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

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

Low intensity repetitive transcranial magnetic stimulation enhances remyelination by newborn and surviving oligodendrocytes in the cuprizone model of toxic demyelination.

In people with multiple sclerosis (MS), newborn and surviving oligodendrocytes (OLs) can contribute to remyelination, however, current therapies are unable to enhance or sustain endogenous repair. Low intensity repetitive transcranial magnetic stimulation (LI-rTMS), delivered as an intermittent theta burst stimulation (iTBS), increases the survival and maturation of newborn OLs in the healthy adult mouse cortex, but it is unclear whether LI-rTMS can promote remyelination. To examine this possibility, we fluorescently labelled oligodendrocyte progenitor cells (OPCs; Pdgfrα-CreER transgenic mice) or mature OLs (Plp-CreER transgenic mice) in the adult mouse brain and traced the fate of each cell population over time. Daily sessions of iTBS (600 pulses; 120 mT), delivered during cuprizone (CPZ) feeding, did not alter new or pre-existing OL survival but increased the number of myelin internodes elaborated by new OLs in the primary motor cortex (M1). This resulted in each new M1 OL producing ~ 471 µm more myelin. When LI-rTMS was delivered after CPZ withdrawal (during remyelination), it significantly increased the length of the internodes elaborated by new M1 and callosal OLs, increased the number of surviving OLs that supported internodes in the corpus callosum (CC), and increased the proportion of axons that were myelinated. The ability of LI-rTMS to modify cortical neuronal activity and the behaviour of new and surviving OLs, suggests that it may be a suitable adjunct intervention to enhance remyelination in people with MS.

The immune cell transcriptome is modulated by vitamin D3 supplementation in people with a first demyelinating event participating in a randomized placebo-controlled trial.

Vitamin D deficiency is a risk factor for developing multiple sclerosis. The PrevANZ trial was conducted to determine if vitamin D3 supplementation can prevent recurrent disease activity in people with a first demyelinating event. As a sub-study of this trial, we investigated the effect of supplementation on peripheral immune cell gene expression. Participants were randomized to 1000, 5000 or 10,000 international units daily of vitamin D3 or placebo. Peripheral blood was collected at baseline and 12 weeks and sent for ribonucleic acid sequencing. Datasets from 55 participants were included. Gene expression was modulated by high dose supplementation. Antigen presentation and viral response pathways were upregulated. Oxidative phosphorylation and immune signaling pathways, including tumor necrosis factor-alpha and interleukin-17 signaling, were downregulated. Overall, vitamin D3 supplementation for 12 weeks modulated the peripheral immune cell transcriptome with induction of anti-inflammatory gene expression profiles. Our results support a dose-dependent effect of vitamin D3 supplementation on immune gene expression.

CVOT Summit Report 2023: new cardiovascular, kidney, and metabolic outcomes.

The 9th Cardiovascular Outcome Trial (CVOT) Summit: Congress on Cardiovascular, Kidney, and Metabolic Outcomes was held virtually on November 30-December 1, 2023. This reference congress served as a platform for in-depth discussions and exchange on recently completed outcomes trials including dapagliflozin (DAPA-MI), semaglutide (SELECT and STEP-HFpEF) and bempedoic acid (CLEAR Outcomes), and the advances they represent in reducing the risk of major adverse cardiovascular events (MACE), improving metabolic outcomes, and treating obesity-related heart failure with preserved ejection fraction (HFpEF). A broad audience of endocrinologists, diabetologists, cardiologists, nephrologists and primary care physicians participated in online discussions on guideline updates for the management of cardiovascular disease (CVD) in diabetes, heart failure (HF) and chronic kidney disease (CKD); advances in the management of type 1 diabetes (T1D) and its comorbidities; advances in the management of CKD with SGLT2 inhibitors and non-steroidal mineralocorticoid receptor antagonists (nsMRAs); and advances in the treatment of obesity with GLP-1 and dual GIP/GLP-1 receptor agonists. The association of diabetes and obesity with nonalcoholic steatohepatitis (NASH; metabolic dysfunction-associated steatohepatitis, MASH) and cancer and possible treatments for these complications were also explored. It is generally assumed that treatment of chronic diseases is equally effective for all patients. However, as discussed at the Summit, this assumption may not be true. Therefore, it is important to enroll patients from diverse racial and ethnic groups in clinical trials and to analyze patient-reported outcomes to assess treatment efficacy, and to develop innovative approaches to tailor medications to those who benefit most with minimal side effects. Other keys to a successful management of diabetes and comorbidities, including dementia, entail the use of continuous glucose monitoring (CGM) technology and the implementation of appropriate patient-physician communication strategies. The 10th Cardiovascular Outcome Trial Summit will be held virtually on December 5-6, 2024 ( http://www.cvot.org ).

