Stratification and monitoring of natalizumab-associated progressive multifocal leukoencephalopathy risk: recommendations from an expert group

The use of natalizumab for highly active relapsing-remitting multiple sclerosis (MS) is influenced by the occurrence of progressive multifocal leukoencephalopathy (PML). Through measurement of the anti-JCV antibody index, and in combination with the presence or absence of other known risk factors, it may be possible to stratify patients with MS according to their risk of developing PML during treatment with natalizumab and detect early suspected PML using MRI including a diffusion-weighted imaging sequence. This paper describes a practical consensus guideline for treating neurologists, based on current evidence, for the introduction into routine clinical practice of anti-JCV antibody index testing of immunosuppressant-naïve patients with MS, either currently being treated with, or initiating, natalizumab, based on their anti-JCV antibody status. Recommendations for the frequency and type of MRI screening in patients with varying index-associated PML risks are also discussed. This consensus paper presents a simple and pragmatic algorithm to support the introduction of anti-JCV antibody index testing and MRI monitoring into standard PML safety protocols, in order to allow some JCV positive patients who wish to begin or continue natalizumab treatment to be managed with a more individualised analysis of their PML risk

Varicella-Zoster viruses associated with post-herpetic neuralgia induce sodium current density increases in the ND7-23 Nav-1.8 neuroblastoma cell line

Post-herpetic neuralgia (PHN) is the most significant complication of herpes zoster caused by reactivation of latent Varicella-Zoster virus (VZV). We undertook a heterologous infection in vitro study to determine whether PHN-associated VZV isolates induce changes in sodium ion channel currents known to be associated with neuropathic pain. Twenty VZV isolates were studied blind from 11 PHN and 9 non-PHN subjects. Viruses were propagated in the MeWo cell line from which cell-free virus was harvested and applied to the ND7/23-Nav1.8 rat DRG x mouse neuroblastoma hybrid cell line which showed constitutive expression of the exogenous Nav 1.8, and endogenous expression of Nav 1.6 and Nav 1.7 genes all encoding sodium ion channels the dysregulation of which is associated with a range of neuropathic pain syndromes. After 72 hrs all three classes of VZV gene transcripts were detected in the absence of infectious virus. Single cell sodium ion channel recording was performed after 72 hr by voltage-clamping. PHN-associated VZV significantly increased sodium current amplitude in the cell line when compared with non-PHN VZV, wild-type (Dumas) or vaccine VZV strains ((POka, Merck and GSK). These sodium current increases were unaffected by acyclovir pre-treatment but were abolished by exposure to Tetrodotoxin (TTX) which blocks the TTX-sensitive fast Nav 1.6 and Nav 1.7 channels but not the TTX-resistant slow Nav 1.8 channel. PHN-associated VZV sodium current increases were therefore mediated in part by the Nav 1.6 and Nav 1.7 sodium ion channels. An additional observation was a modest increase in message levels of both Nav1.6 and Nav1.7 mRNA but not Nav 1.8 in PHN virally infected cells

Hydrogeologic field investigation and groundwater flow model of the southern Willamette Valley, Oregon

