Non Clinical Model to Assess the Mechanism of Action of a Combined Hyaluronic Acid, Chondroitin Sulfate and Calcium Chloride: HA+CS+CaCl2 Solution on a 3D Human Reconstructed Bladder Epithelium.

Purpose: Medical Device Regulation (EU) 2017/745 requires the principal mode of action (MoA) to be demonstrated by experimental data. The MoA of Ialuril® Prefill (combined as HA+CS+CaCl2: sodium hyaluronate 1.6%, sodium chondroitin sulphate 2% w/v and calcium chloride 0.87%) Class III medical device, indicated for intravesical instillation to reduce urinary tract infections, has been evaluated on a 3D reconstructed human bladder epithelium (HBE). Methods: Three experimental designs; i) E. coli strain selection (DSM 103538, DSM 1103) to investigate the HA+CS+CaCl2 properties in modifying bacterial growth in liquid broth (CFU 4h and 24h) at 80%, 50% and 25% concentrations; ii) evaluation of film forming properties on HBE after 15 min exposure by quantifying caffeine permeation across the epithelium; iii) capacity to counteract E. coli adhesion and biofilm formation on colonized HBE by viable counts and ultrastructural analysis by scanning electron microscopy (SEM) using ciprofloxacin as the reference antimicrobial molecule. Results: No significant differences were observed in bacterial viability for both the E. coli strains. HA+CS+CaCl2 reduced caffeine permeation of 51.7% and 38.1% at 1h and 2h, respectively and determined a significant decrease in caffeine permeation rate at both timepoints supporting HA+CS+CaCl2 capacity to firmly adhere to the bladder epithelium creating a physical barrier on the surface. The viable counts in HBE treated tissues then infected with E. coli resulted not different from the negative control suggesting that the device did not inhibit E. coli growth. SEM images showed homogenous product distribution over the HBE surface and confirmed the capacity of HA+CS+CaCl2 to adhere to the bladder epithelium, counteracting biofilm formation. Conclusion: The results support the capacity of HA+CS+CaCl2 to counteract bacterial invasion by using a physico-mechanical mode of action: this medical device represents a valid alternative to antibiotics in the treatment of recurrent UTIs.

Clinical relevance of thymic and bone marrow outputs in multiple sclerosis patients treated with alemtuzumab.

Thymic and bone marrow outputs were evaluated in 13 sequential samples of 68 multiple sclerosis patients who initiated alemtuzumab and were clinically followed for 48 months. Three months after alemtuzumab infusions, the levels of new T lymphocytes were significantly reduced, but progressively increased reaching the highest values at 36 months, indicating the remarkable capacity of thymic function recovery. Newly produced B cells exceeded baseline levels as early as 3 months after alemtuzumab initiation. Heterogeneous patterns of new T- and B-cell recovery were identified, but without associations with age, sex, previous therapies, development of secondary autoimmunity or infections, and disease re-emergence. Trial registration version 2.0-27/01/2016.

Nabiximols oromucosal spray in patients with multiple sclerosis-related bladder dysfunction: A prospective study.

BACKGROUND: Spasticity and urinary disturbances can profoundly impact the daily lives of persons with multiple sclerosis (pwMS). Cannabis has been associated with improvement in sphincteric disturbances. To our knowledge, few studies have evaluated the effect of nabiximols oromucosal spray (Sativex®) on urinary disturbances by instrumental methods. OBJECTIVES: This longitudinal study was conducted to assess the effect of nabiximols oromucosal spray on urinary disturbances by clinical and urodynamic evaluation in pwMS. MATERIALS AND METHODS: Neurological, spasticity, and quality of life (QoL) assessments were performed before (T0), and at one (T1) and six (T6) months after the start of nabiximols treatment. At these same time points, patients were assessed for urinary disturbances by the International Prostatic Symptoms Score (IPSS) and a urodynamic test evaluating maximum detrusor pressure (Pdet), bladder filling capacity (CCmax), uninhibited detrusor contractions (UDC), bladder volume at first desire (BVFD), post-void residual volume (PVR) and voluntary abdominal pressure (PA). RESULTS: Of 31 pwMS enrolled in the study, 25 reached T1 and 18 reached T6. Mean IPSS total score, its subscores, and IPSS QoL decreased significantly from T0 to T6 (p = 0.000), with no differences according to sex, age, MS type, disease duration and disability at baseline. Pdet improved significantly from T0 to T6 (p = 0.0171), and CCmax changed only marginally (p = 0.0494); results were similar in patient subgroups naïve to or previously exposed to urological treatment. All patients with overactive bladder showed improvement in their urodynamic assessment based on significant reduction of Pdet (p = 0.0138). In patients with mainly hypotonic bladder, mean Pdet decreased from T0 to T6 without reaching statistical significance; most urodynamic parameters showed a trend to improve. Mean numerical scale scores for MS spasticity, and for spasms, pain and tremors, decreased significantly from T0 to T6. The mean 'physical health composite' score of the MS Quality of Life-54 questionnaire increased significantly from T0 to T6 (p = 0.0126). DISCUSSION AND CONCLUSION: Our data suggest that nabiximols has an appreciable effect on ameliorating subjective perception of urinary disturbances and appears to have a positive effect on objective urodynamic parameters, particularly in patients with hyperactive bladder.

