We investigated the impact of dimethyl fumarate (DMF), an oral therapy for relapsing multiple sclerosis (MS), on blood microRNA (miRNA) signatures and neurofilament light (NFL) levels. DMF normalized ...miR-660-5p and modulated various miRNAs associated with the NF-kB pathway. These alterations reached a peak 4–7 months after treatment. Notably, particular miRNAs correlated with high or low NFL levels, implying their potential role as markers of treatment efficacy. Our findings broaden the understanding of DMF's immunomodulatory effects and may aid in predicting treatment responses.
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•Composite blood microRNAs levels peak during short-term dimethyl fumarate (DMF) treatment in patients with MS (pwMS).•DMF treatment alters levels of specific miRNAs involved in the NFκB-pathway.•Level of miR-660-5p is reduced in untreated pwMS, and DMF normalizes its level.•miR-320 that induces Th1 differentiation is upregulated before treatment.•miR-16-5p and miR-4306 dysregulation is associated with low neurofilament light (NFL) levels.•miR-940 and miR-4665-3p dysregulation is associated with high NFL levels.
Investigation of cerebrospinal fluid (CSF) in the diagnostic work-up in suspected multiple sclerosis (MS) patients has regained attention in the latest version of the diagnostic criteria due to its ...good diagnostic accuracy and increasing issues with misdiagnosis of MS based on over interpretation of neuroimaging results. The hallmark of MS-specific changes in CSF is the detection of oligoclonal bands (OCB) which occur in the vast majority of MS patients. Lack of OCB has a very high negative predictive value indicating a red flag during the diagnostic work-up, and alternative diagnoses should be considered in such patients. Additional molecules of CSF can help to support the diagnosis of MS, improve the differential diagnosis of MS subtypes and predict the course of the disease, thus selecting the optimal therapy for each patient.
Neurologic manifestations are well-recognized features of coronavirus disease 2019 (COVID-19). However, the longitudinal association of biomarkers reflecting CNS impact and neurological symptoms is ...not known. We sought to determine whether plasma biomarkers of CNS injury were associated with neurologic sequelae after COVID-19.
Patients with confirmed acute COVID-19 were studied prospectively. Neurological symptoms were recorded during the acute phase of the disease and at six months follow-up, and blood samples were collected longitudinally. Healthy age-matched individuals were included as controls. We analysed plasma concentrations of neurofilament light-chain (NfL), glial fibrillary acidic protein (GFAp), and growth differentiation factor 15 (GDF-15).
One hundred patients with mild (n = 24), moderate (n = 28), and severe (n = 48) COVID-19 were followed for a median (IQR) of 225 (187–262) days. In the acute phase, patients with severe COVID-19 had higher concentrations of NfL than all other groups (all p < 0·001), and higher GFAp than controls (p < 0·001). GFAp was also significantly increased in moderate disease (p < 0·05) compared with controls. NfL (r = 0·53, p < 0·001) and GFAp (r = 0·39, p < 0·001) correlated with GDF-15 during the acute phase. After six months, NfL and GFAp concentrations had normalized, with no persisting group differences. Despite this, 50 patients reported persistent neurological symptoms, most commonly fatigue (n = 40), “brain-fog” (n = 29), and changes in cognition (n = 25). We found no correlation between persistent neurological symptoms and CNS injury biomarkers in the acute phase.
The normalization of CNS injury biomarkers in all individuals, regardless of previous disease severity or persisting neurological symptoms, indicates that post COVID-19 neurological sequelae are not accompanied by ongoing CNS injury.
The Swedish State Support for Clinical Research, SciLifeLab Sweden, and the Knut and Alice Wallenberg Foundation have provided funding for this project.
Background: Acute ruptures of the ulnar collateral ligament (UCL) of the thumb are common injuries in sports. Surgical repair of complete tears has yielded excellent results in elite athletes. ...Methods: National Football League (NFL) players who underwent thumb UCL surgery and matched controls were identified. Demographic and performance data were collected. Performance scores were calculated using a standardized scoring system. Return to sport (RTS) in the NFL was defined as playing in at least 1 NFL game after thumb UCL surgery. Comparisons between case and control groups and preoperative and postoperative time points were made using paired-samples Student t tests. Results: Twenty-three players were identified (mean age: 28.8 ± 3.4 years and mean experience in the NFL: 5.9 ± 3.4 years). Twenty-two players (95.7%) were able to return to sport in the NFL at an average of 132.2 ± 126.1 days. The overall 1-year NFL career survival rate of players undergoing thumb UCL surgery was 87.0%. There was not a statistically significant decrease in games per season and career length for any position following surgery. No positions had a significant difference in postoperative performance when compared with preoperative performance, and there was no significant performance difference postoperatively when compared with matched controls. Conclusions: There is a high rate of RTS in the NFL following thumb UCL surgery. Players who underwent thumb UCL surgery played in a similar number of games per season and had similar career lengths in the NFL as controls. No position group had any significant postoperative performance score differences when compared with postindex matched controls.
