Inflammatory Activity on Natalizumab Predicts Short-term but not Long-term Disability in Multiple Sclerosis

BACKGROUND: In people with multiple sclerosis treated with interferon-beta or glatiramer acetate, new MRI lesions and relapses during the first year of treatment predict a poor prognosis. OBJECTIVE: To study this association in those receiving natalizumab. METHODS: Data were collected on relapses, new MRI activity, and Modified Rio Score after initiation of natalizumab in an observational cohort of 161 patients with high baseline disability. These were correlated with Expanded Disability Status Scale (EDSS) progression at years 1, 2, 3, and 3-7 after treatment initiation, versus pre-treatment baseline. RESULTS: 46/161 patients had a relapse in the first year and 44/161 had EDSS progression by year 2. Relapses and Modified Rio Score in the first year of treatment predicted EDSS progression at year 1 and 2 after treatment initiation. However, this effect disappeared with longer follow-up. Paradoxically, there was a trend towards inflammatory activity on treatment (first year Modified Rio Score, relapses, and MRI activity) predicting a lower risk of EDSS progression by years 3-7, although this did not reach statistical significance. Those with and without EDSS progression did not differ in baseline age, EDSS, or pre-treatment relapse rate. Relapses in year 0-1 predicted further relapses in years 1-3. CONCLUSIONS: Breakthrough inflammatory activity after natalizumab treatment is predictive of short-term outcome measures of relapses or EDSS progression, but does not predict longer term EDSS progression, in this cohort with high baseline disability

Raising concerns in the current NHS climate: a qualitative study exploring junior doctors’ attitudes to training and teaching

BACKGROUND: High profile cases continue to demonstrate failures to raise concerns with detrimental effects on patient safety. This research sought to establish what educational support junior doctors needed to effectively raise clinical and professional concerns. // STUDY DESIGN: A qualitative study with 16 participants taking part in three focus groups. The transcripts were thematically analysed. // RESULTS: All the data could be coded into four themes: past experiences of teaching; suggested teaching; reporting mechanisms and educational challenges. Most participants were dissatisfied with the teaching they had received on raising concerns. Current systems were thought to be good for raising patient safety issues but not for concerns about professional behaviour of healthcare staff. // CONCLUSIONS: There is a need for improved education to tackle the way this is taught in postgraduate curricula. Frequent rotations and a lack of meaningful relationships left junior doctors feeling less invested in improving organisational culture. Junior doctors are apprehensive about raising concerns because of personal risk to their career trajectory

Mononuclear cell transcriptome changes associated with dimethyl fumarate in MS.

ObjectiveTo identify short-term changes in gene expression in peripheral blood mononuclear cells (PBMCs) associated with treatment response to dimethyl fumarate (DMF, Tecfidera) in patients with relapsing-remitting MS (RRMS).MethodsBlood samples were collected from 24 patients with RRMS (median Expanded Disability Status Scale score, 2.0; range 1-7) at baseline, 6 weeks, and 15 months after the initiation of treatment with DMF (BG-12; Tecfidera). Seven healthy controls were also recruited, and blood samples were collected over the same time intervals. PBMCs were extracted from blood samples and sequenced using next-generation RNA sequencing. Treatment responders were defined using the composite outcome measure "no evidence of disease activity" (NEDA-4). Time-course and cross-sectional differential expression analyses were performed to identify transcriptomic markers of treatment response.ResultsTreatment responders (NEDA-4 positive, 8/24) over the 15-month period had 478 differentially expressed genes (DEGs) 6 weeks after the start of treatment. These were enriched for nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and inhibition of nuclear factor κB (NFκB) pathway transcripts. For patients who showed signs of disease activity, there were no DEGs at 6 weeks relative to their (untreated) baseline. Contrasting transcriptomes expressed at 6 weeks with those at 15 months of treatment, 0 and 1,264 DEGs were found in the responder and nonresponder groups, respectively. Transcripts in the nonresponder group (NEDA-4 negative, 18/24) were enriched for T-cell signaling genes.ConclusionShort-term PBMC transcriptome changes reflecting activation of the Nrf2 and inhibition of NFκB pathways distinguish patients who subsequently show a medium-term treatment response with DMF. Relative stabilization of gene expression patterns may accompany treatment-associated suppression of disease activity

Revalidation and quality assurance: the application of the MUSIQ framework in independent verification visits to healthcare organisations

Objectives We present a national evaluation of the impact of independent verification visits (IVVs) performed by National Health Service (NHS) England as part of quality assuring medical revalidation. Organisational visits are central to NHS quality assurance. They are costly, yet little empirical research evidence exists concerning their impact, and what does exist is conflicting. Setting The focus was on healthcare providers in the NHS (in secondary care) and private sector across England, who were designated bodies (DBs). DBs are healthcare organisations that have a statutory responsibility, via the lead clinician, the responsible officer (RO), to implement medical revalidation. Participants All ROs who had undergone an IVV in England in 2014 and 2015 were invited to participate. 46 ROs were interviewed. Ethnographic data were gathered at 18 observations of the IVVs and 20 IVV post visit reports underwent documentary analysis. Primary and secondary outcome measures Primary outcomes were the findings pertaining to the effectiveness of the IVV system in supporting the revalidation processes at the DBs. Secondary outcomes were methodological, relating to the Model for Understanding Success in Quality (MUSIQ) and how its application to the IVV reveals the relevance of contextual factors described in the model. Results The impact of the IVVs varied by DB according to three major themes: the personal context of the RO; the organisational context of the DB; and the visit and its impact. ROs were largely satisfied with visits which raised the status of appraisal within their organisations. Inadequate or untimely feedback was associated with dissatisfaction. Conclusions Influencing teams whose prime responsibility is establishing processes and evaluating progress was crucial for internal quality improvement. Visits acted as a nudge, generating internal quality review, which was reinforced by visit teams with relevant expertise. Diverse team membership, knowledge transfer and timely feedback made visits more impactful

