Vitamin D did not reduce multiple sclerosis disease activity after a clinically isolated syndrome.

Low serum levels of 25-hydroxyvitamin D [25(OH)D] and low sunlight exposure are known risk factors for the development of multiple sclerosis. Add-on vitamin D supplementation trials in established multiple sclerosis have been inconclusive. The effects of vitamin D supplementation to prevent multiple sclerosis is unknown. We aimed to test the hypothesis that oral vitamin D3 supplementation in high-risk clinically isolated syndrome (abnormal MRI, at least three T2 brain and/or spinal cord lesions), delays time to conversion to definite multiple sclerosis, that the therapeutic effect is dose-dependent, and that all doses are safe and well tolerated. We conducted a double-blind trial in Australia and New Zealand. Eligible participants were randomized 1:1:1:1 to placebo, 1000, 5000 or 10 000 international units (IU) of oral vitamin D3 daily within each study centre (n = 23) and followed for up to 48 weeks. Between 2013 and 2021, we enrolled 204 participants. Brain MRI scans were performed at baseline, 24 and 48 weeks. The main study outcome was conversion to clinically definite multiple sclerosis based on the 2010 McDonald criteria defined as either a clinical relapse or new brain MRI T2 lesion development. We included 199 cases in the intention-to-treat analysis based on assigned dose. Of these, 116 converted to multiple sclerosis by 48 weeks (58%). Compared to placebo, the hazard ratios (95% confidence interval) for conversion were 1000 IU 0.87 (0.50, 1.50); 5000 IU 1.37 (0.82, 2.29); and 10 000 IU 1.28 (0.76, 2.14). In an adjusted model including age, sex, latitude, study centre and baseline symptom number, clinically isolated syndrome onset site, presence of infratentorial lesions and use of steroids, the hazard ratios (versus placebo) were 1000 IU 0.80 (0.45, 1.44); 5000 IU 1.36 (0.78, 2.38); and 10 000 IU 1.07 (0.62, 1.85). Vitamin D3 supplementation was safe and well tolerated. We did not demonstrate reduction in multiple sclerosis disease activity by vitamin D3 supplementation after a high-risk clinically isolated syndrome.

Oral corticosteroid dosage and taper duration at onset in myelin oligodendrocyte glycoprotein antibody-associated disease influences time to first relapse.

BACKGROUND: We sought to identify an optimal oral corticosteroid regimen at the onset of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), which would delay time to first relapse while minimising cumulative corticosteroid exposure. METHODS: In a retrospective multicentre cohort study, Cox proportional hazards models examined the relationship between corticosteroid course as a time-varying covariate and time to first relapse. Simon-Makuch and Kaplan-Meier plots identified an optimal dosing strategy. RESULTS: We evaluated 109 patients (62 female, 57%; 41 paediatric, 38%; median age at onset 26 years, (IQR 8-38); median follow-up 6.2 years (IQR 2.6-9.6)). 76/109 (70%) experienced a relapse (median time to first relapse 13.7 months; 95% CI 8.2 to 37.9). In a multivariable model, higher doses of oral prednisone delayed time to first relapse with an effect estimate of 3.7% (95% CI 0.8% to 6.6%; p=0.014) reduced hazard of relapse for every 1 mg/day dose increment. There was evidence of reduced hazard of relapse for patients dosed ≥12.5 mg/day (HR 0.21, 95% CI 0.07 to 0.6; p=0.0036), corresponding to a 79% reduction in relapse risk. There was evidence of reduced hazard of relapse for those dosed ≥12.5 mg/day for at least 3 months (HR 0.12, 95% CI 0.03 to 0.44; p=0.0012), corresponding to an 88% reduction in relapse risk compared with those never treated in this range. No patient with this recommended dosing at onset experienced a Common Terminology Criteria for Adverse Events grade >3 adverse effect. CONCLUSIONS: The optimal dose of 12.5 mg of prednisone daily in adults (0.16 mg/kg/day for children) for a minimum of 3 months at the onset of MOGAD delays time to first relapse.

The MOG antibody non-P42 epitope is predictive of a relapsing course in MOG antibody-associated disease.

BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG) IgG seropositivity is a prerequisite for MOG antibody-associated disease (MOGAD) diagnosis. While a significant proportion of patients experience a relapsing disease, there is currently no biomarker predictive of disease course. We aim to determine whether MOG-IgG epitopes can predict a relapsing course in MOGAD patients. METHODS: MOG-IgG-seropositive confirmed adult MOGAD patients were included (n=202). Serum MOG-IgG and epitope binding were determined by validated flow cytometry live cell-based assays. Associations between epitopes, disease course, clinical phenotype, Expanded Disability Status Scale and Visual Functional System Score at onset and last review were evaluated. RESULTS: Of 202 MOGAD patients, 150 (74%) patients had MOG-IgG that recognised the immunodominant proline42 (P42) epitope and 115 (57%) recognised histidine103/serine104 (H103/S104). Fifty-two (26%) patients had non-P42 MOG-IgG and showed an increased risk of a relapsing course (HR 1.7; 95% CI 1.15 to 2.60, p=0.009). Relapse-freedom was shorter in patients with non-P42 MOG-IgG (p=0.0079). Non-P42 MOG-IgG epitope status remained unchanged from onset throughout the disease course and was a strong predictor of a relapsing course in patients with unilateral optic neuritis (HR 2.7, 95% CI 1.06 to 6.98, p=0.038), with high specificity (95%, 95% CI 77% to 100%) and positive predictive value (85%, 95% CI 45% to 98%). CONCLUSIONS: Non-P42 MOG-IgG predicts a relapsing course in a significant subgroup of MOGAD patients. Patients with unilateral optic neuritis, the most frequent MOGAD phenotype, can reliably be tested at onset, regardless of age and sex. Early detection and specialised management in these patients could minimise disability and improve long-term outcomes.

Changes in employment status over time in multiple sclerosis following a first episode of central nervous system demyelination, a Markov multistate model study.

BACKGROUND AND PURPOSE: Understanding predictors of changes in employment status among people living with multiple sclerosis (MS) can assist health care providers to develop appropriate work retention/rehabilitation programs. We aimed to model longitudinal transitions of employment status in MS and estimate the probabilities of retaining employment status or losing or gaining employment over time in individuals with a first clinical diagnosis of central nervous system demyelination (FCD). METHODS: This prospective cohort study comprised adults (aged 18-59 years) diagnosed with FCD (n = 237) who were followed for more than 11 years. At each review, participants were assigned to one of three states: unemployed, part-time, or full-time employed. A Markov multistate model was used to examine the rate of state-to-state transitions. RESULTS: At the time of FCD, participants with full-time employment had an 89% chance of being in the same state over a 1-year period, but this decreased to 42% over the 10-year follow-up period. For unemployed participants, there was a 92% likelihood of remaining unemployed after 1 year, but this probability decreased to 53% over 10 years. Females, those who progressed to clinically definite MS, those with a higher relapse count, and those with a greater level of disability were at increased risk of transitioning to a deteriorated employment state. In addition, those who experienced clinically significant fatigue over the follow-up period were less likely to gain employment after being unemployed. CONCLUSIONS: In our FCD cohort, we found a considerable rate of employment transition during the early years post-diagnosis. Over more than a decade of follow-up post-FCD, we found that females and individuals with a greater disability and a higher relapse count are at higher risk of losing employment.

Genetically determined serum serine level has a novel causal effect on multiple sclerosis risk and predicts disability progression.

