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Introduction Understanding protein expression profiles of apical periodontitis may contribute to the discovery of novel diagnostic or therapeutic molecular targets. Methods Periapical tissue samples ( n = 5) of patients with lesions characterized as nonhealing were submitted for proteomic analysis. Two differentially expressed proteins (heat shock protein 27 [HSP27] and serpin family B member 1 [SERPINB1]) were selected for characterization, localization by immunofluorescence, and association with known biomarkers of acute inflammatory response in human apical periodontitis ( n = 110) and healthy periodontal ligaments ( n = 26). Apical periodontitis samples were categorized as stable/inactive ( n = 70) or progressive/active ( n = 40) based on the ratio of expression of receptor activator of nuclear factor kappa-B ligand ( RANKL )/osteoprotegerin ( OPG ). Next, the expression of HSP27 , SERPINB1 , C-X-C motif Chemokine Receptor 1 ( CXCR1 ), matrix metalloproteinase 8 ( MMP8 ), myeloperoxidase ( MPO ), and cathepsin G ( CTSG ) messenger RNA was evaluated using real-time polymerase chain reaction. Data analysis was performed using the Shapiro-Wilk test, analysis of variance, and the Pearson test. P values <.05 were considered statistically significant. Results Proteomic analysis revealed 48 proteins as differentially expressed in apical periodontitis compared with a healthy periodontium, with 30 of these proteins found to be expressed in all 4 lesions. The expression of HSP27 and SERPINB1 was ∼2-fold higher in apical periodontitis. Next, an increased expression of HSP27 was detected in epithelial cells, whereas SERPINB1 expression was noted in neutrophils and epithelial cells. HSP27 and SERPINB1 transcripts were highly expressed in stable/inactive lesions ( P < .05). Significant negative correlations were found between the expression of HSP27 and SERPINB1 with biomarkers of acute inflammation including CXCR1 , MPO , and CTSG . Conclusions Our data suggest HSP27 and SERPINB1 as potential regulators of the inflammatory response in apical periodontitis. Additional functional studies should be performed to further characterize the role of these molecules during the development/progression of apical periodontitis. [ABSTRACT FROM AUTHOR]

Introduction Vascular endothelial growth factor (VEGF) is a signal protein that stimulates angiogenesis and vasculogenesis and has been used in tissue regeneration and pulp regeneration experimental models. The purpose of this study was to develop a delivery system composed of a biodegradable fiber and controlled release of VEGF to promote cell viability and secure an adequate blood supply for the survival of human stem cells of the apical papilla (SCAP) favoring endodontic regenerative procedures. Methods We developed a polydioxanone fiber, 50 μm in diameter, loaded with VEGF at a linear concentration of 12.2 ng/cm. Cytotoxic effects of the VEGF-loaded fiber (VF) on SCAP and mouse fibroblasts were assessed by using a multiparametric assay kit (XTT-NR-CVDE [Xenometrix, Allschwil, Switzerland]). We evaluated VF-induced mRNA expression of downstream growth factors by using a human growth factor Taqman array in real-time polymerase chain reaction. We also assessed the in vivo subcutaneous reaction of C57BL/6 mice to implants of VF alone and human root fragments (10 mm in length) filled with VF after 10, 20, and 45 days. Statistical analyses were performed by using analysis of variance and Student t tests or non-parametric alternatives. Results Enzyme-linked immunosorbent assay verified detectable concentrations of released VEGF in solution for 25 days. No cytotoxicity was observed on SCAP and mouse fibroblasts treated with VEGF. In addition, VEGF treatment also induced the expression of additional growth factors with roles in tissue and blood vessel formation and neuroprotective function. Implantation of VF and root fragments filled with VF showed biocompatibility in vivo , promoting new blood vessels and connective tissue formation into the root canal space with negligible inflammation. Conclusions Our results show that the VF used in this study is biocompatible and may be a promising scaffold for additional optimization and use in endodontic regenerative procedures. [ABSTRACT FROM AUTHOR]

