Although recent studies indicate that fluvial systems can be accumulation areas for microplastics (MPs), the common perception still treats rivers and streams primarily as pure transport vectors for ...MPs. In this study we investigate the occurrence of MPs in a yet unnoticed but essential compartment of fluvial ecosystems - the hyporheic zone (HZ). Larger MP particles (500-5,000 µm) were detected using attenuated total reflectance (ATR) - Fourier-transform infrared (FTIR) spectroscopy. Our analysis of MPs (500-5,000 µm) in five freeze cores extracted for the Roter Main River sediments (Germany) showed that MPs were detectable down to a depth of 0.6 m below the streambed in low abundances (≪1 particle per kg dry weight). Additionally, one core was analyzed as an example for smaller MPs (20-500 µm) with focal plane array (FPA)- based µFTIR spectroscopy. Highest MP abundances (~30,000 particles per kg dry weight) were measured for pore scale particles (20-50 µm). The detected high abundances indicate that the HZ can be a significant accumulation area for pore scale MPs (20-50 µm), a size fraction that yet is not considered in literature. As the HZ is known as an important habitat for invertebrates representing the base of riverine food webs, aquatic food webs can potentially be threatened by the presence of MPs in the HZ. Hyporheic exchange is discussed as a potential mechanism leading to a transfer of pore scale MPs from surface flow into streambed sediments and as a potential vector for small MPs to enter the local aquifer. MPs in the HZ therefore may be a potential risk for drinking water supplies, particularly during drinking water production via river bank filtration.
Pain is a serious consequence of spinal cord injury (SCI). Our aim was to investigate the temporal aspects of different types of pain following traumatic SCI and to determine possible predictors of ...neuropathic pain. Prospective data on 90 patients were collected at 1, 6, and 12 months after traumatic SCI. The patients completed questionnaires on pain severity, descriptors, and impact and underwent clinical examination with bedside sensory testing. Eighty-eight patients completed the 12-month follow-up. Approximately 80% of patients reported any type of pain at all 3 time points. Neuropathic pain related to SCI increased over time, and musculoskeletal pain decreased slightly, with both being present in 59% of patients at 12 months; other neuropathic pain not related to SCI and visceral pain were present in 1 to 3%. At-level neuropathic pain present at 1 month resolved in 45% and below-level pain resolved in 33%. Early (1 month) sensory hypersensitivity (particularly cold-evoked dysesthesia) was a predictor for the development of below-level, but not at-level, SCI pain at 12 months. In conclusion, the present study demonstrates phenotypical differences between at-level and below-level SCI pain, which is important for future studies aiming to uncover underlying pain mechanisms.
The finding that early sensory hypersensitivity predicts later onset of below-level central neuropathic pain may help to identify patients at risk of developing neuropathic pain conditions after traumatic spinal cord injury. Information about onset of pain may help to identify different phenotypes in neuropathic pain conditions.
B-cell depleting therapies are highly efficacious in relapsing-remitting multiple sclerosis but one such therapy, rituximab, is not approved for multiple sclerosis and no phase 3 trial data are ...available. We therefore examined the safety and efficacy of rituximab compared with dimethyl fumarate in patients with relapsing-remitting multiple sclerosis to obtain data that might allow inclusion of rituximab in treatment guidelines.
RIFUND-MS was a multicentre, rater-blinded, active-comparator, phase 3, randomised controlled trial done at 17 Swedish university and community hospitals. Key inclusion criteria for participants were: age 18–50 years; relapsing-remitting multiple sclerosis or clinically isolated syndrome according to prevailing McDonald criteria; 10 years or less since diagnosis; untreated or only exposed to interferons or glatiramer acetate; and with clinical or neuroradiological disease activity in the past year. Patients were automatically randomly assigned (1:1) by the treating physician using a randomisation module in the Swedish multiple sclerosis registry, without stratification, to oral dimethyl fumarate 240 mg twice daily or to intravenous rituximab 1000 mg followed by 500 mg every 6 months. Relapse evaluation, Expanded Disability Status Scale rating, and assessment of MRI scans were done by examining physicians and radiologists masked to treatment allocation. The primary outcome was the proportion of patients with at least one relapse (defined as subacute onset of new or worsening neurological symptoms compatible with multiple sclerosis with a duration of more than 24 h and preceded by at least 30 days of clinical stability), assessed in an intention-to-treat analysis using log-binomial regression with robust standard errors. This trial is registered at ClinicalTrials.gov, NCT02746744.
