University staff perspectives on determinants of high-quality health professions student placements in regional, rural and remote Australia: protocol for a mixed-method study.

INTRODUCTION: In rural areas, work-integrated learning in the form of health student placements has several potential benefits, including contributing to student learning, enhancing rural health service capacity and attracting future rural health workforce. Understanding what constitutes a high-quality rural placement experience is important for enhancing these outcomes. There is no current standardised definition of quality in the context of rural health placements, nor is there understanding of how this can be achieved across different rural contexts. This study is guided by one broad research question: what do university staff believe are the determinants of high-quality health professions student placements in regional, rural and remote Australia? METHODS AND ANALYSIS: This study will adopt a convergent mixed-method design with two components. Component A will use explanatory sequential mixed methods. The first phase of component A will use a survey to explore determinants that contribute to the development of high-quality health student placements from the perspective of university staff who are not employed in University Departments of Rural Health and are involved in the delivery of health student education. The second phase will use semistructured interviews with the same stakeholder group (non-University Department of Rural Health university staff) to identify the determinants of high-quality health student placements. Component B will use a case study Employing COnceptUal schema for policy and Translation Engagement in Research mind mapping method to capture determinants that contribute to the development of high-quality health student placements from the perspective of University Department of Rural Health university staff. ETHICS AND DISSEMINATION: The University of Melbourne Human Ethics Committee approved the study (2022-23201-33373-5). Following this, seven other Australian university human research ethics committees provided external approval to conduct the study. The results of the study will be presented in several peer-review publications and summary reports to key stakeholder groups.

Metabolomics of Multiple Sclerosis Lesions Demonstrates Lipid Changes Linked to Alterations in Transcriptomics-Based Cellular Profiles.

BACKGROUND AND OBJECTIVES: People with multiple sclerosis (MS) have a dysregulated circulating metabolome, but the metabolome of MS brain lesions has not been studied. The aims of this study were to identify differences in the brain tissue metabolome in MS compared with controls and to assess its association with the cellular profile of corresponding tissue. METHODS: MS tissues included samples from the edge and core of chronic active or inactive lesions and periplaque white matter (WM). Control specimens were obtained from normal WM. Metabolomic analysis was performed using mass-spectrometry coupled with liquid/gas chromatography and subsequently integrated with single-nucleus RNA-sequencing data by correlating metabolite abundances with relative cell counts, as well as individual genes using Multiomics Factor Analysis (MOFA). RESULTS: Seventeen samples from 5 people with secondary progressive MS and 8 samples from 6 controls underwent metabolomic profiling identifying 783 metabolites. MS lesions had higher levels of sphingosines (false discovery rate-adjusted p-value[q] = 2.88E-05) and sphingomyelins and ceramides (q = 2.15E-07), but lower nucleotide (q = 0.05), energy (q = 0.001), lysophospholipid (q = 1.86E-07), and monoacylglycerol (q = 0.04) metabolite levels compared with control WM. Periplaque WM had elevated sphingomyelins and ceramides (q = 0.05) and decreased energy metabolites (q = 0.01) and lysophospholipids (q = 0.05) compared with control WM. Sphingolipids and membrane lipid metabolites were positively correlated with astrocyte and immune cell abundances and negatively correlated with oligodendrocytes. On the other hand, long-chain fatty acid, endocannabinoid, and monoacylglycerol pathways were negatively correlated with astrocyte and immune cell populations and positively correlated with oligodendrocytes. MOFA demonstrated associations between differentially expressed metabolites and genes involved in myelination and lipid biosynthesis. DISCUSSION: MS lesions and perilesional WM demonstrated a significantly altered metabolome compared with control WM. Many of the altered metabolites were associated with altered cellular composition and gene expression, indicating an important role of lipid metabolism in chronic neuroinflammation in MS.

Structural MRI measures are associated with fatigue severity and persistence in a large, real-world cohort of people with multiple sclerosis.

