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OBJECTIVE: Blood biomarkers of neuronal injury such as neurofilament light (NfL) show promise to improve diagnosis of neurodegenerative disorders and distinguish neurodegenerative from primary psychiatric disorders (PPD). This study investigated the diagnostic utility of plasma NfL to differentiate behavioural variant frontotemporal dementia (bvFTD, a neurodegenerative disorder commonly misdiagnosed initially as PPD), from PPD, and performance of large normative/reference data sets and models. METHODS: Plasma NfL was analysed in major depressive disorder (MDD, n = 42), bipolar affective disorder (BPAD, n = 121), treatment-resistant schizophrenia (TRS, n = 82), bvFTD (n = 22), and compared to the reference cohort (Control Group 2, n = 1926, using GAMLSS modelling), and age-matched controls (Control Group 1, n = 96, using general linear models). RESULTS: Large differences were seen between bvFTD (mean NfL 34.9 pg/mL) and all PPDs and controls (all < 11 pg/mL). NfL distinguished bvFTD from PPD with high accuracy, sensitivity (86%), and specificity (88%). GAMLSS models using reference Control Group 2 facilitated precision interpretation of individual levels, while performing equally to or outperforming models using local controls. Slightly higher NfL levels were found in BPAD, compared to controls and TRS. CONCLUSIONS: This study adds further evidence on the diagnostic utility of NfL to distinguish bvFTD from PPD of high clinical relevance to a bvFTD differential diagnosis, and includes the largest cohort of BPAD to date. Using large reference cohorts, GAMLSS modelling and the interactive Internet-based application we developed, may have important implications for future research and clinical translation. Studies are underway investigating utility of plasma NfL in diverse neurodegenerative and primary psychiatric conditions in real-world clinical settings.

INTRODUCTION: Newcastle, Australia, has been serially studied for MS epidemiology since 1961, showing consistently increasing prevalence estimates and incidence rates, including to our 2011 study. OBJECTIVES: To assess the 2011-2021 epidemiology of MS in Newcastle and to compare with previous measures. METHODS: Demographic and clinical data were extracted from medical records of MS cases residing in Newcastle, as identified by public and private clinicians. Prevalence (2011 and 2021) and incidence rates (2011-2021, from onset and from diagnosis) and mortality rate (2011-2021) were estimated and age-standardised to the 2021 Australian population. RESULTS: The 2021 prevalence was 173.1/100,000 (age-standardised = 178.7/100,000, F/M-sex-ratio = 3.3), a 42.2 % increase from 2011 (F/M-sex-ratio = 3.1), 175.0 % from 1996 (F/M-sex-ratio = 2.6), and 831.0 % from 1961 (F/M-sex-ratio = 1.2). The 2011-21 age-standardised onset incidence rate was 3.5/100,000 person-years (F/M-sex-ratio = 2.8), a 68.7 % increase from 1971 to 81 (F/M-sex-ratio = 1.1) and 44.5 % from 1986 to 96 (F/M-sex-ratio = 2.3). The age-standardised diagnosis incidence rate was 6.1/100,000 (F/M-sex-ratio = 2.2), statistically unchanged from that in 2001-2011 (6.8/100,000, F/M-sex-ratio = 3.2). The 2011-21 mortality rate was 2.1/100,000 person-years (2.2 age-standardised, F/M-sex-ratio = 1.4), with a standardised mortality ratio of 1.6. CONCLUSION: The Newcastle region continues to be a high frequency zone for MS. The incidence rate from onset is significantly increased from previous estimates, but incidence rate from diagnosis is stable. Prevalence and incidence sex ratios have stabilised at roughly 3.0, similar to other Australian sites.

BACKGROUND: Fatigue and disability are indicators of disease progression experienced by many people with multiple sclerosis (pwMS). Understanding trajectories of these outcomes, and their predictors, may provide insight to potential interventions for MS management. METHODS: Survey data from 839 pwMS from the Health Outcomes and Lifestyle in pwMS study were analysed. Fatigue was defined as mean Fatigue Severity Scale >5, and severe disability as Patient Determined Disease Steps >5. Group-based trajectory modelling was used to identify fatigue and disability trajectories over five-years. Dietary predictors associated with outcome trajectory group membership were assessed using log-binomial regression. Demographic and clinical characteristics were considered in multivariable models. RESULTS: Distinct trajectories for fatigue and disability were identified. For fatigue, 58 % of pwMS were assigned to low-, and 42 % to high-, fatigue trajectory groups. For disability, 85 % of pwMS were assigned to low-, and 15 % to high-, disability groups. Baseline high-quality diet, and omega-3 and vitamin D supplement use, were associated with reduced risk of being in high-fatigue and high-disability trajectories, while meat and dairy consumption were associated with increased risk. CONCLUSIONS: A high-quality diet, avoiding meat and dairy, and omega-3 and vitamin D supplement use, individually predict better fatigue and disability trajectories. Dietary modifications should be considered in MS management.

BACKGROUND AND PURPOSE: Healthy lifestyle behaviour modification may improve health outcomes in people with multiple sclerosis (pwMS), but empirical evidence is needed to confirm prior study findings. We developed an online multimodal lifestyle intervention (Multiple Sclerosis Online Course) to examine the impact of lifestyle modification on health outcomes in pwMS via a randomized control trial (RCT). However, the present study specifically analyses baseline data to assess engagement with healthy lifestyles by RCT participants and cross-sectional associations with health outcomes. METHODS: Baseline engagement with six "healthy lifestyle behaviours" of the intervention course (high-quality, plant-based diet; ≥5000 IU/day vitamin D; omega-3 supplementation; ≥30 min physical activity 5 times/week; ≥30 min/week meditation; and nonsmoking) was examined. Associations between individual versus collective behaviours (individual behaviours summated) and health outcomes (quality of life [QoL]/fatigue/disability) were evaluated using multivariate modelling (linear/log-binomial/multinomial). RESULTS: At baseline, 33.7% and 30.0% of participants (n = 857) engaged in one or two healthy behaviours, respectively. In total, engagement with healthy lifestyles by participants was as follows: nonsmoking, 90.7%; omega-3 supplementation, 34.5%; vitamin D supplementation, 29.8%; physical activity, 29.4%; diet, 10.7%; and meditation, 10.5%. Individual behaviours (nonsmoking/physical activity/diet) were independently associated with better health outcomes. Engagement with multiple behaviours, especially diet and physical activity, was associated with better outcomes; engaging with ≥4 behaviours was associated with a 9.0-point higher mental QoL and a 9.5-point higher physical QoL, as well as 23% and 56% lower prevalence of fatigue and moderate disability, respectively. CONCLUSIONS: Baseline engagement with ≥4 healthy behaviours, including diet and physical activity, was associated with bett

Diet and inflammation may contribute to the development of multiple sclerosis (MS). The aim of this systematic review and meta-analysis was to assess the association between proinflammatory diet, as estimated by the Dietary Inflammatory Index (DII®), and the likelihood of developing MS or other demyelinating autoimmune diseases. A systematic search was performed of search engines and databases (PubMed, ISI Web of Sciences, Scopus, and Embase) to identify relevant studies before 10th June 2023. The search identified 182 potential studies, from which 39 full-text articles were screened for relevance. Five articles with case-control design (n = 4,322, intervention group: 1714; control group: 2608) met the study inclusion criteria. The exposure variable was DII, with studies using two distinct models: quartile-based comparisons of DII and assessment of continuous DII. The meta-analysis of high versus low quartiles of DII with four effect sizes showed a significant association with MS/demyelinating autoimmune disease likelihood, with an odds ratio (OR) of 3.26 (95% confidence interval (CI) 1.16, 9.10). The meta-analysis of four studies with DII fit as a continuous variable showed a 31% increased likelihood of MS per unit increment; which was not statistically significant at the nominal alpha equals 0.05 (OR 1.31; 95% CI 0.95, 1.81). In conclusion, this systematic review and meta-analysis provides evidence of a positive association between higher DII scores with the likelihood of developing MS, highlighting that diet-induced inflammation could play a role in MS or other demyelinating autoimmune diseases risk.

