MRI-derived g-ratio and lesion severity in newly diagnosed multiple sclerosis

Myelin loss is associated with axonal damage in established multiple sclerosis. This relationship is challenging to study in vivo in early disease. Here, we ask whether myelin loss is associated with axonal damage at diagnosis, by combining non-invasive neuroimaging and blood biomarkers. We performed quantitative microstructural MRI and single molecule ELISA plasma neurofilament measurement in 73 patients with newly diagnosed, immunotherapy naïve relapsing-remitting multiple sclerosis. Myelin integrity was evaluated using aggregate g-ratios, derived from magnetization transfer saturation (MTsat) and neurite orientation dispersion and density imaging (NODDI) diffusion data. We found significantly higher g-ratios within cerebral white matter lesions (suggesting myelin loss) compared with normal-appearing white matter (0.61 vs 0.57, difference 0.036, 95% CI 0.029 to 0.043, p < 0.001). Lesion volume (Spearman’s rho rs= 0.38, p < 0.001) and g-ratio (rs= 0.24 p < 0.05) correlated independently with plasma neurofilament. In patients with substantial lesion load (n = 38), those with higher g-ratio (defined as greater than median) were more likely to have abnormally elevated plasma neurofilament than those with normal g-ratio (defined as less than median) (11/23 [48%] versus 2/15 [13%] p < 0.05). These data suggest that, even at multiple sclerosis diagnosis, reduced myelin integrity is associated with axonal damage. MRI-derived g-ratio may provide useful additional information regarding lesion severity, and help to identify individuals with a high degree of axonal damage at disease onset. York, Martin et al. simultaneously measured g-ratio and plasma neurofilament in 73 relapsing-remitting multiple sclerosis patients at diagnosis using advanced MRI and single molecule ELISA. They demonstrate that g-ratio of cerebral white matter lesions varies at diagnosis, and show that high g-ratio of lesions is associated with elevated plasma neurofilament

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

ERK/MAPK regulates hippocampal histone phosphorylation following contextual fear conditioning

Long-term memory formation is regulated by many distinct molecular mechanisms that control gene expression. An emerging model for effecting a stable, coordinated pattern of gene transcription involves epigenetic tagging through modifications of histones or DNA. In this study, we investigated the regulation of histone phosphorylation in the hippocampus by the ERK/MAPK (extracellular signal-regulated kinase/mitogen-activated protein kinase) pathway. We found that activation of ERK/MAPK in vitro significantly increased histone H3 phosphorylation in hippocampal area CA1. Furthermore, we found that contextual fear conditioning in vivo leads to a rapid time-dependent increase in histone H3 phosphorylation in area CA1. This increase paralleled the time course of contextual fear-dependent activation of ERK, and was inhibited in vivo by a latent inhibition paradigm as well as by injection of an N-methyl-d-aspartic acid receptor (NMDA-R) antagonist. Finally, injection of an inhibitor of MEK (MAP kinase/ERK kinase), the unique dual-specificity kinase upstream of ERK, blocked the increase in histone H3 phosphorylation seen after contextual fear conditioning. These results demonstrate that changes in histone phosphorylation in the hippocampus are regulated by ERK/MAPK following a behavioral fear conditioning paradigm

Symptomatic therapy in multiple sclerosis: a review for a multimodal approach in clinical practice

As more investigations into factors affecting the quality of life of patients with multiple sclerosis (MS) are undertaken, it is becoming increasingly apparent that certain comorbidities and associated symptoms commonly found in these patients differ in incidence, pathophysiology and other factors compared with the general population. Many of these MS-related symptoms are frequently ignored in assessments of disease status and are often not considered to be associated with the disease. Research into how such comorbidities and symptoms can be diagnosed and treated within the MS population is lacking. This information gap adds further complexity to disease management and represents an unmet need in MS, particularly as early recognition and treatment of these conditions can improve patient outcomes. In this manuscript, we sought to review the literature on the comorbidities and symptoms of MS and to summarize the evidence for treatments that have been or may be used to alleviate them

Point of View: The future of graduate and postdoctoral training in the biosciences

This article summarizes the outcomes of the second national conference on the Future of Bioscience Graduate and Postdoctoral Training. Five topics were addressed during the conference: diversity in leadership positions; mentoring; modernizing the curriculum; experiential learning; and the need for better data on trainees. The goal of the conference was to develop a consensus around these five topics and to recommend policies that can be implemented by academic and research institutions and federal funding agencies in the United States

Dupilumab efficacy in patients with uncontrolled, moderate-to-severe allergic asthma

BACKGROUND: Dupilumab blocks the shared receptor component for IL-4 and IL-13, key drivers of type 2 inflammation, including IgE-mediated allergic inflammation in asthma. In the LIBERTY ASTHMA QUEST (NCT02414854) study, dupilumab reduced severe asthma exacerbations and improved forced expiratory volume in 1 second (FEV1) in patients with uncontrolled, moderate-to-severe asthma with greater efficacy observed in patients with elevated type 2 inflammatory biomarkers (blood eosinophils and fractional exhaled nitric oxide) at baseline. OBJECTIVE: We assessed dupilumab's effect on key asthma outcomes in QUEST patients with/without evidence of allergic patients with uncontrolled, moderate-to-severe asthma with greater efficacy observed in patients with elevated type 2 inflammatory biomarkers (blood eosinophils and fractional exhaled nitric oxide) at baseline. OBJECTIVE: We assessed dupilumab's effect on key asthma outcomes in QUEST patients with/without evidence of allergic asthma (total serum IgE >= 30 IU/mL and >= 1 perennial aeroallergen-specific IgE >= 0.35 kU/L at baseline). METHODS: Severe exacerbation rates and change from baseline in FEV1, asthma control, and markers of type 2 inflammation during the 52-week treatment period were assessed. RESULTS: In the allergic asthma subgroup (n = 1083), dupilumab 200/300 mg every 2 weeks versus placebo reduced severe asthma exacerbation rates (-36.9%/-45.5%; both P < .01), improved FEV1 at week 12 (0.13 L/0.16 L; both P < .001; improvements were evident by the first evaluation at week 2) with greater efficacy observed in patients with elevated type 2 inflammatory biomarkers at baseline, and improved asthma control. Dupilumab treatment also resulted in rapid and sustained reductions in type 2 inflammatory biomarkers. Comparable results were observed in patients without evidence of allergic asthma (n = 819). CONCLUSION: Dupilumab reduced severe exacerbation rates, improved FEV1 and asthma control, and suppressed type 2 inflammatory biomarkers in patients with uncontrolled, moderate-to-severe asthma with or without evidence of allergic asthma, highlighting the key role of IL-4 and IL-13 in airway inflammation. (C) 2019 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunolog