Assessment of Microplastics in Southeastern Florida Forage Fishes

Microplastics threaten the health of numerous marine organisms at all trophic levels. Currently, the topic is well studied among larger predators such as marine birds, dolphins, pelagic fishes, and even herbivorous organisms such as manatees. However, knowledge of microplastics present in organisms at lower trophic levels is poorly understood. The aim of this study was to assess the presence of microplastics in lower trophic level forage fishes. To gain a clear depiction of microplastics in the forage fishes of South Florida, four locations were sampled. These locations were classified into two categories, urban (Port Everglades and Northern Biscayne Bay) and non-urban (Islamorada and Marathon, in the Florida Keys). Five species were sampled: Striped Mullet, Scaled Sardine, Needlefish, Pinfish, and Irish Mojarra. Every sampled fish except one (n= 248) had microplastics within their systems, with a total of 2,126 pieces found. There was no significant difference in microplastics concentration among forage fish species. However, location had a significant effect on the frequency of microplastics found within the sampled fishes, with Northern Biscayne Bay being greater compared to the other three sample locations. There was no significant difference in microplastic frequency amongst the three feeding habits within the five sampled species. However, as Redfin Needlefish and Pinfish matured, an increase in microplastic frequency was observed. With a frequency of 99.6% of microplastic contamination within the sampled fishes, significant conservation efforts should be warranted

Blood neurofilament light as a potential endpoint in Phase 2 studies in MS

Objectives To assess whether neurofilament light chain (NfL) could serve as an informative endpoint in Phase 2 studies in patients with relapsing-remitting multiple sclerosis (RRMS) and estimate the sample size requirements with NfL as the primary endpoint. Methods Using data from the Phase 3 FREEDOMS study, we evaluated correlation of NfL at Month 6 with 2-year outcomes: relapses, confirmed disability worsening (CDW), new or enlarging T2 lesions (active lesions), and brain volume loss (BVL). We compared the proportion of treatment effect (PTE) on 2-year relapses and BVL explained by 6-month log-transformed NfL levels with the PTE explained by the number of active lesions over 6 months. We estimated sample size requirements for different treatment effects. Results At Month 6, blood NfL levels (pg/mL, median [range]) were lower in the fingolimod arm (fingolimod (n = 132) 18 [8-247]; placebo (n = 114) 26 [8-159], P < 0.001). NfL at 6 months correlated with number of relapses (r = 0.25, P < 0.001), 6-month CDW (hazard ratio 1.83, P = 0.012), active lesions (r = 0.46, P < 0.001), and BVL (r = -0.41, P < 0.001) at Month-24. The PTE (95% CI) on 24-month relapses and BVL explained by 6-month NfL was 25% (8-60%) and 60% (32-132%), and by 6-month active lesions was 28% (11-66%) and 45% (18-115%), respectively. Assuming a 20-40% treatment-related reduction in NfL levels, 143-28 patients per arm will be required. Conclusions Blood NfL may qualify as an informative and easy-to-measure endpoint for future Phase 2 clinical studies that captures both inflammatory- and noninflammatory-driven neuroaxonal injury in RRMS

Learning ability correlates with brain atrophy and disability progression in RRMS

Objective To assess the prognostic value of practice effect on Paced Auditory Serial Addition Test (PASAT) in multiple sclerosis. Methods We compared screening (day a '14) and baseline (day 0) PASAT scores of 1009 patients from the FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis (FREEDOMS) trial. We grouped patients into high and low learners if their PASAT score change was above or below the median change in their screening PASAT quartile group. We used Wilcoxon test to compare baseline disease characteristics between high and low learners, and multiple regression models to assess the respective impact of learning ability, baseline normalised brain volume and treatment on brain volume loss and 6-month confirmed disability progression over 2 years. Results The mean PASAT score at screening was 45.38, increasing on average by 3.18 from day a '14 to day 0. High learners were younger (p=0.003), had lower Expanded Disability Status Scale score (p=0.031), higher brain volume (p<0.001) and lower T2 lesion volume (p=0.009) at baseline. Learning status was not significantly associated with disability progression (HR=0.953, p=0.779), when adjusting for baseline normalised brain volume, screening PASAT score and treatment arm. However, the effect of fingolimod on disability progression was more pronounced in high learners (HR=0.396, p<0.001) than in low learners (HR=0.798, p=0.351; p for interaction=0.05). Brain volume loss at month 24 tended to be higher in low learners (0.17%, p=0.058), after adjusting for the same covariates. Conclusions Short-term practice effects on PASAT are related to brain volume, disease severity and age and have clinically meaningful prognostic implications. High learners benefited more from fingolimod treatment