Evaluation of Antimicrobial, Antiadhesive and Co-Aggregation Activity of a Multi-Strain Probiotic Composition against Different Urogenital Pathogens.

The urogenital microbiota is dominated by Lactobacillus that, together with Bifidobacterium, creates a physiological barrier counteracting pathogen infections. The aim of this study was to evaluate the efficacy of a multi-strain probiotic formulation (Lactiplantibacillus plantarum PBS067, Lacticaseibacillus rhamnosus LRH020, and Bifidobacterium animalis subsp. lactis BL050) to inhibit adhesion and growth of urogenital pathogens. The antimicrobial and antiadhesive properties of the probiotic strains and their mixture were evaluated on human vaginal epithelium infected with Candida glabrata, Neisseria gonorrheae, Trichomonas vaginalis, and Escherichia coli-infected human bladder epithelium. The epithelial tissue permeability and integrity were assessed by transepithelial/transendothelial electrical resistance (TEER). Co-aggregation between probiotics and vaginal pathogens was also investigated to elucidate a possible mechanism of action. The multi-strain formulation showed a full inhibition of T. vaginalis, and a reduction in C. glabrata and N. gonorrheae growth. A relevant antimicrobial activity was observed for each single strain against E. coli. TEER results demonstrated that none of the strains have negatively impaired the integrity of the 3D tissues. All the probiotics and their mixture were able to form aggregates with the tested pathogens. The study demonstrated that the three strains and their mixture are effective to prevent urogenital infections.

Prognostic relevance of quantitative and longitudinal MOG antibody testing in patients with MOGAD: a multicentre retrospective study.

BACKGROUND: IgG antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG) define a subset of associated disorders (myelin oligodendrocyte glycoprotein associated disorders (MOGAD)) that can have a relapsing course. However, information on relapse predictors is scarce. The utility of retesting MOG-IgG over time and measuring their titres is uncertain. We aimed to evaluate the clinical relevance of longitudinal MOG-IgG titre measurement to predict relapses in patients with MOGAD. METHODS: In this retrospective multicentre Italian cohort study, we recruited patients with MOGAD and available longitudinal samples (at least one >3 months after disease onset) and tested them with a live cell-based assay with endpoint titration (1:160 cut-off). Samples were classified as 'attack' (within 30 days since a disease attack (n=59, 17%)) and 'remission' (≥31 days after attack (n=295, 83%)). RESULTS: We included 102 patients with MOGAD (57% adult and 43% paediatric) with a total of 354 samples (83% from remission and 17% from attack). Median titres were higher during attacks (1:1280 vs 1:640, p=0.001). Median onset titres did not correlate with attack-related disability, age or relapses. Remission titres were higher in relapsing patients (p=0.02). When considering the first remission sample available for each patient, titres >1:2560 were predictors of relapsing course in survival (log rank, p<0.001) and multivariate analysis (p<0.001, HR: 10.9, 95% CI 3.4 to 35.2). MOG-IgG seroconversion to negative was associated with a 95% relapse incidence rate reduction (incidence rate ratio: 0.05, p<0.001). CONCLUSIONS: Persistent MOG-IgG positivity and high remission titres are associated with an increased relapse risk. Longitudinal MOG-IgG titres could be useful to stratify patients to be treated with long term immunosuppression.