Geographical variations in the incidence and prevalence of multiple sclerosis have been reported globally. Latitude as a surrogate for exposure to ultraviolet radiation but also other lifestyle and environmental factors are regarded as drivers of this variation. No previous studies evaluated geographical variation in the risk of secondary progressive multiple sclerosis, an advanced form of multiple sclerosis that is characterized by steady accrual of irreversible disability. We evaluated differences in the risk of secondary progressive multiple sclerosis in relation to latitude and country of residence, modified by high-to-moderate efficacy immunotherapy in a geographically diverse cohort of patients with relapsing-remitting multiple sclerosis. The study included relapsing-remitting multiple sclerosis patients from the global MSBase registry with at least one recorded assessment of disability. Secondary progressive multiple sclerosis was identified as per clinician diagnosis. Sensitivity analyses used the operationalized definition of secondary progressive multiple sclerosis and the Swedish decision tree algorithm. A proportional hazards model was used to estimate the cumulative risk of secondary progressive multiple sclerosis by country of residence (latitude), adjusted for sex, age at disease onset, time from onset to relapsing-remitting phase, disability (Multiple Sclerosis Severity Score) and relapse activity at study inclusion, national multiple sclerosis prevalence, government health expenditure, and proportion of time treated with high-to-moderate efficacy disease-modifying therapy. Geographical variation in time from relapsing-remitting phase to secondary progressive phase of multiple sclerosis was modelled through a proportional hazards model with spatially correlated frailties. We included 51 126 patients (72% female) from 27 countries. The median survival time from relapsing-remitting phase to secondary progressive multiple sclerosis among all patients wa

BACKGROUND: We previously reported an association between household chemical exposures and an increased risk of paediatric-onset multiple sclerosis. METHODS: Using a case-control paediatric multiple sclerosis study, gene-environment interaction between exposure to household chemicals and genotypes for risk of paediatric-onset multiple sclerosis was estimated.Genetic risk factors of interest included the two major HLA multiple sclerosis risk factors, the presence of DRB1*15 and the absence of A*02, and multiple sclerosis risk variants within the metabolic pathways of common household toxic chemicals, including IL-6 (rs2069852), BCL-2 (rs2187163) and NFKB1 (rs7665090). RESULTS: 490 paediatric-onset multiple sclerosis cases and 716 controls were included in the analyses. Exposures to insect repellent for ticks or mosquitos (OR 1.47, 95% CI 1.06 to 2.04, p=0.019), weed control products (OR 2.15, 95% CI 1.51 to 3.07, p<0.001) and plant/tree insect or disease control products (OR 3.25, 95% CI 1.92 to 5.49, p<0.001) were associated with increased odds of paediatric-onset multiple sclerosis. There was significant additive interaction between exposure to weed control products and NFKB1 SNP GG (attributable proportions (AP) 0.48, 95% CI 0.10 to 0.87), and exposure to plant or disease control products and absence of HLA-A*02 (AP 0.56; 95% CI 0.03 to 1.08). There was a multiplicative interaction between exposure to weed control products and NFKB1 SNP GG genotype (OR 2.30, 95% CI 1.00 to 5.30) but not for other exposures and risk variants. No interactions were found with IL-6 and BCL-2 SNP GG genotypes. CONCLUSIONS: The presence of gene-environment interactions with household toxins supports their possible causal role in paediatric-onset multiple sclerosis.

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.

BACKGROUND: Health state utilities (HSU) are a health-related quality-of-life (HRQoL) input for cost-utility analyses used for resource allocation decisions, including medication reimbursement. New Zealand (NZ) guidelines recommend the EQ-5D instruments; however, the EQ-5D-5L may not sufficiently capture psychosocial health. We evaluated HRQoL among people with multiple sclerosis (MS) in NZ using the EQ-5D-5L and assessed the instrument's discriminatory sensitivity for a NZ MS cohort. METHODS: Participants were recruited from the NZ MS Prevalence Study. Participants self-completed a 45-min online survey that included the EQ-5D-5L/EQ-VAS. Disability severity was classified using the Expanded Disability Status Scale (EDSS) to categorise participant disability as mild (EDSS: 0-3.5), moderate (EDSS: 4.0-6.0) and severe (EDSS: 6.5-9.5). Anxiety/depression were also measured using the Hospital Anxiety and Depression Score (HADS). In the absence of an EQ-5D-5L NZ tariff, HSUs were derived using an Australian tariff. We evaluated associations between HSUs and participant characteristics with linear regression models. RESULTS: 254 participants entered the study. Mean age was 55.2 years, 79.5% were female. Mean (SD) EQ-5D-5L HSU was 0.58 (0.33). Mean (SD) HSUs for disability categories were: mild 0.80 ± 0.17, moderate 0.57 ± 0.21 and severe 0.14 ± 0.32. Twelve percent reported HSU = 1.0 (i.e., no problems in any domain). Participants who had never used a disease-modifying therapy reported a lower mean HSU. Multivariable modelling found that the HADS anxiety score was not associated with EQ-5D-5L. CONCLUSIONS: HRQoL for people with MS in NZ was lower than comparable countries, including Australia. We suggest a comparison with other generic tools that may have improved sensitivity to mental health.

BACKGROUND: Multiple sclerosis (MS) is an inflammatory, neurodegenerative disease of the central nervous system which results in disability over time and reduced quality of life. To increase the sensitivity of the EQ-5D-5L for psychosocial health, four bolt-on items from the AQoL-8D were used to create the nine-item EQ-5D-5L-Psychosocial. We aimed to externally validate the EQ-5D-5L-Psychosocial in a large cohort of people with MS (pwMS) and explore the discriminatory power of the new instrument with EQ-5D-5L/AQoL-8D. METHODS: A large representative sample from the Australian MS Longitudinal Study completed the AQoL-8D and EQ-5D-5L (including EQ VAS) and both instruments health state utilities (HSUs) were scored using Australian tariffs. Sociodemographic/clinical data were also collected. External validity of EQ-5D-5L-Psychosocial scoring algorithm was assessed with mean absolute errors (MAE) and Spearman's correlation coefficient. Discriminatory sensitivity was assessed with an examination of ceiling/floor effects, and disability severity classifications. RESULTS: Among 1683 participants (mean age: 58.6 years; 80% female), over half (55%) had moderate or severe disability. MAE (0.063) and the distribution of the prediction error were similar to the original development study. Mean (± standard deviation) HSUs were EQ-5D-5L: 0.58 ± 0.32, EQ-5D-5L-Psychosocial 0.62 ± 0.29, and AQoL-8D: 0.63 ± 0.20. N = 157 (10%) scored perfect health (i.e. HSU = 1.0) on the EQ-5D-5L, but reported a mean HSU of 0.90 on the alternative instruments. The Sleep bolt-on dimension was particularly important for pwMS. CONCLUSIONS: The EQ-5D-5L-Psychosocial is more sensitive than the EQ-5D-5L in pwMS whose HSUs approach those reflecting full health. When respondent burden is taken into account, the EQ-5D-5L-Psychosocial is preferential to the AQoL-8D. We suggest a larger confirmatory study comparing all prevalent multi-attribute utility instruments for pwMS.