BACKGROUND: Results of research on radiological hallmarks of multiple sclerosis (MS) fatigue have been conflicting. OBJECTIVE: To investigate the associations of lesion and brain compartment volumes with fatigue severity and persistence in people with multiple sclerosis (PwMS). METHODS: The Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) network collects standardized data during routine care of PwMS from 10 healthcare institutions. Magnetic resonance imaging (MRI) predictors included baseline brain parenchymal (BPF) and gray matter fractions (GMF) and T2 lesion volume (T2LV). The Quality of Life in Neurological Disorders (Neuro-QOL) fatigue subscore was analyzed linearly and categorically using T-score cutpoints, with a period of elevated symptoms defined as T-score ⩾ mean + 0.5 SD over follow-up. RESULTS: At baseline, of 4012 participants (average age: 45.6 ± 11.8 years; 73% female; 31% progressive MS), 2058 (51%) had no fatigue, 629 (16%) had mild fatigue, and 1325 (33%) had moderate-to-severe fatigue. One SD greater baseline BPF and GMF were associated with 0.83 (p < 0.001) and 0.38 (p = 0.02) lower values in the baseline Neuro-QOL fatigue T-score. A 1 SD lower log of total T2LV was associated with a 0.49 (p < 0.001) lower baseline fatigue T-score. Higher BPF and lower T2LV at baseline were associated with lower odds of subsequent periods of elevated fatigue. CONCLUSION: Baseline lesion burden and lower generalized whole-brain volumes were associated with MS fatigue in cross-sectional and longitudinal analyses in a large, real-world cohort of PwMS.

Investigating the Prevalence of Comorbidity in Multiple Sclerosis Clinical Trial Populations.

BACKGROUND AND OBJECTIVES: Comorbidity is common in multiple sclerosis (MS) with the most prevalent conditions being depression, anxiety, hypertension, and hyperlipidemia. Limited information regarding the representation of comorbidity status is available from phase III clinical trials in MS leading to concern about the potential underrepresentation of individuals with comorbidity in clinical trials. The objective was to estimate the prevalence of comorbidities in MS clinical trial populations. METHODS: Individual-level data from multiple sponsors were requested for a 2-stage meta-analysis of phase III clinical trials of MS disease-modifying therapies. To ensure consistency of our approach across trials, we followed the Maelstrom retrospective harmonization guidelines. Chronic comorbidities at clinical trial enrollment recommended by the International Advisory Committee on Clinical Trials in MS were considered (depression, anxiety, hypertension, hyperlipidemia, migraine, diabetes, chronic lung disease). Additional comorbidities were also classified. Classification was based on medical history data. Individual comorbidities were summed and categorized as 0, 1, 2, or ≥3. We report the pooled prevalence (95% confidence interval [95% CI]) of comorbidity. The pooled prevalence and prevalence ratios across age, sex, race, disability level, and treatment were also reported. Heterogeneity was assessed using the I2 statistic. RESULTS: Seventeen trials involving 17,926 participants were included. Fourteen trials enrolled participants with relapsing MS (RMS) while 3 enrolled participants with progressive MS (PMS). The distributions of sex, age, and disability level were generally consistent within RMS and PMS trials. When pooled, almost half of trial participants (46.5%) had ≥1 comorbidity (1: 25.0%, 95% CI 23.0-27.0, I2 = 89.9; 2: 11.4% [9.3-14.0], I2 = 96.3; ≥3: 6.0% [4.2-8.4], I2 = 97.7). Depression (16.45% [12.96-20.88], I2 = 98.3) was the most prevalent comorbidity reported, followed by hypertension (10.16% [8.61-11.98], I2 = 93.2). Heterogeneity was high across trials. Older age and female participants were associated with increased number of comorbidities. Older individuals and male participants had a higher prevalence of hyperlipidemia, while older individuals and female participants had a higher prevalence of depression and anxiety. DISCUSSION: Individuals with comorbidities are included in clinical trials, although they may still be underrepresented compared with the general MS population. Given the comorbidity prevalence in the trial populations and studies suggesting an association of comorbidities with disease activity, comorbidity may influence outcomes in clinical trials.

Barriers and enablers of dementia training in healthcare workers in rural and remote Australia: A scoping review to inform future approaches to training.

INTRODUCTION: Dementia is now responsible for the greatest burden of disease of any chronic illness in older Australians. Rural and remote communities bear the impacts of this disproportionately. Additional training and education for healthcare staff to support people living with dementia is needed. OBJECTIVE: The objective of this scoping review was to map and synthesise the evidence related to barriers and enablers of accessing dementia training for Australian healthcare workers located in rural and remote areas. DESIGN: This scoping review systematically searched multiple databases in January 2023 for peer-reviewed literature on the topic. Reviewers used Covidence to screen titles and abstracts of located sources, and to screen full-text articles. FINDINGS: From 187 articles screened, seven peer-reviewed journal articles were included in the final data analysis; all were from Australia or Canada. The most common barrier described was low staffing, precluding release of staff for dementia training. Enablers to participation in dementia training were availability of online training programs, as well as training providers collaborating with end users to ensure the training met their learning needs. DISCUSSION: This review provides evidence of barriers and enablers specific to rural and remote healthcare workers accessing dementia training. It also explores other approaches to training that have been trialled successfully in different settings. CONCLUSION: Addressing the identified barriers and enablers may assist in developing training approaches appropriate for existing staff, and in meeting training needs for the future workforce.