Exploring the cost-effectiveness of EBV vaccination to prevent multiple sclerosis in an Australian setting.

BACKGROUND: Increasing evidence suggests the potential of Epstein-Barr virus (EBV) vaccination in preventing multiple sclerosis (MS). We aimed to explore the cost-effectiveness of a hypothetical EBV vaccination to prevent MS in an Australian setting. METHODS: A five-state Markov model was developed to simulate the incidence and subsequent progression of MS in a general Australian population. The model inputs were derived from published Australian sources. Hypothetical vaccination costs, efficacy and strategies were derived from literature. Total lifetime costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) were estimated for two hypothetical prevention strategies versus no prevention from the societal and health system payer perspectives. Costs and QALYs were discounted at 5% annually. One-way, two-way and probabilistic sensitivity analyses were performed. RESULTS: From societal perspective, EBV vaccination targeted at aged 0 and aged 12 both dominated no prevention (ie, cost saving and increasing QALYs). However, vaccinating at age 12 was more cost-effective (total lifetime costs reduced by $A452/person, QALYs gained=0.007, ICER=-$A64 571/QALY gained) than vaccinating at age 0 (total lifetime costs reduced by $A40/person, QALYs gained=0.003, ICER=-$A13 333/QALY gained). The probabilities of being cost-effective under $A50 000/QALY gained threshold for vaccinating at ages 0 and 12 were 66% and 90%, respectively. From health system payer perspective, the EBV vaccination was cost-effective at age 12 only. Sensitivity analyses demonstrated the cost-effectiveness of EBV vaccination to prevent MS under a wide range of plausible scenarios. CONCLUSIONS: MS prevention using future EBV vaccinations, particularly targeted at adolescence population, is highly likely to be cost-effective.

Long-term disability trajectories in multiple sclerosis: a group-based trajectory analysis of the AusLong cohort.

BACKGROUND: Previous natural history studies highlighted a consistent heterogeneity of disability trajectories among individuals with primary or secondary progressive multiple sclerosis (MS). However, evidence on disability progression in relapsing onset MS is scarce.The aim of this study was to investigate heterogeneity in disability accumulation over 10 years following a first clinical diagnosis of central nervous system demyelination (FCD) and identify genetic, demographic, environmental and clinical factors associated with these trajectories. METHODS: We used group-based trajectory models to measure heterogeneity in disability trajectories based on the Expanded Disability Status Scale (EDSS) in a prospectively assessed cohort of 263 participants. To capture sustained neurological impairments and avoid issues related to significant changes in EDSS associated with relapse, we did not consider EDSS points recorded within 3 months of a relapse. RESULTS: We identified three distinct and clinically meaningful disability trajectories: No/minimal, moderate and severe. Those in the no/minimal disability trajectory showed no appreciable progression of disability (median EDSS∼1 at 10-year review) while those in the moderate and severe disability trajectories experienced disability worsening (median time to reach EDSS 4 was 9 and 7 years, respectively). Compared with the no/minimal disability trajectory, those with older age, a higher number of relapses within the first 5 years post-FCD, and a higher number of comorbidities at baseline were more likely to be in the worse disability trajectory. Surprisingly, baseline MRI and anatomical site of initial symptoms did not influence long-term outcomes. CONCLUSIONS: Those at higher risk of faster MS disability progression can be identified based on their early clinical characteristics with potential therapeutic implications for early intervention and treatment escalation.

Changes in Partner-Seeking and Sexual Behavior Among US Adults During the First 2 Years of the COVID-19 Pandemic.

BACKGROUND: The COVID-19 pandemic may have influenced partner-seeking and sexual behaviors of adults. METHODS: We examined cross-sectional survey data collected at the end of the first year (n = 1161) and second year (n = 1233) of the COVID-19 pandemic by the National Opinion Research Center's nationally representative, probability-based AmeriSpeak panel. Data were analyzed to (1) quantify behavioral changes across pandemic years, (2) examine changes of in-person dating prevalence during year 2, and (3) assess risk perception for acquiring COVID-19 or HIV/STIs through new partnerships during year 2. Weighted percentages were calculated for responses; univariate relationships between demographic characteristics and outcomes were assessed. RESULTS: Prevalence of new partners for dating remained stable across pandemic years (year 1: n = 1157 [10%]; year 2: n = 1225 [12%]). The prevalence of in-person sex with new partners was also stable (year 1: n = 1157 [7%], year 2: n = 1225 [6%]), marking a decline from a prepandemic estimate (2015-2016: 16%). Partner-seeking experiences varied by age and sexual identity in both years, and by race/ethnicity during year 2. Reports of in-person dating fluctuated throughout year 2, without clear relationship to viral variants. Respondents who met new partners in person during year 2 generally reported greater concern and preparedness for reducing risks associated with HIV/STIs than COVID-19. CONCLUSIONS: The prevalence of US adults seeking new partners for dating or sex remained stable across pandemic years. During future public health emergencies, public health officials are encouraged to offer guidance for reducing disease risks in partnerships, while emphasizing sexual health and providing tailored messaging for persons more susceptible to infection.

The disease-modifying therapy utilisation and cost trend for multiple sclerosis in Australia between 2013 and 2022.

BACKGROUND: The MS disease-modifying therapies (DMTs) prescribing landscape in Australia have changed over time. OBJECTIVES: This study evaluated the utilisation and cost trends of MS-related DMTs in Australia over 10 years and investigated differences between States/Territories. METHODS: The prescription and costs of 16 DMTs were extracted from the Pharmaceutical Benefits Scheme for 2013-2022. Descriptive approaches analysed the total number of people prescribed DMTs and total DMT costs per 10,000 population, proportions of prescriptions/costs by DMT groups and the number of people prescribed each individual DMT and costs of each DMT over the 10-year period. All estimates were for Australia and each State/Territory individually. RESULTS: The number of people prescribed DMT and costs per 10,000 population had substantial growth between 2013 and 2022: 125%/164% for Australia, and 94%-251%/129%-373% for individual States/Territories. Higher efficacy group accounted for 54% of total people prescribed DMTs in 2013 and 75% in 2022. Fingolimod was the most popular DMT until 2020, then was dominated by ocrelizumab. The trends of individual DMT prescriptions and costs differed between states particularly in Western Australia (WA), Tasmania and Northern Territory (NT). CONCLUSION: DMT prescriptions and costs continuously increased over the last decade, particularly for higher efficacy DMTs, and their trends differed between States/Territories.

The association of comorbidities with sleep quality among Australians with multiple sclerosis: Insights from the Australian Multiple Sclerosis Longitudinal Study.

BACKGROUND: Comorbidities and poor sleep quality are prevalent among individuals with multiple sclerosis (MS). Our understanding of the effects of comorbidities on sleep quality in MS remains limited. OBJECTIVES: The objectives were to investigate whether the number and presence of specific comorbidities have associations with sleep quality and to assess the relative contribution of comorbidity groups to sleep quality. METHODS: We collected data on sleep quality (using Pittsburgh Sleep Quality Index (PSQI)) and presence of comorbidities in people with MS (n = 1597). Associations between comorbidities and sleep quality were examined using linear regression and dominance analysis. RESULTS: Having more comorbidities was associated with poorer sleep quality (p for trend < 0.001). All 13 groups of comorbidities explained 12.9% of the variance in PSQI from which half of the variance was contributed by mental health disorders. In total, 16 of the 28 comorbidities were associated with significantly worse sleep quality, with the strongest associations seen for 'other autoimmune diseases' (ß = 1.98), depression (ß = 1.76), anxiety (ß = 1.72) and rheumatoid arthritis (ß = 1.62). CONCLUSIONS: Many individual comorbidities are associated with poorer sleep quality, with mental health disorders making the largest relative contribution. Optimal management of comorbidities that make the greatest contributions could have the largest benefit for improving sleep in MS.