BACKGROUND: Digital health interventions have revolutionized multiple sclerosis (MS) care by supporting people with MS to better self-manage their disease. It is now understood that the technological elements that comprise this category of digital health interventions can influence participant engagement in self-management programs, and people with MS can experience significant barriers, influenced by these elements, to remaining engaged during a period of learning. It is essential to explore the influence of technological elements in mitigating attrition. OBJECTIVE: This study aimed to examine the study design and technological elements of documented digital health interventions targeted at people with MS-digital health interventions that were intended to support a program of engagement over a defined period-and to explore how these correlated with attrition among participants of randomized controlled trials (RCTs). METHODS: We conducted a systematic review and meta-analysis of RCTs (n=32) describing digital health self-management interventions for people with MS. We analyzed attrition in included studies, using a random-effects model and meta-regression to measure the association between potential moderators. RESULTS: There were no measured differences in attrition between the intervention and control arms; however, some of the heterogeneity observed was explained by the composite technological element score. The pooled attrition rates for the intervention and control arms were 14.7% and 15.6%, respectively. CONCLUSIONS: This paper provides insight into the technological composition of digital health interventions designed for people with MS and describes the degree of attrition in both study arms. This paper will aid in the design of future studies in this area, particularly for digital health interventions of this type.

BACKGROUND: There is increasing interest in the role of diet in multiple sclerosis (MS) progression and whether a healthier diet may lead to improved health and wellbeing in people living with MS (plwMS). OBJECTIVE: To assess the prospective relationship of the quality of dietary intakes with quality of life (QoL) in an international cohort of plwMS followed over 7.5 years. METHODS: Data from the Health Outcomes and Lifestyle In a Sample of people with Multiple sclerosis (HOLISM) cohort from baseline to 7.5-year review were analysed. Quality of the diet was assessed using the Diet Habits Questionnaire (DHQ). QoL was measured by the MSQOL-54, including physical and mental health composite scores and multiple subdomains. Linear regression was used to determine cross-sectional and prospective relationships with QoL, adjusted for clinical and demographic covariates. RESULTS: Amongst 948 participants, median physical- and mental-health QoL scores at 7.5-year review were 66.9 and 78.2, respectively. Baseline total DHQ was positively associated with subsequent change in physical-QoL to 7.5-year review, such that participants in the top two quartiles of baseline DHQ had 0.65 and 0.64 higher physical-QoL per year, though a similar association with mental-QoL did not persist on adjustment. Baseline meat consumption was associated with 0.38 lower physical-QoL per year, while baseline dairy consumption was associated with 0.50 and 0.41 lower physical- and mental-QoL per year, respectively. CONCLUSIONS: These results suggest efforts to improve the quality of dietary intake could be beneficial to the wellbeing of plwMS. Subject to replication, this aspect of lifestyle could be a useful intervention in better managing MS.

BACKGROUND: Multiple sclerosis is a demyelinating autoimmune disease, presenting with heterogenous symptoms that impact daily living. Undertaking stress-reducing activities may reduce symptoms including depression and fatigue, and enhance mastery, the sense of control of one's life. We assessed cross-sectional associations of undertaking stress-reducing activities or meditation on depression, fatigue, and mastery, and 5-year prospective relationships between meditation and these outcomes. METHODS: Data were extracted from the longitudinal Health Outcomes and Lifestyle In a Sample of people with Multiple sclerosis (HOLISM) study. Stress-reducing activities were categorised to relaxation, physical, mind-body, and spiritual. Meditation was analysed as a dichotomous term, and for duration and frequency of practice. Depression, fatigue, and mastery were assessed by Patient's Health Questionnaire-9, Fatigue Severity Scale, and Pearlin Mastery Scale, respectively. Associations with depression, fatigue and mastery were assessed by log-binomial regression. Models were adjusted for age, sex, symptoms due to relapse, socioeconomic status, employment status, and antidepressant and anti-fatigue medication use, as appropriate. RESULTS: Cross-sectionally, physical and relaxation activities were associated with 40% and 33% lower frequencies of depression, respectively. Physical activities were additionally associated with 19% lower frequency of fatigue. Meditation was associated with 30% lower frequency of depression and 17% higher mastery. Prospectively, meditation was associated with 28% decreased depression, and 48% reduction of developing depression at 5-year follow-up. CONCLUSION: Potential benefits of undertaking stress-reducing activities, or meditation, on depression, fatigue, and mastery are promising and should be further assessed prospectively. Meditation practice should be encouraged as a safe and inexpensive intervention for prevention of depression.

BACKGROUND: Mastery is the extent to which an individual perceives their life circumstances as being under their control and not predominantly influenced by external factors. The relationship of mastery with clinical outcomes in people with multiple sclerosis (pwMS) has not been well-researched. We assessed the relationships of mastery with fatigue, disability, relapse number, and depression risk among pwMS over 2.5 years' follow-up. METHODS: Data from the Health Outcomes and Lifestyle in a Sample of people with Multiple sclerosis study, among 839 participants who completed the 2.5 and 5-year reviews, were analysed. Mastery was measured by the Pearlin Mastery Scale, fatigue by Fatigue Severity Scale, depression risk by Patient Health Questionnaire-9, and disability by Patient-Determined Disease Steps, and diagnosed relapse number in the previous 12 months was queried. Cross-sectional and prospective analyses were undertaken by log-binomial, log-multinomial, and Poisson regression, as appropriate, adjusted for relevant confounders. RESULTS: Cross-sectionally, pwMS with the highest quartile mastery (> 25/28) had 90% lower frequency of depression risk, 60% lower frequency of clinically significant fatigue, and 77% fewer had severe disability, all largely robust to adjustment. Prospectively, those in the top two quartiles of mastery (> 21-25, > 25/28) had 66% and 74% lower subsequent depression risk, robust to adjustment. No significant associations were seen prospectively for change in fatigue, disability, or relapse number, however, and no robust associations of mastery with relapse number were evident. CONCLUSIONS: Prospectively, a protective relationship of mastery with subsequent risk of depression was observed, suggesting this may be a point of intervention to improve wellbeing in pwMS.

BACKGROUND AND PURPOSE: Modifiable lifestyle factors, including diet, may affect clinical outcomes in multiple sclerosis (MS). This study assessed the relationships between diet, and disability, fatigue, and depression risk in people with MS. METHODS: Participants from the Health Outcomes and Lifestyle In a Sample of people with Multiple sclerosis (HOLISM) international cohort were assessed over 2.5 years. Dietary data were obtained using a modified Diet Habits Questionnaire (DHQ), disability using the calculated Patient-determined MS Severity Score (P-MSSS), fatigue using the Fatigue Severity Scale, and depression risk using the Patient Health Questionnaire-2. Participants reported whether they were experiencing symptoms due to a recent relapse. Cross-sectional and prospective relationships of diet and disease outcomes were explored, adjusted for relevant confounders. RESULTS: Among 1,346 participants, higher DHQ scores showed significant dose-dependent associations with lower frequencies of severe disability, fatigue, and depression risk, cross-sectionally. Prospectively, higher baseline DHQ scores were associated with a lower risk of increasing disability, those above the median having 41% and 36% lower risk of increasing disability, and 0.30 P-MSSS points less disability progression, but were not associated with fatigue or depression risk. Meat consumption was associated with 0.22 P-MSSS points higher disability cross-sectionally, while prospectively, baseline meat consumption was associated with 76% higher risk of increasing disability and 0.18 P-MSSS points higher disability progression. Dairy consumption showed mixed associations cross-sectionally and prospectively. CONCLUSIONS: These results show that better quality of diet, as well as not consuming meat, were associated with reduced disability progression in people with MS. Substantiation of these findings in other settings may inform opportunities to manage disability progression in people with MS using di

