Butyrylcholinesterase and Acetylcholinesterase polymorphisms in Multiple Sclerosis patients: Implication in peripheral inflammation

Multiple Sclerosis (MS) is an autoimmune disease, having not fully understood aetiology, and both genetic and environmental factors contribute to the pathogenesis of the disease. The cholinergic system has been indicated as a mediator of neuro-immune interactions, as well as an internal regulator of immune responses. The aim of the present research was to assess the associations between BChE and AChE genetic variations and serum cholinergic and inflammatory profiles in 102 Relapsing Remitting-MS patients and 117 healthy controls. An increased frequency of the BChE K-allele in MS patients as compared to controls was found. In addition, data showed that patients had higher BChE enzymatic activity, which is increased by the presence of the polymorphic allele and reduced amounts of circulating ACh. AChE polymorphism was significantly associated to reduced activity in both patients and controls. We propose that serum BChE and AChE activity may be used as a secondary markers to assess the role of non-neuronal cholinergic system in regulating peripheral inflammation via ACh regulation. This pilot study shed light on the role of the non-neuronal cholinergic system in immune cells to better understand MS pathogenesis. The cross-talk between the periphery and the CNS could have a new undescribed crucial role for MS, regarded as a systemic disease

The other side of COVID-19. A cross-sectional study on mental health in a sample of Italian nurses during the second wave

Introduction: The COVID-19 pandemic has led to a drastic increase in the workload of healthcare professionals, particularly nurses, with serious consequences for their psychological well-being. Our study aimed to identify demographic and work-related factors, as well as clinical predictors of post-traumatic stress disorder (PTSD) and generalized anxiety disorder (GAD), in nurses employed during the COVID-19 pandemic. Methods: We carried out a cross-sectional study between December 2020 and April 2021 on nurses employed during the COVID-19 second wave (October - December 2020). We evaluated PTSD and GAD using two validated questionnaires: i) the Impact of Event Scale – Revised (IES-R); and ii) General Anxiety Disorder –7 (GAD-7). Results: Overall, 400 nurses, whose mean age was 34.3 years (SD ± 11.7), were included in the study. Most were female (78.5%), unmarried (58.5%) and employed in the central (61.5%) regions of Italy. A total of 56.8% of all participants had clinical predictors of PTSD, recording a median IES-R score (IQR) of 37.0 (22.0, 51.0) (range 1-84; cut-off >33 for PTSD). Furthermore, 50% of respondents reported moderate-to-severe symptoms consistent with GAD, recording a median GAD-7 score (IQR) of 9.5 (6.0,14.0) (range 0-21; cut-off >10 for GAD). Multivariable analysis showed that moderate-to-severe GAD (aOR = 4.54, 95% CI: 2.93 - 7.05), being employed in the critical care area (aOR = 1.74, 95% CI: 1.01 - 3.00) and being female (aOR= 1.88, 95% CI: 1.09 - 3.22) were significantly associated with the presence of clinical predictors of PTSD. Discussion: The levels of PTSD symptoms and anxiety among nurses were high during the pandemic. PTSD and GAD represent a public health problem that should be addressed in the post-pandemic period. Healthcare organizations need to activate specific support and rehabilitation networks and programs for healthcare professionals employed during the COVID-19 pandemic

Healthcare Resources Use in Patients with Human Immunodeficiency Virus (HIV). Real-World Evidence From Six Italian Local Health Units

AIM: The aim of the study was to evaluate healthcare resource use and related costs for the management of people living with Human Immunodeficiency Virus (PLWHIV) with and without comorbidities, and to compare the burden of comorbidities in PLWHIV to the general population.METHODS: An observational retrospective analysis, based on administrative and laboratory databases from 6 Italian Local Health Units (LHUs) was performed. Individuals receiving either an HIV treatment [Antiretroviral therapy (ART) – ATC code: J05A)], or with an HIV positive laboratory test result between January 1st, 2014 and December 31st, 2014 were included. The date of first ART prescription or positive test of HIV was used as the Index Date (ID). Patients enrolled were followed-up for all time available from the ID (follow-up period) and their clinical characteristics were investigated from one year prior to the ID (characterization period). Comorbidities were measured by using the Charlson Comorbidity Index; findings were compared with those of a sample of the general population with the same age and sex distribution (OsMed 2015). Healthcare resource use and related cost was evaluated during the follow-up period.RESULTS: 1,214 patients were included, 837 were PLWHIV without any comorbidities and 377 were PLWHIV with at least one comorbidity. Mean prevalence of prescriptions for treatment of comorbidities was higher in the HIV-infected population than in the Italian general population. The annual healthcare cost of managing HIV patients with comorbidities, was significantly higher than that for patients without comorbidities (€ 10,615 vs. € 8,665, p < 0.001).CONCLUSIONS: Study results showed that 30% of PLWHIV had at least one comorbidity. The cost of managing PLWHIV who have comorbidities was significantly higher than that of managing PLWHIV without comorbidities. Our data confirm that care and treatment services should be adapted to address the specific needs of people living with both HIV and comorbidities