BACKGROUND: There are currently no specific biomarkers for multiple sclerosis (MS). Identifying robust biomarkers for MS is crucial to improve disease diagnosis and management. METHODS: This study first used six Mendelian randomisation methods to assess causal relationship of 174 metabolites with MS, incorporating data from European-ancestry metabolomics (n=8569-86 507) and MS (n=14 802 MS cases, 26 703 controls) genomewide association studies. Genetic scores for identified causal metabolite(s) were then computed to predict MS disability progression in an independent longitudinal cohort (AusLong study) of 203 MS cases with up to 15-year follow-up. RESULTS: We found a novel genetic causal effect of serine on MS onset (OR=1.67, 95% CI 1.51 to 1.84, p=1.73×10-20), such that individuals whose serine level is 1 SD above the population mean will have 1.67 times the risk of developing MS. This is robust across all sensitivity methods (OR ranges from 1.49 to 1.67). In an independent longitudinal MS cohort, we then constructed time-dynamic and time-fixed genetic scores based on serine genetic instrument single-nucleotide polymorphisms, where higher scores for raised serum serine level were associated with increased risk of disability worsening, especially in the time-dynamic model (RR=1.25, 95% CI 1.10 to 1.42, p=7.52×10-4). CONCLUSIONS: These findings support investigating serine as an important candidate biomarker for MS onset and disability progression.

A pro-inflammatory diet in people with multiple sclerosis is associated with an increased rate of relapse and increased FLAIR lesion volume on MRI in early multiple sclerosis: A prospective cohort study.

BACKGROUND: A pro-inflammatory diet has been posited to induce chronic inflammation within the central nervous system (CNS), and multiple sclerosis (MS) is an inflammatory disease of the CNS. OBJECTIVE: We examined whether Dietary Inflammatory Index (DII®)) scores are associated with measures of MS progression and inflammatory activity. METHODS: A cohort with a first clinical diagnosis of CNS demyelination was followed annually (10 years, n = 223). At baseline, 5- and 10-year reviews, DII and energy-adjusted DII (E-DIITM) scores were calculated (food frequency questionnaire) and assessed as predictors of relapses, annualised change in disability (Expanded Disability Status Scale) and two magnetic resonance imaging measures; fluid-attenuated inversion recovery (FLAIR) lesion volume and black hole lesion volume. RESULTS: A more pro-inflammatory diet was associated with a higher relapse risk (highest vs. lowest E-DII quartile: hazard ratio = 2.24, 95% confidence interval (CI) = -1.16, 4.33, p = 0.02). When we limited analyses to those assessed on the same manufacturer of scanner and those with a first demyelinating event at study entry (to reduce error and disease heterogeneity), an association between E-DII score and FLAIR lesion volume was evident (ß = 0.38, 95% CI = 0.04, 0.72, p = 0.03). CONCLUSION: There is a longitudinal association between a higher DII and a worsening in relapse rate and periventricular FLAIR lesion volume in people with MS.

Long-term trajectories of employment status, workhours and disability support pension status, after a first episode of CNS demyelination.

BACKGROUND: People with multiple sclerosis face significant employment-related challenges, with little known of the drivers of these outcomes. OBJECTIVE: We examined prospective trajectories of employment-related outcomes up to 11 years following a first episode of central nervous system (CNS) demyelination (FCD). METHODS: Participants were aged 18-59 years, at FCD, with at least two observations and were employed at study entry or anytime during follow-up (n = 207). Outcomes were employment status (full-time, part-time and unemployed), average workhours per week and disability support pension (DSP; receiving/not receiving). We used group-based trajectory modelling to identify groups with common trajectories. Factors associated with trajectory membership were explored using log-multinomial regression. RESULTS: Distinct trajectories were identified for employment (4), workhours (4) and DSP (2). Compared with stable full-time, female sex was strongly associated with being in the stable part-time trajectory (risk ratio (RR): 5.35; 95% confidence interval (CI) = 2.56-11.20; p < 0.001). A greater level of disability at 5-year review (RR: 1.35; 95% CI = 1.19-1.53) and having more than two comorbidities at baseline (RR: 2.77; 95% CI = 1.37-5.64) were associated with being in early and late deteriorated employment trajectories, respectively. Compared with the increased part-time trajectory, every additional relapse during the 5 years post-FCD was associated with a 10% increased risk of being in the reduced part-time trajectory (RR = 1.10; 95%CI = 1.00-1.22). For every additional EDSS point at 5-year review, the risk of being in the DSP trajectory increased (RR = 1.21; 95% CI = 1.05-1.41). CONCLUSION: These trajectories indicate substantial heterogeneity and the complex impact of MS on employment from its earliest timepoints. Understanding these trends could enable better targeting of interventions to facilitate workforce retention, particularly for females, those with a higher number of comorbidities, more frequent relapses and greater rate of disability accrual.