OBJECTIVE: To explore the feasibility of a randomised controlled trial of a multiple sclerosis online course (MSOC) via qualitative analysis of participant semi-structured interviews. METHODS: The MSOC was developed in two arms: intervention arm which contained evidence-based lifestyle modification recommendations, and standard-care arm which delivered information from MS websites reflecting standard advice. Participants were recruited via online advertisements, completed a baseline questionnaire, and randomised. Seven modules were delivered over six weeks. Course completers were invited to participate in semi-structured interviews. Within a qualitative paradigm, interviews were analysed using reflexive thematic analysis. RESULTS: Fourteen of the 17 course completers were interviewed: 86% (12/14) female; mean age 50 years; residing in Australia, New Zealand, and the USA, predominantly had relapsing-remitting MS, mean time from diagnosis 9.5 years, and patient-determined disease steps disability assessment distributed evenly across all three categories. Four themes were identified: 1) "Hearing our stories" (hope for the future, feeling represented, exploring the journey of others with MS, learning from diversity, and wanting to connect with others); 2) "Taking the plunge" (not wanting to be first, feelings of nervousness or reluctance and feeling confronted); 3) "The accessibility and safety of being online" (ease of access, going at your own pace, making it work and not letting others down); and 4) "unpacking the course" (ease of navigation, visuals, understandability, and length and timing). CONCLUSION: Participants felt represented, found the course accessible and content was easy to understand. These experiences provide important insights and considerations for this digital health intervention.

Advances in genome sequencing technologies have unlocked new possibilities in identifying disease-associated and causative genetic markers, which may in turn enhance disease diagnosis and improve prognostication and management strategies. With the capability of examining genetic variations ranging from single-nucleotide mutations to large structural variants, whole-genome sequencing (WGS) is an increasingly adopted approach to dissect the complex genetic architecture of neurologic diseases. There is emerging evidence for different structural variants and their roles in major neurologic and neurodevelopmental diseases. This review first describes different structural variants and their implicated roles in major neurologic and neurodevelopmental diseases, and then discusses the clinical relevance of WGS applications in neurology. Notably, WGS-based detection of structural variants has shown promising potential in enhancing diagnostic power of genetic tests in clinical settings. Ongoing WGS-based research in structural variations and quantifying mutational constraints can also yield clinical benefits by improving variant interpretation and disease diagnosis, while supporting biomarker discovery and therapeutic development. As a result, wider integration of WGS technologies into health care will likely increase diagnostic yields in difficult-to-diagnose conditions and define potential therapeutic targets or intervention points for genome-editing strategies.

BACKGROUND: Modifiable lifestyle factors are important to aid people with multiple sclerosis in the self-management of their disease. Current self-management programs are limited by their face-to-face mode of delivery but there is immense potential with the internet to deliver these programs effectively. OBJECTIVE: The aims of this study are to assess the feasibility of a digitalized educational lifestyle self-management program for people with MS. METHODS: In this randomized controlled trial, people with MS were randomly allocated to participate in a 6-week tailored web-based educational lifestyle program or 6-week generic standard-care educational course, and were blinded to their allocation. Participants were recruited through multiple sclerosis (MS) Societies in four countries: Australia, New Zealand, Canada, and the United States. The primary outcome was to assess acceptability of the program defined as percentage completion of all modules at 6-weeks post-course commencement. Secondary outcomes included evaluating participant responses to the follow-up survey across three domains: accessibility, learnability, and desirability. RESULTS: Thirty-five participants from Australia, Canada, New Zealand, and the US completed the baseline survey and were randomized. Four participants were deemed ineligible due to incomplete baseline data; therefore, nine out of 15 and eight out of 16 participants completed 100% of the course in the intervention and standard-care arm courses, respectively. CONCLUSIONS: This study found that this web-based educational lifestyle program is a feasible means of delivering educational content to people with MS via the internet according to our a priori targets of >40% of participants in the intervention arm, and >25% in the control arm to completing 100% of the course. It is therefore appropriate to evaluate this intervention further in a large, randomized controlled trial. TRIAL REGISTRATION: This study was prospectively registered with the

BACKGROUND AND OBJECTIVES: Certain demographic and clinical characteristics, including the use of some disease-modifying therapies (DMTs), are associated with severe acute respiratory syndrome coronavirus 2 infection severity in people with multiple sclerosis (MS). Comprehensive exploration of these relationships in large international samples is needed. METHODS: Clinician-reported demographic/clinical data from 27 countries were aggregated into a data set of 5,648 patients with suspected/confirmed coronavirus disease 2019 (COVID-19). COVID-19 severity outcomes (hospitalization, admission to intensive care unit [ICU], requiring artificial ventilation, and death) were assessed using multilevel mixed-effects ordered probit and logistic regression, adjusted for age, sex, disability, and MS phenotype. DMTs were individually compared with glatiramer acetate, and anti-CD20 DMTs with pooled other DMTs and with natalizumab. RESULTS: Of 5,648 patients, 922 (16.6%) with suspected and 4,646 (83.4%) with confirmed COVID-19 were included. Male sex, older age, progressive MS, and higher disability were associated with more severe COVID-19. Compared with glatiramer acetate, ocrelizumab and rituximab were associated with higher probabilities of hospitalization (4% [95% CI 1-7] and 7% [95% CI 4-11]), ICU/artificial ventilation (2% [95% CI 0-4] and 4% [95% CI 2-6]), and death (1% [95% CI 0-2] and 2% [95% CI 1-4]) (predicted marginal effects). Untreated patients had 5% (95% CI 2-8), 3% (95% CI 1-5), and 1% (95% CI 0-3) higher probabilities of the 3 respective levels of COVID-19 severity than glatiramer acetate. Compared with pooled other DMTs and with natalizumab, the associations of ocrelizumab and rituximab with COVID-19 severity were also more pronounced. All associations persisted/enhanced on restriction to confirmed COVID-19. DISCUSSION: Analyzing the largest international real-world data set of people with MS with suspected/confirmed COVID-19 confirms that the use of anti-CD20 m

BACKGROUND: Modification of lifestyle-related risk factors for multiple sclerosis (MS) has been associated with improved health outcomes when compared with standard medical management alone. Based on an existing lifestyle modification program offered as a residential workshop, the MS Online Course (MSOC) was developed to translate the workshop into an online intervention. We performed a pilot randomized controlled trial (RCT), to assess the feasibility concepts of accessibility, learnability and desirability through quantitative and qualitative analyzes. In the present study, we performed additional qualitative analyzes to explore participants' motivations, expectations, and experiences of the MSOC. This study aims to complement prior feasibility analyzes and inform recruitment strategies and course content redevelopment so that its effectiveness may be assessed by examining behavior change and health outcomes in a future larger RCT. METHODS: Participants were recruited via online advertisements and randomized to either: the standard care course, containing material sourced from public facing MS websites; or the intervention course, based on an evidence-based lifestyle modification program for people with MS. Course completers were invited to participate in semi-structured interviews. Within a qualitative paradigm, reflexive thematic analysis of interviews was undertaken. RESULTS: Of 31 eligible participants, 17 completed the MSOC and 14 agreed to be interviewed. Four themes were identified in this analysis: (1) "Wanting to help others" (helping through volunteering, contributing to knowledge base, spreading the word; (2) "Seeking knowledge" (confirmation of existing knowledge; obtaining new knowledge, relevant, credible information); (3) "Doing what I can to help myself" (understanding lifestyle modification, changing my lifestyle, remaining well); and (4) "Changing attitudes" (finding positivity, feeling more confident and in control). CONCLUSIONS: Participants we

