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Objective: To evaluate the safety of COVID-19 vaccines in patients with multiple sclerosis (MS) by assessing their impact on serum neurofilament light chain (sNfL) levels as a marker of neuroaxonal damage., Methods: Single-center observational longitudinal study including patients with MS who consecutively received their initial vaccination against SARS-CoV-2 at Hospital Universitario Ramón y Cajal, following the first national immunization program in Spain. Serum samples were collected at baseline and after receiving the second dose of the vaccine. sNfL levels were quantified using the single molecule array (SIMOA) technique. Adverse events, including clinical or radiological reactivation of the disease, were recorded., Results: Fifty-two patients were included (median age, 39.7 years [range, 22.5-63.3]; 71.2% female). After SARS-CoV-2 vaccination, no increased inflammatory activity, either determined by the presence of relapses and/or new MRI lesions and/or high sNfL levels, was detected. Accordingly, there was no difference between median sNfL levels before and after vaccination (5.39 vs. 5.76 pg/ml, p=0.6). Despite this, when looking at baseline patient characteristics before vaccination, younger age associated with disease activity after vaccination (OR 0.87, 95% CI: 0.77-0.98, p=0.022). Larger studies are needed to validate these results., Conclusion: COVID-19 vaccines did not cause reactivation of disease at a clinical, radiological or molecular level, thus suggesting that they are safe in MS patients., Competing Interests: SS received research grants, travel support or honoraria for speaking engagements from Almirall, Biogen, Bristol Myers Squibb, Janssen, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva. EM received research grants, travel support or honoraria for speaking engagements from Almirall, Biogen, Janssen, Merck, Novartis, Roche, and Sanofi-Genzyme. JC-G has received honorary for speaking engagements or consulting services from Biogen, Bayer, Bial, Bristol-Myers, Johnson&Johnson and Sanofi-Genzyme. FR-J has received honorary for speaking engagements or consulting services from Bial, Biogen, Johnson&Johnson and Sanofi-Genzyme. RS-A has received honorary for speaking engagements from Johnson&Johnson. LC-F received speaker fees, travel support, and/or served on advisory boards by Almirall, Bayer, Biogen, Biopas, Bristol Myers Squibb, Celgene, Ipsen, Janssen, Merck, Novartis, Roche, Sanofi and Teva. LV received research grants, travel support or honoraria for speaking engagements from Biogen, Bristol Myers Squibb, Merck, Novartis, Roche and Sanofi-Genzyme. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Sainz de la Maza, Rodero-Romero, Monreal, Chico-García, Villarrubia, Rodríguez-Jorge, Fernández-Velasco, Sainz-Amo, Costa-Frossard, Masjuan and Villar.)

Introduction: Alemtuzumab is a highly effective pulsed immune reconstitution therapy for multiple sclerosis (MS)., Aim: To evaluate serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) in patients with relapsing-remitting MS who have been treated with Alemtuzumab over the course of 2 years., Methods: This prospective study involved MS patients treated with Alemtuzumab at a referral MS center. Both sNfL and sGFAP were analyzed at baseline and then again at 6, 12, and 24 months post-treatment using the single molecule array (SiMoA) technique. We also recruited matched healthy controls (HCs) for comparison., Results: The study included 46 patients (with a median age of 34.2 [Interquartile range (IQR), 28.7-42.3] years, 27 of which were women [58%]) and 76 HCs. No differences in demographic characteristics were observed between patients and HC. The median disease duration was 6.22 (IQR, 1.56-10.13) years. The median annualized relapse rate before treatment was 2 (IQR, 1-3). At baseline, sNfL and sGFAP levels were higher in MS patients (median of 18.8 [IQR, 10.7-52.7] pg/ml and 158.9 [IQR, 126.9-255.5] pg/ml, respectively) when compared to HC (6.11 [IQR, 2.03-8.54] pg/ml and 91.0 [72.6-109] pg/ml, respectively) (p<0.001 for both comparisons). The data indicates that 80% of patients had high (≥10 pg/ml) sNfL values at baseline. We observed a significant decrease in sNfL levels at 6 (65%, p = 0.02), 12 (70.8%, p<0.001), and 24 (78.1%, p<0.001) months. sNfL reached similar levels to HC only after 24 months of Alemtuzumab treatment. During the follow-up period, no changes were identified in the sGFAP values., Conclusion: Alemtuzumab leads to the normalization of sNfL values in MS patients after 2 years of treatment, with no apparent effect on sGFAP values., Competing Interests: RS-A reported receiving research travel support from Roche and Janssen outside the submitted work. EM reported receiving research grants, travel support, or honoraria for speaking engagements from Biogen, Sanofi, Merck, Novartis, Almirall, Roche, Bristol Myers Squibb, and Janssen outside the submitted work. JF reported receiving research travel support from Roche and Janssen outside the submitted work. SM reported receiving personal fees from Almirall, Bristol Myers Squibb, and Teva outside the submitted work and receiving compensation for lectures or travel expenses from Merck Serono, Biogen, Sanofi Genzyme, Roche, Janssen, and Novartis. JC reported receiving personal fees from Sanofi outside the submitted work and receiving speaker honoraria from Biogen Idec and Sanofi. FR reported receiving personal fees from Sanofi outside the submitted work and receiving speaker honoraria from Biogen Idec and Sanofi. LF reported receiving speaker fees and travel support and/or serving on advisory boards for Biogen, Sanofi, Merck, Bayer, Novartis, Roche, Teva, Celgene, Ipsen, Biopas, Bristol Myers Squibb, Janssen, and Almirall. LV reported receiving grants and personal fees from Merck, Roche, Sanofi Genzyme, Bristol Myers Squibb, Celgene, Biogen, and Novartis outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Sainz-Amo, Rodero Romero, Monreal, Chico García, Fernández Velasco, Villarrubia, Veiga González, Sainz de la Maza, Rodríguez Jorge, Masjuan, Costa-Frossard and Villar.)

Polysaccharides are an excellent renewable source for developing food-packing materials. It is expected that these packages can be an efficient barrier against oxygen; can reduce lipid peroxidation, and can retain the natural aroma of a food commodity. Starch has tremendous potential to be explored in the preparation of food packaging; however, due to their high hydrophilic nature, packaging films produced from starch possess poor protective moisture barriers and low mechanical properties. This scenario limits their applications, especially in humid conditions. In contrast, lignin's highly complex aromatic hetero-polymer network of phenylpropane units is known to play a filler role in polysaccharide films. Moreover, lignin can limit the biodegradability of polysaccharides films by a physical barrier, mainly, and by non-productive bindings. The main interactions affecting lignin non-productive bindings are hydrophobic interactions, electrostatic interactions, and hydrogen-bonding interactions, which are dependent on the total phenolic -OH and -COOH content in its chemical structure. In this review, the use of lignin as a reinforcement to improve the biodegradability of starch-based films in wet environments is presented. Moreover, the characteristics of the used lignins, the mechanisms of molecular interaction among these materials, and the sensitive physicochemical parameters for biodegradability detection are related.

The potential of combining serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) levels to predict disability worsening in multiple sclerosis (MS) remains underexplored. We aimed to investigate whether sNfL and sGFAP values identify distinct subgroups of patients according to the risk of disability worsening and their response to disease-modifying treatments (DMTs). This multicentre study, conducted across thirteen European hospitals, spanned from July 15, 1994, to August 18, 2022, with follow-up until September 26, 2023. We enrolled MS patients who had serum samples collected within 12 months from disease onset and before initiating DMTs. Multivariable regression models were used to estimate the risk of relapse-associated worsening (RAW), progression independent of relapse activity (PIRA), and Expanded Disability Status Scale (EDSS) score of 3. Of the 725 patients included, median age was 34.2 years (IQR, 27.6-42.4), and 509 patients (70.2%) were female. Median follow-up duration was 6.43 years (IQR, 4.65-9.81). Higher sNfL values associated with an elevated risk of RAW (HR of 1.45; 95% CI 1.19-1.76; P < 0.001), PIRA (HR of 1.43; 95% CI 1.13-1.81; P = 0.003), and reaching an EDSS of 3 (HR of 1.55; 95% CI 1.29-1.85; P < 0.001). Moreover, higher sGFAP levels were linked to a higher risk of achieving an EDSS score of 3 (HR of 1.36; 95% CI 1.06-1.74; P = 0.02) and, in patients with low sNfL values, to PIRA (HR of 1.86; 95% CI 1.01-3.45; P = 0.04). We further examined the combined effect of sNfL and sGFAP levels. Patients with low sNfL and sGFAP values (NLGL) exhibited a low risk of all outcomes and served as reference. Untreated patients with high sNfL levels showed a higher risk of RAW, PIRA, and reaching an EDSS of 3. Injectable or oral DMTs reduced the risk of RAW in these patients but failed to mitigate the risk of PIRA and reaching an EDSS of 3. Conversely, high-efficacy DMTs counteracted the heightened risk of these outcomes, except for the risk of PIRA in patients with high sNfL and sGFAP levels. Patients with low sNfL and high sGFAP values (NLGH) showed an increased risk of PIRA and achieving an EDSS of 3, which remained unchanged with either high-efficacy or other DMTs. In conclusion, evaluating sNfL and sGFAP levels at disease onset in MS may identify distinct phenotypes associated with diverse immunological pathways of disability acquisition and therapeutic response., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Multiple studies have shown the importance of blood-based biomarkers indicating axonal damage (serum neurofilament light chains [sNfL]) or astroglia activation (serum glial fibrillary acidic protein [sGFAP]) for monitoring different neurological diseases. However, normal values of these variables remain to be clearly defined, partly due to the influence of different demographic factors. We investigated demographic differences in a cohort of healthy volunteers. A cross-sectional study was conducted including 116 healthy controls with ages between 18 and 69 years (67.5% females; n = 79). sNfL and sGFAP concentrations were measured using single-molecule arrays. Age and body mass index affected sNfL values, and age was found to be the most important factor. The normal values changed with age, and we established normal values for individuals younger than 45 years as <10 pg/mL and for controls older than 45 years as <15 pg/mL. We established normal values at <10 pg/mL for individuals younger than 45 years and <15 pg/mL for older individuals. Alternatively, a Z-score of 1.5 was relevant for all controls. sGFAP was only affected by age. Differences in normal values were evident by 55 years. The highest normality limit for sGFAP was 140 pg/mL for controls under 55 years and 280 for older controls. We defined normal levels for sNfL and sGFAP and their corresponding age-associated changes. These data may contribute to the application of such variables in clinical practice.