Significantly increasing multiple sclerosis prevalence in Australia from 2010 to 2021.

BACKGROUND: Multiple sclerosis (MS) prevalence is increasing globally. OBJECTIVES: To determine whether increased prevalence is continuing within Australia using our validated prescription-based ascertainment method. METHODS: We used methods employed in our 2010 and 2017 prevalence estimates. Disease-modifying therapy (DMT) prescriptions were extracted from Australia's Pharmaceutical Benefits Scheme data for January-December 2021. DMT penetrance was calculated using data from the Australian MS Longitudinal Study. We divided the total number of monthly prescriptions by 12 or 2 (except alemtuzumab), adjusted for DMT penetrance and Australian population estimates. Prevalences in Australian states/territories were age-standardised. 2021 prevalence estimates were compared with 2010 and 2017 prevalence estimates using Poisson regression. RESULTS: Number of people with MS in Australia in 2021 was 33,335; an increase of 7728 from 2017 (30.2%) and 12,092 from 2010 (56.6%) and increasing at a faster rate than population change (+10.1%, +14.1%). Age-standardised prevalence was 136.1/100,000 (increased from 103.7/100,000 in 2017). The previously demonstrated positive latitudinal gradient in 2010 and 2017 persisted in 2021, with Tasmania (southernmost state) having the highest prevalence (age-standardised: 203.5/100,000) while northernmost states had the lowest. CONCLUSIONS: In line with global trends, MS prevalence is escalating in Australia, particularly in higher-latitude states. MS prevention is crucial to halt this disturbing trend.

No evidence for association between rs10191329 severity locus and longitudinal disease severity in 1813 relapse-onset multiple sclerosis patients from the MSBase registry.

BACKGROUND: The International Multiple Sclerosis Genetics Consortium and MultipleMS Consortium recently reported a genetic variant associated with multiple sclerosis (MS) severity. However, it remains unclear if these variants remain associated with more robust, longitudinal measures of disease severity. METHODS: We examined the top variant, rs10191329, from Harroud et al.'s study in 1813 relapse-onset MS patients from the MSBase Registry to assess association with longitudinal disease severity. RESULTS: Our analysis revealed no significant association between rs10191329 genotype and longitudinal binary disease severity (p > 0.05). CONCLUSION: These findings highlight the complexity of genetic factors mediating long-term MS outcomes and the need for further research.

Low sun exposure is associated with both progressive-onset and relapse-onset multiple sclerosis risk: a case-control study.

BACKGROUND: Sun exposure has consistently been associated with Multiple Sclerosis (MS) onset, but case samples are predominantly relapse-onset MS (ROMS), and risk estimates have rarely been reported separately for ROMS and progressive-onset MS (POMS). We aimed to determine whether sun exposure prior to disease onset was associated with POMS, and whether the effect differed between POMS and ROMS. METHODS: This nationwide case-control study included 153 POMS cases, 204 incident ROMS cases, and 558 community controls with data from two separate datasets: the PPMS Study (2015-2019) and the Ausimmune Study (2003-2006). Information on time spent in the sun before first MS symptom, skin phenotype, sun protection behavior was collected. Satellite data on ambient ultraviolet radiation (UVR) was used to calculate cumulative UVR dose. Unconditional logistic regression was used with adjustment for covariates. RESULTS: There were consistent dose-response associations, with higher levels of UVR exposure associated with a reduced risk of POMS, both for leisure-time and occupational UVR from age 6 to symptom onset. Associations were overall stronger for POMS than ROMS. For example, cumulative leisure-time UVR dose (per 100 kJ/m2 increment) was associated with POMS (aOR 0.93, 95% CI 0.91-0.95) and the association was slightly weaker for ROMS (aOR 0.96, 95% CI 0.94-0.99) for age 6 to symptom onset (test for interaction p<0.001). CONCLUSIONS: Low levels of sun exposure, throughout the whole life span, are associated with increased risk of POMS and ROMS onset. The sun effects are usually stronger for POMS than ROMS.