INTRODUCTION: Generic multiattribute utility instruments (MAUIs) are efficient tools for determining and enumerating health-related quality of life. MAUIs accomplish this by generating health state utilities (HSUs) via algorithms. Minimal important differences (MIDs) assist with the interpretation of HSUs by estimating minimum changes that are clinically significant. The overall goal of the proposed systematic review and meta-analysis is the development of comprehensive guidelines for MID estimation. METHODS AND ANALYSIS: This protocol defines a systematic review and meta-analysis of MIDs for generic MAUIs. The proposed research will involve a comprehensive investigation of 10 databases (EconLit, IDEAs database, INAHTA database, Medline, PsycINFO, Embase, Emcare, JBIEBP and CINAHL) from 1 June 2022 to 7 June 2022, and will be performed and reported in accordance with several validated guidelines, principally the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The quality of papers, considered for inclusion in the review, will be appraised using the COnsensus-based Standards for the selection of health Measurement INstruments, inter alia.Narrative analysis will involve identifying the characteristics of MIDs including methods of calculation, sources of heterogeneity, and validation. Meta-analysis will also be conducted. The descriptive element of meta-analysis will involve the generation of I2 statistics and Galbraith plots of MID heterogeneity. Together with narrative analysis, this will allow sources of MID heterogeniety to be identified. A multilevel mixed model, estimated via restricted maximum likelihood estimation, will be constructed for the purposes of meta-regression. Meta-regression will attempt to enumerate the effects of sources of heterogeneity on MID estimates. Meta-analysis will be concluded with pooling of MIDs via a linear random-effects model. ETHICS AND DISSEMINATION: Ethics approval is not required for this review, a

Understanding the dietary characteristics of people living with multiple sclerosis (plwMS) may assist in the planning of nutrition interventions for multiple sclerosis; yet dietary assessment methods in existing studies are not well established. The aim of this study was to validate the psychometric properties (construct validity and internal consistency) of the Dietary Habits Questionnaire (DHQ) against repeated online 24-h recall dietary assessments. The DHQ is a 24-item tool that is scored using ten dietary sub-scores. Total DHQ scores can range from 20−100 and are considered indicative of the quality of dietary intake with higher scores reflecting increased quality. People living with a relapsing-remitting MS phenotype who had completed a modified DHQ were recruited from the international Health Outcomes and Lifestyle In a Sample of people with Multiple sclerosis (HOLISM) cohort. Repeated 24-h recall via the online Automated Self-administered Assessment-24 (ASA-24) tool were modelled to reflect usual dietary intakes using the Multiple Source Method. DHQ scores of eight sub-scores: three key nutrients, three food groups and two food preparation practices, were calculated and statistically compared with ASA-24 usual intake data. Principal component analysis of the ASA-24 data was undertaken to understand dietary patterns of the sample. Of the 105 participants, valid 24-h recall data were available for 96 plwMS (n = 66 1 day, n = 30 ≥ 2 day). The median total DHQ score was 84.50 (IQR: 77.04, 91.83) points. The highest absolute correlations were between the DHQ scores and ASA-24 data for cereal (r = 0.395, p < 0.001), fruit and vegetables (r = 0.436, p < 0.001), and total dietary fiber (r = 0.482, p < 0.001). Five dietary patterns emerged from the data explaining 42.12% variance and reflecting exposure of plwMS to the influence of ‘MS diets’. The DHQ appears to be appropriate for screening participants with relapsing-remitting MS. Evidence-based dietary models focus

BACKGROUND: Primary biliary cholangitis (PBC) is a chronic progressive liver disease of unknown aetiology characterised by immune-mediated destruction of small and medium-sized intrahepatic bile ducts. There are few well-established risk factors and epidemiological studies are needed to further evaluate the pathogenesis of the disease. AIM: To evaluate the relationship between alcohol intake, smoking and marijuana use with PBC development. METHODS: We conducted a prevalent case control study of 200 cases and 200 age (within a five year age band) and sex-matched controls, identified from the Victorian PBC prevalence study. We assessed lifetime alcohol intake and smoking behaviour (both tobacco and marijuana) prior to PBC onset and used conditional logistic regression for analyses. RESULTS: Alcohol intake consistently showed a dose-dependent inverse association with case status, and this was most substantial for 21-30 years and 31-40 years (P trend < 0.001). Smoking was associated with PBC, with a stronger association with a longer duration of smoking [e.g., adjusted OR 2.27 (95%CI: 1.12- 4.62) for those who had smoked for 20-35 years]. There was no association between marijuana use and PBC. CONCLUSION: Alcohol appears to have an inverse relationship with PBC. Smoking has been confirmed as an environmental risk factor for PBC. There was no association between marijuana use and PBC.

Limited studies have been conducted to identify and validate multiple sclerosis (MS) genetic loci associated with disability progression. We aimed to identify MS genetic loci associated with worsening of disability over time, and to develop and validate ensemble genetic learning model(s) to identify people with MS (PwMS) at risk of future worsening. We examined associations of 208 previously established MS genetic loci with the risk of worsening of disability; we learned ensemble genetic decision rules and validated the predictions in an external dataset. We found 7 genetic loci (rs7731626: HR 0.92, P = 2.4 × 10-5; rs12211604: HR 1.16, P = 3.2 × 10-7; rs55858457: HR 0.93, P = 3.7 × 10-7; rs10271373: HR 0.90, P = 1.1 × 10-7; rs11256593: HR 1.13, P = 5.1 × 10-57; rs12588969: HR = 1.10, P = 2.1 × 10-10; rs1465697: HR 1.09, P = 1.7 × 10-128) associated with risk worsening of disability; most of which were located near or tagged to 13 genomic regions enriched in peptide hormones and steroids biosynthesis pathways by positional and eQTL mapping. The derived ensembles produced a set of genetic decision rules that can be translated to provide additional prognostic values to existing clinical predictions, with the additional benefit of incorporating relevant genetic information into clinical decision making for PwMS. The present study extends our knowledge of MS progression genetics and provides the basis of future studies regarding the functional significance of the identified loci.

BACKGROUND: One of the major objectives of the Multiple Sclerosis Data Alliance (MSDA) is to enable better discovery of multiple sclerosis (MS) real-world data (RWD). METHODS: We implemented the MSDA Catalogue, which is available worldwide. The current version of the MSDA Catalogue collects descriptive information on governance, purpose, inclusion criteria, procedures for data quality control, and how and which data are collected, including the use of e-health technologies and data on collection of COVID-19 variables. The current cataloguing procedure is performed in several manual steps, securing an effective catalogue. RESULTS: Herein we summarize the status of the MSDA Catalogue as of January 6, 2021. To date, 38 data sources across five continents are included in the MSDA Catalogue. These data sources differ in purpose, maturity, and variables collected, but this landscaping effort shows that there is substantial alignment on some domains. The MSDA Catalogue shows that personal data and basic disease data are the most collected categories of variables, whereas data on fatigue measurements and cognition scales are the least collected in MS registries/cohorts. CONCLUSIONS: The Web-based MSDA Catalogue provides strategic overview and allows authorized end users to browse metadata profiles of data cohorts and data sources. There are many existing and arising RWD sources in MS. Detailed cataloguing of MS RWD is a first and useful step toward reducing the time needed to discover MS RWD sets and promoting collaboration.