Background: Although fingolimod, a sphingosine 1-phosphate receptor agonist, has shown to be an effective treatment reducing relapse rate and also slowing down the disability progression in relapsing-remitting multiple sclerosis (RRMS) patients, it is important to quickly identify those suboptimal responders., Objective: The main objective was to assess different clinical, radiological, genetic and environmental factors as possible early predictors of response in MS patients treated with fingolimod for 24 months. The secondary objective was to analyze the possible contribution of the environmental factors analyzed to the progression and activity of the disease along the 2-years of follow-up., Methods: A retrospective study with 151 patients diagnosed with MS, under fingolimod treatment for 24 months, with serum samples at initiation and six months later, and with clinical and radiological data at initiation and 24 months later, were included in the study. Clinical and radiological variables were collected to establish NEDA-3 (no evidence of disease activity: patients without relapses, disability progression and new T2 lesions or Gd+ lesions) and EDA (evidence of disease activity: patients with relapses and/or progression and/or new T2 lesions or gadolinium-positive [Gd+] lesions) conditions. Human leukocyte antigen II (HLA-II), EBNA-1 IgG and VCA IgG from Epstein-Barr virus (EBV) and antibody titers against Human herpesvirus 6A/B (HHV-6A/B) were also analyzed., Results: A total of 151 MS patients fulfilled the inclusion criteria: 27.8% was NEDA-3 (37.5% among those previously treated with high efficacy therapies >24 months). The following early predictors were statistically significantly associated with NEDA-3 condition: sex (male; p=0.002), age at baseline (older; p=0.009), relapses 2-years before fingolimod initiation ≤1 (p=0.010), and absence of Gd+ lesions at baseline (p=0.006). Regarding the possible contribution of the environmental factors included in the study to the activity or the progression of the disease, we only found that EBNA-1 IgG titers decreased in 20.0% of PIRA (progression independent from relapse activity) patients vs. 73.3% of RAW (relapse-associated worsening) patients (p=0.006; O.R. = 11.0)., Conclusion: MS patients that are male, older, and with a low clinical and radiological activity at fingolimod initiation have a greater probability to reach NEDA-3 condition after two years with this therapy. An intriguing association of EBV with the progression of the disease has also been described, but it should be further study in a larger cohort to confirm these results., Competing Interests: VG has received support for attending meetings and speaking honoraria from Merck, Biogen, Novartis and Sanofi-Genzyme. LR-T has received compensation for consulting services and speaking honoraria from Biogen, Novartis, Bayer, Merck, Sanofi, Genzyme, Janssen, Horizon, Teva Pharmaceutical Industries Ltd, Almirall. AQ has received travel support from Merck and Novartis for conference attendance. LV has served at scientific advisory boards, participated in meetings sponsored by, received speaking honoraria or travel funding or research grants from Roche, Sanofi, Merck, Biogen, Bristol Myers, and Novartis. LC-F reports compensation for consulting services and speaker honoraria from Biogen, Bristol Myers Squibb, Janssen, Merck-Serono, Novartis, Sanofi, Roche, and Teva. RA has been a speaker or has participated in the advisory board of Novartis, Teva, Roche, Bristol, Janssen, Biogen, Merck and Sanofi-Genzyme. RA-L has received support for attending meetings from Biogen, Merck, Novartis and Sanofi-Genzyme. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Dominguez-Mozo, Galán, Ramió-Torrentà, Quiroga, Quintana, Villar, Costa-Frossard, Fernández-Velasco, Villarrubia, Garcia-Martinez, Arroyo and Alvarez-Lafuente.)

Objective: Soluble CD27 is a promising cerebrospinal fluid inflammatory biomarker in multiple sclerosis. In this study, we investigate relevant immune and neuro-pathological features of soluble CD27 in multiple sclerosis., Methods: Protein levels of soluble CD27 were correlated to inflammatory cell subpopulations and inflammatory cytokines and chemokines detected in cerebrospinal fluid of 137 patients with multiple sclerosis and 47 patients with inflammatory and non-inflammatory neurological disease from three independent cohorts. Production of soluble CD27 was investigated in cell cultures of activated T and B cells and CD27-knockout T cells. In a study including matched cerebrospinal fluid and post-mortem brain tissues of patients with multiple sclerosis and control cases, levels of soluble CD27 were correlated with perivascular and meningeal infiltrates and with neuropathological features., Results: We demonstrate that soluble CD27 favours the differentiation of interferon-γ-producing T cells and is released through a secretory mechanism activated by TCR engagement and regulated by neutral sphingomyelinase. We also show that the levels of soluble CD27 correlate with the representation of inflammatory T cell subsets in the CSF of patients with relapsing-remitting multiple sclerosis and with the magnitude of perivascular and meningeal CD27 + CD4 + and CD8 + T cell infiltrates in post-mortem central nervous system tissue, defining a subgroup of patients with extensive active inflammatory lesions., Interpretation: Our results demonstrate that soluble CD27 is a biomarker of disease activity, potentially informative for personalized treatment and monitoring of treatment outcomes., (© 2024. The Author(s).)

Red propolis is an active ingredient of great nutritional interest which offers numerous benefits as an antioxidant and antimicrobial agent. Thus, the objective of this research was to evaluate the application of an edible and antimicrobial gelatine coating containing red propolis to increase the shelf life of grapes. Gelatine films with an addition of 5, 10, 15, 20 and 25% of red propolis extract were produced to evaluate their antimicrobial activity using the disk diffusion test in solid media. The films with 25% red propolis extract showed antimicrobial activity against the bacteria Staphylococcus aureus and Pseudomonas aeruginosa . The grapes were coated with pure gelatine, without a plasticizer and with gelatine with 25% red propolis and then stored for 1, 4, 10, 19 and 25 days at temperatures of 25 °C and 5 °C. The results showed that the gelatine coating with propolis reduced the mass loss of grapes stored at 25 °C for 19 days by 7.82% and by 21.20% for those kept at 5 °C for 25 days. The pH, total titratable acidity, soluble solids and color of the grapes increased due to the ripening process. Furthermore, the sensory acceptability indexes of the refrigerated grapes with coatings were superior (>78%) to those of the control samples (38%), proving the effectiveness of the coatings in maintaining the quality of grapes during storage.