• An association between intercurrent infections and MS disease activity has been often reported. • There is uncertainty as to whether this is causality or mere temporal coincidence. • The SARS-CoV-2 pandemic can represent a model to assess the relationship between infections and MS disease activity. • In our cohort no differences in MS disease activity are observed between MS patients exposed and not exposed to SARS-CoV-2. An association between intercurrent viral respiratory infections and exacerbations of Multiple Sclerosis (MS) disease activity has been proposed by several studies. Considering the rapid spread of SARS-CoV2 worldwide and the systematic effort to immediately detect all incident cases with specific diagnostic tests, the pandemic can represent an interesting experimental model to assess the relationship between viral respiratory infections and MS disease activity. In this study, we have performed a propensity score matched case-control study with a prospective clinical/MRI follow-up, on a cohort of relapsing-remitting MS (RRMS) patients who tested positive for SARS-CoV2 in the period 2020–2022, with the aim to evaluate if the SARS-CoV2 infection influences the short-term risk of disease activity. Controls (RRMS patients not exposed to SARS-CoV-2, using 2019 as the reference period) were matched 1:1 with cases for age, EDSS, sex and disease-modifying treatment (DMT) (moderate efficacy vs high efficacy). Differences in relapses, MRI disease activity and confirmed disabilty worsening (CDW) between cases in the 6 months following the SARS-CoV-2 infection, and controls in a similar 6 months reference period in 2019 were compared. We identified 150 cases of SARS-CoV2 infection in the period March 2020 - March 2022, out of a total population of approximately 1500 MS patients, matched with 150 MS patients not exposed to SARS-CoV2 (controls). Mean age was 40.9 ± 12.0 years in cases and 42.0 ± 10.9 years in controls, mean EDSS was 2.54±1.36 in cases and 2.60±1.32 in controls. All patients were treated with a DMT, and a considerable proportion with a high efficacy DMT (65.3% in cases and 66% in controls), reflecting a typical real world RRMS population. 52.8% of patients in this cohort had been vaccinated with a mRNA Covid-19 vaccine. We did not observe a significant difference in relapses (4.0% cases, 5.3% controls; p = 0.774), MRI disease activity (9.3% cases, 8.0% controls; p = 0.838), CDW (5.3% cases, 6.7% controls; p = 0.782) in the 6 months after SARS-CoV-2 infection between cases and controls. Using a propensity score matching design and including both clinical and MRI data, this study does not suggest an increased risk of MS disease activity following SARS-CoV-2 infection. All MS patients in this cohort were treated with a DMT, and a considerable number with a high efficacy DMT. These results therefore may not be applicable to untreated patients, for which the risk of increased MS disease activity after SARS-CoV-2 infection may not be excluded. A possible hypothesis explaining these results could be that SARS-CoV2 is less prone, compared to other viruses, to induce exacerbations of MS disease activity; another possible interpretation of these data might be that DMT is able to effectively suppress the increase of disease activity triggered by SARS-CoV2 infection. [ABSTRACT FROM AUTHOR]

Introduction: Tumor necrosis factor alpha (TNF-α) levels are significantly upregulated in the synovial fluid of patients with temporomandibular joint disorder (TMD). The TNF-α influences pain generation and maintenance. Therefore, the aim of this study was to investigate the influence of single nucleotide polymorphism TNFA-308 (rs1800629) on TMD risk and on the pressure pain threshold.Methods: The genotypic and allelic frequencies of candidate single nucleotide polymorphisms were compared among 152 TMD patients and 91 sex- and age-matched healthy subjects in the control group using the real-time polymerase chain reaction technique. The pressure pain threshold in the temporomandibular joint, anterior fascicle of the temporal muscle, masseter muscle, and Achilles tendon were recorded with an algometer. After the pressure test, all participants received a complete physical examination, including masticatory muscle evaluation, temporomandibular joint palpation, and assessment of mandibular range of motion.Results: The TNFA-308 polymorphism is positively associated with TMD. Subjects with TMD had a 2.87 (95% confidence interval, 1.256-6.569) times greater chance of having the GA genotype than did the control group. Rare A-allele homozygotes demonstrated decreased pain sensitivity for the temporomandibular joint and anterior fascicle of the temporal muscle in the pressure pain threshold test compared with ancestral allele homozygotes.Conclusions: This study presents an unprecedented association between the TNFA-308 (rs1800629) polymorphism and TMD. Future studies are needed to enlighten the association between TNFA-308 G/A single nucleotide polymorphism and mechanical pain sensitivity. [ABSTRACT FROM AUTHOR]