Association between demographics, socioeconomics, and disease-related factors and the perception of stigma in people with MS.

BACKGROUND: Stigma is prevalent among individuals with chronic diseases, such as multiple sclerosis (MS) and those with comorbid mental health disorders, but its associated factors are poorly understood. OBJECTIVE: To investigate the prevalence and correlates of stigma in people living with MS. METHODS: We analyzed data from the MS Partners Advancing Technology and Health Solutions (MS PATHS) network, which collected patient information and outcomes during routine clinic visits. We used a multinomial logistic regression model to examine the cross-sectional association between stigma and demographic, socioeconomics, and MS-related factors. RESULTS: We included 11,634 participants. The mean Neuro-QoL stigma T-score was 47.2 ± 8.6, and 17.7% of participants were classified as having moderate to severe stigma using established cutoffs. Multinomial logistic regression models suggest that higher disability levels, progressive form of the disease, shorter duration of the disease, and unemployment were associated with higher stigma while being male, married, undergoing treatment with high-efficacy disease-modifying therapies (DMTs), and being from European MS centers were associated with lower stigma perception. Disability levels, measured by Patient-Determined Disease Steps (PDDS), had the strongest independent association with stigma. CONCLUSION: Stigma remains a relevant issue for people living with MS. Factors, such as physical and cognitive disability, DMT, and employment status may influence the severity of perceived stigma.

Bile acid metabolites predict multiple sclerosis progression and supplementation is safe in progressive disease.

Background: Bile acid metabolism is altered in multiple sclerosis (MS) and tauroursodeoxycholic acid (TUDCA) supplementation ameliorated disease in mouse models of MS. Methods: Global metabolomics was performed in an observational cohort of people with MS followed by pathway analysis to examine relationships between baseline metabolite levels and subsequent brain and retinal atrophy. A double-blind, placebo-controlled trial, was completed in people with progressive MS (PMS), randomized to receive either TUDCA (2g daily) or placebo for 16 weeks. Participants were followed with serial clinical and laboratory assessments. Primary outcomes were safety and tolerability of TUDCA, and exploratory outcomes included changes in clinical, laboratory and gut microbiome parameters. Results: In the observational cohort, higher primary bile acid levels at baseline predicted slower whole brain, brain substructure and specific retinal layer atrophy. In the clinical trial, 47 participants were included in our analyses (21 in placebo arm, 26 in TUDCA arm). Adverse events did not significantly differ between arms (p=0.77). The TUDCA arm demonstrated increased serum levels of multiple bile acids. No significant differences were noted in clinical or fluid biomarker outcomes. Central memory CD4+ and Th1/17 cells decreased, while CD4+ naïve cells increased in the TUDCA arm compared to placebo. Changes in the composition and function of gut microbiota were also noted in the TUDCA arm compared to placebo. Conclusion: Bile acid metabolism in MS is linked with brain and retinal atrophy. TUDCA supplementation in PMS is safe, tolerable and has measurable biological effects that warrant further evaluation in larger trials with a longer treatment duration.

Extended interval dosing of ocrelizumab in patients with multiple sclerosis is not associated with meaningful differences in disease activity.

Risk concerns related to ocrelizumab treatment for multiple sclerosis (MS) during the COVID-19 pandemic caused infusion delays with extended interval dosing (EID). We reviewed medical records of patients on ocrelizumab to determine whether EID maintains its effectiveness compared to standard interval dosing (SID). Among 361 patients, 231 (64%) and 123 (34%) had at least one infusion with infusion intervals of ⩾8 months and ⩾12 months, respectively. There were no differences in demographics or clinical profiles between the SID and EID groups. No significant differences between rates of breakthrough activity among relapsing-remitting patients were observed between SID (three patients) and EID (seven patients).