Background: Patient disability, relapse rate, and age are used for family planning in multiple sclerosis (MS). However, the need for more accurate biomarkers is widely recognized. We aimed to explore the influence of age on neurofilament light chain (sNfL), which reflects acute inflammation; glial fibrillary acidic protein (GFAP), associated with disability progression independent of relapses; and anti-Müllerian hormone (AMH), reflecting ovarian reserve, to provide a tailored family planning strategy., Methods: This case-control study included 95 MS patients and 61 healthy control women (HCW). sNfL and GFAP levels were measured using a sensitive single-molecule array assay. AMH levels were measured by the automated Elecsys ® Anti-Müllerian Hormone Assay., Results: We observed no significant differences in AMH values between MS patients and the control group within any of the age-matched categories. Age exhibited a negative correlation with AMH values in both groups, as expected. Nevertheless, our findings suggest a slight tendency toward reduced ovarian reserve in MS patients (rho MS patients = -0.67, p < 0.0001; rho HCW = -0.43, p = 0.0006). Interestingly, among the 76 MS participants under 40 years old, we identified ten individuals (13.1%) with AMH levels below 0.7 ng/ml, indicative of a low ovarian reserve, and an additional six individuals (7.8%) with AMH levels between 0.7 ng/ml and 0.9 ng/ml, suggesting a potential risk of premature ovarian failure. Conversely, sNfL and GFAP levels in the MS group exhibited high variability but showed no significant association with age intervals., Conclusion: We found no significant differences in AMH, sNfL or GFAP values between MS patients and the control group within any of the age-matched categories. The assessment of AMH, sNFL and GFAP levels at MS onset facilitates personalized therapeutic and family planning strategies for childbearing-age women., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Cuello, Meldaña Rivera, Monreal, Gómez Lozano, García Cano, García Domínguez, Fernández Velasco, Costa-Frossard França, Goicochea, Higueras, De León-Luis, Sainz De La Maza, Villarrubia, Arribas Gómez, Ruiz Perez, Martinez Ginés and Villar.)

Introduction: The immunoglobulin kappa free light chain (KFLC) index has been proposed as a potentially suitable alternative to oligoclonal IgG bands (OCGB) for diagnosing multiple sclerosis (MS), offering automation and reduced processing time. However, there is no consensus on the preferred approach or how to combine both techniques., Methods: This prospective cohort study aimed to determine the best utilization of OCGB and KFLC index in patients with a clinically isolated syndrome (CIS) followed for at least two years. OCGB and KFLC were assessed using isoelectric focusing and immunoblotting and turbidimetry, respectively. Sensitivity, specificity, and accuracy for diagnosing MS were calculated for each method., Results: The study included 371 patients, with 260 (70.1 %) being women, and a median age of 34.9 (27.8 - 43.9) years. Using a cut-off value of 6.1, the KFLC index demonstrated a sensitivity and specificity of 86.3% and 93.9%, respectively. The sensitivity of OCGB (95.3%) was higher (p < 0.001 vs. KFLC index) and the specificity (100%) was comparable to that of the KFLC index (p = 0.5). The concordance between the methods was not uniform across all patients, with 97.8% agreement in patients with KFLC index ≥ 6.1 and 56.0 % in patients with KFLC index < 6.1. In patients with a KFLC index < 6.1, OCGB still identified 75.0 % of MS patients due to its higher sensitivity. An algorithm using the KFLC index as a screening tool and OCGB as an alternative for patients with a negative KFLC index result achieved an accuracy of 96.3 %., Discussion: Combining the KFLC index and OCGB can provide an easily reproducible and accurate method for diagnosing MS, with OCGB primarily reserved for patients with a KFLC index < 6.1., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Monreal, Fernández-Velasco, García-Soidán, Sainz de la Maza, Espiño, Villarrubia, Rodríguez-Jorge, Chico-García, Sainz-Amo, Masjuan, Costa-Frossard and Villar.)

This single-center study included 68 multiple sclerosis (MS) patients who received the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination from one of several approved vaccine preparations in Spain. Blood samples were collected one to three months after the second dose of the vaccine had been administered. Cellular immune responses to the vaccine were assessed using QuantiFERON analysis, and peripheral blood mononuclear cell subsets were assayed using flow cytometry. Response associated with higher percentages of total lymphocytes, naïve CD4+ T-cells ( p = 0.028), CD8+ T-cells ( p = 0.013), and, mostly, naïve CD8+ T-cells ( p = 0.0003). These results were confirmed by analyzing absolute numbers ( p = 0.019; p = 0.002, and p = 0.0003, respectively). Naïve CD8 T-cell numbers higher than 17 cells/μL were closely associated with an optimal cellular response to SARS-CoV-2 vaccination (odds ratio: 24.0, confidence interval: 4.8-460.3; p = 0.0001). This finding clearly shows that independent of the treatment received, higher numbers of naïve CD8+ T-cells yield a strong cellular response to SARS-CoV-2 vaccines in MS patients. If this finding is validated with other viruses/vaccines, it could provide a good tool for identifying MS patients undergoing treatment who will develop strong cellular responses to anti-virus vaccines.

Importance: The value of serum neurofilament light chain (sNfL) levels for predicting long-term disability in patients with multiple sclerosis (MS) remains controversial., Objective: To assess whether high sNfL values are associated with disability worsening in patients who underwent their first demyelinating MS event., Design, Setting, and Participants: This multicenter cohort study included patients who underwent their first demyelinating event suggestive of MS at Hospital Universitario Ramón y Cajal (development cohort; June 1, 1994, to September 31, 2021, with follow-up until August 31, 2022) and 8 Spanish hospitals (validation cohort; October 1, 1995, to August 4, 2020, with follow-up until August 16, 2022)., Exposures: Clinical evaluations at least every 6 months., Main Outcomes and Measures: The main outcomes were 6-month confirmed disability worsening (CDW) and an Expanded Disability Status Scale (EDSS) score of 3. Levels of sNfL were measured in blood samples obtained within 12 months after disease onset using a single molecule array kit. The cutoffs used were sNfL level of 10 pg/mL and a standardized score (z score) of 1.5. Multivariable Cox proportional hazards regression models were used to evaluate outcomes., Results: Of the 578 patients included in the study, 327 were in the development cohort (median age at sNfL analysis, 34.1 years [IQR, 27.2-42.7 years]; 226 female [69.1%]) and 251 patients were in the validation cohort (median age at sNfL analysis, 33.3 years [IQR, 27.4-41.5 years]; 184 female [73.3%]). The median follow-up was 7.10 years (IQR, 4.18-10.0 years). Levels of sNfL greater than 10 pg/mL were independently associated with higher risk of 6-month CDW and an EDSS of 3 in the development cohort (6-month CDW: hazard ratio [HR], 2.39; 95% CI, 1.39-4.12; P = .002; EDSS of 3: HR, 4.12; 95% CI, 2.18-7.77; P < .001) and the validation cohort (6-month CDW: HR, 1.61; 95% CI, 1.07-2.42; P = .02; EDSS of 3: HR, 2.03; 95% CI, 1.23-3.33; P = .005). Highly effective disease-modifying treatments were associated with lower risks of 6-month CDW and an EDSS of 3 in patients with high baseline sNfL values., Conclusions and Relevance: This cohort study found that high sNfL values obtained within the first year of disease were associated with long-term disability worsening in MS, suggesting that sNfL level measurement may help identify optimal candidates for highly effective disease-modifying treatments.

Introduction: Recent works demonstrate that patients with multiple sclerosis (pwMS) and oligoclonal M bands (OCMB) in cerebrospinal fluid (CSF) are at higher risk of conversion to secondary progressive course, suggesting a distinct pathophysiology pathway in these patients., Objectives: To analyze the relationship of serum neurofilament light chain (s-NFL) in absence of inflammatory activity in people with multiple sclerosis (pwMS) according to the presence of OCMB versus healthy controls (HC), and the effect of aging., Methods: Two cohorts of HC were compared to a cohort of pwMS without clinical or radiological signs of acute inflammation. Lack of inflammation was defined as the absence of relapses or gadolinium-enhancing lesions (GEL) brain in an MRI performed within three months before and after s-NFL determination. S-NFL was measured with SIMOa technology. OCMB in the cerebrospinal fluid (CSF) were analyzed with isoelectric focusing and immunoblotting., Results: 254 people were studied: 124 healthy voluntary controls and 130 pwMS. Despite the absence of inflammatory activity, pwMS and OCMB showed higher levels of s-NFL compared to those without OCMB and HC (11.4 pg/mL, 8.9 pg/mL and 9.0 pg/mL, respectively). A positive and exponential correlation between age and s-NFL was observed, with highest increases among pwMS and OCMB in the CSF., Discussion: In absence of overt inflammatory activity, pwMS and OCMB exhibit higher s-NFL levels, and a greater age-related increase. Thus, OCMB may portray an underlying inflammatory process not detected by conventional MRI studies and may explain the poorer prognosis of these patients., (Copyright © 2022. Published by Elsevier B.V.)

This study aimed to produce and characterized active biodegradable packages by extrusion of cassava starch, biodegradable polyester, plasticizer, and acai extract (EA 0, 1, 2, 3 and 4%) and to evaluate its effects on extra virgin olive oil (EVOO) for 120 days. All analyses were performed at the beginning (day 0) and the end of the experiment (day 120). The oil was characterized for acidity index (IA), peroxide index (IP), thiobarbituric acid reactive substances (TBARS), conjugated dienes (CD), phenolic compounds (PC) and color parameters. The incorporation of EA at the initial time caused increased thickness, mechanical properties, solubility in water and oil in all formulations. The some values of properties increased or decreased, due to the interaction of the stored product and packaging. At the end of the storage period, the values of IA and IP were below the limits established by current legislation. The EVOO showed a gradual decrease in PC from day 1 to day 120, for all treatments., (Copyright © 2022. Published by Elsevier Ltd.)