Pharmacodynamics of interferon beta in multiple sclerosis patients with or without serum neutralizing antibodies

Abstract : To analyze the in vivo biological effect of anti-interferon beta (IFN-beta) neutralizing antibodies (NABs), blood concentrations of neopterin, beta2microglobulin (Beta2-MG), mRNA-dependent myxovirusresistant protein A (MxA) and dsRNA-dependent protein kinase (PKR) were measured before (predose) and 24 hours after (postdose) IFN-beta administration in 49 patients with multiple sclerosis (MS) with (n = 25) and without (n = 24) NABs. The results indicated that predose levels of MxA-mRNA and PKR-mRNA were highly variable [coefficient of variation (CV) > 100%] among patients. A lower inter-individual variability was observed for pre-dose levels of Beta2-MG and neopterin (CVs of 29% and 44%, respectively). Significantly lower pre- and post-dose blood levels of IFN induced markers, except for postdose PKR-mRNA (p = 0.09), were seen in NAB+ compared with NAB-patients and between patients with high (> 200 t1/10) and low (£ 200 t1/10) NAB titers. A significant inverse correlation between NAB titer and pre-dose levels of the above IFN-induced markers was found. In summary, our findings confirm that NABs affect absolute concentrations of IFN-beta induced markers and suggest that such an effect occurs in a titer-dependent manne

Long-term safety and effectiveness of natalizumab treatment in clinical practice: 10 years of real-world data from the Tysabri Observational Program (TOP)

ObjectiveThe Tysabri Observational Programme (TOP), which began >10 years ago, is an open-label, multinational, prospective observational study evaluating the long-term safety and effectiveness of natalizumab in relapsing-remitting multiple sclerosis patients.MethodsThese data provide a 10-year interim analysis of safety and effectiveness in TOP. Annualised relapse rates (ARRs) and disability progression/improvement were analysed using the Poisson model and the Kaplan-Meier method, respectively. Analyses included patients on natalizumab and those who discontinued natalizumab but remained in TOP.ResultsAs of November 2017, TOP included 6148 patients. Overall, 829 patients (13.5%) experienced ≥1 serious adverse event (SAE), with infection the most common (4.1%). Fifty-three patients (0.9%) had confirmed progressive multifocal leukoencephalopathy. SAE data were consistent with natalizumab's known safety profile; no new safety signals were identified. A total of 3210 patients (52.2%) discontinued natalizumab; 2117 (34.4%) withdrew from TOP. Median time on natalizumab was 3.3 (range 0–11.6) years; median follow-up time was 5.2 (range 0–10.8) years. The on-natalizumab ARR was 0.15, a 92.5% reduction from the year before initiation. Ten-year cumulative probabilities of disability worsening and improvement were 27.8% and 33.1%, respectively. On-natalizumab ARRs were similar between patients who discontinued or remained on natalizumab, suggesting limited attrition bias.ConclusionsSince the TOP 5-year interim analysis (December 2012), cohort size (6148 vs 4821), median exposure (3.3 vs 1.8 years) and median follow-up time (62 vs 26 months) have increased. This 10-year interim analysis further supports the robust real-world effectiveness and well-established safety profile of natalizumab.Trial registration numberNCT00493298

Harmonizing Definitions for Progression Independent of Relapse Activity in Multiple Sclerosis: A Systematic Review

IMPORTANCE: Emerging evidence suggests that progression independent of relapse activity (PIRA) is a substantial contributor to long-term disability accumulation in relapsing-remitting multiple sclerosis (RRMS). To date, there is no uniform agreed-upon definition of PIRA, limiting the comparability of published studies. OBJECTIVE: To summarize the current evidence about PIRA based on a systematic review, to discuss the various terminologies used in the context of PIRA, and to propose a harmonized definition for PIRA for use in clinical practice and future trials. EVIDENCE REVIEW: A literature search was conducted using the search terms multiple sclerosis, PIRA, progression independent of relapse activity, silent progression, and progression unrelated to relapses in PubMed, Embase, Cochrane, and Web of Science, published between January 1990 and December 2022. FINDINGS: Of 119 identified single records, 48 eligible studies were analyzed. PIRA was reported to occur in roughly 5% of all patients with RRMS per annum, causing at least 50% of all disability accrual events in typical RRMS. The proportion of PIRA vs relapse-associated worsening increased with age, longer disease duration, and, despite lower absolute event numbers, potent suppression of relapses by highly effective disease-modifying therapy. However, different studies used various definitions of PIRA, rendering the comparability of studies difficult. CONCLUSION AND RELEVANCE: PIRA is the most frequent manifestation of disability accumulation across the full spectrum of traditional MS phenotypes, including clinically isolated syndrome and early RRMS. The harmonized definition suggested here may improve the comparability of results in current and future cohorts and data sets