Magnetic resonance imaging in neuromyelitis optica spectrum disorder.

Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disease of the central nervous system (CNS) associated with antibodies to aquaporin-4 (AQP4), which has distinct clinical, radiological and pathological features, but also has some overlap with multiple sclerosis and myelin oligodendrocyte glycoprotein (MOG) antibody associated disease. Early recognition of NMOSD is important because of differing responses to both acute and preventive therapy. Magnetic resonance (MR) imaging has proved essential in this process. Key MR imaging clues to the diagnosis of NMOSD are longitudinally extensive lesions of the optic nerve (more than half the length) and spinal cord (three or more vertebral segments), bilateral optic nerve lesions and lesions of the optic chiasm, area postrema, floor of the IV ventricle, periaqueductal grey matter, hypothalamus and walls of the III ventricle. Other NMOSD-specific lesions are denoted by their unique morphology: heterogeneous lesions of the corpus callosum, 'cloud-like' gadolinium (Gd)-enhancing white matter lesions and 'bright spotty' lesions of the spinal cord. Other lesions described in NMOSD, including linear periventricular peri-ependymal lesions and patch subcortical white matter lesions, may be less specific. The use of advanced MR imaging techniques is yielding further useful information regarding focal degeneration of the thalamus and optic radiation in NMOSD and suggests that paramagnetic rim patterns and changes in normal appearing white matter are specific to MS. MR imaging is crucial in the early recognition of NMOSD and in directing testing for AQP4 antibodies and guiding immediate acute treatment decisions. Increasingly, MR imaging is playing a role in diagnosing seronegative cases of NMOSD.

Efficacy of alemtuzumab over 6 years in relapsing-remitting multiple sclerosis patients who relapsed between courses 1 and 2: Post hoc analysis of the CARE-MS studies.

BACKGROUND: Alemtuzumab is administered as two annual courses for relapsing-remitting multiple sclerosis (MS). Patients may relapse before completing the two-course regimen. OBJECTIVE: The objective was to evaluate 6-year outcomes in patients who relapsed between alemtuzumab Courses 1 and 2 (early relapsers). METHODS: Post hoc analysis of patients from the Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis (CARE-MS) studies who enrolled in the extension. RESULTS: Early relapsers (CARE-MS I: 15%; CARE-MS II: 24%) had more relapses in 1-2 years pre-alemtuzumab and higher mean baseline Expanded Disability Status Scale score than patients without relapse. Their annualized relapse rate declined from Year 1 (CARE-MS I: 1.3; CARE-MS II: 1.2) to Year 2 following Course 2 (0.3; 0.5) and remained low thereafter. Over 6 years, 60% remained free of 6-month confirmed disability worsening; 24% (CARE-MS I) and 34% (CARE-MS II) achieved 6-month confirmed disability improvement. During Year 6, 69% (CARE-MS I) and 68% (CARE-MS II) were free of magnetic resonance imaging (MRI) disease activity. Median percent yearly brain volume loss (Year 1: -0.67% (CARE-MS I); -0.47% (CARE-MS II)) declined after Course 2 (Year 6: -0.24%; -0.13%). CONCLUSION: Early relapsers' outcomes improved after completing the second alemtuzumab course. These findings support administering the approved two-course regimen to maximize clinical benefit. CLINICALTRIALS.GOV REGISTRATION NUMBERS: CARE-MS I, II, extension: NCT00530348, NCT00548405, NCT00930553.

Effects of cannabinoids in Amyotrophic Lateral Sclerosis (ALS) murine models: a systematic review and meta-analysis.

