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Multiple sclerosis (MS) is a common, complex neurological disease. The precise aetiology of MS is not yet known, although epidemiological data indicate that both genetic and environmental factors are important. The evidence that the environment acts long before MS becomes clinically evident is well established and suggests the existence of a prodromal phase for the disease. The increasing incidence of MS emphasises the need for strategies to prevent this chronic disorder, and the possibility of a prodrome indicates a window of opportunity to potentially reverse early disease processes before clinical disease becomes evident. Studying a prodrome requires techniques other than clinical observation such as monitoring endophenotypes that result from associated risk factors. However, our current knowledge of causal pathways and endophenotypes in MS is limited. Identifying and studying individuals with a high risk of developing the disease provides a powerful opportunity to understand the MS causal cascade and is highly relevant to strategies that are aimed at preventing this debilitating disease.

Background Epstein-Barr Virus (EBV) is a ubiquitous gamma-herpesvirus with which ~ 95% of the healthy population is infected. EBV infection has been implicated in a range of haematological malignancies and autoimmune diseases. Delayed primary EBV infection increases the risk of subsequent complications. Contemporaneous seroepidemiological data is needed to establish best approaches for successful vaccination strategies in the future. Methods We conducted a sero-epidemiological survey using serum samples from 2325 individuals between 0 and 25 years old to assess prevalence of detectable anti-EBV antibodies. Second, we conducted a retrospective review of Hospital Episode Statistics to examine changes in Infectious Mononucleosis (IM) incidence over time. We then conducted a large case-control study of 6306 prevalent IM cases and 1,009,971 unmatched controls extracted from an East London GP database to determine exposures associated with IM. Results 1982/2325 individuals (85.3%) were EBV seropositive. EBV seropositivity increased more rapidly in females than males during adolescence (age 10–15). Between 2002 and 2013, the incidence of IM (derived from hospital admissions data) increased. Exposures associated with an increased risk of IM were lower BMI, White ethnicity, and not smoking. Conclusions We report that overall EBV seroprevalence in the UK appears to have increased, and that a sharp increase in EBV seropositivity is seen in adolescent females, but not males. The incidence of IM requiring hospitalisation is increasing. Exposures associated with prevalent IM in a diverse population include white ethnicity, lower BMI, and never-smoking, and these exposures interact with each other. Lastly, we provide pilot evidence suggesting that antibody responses to vaccine and commonly encountered pathogens do not appear to be diminished among EBV-seronegative individuals. Our findings could help to inform vaccine study designs in efforts to prevent IM and late complications of EBV infection, such as Multiple Sclerosis.

The use of high-efficacy disease-modifying therapies (DMTs) early in the course of multiple sclerosis (MS) has been shown to improve clinical outcomes and is becoming an increasingly popular treatment strategy. As a result, monoclonal antibodies, including natalizumab, alemtuzumab, ocrelizumab, ofatumumab, and ublituximab, are frequently used for the treatment of MS in women of childbearing age. To date, only limited evidence is available on the use of these DMTs in pregnancy. We aim to provide an updated overview of the mechanisms of action, risks of exposure and treatment withdrawal, and pre-conception counseling and management during pregnancy and post-partum of monoclonal antibodies in women with MS. Discussing treatment options and family planning with women of childbearing age is essential before commencing a DMT in order to make the most suitable choice for each individual patient.

Clinical syndromes associated with antibodies against myelin oligodendrocyte glycoprotein (MOG) are now recognized as a distinct neurological disease entity, and are gaining increasing attention. The pathogenic mechanisms underlying MOG-antibody disease (MOGAD) remain incompletely understood. Case series, facilitated by registries, and observational studies over the past few years have shed increasing light on the clinical aspects and therapeutic approaches of MOGAD. MOGAD may manifest with a variety of clinical syndromes, including acute disseminated encephalomyelitis (ADEM), autoimmune encephalitis, optic neuritis (ON) and transverse myelitis (TM). MOGAD can be either monophasic or relapsing. This review aims to provide a comprehensive updated description of the clinical spectrum, paraclinical features, and prognosis of MOG-antibody disease, as well as summarize its therapeutic considerations. Randomized clinical trials, standardized diagnostic criteria and treatment guidelines are the steps forward.