Significance and clinical suggestions for the somatosensory evoked potentials increased in amplitude revealed by a large sample of neurological patients.

OBJECTIVES: To investigate the relationship between N20-P25 peak-to-peak amplitude (N20p-P25p) of somatosensory evoked potentials (SEPs) and the occurrence of abnormalities of the peripheral and/or central sensory pathways and of myoclonus/epilepsy, in 308 patients with increased SEPs amplitude from upper limb stimulation. METHODS: We compared cortical response (N20p-P25p) in different groups of patients identified by demographic, clinical, and neurophysiological factors and performed a cluster analysis for classifying the natural occurrence of subgroups of patients. RESULTS: No significant differences of N20p-P25p were found among different age-dependent groups, and in patients with or without PNS/CNS abnormalities of sensory pathways, while myoclonic/epileptic patients showed higher N20p-P25p than other groups. Cluster analysis identified four clusters of patients including myoclonus/epilepsy, central sensory abnormalities, peripheral sensory abnormalities, and absence of myoclonus and sensory abnormalities. CONCLUSIONS: Increased N20p-P25p prompts different possible pathophysiological substrates: larger N20p-P25p in patients with cortical myoclonus and/or epilepsy is likely sustained by strong cortical hyperexcitability, while milder increase of N20p-P25p could be underpinned by plastic cortical changes following abnormalities of sensory pathways, or degenerative process involving the cortex. SEPs increased in amplitude cannot be considered an exclusive hallmark of myoclonus/epilepsy. Indeed, in several neurological disorders, it may represent a sign of adaptive, plastic, and/or degenerative cortical changes.

LightBot: A Multi-Light Position Robotic Acquisition System for Adaptive Capturing of Cultural Heritage Surfaces.

Multi-light acquisitions and modeling are well-studied techniques for characterizing surface geometry, widely used in the cultural heritage field. Current systems that are used to perform this kind of acquisition are mainly free-form or dome-based. Both of them have constraints in terms of reproducibility, limitations on the size of objects being acquired, speed, and portability. This paper presents a novel robotic arm-based system design, which we call LightBot, as well as its applications in reflectance transformation imaging (RTI) in particular. The proposed model alleviates some of the limitations observed in the case of free-form or dome-based systems. It allows the automation and reproducibility of one or a series of acquisitions adapting to a given surface in two-dimensional space.

Anti-Spike IgG in multiple sclerosis patients after BNT162b2 vaccine: An exploratory case-control study in Italy.

BACKGROUND: Patients with neuroimmunological conditions such as multiple sclerosis (MS) often receive disease-modifying therapies (DMTs) or immunosuppressants which may reduce the response to vaccines. BNT162b2 (Pfizer-BioNTech) is the first COVID-19 vaccine authorized in Italy. Its clinical efficacy and serological response were not evaluated in MS patients receiving DMTs or immunosuppressants. This early multicenter study evaluated serological response to BNT162b2 and safety in these patients. METHODS: From February 2021 we enrolled consecutive MS patients, treated with at least one DMT and all healthcare workers (HCWs), having received or being scheduled to receive the first dose of BNT162b2. Blood samples were collected after the second vaccine dose and analyzed to quantitatively detect the presence of anti-Spike antibodies. Serological response was compared to the one from a control population of HCWs, with neither neuroimmunological conditions nor receiving immunosuppressants. Patients receiving treatments associated with a possible reduced response (Under-scrutiny treatment group) were also compared to those undergoing other treatments. Anti-Spike levels were described as median and interquartile range (IQR). Comparisons were performed with Wilcoxon-Mann-Whitney test. Solicited and unsolicited adverse events (AEs) were collected. RESULTS: 39 MS patients and a control population of 273 HCWs were included. One patient, under treatment with ocrelizumab, did not respond to BNT162b2, while all the remaining patients and all controls developed a serological response to the vaccine. Median anti-Spike levels were similar between patients (1471.0 BAU/ml; IQR 779.7 to 2357.0) and controls (1479.0 BAU/ml; IQR 813.1 to 2528.0) (p = 0.53). Patients included in the Under-scrutiny treatments group showed reduced anti-Spike levels (156.4 BAU/ml; IQR 33.4 to 559.1) compared to those receiving other treatments (1582.4 BAU/ml; IQR 1296.5 to 2219.0) (p = 0.001). Solicited AEs were all mild to moderate in severity, generally reported in the first days after vaccination, and resolved in the following days. Two MS patients reported a clinical relapse after the second vaccine dose. CONCLUSION: BNT162b2 induced a serological response in MS patients treated with DMTs similar to controls not receiving DMTs or immunosuppressants. Some treatments were associated with reduced levels of anti-Spike antibodies in patients. These observations have relevant implications for treated patients receiving BNT162b2 and the community.