Expanding clinical profiles and prognostic markers in stiff person syndrome spectrum disorders.

OBJECTIVE: To describe the clinical features of a cohort of individuals with stiff person syndrome spectrum disorders (SPSD) and identify potential early predictors of future disability. BACKGROUND: There is a need to better understand the full spectrum of clinical and paraclinical features and long-term impact of SPSD. DESIGN/METHODS: Observational study from 1997 to 2022 at Johns Hopkins. Clinical phenotypes included classic SPS, partial SPS (limb or trunk limited), SPS-plus (classic features plus cerebellar/brainstem involvement), and progressive encephalomyelitis with rigidity and myoclonus (PERM). Outcome measures were modified Rankin scale (mRS) and use of assistive device for ambulation. Multivariate logistic regression was used to assess significant predictors of outcomes. RESULTS: Cohort included 227 individuals with SPSD with mean follow-up of 10 years; 154 classic, 48 SPS-plus, 16 PERM, and 9 partial. Mean age at symptom onset was 42.9 ± 14.1 years, majority were white (69.2%) and female (75.8%). Median time to diagnosis was 36.2 months (longest for SPS-plus and PERM) and 61.2% were initially misdiagnosed. Most had systemic co-morbidities and required assistive devices for ambulation. Female sex (OR 2.08; CI 1.06-4.11) and initial brainstem/cerebellar involvement (OR 4.41; CI 1.63-14.33) predicted worse outcome by mRS. Older age at symptom onset (OR 1.04; CI 1.01-1.06), female sex (OR 1.99; CI 1.01-4.01), Black race (OR 4.14; CI 1.79-10.63), and initial brainstem/cerebellar involvement (OR 2.44; CI 1.04-7.19) predicted worse outcome by use of assistive device. Early implementation of immunotherapy was associated with better outcomes by either mRS (OR 0.45; CI 0.22-0.92) or use of assistive device (OR 0.79; CI 0.66-0.94). CONCLUSIONS: We present the expanding phenotypic variability of this rare spectrum of disorders and highlight potential predictors of future disability.

Agreement Between Published Reference Resources for Neurofilament Light Chain Levels in People With Multiple Sclerosis.

OBJECTIVES: To examine the agreement between published reference resources for neurofilament light chain (NfL) applied to a large population of people with multiple sclerosis (MS). METHODS: Six published reference resources were used to classify NfL in participants in the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) network as elevated or normal and to derive age-specific NfL Z-scores. NfL values were classified as elevated if they exceeded the >95th percentile (i.e., Z-score >1.645) of the age-specific reference range. Furthermore, age-specific NfL Z-scores could be derived for 4 of 6 reference resources. RESULTS: NfL measurements were assessed from 12,855 visits of 6,687 people with MS (median 2 samples per individual [range 1-7]). The mean ± SD age was 47.1 ± 11.7 years, 72.1% of participants were female, disease duration was 15.0 ± 10.6 years, body mass index was 28.6 ± 6.9 kg/m2, and serum NfL was 12.87 ± 12.86 pg/mL. Depending on the selection of the reference resource, the proportion of NfL measurements classified as elevated varied from 3.7% to 30.9%. The kappa coefficient across the 6 reference resources used was 0.576 (95% CI 0.571-0.580) indicating moderate agreement. Spearman correlations between Z-scores derived from the various reference resources exceeded 0.90; however, concordance coefficients were lower, ranging from 0.72 to 0.89. DISCUSSION: Interpretation of blood NfL values may vary markedly depending on the selection of the reference resource. Borderline elevated values should be interpreted with caution, and future studies should focus on standardizing NfL measurement and reporting across laboratories/platforms, better characterizing the effects of confounding/influencing factors, and defining the performance of NfL (including as part of multimodal predictive algorithms) for prediction of disease-specific outcomes.

Depression symptoms and cognition in multiple sclerosis: Longitudinal evidence of a specific link to executive control.

