NEDA-3 achievement in early highly active relapsing remitting multiple sclerosis patients treated with Ocrelizumab or Natalizumab.

BACKGROUND: in the early stages of Multiple Sclerosis (MS), initiating high-efficacy disease-modifying therapy (HE DMTs) may represent an optimal strategy for delaying neurological damage and long-term disease progression, especially in highly active MS patients (HAMS). Natalizumab (NAT) and Ocrelizumab (OCR) are recognized as HE DMTs with significant anti-inflammatory effects. This study investigates NEDA-3 achievement in treatment-naïve HAMS patients receiving NAT or OCR over three years. METHODS: we retrospectively enrolled treatment-naïve HAMS patients undergoing NAT or OCR, collecting demographic, clinical, and instrumental data before and after treatment initiation to compare with propensity score analysis disease activity, time to disability worsening, and NEDA-3 achievement. RESULTS: we recruited 281 HAMS patients with a mean age of 32.7 years (SD 10.33), treated with NAT (157) or OCR (124). After three years, the Kaplan-Meier probability of achieving NEDA-3 was 66.0 % (95 % CI: 57.3 % - 76.0 %) with OCR and 68.2 % (95 % CI: 59.9 % - 77.7 %) with NAT without significant differences between the two groups (p = 0.27) DISCUSSION AND CONCLUSION: starting HE DMT with monoclonal antibodies for HAMS could achieve NEDA-3 in a high percentage of patients without differences between NAT or OCR.

Multiple Sclerosis Onset before and after COVID-19 Vaccination: Can HLA Haplotype Be Determinant?

A few cases of multiple sclerosis (MS) onset after COVID-19 vaccination have been reported, although the evidence is insufficient to establish causality. The aim of this study is to compare cases of newly diagnosed relapsing-remitting MS before and after the outbreak of the COVID-19 pandemic and the impact of COVID-19 vaccination. Potential environmental and genetic predisposing factors were also investigated, as well as clinical patterns. This is a single-centre retrospective cohort study including all patients who presented with relapsing-remitting MS onset between January 2018 and July 2022. Data on COVID-19 vaccination administration, dose, and type were collected. HLA-DRB1 genotyping was performed in three subgroups. A total of 266 patients received a new diagnosis of relapsing-remitting MS in our centre, 143 before the COVID-19 pandemic (until and including March 2020), and 123 during the COVID-19 era (from April 2020). The mean number of new MS onset cases per year was not different before and during the COVID-19 era and neither were baseline patients' characteristics, type of onset, clinical recovery, or radiological patterns. Fourteen (11.4%) patients who subsequently received a new diagnosis of MS had a history of COVID-19 vaccination within one month before symptoms onset. Patients' characteristics, type of onset, clinical recovery, and radiological patterns did not differ from those of patients with non-vaccine-related new diagnoses of MS. The allele frequencies of HLA-DRB1*15 were 17.6% and 22.2% in patients with non-vaccine-related disease onset before and during the COVID-19 era, respectively, while no case of HLA-DRB1*15 was identified among patients with a new diagnosis of MS post-COVID-19 vaccine. In contrast, HLA-DRB1*08+ or HLA-DRB1*10+ MS patients were present only in this subgroup. Although a causal link between COVID-19 vaccination and relapsing-remitting MS cannot be detected, it is interesting to note and speculate about the peculiarities and heterogeneities underlying disease mechanisms of MS, where the interactions of genetics and the environment could be crucial also for the follow-up and the evaluation of therapeutic options.

Robust Isolated Attosecond Pulse Generation with Self-Compressed Subcycle Drivers from Hollow Capillary Fibers.

