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Neutrophils activation plays a pivotal role in the pathogenesis of atherosclerotic plaque formation, progression and rupture. An association between the leukocyte count and the risk of developing myocardial infarction has been well known for many years; however, only recently did Mendelian randomization studies show that a high neutrophil count is a causal risk factor for atherosclerotic cardiovascular disease. On the other hand, experimental studies show that depletion of circulating neutrophils impairs plaque development. Clopidogrel, an antiplatelet agent, is widely used in combination with aspirin to reduce the incidence of ischemic events in patients treated with coronary stenting. Chronic treatment with this drug reduces inflammatory markers and neutrophil numbers, rarely causing severe leukopenia. The purpose of this review is to present recent evidence showing the link between neutrophil number and the development of cardiovascular diseases and to discuss how the clopidogrel-induced reduction in the neutrophil count may be a beneficial off-target effect of this drug., (Copyright © 2024 Italian Federation of Cardiology - I.F.C. All rights reserved.)

'Active' and 'non-active' secondary progressive MS (SPMS) have distinct pathophysiological mechanisms and clinical characteristics, but there is still no consensus regarding the frequency of these MS forms in the real-world setting. We aimed to evaluate the frequency of 'active' and 'non-active' SPMS in a large cohort of Italian MS patients and the differences in terms of clinical and MRI characteristics and disease progression. This multicenter study collected data about MS patients who have transitioned to the SP form in the period between 1st January 2014 and 31st December 2019 and followed by the MS centers contributing to the Italian MS Registry. Patients were divided into 'active SPMS' and 'non-active SPMS', based on both reported MRI data and relapse activity in the year before conversion to SPMS. Out of 68,621, 8,316 (12.1%) patients were diagnosed with SPMS. Out of them, 872 (10.5%) were classified into patients with either 'active' or 'non-active' SPMS. A total of 237 were classified into patients with 'active SPMS' (27.2%) and 635 as 'non-active SPMS' (72.8%). 'Non-active SPMS' patients were older, with a longer disease duration compared to those with 'active SPMS'. The percentages of patients showing progression independent of relapse activity (PIRA) at 24 months were similar between 'active' and 'non-active' SPMS patients (67 [27.4%] vs 188 [29.6%]; p = 0.60). In the 'active' group, 36 (15.2%) patients showed relapse-associated worsening (RAW). Comparison of the survival curves to EDSS 6 and 7 according to disease activity did not show significant differences (p = 0.68 and p = 0.71). 'Active' and 'non-active' SPMS patients had a similar risk of achieving disability milestones, suggesting that progression is primarily attributed to PIRA and only to a small extent to disease activity., (© 2024. The Author(s).)

Background: Gender differences in the access to advanced therapies for Parkinson's disease (PD) are poorly investigated., Objective: The objective of this study was to investigate the presence of any gender disparity in the access to advanced therapies for PD., Design: Retrospective study., Methods: Data from patients with consistent access to the Parkinson's and Movement Disorder Center of L'Aquila over the last 10-year period were screened. Patients selected for advanced therapies were included., Results: Out of 1,252 patients, 200 (mean age ± SD 71.02 ± 9.70; 72% males; median Hoen Yahr level: 3, minimum 1 maximum 5) were selected for advanced therapies: 133 for Magnetic Resonance guided Focused Ultrasound (MRgFUS) thalamotomy (mean age ± SD 70.0 ± 8.9; 77% males), 49 for Levodopa/Carbidopa Intestinal Gel (LCIG) infusion (mean age ± SD 74.3 ± 11.4; 59% males), 12 for Deep Brain Stimulation (DBS) (mean age ± SD 71.2 ± 6.3; 75% males), and 7 for Continuous Subcutaneous Apomorphine Infusion (CSAI) (mean age ± SD 69.7 ± 5.5; 43% males). No sex differences were found in relation to age (MRgFUS group: males vs. females 70.2 ± 8.9 vs. 70.8 ± 8.9, p -value = 0.809; LCIG group: males vs. females 73.5 ± 13.0 vs. 75.5 ± 8.5, p -value = 0.557; DBS group: males vs. females 77.2 ± 8.1 vs. 67.3 ± 8.6, p -value = 0.843; CSAI group: males vs. females 73.3 ± 4.0 vs. 67.0 ± 5.2, p -value = 0.144) and disease duration (MRgFUS group: males vs. females 8.3 ± 4.4 vs. 9.6 ± 6.7, p -value = 0.419; LCIG group: males vs. females 14.5 ± 5.81 vs. 17.3 ± 5.5; p -value = 0.205; DBS group: males vs. females 15.0 ± 9.6 vs. 15.5 ± 7.7, p -value = 0.796; CSAI group: males vs. females 11.7 ± 3.7 vs. 10.3 ± 3.7, p -value = 0.505)., Conclusion: The predominance of males is higher than that expected based on the higher prevalence of PD in men. Women are less confident in selecting advanced therapies during the natural progression of their disease. Factors accounting for this discrepancy deserve further investigation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Maccarrone, Saporito, Sucapane, Rizi, Bruno, Catalucci, Pistoia, Splendiani, Ricci, Di Cesare, Rizzo, Totaro and Pistoia.)