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder that results from motor neuron damage. Cannabinoids have been proposed as treatments for ALS because of their anti-excitotoxicity, anti-oxidant and anti-inflammatory effects. Preclinical studies in mice models of ALS have been published using a range of cannabinoid formulations and doses. To date, there has been no rigorous evaluation of these trials to assess a potential cannabinoid treatment effect. This review and meta-analysis was undertaken to provide evidence for or against a treatment effect of cannabinoids in murine ALS models. Evidence of a treatment effect in mice may provide motivation for trials in human ALS. We identified a total of 10 studies; nine studies using cannabinoid treatment in transgenic SOD1-G93A ALS-model mice and one study in TDP-43 transgenic mice. Eight of the nine studies that used SOD1-G93A mice expressed similarly high copy numbers of the transgene while one study used a low-copy number line. Outcomes evaluated were survival time and disease progression. The latter was measured by motor function and bodyweight decline. Meta-analysis of the mean difference in survival time across the seven studies showed an increase in survival of 3.84 days (95% CI: 0.35-7.32 days; p = 0.031) for cannabinoid treated compared to control SOD1-G93A mice. It was not possible to conduct meta-analyses for motor function decline or weight loss. However, eight of nine studies reported significant improvements in measures of motor function decline and one reported non-significant improvements. Weight loss was significantly attenuated in four of five studies reporting this measure while the other study reported a non-significant attenuation. This review provides some evidence for the efficacy of cannabinoids in prolonging survival time in an ALS mouse model. A delay in disease progression is also suggested following cannabinoid treatment though it was not possible to consolidate the results from reviewed studies. However, studies have moderate to high risk of bias and are highly heterogeneous. Although this review provides some evidence to support the conduct of a cannabinoid trial in human ALS, more standardized studies on specific cannabinoids are necessary before supporting therapeutic potential of cannabinoids in treating patients with ALS. OPEN SCIENCE BADGES: This article has received a badge for *Preregistration* because the study was pre-registered at https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=89274. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/. Read the Editorial Highlight for this article on page 168.

Leasing a medical curriculum: What's it worth?

Introduction: The early part of this century saw an unprecedented growth in number and size of Australian medical schools. There was some partnering of the new schools with existing programs. Griffith, Deakin and Curtin Universities leased an established curriculum from Flinders University. Nature and rationale for curriculum leasing: The new schools had short startup times and leasing a curriculum enabled them to appoint key staff, develop facilities and meet accreditation requirements in a timely way. However, the lease arrangements were costly and the curriculum was largely determined before the Dean and key staff appointments. Outcomes of leasing: There was differential adoption of the leased curriculum. The first two years of the courses at Flinders were transferred with little change. The final two years of predominantly clinical studies were developed differently. This is explained through Michael Fullan's work on context in educational change. The context of the clinical years of the courses involved negotiations with local health services and other schools using those health services. The advantage of the leasing arrangements was that the new schools could proceed through early development and accreditation, while having time and opportunity to negotiate a clinical curriculum that engaged local health services and fulfilled the new schools' missions.

Clinical course, therapeutic responses and outcomes in relapsing MOG antibody-associated demyelination.

OBJECTIVE: We characterised the clinical course, treatment and outcomes in 59 patients with relapsing myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination. METHODS: We evaluated clinical phenotypes, annualised relapse rates (ARR) prior and on immunotherapy and Expanded Disability Status Scale (EDSS), in 218 demyelinating episodes from 33 paediatric and 26 adult patients. RESULTS: The most common initial presentation in the cohort was optic neuritis (ON) in 54% (bilateral (BON) 32%, unilateral (UON) 22%), followed by acute disseminated encephalomyelitis (ADEM) (20%), which occurred exclusively in children. ON was the dominant phenotype (UON 35%, BON 19%) of all clinical episodes. 109/226 (48%) MRIs had no brain lesions. Patients were steroid responsive, but 70% of episodes treated with oral prednisone relapsed, particularly at doses <10 mg daily or within 2 months of cessation. Immunotherapy, including maintenance prednisone (P=0.0004), intravenous immunoglobulin, rituximab and mycophenolate, all reduced median ARRs on-treatment. Treatment failure rates were lower in patients on maintenance steroids (5%) compared with non-steroidal maintenance immunotherapy (38%) (P=0.016). 58% of patients experienced residual disability (average follow-up 61 months, visual loss in 24%). Patients with ON were less likely to have sustained disability defined by a final EDSS of ≥2 (OR 0.15, P=0.032), while those who had any myelitis were more likely to have sustained residual deficits (OR 3.56, P=0.077). CONCLUSION: Relapsing MOG antibody-associated demyelination is strongly associated with ON across all age groups and ADEM in children. Patients are highly responsive to steroids, but vulnerable to relapse on steroid reduction and cessation.