• Vitamin D has immunomodulatory effects. • Vitamin D deficiency is associated with a higher likelihood of disease activity in MS. • Low vitamin D serum levels might be associated to early B cell repopulation. Several observational studies have shown an association between low circulating levels of 25-hydroxy- vitamin D (25(OH)D) and an increase in inflammatory activity in Multiple Sclerosis (MS). Among its immunomodulatory functions, 25(OH)D suppresses proliferation and immunoglobulin production of B cells. 25(OH)D supplementation has been associated with better radiological outcomes in MS patients treated with interferon (IFN)-B, glatiramer acetate, fingolimod, natalizumab and rituximab. Our study is aimed at analyzing the association of 25(OH)D serum levels and supplementation with B cell kinetics and clinical-radiological outcomes of people with MS treated with ocrelizumab. We have retrospectively collected clinical and radiological data from 136 MS patients who have been treated with ocrelizumab, have undergone at least two treatment cycles and for whom data on serum 25(OH)D levels and intake were available. The patients were divided into three groups according to baseline 25(OH)D serum levels: deficient (≤19,9 ng/ml), insufficient (20-29,9 ng/ml), and normal range 25(OH)D (>30 ng/ml). According to 25(OH)D intake, we divided our population into users and non-users. To explore B cell kinetics at six- and twelve-month follow-ups, the patients were divided into two groups: with fast repopulation (FR) and slow repopulation rate (SR), based on the reappearance or non- appearance of CD19 at each time point. When considering the entire population, the mean 25(OH)D serum level (sd) was 26.27 ng/ml (14.15). 43 (31,62%) patients were classified as deficient, 52 (38,24%) were classified as insufficient, and 41 (30,14%) showed 25(OH)D serum levels within the normal range. 60.29% (82/136) of the patients were classified as users, and 39.70% (54/136) as non-users. Over the eighteen-month treatment period, we observed a significant difference between the 25(OH)D users and the non-users as concerns the number of scans with at least one new/enlarging T2 lesion (2% vs 15.38%, respectively; p= 0.025). In the multinomial regression model, 25(OH)D deficiency (serum levels ≤19,9 ng/ml) was significantly associated with a higher likelihood of disease activity during a follow-up of eighteen months (p = 0.029, RRR = 4.84, Confidence Interval (CI) 1.17 - 20.01). After six months, there were 30/136 FR patients (22,05%), whereas only 22/136 (16,17%) showed early B cell reappearance at twelve month follow up. 86.66% of the patients in the FR group showed 25(OH)D levels lower than 30 ng/ml (25(OH)D deficiency or insufficiency), whereas only 65.09% of the SR patients presented vitamin D levels lower than 30 ng/ml (p= 0.024). In the logistic regression model, 25(OH)D serum levels below 30 ng/ml were associated with a higher likelihood of early B cell reappearance at six month follow up (p= 0.042). 25(OH)D supplementation and serum levels might be associated with B cell kinetics and radiological activity of patients with MS treated with ocrelizumab. [ABSTRACT FROM AUTHOR]

• PM2.5, PM10 and NO2 are risk factors for Covid-19 pneumonia among MS patients. • We studied the joint exposure to the three pollutants as an environmental mixture. • The most dangerous pollutants within the mixture were NO2 and PM2.5. Many studies investigated the association between air pollution and Covid-19 severity but the only study focusing on patients with Multiple Sclerosis (MS) exclusively evaluated exposure to PM2.5. We aim to study, in a sample of MS patients, the impact of long-term exposure to PM2.5, PM10 and NO2 on Covid-19 severity, described as occurrence of pneumonia. A 1:2 ratio case-control study was designed, differentiating cases and controls based on Covid-19 pneumonia. Associations between pollutants and outcome were studied using logistic regression. Weighted quantile sum (WQS) logistic regression was used to identify the individual contribution of each pollutant within the mixture; Least Absolute