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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., Competing Interests: Declaration of competing interest No conflicts of interest to disclose., (Copyright © 2024. Published by Elsevier B.V.)

Background: People diagnosed with multiple sclerosis (MS) often seek to modify their diet guided by online advice, however this advice may not align with national dietary guidelines. The aim of this study was to simulate an online search for dietary advice conducted by a person with MS and evaluate the content. It was hypothesised that a variety of eating patterns are promoted for MS online and these dietary approaches can be contradictory., Methods: An online search was simulated using Google Trends-informed search terms and Google and Bing search engines. URLs were extracted using R. Nutrition data were extracted including recommendations for diets, foods, supplements, and health professional consultation. Statistical analyses were conducted using R., Results: 73 URLs from 49 websites were extracted, with only 14 results common to both search engines. Dietary recommendations included overall eating patterns (58 webpages, 79%), individual foods (55 webpages, 75%), and supplements (33 webpages, 45%). The most promoted eating pattern for MS was a balanced diet (33 recommendations, 48%), more likely by nonprofit organisations and health information websites (14 and 17 recommendations, 100% and 89%); lifestyle program websites were more likely to recommend restrictive diets (19 recommendations, 100%) (p<0.001). 52% pages advised consulting a health professional, most often a doctor or dietitian., Conclusion: A balanced diet is the most recommended eating pattern for MS online, though advice promoting restrictive diets persists., Competing Interests: Declaration of competing interest YP has received research grants from Multiple Sclerosis Research Australia, a fellowship from Multiple Sclerosis Australia, is a reviewer for a range of multiple sclerosis scientific journals, and has received honoraria from Multiple Sclerosis Research Australia. YP is also a person living with multiple sclerosis., (Copyright © 2024. Published by Elsevier B.V.)

Background: Although many people with MS (pwMS) modify their diet after diagnosis, there is still no consensus on dietary recommendations for pwMS. A number of observational studies have explored associations of diet and MS progression, but no studies have systematically reviewed the evidence. This systematic review aimed to provide an objective synthesis of the evidence for associations between diet and MS progression, including symptoms and clinical outcomes from observational studies., Methods: We performed a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Electronic database searches were performed for studies completed up to 26 July 2023 using PubMed (Medline), Web of Science, CINAHL, Embase (Ovid), and Scopus, followed by citation and reference list checking. We included studies using diet quality scores or dietary indices. Studies assessing individual foods, nutrients, or dietary supplements were excluded. We used the Newcastle-Ottawa Scale to assess the risk of bias of included studies., Results: Thirty-two studies met the inclusion criteria. Of these, 20 were cross-sectional and 12 prospective. The most frequent outcomes assessed were disability (n = 19), quality of life (n = 12), fatigue (n = 12), depression (n = 9), relapse (n = 8), anxiety (n = 3), and magnetic resonance imaging (MRI) outcomes (n = 4). Based on prospective studies, this review suggests that diet might be associated with quality of life and disability. There were also potential effects of higher diet quality scores on improved fatigue, disability, depression, anxiety, and MRI outcomes but more evidence is needed from prospective studies., Conclusions: Observational studies show some evidence for an association between diet and MS symptoms, particularly quality of life and disability. However, the impact of diet on other MS outcomes remains inconclusive. Ultimately, our findings suggest more evidence is needed from prospective studies and well-designed tailored intervention studies to confirm associations., Competing Interests: Declaration of competing interest SSY, with eight studies, JCR, with two studies, and LJB, with one study, were co-authors of publications included in this review. However, these co-authors were not involved in the search for relevant articles, article selection or data extraction. We, the authors of the article “Associations between diet and disease progression and symptomatology in multiple sclerosis: A systematic review of observational studies”, hereby declare that we have no conflicts of interest to disclose for the submission of this article to the Multiple Sclerosis and Related Disorders journal., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of competing interest GJ is the author of “Overcoming Multiple Sclerosis” and co-editor of “Overcoming Multiple Sclerosis Handbook. Roadmap to Good Health”. SN is a co-editor of “Overcoming Multiple Sclerosis Handbook. Roadmap to Good Health”. GJ and SN receive royalties from authored publications, have previously received remuneration from facilitation of Overcoming MS residential workshops. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Background: Multiple sclerosis is characterised by acute and chronic inflammation in the CNS. Diet may influence inflammation, and therefore MS outcomes., Objective: To determine whether the Dietary Inflammatory Index (DII ®) ) is associated with depression, anxiety, and fatigue in a prospective cohort of people with MS., Methods: People with a first clinical diagnosis of demyelination were followed over 10 years (n=223). DII and energy-adjusted DII (E-DII TM ) scores were calculated from the dietary intake in the preceding 12 months measured by food frequency questionnaire. Depression and anxiety were assessed by the Hospital Anxiety and Depression Scale (HADS-A and HADS-D, respectively), and fatigue by the Fatigue Severity Scale., Results: A higher E-DII score was associated with higher levels of depression and anxiety five years later (e.g., highest vs lowest E-DII quartile, HADS-D score: β=2.23, 95%CI=0.98,3.48, p<0.001; HADS-A score: β=1.90, 95%CI=0.59,3.21, p<0.001). A cumulative E-DII score was associated with depression (p<0.01) and anxiety (p=0.05) at the 10-year review. No associations were seen for fatigue., Conclusion: Our findings suggest that, in people with MS, a more pro-inflammatory diet may long-term adverse impact on depression and anxiety, but not fatigue., Competing Interests: Declaration of competing interest Dr. James R. Hébert owns controlling interest in Connecting Health Innovations LLC (CHI), a company that has licensed the right to his invention of the dietary inflammatory index (DII®) from the University of South Carolina in order to develop computer and smart phone applications for patient counselling and dietary intervention in clinical settings. Dr. Nitin Shivappa is an employee of CHI., (Copyright © 2024. Published by Elsevier B.V.)

Multiple sclerosis (MS) is a chronic inflammatory and autoimmune neurodegenerative disease characterized by the destruction of myelin in the central nervous system, leading to significant health and quality of life burdens for patients. MS is most prevalent in younger individuals aged 20-40, a critical period when many patients hope to establish relationships and start families. While neurological disability, such as fatigue, sensory dysfunction, spasticity, and cognitive dysfunction, have been greatly improved with the advances in managing MS, physicians are frequently confronted with sexual and reproductive problems among younger male people with MS (PwMS). These issues mainly include erectile dysfunction, ejaculatory disorders, reduced libido, decreased sperm quality, and impaired male fertility. Despite recent studies indicating that MS negatively impacts the sexuality and fertility of male PwMS, these issues have not received sufficient attention. Genetic factors, autoimmunity, chronic inflammation, psychological factors, and the use of drugs may contribute to sexual/reproductive dysfunction in PwMS. However, like the overall understanding of MS pathophysiology, the complete mechanisms of its development remain unclear. In this study, we review the existing literature to summarize the range of sexual and reproductive issues unique to males with MS, explore potential underlying mechanisms, and aim to improve these issues in male PwMS. By shedding light on this overlooked aspect of MS, we hope to enhance the care and well-being of male PwMS facing these challenges., Competing Interests: Declaration of Competing Interest All authors declare that they have no competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The influence of diet quality on multiple sclerosis (MS) progression or inflammatory activity is not well understood., Methods: Study participants with MS from the AusLong cohort, were followed annually (10 years, n = 223 post-onset). At baseline, 5 and 10-year reviews, indices of dietary quality - the Australian Recommended Food Score (ARFS) and Diet Quality Tracker (DQT) - were calculated from self-reported dietary intake data of the preceding 12 months (Food Frequency Questionnaire, Dietary Questionnaire for Epidemiological Studies v2). Associations were examined between measures of dietary quality with measures of MS progression and inflammatory activity hazard of relapse, annualised disability progression (Expanded Disability Status Scale, EDSS) and Magnetic Resonance Imaging (MRI) outcomes. MRI outcomes included fluid-attenuated inversion recovery (FLAIR, T2 MRI) lesion volume and black hole volume (T1 MRI) in the juxtacortical, periventricular, and infratentorial regions of the brain, as well as total calculated from the sum of the three regions., Results: A higher diet quality (at least with the ARFS) was associated with lower FLAIR lesion volume in the periventricular region only (highest vs lowest quartile: β=-1.89,95%CI=-3.64, -0.13, p = 0.04, periventricular FLAIR region median (IQR) for 5-year review: 4.41 (6.06) and 10-year review: 4.68 (7.27)). Associations with black hole lesion volume, hazard of relapse, and annualised EDSS progression, lacked