Adopting genetics: motivations and outcomes of personal genomic testing in adult adoptees.

PURPOSE: American adult adoptees may possess limited information about their biological families and turn to direct-to-consumer personal genomic testing (PGT) for genealogical and medical information. We investigated the motivations and outcomes of adoptees undergoing PGT using data from the Impact of Personal Genomics (PGen) Study. METHODS: The PGen Study surveyed new 23andMe and Pathway Genomics customers before and 6 months after receiving PGT results. Exploratory analyses compared adoptees' and nonadoptees' PGT attitudes, expectations, and experiences. We evaluated the association of adoption status with motivations for testing and postdisclosure actions using logistic regression models. RESULTS: Of 1,607 participants, 80 (5%) were adopted. As compared with nonadoptees, adoptees were more likely to cite limited knowledge of family health history (OR = 10.1; 95% CI = 5.7-19.5) and the opportunity to learn genetic disease risks (OR = 2.7; 95% CI = 1.6-4.8) as strong motivations for PGT. Of 922 participants who completed 6-month follow-up, there was no significant association between adoption status and PGT-motivated health-care utilization or health-behavior change. CONCLUSION: PGT allows adoptees to gain otherwise inaccessible information about their genetic disease risks and ancestry, helping them to fill the void of an incomplete family health history.Genet Med 18 9, 924-932.

Genetic variants are major determinants of CSF antibody levels in multiple sclerosis.

Immunological hallmarks of multiple sclerosis include the production of antibodies in the central nervous system, expressed as presence of oligoclonal bands and/or an increased immunoglobulin G index-the level of immunoglobulin G in the cerebrospinal fluid compared to serum. However, the underlying differences between oligoclonal band-positive and -negative patients with multiple sclerosis and reasons for variability in immunoglobulin G index are not known. To identify genetic factors influencing the variation in the antibody levels in the cerebrospinal fluid in multiple sclerosis, we have performed a genome-wide association screen in patients collected from nine countries for two traits, presence or absence of oligoclonal bands (n = 3026) and immunoglobulin G index levels (n = 938), followed by a replication in 3891 additional patients. We replicate previously suggested association signals for oligoclonal band status in the major histocompatibility complex region for the rs9271640*A-rs6457617*G haplotype, correlated with HLA-DRB1*1501, and rs34083746*G, correlated with HLA-DQA1*0301 (P comparing two haplotypes = 8.88 × 10(-16)). Furthermore, we identify a novel association signal of rs9807334, near the ELAC1/SMAD4 genes, for oligoclonal band status (P = 8.45 × 10(-7)). The previously reported association of the immunoglobulin heavy chain locus with immunoglobulin G index reaches strong evidence for association in this data set (P = 3.79 × 10(-37)). We identify two novel associations in the major histocompatibility complex region with immunoglobulin G index: the rs9271640*A-rs6457617*G haplotype (P = 1.59 × 10(-22)), shared with oligoclonal band status, and an additional independent effect of rs6457617*G (P = 3.68 × 10(-6)). Variants identified in this study account for up to 2-fold differences in the odds of being oligoclonal band positive and 7.75% of the variation in immunoglobulin G index. Both traits are associated with clinical features of disease such as female gender, age at onset and severity. This is the largest study population so far investigated for the genetic influence on antibody levels in the cerebrospinal fluid in multiple sclerosis, including 6950 patients. We confirm that genetic factors underlie these antibody levels and identify both the major histocompatibility complex and immunoglobulin heavy chain region as major determinants.

Regulatory T, natural killer T and γδ T cells in multiple sclerosis and chronic fatigue syndrome/myalgic encephalomyelitis: a comparison.