Analysis of cerebrospinal fluid (CSF) represents a valuable window into the pathogenesis of neuroinflammatory diseases, such as multiple sclerosis (MS). However, analysis of the cellular fraction of CSF is often neglected because CSF cells die rapidly ex vivo. Immunophenotyping of CSF cells in multicenter clinical trials requires sample preservation and shipping to a centralized lab. Yet, there is no consensus on the best method to preserve intact CSF cells and no detailed evaluation of subset-specific cell loss. We used flow cytometry to compare major leukocyte populations in fresh CSF (processed within 2 h) to cells fixed for 48 h with TransFix-EDTA® or cryopreserved and thawed after 96 h. We observed a statistically significant loss of total mononuclear cells, total T cells, CD3+ CD8- T cells, and CD3+ CD8+ T cells after cryopreservation compared to fresh or fixed (p < 0.001), with no significant difference between fresh and fixed. Thus, our results demonstrate that TransFix-EDTA® was superior to cryopreservation for preserving intact CSF T cells. Surprisingly, neither cryopreservation nor fixation had a significant effect on recovery of low frequency cell subsets in CSF, including B cells, NK cells, NKT-like cells, CD14+ monocytes, or CD123+ DCs, versus fresh CSF. To determine the effect of prolonged fixation on cell recovery, we analyzed major CSF cell subsets by flow cytometry after 24, 48, or 72 h of fixation with TransFix-EDTA®. We observed a consistent and progressive loss in the absolute counts of all subsets over time, although this effect was not statistically significant. We conclude that for immunophenotyping of major CSF cell subsets by flow cytometry, fixation with TransFix-EDTA®, shipment to a central lab, and analysis within 48 h is a feasible method to ensure stability of both absolute cell number and relative frequency. This method is a valuable alternative to fresh CSF analysis and can be implemented in multicenter clinical trials., Competing Interests: Declaration of Competing Interest LAC, NL, TZ, JIF-V: None. IM: Currently employed by Sanofi. LMV: Served on scientific advisory boards, participated in meetings sponsored by, received speaking honoraria, travel funding, or research grants from Roche, Sanofi, Merck, Biogen, Bristol Myers, and Novartis. PAM: Received travel support and speaker honoraria from unrestricted educational activities organized by Novartis, Bayer HealthCare, Bayer Pharma, Biogen Idec, Merck-Serono and Sanofi Aventis. Consulted for Magenta Therapeutics and Jasper Therapeutics. KMH: Currently employed by and holds equity in Rubius Therapeutics. AB-O: Participated as a speaker in meetings sponsored by and received consulting fees from Accure, Atara Biotherapeutics, Biogen, BMS/Celgene/Receptos, GlaxoSmithKline, Gossamer, Janssen/Actelion, Medimmune, Merck/EMD Serono, Novartis, Roche/Genentech, Sanofi-Genzyme; and has received grant support to the University of Pennsylvania from Biogen Idec, Roche/Genentech, Merck/EMD Serono and Novartis., (Published by Elsevier B.V.)

Background and Purpose: Short-chain fatty acids (SCFAs) can have pro- or anti-inflammatory properties, but their relationship with multiple sclerosis (MS) relapses during pregnancy remains unknown. This study aimed to explore SCFA profiles in MS patients during pregnancy and to assess their association with the appearance of relapses during pregnancy and postpartum., Methods: We prospectively included 53 pregnant MS patients and 21 healthy control women. Patients were evaluated during pregnancy and puerperium. SCFAs were measured by liquid chromatography-mass spectrometry., Results: Sixteen patients (32%) had relapses during pregnancy or puerperium, and 37 (68%) did not. All MS patients showed significant increases in acetate levels during pregnancy and the postpartum period compared to non-MS women. However, propionate and butyrate values were associated with disease activity. Their values were higher in nonrelapsing patients and remained similar to the control group in relapsing patients. The variable that best identified active patients was the propionate/acetate ratio. Ratios of <0.36 during the first trimester were associated with higher inflammatory activity (odds ratio = 165, 95% confidence interval = 10.2-239.4, p < 0.01). Most nonrelapsing patients showed values of >0.36, which were similar to those in healthy pregnant women., Conclusions: Low propionate/acetate ratio values during the first trimester of gestation identified MS patients at risk of relapses during pregnancy and the postpartum period., (© 2021 European Academy of Neurology.)

A series of pressure-sensitive adhesives (PSA) were prepared by emulsion polymerization in order to obtain a PSA that meet with the current label market requirements. For it, the effect of the incorporation of acrylonitrile (ACN) as hard monomer was investigated in a n -butyl acrylate ( n -BA) and acrylic acid (AA) system. Great differences were found in the adhesive performance according to the ACN weight ratio. Its increased resulted in a considerable rise in the average sol molecular weight and in the glass transition temperature. This was reflected in a decrease of adhesion forces (peel resistance and tack) and an increase of the cohesion forces (shear resistance). Moreover, the incorporation of the minimum amount of ACN studied showed a great change in the elastic modulus determined by dynamic shear resistance with respect to the based formulation that did not contain ACN. Finally, the ice bucket test was carried out to check the adhesive performance in cold and wet environments.

Packages from renewable sources have been the focus of many studies, due to the consumer needs for high-quality food, environmental concern related to the inadequate discard of packaging, low percentage of packaging recycling, and starch application by a viable method. Thus, this work aimed to develop bioactive packages based on white, red, and black rice starch and analyze the influence of macromolecule and plasticizer type, even its blends, on the characteristics of films. Films were characterized by color, opacity, thickness, water solubility, water vapor permeability, and bioactive properties. The use of rice starch in the development of edible and/or biodegradable films was feasible, with all the formulations tested presenting a homogeneous matrix and the films obtained varying in hue, to the naked eye, as a function of the starch used. Variation of the type of starch and plasticizer, as well as the concentrations of the same, resulted in films with differences in all studied properties. Films prepared with 5% of starch and 30% of sorbitol showed phenolic compounds and antioxidant capacity, using the DPPH and ABTS methods, indicating that these can be considered bioactive packages and also suitable for food application.

A woman with mild coronavirus disease 2019 developed cervical adenopathy, being diagnosed of Epstein-Barr virus infectious mononucleosis. We performed fine needle aspiration, and demonstrate that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is found in lymph nodes even in mild disease along with a strong expansion of terminally differentiated effector memory CD4+ T cells, a cell population that is practically absent in lymph nodes., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objective: To explore if baseline blood lymphocyte profile could identify relapsing remitting multiple sclerosis (RRMS) patients at higher risk of developing secondary autoimmune adverse events (AIAEs) after alemtuzumab treatment., Methods: Multicenter prospective study including 57 RRMS patients treated with alemtuzumab followed for 3.25 [3.5-4.21] years, (median [interquartile range]). Blood samples were collected at baseline, and leukocyte subsets determined by flow cytometry. We had additional samples one year after the first cycle of alemtuzumab treatment in 39 cases., Results: Twenty-two patients (38.6%) developed AIAEs during follow-up. They had higher B-cell percentages at baseline (p=0.0014), being differences mainly due to plasmablasts/plasma cells (PB/PC, p=0.0011). Those with no AIAEs had higher percentages of CD4+ T cells (p=0.013), mainly due to terminally differentiated (TD) (p=0.034) and effector memory (EM) (p=0.031) phenotypes. AIAEs- patients also showed higher values of TNF-alpha-producing CD8+ T cells (p=0.029). The percentage of PB/PC was the best variable to differentiate both groups of patients. Baseline values >0.10% closely associated with higher AIAE risk (Odds ratio [OR]: 5.91, 95% CI: 1.83-19.10, p=0.004). When excluding the 12 patients with natalizumab, which decreases blood PB/PC percentages, being the last treatment before alemtuzumab, baseline PB/PC >0.1% even predicted more accurately the risk of AIAEs (OR: 11.67, 95% CI: 2.62-51.89, p=0.0007). The AIAEs+ group continued having high percentages of PB/PC after a year of alemtuzumab treatment (p=0.0058)., Conclusions: A PB/PC percentage <0.1% at baseline identifies MS patients at low risk of secondary autoimmunity during alemtuzumab treatment.​., Competing Interests: EM received research grants, travel support or honoraria for speaking engagements from Biogen, Merck, Novartis, Roche, and Sanofi-Genzyme. SS received payment for lecturing or travel expenses from Almirall, Biogen, Merck-Serono, Novartis Roche, Sanofi-Genzyme, and Teva. MC has received compensation for consulting services and speaking honoraria from Bayer Schering Pharma, Merk Serono, Biogen-Idec, Teva Pharmaceuticals, Sanofi-Aventis, Genzyme, and Novartis. LR-T has received speaking honoraria and travel expenses for scientific meetings and has participated in advisory boards in the past years with Bayer Schering Pharma, Biogen, EMD Merck Serono, Sanofi Genzyme, Novartis, Sanofi-Aventis, Teva Phramaceuticals, Almirall and Roche. XM has received speaking honoraria and travel expenses for participation in scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Actelion, Alexion, Bayer, Biogen, Celgene, EMD Serono, Genzyme, Immunic, Medday, Merck KGaA, Darmstadt Germany, Mylan, Nervgen, Novartis, Roche, Sanofi-Genzyme, Teva MSIF and NMSS. LM has received travel funding from Genzyme, Roche, Biogen Idec and Novartis, and personal fee for lectures from Roche. JM-L received grants and consulting or speaking fees from Almirall, Biogen, Celgene, Genzyme, Merck, Novartis, Roche and Teva. RA-L reports grants and personal fees from Merck Serono, personal fees and non-financial support from Biogen IDEC, grants, personal fees and non-financial support from Novartis Pharmaceuticals S.A., grants and personal fees from Genzyme, non-financial support from TEVA Pharma, S.L. LC-F received speaker fees, travel support, and/or served on advisory boards by Biogen, Sanofi, Merck, Bayer, Novartis, Roche, Teva, Celgene, Ipsen, Biopas, Almirall. LV received research grants, travel support or honoraria for speaking engagements from Biogen, Merck, Novartis, Roche, Sanofi-Genzyme and Bristol-Myers. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Walo-Delgado, Monreal, Medina, Quintana, Sainz de la Maza, Fernández-Velasco, Lapuente, Comabella, Ramió-Torrentà, Montalban, Midaglia, Villarrubia, Carrasco-Sayalero, Rodríguez-Martín, Roldán, Meca-Lallana, Alvarez-Lafuente, Masjuan, Costa-Frossard and Villar.)