Identification of reliable and accessible biomarkers to characterize ischemic stroke patients’ prognosis remains a clinical challenge. Neurofilament light chain (NfL) and glial fibrillary acidic ...protein (GFAP) are markers of brain injury, detectable in blood by high-sensitive technologies. Our aim was to measure serum NfL and GFAP after stroke, and to evaluate their correlation with functional outcome and the scores in rehabilitation scales at 3-month follow-up. Stroke patients were prospectively enrolled in a longitudinal observational study within 24 hours from symptom onset (D1) and monitored after 7 (D7), 30 ± 3 (M1) and 90 ± 5 (M3) days. At each time-point serum NfL and GFAP levels were measured by Single Molecule Array and correlated with National Institute of Health Stroke Scale (NIHSS), modified Rankin scale (mRS), Trunk Control Test (TCT), Functional Ambulation Classification (FAC) and Functional Independence Measure (FIM) scores. Serum NfL and GFAP showed different temporal profiles: NfL increased after stroke with a peak value at D7; GFAP showed an earlier peak at D1. NfL and GFAP concentrations correlated with clinical/rehabilitation outcomes both longitudinally and prospectively. Multivariate analysis revealed that NfL-D7 and GFAP-D1 were independent predictors of 3-month NIHSS, TCT, FAC and FIM scores, with NfL being the biomarker with the best predictive performance.
The elicitation of broadly neutralizing antibodies (bNAbs) against the HIV-1 envelope glycoprotein (Env) trimer remains a major vaccine challenge. Most cross-conserved protein determinants are ...occluded by self-N-glycan shielding, limiting B cell recognition of the underlying polypeptide surface. The exceptions to the contiguous glycan shield include the conserved receptor CD4 binding site (CD4bs) and glycoprotein (gp)41 elements proximal to the furin cleavage site. Accordingly, we performed heterologous trimer-liposome prime:boosting in rabbits to drive B cells specific for cross-conserved sites. To preferentially expose the CD4bs to B cells, we eliminated proximal N-glycans while maintaining the native-like state of the cleavage-independent NFL trimers, followed by gradual N-glycan restoration coupled with heterologous boosting. This approach successfully elicited CD4bs-directed, cross-neutralizing Abs, including one targeting a unique glycan-protein epitope and a bNAb (87% breadth) directed to the gp120:gp41 interface, both resolved by high-resolution cryoelectron microscopy. This study provides proof-of-principle immunogenicity toward eliciting bNAbs by vaccination.
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•Removal of N-glycans proximal to the CD4 binding site increases B cell accessibility•Heterologous Env trimer-liposome regimen drives B cells to cross-conserved sites•Vaccine elicitation of an N-glycan-dependent CD4 binding site neutralizing antibody•Elicitation of an interface-directed antibody with 87% HIV neutralization breadth
Eliciting broadly neutralizing HIV antibodies by vaccination remains a challenge. Dubrovskaya et al. use an immunization regimen incorporating targeted N-glycan removal and heterologous prime:boosting with NFL trimer-liposomes in rabbits to elicit broadly neutralizing responses to cross-conserved HIV-1 epitopes, including an antibody with 87% neutralization breadth. Further structural analyses highlight similarities between the vaccine-elicited antibodies and the human broadly neutralizing antibodies.
Disease-modifying treatments are currently being trialled in multiple system atrophy. Approaches based solely on clinical measures are challenged by heterogeneity of phenotype and pathogenic ...complexity. Neurofilament light chain protein has been explored as a reliable biomarker in several neurodegenerative disorders but data on multiple system atrophy have been limited. Therefore, neurofilament light chain is not yet routinely used as an outcome measure in multiple system atrophy. We aimed to comprehensively investigate the role and dynamics of neurofilament light chain in multiple system atrophy combined with cross-sectional and longitudinal clinical and imaging scales and for subject trial selection. In this cohort study, we recruited cross-sectional and longitudinal cases in a multicentre European set-up. Plasma and CSF neurofilament light chain concentrations were measured at baseline from 212 multiple system atrophy cases, annually for a mean period of 2 years in 44 multiple system atrophy patients in conjunction with clinical, neuropsychological and MRI brain assessments. Baseline neurofilament light chain characteristics were compared between groups. Cox regression was used to assess survival; receiver operating characteristic analysis to assess the ability of neurofilament light chain to distinguish between multiple system atrophy patients and healthy controls. Multivariate linear mixed-effects models were used to analyse longitudinal neurofilament light chain changes and correlated with clinical and imaging parameters. Polynomial models were used to determine the differential trajectories of neurofilament light chain in multiple system atrophy. We estimated sample sizes for trials aiming to decrease neurofilament light chain levels. We show that in multiple system atrophy, baseline plasma neurofilament light chain levels were better predictors of clinical progression, survival and degree of brain atrophy than the neurofilament light chain rate of change. Comparative analysis of multiple system atrophy progression over the course of disease, using plasma neurofilament light chain and clinical rating scales, indicated that neurofilament light chain levels rise as the motor symptoms progress, followed by deceleration in advanced stages. Sample size prediction suggested that significantly lower trial participant numbers would be needed to demonstrate treatment effects when incorporating plasma neurofilament light chain values into multiple system atrophy clinical trials in comparison to clinical measures alone. In conclusion, neurofilament light chain correlates with clinical disease severity, progression and prognosis in multiple system atrophy. Combined with clinical and imaging analysis, neurofilament light chain can inform patient stratification and serve as a reliable biomarker of treatment response in future multiple system atrophy trials of putative disease-modifying agents.
In this paper, we critically evaluate the performance of nine machine learning classification techniques when applied to the match outcome prediction problem presented by American Football. ...Specifically, we implement and test nine techniques using real-world datasets of 1280 games over 5 seasons from the National Football League (NFL). We test the nine different classifier techniques using a total of 42 features for each team and we find that the best performing algorithms are able to improve one previous published works. The algoriothms achieve an accuracy of between 44.64% for a Guassian Process classifier to 67.53% with a Naïve Bayes classifer. We also test each classifier on a year by year basis and compare our results to those of the bookmakers and other leading academic papers.
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