROIM.2012.05.003
Abstract: We performed high-resolution (4-digit) HLA-DRB1 genotyping in an Australian cohort of 105s-IBM patients and 189 controls. Our findings showed that whilst the strongest association was with the HLA-DRB1*03:01 allele and the HLA-DRB1*03:01/*01:01 diplotype, HLA-DRB1*01:01 and HLA-DRB1*13:01 are also risk alleles. A number of other alleles, HLA-DRB1*04:01, *04:04, *07:01, *09:01, *11:01 and *15:01, as well as the HLA-DRB1*03:01/*04:01 and HLA-DRB1*03:01/*07:01 diplotypes were reduced in s-IBM cases and may be protective. The HLA-DRB1*03:01 and HLA-DRB1*13:01 alleles also appear to have an influence on the age at onset of the disease and severity of muscle weakness. Our findings indicate that the influence of HLA-DRB1 in s-IBM is complex and that epistatic interactions at the HLA-DRB1 locus contribute both to disease susceptibility and to the clinical phenotype.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 23-03-2021
DOI: 10.1212/WNL.0000000000011626
Abstract: To assess long-term (2 years) effects of bimagrumab in participants with sporadic inclusion body myositis (sIBM). Participants (aged 36–85 years) who completed the core study (RESILIENT [Efficacy and Safety of Bimagrumab/BYM338 at 52 Weeks on Physical Function, Muscle Strength, Mobility in sIBM Patients]) were invited to join an extension study. In iduals continued on the same treatment as in the core study (10 mg/kg, 3 mg/kg, 1 mg/kg bimagrumab or matching placebo administered as IV infusions every 4 weeks). The co–primary outcome measures were 6-minute walk distance (6MWD) and safety. Between November 2015 and February 2017, 211 participants entered double-blind placebo-controlled period of the extension study. Mean change in 6MWD from baseline was highly variable across treatment groups, but indicated progressive deterioration from weeks 24–104 in all treatment groups. Overall, 91.0% (n = 142) of participants in the pooled bimagrumab group and 89.1% (n = 49) in the placebo group had ≥1 treatment-emergent adverse event (AE). Falls were slightly higher in the bimagrumab 3 mg/kg group vs 10 mg/kg, 1 mg/kg, and placebo groups (69.2% [n = 36 of 52] vs 56.6% [n = 30 of 53], 58.8% [n = 30 of 51], and 61.8% [n = 34 of 55], respectively). The most frequently reported AEs in the pooled bimagrumab group were diarrhea 14.7% (n = 23), involuntary muscle contractions 9.6% (n = 15), and rash 5.1% (n = 8). Incidence of serious AEs was comparable between the pooled bimagrumab and the placebo group (18.6% [n = 29] vs 14.5% [n = 8], respectively). Extended treatment with bimagrumab up to 2 years produced a good safety profile and was well-tolerated, but did not provide clinical benefits in terms of improvement in mobility. The extension study was terminated early due to core study not meeting its primary endpoint. Clinicaltrials.gov identifier NCT02573467. This study provides Class IV evidence that for patients with sIBM, long-term treatment with bimagrumab was safe, well-tolerated, and did not provide meaningful functional benefit. The study is rated Class IV because of the open-label design of extension treatment period 2.
Publisher: Springer Science and Business Media LLC
Date: 27-01-2016
Publisher: BMJ
Date: 12-02-2008
Abstract: There have been few studies of the variability in the clinical phenotype in sporadic inclusion body myositis (sIBM) and it is not known whether the human leucocyte antigen (HLA) haplotype influences the phenotype and course of the disease. We studied a large cohort of patients with sIBM in order to determine the degree of phenotypic variability and different modes of presentation, as well as the influence of HLA haplotypes. A cross-sectional study of 57 biopsy-proven sIBM cases from three Australian centres was performed. Patients were interviewed and examined by a single investigator, and had HLA typing and autoantibody studies. Although the initial symptoms in the majority of cases were attributable to quadriceps weakness (79%), a proportion of patients presented due to finger weakness (12%), foot drop (7%) or dysphagia (1.8%). Although the majority had the classic combination of quadriceps and forearm muscle involvement, some patients had predominantly forearm weakness with sparing of the quadriceps, or severe involvement of the anterior tibial muscles. Asymmetrical involvement was common (82%), particularly of the forearm muscles, with the non-dominant side being more severely affected in most cases. Carriage of the HLA-DRB1*0301 (DR3) allele was associated with lower quadriceps muscle strength and a more rapid decline in strength. The findings emphasise the variability in the mode of presentation, patterns of muscle involvement and clinical course of sIBM in this population, and indicate that the HLA-DRB1*0301 (DR3) allele may influence the rate of progression as well as susceptibility to the disease.