BACKGROUND: Depression symptoms are prevalent in multiple sclerosis (MS) and associated with poorer cognition in cross-sectional studies; it is unknown whether changes in depression symptoms track with cognitive changes longitudinally. OBJECTIVE: Investigate whether changes in depression symptoms correspond with cognitive changes over time in MS, and identify specific cognitive functions related to depression symptoms. METHOD: Persons with early relapse-onset MS (n = 165) completed a depression questionnaire (Beck Depression Inventory FastScreen) and tests of cognitive speed, executive control, and memory at baseline and 3-year follow-up. One-way ANOVAs assessed differences in cognitive change across participants with worsened, stable, or improved depression symptoms from baseline to year 3. RESULTS: Change in depression symptoms was related to change in executive control (p = 0.001, ηp2 = 0.08; worsened mood with worsened executive control; improved mood with improved executive control), even when adjusting for cognitive speed (p = 0.002, ηp2 = 0.08). There were no links to cognitive speed (p = 0.826) or memory (p = 0.243). Regarding individual depression symptoms, executive control was related to loss of pleasure and suicidal thoughts. CONCLUSIONS: Executive control tracks with depression symptoms, raising hope that management of mood may improve executive control. The specific link between executive control and anhedonia implicates dysfunctional reward processing as a key component of MS depression.

Gut Microbiota and Cognitive Function Among Women Living with HIV.

BACKGROUND: Altered gut microbiota has been associated with cognitive dysfunction and Alzheimer's disease, but little is known among people living with HIV. OBJECTIVE: To examine associations between gut microbiota and cognitive impairment among women with or without HIV. METHODS: This is a cross-sectional study of 446 women (302 HIV+) who had completed a neuropsychological test battery and stool sample collected within 1 year. Gut microbiota composition was quantified using 16SV4 rRNA gene sequencing and microbial functional pathways were predicted using PICRUSt. Cognitive domains included attention, executive function, learning, memory, fluency, processing speed, and motor function. Cognitive impairment was defined as two or more domains with T scores < 1 SD below mean. ANCOM-II was used to identify taxa and functional pathways associated with cognitive impairment, and the associations were further examined by multivariable logistic regression. RESULTS: In overall sample, adjusting for multiple covariates including HIV status, we found that higher abundance of Methanobrevibacter, Odoribacter, Pyramidobacter, Eubacterium, Ruminococcus, and Gemmiger, and lower abundance of Veillonella were associated with cognitive impairment. The associations between these taxa and cognitive impairment were more profound in HIV+ women compared to HIV- women. Most associations with bacterial taxa were observed for learning and memory. We found accompanying microbial functional differences associated with cognitive impairment, including twelve enriched pathways and three depleted pathways. CONCLUSIONS: In women with or without HIV infection, this study identified multiple altered gut bacterial taxa and functional pathways associated with cognitive impairment, supporting the potential role of gut microbiota in cognitive dysfunction and Alzheimer's disease.

Multiple Sclerosis Pathogenesis and Updates in Targeted Therapeutic Approaches.

PURPOSE OF REVIEW: In this review, we provide a comprehensive update on current scientific advances and emerging therapeutic approaches in the field of multiple sclerosis. RECENT FINDINGS: Multiple sclerosis (MS) is a common disorder characterized by inflammation and degeneration within the central nervous system (CNS). MS is the leading cause of non-traumatic disability in the young adult population. Through ongoing research, an improved understanding of the disease underlying mechanisms and contributing factors has been achieved. As a result, therapeutic advancements and interventions have been developed specifically targeting the inflammatory components that influence disease outcome. Recently, a new type of immunomodulatory treatment, known as Bruton tyrosine kinase (BTK) inhibitors, has surfaced as a promising tool to combat disease outcomes. Additionally, there is a renewed interested in Epstein-Barr virus (EBV) as a major potentiator of MS. Current research efforts are focused on addressing the gaps in our understanding of the pathogenesis of MS, particularly with respect to non-inflammatory drivers. Significant and compelling evidence suggests that the pathogenesis of MS is complex and requires a comprehensive, multilevel intervention strategy. This review aims to provide an overview of MS pathophysiology and highlights the most recent advances in disease-modifying therapies and other therapeutic interventions.

Effects of Ibudilast on Retinal Atrophy in Progressive Multiple Sclerosis Subtypes: Post Hoc Analyses of the SPRINT-MS Trial.