Between July 1, 2016, and Dec 18, 2018, 322 patients were screened for eligibility, 200 of whom were randomly assigned to a treatment group (100 assigned to rituximab and 100 assigned to dimethyl fumarate). The last patient completed 24-month follow-up on April 21, 2021. 98 patients in the rituximab group and 97 patients in the dimethyl fumarate group were eligible for the primary outcome analysis. Three (3%) patients in the rituximab group and 16 (16%) patients in the dimethyl fumarate group had a protocol-defined relapse during the trial, corresponding to a risk ratio of 0·19 (95% CI 0·06–0·62; p=0·0060). Infusion reactions (105 events 40·9 per 100 patient-years) in the rituximab group and gastrointestinal reactions (65 events 47·4 per 100 patient-years) and flush (65 events 47·4 per 100 patient-years) in the dimethyl fumarate group were the most prevalent adverse events. There were no safety concerns.
RIFUND-MS provides evidence that rituximab given as 1000 mg followed by 500 mg every 6 months is superior to dimethyl fumarate in preventing relapses over 24 months in patients with early relapsing-remitting multiple sclerosis. Health economic and long-term safety studies of rituximab in patients with multiple sclerosis are needed.
Swedish Research Council.
Objective
Magnetic resonance imaging (MRI) is essential for multiple sclerosis diagnostics but is conventionally not specific to demyelination. Myelin imaging is often hampered by long scanning ...times, complex postprocessing, or lack of clinical approval. This study aimed to assess the specificity, robustness, and clinical value of Rapid Estimation of Myelin for Diagnostic Imaging, a new myelin imaging technique based on time‐efficient simultaneous T1/T2 relaxometry and proton density mapping in multiple sclerosis.
Methods
Rapid myelin imaging was applied using 3T MRI ex vivo in 3 multiple sclerosis brain samples and in vivo in a prospective cohort of 71 multiple sclerosis patients and 21 age/sex‐matched healthy controls, with scan–rescan repeatability in a subcohort. Disability in patients was assessed by the Expanded Disability Status Scale and the Symbol Digit Modalities Test at baseline and 2‐year follow‐up.
Results
Rapid myelin imaging correlated with myelin‐related stains (proteolipid protein immunostaining and Luxol fast blue) and demonstrated good precision. Multiple sclerosis patients had, relative to controls, lower normalized whole‐brain and normal‐appearing white matter myelin fractions, which correlated with baseline cognitive and physical disability. Longitudinally, these myelin fractions correlated with follow‐up physical disability, even with correction for baseline disability.
Interpretation
Rapid Estimation of Myelin for Diagnostic Imaging provides robust myelin quantification that detects diffuse demyelination in normal‐appearing tissue in multiple sclerosis, which is associated with both cognitive and clinical disability. Because the technique is fast, with automatic postprocessing and US Food and Drug Administration/CE clinical approval, it can be a clinically feasible biomarker that may be suitable to monitor myelin dynamics and evaluate treatments aiming at remyelination. ANN NEUROL 2020;87:710–724
To investigate the association between plasma neurofilament light chain (pNfL) levels and the risk of developing sustained disability worsening.
Concentrations of pNfL were determined in 4,385 ...persons with multiple sclerosis (MS) and 1,026 randomly selected population-based sex- and age-matched controls using the highly sensitive Single Molecule Array (SimoaTM) NF-Light Advantage Kit. We assessed the impact of age-stratified pNfL levels above the 80th, 95th, and 99th percentiles among controls on the risk of Expanded Disability Status Scale (EDSS) worsening within the following year and reaching sustained EDSS scores of 3.0, 4.0, and 6.0 and conversion to secondary progressive multiple sclerosis (SPMS).