With the recent introduction of a number of highly effective disease-modifying treatments (DMTs) and the resulting almost complete prevention of acute relapses in many patients with multiple sclerosis (MS), the interest of MS clinicians has gradually shifted from relapse prevention to counteraction of disease progression and the treatment of residual symptoms. Targeting the cannabinoid system with nabiximols is an approved and effective strategy for the treatment of spasticity secondary to MS. Recently, the concept of spasticity plus syndrome (SPS) was introduced to account for the evidence that spasticity often appears in MS patients in clusters with other symptoms (such as pain, bladder dysfunction, sleep, and mood disorders), where cannabinoids can also be effective due to their broader action on many immune and neuronal functions. Interestingly, outside these symptomatic benefits, extensive pre-clinical and clinical research indicated how the modulation of the cannabinoid system results in significant anti-inflammatory and neuroprotective effects, all potentially relevant for MS disease control. This evidence makes nabiximols a potential disease modifying symptomatic treatment (DMST), a concept introduced in an attempt to overcome the often artificial distinction between DMTs and symptomatic therapies (STs)., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

In multiple sclerosis (MS), alongside the physical symptoms, individuals often grapple with anxiety and depressive symptoms as prevalent comorbidity. Mood disturbances, frequently undertreated in clinical practice, significantly impact the quality of life of individuals with MS, exacerbating disability and hindering overall well-being. Furthermore, traditional antidepressant therapies are often associated with adverse events, such as sexual side effect, weight gain, which could limit their use in these patients. Vortioxetine is one of the most innovative antidepressant drugs in the current pharmacopeia. Its pharmacological profile includes serotonin reuptake inhibition, antagonism for hydroxytryptamine (HT) receptors 5-HT3, 5-HT1D and 5-HT7, partial agonism for 5-HT1B, and agonism for 5-HT1A. It has been shown to have a beneficial effect on depression-related cognitive dysfunction, as well as on anxiety, depression, anhedonia and emotional blunting. Recently a potential anti-inflammatory action was also described. Limited clinical studies have specifically explored the efficacy of vortioxetine in treating depressive symptoms in MS. However, extrapolating from existing research in major depressive disorder, it is plausible that vortioxetine's multimodal mechanism could provide a favorable therapeutic approach. This position paper, which summarizes the output of annual clinical meeting held by the DMSTs in MS Italian Study Group, is focused on the possible role that vortioxetine could play as symptomatic treatment (ST) of depressed patients with MS, hypothesizing a direct impact on the clinical course of the disease., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background and Objectives: In multiple sclerosis (MS), MRI markers can measure the potential neuroprotective effects of fingolimod beyond its anti-inflammatory activity. In this study we aimed to comprehensively explore, in the real-word setting, whether fingolimod not only reduces clinical/MRI inflammatory activity, but also influences the progression of irreversible focal and whole brain damage in relapsing-remitting [RR] MS patients., Methods: The "EVOLUTION" study, a 24-month observational, prospective, single-arm, multicenter study, enrolled 261 RRMS patients who started fingolimod at 32 Italian MS centers and underwent biannual neurological assessments and annual MRI evaluations. Study outcomes included the proportions of evaluable RRMS patients achieving at 24 months: (1) no new/enlarging T 2 -hyperintense white matter (WM) lesions and/or clinical relapses; (2) a modified classification of "No Evidence of Disease Activity 4" ("modified NEDA-4") defined as no new/enlarging T 2 -hyperintense WM lesions, clinical relapses, and 6-month confirmed disability progression, and a yearly percentage lateral ventricular volume change on T 2 -FLAIR images < 2%; (3) less than 40% of active lesions at baseline and month 12 evolving to permanent black holes (PBHs)., Results: At month 24, 76/160 (47.5%; 95% confidence interval [CI] = 39.8%;55.2%) RRMS patients had no clinical/MRI activity. Thirty-nine of 170 RRMS patients (22.9%; 95% CI = 16.6%;29.3%) achieved "modified NEDA-4" status. Forty-four of 72 RRMS patients (61.1%; 95% CI = 49.8%;72.4%) had less than 40% of active WM lesions evolving to PBHs. The study