BACKGROUND AND OBJECTIVES: Ganglion cell + inner plexiform layer (GCIPL) thinning, measured by optical coherence tomography (OCT), reflects global neurodegeneration in multiple sclerosis (MS). Atrophy of the inner (INL) and outer nuclear layer (ONL) may also be prominent in progressive MS (PMS). The phase 2, SPRINT-MS trial found reduced brain atrophy with ibudilast therapy in PMS. In this post hoc analysis of the SPRINT-MS trial, we investigate (1) retinal atrophy (2) differences in response by subtype and (3) associations between OCT and MRI measures of neurodegeneration. METHODS: In the multicenter, double-blind SPRINT-MS trial, participants with secondary progressive MS (SPMS) or primary progressive MS (PPMS) were randomized to ibudilast or placebo. OCT and MRI data were collected every 24 weeks for 96 weeks. Extensive OCT quality control and algorithmic segmentation produced consistent results across Cirrus HD-OCT and Spectralis devices. Primary endpoints were GCIPL, INL, and ONL atrophy, assessed by linear mixed-effects regression. Secondary endpoints were associations of OCT measures, brain parenchymal fraction, and cortical thickness, assessed by partial Pearson correlations. RESULTS: One hundred thirty-four PPMS and 121 SPMS participants were included. GCIPL atrophy was 79% slower in the ibudilast (-0.07 ± 0.23 µm/y) vs placebo group (-0.32 ± 0.20 µm/y, p = 0.003). This effect predominated in the PPMS cohort (ibudilast: -0.08 ± 0.29 µm/y vs placebo: -0.60 ± 0.29 µm/y, a decrease of 87%, p < 0.001) and was not detected in the SPMS cohort (ibudilast: -0.21 ± 0.28 µm/y vs placebo: -0.14 ± 0.27 µm/y, p = 0.55). GCIPL, INL, and ONL atrophy rates correlated with whole brain atrophy rates across the cohort (r = 0.27, r = 0.26, and r = 0.20, respectively; p < 0.001). Power calculations from these data show future trials of similar size and design have ≥80% power to detect GCIPL atrophy effect sizes of approximately 40%. DISCUSSION: Ibudilast treatment decreased GCIPL atrophy in PMS, driven by the PPMS cohort, with no effect seen in SPMS. Modulated atrophy of retinal layers may be detectable in sample sizes smaller than the SPRINT-MS trial and correlate with whole brain atrophy in PMS, further highlighting their utility as outcomes in PMS. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that ibudilast reduces composite ganglion cell + inner plexiform layer atrophy, without reduction of inner or outer nuclear layer atrophy, in patients with primary progressive MS but not those with secondary progressive MS.

A Phase 1b, Open-Label Study to Evaluate the Safety and Tolerability of the Putative Remyelinating Agent, Liothyronine, in Individuals with MS.

Thyroid hormones are essential during developmental myelination and may play a direct role in remyelination and repair in the adult central nervous system by promoting the differentiation of oligodendrocyte precursor cells into mature oligodendrocytes. Since tri-iodothyronine (T3) is believed to mediate the majority of important thyroid hormone actions, liothyronine (synthetic T3) has the potential to induce reparative mechanisms and limit neurodegeneration in multiple sclerosis (MS). We completed a phase 1b clinical trial to determine the safety and tolerability of ascending doses of liothyronine in individuals with relapsing and progressive MS. A total of 20 people with MS were enrolled in this single-center trial of oral liothyronine. Eighteen participants completed the 24-week study. Our study cohort included mostly women (11/20), majority relapsing MS (12/20), mean age of 46, and baseline median EDSS of 3.5. Liothyronine was tolerated well without treatment-related severe/serious adverse events or evidence of disease activation/clinical deterioration. The most common adverse events included gastrointestinal distress and abnormal thyroid function tests. No clinical thyrotoxicosis occurred. Importantly, we did not observe a negative impact on secondary clinical outcome measures. The CSF proteomic changes suggest a biological effect of T3 treatment within the CNS. We noted changes primarily in proteins associated with immune cell function and angiogenesis. Liothyronine appeared safe and was well tolerated in people with MS. A larger clinical trial will help assess whether liothyronine can promote oligodendrogenesis and enhance remyelination in vivo, limit axonal degeneration, or improve function.

Assessment of differential item functioning of the PHQ-9, HADS-D and PROMIS-depression scales in persons with and without multiple sclerosis.

