Routine CSF parameters as predictors of disease course in multiple sclerosis: an MSBase cohort study.

BACKGROUND: It remains unclear whether routine cerebrospinal fluid (CSF) parameters can serve as predictors of multiple sclerosis (MS) disease course. METHODS: This large-scale cohort study included persons with MS with CSF data documented in the MSBase registry. CSF parameters to predict time to reach confirmed Expanded Disability Status Scale (EDSS) scores 4, 6 and 7 and annualised relapse rate in the first 2 years after diagnosis (ARR2) were assessed using (cox) regression analysis. RESULTS: In total, 11 245 participants were included of which 93.7% (n=10 533) were persons with relapsing-remitting MS (RRMS). In RRMS, the presence of CSF oligoclonal bands (OCBs) was associated with shorter time to disability milestones EDSS 4 (adjusted HR=1.272 (95% CI, 1.089 to 1.485), p=0.002), EDSS 6 (HR=1.314 (95% CI, 1.062 to 1.626), p=0.012) and EDSS 7 (HR=1.686 (95% CI, 1.111 to 2.558), p=0.014). On the other hand, the presence of CSF pleocytosis (≥5 cells/µL) increased time to moderate disability (EDSS 4) in RRMS (HR=0.774 (95% CI, 0.632 to 0.948), p=0.013). None of the CSF variables were associated with time to disability milestones in persons with primary progressive MS (PPMS). The presence of CSF pleocytosis increased ARR2 in RRMS (adjusted R2=0.036, p=0.015). CONCLUSIONS: In RRMS, the presence of CSF OCBs predicts shorter time to disability milestones, whereas CSF pleocytosis could be protective. This could however not be found in PPMS. CSF pleocytosis is associated with short-term inflammatory disease activity in RRMS. CSF analysis provides prognostic information which could aid in clinical and therapeutic decision-making.

Long-term clinical outcomes in patients with multiple sclerosis who are initiating disease-modifying therapy with natalizumab compared with BRACETD first-line therapies.

Background: Aggressive disease control soon after multiple sclerosis (MS) diagnosis may prevent irreversible neurological damage, and therefore early initiation of a high-efficacy disease-modifying therapy (DMT) is of clinical relevance. Objectives: Evaluate long-term clinical outcomes in patients with MS who initiated treatment with either natalizumab or a BRACETD therapy (interferon beta, glatiramer acetate, teriflunomide, or dimethyl fumarate). Design: This retrospective analysis utilized data from MSBase to create a matched population allowing comparison of first-line natalizumab to first-line BRACETD. Methods: This study included patients who initiated treatment either with natalizumab or a BRACETD DMT within 1 year of MS diagnosis and continued treatment for ⩾6 months, after which patients could switch DMTs or discontinue treatment. Patients had a minimum follow-up time of ⩾60 months from initiation. A subgroup analysis compared the natalizumab group to patients in the BRACETD group who escalated therapy after 6 months. Outcomes included unadjusted annualized relapse rates (ARRs), time-to-first relapse, time-to-first confirmed disability improvement (CDI), and time-to-first confirmed disability worsening (CDW). Results: After 1:1 propensity score matching, 355 BRACETD patients were matched to 355 natalizumab patients. Patients initiating natalizumab were less likely to experience a relapse over the duration of follow-up, with ARRs [95% confidence interval (CI)] of 0.080 (0.070-0.092) for natalizumab patients and 0.191 (0.178-0.205) for BRACETD patients (p < 0.0001). A Cox regression model of time-to-first relapse showed a reduced risk of relapse for natalizumab patients [hazard ratio (95% CI) of 0.52 (0.42-0.65); p < 0.001] and a more favorable time-to-first CDI. The risk of CDW was similar between groups. The subgroup analysis showed an increased relapse risk as well as a significantly higher risk of CDW for BRACETD patients. Conclusion: Early initiation of natalizumab produced long-term benefits in relapse outcomes in comparison with BRACETD, regardless of a subsequent escalation in therapy.

The Efficacy, Adverse Effects and Economic Implications of Oral Versus Intravenous Methylprednisolone for the Treatment of Optic Neuritis: A Systematic Review.