Background Recently, patient and public involvement (PPI) in research has gained significant attention, particularly within the United Kingdom. Although there has been a growing focus on the impact of PPI on research outcomes, there remains an important gap in understanding its effects on the individuals involved and the value they gain from their participation. Objective This scoping review aims to critically examine how PPI benefits both people with lived experience and researchers, shedding light on the value of their involvement in shaping research. Methods We searched MEDLINE, PsycINFO, EMBASE, Cochrane and Web of Science for full‐text articles published in English after 1996. Grey literature searches reviewed policies from international research funders and patient organisations. Two reviewers independently carried out the , title and full‐text article screening stages. Data ion was performed by one reviewer and verified by a second reviewer. Thematic analysis synthesised the findings. Results After searching 3024 citations, 107 published articles and nine unpublished resources were included in the review. Most of the studies were conducted in the United Kingdom in the last 10 years. Thematic analysis of the value of PPI revealed four main themes: (1) value from contributing to research, (2) importance of relationships, (3) attitudes and support for PPI and (4) emotional labour of involvement. Discussion This scoping review reveals the significant contributions alongside systemic challenges of PPI in health research. Being valued was framed as an impact of PPI to both PPI advisors and researchers. It emphasises the importance of social capital in developing relationships between researchers and people with lived experience yet highlights barriers that can hinder effective collaboration. This can lead to experiential knowledge being undervalued as a crucial perspective to inform research. Despite people being chosen to take part on account of their knowledge, skills and lived experience, these resources were not always used to their full potential due to researchers' expectations and restrictive research and institutional processes. The review calls for coordinated efforts to improve how PPI is valued and practised beyond a process or method to ensure PPI is done thoughtfully and effectively.

Multi-system comorbidities are common in patients with multiple sclerosis (PwMS) and significantly influence the disease’s presentation and progression. A comorbidity is defined as an illness other than the specific disease of interest (in this case, MS). Generally, chronic or recurrent conditions are included, while transient conditions such as infection or concussion are excluded. Certain modifiable metabolic diseases in PwMS, such as hypertension, diabetes, dyslipidemia, and modifiable health factors such as smoking, alcohol, and obesity, are also considered part of MS comorbidity in this review, since these are risk factors not only for poor outcomes in MS but also for other vascular comorbidities in PwMS. Cohort studies and clinical trials have reported that comorbidity could have multiple adverse effects on MS. The purpose of this review is to summarize studies investigating modifiable risk factors of comorbidity of MS, as well as multiple body system comorbidities in MS, focusing on the influence these comorbidities have on MS outcomes. We aim to emphasize that the management of MS involves not only disease-modifying therapy, but also requires controlling and preventing modifiable risk factors for comorbidities and appropriate treatment of comorbidities, as these interventions may be equally crucial in improving the prognosis of MS.

Neuronal damage is the morphological substrate of persisting neurological disability. Neurofilaments (Nf) are cytoskeletal proteins of neurons and their release into cerebrospinal fluid has shown encouraging results as a biomarker for neurodegeneration. This study aimed to validate the quantification of the Nf light chain (NfL) in blood samples, as a biofluid source easily accessible for longitudinal studies. We developed and applied a highly sensitive electrochemiluminescence (ECL) based immunoassay for quantification of NfL in blood and CSF. Patients with Alzheimer's disease (AD) (30.8 pg/ml, n=20), Guillain-Barré-syndrome (GBS) (79.4 pg/ml, n=19) or amyotrophic lateral sclerosis (ALS) (95.4 pg/ml, n=46) had higher serum NfL values than a control group of neurological patients without evidence of structural CNS damage (control patients, CP) (4.4 pg/ml, n=68, p<0.0001 for each comparison, p=0.002 for AD patients) and healthy controls (HC) (3.3 pg/ml, n=67, p<0.0001). Similar differences were seen in corresponding CSF samples. CSF and serum levels correlated in AD (r=0.48, p=0.033), GBS (r=0.79, p<0.0001) and ALS (r=0.70, p<0.0001), but not in CP (r=0.11, p=0.3739). The sensitivity and specificity of serum NfL for separating ALS from healthy controls was 91.3% and 91.0%. We developed and validated a novel ECL based sandwich immunoassay for the NfL protein in serum (NfL(Umea47:3)); levels in ALS were more than 20-fold higher than in controls. Our data supports further longitudinal studies of serum NfL in neurodegenerative diseases as a potential biomarker of on-going disease progression, and as a potential surrogate to quantify effects of neuroprotective drugs in clinical trials.