Elevated groundwater nitrate (NO3 -) concentrations in the Southern Willamette Valley (SWV) caused the Oregon Department of Environmental Quality (ODEQ) to declare a Groundwater Management Area (GWMA) in Spring, 2004. To better understand direction of groundwater flow, groundwater age, and nitrate transport pathways of the SWV we developed a steady-state numerical groundwater flow model using MODFLOW with MODPATH. Model development was supplemented by field investigations of local outcrops, pump and slug tests, and laboratory analyses to determine groundwater age and groundwater chemistry. Field work included the construction/collection of cross-sections and stratigraphic columns; 12 slug tests and 3 pump tests to determine hydraulic conductivity and storativity; 10 groundwater ages using CFC-11, CFC-12, and CFC-113; 3 wells instrumented to collect long-term continuous water level measurements; 42 wells selected for quarterly manual water level measurements; and 14 groundwater samples to determine pH, dissolved oxygen, specific electrical conductance, chloride, sulfate, and nitrate concentrations. Slug tests determined horizontal hydraulic conductivities (Kx) from 4.19 x 10-8 m/s to 4.62 x 10-4 m/s. Pump tests determined Kx-values from 3.59 x 10-4 m/s to 7.22 x 10-3 m/s, vertical hydraulic conductivities (Kv) from 3.48 x 10-6 m/s to 3.84 x 10-6 m/s, and storage coefficients from 0.05 to 0.15. Groundwater age ranged from 13 years to >50 years, with the greatest ages resulting from wells that penetrated the semi-confining Willamette Silt. Groundwater ages were compared to model particle travel times using MODPATH and used as calibration targets. Groundwater ages along with nitrate, chloride, sulfate, and dissolved oxygen concentrations were used to reconstruct past contaminant loading and observe data trends. Spatial distributions of hydraulic conductivity were estimated using wells with specific capacity data and an empirical relationship (T = 158.48sc, where T = transmissivity (ft2/d) and sc = (gal/min/ft); R2 = 0.61) between wells in the study area that contained both specific capacity and aquifer test data. The calibrated groundwater flow model is intended to help make management decisions, establish monitoring programs, and to be used as an outreach education tool. Model simulations were run in key areas to demonstrate model capabilities and create visual aids for outreach education. This study suggests it may take 10’s of years to see measurable declines of groundwater nitrate in some locations. It is our hope that educating stakeholders about local groundwater flow along with stressing the use of Best Management Practices (BMPs) will result in better decision making and lead to a reduction of groundwater nitrate concentration in the SWV

Setting a national consensus for managing mild and blast traumatic brain injury: post-meeting consensus report

A meeting was held on Wednesday 15 January 2020 to examine the current evidence for non-routine imaging and for neuroendocrine screening in the management of military personnel with brain injury and overlapping symptom domains. The Summit aimed to specifically address the relative utility of magnetoencephalography (MEG), diffusion tensor imaging (DTI) and susceptibility weighted imaging (SWI) in the UK context. This Consensus Report discusses points of consensus, points for further discussion/points of equipoise and recommendations that arose during, and following, the meeting

From ‘rock stars’ to ‘hygiene factors’:teachers at private accountancy tuition providers

In this paper, we examine the role, status and autonomy of teachers at English private accountancy tuition providers from 1980 to the present. We argue that, during this period, teachers transformed from ‘rock stars’ who enjoyed significant status and autonomy over their work to ‘hygiene factors’ in a largely standardised and commodified teaching environment. Growing cost pressures on tuition providers and an increasing emphasis on the quality and consistency of the learning experience are identified as significant factors in this transformation. We discuss these findings with reference to current developments towards corporatisation and marketisation in the English higher education sector

Optical coherence tomography in secondary progressive multiple sclerosis: cross-sectional and longitudinal exploratory analysis from the MS-SMART randomised controlled trial