BACKGROUND: Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME), and Multiple Sclerosis (MS) may share some similarities in relation to reduced NK cell activity. It is likely that other cells such as regulatory T (Tregs), invariant Natural Killer T (iNKT) and gamma delta T (γδ T) cells may also be dysregulated in CFS/ME and MS. OBJECTIVE: To evaluate and compare specific immune regulatory cells of patients with CFS/ME, patients with MS and healthy controls. METHOD: Sixty three volunteers were included in this study: 24 were CFS/ME patients, 11 were MS patients and 27 were healthy controls. Blood samples were obtained from all participants for flow cytometry analysis of iNKT cells, Tregs and γδ T cell phenotypes. RESULTS: We observed a significant increase in Tregs in the CFS/ME group (p≤0.05) compared to the healthy control group. Total γδ and γδ2 T cells were significantly reduced in MS patients in comparison with the healthy control group. Conversely, CD4+iNKT percentage of iNKT, was significantly increased in the CFS/ME group compared with healthy controls and the double-negative iNKT percentage of iNKT significantly decreased compared with the healthy control group. CONCLUSIONS: This study has not identified any immunological disturbances that are common in both MS and CFS/ME patients. However, the differential expression of cell types between the conditions investigated suggests different pathways of disease. These differences need to be explored in further studies.

A new era in the treatment of multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system with a multifactorial aetiology and highly variable natural history. A growing understanding of the immunopathogenesis of the condition has led to an expanding array of therapies for this previously untreatable disease. While a cure for MS remains elusive, the potential to reduce inflammatory disease activity by preventing relapses and minimising disease progression is achievable. The importance of early treatment in minimising long-term disability is increasingly recognised. Most of the newer, more effective therapies are associated with risks and practical problems that necessitate an active management strategy and continuous vigilance. While the initiation of these therapies is likely to remain the responsibility of neurologists, other specialist physicians and general practitioners will be involved in the identification and management of adverse effects.

Longlook: initial outcomes of a longitudinal integrated rural clinical placement program.

OBJECTIVE: To assess outcomes in terms of academic performance and subsequent career choice in medical students undertaking a longitudinal integrated rural clinical placement. DESIGN: This was a retrospective, observational, cohort study. SETTING: The 'Longlook' program is a longitudinal integrated rural clinical placement run collaboratively by Griffith University, Queensland Rural Medical Education and Queensland Health as part of the Griffith medical program. PARTICIPANTS: Participants in this study were students completing years 3 and 4 in the Griffith medical program between 2010 and 2013. Assessment data were available for 683 participants, and internship location was available for all 472 students allocated within Queensland (87% of graduated students). INTERVENTIONS: Introduction of Longlook program. MAIN OUTCOME MEASURES: The primary outcome measures were performance in overall and clinical assessments, and intern location (rural versus urban). RESULTS: When performance in prior year was taken into account, there were no statistically significant differences in academic performance in year 3 or 4 for rural and urban students. Of Longlook students who have graduated, 31/46 (67%) have undertaken internship at a rural location compared with 63/426 (15%) for urban hospital-based students (odds ratio 11.91; 95% confidence interval 6.08-23.32). CONCLUSIONS: We have demonstrated that it is feasible to implement a parallel longitudinal integrated rural clinical placement in an established conventional postgraduate medical program and provide similar learning outcomes. Initial findings suggest that this experience is translating into positive outcomes in terms of future careers in rural settings. There is a need to reappraise the structure of initiatives aimed at promoting rural careers in medicine.

Ribosomal protein S6 mRNA is a biomarker upregulated in multiple sclerosis, downregulated by interferon treatment, and affected by season.

BACKGROUND: Multiple Sclerosis (MS) is an immune-mediated disease of the central nervous system which responds to therapies targeting circulating immune cells. OBJECTIVE: Our aim was to test if the T-cell activation gene expression pattern (TCAGE) we had previously described from whole blood was replicated in an independent cohort. METHODS: We used RNA-seq to interrogate the whole blood transcriptomes of 72 individuals (40 healthy controls, 32 untreated MS). A cohort of 862 control individuals from the Brisbane Systems Genetics Study (BSGS) was used to assess heritability and seasonal expression. The effect of interferon beta (IFNB) therapy on expression was evaluated. RESULTS: The MS/TCAGE association was replicated and rationalized to a single marker, ribosomal protein S6 (RPS6). Expression of RPS6 was higher in MS than controls (p<0.0004), and lower in winter than summer (p<4.6E-06). The seasonal pattern correlated with monthly UV light index (R=0.82, p<0.002), and was also identified in the BSGS cohort (p<0.0016). Variation in expression of RPS6 was not strongly heritable. RPS6 expression was reduced by IFNB therapy. CONCLUSIONS: These data support investigation of RPS6 as a potential therapeutic target and candidate biomarker for measuring clinical response to IFNB and other MS therapies, and of MS disease heterogeneity.

Enhancing cognitive-behavioural therapy for recurrent headache: design of a randomised controlled trial.

BACKGROUND: We have argued against the traditional approach of counselling avoidance of all triggers of headaches and migraine. Problems with this approach include the impossibility of avoiding all triggers and the high costs associated with trying to do so, and that avoidance could lead to reduced tolerance for the triggers. We have developed an alternative approach called Learning to Cope with Triggers (LCT) that encourages avoidance of triggers that are detrimental to health and wellbeing, but uses exposure to other triggers to desensitise headache sufferers to the triggers. This approach has been shown to be more effective than advising avoidance of all triggers. Trigger management is only one component of a comprehensive treatment program and the current study is designed to evaluate a new approach to treating headaches in which LCT has been integrated into an established cognitive-behavioural therapy (CBT) package (LCT/CBT). METHODS/DESIGN: A target sample of 120 adult participants who suffer from migraine or tension-type headache, at least six days per month, and have done so for at least 12 months will be recruited. Participants will be randomly assigned to one of three groups: LCT/CBT; Avoid/CBT (CBT combined with instructions to avoid all triggers); and waiting-list control. Measures will include: daily diaries for recording headaches, triggers and medication consumption; headache disability and quality of life; trigger avoidance; locus of control and self-efficacy; and coping strategies. Treatment will involve 12 60-minute sessions scheduled weekly. Assessment will be completed before and after treatment, and at 4 and 12 month follow-up. The data will be analysed to determine which approach is most effective, and predictors of response to treatment. DISCUSSION: Migraine and tension-type headache are common and can be disabling. CBT has been demonstrated to be an efficacious treatment for both disorders. However, there is room for improvement. This study aims to increase the efficacy of behavioural approaches and identify factors predictive of a positive response. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTRN12614000435684 .

Long-term outcomes of ADEM-like and tumefactive presentations of CNS demyelination: a case-comparison analysis.

A minority of initial multiple sclerosis (MS) presentations clinically or radiologically resemble other central nervous system (CNS) pathologies, acute disseminated encephalomyelitis (ADEM) or tumefactive demyelination (atypical demyelination presentations). With the aim of better defining the long-term outcomes of this group we have performed a retrospective cohort comparison of atypical demyelination versus 'typical' MS presentations. Twenty-seven cases with atypical presentations (both first and subsequent demyelinating events) were identified and compared with typical MS cases. Disease features analysed included relapse rates, disability severity, whole brain and lesion volumes, lesion number and distribution. Atypical cases represented 3.9% of all MS cases. There was considerable overlap in the magnetic resonance imaging (MRI) features of ADEM-like and tumefactive demyelination cases. ADEM-like cases tended to be younger but not significantly so. Atypical cases showed a trend towards higher peak expanded disability severity score (EDSS) score at the time of their atypical presentation. Motor, cranial nerve, cerebellar, cerebral and multifocal presentations were all more common in atypical cases, and less likely to present with optic neuritis. Cerebrospinal fluid (CSF) white cell counts were higher in atypical cases (p = 0.002). One atypical case was associated with peripheral blood myelin oligodendrocyte glycoprotein (MOG) antibodies, but subsequent clinical and radiological course was in keeping with MS. There was no difference in long-term clinical outcomes including annualised relapse rates (ARR), brain volume, lesion numbers or lesion distributions. Atypical demyelination cases were more likely to receive high potency disease modifying therapy early in the course of their illness. Despite the severity of initial illness, our cohort analysis suggests that atypical demyelination presentations do not confer a higher risk of long-term adverse outcomes.