Serum Neurofilament Light and Multiple Sclerosis Progression Independent of Acute Inflammation

Introduction Efforts to explore the utility of neurofilament light (NfL) as a biomarker associated with disability progression in multiple sclerosis (MS) have accelerated in recent years in the absence of pharmacodynamic or treatment response markers for clinical trials or patient care.1 The International Progressive MS Alliance stated in 2020 that serum NfL (sNfL) measurements may serve as a useful biomarker associated with progressive MS, although further work is needed to define the relative contributions of inflammatory activity and neurodegeneration to longitudinal changes in disability and sNfL.2 Using data from a large clinical trial of patients with secondary progressive MS (a phase 3, randomized, double-blind, placebo-controlled trial exploring the effect of natalizumab on disease progression in participants with Secondary Progressive Multiple Sclerosis [ASCEND in SPMS]; NCT01416181), we investigated whether sNfL could be used as a dynamic biomarker associated with progressive MS disease course. That is, we investigated whether longitudinal changes in sNfL concentration were associated with disability progression measures in the absence of relapses and magnetic resonance imaging (MRI) evidence of inflammatory activit

Attitudes towards attrition among UK trainees in obstetrics and gynaecology

Physician dissatisfaction in the workplace has consequences for patient safety. Currently in the UK, 1 in 5 doctors who enter specialist training in obstetrics and gynaecology leave the programme before completion. Trainee attrition has implications for workforce planning, organization of health-care services and patient care. The authors conducted a survey of current trainees' and former trainees' views concerning attrition and ‘peri-attrition’ – a term coined to describe the trainee who has seriously considered leaving the specialty. The authors identified six key themes which describe trainees' feelings about attrition in obstetrics and gynaecology: morale and undermining; training processes and paperwork; support and supervision; work–life balance and realities of life; NHS environment; and job satisfaction. This article discusses themes of an under-resourced health service, bullying, lack of work–life balance and poor personal support

Breaking the cycle: reversal of flux in the tricarboxylic acid cycle by dimethyl fumarate

Objective To infer molecular effectors of therapeutic effects and adverse events for dimethyl fumarate (DMF) in relapsing-remitting MS patients (RRMS) using untargeted plasma metabolomics. Methods Plasma from 27 RRMS patients was collected at baseline and six-weeks after initiating DMF. Patients were separated into discovery (n=15) and validation cohorts (n=12). Ten healthy controls were also recruited. Metabolomic profiling using ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS) was performed on the discovery cohort and healthy controls at Metabolon Inc. (Durham, NC). UPLC-MS was performed on the validation cohort at the National Phenome Centre (London, UK). Plasma neurofilament concentration (pNfL) was assayed using the Simoa platform (Quanterix, Lexington, MA). Time course and cross-sectional analyses were performed to identify pharmacodynamic changes in the metabolome secondary to DMF and relate these to adverse events. Results In the discovery cohort, tricarboxylic acid (TCA) cycle intermediates fumarate and succinate and TCA cycle metabolites succinyl-carnitine and methyl succinyl-carnitine increased 6-weeks following treatment (q < 0.05). Methyl succinyl carnitine increased in the validation cohort (q < 0.05). These changes were not observed in the control population. Increased succinyl-carnitine and methyl succinyl-carnitine were associated with adverse events from DMF (flushing, abdominal symptoms). pNfL concentration was higher in RRMS patients than controls and reduced over 15-months treatment. Conclusion TCA cycle intermediates and metabolites are increased in RRMS patients treated with DMF. The results suggest reversal of flux through the succinate dehydrogenase complex. The contribution of succinyl-carnitine ester agonism at hydroxylic acid receptor-2 to both therapeutic effects and adverse events requires investigation

Glial fibrillary acidic protein and multiple sclerosis progression independent of acute inflammation

Background: The clinical relevance of serum glial fibrillary acidic protein (sGFAP) concentration as a biomarker of MS disability progression independent of acute inflammation has yet to be quantified.// Objective: To test whether baseline values and longitudinal changes in sGFAP concentration are associated with disability progression without detectable relapse of magnetic resonance imaging (MRI) inflammatory activity in participants with secondary-progressive multiple sclerosis (SPMS).// Methods: We retrospectively analyzed longitudinal sGFAP concentration and clinical outcome data from the Phase 3 ASCEND trial of participants with SPMS, with no detectable relapse or MRI signs of inflammatory activity at baseline nor during the study (n = 264). Serum neurofilament (sNfL), sGFAP, T2 lesion volume, Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT), and composite confirmed disability progression (CDP) were measured. Linear and logistic regressions and generalized estimating equations were used in the prognostic and dynamic analyses.// Results: We found a significant cross-sectional association between baseline sGFAP and sNfL concentrations and T2 lesion volume. No or weak correlations between sGFAP concentration and changes in EDSS, T25FW, and 9HPT, or CDP were observed.// Conclusion: Without inflammatory activity, changes in sGFAP concentration in participants with SPMS were neither associated with current nor predictive of future disability progression./