Publisher: Elsevier BV
Date: 11-2016
Publisher: Wiley
Date: 08-08-2022
DOI: 10.1002/MUS.27681
Abstract: In this study we investigated COVID‐19 vaccination–related adverse events (ADEs) 7 days postvaccination in patients with idiopathic inflammatory myopathies (IIMs) and other systemic autoimmune and inflammatory disorders (SAIDs). Seven‐day vaccine ADEs were collected in an international patient self‐reported e‐survey. Descriptive statistics were obtained and multivariable regression was performed. Ten thousand nine hundred respondents were analyzed (1227 IIM cases, 4640 SAID cases, and 5033 healthy controls [HCs] median age, 42 [interquartile range, 30‐455] years 74% female 45% Caucasian 69% completely vaccinated). Major ADEs were reported by 76.3% of the IIM patients and 4.6% reported major ADEs. Patients with active IIMs reported more frequent major (odds ratio [OR], 2.7 interquartile range [IQR], 1.04‐7.3) and minor (OR, 1.5 IQR, 1.1‐2.2) ADEs than patients with inactive IIMs. Rashes were more frequent in IIMs (OR, 2.3 IQR, 1.2‐4.2) than HCs. ADEs were not impacted by steroid dose, although hydroxychloroquine and intravenous/subcutaneous immunoglobulins were associated with a higher risk of minor ADEs (OR, 1.9 IQR, 1.1‐3.3 and OR, 2.2 IQR, 1.1‐4.3, respectively). Overall, ADEs were less frequent in inclusion‐body myositis (IBM) and BNT162b2 (Pfizer) vaccine recipients. Seven‐day postvaccination ADEs were comparable in patients with IIMs, SAIDs, and HCs, except for a higher risk of rash in IIMs. Patients with dermatomyositis with active disease may be at higher risk, and IBM patients may be at lower risk of specific ADEs. Overall, the benefit of preventing severe COVID‐19 through vaccination likely outweighs the risk of vaccine‐related ADEs. Our results may inform future guidelines regarding COVID‐19 vaccination in patients with SAIDs, specifically in those with IIMs. Studies to evaluate long‐term outcomes and disease flares are needed to shed more light on developing future COVID‐19 vaccination guidelines.
Publisher: Elsevier BV
Date: 02-2023
DOI: 10.1016/J.SEMARTHRIT.2022.152111
Abstract: 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. 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. 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. 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.
Publisher: Oxford University Press (OUP)
Date: 17-06-2022
DOI: 10.1093/RHEUMATOLOGY/KEAC305
Abstract: COVID-19 vaccines have been proven to be safe in the healthy population. However, gaps remain in the evidence of their safety in patients with systemic autoimmune and inflammatory disorders (SAIDs). COVID-19 vaccination-related adverse events (AEs) in patients with SAIDs and healthy controls (HC) seven days post-vaccination were assessed in the COVAD study, a patient self-reported cross-sectional survey. The survey was circulated in early 2021 by & collaborators (94 countries) to collect SAID details, COVID-19 vaccination details and 7-day vaccine AEs, irrespective of respondent vaccination status. Analysis was performed based on data distribution and variable type. Ten thousand nine hundred respondents [median (interquartile range) age 42 (30–55) years, 74% females and 45% Caucasians] were analysed 5867 patients (54%) with SAIDs were compared with 5033 HCs. Seventy-nine percent had minor and only 3% had major vaccine AEs requiring urgent medical attention (but not hospital admission) overall. Headache [SAIDs = 26%, HCs = 24% odds ratio (OR) = 1.1 (95% CI: 1.03, 1.3) P = 0.014], abdominal pain [SAIDs = 2.6%, HCs = 1.4% OR = 1.5 (95% CI: 1.1, 2.3) P = 0.011], and dizziness [SAIDs = 6%, HCs = 4% OR = 1.3 (95% CI: 1.07, 1.6) P = 0.011], were slightly more frequent in SAIDs. Overall, major AEs [SAIDs = 4%, HCs = 2% OR = 1.9 (95% CI: 1.6, 2.2) P & 0.001] and, specifically, throat closure [SAIDs = 0.5%, HCs = 0.3% OR = 5.7 (95% CI: 2.9, 11) P = 0.010] were more frequent in SAIDs though absolute risk was small (0–4%). Major AEs and hospitalizations (& %) were comparable across vaccine types in SAIDs. Vaccination against COVID-19 is safe in SAID patients. SAIDs were at a higher risk of major AEs than HCs, though absolute risk was small. There are small differences in minor AEs between vaccine types in SAID patients.