High-order harmonic generation (HHG) arising from the nonperturbative interaction of intense light fields with matter constitutes a well-established tabletop source of coherent extreme-ultraviolet and soft X-ray radiation, which is typically emitted as attosecond pulse trains. However, ultrafast applications increasingly demand isolated attosecond pulses (IAPs), which offer great promise for advancing precision control of electron dynamics. Yet, the direct generation of IAPs typically requires the synthesis of near-single-cycle intense driving fields, which is technologically challenging. In this work, we theoretically demonstrate a novel scheme for the straightforward and compact generation of IAPs from multicycle infrared drivers using hollow capillary fibers (HCFs). Starting from a standard, intense multicycle infrared pulse, a light transient is generated by extreme soliton self-compression in a HCF with decreasing pressure and is subsequently used to drive HHG in a gas target. Owing to the subcycle confinement of the HHG process, high-contrast IAPs are continuously emitted almost independently of the carrier-envelope phase (CEP) of the optimally self-compressed drivers. This results in a CEP-robust scheme which is also stable under macroscopic propagation of the high harmonics in a gas target. Our results open the way to a new generation of integrated all-fiber IAP sources, overcoming the efficiency limitations of usual gating techniques for multicycle drivers.

Assessing treatment response to oral drugs for multiple sclerosis in real-world setting: a MAGNIMS Study.

BACKGROUND: The assessment of treatment response is a crucial step for patients with relapsing-remitting multiple sclerosis on disease-modifying therapies (DMTs). We explored whether a scoring system developed within the MAGNIMS (MRI in Multiple Sclerosis) network to evaluate treatment response to injectable drugs can be adopted also to oral DMTs. METHODS: A multicentre dataset of 1200 patients who started three oral DMTs (fingolimod, teriflunomide and dimethyl fumarate) was collected within the MAGNIMS network. Disease activity after the first year was classified by the 'MAGNIMS' score based on the combination of relapses (0-≥2) and/or new T2 lesions (<3 or ≥3) on brain MRI. We explored the association of this score with the following 3-year outcomes: (1) confirmed disability worsening (CDW); (2) treatment failure (TFL); (3) relapse count between years 1 and 3. The additional value of contrast-enhancing lesions (CELs) and lesion location was explored. RESULTS: At 3 years, 160 patients experienced CDW: 12% of them scored '0' (reference), 18% scored '1' (HR=1.82, 95% CI 1.20 to 2.76, p=0.005) and 37% scored '2' (HR=2.74, 95% CI 1.41 to 5.36, p=0.003) at 1 year. The analysis of other outcomes provided similar findings. Considering the location of new T2 lesions (supratentorial vs infratentorial/spinal cord) and the presence of CELs improved the prediction of CDW and TFL, respectively, in patients with minimal MRI activity alone (one or two new T2 lesions). CONCLUSIONS: Early relapses and substantial MRI activity in the first year of treatment are associated with worse short-term outcomes in patients treated with some of the oral DMTs.

Serum-Circulating microRNAs in Sporadic Inclusion Body Myositis.

BACKGROUND: Sporadic inclusion body myositis (s-IBM) represents a unique disease within idiopathic inflammatory myopathies with a dual myodegenerative-autoimmune physiopathology and a lack of an efficacious treatment. Circulating miRNA expression could expand our knowledge of s-IBM patho-mechanisms and provide new potential disease biomarkers. To evaluate the expression of selected pre-amplified miRNAs in the serum of s-IBM patients compared to those of a sex- and age-matched healthy control group, we enrolled 14 consecutive s-IBM patients and 8 sex- and age-matched healthy controls. By using two different normalization approaches, we found one downregulated and three upregulated miRNAs. hsa-miR-192-5p was significantly downregulated, while hsa-miR-372-3p was found to be upregulated more in the s-IBM patients compared to the level of the controls. The other two miRNAs had a very low expression levels (raw Ct data > 29). hsa-miR-192-5p and hsa-miR-372-3p were found to be significantly dysregulated in the serum of s-IBM patients. These miRNAs are involved in differentiation and regeneration processes, thus possibly reflecting pathological mechanisms in s-IBM muscles and potentially representing disease biomarkers.

Current Status of Oral Disease-Modifying Treatment Effects on Cognitive Outcomes in Multiple Sclerosis: A Scoping Review.