confirmed the established safety and tolerability profile of fingolimod., Discussion: By comparing our results with those from the literature, the EVOLUTION study seems to indicate a neuroprotective effect of fingolimod, limiting inflammatory activity, brain atrophy and PBH development., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: We investigated the occurrence and relative contribution of relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA) to confirmed disability accrual (CDA) and transition to secondary progression (SP) in relapsing multiple sclerosis (MS)., Methods: Relapsing-onset MS patients with follow-up > / = 5 years (16,130) were extracted from the Italian MS Registry. CDA was a 6-month confirmed increase in Expanded Disability Status Scale (EDSS) score. Sustained disability accumulation (SDA) was a CDA with no EDSS improvement in all subsequent visits. Predictors of PIRA and RAW and the association between final EDSS score and type of CDA were assessed using logistic multivariable regression and multivariable ordinal regression models, respectively., Results: Over 11.8 ± 5.4 years, 16,731 CDA events occurred in 8998 (55.8%) patients. PIRA (12,175) accounted for 72.3% of CDA. SDA occurred in 8912 (73.2%) PIRA and 2583 (56.7%) RAW (p < 0.001). 4453 (27.6%) patients transitioned to SPMS, 4010 (73.2%) out of 5476 patients with sustained PIRA and 443 (24.8%) out of 1790 patients with non-sustained PIRA. In the multivariable ordinal regression analysis, higher final EDSS score was associated with PIRA (estimated coefficient 0.349, 95% CI 0.120-0.577, p = 0.003)., Discussion: In this real-world relapsing-onset MS cohort, PIRA was the main driver of disability accumulation and was associated with higher disability in the long term. Sustained PIRA was linked to transition to SP and could represent a more accurate PIRA definition and a criterion to mark the putative onset of the progressive phase., (© 2024. The Author(s).)

Use of extracorporeal membrane oxygenation (ECMO) for cardiorespiratory failure remains complicated by blood clot formation (thrombosis), triggered by biomaterial surfaces and flow conditions. Thrombosis may result in ECMO circuit changes, cause red blood cell hemolysis, and thromboembolic events. Medical device thrombosis is potentiated by the interplay between biomaterial properties, hemodynamic flow conditions and patient pathology, however, the contribution and importance of these factors are poorly understood because many in vitro models lack the capability to customize material and flow conditions to investigate thrombosis under clinically relevant medical device conditions. Therefore, an ECMO thrombosis-on-a-chip model is developed that enables highly customizable biomaterial and flow combinations to evaluate ECMO thrombosis in real-time with low blood volume. It is observed that low flow rates, decelerating conditions, and flow stasis significantly increased platelet adhesion, correlating with clinical thrombus formation. For the first time, it is found that tubing material, polyvinyl chloride, caused increased platelet P-selectin activation compared to connector material, polycarbonate. This ECMO thrombosis-on-a-chip model can be used to guide ECMO operation, inform medical device design, investigate embolism, occlusion and platelet activation mechanisms, and develop anti-thrombotic biomaterials to ultimately reduce medical device thrombosis, anti-thrombotic drug use and therefore bleeding complications, leading to safer blood-contacting medical devices., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Background: Episodic migraine (EM) is the second most prevalent neurological disorder worldwide and is responsible for more disability than all other neurological disorders combined. Triggers for the development of migraine include, stress, emotional burden, low blood sugar levels, tobacco, skipped meals, anxious and depressive feelings. Migraine affects both children and adults, occurring three times more frequently in women than in men., Objective: The aim of this study was to evaluate the psychological profile of EM patients and the relationship among negative emotions in EM patients, analyzing self-efficacy measures in pain management., Design: We performed an observational study in 60 outpatients aged 18-55 years (mean age 33.8; SD ±10.4) with EM., Methods: All patients have been enrolled at the Headache Center of the San Salvatore Hospital of L'Aquila. The assessment comprised five standardized psychological self-assessments investigating relevant emotional dimensions and pain self-efficacy, along with two questionnaires assessing migraine-related disability. A network analysis of negative emotions was performed to evaluate which emotional traits and relationships play a crucial role in pain coping and management., Results: Our findings indicate that migraine significantly impairs the quality of life of patients in their daily lives. Over half of the patients reported experiencing severe disability, with negative emotions significantly influencing their ability to cope with pain and maintain productivity during migraine attacks. Dysphoric variables (irritability, interpersonal resentment, and surrender) were correlated with difficulties in emotion regulation ability and with the capacity of engaging in goal-directed behaviors despite experiencing pain. The ability to regulate one's emotions and manage dysphoria were positively correlated with pain self-efficacy, whereas positive mental health was associated with individuals' confidence in performing activities despite experiencing pain., Conclusion: Negative emotions had a negative correlation with positive mental health and were linked to a lower capacity to carry out daily activities despite experiencing migraine pain. This suggests that psychological interventions could improve mental health and potentially surpassing the effects of pharmacological interventions alone in migraine management. An integrated, patient-centered approach may represent an effective paradigm to address and reduce the burden of migraine, leading to a reduction in healthcare costs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Guerra, Di Giacomo, Ranieri, Saporito, Sucapane, Totaro and Pistoia.)

Treatment options for secondary progressive MS (SPMS) are limited, especially considering that the new drugs recently approved are licensed for actively relapsing patients. We aimed to compare the disability progression in a real-world cohort of SPMS patients treated with natalizumab (NTZ) or interferon beta-1b (IFNb-1b). This multicenter retrospective enrolled patients with a diagnosis of SPMS according to 2014 Lublin criteria, who received NTZ or IFNb-1b for at least 48 months between the 1st June 2012 and the 15th May 2018 ​at 33 Italian MS centers contributing to the Italian MS Registry NTZ or IFNb-1b. Confirmed Expanded Disability Status Scale worsening (CEW) and progression independent of relapse (PIRA) were evaluated. In order to correct for non-randomization, a propensity score matching of the groups was performed. Out of 5206 MS patients identified at the time of data extraction, 421 SPMS patients treated with NTZ (224 [53.2%] females, mean age 45.3 ​± ​25.4 years) and 353 with IFNb-1b (133 [37.8%] females, mean age 48.5 ​± ​19.8 years) were enrolled. After applying the matching procedure, 102 patients were retained in the NTZ group and 98 in the IFNb-2b group. The proportion of patients who reached the 48-month 1-point CEW was significantly higher in IFNb-1b compared to NTZ group (58.2% versus 30.4%, p ​= ​0.01). The proportion of patients who developed PIRA at 48 months were significantly higher in IFNb-1b compared to NTZ (72.4% versus 40.2%, p ​= ​0.01). EDSS before treatment initiation and SPMS duration were risk factors for disability progression in terms of PIRA (HR 2.54, 25%CI 1.67-5.7; p ​= ​0.006 and HR 2.04, 25%CI 1.22-3.35; p ​= ​0.01, respectively). Patients treated with IFNb-1b were 1.64 times more to likely to develop PIRA (HR 1.64, 25%CI 1.04-4.87; p ​= ​0.001). Treatment with NTZ in SPMS patients showed more favorable disability outcomes compared to IFNb-1b with beneficial effects over 48 months., Competing Interests: Declaration of competing interest CGC has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. UA reports no disclosures relevant to the manuscript. MPA has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. RB reports no disclosures relevant to the manuscript. AB has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. SB served as speaker and/or advisory board fee, and/or travel grant from Novartis, Teva, Sanofi-Genzyme, Roche, Biogen-Idec, Merck-Serono. VBM received fees for consultancies or public speaking from Merck, Novartis, Biogen, Roche, Genzyme and Biogen. PC has served as an advisory board member for Almirall, Biogen, Merck-Serono, Sanofi-Genzyme, Roche, Teva; she has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. EC reports no disclosures relevant to the manuscript. AC reports no disclosures relevant to the manuscript. SC has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. GDL reports no disclosures relevant to the manuscript. ADS reports no disclosures relevant to the manuscript. MF is Editor-in-Chief of the Journal of Neurology; received compensation for consulting services and/or speaking activities