Background: Prognostic markers are needed to guide multiple sclerosis (MS) management in the context of large availability of disease-modifying drugs (DMDs)., Objective: To investigate the role of cerebrospinal fluid (CSF) markers to inform long-term MS outcomes., Methods: Demographic features, IgM index, oligoclonal IgM bands (OCMB), lipid-specific OCMB, CSF neurofilament light chain protein levels, expanded disability status scale (EDSS), relapses and DMD use over the study period and peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell plus inner plexiform layer (GCIPL) thicknesses in non-optic neuritis eyes (end of follow-up) were collected from relapsing MS (RMS) patients with CSF obtained ⩽2 years after MS onset prospectively followed at the Hospital Clinic of Barcelona. We assessed associations between CSF markers and MS outcomes using multivariable models., Results: A total of 89 patients (71 females; median 32.9 years of age) followed over a median of 9.6 years were included. OCMB were associated with a 33% increase in the annualized relapse rate (ARR; p = 0.06), higher odds for high-efficacy DMDs use (OR = 4.8; 95% CI = (1.5, 16.1)), thinner pRNFL (β = -4.4; 95% CI = (-8.6, -0.2)) and GCIPL (β = -2.9; 95% CI = (-5.9, +0.05)), and higher rates to EDSS ⩾ 3.0 (HR = 4.4; 95% CI = (1.6, 11.8)) and EDSS ⩾ 4.0 (HR = 5.4; 95% CI = (1.1, 27.1)). No overall associations were found for other CSF markers., Conclusion: The presence of OCMB was associated with unfavorable long-term outcomes. OCMB should be determined in RMS to inform long-term prognosis.

The aim of this study was to incorporate the active compounds present in purple araçá ( Psidium myrtoides ) in pea starch-based films and to verify the influence of different plasticizers (glycerol, sorbitol, and polyethylene glycol 400) on film properties. Films were produced and characterized in relation to visual appearance, active compounds, antimicrobial activity, and mechanical and barrier properties. Pea starch has a high amylose content and a final viscosity of 5371.5 RVU, which contributes to the elaboration of films even without the addition of plasticizers. Purple araçá and pea starch formed films with good water vapor barrier characteristics (0.398 g·mm/m 2 ·h·KPa) and low solubility (33.30%). Among plasticizers, sorbitol promoted a lower permeability to water vapor. The selected formulations, 0%, 20%, and 30% sorbitol, presented a high concentration of phenolic compounds (1194.55, 1115.47, and 1042.10 mg GAE 100 g -1 , respectively) and were able to inhibit the growth of Staphylococcus aureus . Therefore, films contained the active compounds of purple araçá and potential to be used as food packaging.

A series of pressure-sensitive adhesives (PSAs) was prepared using a constant monomeric composition and different preparation processes to investigate the best combination to obtain the best balance between peel resistance, tack, and shear resistance. The monomeric composition was a 1:1 combination of two different water-based acrylic polymers-one with a high shear resistance (A) and the other with a high peel resistance and tack (B). Two different strategies were applied to prepare the adhesives: physical blending of polymers A and B and in situ emulsion polymerization of A + B, either in one or two steps; in this last case, by polymerizing A or B first. To characterize the polymer, the average particle size and viscosity were analyzed. The glass transition temperature (Tg) was determined by differential scanning calorimetry (DSC). The tetrahydrofuran (THF) insoluble polymer fraction was used to calculate the gel content, and the soluble part was used to determine the average sol molecular weight by means of gel permeation chromatography (GPC). The adhesive performance was assessed by measuring tack as well as peel and shear resistance. The mechanical properties were obtained by calculating the shear modulus and determination of maximum stress and the deformation energy. Moreover, an adhesive performance index (API) was designed to determine which samples are closest to the requirements demanded by the self-adhesive label market.

Objective: To determine the best method to measure intrathecal immunoglobulin (Ig) M synthesis (ITMS), a biomarker of worse prognosis in multiple sclerosis (MS). We compared the ability for predicting a poor evolution of 4 methods assessing ITMS (IgM oligoclonal bands [OCMBs], lipid-specific OCMBs [LS-OCMBs], Reibergram, and IgM index) in patients with a clinically isolated syndrome (CIS)., Methods: Prospective study with consecutive patients performed at a referral MS center. We used unadjusted and multivariate Cox regressions for predicting a second relapse, Expanded Disability Status Scale (EDSS) scores of 4 and 6, and development of secondary progressive MS (SPMS)., Results: A total of 193 patients were included, with a median (interquartile range) age of 31 (25-38) years and a median follow-up of 12.9 years. Among all methods, only OCMB, LS-OCMB, and Reibergram significantly identified patients at risk of some of the pre-established outcomes, being LS-OCMB the technique with the strongest associations. Adjusted hazard ratio (aHR) of LS-OCMB for predicting a second relapse was 2.50 (95% CI 1.72-3.64, p < 0.001). The risk of reaching EDSS scores of 4 and 6 and SPMS was significantly higher among patients with LS-OCMB (aHR 2.96, 95% CI 1.54-5.71, p = 0.001; aHR 4.96, 95% CI 2.22-11.07, p < 0.001; and aHR 2.31, 95% CI 1.08-4.93, p = 0.03, respectively)., Conclusions: ITMS predicts an aggressive MS at disease onset, especially when detected as LS-OCMB., Classification of Evidence: This study provides Class II evidence that lipid-specific IgM oligoclonal bands can predict progression from CIS to MS and a worse disease course over a follow-up of at least 2 years., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Patients with multiple sclerosis (MS) suffer with age an early immunosenescence process, which influence the treatment response and increase the risk of infections. We explored whether lipid-specific oligoclonal IgM bands (LS-OCMB) associated with highly inflammatory MS modify the immunological profile induced by age in MS. This cross-sectional study included 263 MS patients who were classified according to the presence (M+, n=72) and absence (M-, n=191) of LS-OCMB. CSF cellular subsets and molecules implicated in immunosenescence were explored. In M- patients, aging induced remarkable decreases in absolute CSF counts of CD4+ and CD8+ T lymphocytes, including Th1 and Th17 cells, and of B cells, including those secreting TNF-alpha. It also increased serum anti-CMV IgG antibody titers (indicative of immunosenescence) and CSF CHI3L1 levels (related to astrocyte activation). In contrast, M+ patients showed an age-associated increase of TIM-3 (a biomarker of T cell exhaustion) and increased values of CHI3L1, independently of age. Finally, in both groups, age induced an increase in CSF levels of PD-L1 (an inductor of T cell tolerance) and activin A (part of the senescence-associated secretome and related to inflammaging). These changes were independent of the disease duration. Finally, this resulted in augmented disability. In summary, all MS patients experience with age a modest induction of T-cell tolerance and an activation of the innate immunity, resulting in increased disability. Additionally, M- patients show clear decreases in CSF lymphocyte numbers, which could increase the risk of infections. Thus, age and immunological status are important for tailoring effective therapies in MS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Picón, Tejeda-Velarde, Fernández-Velasco, Comabella, Álvarez-Lafuente, Quintana, Sainz de la Maza, Monreal, Villarrubia, Álvarez-Cermeño, Domínguez-Mozo, Ramió-Torrentà, Rodríguez-Martín, Roldán, Aladro, Medina, Espiño, Masjuan, Matute-Blanch, Muñoz-San Martín, Espejo, Guaza, Muriel, Costa-Frossard and Villar.)