INTRODUCTION: Optic neuritis may occur in a variety of conditions, including as a manifestation of multiple sclerosis. Despite significant research into the efficacy of corticosteroids as a first-line treatment, the optimal route of administration has not been well defined. This review aims to explore the efficacy, adverse effects and economic implications of using oral versus intravenous methylprednisolone to treat acute optic neuritis. METHODS: A systematic search of the databases PubMed/MEDLINE, Embase and CENTRAL was performed to July 2022, prior to data collection and risk of bias analysis in accordance with the PRISMA guidelines. RESULTS: Six articles fulfilled the inclusion criteria. The results showed that in the treatment of acute optic neuritis, oral methylprednisolone has a non-inferior efficacy and adverse effect profile in comparison to intravenous methylprednisolone. In a cost analysis, oral methylprednisolone to be more cost-effective than intravenous methylprednisolone. CONCLUSIONS: Oral methylprednisolone has comparable efficacy and adverse effect profiles to intravenous methylprednisolone for the treatment of optic neuritis. The analysis suggests oral administration is more cost-effective than intravenous administration; however, further analyses of the formal cost-benefit ratio are required.

DNA Methylation Signatures of Multiple Sclerosis Occur Independently of Known Genetic Risk and Are Primarily Attributed to B Cells and Monocytes.

Epigenetic mechanisms can regulate how DNA is expressed independently of sequence and are known to be associated with various diseases. Among those epigenetic mechanisms, DNA methylation (DNAm) is influenced by genotype and the environment, making it an important molecular interface for studying disease etiology and progression. In this study, we examined the whole blood DNA methylation profiles of a large group of people with (pw) multiple sclerosis (MS) compared to those of controls. We reveal that methylation differences in pwMS occur independently of known genetic risk loci and show that they more strongly differentiate disease (AUC = 0.85, 95% CI 0.82-0.89, p = 1.22 × 10-29) than known genetic risk loci (AUC = 0.72, 95% CI: 0.66-0.76, p = 9.07 × 10-17). We also show that methylation differences in MS occur predominantly in B cells and monocytes and indicate the involvement of cell-specific biological pathways. Overall, this study comprehensively characterizes the immune cell-specific epigenetic architecture of MS.

A systematic review of the symptomatic management of Lhermitte's phenomenon.

INTRODUCTION: Lhermitte's phenomenon (LP) is a transient shock-like sensation that radiates down the spine into the extremities, usually with neck flexion. The potential efficacy and tolerability of various symptomatic therapies in the management of LP have not been systematically reviewed previously. METHOD: A systematic review was conducted using PubMed, EMBASE, and the Cochrane Library from inception to August 2022 for peer-reviewed articles describing the treatment of patients with Lhermitte's phenomenon. The review adheres to the PRISMA guidelines and was registered on PROSPERO. RESULTS: This systematic review included sixty-six articles, which included 450 patients with LP. Treatment of the underlying cause varied by aetiology. Whilst LP is most commonly considered in the context of structural pathology of the cervical cord, medication-induced LP was a common theme in the literature. The most common cause of medication-induced LP was platinum-based chemotherapy agents such as cisplatin and oxaliplatin. In medication-induced LP, symptoms typically resolved with cessation of the causative agent. Non-pharmacological treatment options were associated with mild-moderate symptomatic improvement. The most commonly used agents to treat patients with LP were carbamazepine and gabapentin, which resulted in variable degrees of symptomatic benefit. CONCLUSIONS: No randomised studies currently exist to support the use of symptomatic therapies to treat LP. Observational data suggest that some therapies may yield a symptomatic benefit in the management of LP. However, this systematic review identified a significant paucity of evidence in the literature, which suggests that further controlled studies are needed to investigate the optimal management of this common neurologic phenomenon.