Publisher: The Journal of Rheumatology
Date: 15-09-2019
Abstract: Patient-reported outcome measures (PROM) that incorporate the patient perspective have not been well established in idiopathic inflammatory myopathies (IIM). As part of our goal to develop IIM-specific PROM, the Outcome Measures in Rheumatology (OMERACT) Myositis special interest group sought to determine which aspects of disease and its effects are important to patients and healthcare providers (HCP). Based on a prior qualitative content analysis of focus groups, an initial list of 24 candidate domains was constructed. We subsequently conducted an international survey to identify the importance of each of the 24 domains to be assessed in clinical research. Patients with IIM, their caregivers, and HCP treating IIM completed the survey. In this survey, a total of 638 respondents completed the survey, consisting of 510 patients, 101 HCP, and 27 caregivers from 48 countries. Overall, patients were more likely to rank “fatigue,” “cognitive impact,” and “difficulty sleeping” higher compared with HCP, who ranked “joint symptoms,” “lung symptoms,” and “dysphagia” higher. Both patients and providers rated muscle symptoms as their top domain. In general, patients from different countries were in agreement on which domains were most important. One notable exception was that patients from Sweden and the Netherlands ranked lung symptoms significantly higher compared to other countries including the United States and Australia (mean weighted rankings of 2.86 and 2.04 vs 0.76 and 0.80, respectively p 0.0001). Substantial differences exist in how IIM is perceived by patients compared to HCP, with different domains prioritized. In contrast, patients’ ratings across the world were largely similar.
Publisher: Oxford University Press (OUP)
Date: 22-11-2022
DOI: 10.1093/RHEUMATOLOGY/KEAC661
Abstract: To determine COVID-19 vaccine-related adverse events (AEs) in the seven-day post-vaccination period in patients with SLE vs autoimmune rheumatic diseases (AIRDs), non-rheumatic autoimmune diseases (nrAIDs), and healthy controls (HC). Data were captured through the COVID-19 Vaccination in Autoimmune Diseases (COVAD) questionnaire (March–December 2021). Multivariable regression models accounted for age, gender, ethnicity, vaccine type and background treatment. Among 9462 complete respondents, 583 (6.2%) were SLE patients (mean age: 40.1 years 94.5% females 40.5% Asian 42.9% Pfizer-recipients). Minor AEs were reported by 83.0% of SLE patients, major by 2.6%, hospitalization by 0.2%. AE and hospitalization frequencies were similar between patients with active and inactive SLE. Rashes were more frequent in SLE patients vs HC (OR 95% CI: 1.2 1.0, 1.5), chills less frequent in SLE vs AIRDs (0.6 0.4, 0.8) and nrAIDs (0.5 0.3, 0.8), and fatigue less frequent in SLE vs nrAIDs (0.6 0.4, 0.9). Pfizer-recipients reported higher overall AE (2.2 1.1, 4.2) and injection site pain (2.9 1.6, 5.0) frequencies than recipients of other vaccines, Oxford/AstraZeneca-recipients more body ache, fever, chills (OR: 2.5, 3.0), Moderna-recipients more body ache, fever, chills, rashes (OR: 2.6, 4.3). Hospitalization frequencies were similar across vaccine types. AE frequencies were similar across treatment groups, although chills were less frequent in antimalarial users vs non-users (0.5 0.3, 0.9). While COVID-19 vaccination-related AEs were reported by four-fifths of SLE patients, those were mostly minor and comparable to AEs reported by healthy in iduals, providing reassurance regarding COVID-19 vaccination safety in SLE.