INTRODUCTION: Cognitive impairment represents one of the most hidden and disabling clinical aspects of multiple sclerosis (MS). In this regard, the major challenges are represented by the need for a comprehensive and standardised cognitive evaluation of each patient, both at disease onset and during follow-up, and by the lack of clear-cut data on the effects of treatments. In the present review, we summarize the current evidence on the effects of the available oral disease-modifying treatments (DMTs) on cognitive outcome measures. MATERIALS AND METHODS: In this systematised review, we extract all the studies that reported longitudinally acquired cognitive outcome data on oral DMTs in MS patients. RESULTS: We found 29 studies that evaluated at least one oral DMT, including observational studies, randomised controlled trials, and their extension studies. Most of the studies (n = 20) evaluated sphingosine-1-phosphate (S1P) modulators, while we found seven studies on dimethyl fumarate, six on teriflunomide, and one on cladribine. The most frequently used cognitive outcome measures were SDMT and PASAT. Most of the studies reported substantial stability or mild improvement in cognitive outcomes in a short-time follow-up (duration of most studies ≤2 years). A few studies also reported MRI measures of brain atrophy. CONCLUSION: Cognitive outcomes were evaluated only in a minority of prospective studies on oral DMTs in MS patients with variable findings. More solid and numerous data are present for the S1P modulators. A standardised cognitive evaluation remains a yet unmet need to better clarify the possible positive effect of oral DMTs on cognition.

Current status of clinical outcome measures in inclusion body myositis: a systematised review.

OBJECTIVES: Sporadic inclusion body myositis (IBM) is a debilitating idiopathic inflammatory myopathy (IIM) which affects hand function, ambulation, and swallowing. There is no approved pharmacological therapy for IBM, and there is a lack of suitable outcome measure to assess the effect of an intervention. The IBM scientific interest group under IMACS reviewed the previously used outcome measures in IBM clinical studies to lay the path for developing a core set of outcome measures in IBM. METHODS: In this systematised review, we have extracted all outcome measures reported in IBM clinical studies to determine what measures were being used and to assess the need for optimising outcome measures in IBM. RESULTS: We found 13 observational studies, 17 open-label clinical trials, and 15 randomised control trials (RCTs) in IBM. Six-minute walk distance, IBM-functional rating scale (IBM-FRS), quantitative muscle testing, manual muscle testing, maximal voluntary isometric contraction testing, and thigh muscle volume measured by MRI were used as primary outcome measures. Twelve different outcome measures of motor function were used in IBM clinical trials. IBM-FRS was the most used measure of functionality. Swallowing function was reported as a secondary outcome measure in only 3 RCTs. CONCLUSIONS: There are inconsistencies in using outcome measures in clinical studies in IBM. The core set measures developed by the IMACS group for other IIMs are not directly applicable to IBM. As a result, there is an unmet need for an IBM-specific core set of measures to facilitate the evaluation of new potential therapeutics for IBM.

COVID-19 presenting as a non-arteritic anterior ischemic optic neuropathy.

We present a case of a 61-year-old woman with an atypical non-arteritic anterior ischemic optic neuropathy (NA-AION) as a unique manifestation of COVID-19. Furthermore, the patient worsened after Pfizer-BioNTech COVID-19 vaccine administration. Our findings suggest that NA-AION could result from microangiopathic/thrombotic events that may occur during SARS-CoV-2 infection and/or vaccination against COVID-19. This report sheds light on possible ophthalmologic complications of COVID-19.

CSF CXCL13 and Chitinase 3-like-1 Levels Predict Disease Course in Relapsing Multiple Sclerosis.