Evaluation of Cell-Specific Epigenetic Age Acceleration in People With Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: In multiple sclerosis (MS), accelerated aging of the immune system (immunosenescence) may be associated with disease onset or drive progression. DNA methylation (DNAm) is an epigenetic factor that varies among lymphocyte subtypes, and cell-specific DNAm is associated with MS. DNAm varies across the life span and can be used to accurately estimate biological age acceleration, which has been linked to a range of morbidities. The objective of this study was to test for cell-specific epigenetic age acceleration (EAA) in people with MS. METHODS: This was a case-control study of EAA using existing DNAm data from several independent previously published studies. Data were included if .idat files from Illumina 450K or EPIC arrays were available for both a case with MS and an age-matched and sex-matched control, from the same study. Multifactor statistical modeling was performed to assess the primary outcome of EAA. We explored the relationship of EAA and MS, including interaction terms to identify immune cell-specific effects. Cell-sorted DNA methylation data from 3 independent datasets were used to validate findings. RESULTS: We used whole blood DNA methylation data from 583 cases with MS and 643 non-MS controls to calculate EAA using the GrimAge algorithm. The MS group exhibited an increased EAA compared with controls (approximately 9 mths, 95% CI 3.6-14.4), p = 0.001). Statistical deconvolution showed that EAA is associated with MS in a B cell-dependent manner (ß int = 1.7, 95% CI 0.3-2.8), p = 0.002), irrespective of B-cell proportions. Validation analysis using 3 independent datasets enriched for B cells showed an EAA increase of 5.1 years in cases with MS compared with that in controls (95% CI 2.8-7.4, p = 5.5 × 10-5). By comparison, there was no EAA difference in MS in a T cell-enriched dataset. We found that EAA was attributed to the DNAm surrogates for Beta-2-microglobulin (difference = 47,546, 95% CI 10,067-85,026; p = 7.2 × 10-5), and smoking pack-years (difference = 8.1, 95% CI 1.9-14.2, p = 0.002). DISCUSSION: This study provides compelling evidence that B cells exhibit marked EAA in MS and supports the hypothesis that premature B-cell immune senescence plays a role in MS. Future MS studies should focus on age-related molecular mechanisms in B cells.

Effectiveness of multiple disease-modifying therapies in relapsing-remitting multiple sclerosis: causal inference to emulate a multiarm randomised trial.

BACKGROUND: Simultaneous comparisons of multiple disease-modifying therapies for relapsing-remitting multiple sclerosis (RRMS) over an extended follow-up are lacking. Here we emulate a randomised trial simultaneously comparing the effectiveness of six commonly used therapies over 5 years. METHODS: Data from 74 centres in 35 countries were sourced from MSBase. For each patient, the first eligible intervention was analysed, censoring at change/discontinuation of treatment. The compared interventions included natalizumab, fingolimod, dimethyl fumarate, teriflunomide, interferon beta, glatiramer acetate and no treatment. Marginal structural Cox models (MSMs) were used to estimate the average treatment effects (ATEs) and the average treatment effects among the treated (ATT), rebalancing the compared groups at 6-monthly intervals on age, sex, birth-year, pregnancy status, treatment, relapses, disease duration, disability and disease course. The outcomes analysed were incidence of relapses, 12-month confirmed disability worsening and improvement. RESULTS: 23 236 eligible patients were diagnosed with RRMS or clinically isolated syndrome. Compared with glatiramer acetate (reference), several therapies showed a superior ATE in reducing relapses: natalizumab (HR=0.44, 95% CI=0.40 to 0.50), fingolimod (HR=0.60, 95% CI=0.54 to 0.66) and dimethyl fumarate (HR=0.78, 95% CI=0.66 to 0.92). Further, natalizumab (HR=0.43, 95% CI=0.32 to 0.56) showed a superior ATE in reducing disability worsening and in disability improvement (HR=1.32, 95% CI=1.08 to 1.60). The pairwise ATT comparisons also showed superior effects of natalizumab followed by fingolimod on relapses and disability. CONCLUSIONS: The effectiveness of natalizumab and fingolimod in active RRMS is superior to dimethyl fumarate, teriflunomide, glatiramer acetate and interferon beta. This study demonstrates the utility of MSM in emulating trials to compare clinical effectiveness among multiple interventions simultaneously.

Defining progression independent of relapse activity (PIRA) in adult patients with relapsing multiple sclerosis: A systematic review✰.

BACKGROUND: Progression Independent of Relapse Activity (PIRA) is heterogeneously described in patients with multiple sclerosis (MS) regarding the frequency and nature of PIRA. This systematic review was conducted to characterise and define the elements of PIRA. METHOD: This systematic review was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A systematic search was conducted of the databases Embase, Medline, Cochrane Central Register of Controlled Trials, Scopus, Web of Science, ClinicalTrials.gov and Google Scholar. RESULTS: 5,812 studies were identified by the initial search. 13 studies satisfied the inclusion criteria and were included in the systematic review. PIRA definitions varied considerably between studies. In the context of these variable definitions, along with other methodological differences relating to disease modifying therapy (DMT) use and follow-up duration, the reported proportion of patients experiencing PIRA varied from 4% to 24%. CONCLUSIONS: The currently available research supports the presence of PIRA in relapsing MS. Based on review of the existing literature, we propose a definition of PIRA that is clinically relevant and minimises confounding from inclusion of patients who have reached the secondary progressive phase of the disease.