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

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

The Patient-Determined Disease Steps scale is not interchangeable with the Expanded Disease Status Scale in mild to moderate multiple sclerosis.

BACKGROUND AND PURPOSE: The validity, reliability, and longitudinal performance of the Patient-Determined Disease Steps (PDDS) scale is unknown in people with multiple sclerosis (MS) with mild to moderate disability. We aimed to examine the psychometric properties and longitudinal performance of the PDDS. METHODS: We included relapsing-remitting MS patients with an Expanded Disability Status Scale (EDSS) score of less than 4. Validity and test-retest reliability was examined. Longitudinal data were analysed with mixed-effect modelling and Cohen's kappa for concordance in confirmed disability progression (CDP). RESULTS: We recruited a total of 1093 participants, of whom 904 had complete baseline data. The baseline correlation between PDDS and EDSS was weak (ρ = 0.45, p < 0.001). PDDS had stronger correlations with patient-reported outcomes (PROs). Conversely, EDSS had stronger correlations with age, disease duration, Kurtzke's functional systems and processing speed test. PDDS test-retest reliability was good to excellent (concordance correlation coefficient = 0.73-0.89). Longitudinally, PDDS was associated with EDSS, age and depression. A higher EDSS score was associated with greater PDSS progression. The magnitude of these associations was small. There was no concordance in CDP as assessed by PDDS and EDSS. CONCLUSION: The PDDS has greater correlation with other PROs but less correlation with other MS-related outcome measures compared to the EDSS. There was little correlation between PDDS and EDSS longitudinally. Our findings suggest that the PDDS scale is not interchangeable with the EDSS.

Novel plasma and brain proteins that are implicated in multiple sclerosis.

Understanding how variations in the plasma and brain proteome contribute to multiple sclerosis susceptibility can provide important insights to guide drug repurposing and therapeutic development for the disease. However, the role of genetically predicted protein abundance in multiple sclerosis remains largely unknown. Integrating plasma proteomics (n = 3301) and brain proteomics (n = 376 discovery; n = 152 replication) into multiple sclerosis genome-wide association studies (n = 14 802 cases and 26 703 controls), we employed summary-based methods to identify candidate proteins involved in multiple sclerosis susceptibility. Next, we evaluated associations of the corresponding genes with multiple sclerosis at tissue-level using large gene expression quantitative trait data from whole-blood (n = 31 684) and brain (n = 1194) tissue. Further, to assess transcriptional profiles for candidate proteins at cell-level, we examined gene expression patterns in immune cell types (Dataset 1: n = 73 cases and 97 controls; Dataset 2: n = 31 cases and 31 controls) for identified plasma proteins, and in brain cell types (Dataset 1: n = 4 cases and 5 controls; Dataset 2: n = 5 cases and 3 controls) for identified brain proteins. In a longitudinal multiple sclerosis cohort (n = 203 cases followed up to 15 years), we also assessed the corresponding gene-level associations with the outcome of disability worsening. We identified 39 novel proteins associated with multiple sclerosis risk. Based on five identified plasma proteins, four available corresponding gene candidates showed consistent associations with multiple sclerosis risk in whole-blood, and we found TAPBPL upregulation in multiple sclerosis B cells, CD8+ T cells and natural killer cells compared with controls. Among the 34 candidate brain proteins, 18 were replicated in a smaller cohort and 14 of 21 available corresponding gene candidates also showed consistent associations with multiple sclerosis risk in brain tissue. In cell-specific analysis, six identified brain candidates showed consistent differential gene expression in neuron and oligodendrocyte cell clusters. Based on the 39 protein-coding genes, we found 23 genes that were associated with disability worsening in multiple sclerosis cases. The findings present a set of candidate protein biomarkers for multiple sclerosis, reinforced by high concordance in downstream transcriptomics findings at tissue-level. This study also highlights the heterogeneity of cell-specific transcriptional profiles for the identified proteins and that numerous candidates were also implicated in disease progression. Together, these findings can serve as an important anchor for future studies of disease mechanisms and therapeutic development.

Not all roads lead to the immune system: the genetic basis of multiple sclerosis severity.