Several biomarkers from multiple sclerosis (MS) patients' biological fluids have been considered to support diagnosis, predict disease course, and evaluate treatment response. In this study, we assessed the CSF concentration of selected molecules implicated in the MS pathological process. To investigate the diagnostic and prognostic significance of CSF concentration of target candidate biomarkers in both relapsing (RMS, n = 107) and progressive (PMS, n = 18) MS patients and in other inflammatory (OIND, n = 10) and non-inflammatory (ONIND, n = 15) neurological disorders. We measured the CSF concentration of APRIL, BAFF, CHI3L1, CCL-2, CXCL-8, CXCL-10, CXCL-12, CXCL-13 through a Luminex Assay. MS patients were prospectively evaluated, and clinical and radiological activity were recorded. CHI3L1 and CXCL13 CSF levels were significantly higher in both MS groups compared to control groups, while CCL2, BAFF, and APRIL concentrations were lower in RMS patients compared to PMS and OIND. Considering RMS patients with a single demyelinating event, higher concentrations of CHI3L1, CXCL10, CXCL12, and CXCL13 were recorded in patients who converted to clinically defined MS(CDMS). RMS patients in the CXCL13 and CHI3L1 high concentration group had a significantly higher risk of relapse (HR 12.61 and 4.57), MRI activity (HR 7.04 and 2.46), and of any evidence of disease activity (HR 12.13 and 2.90) during follow-up. CSF CXCL13 and CHI3L1 levels represent very good prognostic biomarkers in RMS patients, and therefore can be helpful in the treatment choice. Higher CSF concentrations of neuro-inflammatory biomarkers were associated with a higher risk of conversion to CDMS in patients with a first clinical demyelinating event. Differential CSF BAFF and APRIL levels between RMS and PMS suggest a different modulation of B-cells pathways in the different phases of the disease.

Liposome-based nanoparticles impact on regulatory and effector phenotypes of macrophages and T cells in multiple Sclerosis patients.

Current available treatments of Multiple Sclerosis (MS) reduce neuroinflammation acting on different targets on the immune system, but potentially lead to severe side effects and have a limited efficacy in slowing the progression of the disease. Here, we evaluated in vitro the immunomodulatory potential of a new class of nanoparticles - liposomes, constituted by a double-layer of phosphatidylserine (PSCho/PS), and double-faced, with an outer layer of phosphatidylserine and an inner layer of phosphatidic acid (PSCho/PA), either alone or in the presence of the myelin basic protein (MBP) peptide (residues 85-99) (PSCho/PS-MBP and PSCho/PA-MBP). Results showed that PSCho/PS are equally and efficiently internalized by pro- and anti-inflammatory macrophages (M1 and M2 respectively), while PSCho/PA were internalized better by M2 than M1. PSCho/PS liposomes were able to inhibit the secretion of innate pro-inflammatory cytokine IL-1ß. PSCho/PS liposomes expanded Tregs, reducing Th1 and Th17 cells, while PSCho/PA liposomes were unable to dampen pro-inflammatory T cells and to promote immune-regulatory phenotype (Treg). The ability of PSCho/PS liposomes to up-regulate Treg cells was more pronounced in MS patients with high basal expression of M2 markers. PSCho/PS liposomes were more effective in decreasing Th1 (but not Th17) cells in MS patients with a disease duration >3 months. On the other hand, down-modulation of Th17 cells was evident in MS patients with active, Gadolinium enhancing lesions at MRI and in MS patients with a high basal expression of M1-associated markers in the monocytes. The same findings were observed for the modulation of MBP-driven Th1/Th17/Treg responses. These observations suggest that early MS associate to a hard-wired pro-Th1 phenotype of M1 that is lost later during disease course. On the other hand, acute inflammatory events reflect a temporary decrease of M2 phenotype that however is amenable to restauration upon treatment with PSCho/PS liposomes. Thus, together these data indicate that monocytes/macrophages may play an important regulatory function during MS course and suggest a role for PSCho/PS and PSCho/PS-MBP as new therapeutic tools to dampen the pro-inflammatory immune responses and to promote its regulatory branch.

Few-Femtosecond C2H4+ Internal Relaxation Dynamics Accessed by Selective Excitation.

Dissociation of the ethylene cation is a prototypical multistep pathway in which the exact mechanisms leading to internal energy conversions are not fully known. For example, it is still unclear how the energy is exactly redistributed among the internal modes and which step is rate-determining. Here we use few-femtosecond extreme-ultraviolet pulses of tunable energy to excite a different superposition of the four lowest states of C2H4+ and probe the subsequent fast relaxation with a short infrared pulse. Our results demonstrate that the infrared pulse photoexcites the cationic ground state (GS) to higher excited states, producing a hot GS upon relaxation, which enhances the fragmentation yield. As the photoexcitation probability of the GS strongly depends on the molecular geometry, the probing by the IR pulse provides information about the ultrafast excited-state dynamics and the type of conical intersection (planar or twisted) involved in the first 20 fs of the nonradiative relaxation.