SARS-CoV-2-Associated ssRNAs Activate Human Neutrophils in a TLR8-Dependent Fashion

COVID-19 disease is characterized by a dysregulation of the innate arm of the immune system. However, the mechanisms whereby innate immune cells, including neutrophils, become activated in patients are not completely understood. Recently, we showed that GU-rich RNA sequences from the SARS-CoV-2 genome (i.e., SCV2-RNA1 and SCV2-RNA2) activate dendritic cells. To clarify whether human neutrophils may also represent targets of SCV2-RNAs, neutrophils were treated with either SCV2-RNAs or, as a control, R848 (a TLR7/8 ligand), and were then analyzed for several functional assays and also subjected to RNA-seq experiments. Results highlight a remarkable response of neutrophils to SCV2-RNAs in terms of TNFα, IL-1ra, CXCL8 production, apoptosis delay, modulation of CD11b and CD62L expression, and release of neutrophil extracellular traps. By RNA-seq experiments, we observed that SCV2-RNA2 promotes a transcriptional reprogramming of neutrophils, characterized by the induction of thousands of proinflammatory genes, similar to that promoted by R848. Furthermore, by using CU-CPT9a, a TLR8-specific inhibitor, we found that SCV2-RNA2 stimulates neutrophils exclusively via TLR8-dependent pathways. In sum, our study proves that single-strand RNAs from the SARS-CoV-2 genome potently activate human neutrophils via TLR8, thus uncovering a potential mechanism whereby neutrophils may contribute to the pathogenesis of severe COVID-19 disease

HuD is a neural translation enhancer acting on mTORC1-responsive genes and counteracted by the Y3 small non-coding RNA

The RNA-binding protein HuD promotes neurogenesis and favors recovery from peripheral axon injury. HuD interacts with many mRNAs, altering both stability and translation efficiency. We generated a nucleotide resolution map of the HuD RNA interactome in motor neuron-like cells, identifying HuD target sites in 1,304 mRNAs, almost exclusively in the 3' UTR. HuD binds many mRNAs encoding mTORC1-responsive ribosomal proteins and translation factors. Altered HuD expression correlates with the translation efficiency of these mRNAs and overall protein synthesis, in a mTORC1-independent fashion. The predominant HuD target is the abundant, small non-coding RNA Y3, amounting to 70% of the HuD interaction signal. Y3 functions as a molecular sponge for HuD, dynamically limiting its recruitment to polysomes and its activity as a translation and neuron differentiation enhancer. These findings uncover an alternative route to the mTORC1 pathway for translational control in motor neurons that is tunable by a small non-coding RNA

Coptos (2022)

Données scientifiques produites : Base de données des objets trouvés à Coptos et conservés dans des collections muséales (conçue et réalisée par V. Desclaux) : https://coptos.mom.frhttps://www.ifao.egnet.net/archeologie/coptos/ 1. Problématique et principaux résultats Étude de l’évolution architecturale et urbaine des centres religieux de la ville, de l’époque pharaonique à l’époque romaine impériale. Découverte et fouille d’un mammisi construit par Ptolémée IV. Identification d’un temple d..