Risk of Getting COVID-19 in People With Multiple Sclerosis: A Case-Control Study.

BACKGROUND AND OBJECTIVES: Several studies have assessed risk factors associated with the severity of COVID-19 outcomes in people with multiple sclerosis (PwMS). The potential role of disease-modifying therapies (DMTs) and demographic and clinical factors on the risk of acquiring SARS-CoV-2 infection has not been evaluated so far. The objective of this study was to assess risk factors of contracting SARS-CoV-2 infection in PwMS by using data collected in the Italian MS Register (IMSR). METHODS: A case-control (1:2) study was set up. Cases included PwMS with a confirmed diagnosis of COVID-19, and controls included PwMS without a confirmed diagnosis of COVID-19. Both groups were propensity score-matched by the date of COVID-19 diagnosis, the date of last visit, and the region of residence. No healthy controls were included in this study. COVID-19 risk was estimated by multivariable logistic regression models including demographic and clinical covariates. The impact of DMTs was assessed in 3 independent logistic regression models including one of the following covariates: last administered DMT, previous DMT sequences, or the place where the last treatment was administered. RESULTS: A total of 779 PwMS with confirmed COVID-19 (cases) were matched to 1,558 PwMS without COVID-19 (controls). In all 3 models, comorbidities, female sex, and a younger age were significantly associated (p < 0.02) with a higher risk of contracting COVID-19. Patients receiving natalizumab as last DMT (OR [95% CI]: 2.38 [1.66-3.42], p < 0.0001) and those who underwent an escalation treatment strategy (1.57 [1.16-2.13], p = 0.003) were at significantly higher COVID-19 risk. Moreover, PwMS receiving their last DMT requiring hospital access (1.65 [1.34-2.04], p < 0.0001) showed a significant higher risk than those taking self-administered DMTs at home. DISCUSSION: This case-control study embedded in the IMSR showed that PwMS at higher COVID-19 risk are younger, more frequently female individuals, and with comorbidities. Long-lasting escalation approach and last therapies that expose patients to the hospital environment seem to significantly increase the risk of SARS-CoV2 infection in PwMS. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that among patients with MS, younger age, being female individuals, having more comorbidities, receiving natalizumab, undergoing an escalating treatment strategy, or receiving treatment at a hospital were associated with being infected with COVID-19. Among patients with MS who were infected with COVID-19, a severe course was associated with increasing age and having a progressive form of MS, whereas not being on treatment or receiving an interferon beta agent was protective.

A real-world study of alemtuzumab in a cohort of Italian patients.

BACKGROUND AND PURPOSE: Real-world data on alemtuzumab are limited and do not provide evidence of its effectiveness after various disease-modifying therapies (DMTs). Our aim was to provide real-world data on the impact of clinical variables and previous DMTs on clinical response to alemtuzumab. METHODS: Sixteen Italian multiple sclerosis centers retrospectively included patients who started alemtuzumab from January 2015 to December 2018, and recorded demographics, previous therapies, washout duration, relapses, Expanded Disability Status Scale (EDSS) score, and magnetic resonance imaging data. Negative binomial regression models were used to assess the effect of factors on annualized relapse (ARR) after alemtuzumab initiation. RESULTS: We studied 322 patients (mean age 36.8 years, median EDSS score 3, median follow-up 1.94 years). Previous treatments were: fingolimod (106), natalizumab (80), first-line oral agents (56), first-line injectables (interferon/glatiramer acetate; 30), and other drugs (15). Thirty-five patients were treatment-naïve. The pre-alemtuzumab ARR was 0.99 and decreased to 0.13 during alemtuzumab treatment (p < 0.001). The number of previous-year relapses was associated with alemtuzumab ARR (adjusted risk ratio [RR] 1.38, p = 0.009). Progression-free survival was 94.5% after 1 year, and 89.2% after 2 years of alemtuzumab treatment. EDSS score improvement occurred in 13.5% after 1 year, and 20.6% after 2 years. Re-baselining patients after 6 months of alemtuzumab treatment, led to no evidence of disease activity status in 71.6% after 1 year and 58.9% after 2 years. CONCLUSIONS: Alemtuzumab decreases ARR independent of previous therapy, including patients with disease activity during natalizumab treatment. Overall, 90% of patients showed no disease progression, and 20% an improvement after 2 years of alemtuzumab.