BackgroundAccurately assessing the safety of disease-modifying therapies (DMT) is important to ensure that patients and clinicians make fully-informed treatment decisions. Clinical trial data are restricted to narrow populations and may be less applicable to groups such as pregnant women, older people, and people from diverse ethnic backgrounds.MethodsOPTIMISE-MS is a multi-centre, pragmatic, longitudinal real-world observational pharmacovigi- lance study recruiting from 15 UK sites. Data were extracted in January 2023.Results2575 participants with complete baseline data were included (74% female, 79.7% White, 79.1% UK born, 92.9% relapsing-remitting MS, median age at diagnosis 34.6, median age at recruitment 44.5), with median follow-up of 2.1 years.At recruitment, 340 participants (13.1%) were taking a first generation DMT (Interferon/Glatiramer) and 1437 (55.5%) a second generation therapy (Natalizumab: 29.3%; Dimethyl Fumarate: 26.4%; Ocrelizumab: 16.1%; Fingolimod: 12.3%; Cladribine 5.9%; Alemtuzumab 4.9%; Teriflunomide: 4.6%).During prospective follow-up, 1227 clinical events were reported, including 609 MS relapses (11.7/100 per- son-years), 133 COVID infections (2.6/100 person-years), 180 opportunistic infections (3.5/100 person-years), 7 deaths (0.1/100 person-years), 11 cases of Herpes Zoster (0.2/100 person-years), and 3 cases of basal cell carcinoma (0.06/100 person-years). No PML cases were reported during follow-up.ConclusionsOPTIMISE-MS will continue to collect real-world data on the safety of MS DMTs. These data will provide insight into the predictors of treatment-related adverse events, and help to inform clinical decision-making.

Parkinson's disease (PD) and osteoporosis are chronic diseases associated with increasing age. Single studies have reported associations between them and the major consequence, namely, increased risk of fractures. The aim of this systematic review and meta-analysis was to evaluate the relationship of PD with osteoporosis, bone mineral density (BMD) and fracture risk. A literature search was undertaken on 4 September 2012 using multiple indexing databases and relevant search terms. Articles were screened for suitability and data extracted where studies met inclusion criteria and were of sufficient quality. Data were combined using standard meta-analysis methods. 23 studies were used in the final analysis. PD patients were at higher risk of osteoporosis (OR 2.61; 95% CI 1.69 to 4.03) compared with healthy controls. Male patients had a lower risk for osteoporosis and osteopenia than female patients (OR 0.45; 95% CI 0.29 to 0.68). PD patients had lower hip, lumbar spine and femoral neck BMD levels compared with healthy controls; mean difference, -0.08, 95% CI -0.13 to -0.02 for femoral neck; -0.09, 95% CI -0.15 to -0.03 for lumbar spine; and -0.05, 95% CI -0.07 to -0.03 for total hip. PD patients were also at increased risk of fractures (OR 2.28; 95% CI 1.83 to 2.83). This systematic review and meta-analysis demonstrate that PD patients are at higher risk for both osteoporosis and osteopenia compared with healthy controls, and that female patients are at greater risk than male patients. Patients with PD also have lower BMD and are at increased risk of fractures.

BackgroundEpidemiological studies conducted in majority White populations have identified multiple potentially modifiable risk factors for Multiple Sclerosis (MS). It is unknown whether these risk factors differ between ethnic groups.MethodsWe conducted a nested case-control study using data from the UK Clinical Practice Research Database. MS cases were identified between 1990 and 2022 and controls were matched on year of birth. We used stratified logistic regression models and formal statistical interaction tests to determine whether the effect of modifiable risk factors for MS differed by ethnicity.ResultsWe included 17,400 MS cases (2.6% Asian, 2.4% Black, 93.2% White) and 158,949 age-matched controls. Significant differences in age at first recorded MS diagnosis and the Female:Male ratio between ethnic groups were seen. Established MS risk factors were consistently associated with MS across all ethnic backgrounds, with similar magnitude and direction of effects across ethnic groups examined.ConclusionsEstablished modifiable risk factors for MS are applicable across diverse ethnic backgrounds. Efforts to reduce the population incidence of MS by tackling these risk factors must be inclusive of people from diverse ethnicities.