OBJECTIVE: We tested for the presence of differential item functioning (DIF) in commonly used measures of depressive symptoms, in people with multiple sclerosis (MS) versus people with a psychiatric disorder without MS. METHODS: Participants included individuals with MS, or with a lifetime history of a depressive or anxiety disorder (Dep/Anx) but no immune-mediated inflammatory disease. Participants completed the Patient Health Questionnaire (PHQ-9), Hospital Anxiety and Depression Scale (HADS), and the Patient Reported Outcome Measurement Information System (PROMIS)-Depression. We assessed unidimensionality of the measures using factor analysis. We evaluated DIF using logistic regression, with and without adjustment for age, gender and body mass index (BMI). RESULTS: We included 555 participants (MS: 252, Dep/Anx: 303). Factor analysis showed that each depression symptom measure had acceptable evidence of unidimensionality. In unadjusted analyses comparing the MS versus Dep/Anx groups we identified multiple items with evidence of DIF, but few items showed DIF effects that were large enough to be clinically meaningful. We observed non-uniform DIF for one PHQ-9 item, and three HADS-D items. We also observed DIF with respect to gender (one HADS-D item), and BMI (one PHQ-9 item). For the MS versus Dep/Anx groups, we no longer observed DIF post-adjustment for age, gender and BMI. On unadjusted and adjusted analyses, we did not observe DIF for any PROMIS-D item. CONCLUSION: Our findings suggest that DIF exists for the PHQ-9 and HADS-D with respect to gender and BMI in clinical samples that include people with MS whereas DIF was not observed for the PROMIS-Depression scale.

Etiology, effects and management of comorbidities in multiple sclerosis: recent advances.

Comorbid conditions commonly affect people with multiple sclerosis (MS). Population-based studies indicate that people with MS have an increased incidence of ischemic heart disease, cerebrovascular disease, peripheral vascular disease, and psychiatric disorders as compared to people without MS. People with MS from underrepresented minority and immigrant groups have higher comorbidity burdens. Comorbidities exert effects throughout the disease course, from symptom onset through diagnosis to the end of life. At the individual level, comorbidity is associated with higher relapse rates, greater physical and cognitive impairments, lower health-related quality of life, and increased mortality. At the level of the health system and society, comorbidity is associated with increased health care utilization, costs and work impairment. A nascent literature suggests that MS affects outcomes from comorbidities. Comorbidity management needs to be integrated into MS care, and this would be facilitated by determining optimal models of care.

Polygenicity of Comorbid Depression in Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Depression is common in multiple sclerosis (MS) and is associated with faster disability progression. The etiology of comorbid depression in MS remains poorly understood. Identification of individuals with a high risk of depression, through polygenic scores (PGS), may facilitate earlier identification. Previous genetic studies of depression considered depression as a primary disorder, not a comorbidity, and thus, findings may not generalize to MS. Body mass index (BMI) is a risk factor of both MS and depression, and its association may highlight differences in depression in MS. To improve the understanding of comorbid depression in MS, we will investigate PGS in people with MS, with the hypothesis that a higher depression PGS is associated with increased odds for comorbid depression in MS. METHODS: Samples from 3 sources (Canada, UK Biobank, and the United States) were used. Individuals were grouped into cases (MS/comorbid depression) and compared with 3 control groups: MS/no depression, depression/no immune disease, and healthy persons. We used 3 depression definitions: lifetime clinical diagnoses, self-reported diagnoses, and depressive symptoms. The PGS were tested in association with depression using regression. RESULTS: A total of 106,682 individuals of European genetic ancestry were used: Canada (n = 370; 213 with MS), UK Biobank (n = 105,734; 1,390 with MS), and the United States (n = 578 with MS). Meta-analyses revealed individuals with MS and depression had a higher depression PGS compared with both individuals with MS without depression (odds ratio range per SD 1.29-1.38, p < 0.05) and healthy controls (odds ratio range per SD 1.49-1.53, p < 0.025), regardless of the definition applied and when sex stratified. The BMI PGS was associated with depressive symptoms (p ≤ 0.001). The depression PGS did not differ between depression occurring as a comorbid condition with MS or as the primary condition (odds ratio range per SD 1.03-1.13, all p > 0.05). DISCUSSION: A higher depression genetic burden was associated with approximately 30%-40% increased odds of depression in European genetic ancestry participants with MS compared with those without depression and was no different compared with those with depression and no comorbid immune disease. This study paves the way for further investigations into the possible use of PGS for assessing psychiatric disorder risk in MS and its application to non-European genetic ancestries.

High-dose vitamin D3 supplementation in relapsing-remitting multiple sclerosis: a randomised clinical trial.