Serum neurofilament light chains (sNfL) are biomarkers of disease activity in multiple sclerosis (MS), but their value to predict response to treatment, and their association with patient immunological profile, need to be further explored. We studied 80 relapsing-remitting MS patients initiating dimethyl fumarate (DMF) treatment. sNfL levels were explored at baseline and at 3, 6 and 12 months by single molecule array. Blood lymphocyte subsets were measured at baseline and at 6 months by flow cytometry. Patients were followed a year and classified as NEDA (no evidence of disease activity) or ODA (ongoing disease activity). NEDA patients had lower sNfL levels at baseline (p = 0.0001), and after three (p = 0.004) and six (p = 0.03) months of DMF treatment. Consequently, low baseline sNfL values (≤ 12 pg/ml) increased the probability of NEDA (OR 5.8; CI 1.82-15.6; p = 0.002, after correcting by disease activity in the previous year), and associated with significant reductions of central memory CD4+ T lymphocytes, interferon-gamma+ CD8+ T lymphocytes, Natural Killer T cells, and memory B cells upon DMF treatment, being the highest differences in memory B cells (p < 0.0001). This shows that low baseline sNfL values identify MS patients with higher probability of optimal response to DMF and of a reduction in effector immune cells.

Epstein-Barr virus (EBV), human herpesvirus 6A/B (HHV-6A/B) and multiple sclerosis (MS)-associated retrovirus (MSRV) have been described as possible MS triggers. We analysed antibody titres against EBV and HHV-6, and MSRV envelope (env) mRNA expression, in the serum of pregnant multiple sclerosis patients (P-MS) to study their possible link to the clinical activity of MS during pregnancy and postpartum and their possible role as relapse predictors. For that purpose, serum samples were collected from 71 pregnant women (50 pregnant MS and 21 pregnant healthy controls-P-HC) during pregnancy and postpartum. Relating to antibody titres, IgM antibody titres against HHV-6A/B were significantly higher in P-MS than in P-HC both in each pregnancy trimester and in the postpartum period. Moreover, IgM antibody titres against HHV-6A/B were higher in P-MS who suffered a relapse during the postpartum. Regarding MSRV env mRNA expression, the prevalence in the first trimester of pregnancy was significantly higher in P-MS who suffered relapses during pregnancy. Summing it up, high IgM antibody titres against HHV-6A/B and MSRV env mRNA expression during the first trimester of pregnancy could act as relapse predictors for the gestation/postpartum periods.

Despite the increasing evidence of the benefit of corticosteroids for the treatment of moderate-severe coronavirus disease 2019 (COVID-19) patients, no data are available about the potential role of high doses of steroids for these patients. We evaluated the mortality, the risk of need for mechanical ventilation (MV), or death and the risk of developing a severe acute respiratory distress syndrome (ARDS) between high (HD) and standard doses (SD) among patients with a severe COVID-19. All consecutive confirmed COVID-19 patients admitted to a single center were selected, including those treated with steroids and an ARDS. Patients were allocated to the HD (≥ 250 mg/day of methylprednisolone) of corticosteroids or the SD (≤ 1.5 mg/kg/day of methylprednisolone) at discretion of treating physician. Five hundred seventy-three patients were included: 428 (74.7%) men, with a median (IQR) age of 64 (54-73) years. In the HD group, a worse baseline respiratory situation was observed and male gender, older age, and comorbidities were significantly more common. After adjusting by baseline characteristics, HDs were associated with a higher mortality than SD (adjusted OR 2.46, 95% CI 1.59-3.81, p < 0.001) and with an increased risk of needing MV or death (adjusted OR 2.35, p = 0.001). Conversely, the risk of developing a severe ARDS was similar between groups. Interaction analysis showed that HD increased mortality exclusively in elderly patients. Our real-world experience advises against exceeding 1-1.5 mg/kg/day of corticosteroids for severe COVID-19 with an ARDS, especially in older subjects. This reinforces the rationale of modulating rather than suppressing immune responses in these patients.

Immunosuppression (IS) and autoimmune disease (AD) are prevalent in patients with severe coronavirus disease 2019 (COVID-19), but their impact on its clinical course is unknown. We investigated relationships between IS, AD, and outcomes in patients hospitalized with COVID-19. Data on consecutive admissions for COVID-19 were extracted retrospectively from medical records. Patients were assigned to one of four cohorts, according to whether or not they had an AD (AD and NAD) or were immunosuppressed (IS and NIS). The primary endpoint was development of severe acute respiratory distress syndrome (ARDS); secondary endpoints included death, and a composite of mechanical ventilation (MV) or death. A total of 789 patients were included: 569 (72.1%) male, 76 (9.6%) with an AD, and 63 (8.0%) with IS. Relative to the NIS-NAD cohort, patients in the IS-AD cohort had a significantly reduced risk of severe ARDS (adjusted hazard ratio [aHR] 0.42; 95% confidence interval [CI] 0.23-0.80; p = 0.008). No significant relationships between IS or AD status and either death or the composite of MV and death were identified, although a trend towards higher mortality was identified in the IS-NAD cohort (aHR vs NIS-NAD 1.71; 95% CI 0.94-3.12; p = 0.081). Patients in this cohort also had higher median serum levels of interleukin-6 compared with IS-AD patients (98.2 vs 21.6 pg/mL; p = 0.0328) and NIS-NAD patients (29.1 pg/mL; p = 0.0057). In conclusion, among patients hospitalized with COVID-19, those receiving immunosuppressive treatment for an AD may have a reduced risk of developing severe ARDS.

Polysulfone nanocomposite foams containing variable amounts of graphene nanoplatelets (0-10 wt%) were prepared by water vapor-induced phase separation (WVIPS) and supercritical CO 2 (scCO 2 ) dissolution. WVIPS foams with two ranges of relative densities were considered, namely, between 0.23 and 0.41 and between 0.34 and 0.46. Foams prepared by scCO 2 dissolution (0.0-2.0 wt% GnP) were obtained with a relative density range between 0.35 and 0.45. Although the addition of GnP affected the cellular structure of all foams, they had a bigger influence in WVIPS foams. The storage modulus increased for all foams with increasing relative density and GnP's concentration, except for WVIPS PSU-GnP foams, as they developed open/interconnected cellular structures during foaming. Comparatively, foams prepared by scCO 2 dissolution showed higher specific storage moduli than similar WVIPS foams (same relative density and GnP content), explained by the microcellular structure of scCO 2 foams. As a result of the plasticizing effect of CO 2 , PSU foams prepared by scCO 2 showed lower glass transition temperatures than WVIPS foams, with the two series of these foams displaying decreasing values with incrementing the amount of GnP.

Although the etiology of multiple sclerosis (MS) is still unknown, it is commonly accepted that environmental factors could contribute to the disease. The objective of this study was to analyze the humoral response to Epstein-Barr virus, human herpesvirus 6A/B and cytomegalovirus, and the levels of 25-hydroxyvitamin D (25(OH)D) and the three main short-chain fatty acids (SCFA), propionate (PA), butyrate (BA) and acetate (AA), in MS patients and healthy controls (HC) to understand how they could contribute to the pathogenesis of the disease. With this purpose, we analyzed the correlations among them and with different clinical variables and a wide panel of cell subsets. We found statistically significant differences for most of the environmental factors analyzed when we compared MS patients and HC, supporting their possible involvement in the disease. The strongest correlations with the clinical variables and the cell subsets analyzed were found for 25(OH)D and SCFAs levels. A correlation was also found between 25(OH)D and PA/AA ratio, and the interaction between these factors negatively correlated with interleukin 17 (IL-17)-producing CD4+ and CD8+ T cells in untreated MS patients. Therapies that simultaneously increase vitamin D levels and modify the proportion of SCFA could be evaluated in the future.