\ua9 Author(s) (or their employer(s)) 2024. Background: Optical coherence tomography (OCT) inner retinal metrics reflect neurodegeneration in multiple sclerosis (MS). We explored OCT measures as biomarkers of disease severity in secondary progressive MS (SPMS). Methods: We investigated people with SPMS from the Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial OCT substudy, analysing brain MRIs, clinical assessments and OCT at baseline and 96 weeks. We measured peripapillary retinal nerve fibre layer (pRNFL) and macular ganglion cell-inner plexiform layer (GCIPL) thicknesses. Statistical analysis included correlations, multivariable linear regressions and mixed-effects models. Results: Of the 212 participants recruited at baseline, 192 attended at 96 weeks follow-up. Baseline pRNFL and GCIPL thickness correlated with Symbol Digit Modalities Test (SDMT) (respectively, r=0.33 (95% CI 0.20 to 0.47); r=0.39 (0.26 to 0.51)) and deep grey matter volume (respectively, r=0.21 (0.07 to 0.35); r=0.28 (0.14 to 0.41)). pRNFL was associated with Expanded Disability Status Scale (EDSS) score change (normalised beta (B)=-0.12 (-0.23 to -0.01)). Baseline pRNFL and GCIPL were associated with Timed 25-Foot Walk change (T25FW) (respectively, B=-0.14 (-0.25 to -0.03); B=-0.20 (-0.31 to -0.10)) and 96-week percentage brain volume change (respectively, B=0.14 (0.03 to 0.25); B=0.23 (0.12 to 0.34)). There were significant annualised thinning rates: pRNFL (-0.83 \ub5m/year) and GCIPL (-0.37 \ub5m/year). Conclusions: In our cohort of people with SPMS and long disease duration, OCT measures correlated with SDMT and deep grey matter volume at baseline; EDSS, T25FW and whole brain volume change at follow-up

Efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis (MS-SMART):a phase 2b, multiarm, double-blind, randomised placebo-controlled trial

Neurodegeneration is the pathological substrate that causes major disability in secondary progressive multiple sclerosis. A synthesis of preclinical and clinical research identified three neuroprotective drugs acting on different axonal pathobiologies. We aimed to test the efficacy of these drugs in an efficient manner with respect to time, cost, and patient resource. Methods: We did a phase 2b, multiarm, parallel group, double-blind, randomised placebo-controlled trial at 13 clinical neuroscience centres in the UK. We recruited patients (aged 25-65 years) with secondary progressive multiple sclerosis who were not on disease-modifying treatment and who had an Expanded Disability Status Scale (EDSS) score of 4·0-6·5. Participants were randomly assigned (1:1:1:1) at baseline, by a research nurse using a centralised web-based service, to receive twice-daily oral treatment of either amiloride 5 mg, fluoxetine 20 mg, riluzole 50 mg, or placebo for 96 weeks. The randomisation procedure included minimisation based on sex, age, EDSS score at randomisation, and trial site. Capsules were identical in appearance to achieve masking. Patients, investigators, and MRI readers were unaware of treatment allocation. The primary outcome measure was volumetric MRI percentage brain volume change (PBVC) from baseline to 96 weeks, analysed using multiple regression, adjusting for baseline normalised brain volume and minimisation criteria. The primary analysis was a complete-case analysis based on the intention-to-treat population (all patients with data at week 96). This trial is registered with ClinicalTrials.gov, NCT01910259

OPTIMISE: MS study protocol: a pragmatic, prospective observational study to address the need for, and challenges with, real world pharmacovigilance in multiple sclerosis

IntroductionThe power of ‘real world’ data to improve our understanding of the clinical aspects of multiple sclerosis (MS) is starting to be realised. Disease modifying therapy (DMT) use across the UK is driven by national prescribing guidelines. As such, the UK provides an ideal country in which to gather MS outcomes data. A rigorously conducted observational study with a focus on pharmacovigilance has the potential to provide important data to inform clinicians and patients while testing the reliability of estimates from pivotal trials when applied to patients in the UK.Methods and analysisThe primary aim of this study is to characterise the incidence and compare the risk of serious adverse events in people with MS treated with DMTs. The OPTIMISE:MS database enables electronic data capture and secure data transfer. Selected clinical data, clinical histories and patient-reported outcomes are collected in a harmonised fashion across sites at the time of routine clinical visits. The first patient was recruited to the study on 24 May 2019. As of January 2021, 1615 individuals have baseline data recorded; follow-up data are being captured and will be reported in due course.Ethics and disseminationThis study has ethical permission (London City and East; Ref 19/LO/0064). Potential concerns around data storage and sharing are mitigated by the separation of identifiable data from all other clinical data, and limiting access to any identifiable data. The results of this study will be disseminated via publication. Participants provide consent for anonymised data to be shared for further research use, further enhancing the value of the study.</jats:sec