Controlling Floquet states on ultrashort time scales.

The advent of ultrafast laser science offers the unique opportunity to combine Floquet engineering with extreme time resolution, further pushing the optical control of matter into the petahertz domain. However, what is the shortest driving pulse for which Floquet states can be realised remains an unsolved matter, thus limiting the application of Floquet theory to pulses composed by many optical cycles. Here we ionized Ne atoms with few-femtosecond pulses of selected time duration and show that a Floquet state can be observed already with a driving field that lasts for only 10 cycles. For shorter pulses, down to 2 cycles, the finite lifetime of the driven state can still be explained using an analytical model based on Floquet theory. By demonstrating that the amplitude and number of Floquet-like sidebands in the photoelectron spectrum can be controlled not only with the driving laser pulse intensity and frequency, but also by its duration, our results add a new lever to the toolbox of Floquet engineering.

Neurosarcoidosis presenting as longitudinally extensive myelitis: Diagnostic assessment, differential diagnosis, and therapeutic approach.

Neurosarcoidosis is an uncommon and multiform clinical entity. Its presentation as an isolated longitudinal extensive transverse myelitis (LETM) is rare and challenging to identify. We report a case of LETM in a 60-year-old patient with no significant systemic symptoms nor relevant medical history. The peculiar spinal magnetic resonance imaging finding characterized by a posterior and central canal subpial contrast enhancement, the so-called "trident sign," together with chest computed tomography scan and lymph node biopsy led to the diagnosis of sarcoidosis. We also discuss the main differential diagnoses of LETM and therapeutic options for sarcoidosis-related myelitis.

The Expanding Role of the Infectious Disease Expert in the Context of the MS Centre.

INTRODUCTION: The complexity of the MS patient's management is constantly growing. Consequently, the MS care unit requires a multidisciplinary approach, including an infectious disease specialist to minimise the risk of infectious complications related both to the disease and DMTs. MATERIALS AND METHODS: We retrospectively evaluated the infectious disease consultations performed from 2015 to 2019 in our MS centre. RESULTS: We identified 107 patients with at least one infectious disease consultation out of 1088 patients. We found a progressive increase in the number of consultations from 2015 to 2019. Nearly half of the consultations were requested at the time of starting MS treatment. The most frequent requests were represented by chronic or acute infections. The most prevalent infectious agents were Herpesviridae and Mycobacterium tuberculosis. Antibiotic or antiviral treatment and prophylactic treatment or vaccination represented together the most frequent outcomes of the consultations. Finally, a treatment delay was significantly associated with the advice of a prophylactic treatment or of a vaccination. CONCLUSION: There is an increasing awareness of the potential infectious complications of MS and of exposure to DMTs. The interaction between the MS neurologist and infectious disease specialist is fundamental to minimise the infectious risk related to the disease and to the DMTs, with a progressive shift from complication management to a broader prevention workup at the time of MS diagnosis, including both vaccination and prophylactic treatments.

Shift of multiple sclerosis onset towards older age.

OBJECTIVE: To explore whether age at onset increased over time despite a shortened interval from the initial clinical demyelinating event to the diagnosis of multiple sclerosis (MS), as promoted by updated diagnostic criteria. METHODS: This was an independent, multicentre, retrospective study based on data from 4345 patients with relapsing-onset MS attending three tertiary MS Clinics in Italy. After stratifying the year of MS onset into four periods (<1991, 1991-2000, 2001-2010, 2011-2021), we analysed the temporal trends in age at onset and interval from onset to diagnosis; we then explored the female-to-male ratio and onset location across different classes of age at onset. RESULTS: We observed an increased mean age at onset, and a shortened mean interval to diagnosis over time (p<0.0001). Accordingly, there were more MS onsets at the older age classes of 40-49, 50-59 and ≥60 years (p<0.0001). In cases with age at onset ≥40 years, we also found an increased female-to-male ratio (p=0.007), more frequent spinal cord (p=0.0004) and less frequent supratentorial onset (p=0.008). CONCLUSION: Our study shows a forward shift towards an older age at onset of MS, thus suggesting considerable thought on the place-in-therapy of most currently used disease-modifying treatments, and on the standard of care to an older population.