from Biogen Idec, Merck-Serono, Novartis, Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Merck-Serono, Novartis, Teva Pharmaceutical Industries, Roche, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA(Fondazione Italiana di Ricerca per la SLA). AG reports no disclosures relevant to the manuscript. CG reports no disclosures relevant to the manuscript. FG received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. GL reports no disclosures relevant to the manuscript. DM reports no disclosures relevant to the manuscript. GTM has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. GAM has served as an advisory board member and received speaker honoraria, congress, travel and accommodation expense compensations from Merck, Teva, Mylan, Bayer, Novartis, Roche, Almirall, Biogen and Sanofi Genzyme. LM reports no disclosures relevant to the manuscript. DP has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. IP reports no disclosures relevant to the manuscript. PR reports no disclosures relevant to the manuscript. MR received travel grants and fees for consulting and public speaking from Almirall, Biogen, Genzyme-Sanofi, Merck Serono, Mylan and Novartis. GS has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. CS has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. RT reports no disclosures relevant to the manuscript. ST reports no disclosures relevant to the manuscript. MT has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. MV reports no disclosures relevant to the manuscript. VL reports no disclosures relevant to the manuscript. MZ has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. FP has received honoraria for speaking activities by Almirall, Bayer Schering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA; he also served as advisory board member the following companies: Bayer Schering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA; he was also funded by Pfizer and FISM for epidemiological studies; he received grants for congress participation from Almirall, Bayer Shering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Essential tremor (ET) and Parkinson's Disease (PD) are debilitating neurodegenerative disorders characterized by tremor as a predominant symptom, significantly impacting patients' quality of life. Magnetic Resonance-guided Focused Ultrasound (MRgFUS) Thalamotomy is an innovative therapeutic option for the treatment of unilateral medically refractory tremor with fewer adverse effects compared to traditional surgical interventions. A recent CE approval allows appropriate patients to have their second side treated., Objective: The objective of this systematic review was to analyze available current knowledge about the use of MRgFUS for the treatment of bilateral ET and PD related tremor, to identify the effectiveness and the risks associated with bilateral treatment., Methods: Eligible studies were identified by searching published studies in PubMed and Scopus databases from May 2014 to January 2024 and by identifying ongoing studies registered on the clinicaltrials.gov website. Data were summarized by considering the following information topics: the number of patients involved, the selected lesion target, the assessment tool used to evaluate clinical changes, the observed improvement, the reported side effects, and the time interval between the two treatments. The study was registered in PROSPERO (ID: CRD42024513178)., Results: Nine studies were eligible for this review, 7 for ET and 2 for PD. The involved population included a variable number of patients, ranging from 1 to 11 subjects for ET and from 10 to 15 subjects for PD. The main lesional targets were the ventral intermediate nucleus of the thalamus, the pallidothalamic tract and the cerebellothalamic tract bilaterally. All studies investigated the tremor relief through the Clinical Rating Scale for Tremor (CRST) in patients with ET, and through the Unified Parkinson's Disease Rating Scale (UPDRS) in patients with PD. A variable degree of improvement was observed, with all patients expressing overall satisfaction with the bilateral treatment. Adverse events were mild and transient, primarily involving gait disturbances, dysarthria, and ataxia. A standardized protocol for administering the two consecutive treatments was not identifiable; typically, the timing of the second treatment was delayed by at least 6 months., Conclusion: Available evidence supports the effectiveness and safety of staged bilateral MRgFUS treatments for ET and PD-related tremor., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Cesarano, Saporito, Sucapane, Bruno, Catalucci, Pistoia, Splendiani, Ricci, Di Cesare, Totaro and Pistoia.)