in significance and/or dose-dependency., Conclusion: We found evidence that diet quality may have a role in modulating one aspect of MS inflammatory activity (periventricular MRI FLAIR lesion volume), but not other MRI and clinical outcome measures., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest regarding the publication of this manuscript. This research was conducted in an ethical and responsible manner, and all potential conflicts of interest have been disclosed., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Townsville (population=195,564, latitude=19.3°S) is the largest city in the Northern Queensland region of Australia, an area previously defined as a low/medium-prevalence zone for multiple sclerosis (MS). However, the epidemiology of MS in this region since 1981 is unknown., Aims: To assess the 2012 to 2022 epidemiology of MS in Townsville., Methods: Demographic/clinical data extracted from medical records of MS cases identified by public and private clinicians. Prevalence, and incidence and mortality rates estimated for 2012 and 2022 and age-standardised to the 2022 Australian population. Differences in estimates assessed by Poisson regression., Results: Females and relapsing-remitting MS comprised most cases. The 2012 prevalence was 45.0/100,000 (50.4/100,000 age-standardised, F/M sex ratio=2.0). Prevalence increased by 188% in 2022, with a crude prevalence of 86.9/100,000 (91.7/100,000 age-standardised, F/M sex ratio=2.7). 2012-22 MS onset incidence rate was 3.8/100,000 person-years (age-standardised 3.5/100,000, F/M sex ratio=2.7). Mean age increased from 49.4 to 57.3 years. Age-standardised mortality rate was 0.9/100,000 person-years, with standardised mortality ratio=1.0., Discussion: These results show that Townsville is a high-frequency region for MS, with prevalence and incidence on par with that seen at higher latitudes in Australia. These results have implications for clinical practice in the region and for organisational resource allocation., Competing Interests: Declaration of Competing Interest Steve Simpson-Yap: nothing to disclose. Duncan Maddox: nothing to disclose. Jeanette Reece: nothing to disclose. Jeannette Lechner-Scott: received travel compensation from Novartis, Biogen, Roche and Merck. Her institution receives the honoraria for talks and advisory board commitment as well as research grants from Biogen, Merck, Roche, TEVA and Novartis. Cameron Shaw: served on scientific advisory boards for Merck, Genzyme, Almirall, and Biogen; received honoraria and travel grants from Sanofi Aventis, Novartis, Biogen, Merck, Genzyme and Teva. Bruce Taylor: received funding for travel and speaker honoraria from Bayer Schering Pharma, CSL Australia, Biogen and Novartis, and has served on advisory boards for Biogen, Novartis, Roche and CSL Australia. Tomas Kalincik: served on scientific advisory boards for MS International Federation and World Health organisation, BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Merck and Biogen, steering committee for Brain Atrophy Initiative by Sanofi Genzyme, received conference travel support and/or speaker honoraria from WebMD Global, Eisai, Novartis, Biogen, Roche, Sanofi-Genzyme, Teva, BioCSL and Merck and received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene and Merck. Anneke van der Walt: served on advisory boards for Novartis, Biogen, Merck and Roche and NervGen. She received unrestricted research grants from Novartis, Biogen, Merck and Roche. She is currently a co-Principal investigator on a co-sponsored observational study with Roche, evaluating a Roche-developed smartphone app, Floodlight-MS. She has received speaker's honoraria and travel support from Novartis, Roche, Biogen and Merck. She serves as the Chief operating Officer of the MSBase Foundation (not for profit). Her primary research support is from the National Health and Medical Research Council of Australia and MS Research Australia. Mike Boggild: has received travel sponsorship and honoraria from Sanofi-Genzyme, Teva, Novartis, Biogen Idec and Roche., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The link between tobacco smoking and Multiple Sclerosis (MS) onset and progression is well-established. While clinical levels of depression and anxiety are highly prevalent in people living with MS (plwMS), and both are recognized as common MS-related symptoms, the relationships between smoking behavior and depression and anxiety are unclear. This systematic review aimed to synthesize evidence on the relationships between current-smoking and former-smoking and depression and anxiety in plwMS., Methods: Systematic review of all studies investigating associations between tobacco smoking and depression and anxiety in plwMS was conducted. Relevant studies published before 26 April 2022 were identified by searching seven databases; MEDLINE® (Ovid and PubMed), Embase, CINAHL®, Cochrane Library and PsycInfo), and citation and reference list checking. Joanna Briggs Institute Critical Appraisal Checklists for respective study designs assessed the risk of bias., Results: Thirteen publications reporting on 12 studies met study inclusion criteria. Nine of 12 