Immune Soluble Factors in the Cerebrospinal Fluid of Progressive Multiple Sclerosis Patients Segregate Into Two Groups.

Primary-progressive (PP) and secondary-progressive (SP) multiple sclerosis (MS) are characterized by neurological deficits caused by a permanent neuronal damage, clinically quantified by the expanded disability status scale (EDSS). Neuronal tissue damage is also mediated by immune infiltrates producing soluble factors, such as cytokines and chemokines, which are released in the cerebrospinal fluid (CSF). The mechanisms regulating the production of a soluble factor are not completely defined. Using multiplex bead-based assays, we simultaneously measured 27 immune soluble factors in the CSF collected from 38 patients, 26 with PP-MS and 12 with SP-MS. Then, we performed a correlation matrix of all soluble factors expressed in the CSF. The CSF from patients with PP-MS and SP-MS had similar levels of cytokines and chemokines; however, the stratification of patients according to active or inactive magnetic resonance imaging (MRI) unveils some differences. Correlative studies between soluble factors in the CSF of patients with PP-MS and SP-MS revealed two clusters of immune mediators with pro-inflammatory functions, namely IFN-γ, MCP-1, MIP-1α, MIP-1ß, IL-8, IP-10, and TNF-α (group 1), and anti-inflammatory functions, namely IL-9, IL-15, VEGF, and IL-1ra (group 2). However, most of the significant correlations between cytokines of group 1 and of group 2 were lost in patients with more severe disability (EDSS ≥ 4) compared to patients with mild to moderate disability (EDSS < 4). These results suggest a common regulation of cytokines and chemokines belonging to the same group and indicate that, in patients with more severe disability, the production of those factors is less coordinated, possibly due to advanced neurodegenerative mechanisms that interfere with the immune response.

Reliability and Repeatability Analysis of Indices to Measure Gait Deterioration in MS Patients during Prolonged Walking.

Gait deterioration caused by prolonged walking represents one of the main consequences of multiple sclerosis (MS). This study aims at proposing quantitative indices to measure the gait deterioration effects. The experimental protocol consisted in a 6-min walking test and it involved nine patients with MS and twenty-six healthy subjects. Pathology severity was assessed through the Expanded Disability Status Scale. Seven inertial units were used to gather lower limb kinematics. Gait variability and asymmetry were assessed by coefficient of variation (CoV) and symmetry index (SI), respectively. The evolution of ROM (range of motion), CoV, and SI was computed analyzing data divided into six 60-s subgroups. Maximum difference among subgroups and the difference between the first minute and the remaining five were computed. The indices were analyzed for intra- and inter-day reliability and repeatability. Correlation with clinical scores was also evaluated. Good to excellent reliability was found for all indices. The computed standard deviations allowed us to affirm the good repeatability of the indices. The outcomes suggested walking-related fatigue leads to an always more variable kinematics in MS, in terms of changes in ROM, increase of variability and asymmetry. The hip asymmetry strongly correlated with the clinical disability.

Clinical characteristics and outcomes of inpatients with neurologic disease and COVID-19 in Brescia, Lombardy, Italy.