Comparative Effectiveness of Autologous Hematopoietic Stem Cell Transplant vs Fingolimod, Natalizumab, and Ocrelizumab in Highly Active Relapsing-Remitting Multiple Sclerosis.

Importance: Autologous hematopoietic stem cell transplant (AHSCT) is available for treatment of highly active multiple sclerosis (MS). Objective: To compare the effectiveness of AHSCT vs fingolimod, natalizumab, and ocrelizumab in relapsing-remitting MS by emulating pairwise trials. Design, Setting, and Participants: This comparative treatment effectiveness study included 6 specialist MS centers with AHSCT programs and international MSBase registry between 2006 and 2021. The study included patients with relapsing-remitting MS treated with AHSCT, fingolimod, natalizumab, or ocrelizumab with 2 or more years study follow-up including 2 or more disability assessments. Patients were matched on a propensity score derived from clinical and demographic characteristics. Exposure: AHSCT vs fingolimod, natalizumab, or ocrelizumab. Main outcomes: Pairwise-censored groups were compared on annualized relapse rates (ARR) and freedom from relapses and 6-month confirmed Expanded Disability Status Scale (EDSS) score worsening and improvement. Results: Of 4915 individuals, 167 were treated with AHSCT; 2558, fingolimod; 1490, natalizumab; and 700, ocrelizumab. The prematch AHSCT cohort was younger and with greater disability than the fingolimod, natalizumab, and ocrelizumab cohorts; the matched groups were closely aligned. The proportion of women ranged from 65% to 70%, and the mean (SD) age ranged from 35.3 (9.4) to 37.1 (10.6) years. The mean (SD) disease duration ranged from 7.9 (5.6) to 8.7 (5.4) years, EDSS score ranged from 3.5 (1.6) to 3.9 (1.9), and frequency of relapses ranged from 0.77 (0.94) to 0.86 (0.89) in the preceding year. Compared with the fingolimod group (769 [30.0%]), AHSCT (144 [86.2%]) was associated with fewer relapses (ARR: mean [SD], 0.09 [0.30] vs 0.20 [0.44]), similar risk of disability worsening (hazard ratio [HR], 1.70; 95% CI, 0.91-3.17), and higher chance of disability improvement (HR, 2.70; 95% CI, 1.71-4.26) over 5 years. Compared with natalizumab (730 [49.0%]), AHSCT (146 [87.4%]) was associated with marginally lower ARR (mean [SD], 0.08 [0.31] vs 0.10 [0.34]), similar risk of disability worsening (HR, 1.06; 95% CI, 0.54-2.09), and higher chance of disability improvement (HR, 2.68; 95% CI, 1.72-4.18) over 5 years. AHSCT (110 [65.9%]) and ocrelizumab (343 [49.0%]) were associated with similar ARR (mean [SD], 0.09 [0.34] vs 0.06 [0.32]), disability worsening (HR, 1.77; 95% CI, 0.61-5.08), and disability improvement (HR, 1.37; 95% CI, 0.66-2.82) over 3 years. AHSCT-related mortality occurred in 1 of 159 patients (0.6%). Conclusion: In this study, the association of AHSCT with preventing relapses and facilitating recovery from disability was considerably superior to fingolimod and marginally superior to natalizumab. This study did not find evidence for difference in the effectiveness of AHSCT and ocrelizumab over a shorter available follow-up time.

Comparison Between Dimethyl Fumarate, Fingolimod, and Ocrelizumab After Natalizumab Cessation.