BACKGROUND: Diet has been associated with the onset and progression of multiple sclerosis (MS). Multiple diets, varying in recommendations, have been proposed as beneficial to people with MS. The characteristics of those who follow specific diet-programs and the relationships of these diet-programs with diet quality is under-explored. METHODS: Data from the HOLISM study were analysed. Adherence to selected MS-specific diets (Ashton Embry Best Bet, McDougall, Overcoming MS (OMS), Palaeolithic, Swank, and Wahls Elimination) were each queried on 5-point Likert scales, and moderate (≥3/5) and rigorous (≥4/5) adherence defined. Sociodemographic and clinical characteristics of adherence were evaluated by log-binomial regression. Relationships of diet-program adherence with diet quality as measured by Diet Habits Questionnaire were assessed by linear and log-binomial regression, as appropriate, adjusted for age, sex, socioeconomic status (SES), education, and clinically significant fatigue. RESULTS: Forty-nine percent of participants reported at least 12-month adherence to a diet-program for their MS. Of these, 31.3% rigorously adhered to OMS, 4.9% to Swank, 1.7% to Wahls, and <1.5% to other diet-programs. Only adherence to any diet-program, OMS, Wahls, and Swank, were quantitatively assessed. Females, and participants of lower-than-average SES and longer disease duration were less adherent to any diet-program for MS, as well as those with higher disability, more clinically significant fatigue, greater depression risk, and more comorbidities. Those with higher-than-average SES were more adherent, as were those with higher physical and mental quality of life. Similar relationships were seen for OMS diet-program adherence. Adherence to Wahls diet-program was higher among those with progressive MS types and longer disease duration. No associations were found for adherence to Swank diet-program. Overall diet quality was higher among participants following any diet-program, par

BACKGROUND: Fatigue is among the most prevalent symptoms for people with multiple sclerosis (pwMS) and is significantly detrimental to mental health-related (mental) quality of life (QoL). We examined the role of depression and physical activity as mediators in the fatigue-QoL relationship in pwMS. METHODS: Using baseline cross-sectional data from an international cohort of 2,104 pwMS, characteristics of fatigue and mental QoL, measured by Fatigue Severity Scale and MSQOL-54 respectively, were assessed using linear and log-binomial regression. Structural Equation Models (SEM) were used to explore the mediating roles of depression and physical activity between fatigue and mental QoL. RESULTS: The median mental QoL score was 71.9/100. The mean fatigue score was 41.5/63, with 65.6% participants having clinically significant fatigue. In the SEM evaluating depression as a mediator of the fatigue-QoL relationship, mental QoL was 14.72 points lower (95% CI: -16.43 -13.01, p<0.001) in participants with clinically significant fatigue, of which depression accounted for 53.0% (-7.80, 95% CI: -9.03 -6.57, p<0.001). In the SEM evaluating physical activity as a mediator of the fatigue-QoL relationship, mental QoL was 10.89 points lower (95% CI: -12.47, -9.32, p<0.001) in participants with clinically significant fatigue, of which the indirect effect via physical activity accounted for only 4.4% (-0.48, 95% CI: -0.81, -0.14, p=0.005). CONCLUSION: Depression accounted for the majority of the fatigue-mental QoL relationship when modelled as a mediator, while physical activity had only a minor role. Our findings may inform the development of treatments for reducing the impacts of fatigue and improving mental QoL in pwMS.

INTRODUCTION: The prevalence of primary biliary cholangitis (PBC) reported in different countries varies significantly and seems to have a latitudinal gradient with the highest prevalence reported in higher latitudes, as has been observed with other autoimmune diseases. This study aimed to determine whether there is a latitudinal gradient of PBC prevalence in Australia using 2 methods of case ascertainment. METHODS: We investigated the latitudinal variation of PBC prevalence across the states and territories of Australia (latitudinal range 18.0°-42.7°S) using pathology-based (private pathology antimitochondrial antibody results and PBC-specific prescription databases (prescriptions for ursodeoxycholic acid, the only publicly subsidized treatment for this disease). RESULTS: PBC prevalence was significantly positively associated with latitude, and the postcodes in the highest quintile of latitude (encompassing the south coastal areas of the Australian mainland and Tasmania; latitude range -37.75° to -42.72°) had a prevalence estimate that was 1.78 times higher using the pathology-based prevalence estimation than those in the lowest quintile (encompassing tropical and southern Queensland; latitude range -18.02° to -27.59°). Comparing prevalence estimates between states/territories, the result was 2.53 and 2.21 times higher in Tasmania compared with Queensland when using the pathology-based and prescription-based methods, respectively. DISCUSSION: Using 2 different case-ascertainment methods, we have demonstrated that prevalence estimates of PBC vary significantly with latitude in Australia. Further studies are needed to determine whether factors such as variations in ultraviolet radiation exposure and/or vitamin D levels are responsible for this observation and to investigate the latitudinal prevalence of PBC in other populations.

Our inability to reliably predict disease outcomes in multiple sclerosis remains an issue for clinicians and clinical trialists. This study aims to create, from available clinical, genetic and environmental factors; a clinical-environmental-genotypic prognostic index to predict the probability of new relapses and disability worsening. The analyses cohort included prospectively assessed multiple sclerosis cases (N = 253) with 2858 repeated observations measured over 10 years. N = 219 had been diagnosed as relapsing-onset, while N = 34 remained as clinically isolated syndrome by the 10th-year review. Genotype data were available for 199 genetic variants associated with multiple sclerosis risk. Penalized Cox regression models were used to select potential genetic variants and predict risk for relapses and/or worsening of disability. Multivariable Cox regression models with backward elimination were then used to construct clinical-environmental, genetic and clinical-environmental-genotypic prognostic index, respectively. Robust time-course predictions were obtained by Landmarking. To validate our models, Weibull calibration models were used, and the Chi-square statistics, Harrell's C-index and pseudo-R 2 were used to compare models. The predictive performance at diagnosis was evaluated using the Kullback-Leibler and Brier (dynamic) prediction error (reduction) curves. The combined index (clinical-environmental-genotypic) predicted a quadratic time-dynamic disease course in terms of worsening (HR = 2.74, CI: 2.00-3.76; pseudo-R 2=0.64; C-index = 0.76), relapses (HR = 2.16, CI: 1.74-2.68; pseudo-R 2 = 0.91; C-index = 0.85), or both (HR = 3.32, CI: 1.88-5.86; pseudo-R 2 = 0.72; C-index = 0.77). The Kullback-Leibler and Brier curves suggested that for short-term prognosis (≤5 years from diagnosis), the clinical-environmental components of disease were more relevant, whereas the genetic components reduced the prediction errors only in the long-term (≥5 years from diagnosis).

BACKGROUND: Dietary patterns and their association with subsequent clinical course have not been well studied in early multiple sclerosis (MS). OBJECTIVES: To describe dietary patterns in people in 5 years following first clinical demyelination and assess associations with MS conversion and relapse. METHODS: This study included baseline food frequency questionnaire dietary intake (entry to the Ausimmune Study) and 5-year follow-up; iterated principal factor analysis was applied. MS conversion and relapse risks were assessed by Cox proportional hazards models, adjusted for age, sex, study site, education, body mass index (BMI), smoking and omega-3 supplement use. RESULTS: In cases with a first clinical diagnosis of central nervous system (CNS) demyelination, we identified three major dietary patterns, 'Prudent', 'High-Vegetable' and 'Mixed', explaining 43%, 37% and 24% of diet variance in dietary intake, respectively. Fruits, vegetables, fish, wholegrains and nuts loaded highly on the Prudent pattern, starchy vegetables and legumes on the High-Vegetable pattern, and meats and alcohol on the Mixed pattern. Diet factor scores were not associated with MS conversion risk. Those with baseline Prudent scores above the median had significantly lower relapse risk (adjusted hazard ratio = 0.54, 95% confidence interval (CI) 0.37, 0.81) with some evidence of a plateau effect. CONCLUSION: Prudent diet factor score above the median was prospectively associated with lower relapse risk in the 5 years following the first clinical demyelinating event.