OBJECTIVE: To report clinical and laboratory characteristics, treatment, and clinical outcomes of patients admitted for neurologic diseases with and without coronavirus disease 2019 (COVID-19). METHODS: In this retrospective, single-center cohort study, we included all adult inpatients with confirmed COVID-19 admitted to a neuro-COVID unit beginning February 21, 2020, who had been discharged or died by April 5, 2020. Demographic, clinical, treatment, and laboratory data were extracted from medical records and compared (false discovery rate corrected) to those of neurologic patients without COVID-19 admitted in the same period. RESULTS: One hundred seventy-three patients were included in this study, of whom 56 were positive and 117 were negative for COVID-19. Patients with COVID-19 were older (77.0 years, interquartile range [IQR] 67.0-83.8 years vs 70.1 years, IQR 52.9-78.6 years, p = 0.006), had a different distribution regarding admission diagnoses, including cerebrovascular disorders (n = 43, 76.8% vs n = 68, 58.1%), and had a higher quick Sequential Organ Failure Assessment (qSOFA) score on admission (0.9, IQR 0.7-1.1 vs 0.5, IQR 0.4-0.6, p = 0.006). In-hospital mortality rates (n = 21, 37.5% vs n = 5, 4.3%, p < 0.001) and incident delirium (n = 15, 26.8% vs n = 9, 7.7%, p = 0.003) were significantly higher in the COVID-19 group. Patients with COVID-19 and without COVID with stroke had similar baseline characteristics, but patients with COVID-19 had higher modified Rankin Scale scores at discharge (5.0, IQR 2.0-6.0 vs 2.0, IQR 1.0-3.0, p < 0.001), with a significantly lower number of patients with a good outcome (n = 11, 25.6% vs n = 48, 70.6%, p < 0.001). In patients with COVID-19, multivariable regressions showed increasing odds of in-hospital death associated with higher qSOFA scores (odds ratio [OR] 4.47, 95% confidence interval [CI] 1.21-16.5, p = 0.025), lower platelet count (OR 0.98, 95% CI 0.97-0.99, p = 0.005), and higher lactate dehydrogenase (OR 1.01, 95% CI 1.00-1.03, p = 0.009) on admission. CONCLUSIONS: Patients with COVID-19 admitted with neurologic disease, including stroke, have a significantly higher in-hospital mortality and incident delirium and higher disability than patients without COVID-19.

Treatment of multiple sclerosis with rituximab: A multicentric Italian-Swiss experience.

BACKGROUND: Rituximab, an anti-CD20 monoclonal antibody leading to B lymphocyte depletion, is increasingly used as an off-label treatment option for multiple sclerosis (MS). OBJECTIVE: To investigate the effectiveness and safety of rituximab in relapsing-remitting (RR) and progressive MS. METHODS: This is a multicenter, retrospective study on consecutive MS patients treated off-label with rituximab in 22 Italian and 1 Swiss MS centers. Relapse rate, time to first relapse, Expanded Disability Status Scale (EDSS) progression, incidence of adverse events, and radiological outcomes from 2009 to 2019 were analyzed. RESULTS: A total of 355/451 enrolled subjects had at least one follow-up visit and were included in the outcome analysis. Annualized relapse rate significantly decreases after rituximab initiation versus the pre-rituximab start year in RRMS (from 0.86 to 0.09, p < .0001) and in secondary-progressive (SP) MS (from 0.34 to 0.06, p < .0001) and had a slight decrease in primary-progressive (PP) MS patients (from 0.12 to 0.07, p = 0.45). After 3 years from rituximab start, the proportion of patients with a confirmed EDSS progression was 14.6% in the RRMS group, 24.7% in the SPMS group, and 41.5% in the PPMS group. No major safety concerns arose. CONCLUSION: Consistently with other observational studies, our data show effectiveness of rituximab in reducing disease activity in patients with MS.

Efficacy of different rituximab therapeutic strategies in patients with neuromyelitis optica spectrum disorders.

OBJECTIVE: To evaluate disease activity according to rituximab (RTX) induction and maintenance regimens in a multicenter real-life dataset of NMOSD patients. METHODS: 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). RESULTS: 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. INTERPRETATION: 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.

Older age, higher perceived disability and depressive symptoms predict the amount and severity of work-related difficulties in persons with multiple sclerosis.