Publisher: Elsevier BV
Date: 05-2010
DOI: 10.1016/J.NMD.2010.03.002
Abstract: We report the first Australian families with inclusion-body myopathy, Paget's disease of the bone and frontotemporal dementia (IBMPFD). The clinical characteristics of the two pedigrees are described including a previously undescribed phenotypic feature of pyramidal tract dysfunction in one family member. A novel mutation in the valosin-containing protein (VCP) gene (p.Arg155Leu) was found in one family while the other family had a previously reported mutation (p.Leu198Trp). Our findings broaden the phenotypic spectrum of IBMPFD and further emphasise the resemblance to amyotrophic lateral sclerosis in some cases.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 18-10-2013
DOI: 10.1212/01.WNL.0000436068.43384.EF
Abstract: To prospectively determine the reliability and validity of serum fibroblast growth factor 21 (FGF-21) as a biomarker for mitochondrial disease in a cross-sectional cohort of adults with mitochondrial disease from a specialist primary care and tertiary referral clinic. We recruited 140 subjects, including 54 adults with mitochondrial disease, 20 patients with nonmitochondrial neuromuscular disease, and 66 control subjects, between November 2011 and October 2012. We compared serum FGF-21 concentrations to classical biomarkers, serum creatine kinase, lactate, pyruvate, and lactate to pyruvate ratio, to determine its validity and reliability as a biomarker of mitochondrial disease. We determined the sensitivity, odds ratio (OR), and overall reliability of FGF-21 as a marker of mitochondrial disease using statistical analyses. Median serum FGF-21 concentrations were significantly elevated in patients with mitochondrial disease and differed significantly between all experimental groups. FGF-21 showed a markedly higher diagnostic OR (45.7 [95% confidence interval = 12.6-166.5], p < 0.0001) when compared to other biomarkers and was the best predictor of disease according to sensitivity and receiver operating characteristic curve analysis. After multivariate logistic regression analysis controlling for potential confounders, FGF-21 was the only measured parameter capable of predicting mitochondrial disease. This prospective study establishes serum FGF-21 levels as a sensitive biomarker of mitochondrial disease and demonstrates that they are the best predictor of this disorder when compared to serum levels of classical indicators: creatine kinase, lactate, pyruvate, and the lactate to pyruvate ratio.
Publisher: Wiley
Date: 06-2021
DOI: 10.1111/IMJ.15358
Abstract: Idiopathic inflammatory myopathy (IIM) is the umbrella term including dermatomyositis (DM), polymyositis (PM), overlap myositis (OM), sporadic inclusion body myositis (IBM) and necrotising autoimmune myopathy (NAM), also known as immune‐mediated necrotising myopathy. There is some debate as to whether PM exists as a discrete entity, or perhaps is an overly generalising term encompassing connective tissue disease associated myositis, or OM, and the previously poorly recognised NAM. As such, PM will not be covered in detail in this review. DM, OM and NAM all present similarly, with proximal weakness and elevated creatine kinase (CK) level. By contrast, IBM preferentially involves the long finger flexors and quadriceps, and presents with a normal or only mildly elevated CK. Developments in serological testing and imaging are shifting the diagnostic paradigm away from a reliance on histopathology. The therapeutic armamentarium for IIM continues to evolve, with intravenous immunoglobulin and rituximab proving to be successful for refractory disease. This review will provide a diagnostic algorithm for the clinician to help distinguish between IIM subtypes – with emphasis on clinical assessment, serology and imaging, as well as discussion of therapeutic options and escalation of immunotherapy.
Publisher: Public Library of Science (PLoS)
Date: 11-04-2023
DOI: 10.1371/JOURNAL.PONE.0283394
Abstract: 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. 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. 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. 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.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 27-06-2014
Publisher: Springer Science and Business Media LLC
Date: 12-06-2021
DOI: 10.1186/S12891-021-04424-0
Abstract: 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. 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. 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). 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.