Multiple sclerosis is a leading cause of neurological disability in adults. Heterogeneity in multiple sclerosis clinical presentation has posed a major challenge for identifying genetic variants associated with disease outcomes. To overcome this challenge, we used prospectively ascertained clinical outcomes data from the largest international multiple sclerosis registry, MSBase. We assembled a cohort of deeply phenotyped individuals of European ancestry with relapse-onset multiple sclerosis. We used unbiased genome-wide association study and machine learning approaches to assess the genetic contribution to longitudinally defined multiple sclerosis severity phenotypes in 1813 individuals. Our primary analyses did not identify any genetic variants of moderate to large effect sizes that met genome-wide significance thresholds. The strongest signal was associated with rs7289446 (ß = -0.4882, P = 2.73 × 10-7), intronic to SEZ6L on chromosome 22. However, we demonstrate that clinical outcomes in relapse-onset multiple sclerosis are associated with multiple genetic loci of small effect sizes. Using a machine learning approach incorporating over 62 000 variants together with clinical and demographic variables available at multiple sclerosis disease onset, we could predict severity with an area under the receiver operator curve of 0.84 (95% CI 0.79-0.88). Our machine learning algorithm achieved positive predictive value for outcome assignation of 80% and negative predictive value of 88%. This outperformed our machine learning algorithm that contained clinical and demographic variables alone (area under the receiver operator curve 0.54, 95% CI 0.48-0.60). Secondary, sex-stratified analyses identified two genetic loci that met genome-wide significance thresholds. One in females (rs10967273; ßfemale = 0.8289, P = 3.52 × 10-8), the other in males (rs698805; ßmale = -1.5395, P = 4.35 × 10-8), providing some evidence for sex dimorphism in multiple sclerosis severity. Tissue enrichment and pathway analyses identified an overrepresentation of genes expressed in CNS compartments generally, and specifically in the cerebellum (P = 0.023). These involved mitochondrial function, synaptic plasticity, oligodendroglial biology, cellular senescence, calcium and G-protein receptor signalling pathways. We further identified six variants with strong evidence for regulating clinical outcomes, the strongest signal again intronic to SEZ6L (adjusted hazard ratio 0.72, P = 4.85 × 10-4). Here we report a milestone in our progress towards understanding the clinical heterogeneity of multiple sclerosis outcomes, implicating functionally distinct mechanisms to multiple sclerosis risk. Importantly, we demonstrate that machine learning using common single nucleotide variant clusters, together with clinical variables readily available at diagnosis can improve prognostic capabilities at diagnosis, and with further validation has the potential to translate to meaningful clinical practice change.

The quality of life impact of the COVID-19 pandemic and lockdowns for people living with multiple sclerosis (MS): evidence from the Australian MS Longitudinal Study.

PURPOSE: People living with multiple sclerosis (PwMS) in metropolitan Victoria, Australia, experienced a 112-day, COVID-19-related lockdown in mid-2020. Contemporaneously, Australian PwMS elsewhere experienced minimal restrictions, resulting in a natural experiment. This study investigated the relationships between lockdowns, COVID-19-related adversity, and health-related quality of life (HRQoL). It also generated health state utilities (HSU) representative of changes in HRQoL. METHODS: Data were extracted from Australian MS Longitudinal Study surveys, which included the Assessment of Quality of Life-Eight Dimensions (AQoL-8D) instrument and a COVID-19 questionnaire. This COVID-19 questionnaire required participants to rank their COVID-19-related adversity across seven health dimensions. Ordered probits were used to identify variables contributing to adversity. Linear and logit regressions were applied to determine the impact of adversity on HRQoL, defined using AQoL-8D HSUs. Qualitative data were examined thematically. RESULTS: N = 1666 PwMS (average age 58.5; 79.8% female; consistent with the clinical presentation of MS) entered the study, with n = 367 (22.0%) exposed to the 112-day lockdown. Lockdown exposure and disability severity were strongly associated with higher adversity rankings (p < 0.01). Higher adversity rankings were associated with lower HSUs. Participants reporting major adversity, across measured health dimensions, had a mean HSU 0.161 (p < 0.01) lower than participants reporting no adversity and were more likely (OR: 2.716, p < 0.01) to report a clinically significant HSU reduction. Themes in qualitative data supported quantitative findings. CONCLUSIONS: We found that COVID-19-related adversity reduced the HRQoL of PwMS. Our HSU estimates can be used in health economic models to evaluate lockdown cost-effectiveness for people with complex and chronic (mainly neurological) diseases.