Shrinkage and Selection Operator (LASSO) penalized regression was performed to confirm the variable selection from WQS. All the analyses were adjusted for confounders selected a priori. Of the 615 eligible patients, 491 patients provided detailed place of exposure and were included in the principal analysis. Higher concentrations of air pollutants were associated with increased odds of developing Covid-19 pneumonia (PM2.5: 3rd vs 1st tercile OR(95% CI)=2.26(1.29;3.96); PM10: 3rd vs 1st tercile OR(95% CI)=2.12(1.22;3.68); NO2: 3rd vs 1st tercile OR(95% CI)=2.12(1.21;3.69)). Pollutants were highly correlated with each other; WQS index was associated to an increased risk of pneumonia (β=0.44; p-value=0.004) and the main contributors to this association were NO2 (41%) and PM2.5 (34%). Consistently, Lasso method selected PM2.5 and NO2. Higher long-term exposure to PM2.5, PM10 and NO2 increased the odds of Covid-19 pneumonia among MS patients and the most dangerous pollutants were NO2 and PM2.5. [ABSTRACT FROM AUTHOR]

• Multiple sclerosis does not seem to adversely affect fetal and neonatal outcomes. • We studied fetoneonatal growth in offsprings of mothers with multiple sclerosis. • Multiple sclerosis in pregnancy does not seem to affect fetal and neonatal growth. • We think that these results represent a very important and reassuring information. Multiple sclerosis does not seem to adversely affect fetal and neonatal outcomes, although some studies reported a possible reduction in mean birth weight and length, and a higher incidence of preterm delivery, mainly in relation to the exposure to disease-modifying drugs (DMDs) during pregnancy. Few data are available on intrauterine fetal growth and postnatal somatic development of newborns from mothers with multiple sclerosis compared to those from healthy women. For these reasons, we decided to investigate fetal growth, neonatal anthropometric parameters, and postnatal somatic development up to 12 months of life in offsprings from MS mothers. This retrospective cohort study included 211 women with multiple sclerosis, and 384 healthy women paired for maternal age and parity as controls. Fetal biometric parameters (biparietal diameter, head circumference, abdominal circumference, and femur length) measured during the third trimester of pregnancy (30–34 weeks' gestation) were retrieved from the computerized database of the Department (EcoPlus*) where the results of ultrasound exams performed in the hospital are stored. Newborn measurements (weight, length and head circumference) at birth were obtained from the hospital's computerized obstetric and neonatal database (Trackare* and Remote* data base); measurements at 6 and 12 months of life were obtained from the regional database (ECWMED*) of family pediatricians of our region. No differences between the two groups were observed for all the fetal parameters considered, expressed as centiles of growth according to gestational age (biparietal diameter: p = 0.40; head circumference: p = 0.40; abdominal circumference: p = 0.32; femur length: p = 0.32). No differences in gestational age at delivery, birthweight, and in the incidence of low birthweight and small for gestational age newborns were observed between the two groups. In the multiple sclerosis group a significantly higher incidence of caesarean section (p = 0.01) and late preterm delivery (at less than 37 weeks'gestation, p = 0.001) were registered. The trends of postnatal growth in weight (F = 0.53; p -value = 0.590) and length (F = 0.44; p -value = 0.645) were superimposable between the two groups. The trends of growth for head circumference showed a slightly, not significantly greater head circumference of infants from mothers with multiple sclerosis at 6 months of life, but the values at twelve months of life in the two groups were similar (F = 0.85; p -value = 0.427). Moreover, the trends of postnatal increase of weight (F = 1.016; p -value = 0.331), length (F = 2.001; p -value = 0.146) and head circumference (F = 1.591; p -value = 0.212) of newborns/infants (from birth to twelve months of life) born to mothers with multiple sclerosis who breastfed, mothers who did not, and in the control group were similar. Multiple sclerosis in pregnancy does not seem to affect fetal growth and postnatal development during the first year of the offspring life. We think that these results represent an important and reassuring information to provide the patients with during preconception counseling. [ABSTRACT FROM AUTHOR]