Reconstruction of ultrafast exciton dynamics with a phase-retrieval algorithm.

The first step to gain optical control over the ultrafast processes initiated by light in solids is a correct identification of the physical mechanisms at play. Among them, exciton formation has been identified as a crucial phenomenon which deeply affects the electro-optical properties of most semiconductors and insulators of technological interest. While recent experiments based on attosecond spectroscopy techniques have demonstrated the possibility to observe the early-stage exciton dynamics, the description of the underlying exciton properties remains non-trivial. In this work we propose a new method called extended Ptychographic Iterative engine for eXcitons (ePIX), capable of reconstructing the main physical properties which determine the evolution of the quasi-particle with no prior knowledge of the exact relaxation dynamics or the pump temporal characteristics. By demonstrating its accuracy even when the exciton dynamics is comparable to the pump pulse duration, ePIX is established as a powerful approach to widen our knowledge of solid-state physics.

Attosecond spectroscopy for the investigation of ultrafast dynamics in atomic, molecular and solid-state physics.

Since the first demonstration of the generation of attosecond pulses (1 as = 10-18s) in the extreme-ultraviolet spectral region, several measurement techniques have been introduced, at the beginning for the temporal characterization of the pulses, and immediately after for the investigation of electronic and nuclear ultrafast dynamics in atoms, molecules and solids with unprecedented temporal resolution. The attosecond spectroscopic tools established in the last two decades, together with the development of sophisticated theoretical methods for the interpretation of the experimental outcomes, allowed to unravel and investigate physical processes never observed before, such as the delay in photoemission from atoms and solids, the motion of electrons in molecules after prompt ionization which precede any notable nuclear motion, the temporal evolution of the tunneling process in dielectrics, and many others. This review focused on applications of attosecond techniques to the investigation of ultrafast processes in atoms, molecules and solids. Thanks to the introduction and ongoing developments of new spectroscopic techniques, the attosecond science is rapidly moving towards the investigation, understanding and control of coupled electron-nuclear dynamics in increasingly complex systems, with ever more accurate and complete investigation techniques. Here we will review the most common techniques presenting the latest results in atoms, molecules and solids.

Influence of Previous Disease-Modifying Drug Exposure on T-Lymphocyte Dynamic in Patients With Multiple Sclerosis Treated With Ocrelizumab.

BACKGROUND AND OBJECTIVES: To investigate the longitudinal dynamic of lymphocyte subsets during treatment with ocrelizumab (OCR) in patients with multiple sclerosis (PwMS). METHODS: A multicenter retrospective study was conducted in 161 PwMS starting treatment with OCR grouped in naive (naive, n = 40), switching from fingolimod (FTY, n = 52), and switching from other immunomodulating drugs (other, n = 69). Mean lymphocyte subset (total, CD3+, CD4+, CD8+, CD20+, and natural killer) counts were analyzed at baseline, 6 months, and 12 months. Rate of lymphocytopenia for each subset was calculated at all time points in all groups. RESULTS: Mean total, CD3+, and CD4+ counts were significantly different among groups (p < 0.001) at all time points, whereas CD8+ and CD20+ counts only at baseline (p = 0.0157; p < 0.001), consistently lower in FTY. After adjustment for baseline values, interaction time*group was not statistically significant (p > 0.05 for each subset). The odds of lymphopenia were significantly higher among FTY patients compared with naive for total, CD3+, CD4+, and CD20+ cells at baseline, for total and CD4+ cells at the sixth month, and for total cells at the 12th month. DISCUSSION: OCR per se exerts a modest depleting effect on T cells that seems rather due to a carryover phenomenon of previous therapies, particularly FTY. These data may help in the overall evaluation of the risk/benefit profile of treatment sequencing.