Background People with multiple sclerosis (MS) are a vulnerable group for severe COVID-19, particularly those taking immunosuppressive disease-modifying therapies (DMTs). We examined the characteristics of COVID-19 severity in an international sample of people with MS. Methods Data from 12 data-sources in 28 countries were aggregated (sources could include patients from 1-12 countries). Demographic (age, sex), clinical (MS phenotype, disability), and DMT (untreated, alemtuzumab, cladribine, dimethyl-fumarate, glatiramer-acetate, interferon, natalizumab, ocrelizumab, rituximab, siponimod, other) covariates were queried, alongside COVID-19 hospitalisation, admission to ICU, requiring artificial ventilation, and death. Characteristics of outcomes were assessed in patients with suspected/confirmed COVID-19 using multilevel mixed-effects logistic regression, adjusted for age, sex, MS phenotype, and EDSS. Results 657 (28.1%) with suspected and 1,683 (61.9%) with confirmed COVID-19 were analysed. Among suspected+confirmed/confirmed-only COVID-19, 20.9%/26.9% were hospitalised, 5.4%/7.2% were admitted to ICU, 4.1%/5.4% required artificial ventilation, and 3.2%/3.9% died. Older age, progressive MS-phenotype, and higher disability were associated with worse COVID-19 outcomes. Compared to dimethyl-fumarate, ocrelizumab and rituximab were associated with hospitalisation (aOR=1.56,95%CI=1.01-2.41; aOR=2.43,95%CI=1.48-4.02) and ICU admission (aOR=2.30,95%CI=0.98-5.39; aOR=3.93,95%CI=1.56-9.89), though only rituximab was associated with higher risk of artificial ventilation (aOR=4.00,95%CI=1.54-10.39). Importantly, associations persisted on restriction to confirmed COVID-19 cases. No associations were observed between DMTs and death. Conclusions Despite the cross-sectional design of this study, the internal and external consistency of these results with prior studies suggests their use may be a risk factor for more severe COVID-19. Key messages Anti-CD20 DMTs may be assoc

BACKGROUND: No studies have assessed changes in employment survival in multiple sclerosis (MS) populations over recent decades, including the introduction of disease-modifying therapies (DMTs). OBJECTIVES: To evaluate factors associated with leaving employment due to MS; to assess whether the risk of leaving employment has changed over recent decades in Australia, stratified by MS phenotype. METHODS: We included 1240 participants who were working before MS diagnosis. Information on employment status, reasons for leaving employment and year of leaving were collected. Data were analysed using competing risk survival analysis. RESULTS: Males, progressive MS, lower education level and older age at diagnosis were associated with a higher sub-distribution hazard of leaving employment. Compared to the period before 2010, the sub-distribution hazard during 2010-2016 for relapsing-remitting multiple sclerosis (RRMS) was reduced by 43% (sub-distribution hazard ratio (sHR) 0.67, 95% confidence interval (CI): 0.50 to 0.90), while no significant reduction was seen for primary-progressive multiple sclerosis (PPMS) (sHR 1.25, 95% CI: 0.72 to 2.16) or secondary-progressive multiple sclerosis (SPMS) (sHR 1.37, 95% CI: 0.84 to 2.25). CONCLUSION: Males, people with progressive MS and those of lower education level were at higher risk of leaving employment. The differential changed risk of leaving employment between people with different MS phenotype after 2010 coincides with the increased usage of high-efficacy DMTs for RRMS.

Multiple sclerosis (MS), a neuroinflammatory disorder, occurs as non-progressive or progressive phenotypes; both forms present with diverse symptoms that may reduce quality of life (QoL). Adherence to healthy lifestyle behaviors has been associated with higher QoL in people with MS; whether these associations differ based on MS phenotype is unknown. Cross-sectional self-reported observational data from 1108 iConquerMS participants were analysed. Associations between lifestyle behaviors and QoL were assessed by linear regression, and phenotype differences via moderation analyses. Diet, wellness, and physical activity, but not vitamin D or omega-3 supplement use, were associated with QoL. Specifically, certain diet types were negatively associated with QoL in relapsing-remitting MS (RRMS), and positively associated in progressive MS (ProgMS). Participation in wellness activities had mixed associations with QoL in RRMS but was not associated in ProgMS. Physical activity was positively associated with QoL in RRMS and ProgMS. Phenotype differences were observed in diet and wellness with physical QoL, and physical activity with most QoL subdomains. Our findings show lifestyle behaviors are associated with QoL and appear to differ based on MS phenotype. Future studies assessing timing, duration, and adherence of adopting lifestyle behaviors may better inform their role in MS management.

BACKGROUND AND PURPOSE: Several modifiable lifestyle factors have been associated with the onset and health outcomes of multiple sclerosis (MS), including clinically significant fatigue. A combined lifestyle score approach represents one method of assessing their relationship with clinical outcomes. The aim was to examine the association of two lifestyle scores with clinically significant fatigue and change thereof over 2.5 years' follow-up using inverse probability treatment weighting (IPTW). METHODS: Data on sociodemographic, lifestyle, and clinical characteristics surveyed from an international cohort of people with MS at baseline and at 2.5-year follow-up were used. Fatigue was defined by the Fatigue Severity Scale (FSS >5) and healthy lifestyle by the Healthy Lifestyle Index Score (HLIS) and the Smoking, Nutrition, Alcohol Consumption and Physical Activity (SNAP) score. Analyses were by IPTW accounting for age, sex, MS type, disability, treated comorbidity number, immunomodulatory medication use, prescription antifatigue medication use, and ongoing relapse symptoms. RESULTS: In total, 1268 participants completed the FSS at both time points; approximately 62% had fatigue. Using doubly robust IPTW, high (>11/20) HLIS (odds ratio [OR] 0.90, 95% confidence interval [CI] 0.81-0.98) and high (>3/5) SNAP (OR 0.82, 95% CI 0.73-0.90) were each associated with lower risk of fatigue at follow-up. Evaluating change in fatigue, a higher SNAP score was associated with a lower risk of fatigue (OR 0.89, 95% CI 0.80-0.97) but the score for HLIS did not reach statistical significance (OR 0.93, 95% CI 0.85-1.01). CONCLUSION: These results suggest a robust role for key lifestyle factors in preventing clinically significant fatigue and may represent a place for lifestyle modification in improving clinical outcomes in MS.