studies examining current-smoking and depression in plwMS identified a positive association. Four prospective studies provided evidence supporting a causal smoking-depression relationship, with 1.3-2.3-fold higher depression prevalence found in current-smokers than non-smokers. Three cross-sectional studies found no smoking-depression association. Four of five included studies found current-smoking was associated with anxiety, with three prospective studies indicating anxiety prevalence was around 20% higher in current-smokers. Former-smoking was associated with increased prevalence of depression, but not anxiety., Conclusion: We provide strong evidence for increased depression prevalence in plwMS who are either current-smokers or former-smokers. However, only current-smoking was associated with increased prevalence of anxiety., Competing Interests: Declaration of Competing Interest SN is a co-editor of Overcoming Multiple Sclerosis Handbook: Roadmap to Good Health. SN is a facilitator of Overcoming MS educational workshops for people with MS., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Diet-dependent acid-base load has been associated with worsening in mental health, but to date no study has examined this in people with multiple sclerosis (PwMS). We examined the association between potential renal acid load (PRAL) and net endogenous acid production (NEAP) scores and depression, anxiety, and fatigue in PwMS., Methods: Participants with a first clinical diagnosis of CNS demyelination were followed prospectively as part of the AusLong Study (aged 18-59 years at cohort entry). At baseline, 5- and 10-year reviews, PRAL and NEAP scores were calculated using dietary intake in the preceding 12 months calculated from a food frequency questionnaire. At 5- and 10-year reviews, the Hospital Anxiety and Depression Scale was used to assess depression and anxiety, and the Fatigue Severity Scale assessed fatigue., Results: Higher PRAL and NEAP scores were associated with increased subsequent absolute value and change in HADS depression scores over five years' follow-up (e.g., highest vs lowest PRAL quartile, 5-year change in HADS-D score: β=+3.01, 95%CI= 1.54, 4.48, p<0.001). The level of depression at the 10-year review was determined by both the baseline dietary acid scores and baseline-5-year changes in dietary acid scores (e.g., PRAL change from baseline to 5-year review, 10-year review HADS-D score: β=+0.09, 95%CI= 0.03, 0.15, p<0.001, NEAP change from baseline to 5-year review, 10-year review HADS-D score: β=+0.07, 95%CI= 0.01, 0.14, p=0.03). Some associations were observed with anxiety and fatigue but were much weaker and less consistent., Conclusion: Our findings indicate that a higher dietary acid load potentially has a long-term influence on the level of depression in PwMS. The evidence is less convincing for anxiety and fatigue., Competing Interests: Declaration of Competing Interest On behalf of all authors, the corresponding author states that there is no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Many people with multiple sclerosis (MS) modify their dietary intake post diagnosis, but there is little evidence that dietary modifications influence MS outcomes., Methods: People with a first clinical diagnosis of central nervous system demyelination were followed annually for 10 years. Depression, anxiety, and fatigue were assessed at the 5-and 10-year reviews using the Hospital Anxiety and Depression Scale and Fatigue Severity Scale, respectively. Dietary intake in the preceding 12 months was assessed at baseline, and 5-and 10-year reviews using a food frequency questionnaire. We used the Australian Recommended Food Score (ARFS) and the Diet Quality Tracker (DQT) to assess diet quality., Results: A higher diet quality in the previous 12 months using the ARFS score, but not the DQT, was associated with lower levels of depression (e.g., highest vs lowest quartile: β=-1.35,95%CI=-2.44,-0.26,p=0.01), but neither score was associated with anxiety or fatigue. After assessing diet quality prospectively with outcomes five years later, we found that higher ARFS score, but not DQT score, was associated with lower levels of subsequent anxiety and depression (highest vs lowest quartile; Anxiety: β=-1.61,95%CI=-2.76,-0.46,p=0.01, Depression: β=-1.25,95%CI=-2.44,-0.07,p=0.04), but not fatigue. No associations were observed between diet quality and subsequent change in depression and anxiety over five years, although an association was observed between diet quality and change in fatigue (e.g., highest vs lowest DQT quartile: β=-1.06,95%CI=-1.92,-0.21,p=0.02). When examining the cumulative effect of diet quality across the study period with our 10-year outcomes, only the cumulative DQT score was associated with depression but not anxiety or fatigue., Conclusion: We found significant inverse associations between diet quality and depression and anxiety, but the effect sizes were modest and there was a lack of consistency between the two diet quality measures (ARFS and DQT). A diet measure that correlates with diet quality might underlie our observed associations., (Copyright © 2022. Published by Elsevier B.V.)