• The aim of this study was to construct such score and to evaluate its performance. • 3852 patients were included in the study and 17% of the patients required hospitalization. • This score can be used as an additional instrument to identify high-risk patients and persuade them to take important measures to prevent Covid-19 infection. Many risk factors for the development of severe forms of Covid-19 have been identified, some applying to the general population and others specific to Multiple Sclerosis (MS) patients. However, a score for quantifying the individual risk of severe Covid-19 in patients with MS is not available. The aim of this study was to construct such score and to evaluate its performance. Data on patients with MS infected with Covid-19 in Italy, Turkey and South America were extracted from the Musc-19 platform. After imputation of missing values, data were separated into training data set (70%) and validation data set (30%). Univariable logistic regression models were performed in the training dataset to identify the main risk factors to be included in the multivariable logistic regression analyses. To select the most relevant variables we applied three different approaches: (1) multivariable stepwise, (2) Lasso regression, (3) Bayesian model averaging. Three scores were defined as the linear combination of the coefficients estimated in the models multiplied by the corresponding value of the variables and higher scores were associated to higher risk of severe Covid-19 course. The performances of the three scores were compared in the validation dataset based on the area under the ROC curve (AUC) and an optimal cut-off was calculated in the training dataset for the score with the best performance. The probability of showing a severe Covid-19 course was calculated based on the score with the best performance. 3852 patients were included in the study (2696 in the training dataset and 1156 in the validation data set). 17% of the patients required hospitalization and risk factors for severe Covid-19 course were older age, male sex, living in Turkey or South America instead of living in Italy, presence of comorbidities, progressive MS, longer disease duration, higher Expanded Disability Status Scale, Methylprednisolone use and anti-CD20 treatment. The score with the best performance was the one derived using the Lasso selection approach (AUC= 0.72) and it was built with the following variables: age, sex, country, BMI, presence of comorbidities, EDSS, methylprednisolone use, treatment. An excel spreadsheet to calculate the score and the probability of severe Covid-19 is available at the following link: https://osf.io/ac47u/?view%5fonly=691814d57b564a34b3596e4fcdcf8580. The originality of this study consists in building a useful tool to quantify the individual risk for Covid-19 severity based on patient's characteristics. Due to the modest predictive ability and to the need of external validation, this tool is not ready for being fully used in clinical practice to make important decisions or interventions. However, it can be used as an additional instrument to identify high-risk patients and persuade them to take important measures to prevent Covid-19 infection (i.e. getting vaccinated against Covid-19, adhering to social distancing, and using of personal protection equipment). [ABSTRACT FROM AUTHOR]

• Lymphopenia is reported in 20.7% of RRMS patients taking Ocrelizumab. • Among T cells, the treatment predominantly impacts CD8 cells. • CD8 T cell decrease is more pronounced in patients with lymphopenia. In the phase III, OPERA I and OPERA II, clinical trial lymphopenia was reported in 20.7% of relapsing–remitting multiple sclerosis (RRMS) patients taking Ocrelizumab (OCR). The objective of this study was to investigate the effect of OCR on lymphocyte subtypes in MS patients with and without lymphopenia. Retrospective study comparing lymphocyte subtypes in OCR-treated MS patients with low (G1) and normal (G2) absolute lymphocyte count (ALC) at the six-month follow-up (cut-off: 1000 × 106/L). Mann Whitney U test was used to compare ALC, CD19, CD4 T, CD8 T and NK cell counts at baseline and at the six-month follow up between the two groups. A linear mixed model was applied to compare changes in ALC, and subset counts and proportions between patients with and without lymphopenia. We performed the same analyses in a subpopulation of naïve to treatment patients to exclude the possible influence of the previous disease modifying therapy (DMT) in the different kinetics observed between the two groups. : One hundred sixty-seven patients were included (G1, n = 34; G2, n = 133). At the six-month follow-up, compared with baseline, in the whole population we observed a significant reduction in ALC (p <0.0001), CD19 (p <0.0001) and CD8 T (p <0.0288) lymphocytes. We also found and increase in CD4/CD8 ratio after six months of treatment (p = 0.0098). G1 showed a lower ALC than G2 at baseline. At six months, mean ALC was 896.41 ± 156.25 × 106/L in G1 and 1909.9 ± 629.07 × 106/L in G2. CD4 and CD8 T cell mean counts were lower (p < 0.0001) in G1 than G2. At the linear mixed model analysis, we found a more pronounced increase in CD8 T percentage in G2 than G1 (p = 0.008). In the naïve to treatment group fifty patients were included. CD4 and CD8 T cell mean counts at six months were lower (p = 0.0074 and p = 0.0032, respectively) in G1 than G2. At the linear mixed model analysis, we found a more pronounced decrease of CD8 T cell count in G1 than G2 (p = 0.0103). Furthermore, we found an increase in CD8 T percentage in G2 whereas a profound decrease of CD8 T percentage was observed in G1 (p = 0.0052). After adjusting for confounders, significantly positive correlations were noted between ALC and both CD4 and CD8 T cell counts. Negative correlation was observed between ALC and CD4/CD8 ratio driven by low CD8 T cell counts. OCR decreases ALC. Among T cells, the treatment predominantly impacts CD8 cells. However, CD8 T cell decrease was more pronounced in patients with lymphopenia. Further studies are needed to establish the relationship between the effect of OCR on ALC and CD8 T cells and its potential implication in the early clinical response and risk for viral infections. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: CXC ligand 12/stromal-derived factor-1 (CXCL12/SDF-1) is a pleiotropic chemokine that regulates the influx of a wide range of leukocytes. The aim of this study was to characterize CXCL12/SDF-1 in apical lesions (ALs) of endodontic origin, with special emphasis in associated immune cell populations. Methods: In this case-control study, 29 individuals with chronic apical periodontitis and 21 healthy volunteers were enrolled. ALs and healthy periodontal ligament samples were obtained for tissue homogenization, immune Western blotting, and enzyme-linked immunosorbent assay to determine CXCL12/SDF-1 forms and levels. Anatomopathologic diagnosis, immunostaining for CXCL12/SDF-1, CD117-CXCL12/SDF-1, and toluidine blue were also performed to identify tissue and cell localization. Finally, a set of tissue samples were digested and analyzed by flow cytometry to identify CXCL12/SDF-1 in different immune cell populations. Data were analyzed with Stata v11 and WinDi 2.9 software, and significance was considered if P < .05. Results: CXCL12/SDF-1 was predominantly identified as monomers; levels of CXCL12/SDF-1 were significantly higher in ALs compared with controls, and it was primarily localized to inflammatory infiltrates. Expression of CXCL12/SDF-1 was colocalized to mast cells in tissue sections. Furthermore, CD117+ mast cells were the second most frequent infiltrating cells and the main CXCL12/SDF-1 expressing cells, followed by CD4+ lymphocytes, monocytes/macrophages, neutrophils, and dendritic cells. Conclusions: ALs of endodontic origin demonstrated higher levels of CXCL12/SDF-1 compared with controls. CXCL12/SDF-1 was identified in immune cell populations, whereas mast cells represented the major CXCL12/SDF-1 expressing cells, suggesting that this chemokine might play a central role in apical tissue destruction, most probably inducing persistent recruitment of immune cells, particularly of mast cells. [Copyright &y& Elsevier]

Using the ImmunoChip custom genotyping array, we analysed 14,498 multiple sclerosis subjects and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (p-value < 1.0 × 10-4). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 multiple sclerosis subjects and 26,703 healthy controls. In these 80,094 individuals of European ancestry we identified 48 new susceptibility variants (p-value < 5.0 × 10-8); three found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants in 103 discrete loci outside of the Major Histocompatibility Complex. With high resolution Bayesian fine-mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalogue of multiple sclerosis risk variants and illustrates the value of fine-mapping in the resolution of GWAS signals.