Predictors of mental health among U.S. adults during COVID-19 early pandemic, mid- pandemic, and post-vaccine eras.

BACKGROUND: A collective trauma like COVID-19 impacts individuals differently due to socio-contextual and individual characteristics. Younger adults, minorities, affiliates of certain political parties, and residents of some regions of the United States reported experiencing poorer mental health during the pandemic. Being diagnosed with COVID-19, or losing a friend/family to it, was related to more adverse mental health symptoms. While the negative impact of COVID-19 on health outcomes has been studied, mental health changes during this pandemic need further exploration. METHODS: In a study of 8,612 U.S. households, using three surveys collected from a nationally representative panel between May 2020 and October 2021, using a repeated cross-sectional design, a linear mixed effect regression model was performed to investigate factors associated with the mental health status, based on the Mental Health Inventory-5, of individuals throughout different phases of the COVID-19 pandemic, and whether an improvement over time, especially after vaccines became available, was observed. RESULTS: An overall improvement in mental health was observed after vaccines became available. Individuals with no COVID-related death in their household, those not wearing masks, those identifying as members of the Republican Party, race/ethnicities other than Asian, men, older adults, and residents of the South were less likely than others to report mental health challenges. CONCLUSIONS: Our results highlight the need for widespread mental health interventions and health promotion to address challenges during the COVID-19 pandemic and beyond. Due to the worse mental health observed among Asians, younger adults, women, low-income families, those with a higher level of concern for COVID-19, people who lost someone to COVID-19, and/or individuals with histories of opioid use disorder and criminal legal involvement, over the period of this study, targeted attention needs to be given to the mental health of these groups.

Gender identity, stimulant drug use, and criminal justice history on internalized stigma among a nationally representative sample of adults who misuse opioids.

PURPOSE: The rise of fatal stimulant use among adults who use opioids is a public health problem. Internalized stigma is a barrier to substance use treatment, which is greater for women and populations with criminal justice involvement. METHODS: Using a nationally representative sample of adults in the United States from a probability-based survey on household opinions in 2021, we examined characteristics of women (n = 289) and men (n = 416) who misuse opioids. In gender-stratified multivariable linear regression, we investigated factors associated with internalized stigma, and tested for the interaction of stimulant use and criminal justice involvement. RESULTS: Compared to men, women reported greater mental health symptom severity (3.2 vs. 2.7 on a 1 to 6 scale, p < 0.001). Internalized stigma was similar between women (2.3 ± 1.1) and men (2.2 ± 0.1). Among women and not men, however, stimulant use was positively associated with internalized stigma (0.36, 95% CI [0.07, 0.65]; p = 0.02). Interaction between stimulant use and criminal justice involvement was negatively associated with internalized stigma among women (- 0.60, 95% CI [- 1.16, -0.04]; p = 0.04); among men, the interaction was not significant. Predictive margins illustrate among women, stimulant use eliminated the gap in internalized stigma such that women with no criminal justice involvement had a similar level of internalized stigma as women with criminal justice involvement. CONCLUSION: Internalized stigma between women and men who misuse opioids differed based on stimulant use and criminal justice involvement. Future research should assess whether internalized stigma influences treatment utilization among women with criminal justice involvement.

Conceptualizing social risk in relation to climate change and assisted ecosystem adaptation.

Realizing positive social and environmental outcomes from assisted ecosystem adaptation requires the management of complex, uncertain, and ambiguous risks. Using assisted coral reef adaptation as a case study, this article presents a conceptual framework that defines social impacts as the physical and cognitive consequences for people of planned intervention and social risks as potential impacts transformed into objects of management through assessment and governance. Reflecting on its multiple uses in the literature, we consider "social risk" in relation to risks to individuals and communities, risks to First Peoples, risks to businesses or project implementation, possibilities for amplified social vulnerability, and risk perceptions. Although much of this article is devoted to bringing clarity to the different ways in which social risk manifests and to the multiple characters of risk and uncertainty, it is apparent that risk governance itself must be an inherently integrative and social process.