Importance: Natalizumab cessation is associated with a risk of rebound disease activity. It is important to identify the optimal switch disease-modifying therapy strategy after natalizumab to limit the risk of severe relapses. Objectives: To compare the effectiveness and persistence of dimethyl fumarate, fingolimod, and ocrelizumab among patients with relapsing-remitting multiple sclerosis (RRMS) who discontinued natalizumab. Design, Setting, and Participants: In this observational cohort study, patient data were collected from the MSBase registry between June 15, 2010, and July 6, 2021. The median follow-up was 2.7 years. This was a multicenter study that included patients with RRMS who had used natalizumab for 6 months or longer and then were switched to dimethyl fumarate, fingolimod, or ocrelizumab within 3 months after natalizumab discontinuation. Patients without baseline data were excluded from the analysis. Data were analyzed from May 24, 2022, to January 9, 2023. Exposures: Dimethyl fumarate, fingolimod, and ocrelizumab. Main Outcomes and Measures: Primary outcomes were annualized relapse rate (ARR) and time to first relapse. Secondary outcomes were confirmed disability accumulation, disability improvement, and subsequent treatment discontinuation, with the comparisons for the first 2 limited to fingolimod and ocrelizumab due to the small number of patients taking dimethyl fumarate. The associations were analyzed after balancing covariates using an inverse probability of treatment weighting method. Results: Among 66 840 patients with RRMS, 1744 had used natalizumab for 6 months or longer and were switched to dimethyl fumarate, fingolimod, or ocrelizumab within 3 months of natalizumab discontinuation. After excluding 358 patients without baseline data, a total of 1386 patients (mean [SD] age, 41.3 [10.6] years; 990 female [71%]) switched to dimethyl fumarate (138 [9.9%]), fingolimod (823 [59.4%]), or ocrelizumab (425 [30.7%]) after natalizumab. The ARR for each medication was as follows: ocrelizumab, 0.06 (95% CI, 0.04-0.08); fingolimod, 0.26 (95% CI, 0.12-0.48); and dimethyl fumarate, 0.27 (95% CI, 0.12-0.56). The ARR ratio of fingolimod to ocrelizumab was 4.33 (95% CI, 3.12-6.01) and of dimethyl fumarate to ocrelizumab was 4.50 (95% CI, 2.89-7.03). Compared with ocrelizumab, the hazard ratio (HR) of time to first relapse was 4.02 (95% CI, 2.83-5.70) for fingolimod and 3.70 (95% CI, 2.35-5.84) for dimethyl fumarate. The HR of treatment discontinuation was 2.57 (95% CI, 1.74-3.80) for fingolimod and 4.26 (95% CI, 2.65-6.84) for dimethyl fumarate. Fingolimod use was associated with a 49% higher risk for disability accumulation compared with ocrelizumab. There was no significant difference in disability improvement rates between fingolimod and ocrelizumab. Conclusion and Relevance: Study results show that among patients with RRMS who switched from natalizumab to dimethyl fumarate, fingolimod, or ocrelizumab, ocrelizumab use was associated with the lowest ARR and discontinuation rates, and the longest time to first relapse.

Functional Characterisation of the Circular RNA, circHTT(2-6), in Huntington's Disease.

Trinucleotide repeat disorders comprise ~20 severe, inherited, human neuromuscular and neurodegenerative disorders, which result from an abnormal expansion of repetitive sequences in the DNA. The most common of these, Huntington's disease (HD), results from expansion of the CAG repeat region in exon 1 of the HTT gene via an unknown mechanism. Since non-coding RNAs have been implicated in the initiation and progression of many diseases, herein we focused on a circular RNA (circRNA) molecule arising from non-canonical splicing (backsplicing) of HTT pre-mRNA. The most abundant circRNA from HTT, circHTT(2-6), was found to be more highly expressed in the frontal cortex of HD patients, compared with healthy controls, and positively correlated with CAG repeat tract length. Furthermore, the mouse orthologue (mmu_circHTT(2-6)) was found to be enriched within the brain and specifically the striatum, a region enriched for medium spiny neurons that are preferentially lost in HD. Transgenic overexpression of circHTT(2-6) in two human cell lines-SH-SY5Y and HEK293-reduced cell proliferation and nuclear size without affecting cell cycle progression or cellular size, or altering the CAG repeat region length within HTT. CircHTT(2-6) overexpression did not alter total HTT protein levels, but reduced its nuclear localisation. As these phenotypic and genotypic changes resemble those observed in HD patients, our results suggest that circHTT(2-6) may play a functional role in the pathophysiology of this disease.

Disability accrual in primary and secondary progressive multiple sclerosis.