SARS-CoV-2 vaccination and multiple sclerosis: a large multicentric study on relapse risk after the third booster dose

Background: COVID-19 vaccines have been recommended to people with multiple sclerosis (pwMS) and, to ensure durable immunity, a third booster dose has been administered in several countries. Data about potential risks associated with the third booster dose in pwMS, such as vaccine-triggered disease exacerbations, are still scarce. Objective: To investigate whether the administration of a third booster dose of mRNA COVID-19 vaccines was associated with an increased risk of short-term disease reactivation in a large cohort of pwMS. Methods: We retrospectively selected 1265 pwMS who received a third booster dose of an mRNA COVID-19 vaccine. Demographic and clinical data were collected, including the presence, number and characteristics of relapses in the 60&nbsp;days prior to and after the third booster dose. Results: In the selected cohort, the relapse rate in the two months after administration of the third booster dose of mRNA COVID-19 vaccines did not increase when compared with the prior two months. Indeed, the percentage of pwMS experiencing relapses in the 60&nbsp;days following the administration of the third booster dose was 2.1%, similar to the percentage recorded in 60&nbsp;days prior to vaccination, which was 1.9%. Conclusions: The third booster dose of mRNA COVID-19 vaccines appeared to be safe for pwMS

Management of hepatitis B virus prophylaxis in patients treated with disease-modifying therapies for multiple sclerosis: a multicentric Italian retrospective study

Background: Patients with multiple sclerosis (MS) often receive disease-modifying therapies (DMTs) that can expose them to reactivation of potential occult hepatitis B virus (HBV) infection (pOBI). We aimed to evaluate the MS Centers behavior regarding HBV screening and prophylaxis in a large cohort of MS patients receiving anti-CD20 or cladribine. Methods: Retrospective, multicentric study recruiting Italian MS patients treated with rituximab, ocrelizumab and cladribine. Results: We included 931 MS patients from 15 centers. All but 38 patients performed a complete HBV screening. Patients' age &gt; 50&nbsp;years was significantly associated with no history of vaccination and HBsAb titres &lt; 100 mIU at baseline (p &lt; 0.001). No significant correlation was found between post-vaccination HBsAb titres and type of treatment (p = 0.5), pre-or post-therapy vaccination (p = 0.2) and number of previous DMTs (p = 0.2). Among pOBI patients (n = 53), 21 received antiviral prophylaxis, while only 13 had HBV DNA monitoring and 19 patients neither monitored HBV DNA nor received prophylaxis. Conclusions: Baseline HBV screening in patients receiving anti-CD20 and cladribine is a consolidated practice. Nonetheless, HBV vaccination coverage is still lacking in such population and age is a significant factor associated with low HBV protection. Rituximab, ocrelizumab and cladribine did not impair HBV vaccine response. Almost 35% of pOBI patients fail to receive HBVr prevention. Management of HBV prophylaxis could be improved in MS patients and further prospective studies are needed to assess the effectiveness of prophylactic strategies in such patients

Long-term disability trajectories in relapsing multiple sclerosis patients treated with early intensive or escalation treatment strategies

Background and aims: No consensus exists on how aggressively to treat relapsing-remitting multiple sclerosis (RRMS) nor on the timing of the treatment. The objective of this study was to evaluate disability trajectories in RRMS patients treated with an early intensive treatment (EIT) or with a moderate-efficacy treatment followed by escalation to higher-efficacy disease modifying therapy (ESC). Methods: RRMS patients with ⩾5-year follow-up and ⩾3 visits after disease modifying therapy (DMT) start were selected from the Italian MS Registry. EIT group included patients who received as first DMT fingolimod, natalizumab, mitoxantrone, alemtuzumab, ocrelizumab, cladribine. ESC group patients received the high efficacy DMT after ⩾1 year of glatiramer acetate, interferons, azathioprine, teriflunomide or dimethylfumarate treatment. Patients were 1:1 propensity score (PS) matched for characteristics at the first DMT. The disability trajectories were evaluated by applying a longitudinal model for repeated measures. The effect of early versus late start of high-efficacy DMT was assessed by the mean annual Expanded Disability Status Scale (EDSS) changes compared with baseline values (delta-EDSS) in EIT and ESC groups. Results: The study cohort included 2702 RRMS patients. The PS matching procedure produced 363 pairs, followed for a median (interquartile range) of 8.5 (6.5-11.7) years. Mean annual delta-EDSS values were all significantly (p &lt; 0.02) higher in the ESC group compared with the EIT group. In particular, the mean delta-EDSS differences between the two groups tended to increase from 0.1 (0.01-0.19, p = 0.03) at 1 year to 0.30 (0.07-0.53, p = 0.009) at 5 years and to 0.67 (0.31-1.03, p = 0.0003) at 10 years. Conclusion: Our results indicate that EIT strategy is more effective than ESC strategy in controlling disability progression over time