Objective: To analyze the changes induced by ocrelizumab in blood immune cells of patients with primary progressive MS (PPMS)., Methods: In this multicenter prospective study including 53 patients with PPMS who initiated ocrelizumab treatment, we determined effector, memory, and regulatory cells by flow cytometry at baseline and after 6 months of therapy. Wilcoxon matched paired tests were used to assess differences between baseline and 6 months' results. p Values were corrected using the Bonferroni test., Results: Ocrelizumab reduced the numbers of naive and memory B cells ( p < 0.0001) and those of B cells producing interleukin (IL)-6, IL-10, granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-alpha (TNFα) ( p < 0.0001 in all cases). By contrast, the proportions of plasmablasts and B cells producing GM-CSF and TNFα increased significantly, suggesting the need for treatment continuation. We also observed a decrease in CD20 + T-cell numbers ( p < 0.0001) and percentages ( p < 0.0001), and a clear remodeling of the T-cell compartment characterized by relative increases of the naive/effector ratios in CD4 + ( p = 0.002) and CD8 + ( p = 0.002) T cells and relative decreases of CD4 + ( p = 0.03) and CD8 + ( p = 0.004) T cells producing interferon-gamma. Total monocyte numbers increased ( p = 0.002), but no changes were observed in those producing inflammatory cytokines. The immunologic variations were associated with a reduction of serum neurofilament light chain (sNfL) levels ( p = 0.008). The reduction was observed in patients with Gd-enhanced lesions at baseline and in Gd- patients with baseline sNfL >10 pg/mL., Conclusions: In PPMS, effector B-cell depletion changed T-cell response toward a low inflammatory profile, resulting in decreased sNfL levels., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Graphene nanoplatelet (GnP)-filled polysulfone (PSU) cellular nanocomposites, prepared by two different methods-namely, water vapor-induced phase separation (WVIPS) and supercritical CO 2 dissolution (scCO 2 ) foaming-were produced with a range of densities from 0.4 to 0.6 g/cm 3 and characterized in terms of their structure and electrical conduction behavior. The GnP content was varied from 0 to 10 wt%. The electrical conductivity values were increased with the amount of GnP for the three different studied foam series. The highest values were found for the microcellular nanocomposites prepared by the WVIPS method, reaching as high as 8.17 × 10 -2 S/m for 10 wt% GnP. The variation trend of the electrical conductivity for each series was analyzed by applying both the percolation and the tunneling models. Comparatively, the tunneling model showed a better fitting in the prediction of the electrical conductivity. The preparation technique of the cellular nanocomposite affected the resultant cellular structure of the nanocomposite and, as a result, the porosity or gas volume fraction ( V g ). A higher porosity resulted in a higher electrical conductivity, with the lightest foams being prepared by the WVIPS method, showing electrical conductivities two orders of magnitude higher than the equivalent foams prepared by the scCO 2 dissolution technique.

The present study evaluated the effect of the incorporation of copaiba oil, in direct and in microencapsulated form, into films based on Xanthosoma mafaffa Schott starch. Initially, the characterization of copaiba oil by gas chromatograph coupled with mass spectrometry (GC-MS) and its antimicrobial activity against gram-positive and gram-negative bacteria was performed. The films were produced by the casting technique and characterized in relation to physical, chemical, structural, and antimicrobial activity. Sesquiterpenes, mainly β-caryophyllene, were the predominant compounds in copaiba oil, showing antimicrobial activity against B. subtilis and S. aureus . The films showed forming capacity, however, was observed a decrease in solubility and revealed an increase in hydrophobic characteristics. However, the oil reduced the tensile strength and elongation, while the microcapsules did not influence the mechanical properties in comparison to the control film. From microstructure analysis, changes in the films roughness and surface were observed after the addition of oil both directly and in microencapsulated form. Films incorporated with microparticles were able to inhibit the gram-positive bacteria tested, forming inhibition zones, indicating that the encapsulation of copaiba oil was more efficient for protecting bioactive compounds from the oil, suggesting the possible application of mangarito starch-based films incorporated with copaiba oil as biodegradable packaging.

Currently, pressure-sensitive adhesives (PSA) are used in more than 80% of all labels in the market today. They do not require any heat, solvent, or water to activate: It only takes light pressure to apply them to a product surface. Many products that come in glass bottles need labels that have staying power in harsh conditions. For that reason, it is necessary to have a good balance between all the polymer adhesive properties. In this study is described how adhesive properties of water-based PSA were affected by varying the amount of functional monomer acrylic acid (AA) and chain transfer agent, tert-dodecyl mercaptan (TDM). Four series of PSA were prepared by emulsion polymerization. Within each polymer series, the AA monomer proportion was held constant between 0.5 and 3.0 phm, and the fraction of the chain transfer agent was varied 0.0 to 0.2 phm. The results showed that the gel content decreased with the increase of the chain transfer agent and with the reduction of AA. All adhesives properties (tack, peel, and shear resistance) improved with increasement of the AA monomer. The increase of chain transfer agent caused decrease of the gel content resulting in higher peel resistance and tack values, but lower shear resistance values.

Background: Gut microbiota has been related to multiple sclerosis (MS) etiopathogenesis. Short-chain fatty acids (SCFA) are compounds derived from microbial metabolism that have a role in gut-brain axis., Objectives: To analyse SCFA levels in plasma of MS patients and healthy donors (HD), and the possible link between these levels and both clinical data and immune cell populations., Methods: Ninety-five MS patients and 54 HD were recruited. Patients were selected according to their score in the Expanded Disability Status Scale (EDSS) (49 EDSS ≤ 1.5, 46 EDSS ≥ 5.0). SCFA were studied in plasma samples by liquid chromatography-mass spectrometry. Peripheral blood mononuclear cells were studied by flow cytometry. Gender, age, treatments, EDSS and Multiple Sclerosis Severity Score (MSSS) were evaluated at the recruitment., Results: Plasma acetate levels were higher in patients than in HD ( p  = 0.003). Patients with EDSS ≥ 5.0 had higher acetate levels than those with EDSS≤ 1.5 ( p  = 0.029), and HD ( p  = 2.97e-4). Acetate levels correlated with EDSS ( r  = 0.387; p  = 1.08e-4) and MSSS ( r  = 0.265;  p  = 0.011). In untreated MS patients, acetate levels correlated inversely with CD4+ naïve T cells ( r  =  - 0.550,  p  = 0.001) and directly with CD8+ IL-17+ cells ( r  = 0.557;  p  = 0.001)., Conclusions: Plasma acetate levels are higher in MS patients than in HD. In MS there exists a correlation between plasma acetate levels, EDSS and increased IL-17+ T cells. Future studies will elucidate the role of SCFA in the disease., Competing Interests: The authors declare there are no competing interests., (©2020 Pérez-Pérez et al.)

Plastic, usually derived from non-renewable sources, is among the most used materials in food packaging. Despite its barrier properties, plastic packaging has a recycling rate below the ideal and its accumulation in the environment leads to environmental issues. One of the solutions approached to minimize this impact is the development of food packaging materials made from polymers from renewable sources that, in addition to being biodegradable, can also be edible. Different biopolymers from agricultural renewable sources such as gelatin, whey protein, starch, chitosan, alginate and pectin, among other, have been analyzed for the development of biodegradable films. Moreover, these films can serve as vehicles for transporting bioactive compounds, extending their applicability as bioactive, edible, compostable and biodegradable films. Biopolymer films incorporated with plant-derived bioactive compounds have become an interesting area of research. The interaction between environment-friendly biopolymers and bioactive compounds improves functionality. In addition to interfering with thermal, mechanical and barrier properties of films, depending on the properties of the bioactive compounds, new characteristics are attributed to films, such as antimicrobial and antioxidant properties, color and innovative flavors. This review compiles information on agro-based biopolymers and plant-derived bioactive compounds used in the production of bioactive films. Particular emphasis has been given to the methods used for incorporating bioactive compounds from plant-derived into films and their influence on the functional properties of biopolymer films. Some limitations to be overcome for future advances are also briefly summarized. This review will benefit future prospects for exploring innovative methods of incorporating plant-derived bioactive compounds into films made from agricultural polymers.