Publisher: Wiley
Date: 25-10-2023
DOI: 10.1002/MUS.27736
Abstract: Rate of disease progression (ΔFS), measured as change in the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS‐R) and body mass index (BMI), are predictors of survival in amyotrophic lateral sclerosis (ALS). Our aim in this study was to assess the utility of these clinical biomarkers along with neurophysiological measures, such as the split hand index (SI), in monitoring disease progression. Clinical trial data were collected from 107 patients recruited into the Tecfidera in ALS trial. The prognostic utility of clinical and neurophysiological measures, including ΔFS, BMI, SI, and neurophysiological index (NPI), were assessed cross‐sectionally and longitudinally (40 weeks). The outcome measures of disease severity and progression included: (i) ALSFRS‐R score (ii) Medical Research Council (MRC) score and (iii) forced vital capacity and sniff nasal inspiratory pressure. Fast‐progressor ALS patients (ΔFS ≥1.1) exhibited significantly lower ALSFRS‐R and total MRC scores at baseline. A baseline ΔFS score ≥1.1 was associated with a greater reduction in ALSFRS‐R ( P = .002) and MRC ( P = .002) scores over 40 weeks. Baseline BMI was also associated with faster reduction of ALSFRS‐R and MRC scores. SI and NPI were associated with disease severity at baseline, but not with subsequent rate of disease progression. Implementation of the assessed clinical and neurophysiological biomarkers may assist in patient management and stratification into clinical trials.
Publisher: Elsevier BV
Date: 08-2014
DOI: 10.1016/J.JOCN.2013.10.028
Abstract: Sickle cell disease can present with neurological manifestations. One such presentation is with posterior reversible leukoencephalopathy also known as reversible posterior leukoencephalopathy. The condition is classically described as reversible over time it commonly presents with oedematous changes involving the white matter of the occipital and parietal regions. Only a few patients with the association between sickle cell disease and posterior reversible leukoencephalopathy have been described in the adult literature. We present two patients from our institutions to emphasise the association between the two conditions and summarise the published cases in the literature.
Publisher: Elsevier BV
Date: 11-2009
DOI: 10.1016/J.NMD.2009.07.015
Abstract: Susceptibility to sIBM is strongly associated with the HLA-DRB1*03 allele and the 8.1 MHC ancestral haplotype (HLA-A1, B8, DRB1*03) but little is known about the effects of allelic interactions at the DRB1 locus or disease-modifying effects of HLA alleles. HLA-A, B and DRB1 genotyping was performed in 80 Australian sIBM cases and the frequencies of different alleles and allele combinations were compared with those in a group of 190 healthy controls. Genotype-phenotype correlations were also investigated. Amongst carriers of the HLA-DRB1*03 allele, DRB1*03/*01 heterozygotes were over-represented in the sIBM group (p<0.003) while. DRB1*03/*04 heterozygotes were under-represented (p<0.008). The mean age-at-onset (AAO) was 6.5 years earlier in DRB1*03/*01 heterozygotes who also had more severe quadriceps muscle weakness than the rest of the cohort. The findings indicate that interactions between the HLA-DRB1*03 allele and other alleles at the DRB1 locus can influence disease susceptibility and the clinical phenotype in sIBM.
Publisher: Springer Science and Business Media LLC
Date: 21-02-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-03-2007
DOI: 10.1212/01.WNL.0000256819.61531.98
Abstract: A 62-year-old Indonesian woman presenting with a progressive supranuclear palsy-like syndrome was confirmed post mortem as dying from a spongiform encephalopathy. Despite an illness duration of only 4 months, brain MRI, EEG, and CSF analysis for 14-3-3 proteins all failed to disclose changes typical of Creutzfeldt-Jakob disease. Neuropathologic examination revealed multicentric, prion protein-positive, amyloid plaques as typically seen in Gerstmann-Sträussler-Scheinker syndrome. Prion protein gene analysis revealed a previously unreported A133V mutation.
Location: Australia
Location: Australia
No related grants have been discovered for Merrilee Needham.