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., (Copyright © 2022. Published by Elsevier B.V.)

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., (Copyright © 2022. Published by Elsevier B.V.)

Background: Infections with Epstein-Barr virus (EBV) and human herpesvirus-6 (HHV-6) have been implicated in multiple sclerosis (MS) onset but little work has studied their relationships in early disease., Objective: Evaluate associations between markers of EBV and HHV-6 infection/reactivation and MS conversion, relapse and EDSS/MSSS amongst 205 CIS participants with EBV/HHV-6 data followed over 5 years., Method: Baseline serological and viral load measures of EBV and HHV-6 exposure/reactivation were measured and infectious mononucleosis (IM) history recorded. Conversion to MS and relapses were assessed annually, and EDSS/MSSS measured at 5-year review. Determinants of MS conversion and relapse assessed by Cox regression, and disability progression by linear regression., Results: IM history showed a strong positive trend with higher relapse risk (aHR=1.45,95%CI=0.97-2.16) but was not associated with MS conversion (aHR=0.92,95%CI=0.57-1.48). Anti-HHV-6 IgG titre>40 also showed strong positive trends with higher relapse (aHR=1.61,95%CI=0.99-2.63) and MS conversion risks (aHR=1.48,95%CI=0.89-2.46). Anti-HHV-6 IgG titre≥640 was significantly associated with higher MSSS (0.15(95%CI=0.00,0.30) and also showed a strong positive trend with higher EDSS 0.10(95%CI=-0.02,0.21). HHV-6 DNA detection showed strong positive trends with 83%(95%CI=-6-357) and 77%(95%CI=-4-328) higher MS conversion and relapse risk. Anti-EBV-EA-D IgG titre was associated with a lower annualised disability progression by EDSS (p trend =0.037) and also showed strong positive trend with higher MSSS (p trend =0.053). No associations were seen for other serological or viral load markers., Conclusion: Overall, our data provides evidence that higher HHV-6 IgG was associated with increased risk of MS conversion and relapse but of borderline significance, and greater annualised disability progression, while that for EBV was more limited., (Copyright © 2022 Elsevier B.V. All rights reserved.)

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, particularly OMS and Swank, but not Wahls., Conclusion: Greater adherence to MS specific diets was associated with higher SES, and higher quality of life. Following any diet program was associated with higher overall diet quality, with those adhering to the OMS diet having the highest diet quality. These results may inform health professionals in providing guidance to patients regarding diet in MS., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Sun exposure and vitamin D, including intake and serum levels, have been associated with reduced risk of MS onset and less progression and may affect quality of life (QoL). We investigated the prospective relationship of these factors with QoL from baseline to 2.5 years' follow-up, in an international cohort of people with MS., Methods: Data derive from the HOLISM international cohort. Sun exposure and vitamin D supplement use were queried at both timepoints. QoL was assessed by MSQOL-54, estimating physical and mental health QoL composite scores. Characteristics of QoL were assessed by linear regression, adjusted for age, sex, socioeconomic status, treated comorbidity number, MS type, disability, clinically significant fatigue, prescription antidepressant medication use, and ongoing relapse symptoms, and baseline QoL score, as appropriate, estimating adjusted coefficients (aβ)., Results: At 2.5-year review, QoL scores were higher among those reporting taking vitamin D supplements (physical: aβ=3.58, 95%CI=1.35-5.80; mental: aβ=3.08, 95%CI=0.72-5.44), particularly average daily dose over 5,000IU/d. Baseline-reported vitamin D supplementation was associated with greater increase in physical (aβ=1.02, 95%CI=0.22-1.81), but not mental QoL (aβ=0.11, 95%CI=-1.00-1.23). Sun exposure was cross-sectionally associated with higher QoL scores at follow-up but was not associated with change in QoL., Conclusions: Self-reported vitamin D supplement use was cross-sectionally associated with higher physical and mental QoL, but prospectively only with increased physical QoL., (Copyright © 2021. Published by Elsevier B.V.)

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., (Copyright © 2020. Published by Elsevier B.V.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)