• Long-term remission of Multiple Sclerosis-related trigeminal neuralgia is uncommon. • Patients with higher disability undergo surgery earlier and more frequently. • Higher disability is associated less frequently with long-term to pain remission. The prevalence of trigeminal neuralgia (TN) in Multiple Sclerosis (MS) patients is higher than in the general population and its management can be particularly challenging. Our aim is to describe the characteristics, treatment and prognostic factors of MS-related TN in a retrospective multicentre study. Neurologists members of the RIREMS group (Rising Researchers in MS) enrolled MS patients with a TN diagnosis and filled out a spreadsheet comprising their clinical data. Population consisted of 298 patients. First-choice preventive treatments were carbamazepine and oxcarbazepine. A surgical procedure was performed in 81 (30%) patients, most commonly gamma knife stereotactic radiosurgery (37%), followed by microvascular decompression (22%) and radiofrequency thermocoagulation (21%); one third of patients underwent at least two procedures. Surgery was associated with higher disability, male sex and longer interval between MS and TN onset. Patients (77%) who stayed on at least one preventive medication at most recent follow-up, after a mean period of 8 years, had a higher disability compared to the untreated group. Furthermore, patients with higher disability at TN onset were less likely to discontinue their first preventive medication due to pain remission, had bilateral TN more frequently and underwent surgical interventions earlier. MS patients with a higher disability at TN onset and with a longer interval between MS and TN onset had differing clinical features and outcomes: pain was more frequently bilateral, surgery was more frequent and anticipated, and preventive medication discontinuation due to pain remission was less common. [ABSTRACT FROM AUTHOR]

• RTX is effective in preventing attacks in patients with NMOSD. • No concerning safety issues occurred in our real-life cohort. • Use of specific induction and maintenance regimen might boost RTX efficacy. • RTX could be less effective in MOG-ab positive patients. To evaluate disease activity according to rituximab (RTX) induction and maintenance regimens in a multicenter real-life dataset of NMOSD patients. This is an observational-retrospective multicentre study including patients with NMOSD treated with RTX in 21 Italian and 1 Swiss centers. Demographics, relapse rate and adverse events over the follow-up were summarized taking into account induction strategy (two-1 g infusions at a 15-day interval (IND-A) vs. 375 mg/m2/week infusions for one month (IND-B)) and maintenance therapy (regimen A (M-A) with fixed time-points infusions vs. regimen B (M-B) based on cytofluorimetric driven reinfusion regimens, the least further subdivided according to CD19+ B cells (M-B1) or CD27+ memory B cells (M-B2) monitoring). 131 subjects were enrolled, 127 patients completed the induction regimen and 119 patients had at least one follow-up visit and were included in the outcome analysis. Median follow-up was 1.7 years (range 0.1–11.6). Annualized relapse rate (ARR) was 1.7 in the year before RTX start and decreased to 0.19 during the follow-up. Both ARR and Time to first relapse (TTFR) analysis showed a trend toward an increased disease activity for IND-B and M-A. No patients with MT-B2 experienced relapses during the follow-up. Number of relapses in the year before RTX initiation and having received a previous treatment were significantly associated with higher ARR and reduced TTFR in the multivariate analysis. We confirm RTX efficacy in NMOSD patients. Use of specific induction and maintenance protocols is warranted in order to foster RTX efficacy and to reduce costs and side effects. [ABSTRACT FROM AUTHOR]