Background: Vitamin D insufficiency is associated with risk of multiple sclerosis (MS) relapse; whether supplementation influences prognosis is unknown. The Vitamin D to Ameliorate MS (VIDAMS) trial aimed to determine if high dose (5000 International Units (IU)/day) versus low dose (600 IU/day) vitamin D3, added to daily glatiramer acetate (GA), reduced the risk of clinical relapse in people with established relapsing remitting MS (RRMS) over 96 weeks. Methods: VIDAMS is a randomised, phase 3, double-blind, multi-centre, controlled trial conducted at sixteen neurology clinics in the United States. Participants with MAGNIMS 2010 RRMS, aged 18-50 years, with recent disease activity were eligible to enroll if they had an Expanded Disability Status Scale score ≤4.0; minimum serum 25-hydroxyvitamin D level of 15 ng/ml within 30 days of screening; and average ≤ 1000 IU supplemental vitamin D3 daily in the 90 days prior to screening. Of 203 screened, 183 were eligible for the 30-day run-in to assess GA adherence, after which 172 were randomised 1:1 to low dose vitamin D3 (LDVD) or high dose vitamin D3 (HDVD), and were followed every 12 weeks for 96 weeks. The primary outcome was the proportion that experienced a confirmed relapse and analyses used Kaplan Meier and Cox proportional hazards models. 165 participants returned for ≥1 follow-up visit and were included in the primary and safety analyses; 140 completed a week 96 visit. This study was registered with ClinicalTrials.gov, NCT01490502. Findings: Between March 22, 2012 and March 8, 2019, 172 participants were enrolled and randomised (83 LDVD, 89 HDVD) and differed at baseline only in gender and race: more males received HDVD (31%) than LDVD (16%), and fewer Black participants received HDVD (12%) than LDVD (22%). Among 165 participants with at least one follow-up visit, the proportion experiencing confirmed relapse did not differ between LDVD and HDVD [at 96 weeks: 32% vs. 34%, p = 0.60; hazard ratio (HR): 1.17 (0.67, 2.05), p = 0.57]. There was no hypercalcaemia. Three participants developed nephrolithiasis or ureterolithiasis (1 in the LDVD and 2 in the HDVD group). Two were possibly related to study drug; and one was presumed related to concomitant treatment with topiramate for migraine. Interpretation: VIDAMS provides evidence that HDVD supplementation, added to GA, does not reduce the risk of clinical relapse in people with RRMS. Taken together with the null findings of previous trials, these results suggest that prescribing higher doses of vitamin D for purposes of modifying the RRMS course may not be beneficial. Funding: This investigation was supported by a grant from the National Multiple Sclerosis Society (RG 4407A2/1). Teva Neuroscience, Inc. provided Copaxone (GA) for the duration of the trial.

Respiratory symptoms are common in stiff person syndrome spectrum disorders and are associated with number of body regions involved.

BACKGROUND AND PURPOSE: Stiff person syndrome (SPS) spectrum disorders (SPSSD) cause spasms and rigidity throughout different body regions and can be associated with apnea and acute respiratory failure. There are limited data on the prevalence and predictors of respiratory symptoms with spasms (RSwS) in SPSSD. We sought to characterize the spirometry patterns and the frequency and predictors of RSwS in a large SPSSD cohort. METHODS: Participants were recruited from the Johns Hopkins SPS Center between 1997 and 2021, as part of an ongoing, longitudinal observational study. Medical records were reviewed to assess demographics and clinical characteristics. Data were analyzed using descriptive statistics and multivariable logistic regression models. RESULTS: One-hundred ninety-nine participants (mean age = 53.4 ± 13.6 years, median time to diagnosis = 36 [IQR 66] months, 74.9% women, 69.8% White, 62.8% classic SPS phenotype) were included in final analyses; 35.2% of participants reported RSwS, of whom 24.3% underwent spirometry as part of routine clinical care. Obstructive (23.5%) and restrictive (23.5%) patterns were most commonly observed in those with SPSSD. An increasing number of body regions involved predicted the presence of RSwS (odds ratio [OR] = 1.95, 95% confidence interval [CI] = 1.50-2.53); those with ≥5 body regions involved (vs. ≤4) had higher odds (OR = 6.19, 95% CI = 2.81-13.62) of experiencing RSwS in adjusted models. Two patients died from SPSSD-associated respiratory compromise. CONCLUSIONS: RSwS are common in SPSSD and may be predicted by an increasing number of body regions involved by SPSSD. Close clinical monitoring and having a low threshold to obtain spirometry should be considered in people with SPSSD.