The aim of this work was to extract and characterize starch from three varieties of pigmented rice (named white, red and black), preserving the bioactive compounds. The extraction yield was 44.0%, 47.0% and 35.7%, respectively. The scanning electron microscopy showed that the granules of the three varieties presented polygonal and angular format and absence of impurities. The chemical analyzes, showed more than 83.0% of carbohydrates in the three compositions. There was retention of the phenolic compounds from the raw material in the starches. With regard to pasting properties of the starches, differences were observed in initial temperature, which was of 80.6 °C, 79.1 °C and 88.8 °C for the starches of white, red and black rice, respectively. Black rice starch also showed slightly higher crystallinity and thermal stability than white and red rice starches. Gels of red rice starch have higher syneresis in five freeze-thaw cycles, when compared to the others., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: To explore the serum cytokine profile associated with disease activity during pregnancy and postpartum in MS, and to assess any potential biomarkers predicting the occurrence of relapses during this period., Methods: We included 53 MS pregnant women recruited between 2007 and 2018. Interferon-gamma, Tumor necrosis factor-alpha, interleukin-17, granulocyte/macrophage-colony stimulating factor, Activin-A, interleukin-10, and programmed-death-ligand-1 (PD-L1) were measured quarterly in serum by ELISA., Results: Seventeen patients (32%) experienced relapses during pregnancy or puerperium and 37(68%) did not. We did not found differences in clinical characteristics or treatment status between the two groups. However, relapsing patients showed at the first trimester of pregnancy considerably lower levels of serum Activin-A (336.4 pg/dl [289.6-491.7], median [IQR] vs. 760.0 pg/dl [493.2-1108.0],p = .003), which correlated positively with serum PD-L1 (r = 0.53,p = .0005) and IL-10 (r = 0.43,p = .004) values. Activin-A levels lower than 515 pg/ml at the first trimester identified patients with high probability of relapsing during pregnancy and postpartum (OR = 13.75, CI: 2.5-76.8, p = .001)., Conclusions: MS patients with no relapses during pregnancy and puerperium showed an early triggering of a tolerogenic innate immune response evidenced by high serum Activin-A concentrations during the first trimester of pregnancy. Thus, serum Activin-A can be a useful biomarker to predict clinical activity during this period., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

A series of Pressure-Sensitive Adhesives (PSAs) with different soft monomer compositions were prepared by using emulsion polymerization. The monomers used were acrylic acid (AA), n-butyl acrylate (n-BA) and 2-ethylhexyl acrylate (2-EHA). Maintaining the same acrylic acid fraction in all polymerizations, the n-BA/2-EHA weight ratio varied from 0 to 1. These polymers were characterized by using Fourier Transformed Infrared Spectroscopy (FTIR), and the Glass Transition Temperature ( T g ) was determined both theoretically from the Fox equation and experimentally by means of differential scanning calorimetry (DSC). The tetrahydrofuran (THF) insoluble polymer fraction was used to calculate the gel content, and the soluble part was used to determine the average molecular weight by means of Gas Permeation Chromatography (GPC). The adhesive performance was assessed by measuring tack, peel and shear resistance. The results showed that with the 2-EHA rate, the elastic modulus slightly decreased and the shear yield strength slightly increased. Consequently, the loop tack and peel resistances decreased. This behavior was attributed to the increase of the gel content with the ratio of comonomers studied. The adhesives were tested in paper labels on glass bottles immersed in a cold-water bath, the so-called ice bucket test, and all of them showed that they could withstand wet and cold environment conditions., Competing Interests: The authors declare no conflict of interest.

Polysulfone (PSU) foams containing 0-10 wt% graphene nanoplatelets (GnP) were prepared using two foaming methods. Alongside the analysis of the cellular structure, their thermal conductivity was measured and analyzed. The results showed that the presence of GnP can affect the cellular structure of the foams prepared by both water vapor induced phase separation (WVIPS) and supercritical CO 2 (scCO 2 ) dissolution; however, the impact is greater in the case of foams prepared by WVIPS. In terms of thermal conductivity, the analysis showed an increasing trend by incrementing the amount of GnP and increasing relative density, with the tortuosity of the cellular structure, dependent on the used foaming method, relative density, and amount of GnP, playing a key role in the final value of thermal conductivity. The combination of all these factors showed the possibility of preparing PSU-GnP foams with enhanced thermal conductivity at lower GnP amount by carefully controlling the cellular structure and relative density, opening up their use in lightweight heat dissipators., Competing Interests: The authors declare no conflict of interest.

The growing global awareness about environmental preservation has stimulated the search for alternatives to replace conventional plastics made from fossil sources. One of the advantages is using polymers from renewable sources, such as starch and gelatin, which, in addition to being biodegradable, may also be edible. The incorporation of cranberry into a polymeric matrix can transfer bioactive composite films, colour and flavour to the film, which are characteristic of this fruit, expanding its application to fruit stripes or colourful coatings for specific foods. In this context, the aim of this work was to evaluate the influence of the incorporation of 0, 5, 15, 25, 35, 45 and 55% (solids mass/biopolymer mass) cranberry powder on the microstructure, thermal properties, ascorbic acid content and sensory analysis of gelatin and arrowroot starch films obtained by casting. Scanning electron microscopy (SEM) images showed that the incorporation of cranberry made the film surface rough and irregular. All films presented an X-ray diffraction pattern typical of a semicrystalline material. The glass transition temperature (T g ) decreased when increasing the concentration of cranberry in films. All films with cranberry presented high ascorbic acid content and were well accepted by the tasters when sensory analysis was performed.

Background and Purpose: Neurofilament light chain is a cytoskeletal protein of neurons. Its levels are increasingly recognized as measures of neuroaxonal damage. The aim of this study was to explore serum neurofilament light chain (sNfL) levels in multiple sclerosis (MS) patients and healthy controls during pregnancy and puerperium., Methods: This was a prospective, longitudinal, single-center study. sNfL concentration was assessed using a highly sensitive single-molecule array during pregnancy and in puerperium, in a cohort of 39 pregnant patients with relapsing multiple sclerosis (P-MS). Twenty-one healthy pregnant women (HPW) served as a control group. Eight P-MS suffered relapses during pregnancy (P-MS-R) in the first or second trimesters., Results: No differences in pregnancy and delivery data were observed between P-MS and HPW. P-MS showed higher sNfL values than HPW in the first trimester, independently of the presence (P = 0.002) or not (P = 0.02) of relapses during pregnancy. However, in the third trimester, only P-MS-R showed higher sNfL values than HPW (P = 0.001). These differences extended to the puerperium, where P-MS-R showed higher sNfL values than those with no relapses during gestation (P = 0.02)., Conclusion: These data strongly suggest that sNfL levels reflect MS activity during pregnancy. Additionally, the absence of relapses during pregnancy may have a beneficial effect on neurodegeneration during puerperium., (© 2019 EAN.)

This research work evaluated the influence of the type of incorporation and variation in the concentration of blackberry pulp (BL) and microencapsulated blackberry pulp (ML) powders by freeze-drying on the chemical and physical properties of arrowroot starch films. Blackberry powders were added to the film-forming suspension in different concentrations, 0%, 20%, 30% and 40% (mass/mass of dry starch) and through two different techniques, directly (D) and by sprinkling (S). Scanning electron microscopy (SEM) images revealed that the incorporation of blackberry powder has rendered the surface of the film rough and irregular. Films incorporated with BL and ML powders showed an increase in thickness and water solubility and a decrease in tensile strength in comparison with the film containing 0% powder. The incorporation of blackberry BL and ML powders into films transferred colour, anthocyanins and antioxidant capacity to the resulting films. Films added with blackberry powder by sprinkling were more soluble in water and presented higher antioxidant capacity than films incorporated directly, suggesting great potential as a vehicle for releasing bioactive compounds into food.

Polyetherimide (PEI) foams with graphene nanoplatelets (GnP) were prepared by supercritical carbon dioxide (scCO₂) dissolution. Foam precursors were prepared by melt-mixing PEI with variable amounts of ultrasonicated GnP (0.1⁻2.0 wt %) and foamed by one-step scCO₂ foaming. While the addition of GnP did not significantly modify the cellular structure of the foams, melt-mixing and foaming induced a better dispersion of GnP throughout the foams. There were minor changes in the degradation behaviour of the foams with adding GnP. Although the residue resulting from burning increased with augmenting the amount of GnP, foams showed a slight acceleration in their primary stages of degradation with increasing GnP content. A clear increasing trend was observed for the normalized storage modulus of the foams with incrementing density. The electrical conductivity of the foams significantly improved by approximately six orders of magnitude with only adding 1.5 wt % of GnP, related to an improved dispersion of GnP through a combination of ultrasonication, melt-mixing and one-step foaming, leading to the formation of a more effective GnP conductive network. As a result of their final combined properties, PEI-GnP foams could find use in applications such as electrostatic discharge (ESD) or electromagnetic interference (EMI) shielding.

The present work deals with the study of phosphorus flame retardant microcellular acrylonitrile⁻butadiene⁻styrene (ABS) parts and the effects of weight reduction on the fire and mechanical performance. Phosphorus-based flame retardant additives (PFR), aluminum diethylphosphinate and ammonium polyphosphate, were used as a more environmentally friendly alternative to halogenated flame retardants. A 25 wt % of such PFR system was added to the polymer using a co-rotating twin-screw extruder. Subsequently, microcellular parts with 10, 15, and 20% of nominal weight reduction were prepared using a MuCell ® injection-molding process. The results indicate that the presence of PFR particles increased the storage modulus and decreased the impact energy determined by means of dynamic-mechanical-thermal analysis and falling weight impact tests respectively. Nevertheless, the reduction of impact energy was found to be lower in ABS/PFR samples than in neat ABS with increasing weight reduction. This effect was attributed to the lower cell sizes and higher cell densities of the microcellular core of ABS/PFR parts. All ABS/PFR foams showed a self-extinguishing behavior under UL-94 burning vertical tests, independently of the weight reduction. Gradual decreases of the second peak of heat release rate and time of combustion with similar intumescent effect were observed with increasing weight reduction under cone calorimeter tests.