• We examine the validity of the MSWS-12 using Rasch analysis. • Included items do not cover the range of impairment of multiple sclerosis patients. • Items assessing use of support, and running ability show problematic functioning. • Items assessing need for support shows signs of multidimensionality and DIF. • A revision of the content of the MSWS-12 is advisable. The Multiple Sclerosis Walking Scale (MSWS-12) has showed good psychometric properties in reports exploring its validity using Classical Test Theory methods. Findings from recent studies using Item Response Theory methods advance the idea that some aspects of the MSWS-12 does not fully comply with some requirements of sound measurement. The present study investigated whether the measurement properties of the Italian version of the MSWS-12 met the assumptions of the Rasch model. Sample consisted of 199 patients with a diagnosis of MS (50% female; Mean age (SD) = 48.15 (12.33)). Analyses were performed using both unidimensional and multidimensional Rasch modeling techniques. Rating scale for items assessing need for support when walking, and ability to run, showed significant functioning problems. A revision of the rating scale improved the measurement properties of these items. Items assessing need for support showed signs of multidimensionality and differential item functioning when controlling for patients' disease course and EDSS score. Additionally, included items did not appear to cover the full range of impairment as observed in the sample. Emerging findings are consistent with those from previous studies in highlighting the need for a revision of the current content of the MSWS-12, and the inclusion of new items assessing impairment at the lower end of the disability continuum. [ABSTRACT FROM AUTHOR]

Abstract Background The coronavirus disease 2019 (COVID-19) pandemic has led to a disruptive increase in the number of intensive care unit (ICU) admissions with acute respiratory distress syndrome (ARDS). ARDS is a severe, life-threatening medical condition characterized by widespread inflammation and vascular leak in the lungs. Although there is no proven therapy to reduce pulmonary vascular leak in ARDS, recent studies demonstrated that the tyrosine kinase inhibitor imatinib reinforces the endothelial barrier and prevents vascular leak in inflammatory conditions, while leaving the immune response intact. Methods This is a randomized, double-blind, parallel-group, placebo-controlled, multicenter clinical trial of intravenous (IV) imatinib mesylate in 90 mechanically ventilated subjects with COVID-19-induced ARDS. Subjects are 18 years or older, admitted to the ICU for mechanical ventilation, meeting the Berlin criteria for moderate-severe ARDS with a positive polymerase chain reaction test for SARS-CoV2. Participants will be randomized in a 1:1 ratio to either imatinib (as mesylate) 200 mg bis in die (b.i.d.) or placebo IV infusion for 7 days, or until ICU discharge or death. The primary study outcome is the change in Extravascular Lung Water Index (EVLWi) between day 1 and day 4. Secondary outcome parameters include changes in oxygenation and ventilation parameters, duration of invasive mechanical ventilation, number of ventilator-free days during the 28-day study period, length of ICU stay, and mortality during 28 days after randomization. Additional secondary parameters include safety, tolerability, and pharmacokinetics. Discussion The current study aims to investigate the efficacy and safety of IV imatinib in mechanically ventilated subjects with COVID-19-related ARDS. We hypothesize that imatinib decreases pulmonary edema, as measured by extravascular lung water using a PiCCO catheter. The reduction in pulmonary edema may reverse hypoxemic respiratory failure and hasten recovery. As pulmonary edema is an important contributor to ARDS, we further hypothesize that imatinib reduces disease severity, reflected by a reduction in 28-day mortality, duration of mechanical ventilation, and ICU length of stay. Trial status Protocol version and date: V3.1, 16 April 2021. Recruitment started on 09 March 2021. Estimated recruitment period of approximately 40 weeks. Trial registration ClinicalTrials.gov NCT04794088 . Registered on 11 March 2021.