BACKGROUND: Some studies comparing primary and secondary progressive multiple sclerosis (PPMS, SPMS) report similar ages at onset of the progressive phase and similar rates of subsequent disability accrual. Others report later onset and/or faster accrual in SPMS. Comparisons have been complicated by regional cohort effects, phenotypic differences in sex ratio and management and variable diagnostic criteria for SPMS. METHODS: We compared disability accrual in PPMS and operationally diagnosed SPMS in the international, clinic-based MSBase cohort. Inclusion required PPMS or SPMS with onset at age ≥18 years since 1995. We estimated Andersen-Gill hazard ratios for disability accrual on the Expanded Disability Status Scale (EDSS), adjusted for sex, age, baseline disability, EDSS score frequency and drug therapies, with centre and patient as random effects. We also estimated ages at onset of the progressive phase (Kaplan-Meier) and at EDSS milestones (Turnbull). Analyses were replicated with physician-diagnosed SPMS. RESULTS: Included patients comprised 1872 with PPMS (47% men; 50% with activity) and 2575 with SPMS (32% men; 40% with activity). Relative to PPMS, SPMS had older age at onset of the progressive phase (median 46.7 years (95% CI 46.2-47.3) vs 43.9 (43.3-44.4); p<0.001), greater baseline disability, slower disability accrual (HR 0.86 (0.78-0.94); p<0.001) and similar age at wheelchair dependence. CONCLUSIONS: We demonstrate later onset of the progressive phase and slower disability accrual in SPMS versus PPMS. This may balance greater baseline disability in SPMS, yielding convergent disability trajectories across phenotypes. The different rates of disability accrual should be considered before amalgamating PPMS and SPMS in clinical trials.

Evaluating the Ability of Open-Source Artificial Intelligence to Predict Accepting-Journal Impact Factor and Eigenfactor Score Using Academic Article Abstracts: Cross-sectional Machine Learning Analysis.

BACKGROUND: Strategies to improve the selection of appropriate target journals may reduce delays in disseminating research results. Machine learning is increasingly used in content-based recommender algorithms to guide journal submissions for academic articles. OBJECTIVE: We sought to evaluate the performance of open-source artificial intelligence to predict the impact factor or Eigenfactor score tertile using academic article abstracts. METHODS: PubMed-indexed articles published between 2016 and 2021 were identified with the Medical Subject Headings (MeSH) terms "ophthalmology," "radiology," and "neurology." Journals, titles, abstracts, author lists, and MeSH terms were collected. Journal impact factor and Eigenfactor scores were sourced from the 2020 Clarivate Journal Citation Report. The journals included in the study were allocated percentile ranks based on impact factor and Eigenfactor scores, compared with other journals that released publications in the same year. All abstracts were preprocessed, which included the removal of the abstract structure, and combined with titles, authors, and MeSH terms as a single input. The input data underwent preprocessing with the inbuilt ktrain Bidirectional Encoder Representations from Transformers (BERT) preprocessing library before analysis with BERT. Before use for logistic regression and XGBoost models, the input data underwent punctuation removal, negation detection, stemming, and conversion into a term frequency-inverse document frequency array. Following this preprocessing, data were randomly split into training and testing data sets with a 3:1 train:test ratio. Models were developed to predict whether a given article would be published in a first, second, or third tertile journal (0-33rd centile, 34th-66th centile, or 67th-100th centile), as ranked either by impact factor or Eigenfactor score. BERT, XGBoost, and logistic regression models were developed on the training data set before evaluation on the hold-out test data set. The primary outcome was overall classification accuracy for the best-performing model in the prediction of accepting journal impact factor tertile. RESULTS: There were 10,813 articles from 382 unique journals. The median impact factor and Eigenfactor score were 2.117 (IQR 1.102-2.622) and 0.00247 (IQR 0.00105-0.03), respectively. The BERT model achieved the highest impact factor tertile classification accuracy of 75.0%, followed by an accuracy of 71.6% for XGBoost and 65.4% for logistic regression. Similarly, BERT achieved the highest Eigenfactor score tertile classification accuracy of 73.6%, followed by an accuracy of 71.8% for XGBoost and 65.3% for logistic regression. CONCLUSIONS: Open-source artificial intelligence can predict the impact factor and Eigenfactor score of accepting peer-reviewed journals. Further studies are required to examine the effect on publication success and the time-to-publication of such recommender systems.