The median (interquartile range IQR) pNfL was 7.5 (4.1) pg/mL in controls and 11.4 (9.6) pg/mL in MS (
< 0.001). The median (IQR) duration of follow-up was 5 (5.1) years. High pNfL was associated with increased adjusted rates of EDSS worsening ranging between 1.4 (95% confidence intervals CIs: 1.1-1.8) and 1.7 (95% CI: 1.4-2.3). High pNfL was also associated with the risk of reaching a sustained EDSS score of 3.0, with adjusted rates ranging between 1.5 (95% CI: 1.2-1.8) and 1.55 (95% CI: 1.3-1.8) over all percentile cutoffs (all
< 0.001). Similar increases were observed for the risk of sustained EDSS score 4.0. In contrast, the risk of reaching sustained EDSS score 6.0 and conversion to SPMS was not consistently significant.
Elevated pNfL levels at early stages of MS are associated with an increased risk of reaching sustained disability worsening. Hence, pNfL may serve as a prognostic tool to assess the risk of developing permanent disability in MS.
Comparative real-world effectiveness studies of initial disease-modifying treatment (DMT) choices for relapsing-remitting multiple sclerosis (RRMS) that include rituximab are lacking.
To assess the ...effectiveness and drug discontinuation rates of rituximab among patients with newly diagnosed RRMS compared with injectable DMTs, dimethyl fumarate, fingolimod, or natalizumab.
This retrospective cohort study used prospectively collected data to examine specialized care of 2 Swedish county-based community samples of patients with RRMS. Patients with RRMS who received diagnoses from January 1, 2012, to October 31, 2015, who resided in Stockholm or Västerbotten Counties were identified from a Swedish multiple sclerosis registry.
All reasons for drug discontinuation of initial treatment choice (main outcome) and specific reasons for switching (secondary outcomes) were analyzed with multivariable Cox regression, including propensity scores.
Among 494 patients (median interquartile range age, 34.4 27.4-43.4 years; 158 men 32.0%), 215 received an injectable DMT (43.5%); 86 (17.4%), dimethyl fumarate; 17 (3.4%), fingolimod; 50 (10.1%), natalizumab; 120 (24.3%), rituximab; and 6 (1.2%), other DMT. Regional preferences were pronounced, with 42 of 52 (81%) and 78 of 442 (18%) receiving rituximab in Västerbotten and Stockholm, respectively. The annual discontinuation rate for rituximab, injectable DMTs, dimethyl fumarate, fingolimod, and natalizumab were 0.03, 0.53, 0.32, 0.38, and 0.29, respectively. Continued disease activity was the main reason for discontinuation of injectable DMTs, dimethyl fumarate, and fingolimod; positive John Cunningham virus serology results were the main reason for discontinuation of natalizumab. Rate of clinical relapses and/or neuroradiologic disease activity were significantly lower for rituximab compared with injectable DMTs and dimethyl fumarate, with a tendency for lower relapse rates also compared with natalizumab and fingolimod. The annual discontinuation rate of initial treatment choice was significantly lower in Västerbotten compared with Stockholm (0.09 and 0.37, respectively).
Rituximab was superior to all other DMT in terms of drug discontinuation and displayed better clinical efficacy compared with injectable DMTs and dimethyl fumarate with borderline significance compared with natalizumab and fingolimod. The county where rituximab constituted the main initial treatment choice displayed better outcomes in most measured variables. Collectively, our findings suggest that rituximab performs better than other commonly used DMTs in patients with newly diagnosed RRMS.
Mounting evidence shows that physical exercise modulates systemic inflammation. However, its effect on cerebrospinal fluid (CSF) immune-marker profiles in man are largely unknown. We here report a ...study on healthy subjects (n = 27, males = 12, mean age 28.7, range 22-52) allocated to either an acute exercise setting over four consecutive days, or a training intervention over 4 weeks. Paired plasma and CSF samples collected at baseline, after 7 days of exercise abstention, and the day after completion of the exercise interventions, were analyzed for protein inflammation markers using a multiplex proximity extension assay and neurotransmitters and kynurenine pathway (KP) metabolites using liquid chromatography, respectively. Routine cell counts, and albumin, immunoglobulin G and neurofilament light chain concentrations in CSF remained unchanged in both paradigms, while several inflammatory proteins became upregulated after acute exercise. However, only changes in three CSF (vascular endothelial growth factor-A, interleukin-7 and matrix metalloproteinase-10) and 12 plasma proteins reached significance levels after adjustment for multiple comparisons and exclusion of less stable proteins. Similarly, KP metabolites only changed among participants after acute exercise, while neurotransmitter levels, except for increased CSF serine, remained stable. Both in plasma and CSF changes in KP metabolites and inflammatory proteins correlated, suggesting that these processes are functionally linked. These findings suggest that acute aerobic physical exercise affects immune markers and KP metabolites systemically and in the CSF.