BACKGROUND AND OBJECTIVES: People with multiple sclerosis (MS) are a vulnerable group for severe coronavirus disease 2019 (COVID-19), particularly those taking immunosuppressive disease-modifying therapies (DMTs). We examined the characteristics of COVID-19 severity in an international sample of people with MS. METHODS: Data from 12 data sources in 28 countries were aggregated (sources could include patients from 1-12 countries). Demographic (age, sex), clinical (MS phenotype, disability), and DMT (untreated, alemtuzumab, cladribine, dimethyl fumarate, glatiramer acetate, interferon, natalizumab, ocrelizumab, rituximab, siponimod, other DMTs) covariates were queried, along with COVID-19 severity outcomes, hospitalization, intensive care unit (ICU) admission, need for artificial ventilation, and death. Characteristics of outcomes were assessed in patients with suspected/confirmed COVID-19 using multilevel mixed-effects logistic regression adjusted for age, sex, MS phenotype, and Expanded Disability Status Scale (EDSS) score. RESULTS: Six hundred fifty-seven (28.1%) with suspected and 1,683 (61.9%) with confirmed COVID-19 were analyzed. Among suspected plus confirmed and confirmed-only COVID-19, 20.9% and 26.9% were hospitalized, 5.4% and 7.2% were admitted to ICU, 4.1% and 5.4% required artificial ventilation, and 3.2% and 3.9% died. Older age, progressive MS phenotype, and higher disability were associated with worse COVID-19 outcomes. Compared to dimethyl fumarate, ocrelizumab and rituximab were associated with hospitalization (adjusted odds ratio [aOR] 1.56, 95% confidence interval [CI] 1.01-2.41; aOR 2.43, 95% CI 1.48-4.02) and ICU admission (aOR 2.30, 95% CI 0.98-5.39; aOR 3.93, 95% CI 1.56-9.89), although only rituximab was associated with higher risk of artificial ventilation (aOR 4.00, 95% CI 1.54-10.39). Compared to pooled other DMTs, ocrelizumab and rituximab were associated with hospitalization (aOR 1.75, 95% CI 1.29-2.38; aOR 2.76, 95% CI 1.87-4.07) and I

People with multiple sclerosis (PwMS) often experience uncertainty and fear about their futures. Partners of PwMS may share their concerns and experience fears about their own futures, limitations on their lives, ability to work, and becoming a carer. For PwMS, modification of lifestyle-related risk factors has been associated with improved health outcomes. For PwMS who attended residential lifestyle modification workshops (RLMW), sustained improved health outcomes have been demonstrated. Whether improved outcomes for PwMS who engage with lifestyle modification translate to improved partner perceptions of the future, is yet to be explored. We explored the perspectives of partners of PwMS who had attended a RLMW and the impact that the person with MS's illness and their engagement with lifestyle modification had on their partners' views of the future. Analysis of 21 semi-structured interviews used a methodology informed by Heidegger's Interpretive Phenomenology. Three themes emerged: 'uncertainty', 'planning for the future' and 'control, empowerment and confidence'. Subthemes included MS and lifestyle modification being a catalyst for positive change; developing a sense of control and empowerment; and hope, optimism and positivity. Lifestyle modification may provide benefits, not only to PwMS, but also to their partners, and should be considered part of mainstream management of MS.

Neurological disorders pose a substantial health and economic burden to the individual and society, necessitating strategies for effective prevention and disease management. Lifestyle behaviours play a role in risk and management of some neurological disorders; however, overlap between lifestyle behaviours across disorders has not been well explored. We used log-binomial regression to assess associations of selected lifestyle behaviours in community-dwelling Australians (n = 192,091), some of whom self-reported Alzheimer's disease (AD), motor neurone disease (MND), multiple sclerosis (MS), Parkinson's disease (PD) or stroke. Of six lifestyle behaviours, undertaking physical activity was inversely associated with the presence of all neurological disorders except PD. Smoking was positively associated with MND and stroke, and inversely associated with PD. Participants with AD and stroke shared inverse associations with cognitive engagement, face-to-face social interaction and stress-reducing activities, and MS was positively associated with online social interaction and stress-reduction activities. Of eleven food and beverage consumption categories, no associations were seen in MND, ten categories were inversely associated with people with AD or stroke, and six of these with PD. Vegetable and soft drink consumption were associated with MS. Further detailed assessment of commonalities in lifestyle behaviours across neurological disorders may inform potential strategies for risk reduction across disorders.

Background: Dietary patterns and their association with subsequent clinical course have not been well studied in early multiple sclerosis (MS). Objectives: To describe dietary patterns in people in 5 years following first clinical demyelination and assess associations with MS conversion and relapse. Methods: This study included baseline food frequency questionnaire dietary intake (entry to the Ausimmune Study) and 5-year follow-up; iterated principal factor analysis was applied. MS conversion and relapse risks were assessed by Cox proportional hazards models, adjusted for age, sex, study site, education, body mass index (BMI), smoking and omega-3 supplement use. Results: In cases with a first clinical diagnosis of central nervous system (CNS) demyelination, we identified three major dietary patterns, ‘Prudent’, ‘High-Vegetable’ and ‘Mixed’, explaining 43%, 37% and 24% of diet variance in dietary intake, respectively. Fruits, vegetables, fish, wholegrains and nuts loaded highly on the Prudent pattern, starchy vegetables and legumes on the High-Vegetable pattern, and meats and alcohol on the Mixed pattern. Diet factor scores were not associated with MS conversion risk. Those with baseline Prudent scores above the median had significantly lower relapse risk (adjusted hazard ratio = 0.54, 95% confidence interval (CI) 0.37, 0.81) with some evidence of a plateau effect. Conclusion: Prudent diet factor score above the median was prospectively associated with lower relapse risk in the 5 years following the first clinical demyelinating event.

BACKGROUND: The potential relationship between perceived cognitive impairment (PCI) and sexual dysfunction in multiple sclerosis (MS) has not been studied. OBJECTIVES: To explore the relationship between cognitive impairment and sexual dysfunction over 2.5 years in people with MS. METHODS: Data were derived from the Health Outcomes and Lifestyle In a Sample of people with Multiple sclerosis (HOLISM) international cohort over 2.5 years' follow-up. Cognitive function and sexual function were assessed by sub-scores of the MS Quality of Life-54. The impact of perceived cognitive impairment on sexual dysfunction was assessed by calculating prevalence ratios (PR) and relative risks (RR) with 95% confidence intervals (CI) using log-binomial regression models. RESULTS: 1958 participants were included at baseline, of whom 555 without perceived cognitive impairment at baseline comprised the longitudinal cohort. The prevalence of perceived cognitive impairment at baseline was 45.6%. At baseline, cognitive impairment was associated with increased frequency of self-reported sexual dysfunction (aPR=1.32, 95% CI: 1.17-1.48). Among the sample without sexual dysfunction at baseline, incident sexual dysfunction was more common among participants with persistent (aRR=1.61, 95% CI: 1.06-3.18) and newly reported cognitive impairment (aRR=1.89, 95% CI: 1.14-3.14). CONCLUSION: Results suggest PCI may be an independent risk factor for sexual dysfunction in PwMS, which may represent an additional dimension whereby MS may adversely affect quality of life.

BACKGROUND: We need high-quality data to assess the determinants for COVID-19 severity in people with MS (PwMS). Several studies have recently emerged but there is great benefit in aligning data collection efforts at a global scale. OBJECTIVES: Our mission is to scale-up COVID-19 data collection efforts and provide the MS community with data-driven insights as soon as possible. METHODS: Numerous stakeholders were brought together. Small dedicated interdisciplinary task forces were created to speed-up the formulation of the study design and work plan. First step was to agree upon a COVID-19 MS core data set. Second, we worked on providing a user-friendly and rapid pipeline to share COVID-19 data at a global scale. RESULTS: The COVID-19 MS core data set was agreed within 48 hours. To date, 23 data collection partners are involved and the first data imports have been performed successfully. Data processing and analysis is an on-going process. CONCLUSIONS: We reached a consensus on a core data set and established data sharing processes with multiple partners to address an urgent need for information to guide clinical practice. First results show that partners are motivated to share data to attain the ultimate joint goal: better understand the effect of COVID-19 in PwMS.