The Icepack Test in the Diagnosis of Myasthenia Gravis with Ocular Features: A Systematic Review of Diagnostic Accuracy, Technique, and Economic Utility.

BACKGROUND: The diagnosis of myasthenia gravis (MG) may be challenging and require multiple specialised testing modalities. Accessing these investigations can involve significant waiting time and costs. The bedside icepack test (IPT) has been proposed to assist with the diagnosis of MG with ocular features, and may prove an economically viable; however, there have been there is heterogeneity in the literature evaluating the IPT. OBJECTIVES: A systematic review was performed examining the accuracy, described techniques, and economic implications of the IPT for the diagnosis of MG with ocular features. METHOD: The databases EMBASE, PubMed, and the Cochrane Library were searched from inception to July 2022. The systematic review adhered to PRISMA guidelines. Eligibility determination was undertaken with a standardised form using appropriate inclusion criteria. The Cochrane risk of bias assessment tool for diagnostic test accuracy was employed to evaluate studies that presented the diagnostic performance of the IPT. The Johanna Briggs Institute Critical Appraisal Checklist for Economic Evaluations was used for the assessment of studies presenting economic evaluations of the IPT. RESULTS: 20 articles met the specified criteria and included a total of 1264 participants. The IPT had a sensitivity ranging from 38.5% to 100%. Specificity was found to be > 95% in six studies. Excluding two outlier results of 25% and 31.3%, the lowest specificity recorded was 62.5%. The most commonly described method of evaluating the IPT involved applying ice to both eyelids and using a >2 mm change as a threshold for a positive test (evaluated with a ruler). There were no adverse effects described with the IPT. There were no studies that formally examined the economic implications of the IPT. CONCLUSIONS: The IPT is a well-tolerated and readily available diagnostic tool that has an important role in the evaluation of possible MG with ocular features in specific contexts. Despite limited economic evaluation of this test, it is likely the use of the IPT may result in significant financial and time savings.

Parity is associated with long-term differences in DNA methylation at genes related to neural plasticity in multiple sclerosis.

BACKGROUND: Pregnancy in women with multiple sclerosis (wwMS) is associated with a reduction of long-term disability progression. The mechanism that drives this effect is unknown, but converging evidence suggests a role for epigenetic mechanisms altering immune and/or central nervous system function. In this study, we aimed to identify whole blood and immune cell-specific DNA methylation patterns associated with parity in relapse-onset MS. RESULTS: We investigated the association between whole blood and immune cell-type-specific genome-wide methylation patterns and parity in 192 women with relapse-onset MS, matched for age and disease severity. The median time from last pregnancy to blood collection was 16.7 years (range = 1.5-44.4 years). We identified 2965 differentially methylated positions in whole blood, 68.5% of which were hypermethylated in parous women; together with two differentially methylated regions on Chromosomes 17 and 19 which mapped to TMC8 and ZNF577, respectively. Our findings validated 22 DMPs and 366 differentially methylated genes from existing literature on epigenetic changes associated with parity in wwMS. Differentially methylated genes in whole blood were enriched in neuronal structure and growth-related pathways. Immune cell-type-specific analysis using cell-type proportion estimates from statistical deconvolution of whole blood revealed further differential methylation in T cells specifically (four in CD4+ and eight in CD8+ T cells). We further identified reduced methylation age acceleration in parous women, demonstrating slower biological aging compared to nulligravida women. CONCLUSION: Differential methylation at genes related to neural plasticity offers a potential molecular mechanism driving the long-term effect of pregnancy on MS outcomes. Our results point to a potential 'CNS signature' of methylation in peripheral immune cells, as previously described in relation to MS progression, induced by parity. As the first epigenome-wide association study of parity in wwMS reported, validation studies are needed to confirm our findings.

Physical examination in functional unresponsiveness.

Functional unresponsiveness can present a diagnostic challenge, but there are many positive physical examination findings that may help to confirm this diagnosis. Some of these are associated with pain or potential tissue damage for the patient, and potentially ethical and legal risk for the practitioner, but several lesser-known physical examination techniques do not carry these risks. Such examination techniques include non-damaging irritative stimuli, a modification to the conventional hand drop test and evaluation of eyelid opening.