Cerebrospinal fluid (CSF) biomarkers can reflect different aspects of the pathophysiology of relapsing‐remitting multiple sclerosis (RRMS). Understanding the impact of different disease modifying ...therapies on the CSF biomarker profile may increase their implementation in clinical practice and their appropriateness for monitoring treatment efficacy. This study investigated the influence of first‐line (interferon beta) and second‐line (natalizumab) therapies on seven CSF biomarkers in RRMS and their correlation with clinical and radiological outcomes. We included 59 RRMS patients and 39 healthy controls. The concentrations of C‐X‐C motif chemokine 13 (CXCL13), C‐C motif chemokine ligand 2 (CCL2), chitinase‐3‐like protein 1 (CHI3L1), glial fibrillary acidic protein, neurofilament light protein (NFL), and neurogranin were determined by ELISA, and chitotriosidase (CHIT1) was analyzed by spectrofluorometry. RRMS patients had higher levels of NFL, CXCL13, CHI3L1, and CHIT1 than controls (p < 0.001). Subgroup analysis revealed higher NFL, CXCL13 and CHIT1 levels in patients treated with first‐line therapy compared to second‐line therapy (p = 0.008, p = 0.001 and p = 0.026, respectively). NFL and CHIT1 levels correlated with relapse status, and NFL and CXCL13 levels correlated with the formation of new magnetic resonance imaging lesions. Furthermore, we found an association between inflammatory and degenerative biomarkers. The results indicate that CSF levels of NFL, CXCL13, CHI3L1, and CHIT1 correlate with the clinical and/or radiological disease activity, providing additional dimensions in the assessment of treatment efficacy.
CSF biomarkers reflect different aspects of the pathophysiology of multiple sclerosis. The present study investigated the influence of interferon beta and natalizumab on seven biomarkers and their correlation with clinical and radiological outcomes. The results indicate that CSF levels of neurofilament light protein (NFL), C‐X‐C motif chemokine 13 (CXCL13), chitinase‐3‐like protein 1 (CHI3L1), and chitotriosidase (CHIT1) correlate with the clinical and/or radiological disease activity, providing additional dimensions in the assessment of treatment efficacy.
Objective:
To compare treatment effectiveness and persistence in relapsing-remitting multiple sclerosis patients who initiated rituximab versus glatiramer acetate (GA) or interferon-beta (IFN-β).
...Methods:
A total of 461 patients from the Swedish MS registry in the rituximab arm were propensity score matched on a 1:2 basis with 922 patients from the IFN-β/GA comparator, between April 2005 and November 2015. Annualised relapse rate (ARR) was compared using the Poisson method. A marginal Cox model was used to analyse time to first relapse, 3-month confirmed disability progression and treatment discontinuation in the matched sample. A signed-rank test was used to compare Expanded Disability Status Scale (EDSS) change from baseline.
Results:
Rituximab was associated with a reduction in ARR (0.003; 95% confidence interval (CI) = 0.001, 0.009) relative to IFN-β/GA (0.026; 95% CI = 0.020, 0.033) (p < 0.001). Rituximab was associated with an 87% reduction in the relapse rate (hazard ratio (HR) = 0.13; 95% CI = 0.04, 0.41) and an 85% reduction in the discontinuation rate (HR = 0.15; 95% CI = 0.11, 0.20) relative to IFN-β/GA. EDSS regression from baseline was greater in the rituximab group at 12 and 24 months.
Conclusion:
Rituximab appears to be superior to first-generation disease-modifying treatments (DMTs) with respect to relapse control and tolerability, whereas superiority on disability outcomes is less clear.
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