Purpose: This cross-sectional study aims to identify the predictors of work-related difficulties in a sample of employed persons with multiple sclerosis as addressed with the Multiple Sclerosis Questionnaire for Job Difficulties. Materials and methods: Hierarchical linear regression analysis was conducted to identify predictors of work difficulties: predictors included demographic variables (age, formal education), disease duration and severity, perceived disability and psychological variables (cognitive dysfunction, depression and anxiety). The targets were the questionnaire's overall score and its six subscales. Results: A total of 177 participants (108 females, aged 21-63) were recruited. Age, perceived disability and depression were direct and significant predictors of the questionnaire total score, and the final model explained 43.7% of its variation. The models built on the questionnaire's subscales show that perceived disability and depression were direct and significant predictors of most of its subscales. Conclusions: Our results show that, among patients with multiple sclerosis, those who were older, with higher perceived disability and higher depression symptoms have more and more severe work-related difficulties. The Multiple Sclerosis Questionnaire for Job Difficulties can be fruitfully exploited to plan tailored actions to limit the likelihood of near-future job loss in persons of working age with multiple sclerosis. Implications for rehabilitation Difficulties with work are common among people with multiple sclerosis and are usually addressed in terms of unemployment or job loss. The Multiple Sclerosis Questionnaire for Job Difficulties is a disease-specific questionnaire developed to address the amount and severity of work-related difficulties. We found that work-related difficulties were associated to older age, higher perceived disability and depressive symptoms. Mental health issues and perceived disability should be consistently included in future research targeting work-related difficulties.

Heart rate variability is differentially altered in multiple sclerosis: implications for acute, worsening and progressive disability.

BACKGROUND: Sympathovagal imbalance has been associated with poor prognosis in chronic diseases, but there is conflicting evidence in multiple sclerosis. OBJECTIVES: The objective of this study was to investigate the autonomic nervous system dysfunction correlation with inflammation and progression in multiple sclerosis. METHODS: Heart rate variability was analysed in 120 multiple sclerosis patients and 60 healthy controls during supine rest and head-up tilt test; the normalised units of low frequency and high frequency power were considered to assess sympathetic and vagal components, respectively. Correlation analyses with clinical and radiological markers of disease activity and progression were performed. RESULTS: Sympathetic dysfunction was closely related to the progression of disability in multiple sclerosis: progressive patients showed altered heart rate variability with respect to healthy controls and relapsing-remitting patients, with higher rest low frequency power and lacking the expected low frequency power increase during the head-up tilt test. In relapsing-remitting patients, disease activity, even subclinical, was associated with lower rest low frequency power, whereas stable relapsing-remitting patients did not differ from healthy controls. Less sympathetic reactivity and higher low frequency power at rest were associated with incomplete recovery from relapse. CONCLUSIONS: Autonomic balance appears to be intimately linked with both the inflammatory activity of multiple sclerosis, which is featured by an overall hypoactivity of the sympathetic nervous system, and its compensatory plastic processes, which appear inefficient in case of worsening and progressive multiple sclerosis.

Difficulties in adjustment to multiple sclerosis: vulnerability and unpredictability of illness in the foreground.

PURPOSE: Multiple Sclerosis (MS) is a progressive neurological disease characterized by an unpredictable risk to develop relevant disability over time. Few studies focused on the core psychological features of difficulties in adjustment to MS. This qualitative study aims to explore the illness experience of people with difficulties in adjustment to MS, paying more attention to both illness representation and shifting perspective. METHOD: Nineteen persons with difficulties in adjustment to MS participated in the study and their interviews were analyzed using thematic analysis. RESULTS: Considering the Shifting Perspective Model, illness is rigidly placed in the foreground, and wellness decisively pushed in the background, with a lack of flexibility in shifting between the two perspectives. The thematic analysis delineated three main topics: illness representation; coping strategies; relationships with others. The illness representation is characterized by invalidating symptoms; unclear cause; sudden onset; unpredictable course and uncertain prognosis; severe impact on person's functioning; and low sense of internal control. Participants reported to mainly use emotion-focused coping strategies. CONCLUSIONS: Adjustment can be supported activating psychological intervention addressed to patients' illness representations and more flexibility in the shifting between illness and wellness in the foreground. Implications for Rehabilitation Adjustment to MS is influenced by illness perception. It is important to pay more attention to contents about vulnerability and unpredictability associated to MS. With regards to the Shifting Perspectives Model, difficulties in adjustment are related to the rigidity that prevents an adequate shift between the two perspectives (illness and wellness), with the predominance of the illness perspective in the foreground. Hence, it is important to assess the shifting perspectives preference and flexibility, and the contents of illness representation of a person with MS. Clinicians can support process of adjustment, activating psychological intervention addressed to patients' illness representations and promotion of a more flexibility in the shifting between illness and wellness in the foreground. The Illness Representation Model should be enriched by a social component, able to take into consideration the impact of the disease on interactions with others.