Cocapture of cognate and bystander antigens can activate autoreactive B cells

Autoantibodies against myelin oligodendrocyte glycoprotein (MOG) are associated with autoimmune central nervous system diseases like acute disseminated encephalomyelitis (ADEM). For ADEM, it is speculated that a preceding infection is the trigger of the autoimmune response, but the mechanism connecting the infection to the production of MOG antibodies remains a mystery. We reasoned that the ability of B cells to capture cognate antigen from cell membranes, along with small quantities of coexpressed “bystander” antigens, might enable B-cell escape from tolerance. We tested this hypothesis using influenza hemagglutinin as a model viral antigen and transgenic, MOG-specific B cells. Using flow cytometry and live and fixed cell microscopy, we show that MOG-specific B cells take up large amounts of MOG from cell membranes. Uptake of the antigen from the membrane leads to a strong activation of the capturing B cell. When influenza hemagglutinin is also present in the membrane of the target cell, it can be cocaptured with MOG by MOG-specific B cells via the B-cell receptor. Hemagglutinin and MOG are both presented to T cells, which in turn are activated and proliferate. As a consequence, MOG-specific B cells get help from hemagglutinin-specific T cells to produce anti-MOG antibodies. In vivo, the transfer of MOG-specific B cells into recipient mice after the cocapture of MOG and hemagglutinin leads to the production of class-switched anti-MOG antibodies, dependent on the presence of hemagglutinin-specific T cells. This mechanism offers a link between infection and autoimmunity. Keywords: tolerance; autoantibodies; antigen capture; antigen presentation; influenz

Evolution from a first clinical demyelinating event to multiple sclerosis in the REFLEX trial: Regional susceptibility in the conversion to multiple sclerosis at disease onset and its amenability to subcutaneous interferon beta-1a

BACKGROUND AND PURPOSE: In the REFLEX trial (ClinicalTrials.gov identifier: NCT00404352), patients with a first clinical demyelinating event (FCDE) displayed significantly delayed onset of multiple sclerosis (MS; McDonald criteria) when treated with subcutaneous interferon β-1a (scIFNβ-1a) versus placebo. This post hoc analysis evaluated the effect of scIFNβ-1a on spatio-temporal evolution of disease activity, assessed by changes in T2 lesion distribution, in specific brain regions of such patients and its relationship with conversion to MS. METHODS: Post hoc analysis of baseline and 24-month MRI data from FCDE patients who received scIFNβ-1a 44 μg once or three times weekly, or placebo in the REFLEX trial. Patients were grouped according to McDonald MS status (converter/non-converter) or treatment (scIFNβ-1a/placebo). For each patient group, a baseline lesion probability map (LPM) and longitudinal new/enlarging and shrinking/disappearing LPMs were created. Lesion location/frequency of lesion occurrence were assessed in the white matter (WM). RESULTS: At Month 24, lesion frequency was significantly higher in the anterior thalamic radiation (ATR) and corticospinal tract (CST) of converters versus non-converters (p<0.05). Additionally, the overall distribution of new/enlarging lesions across the brain at Month 24 was similar in placebo- and scIFNβ-1a-treated patients (ratio: 0.95). Patients treated with scIFNβ-1a versus placebo showed significantly lower new lesion frequency in specific brain regions (cluster corrected): ATR (p=0.025), superior longitudinal fasciculus (p=0.042), CST (p=0.048), and inferior longitudinal fasciculus (p=0.048). CONCLUSIONS: T2 lesion distribution in specific brain locations predict conversion to McDonald MS and show significantly reduced new lesion occurrence after treatment with scIFNβ-1a in an FCDE population

The 11-year long-term follow-up study from the randomized BENEFIT CIS trial

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