COVID-19 vaccine hesitancy among Italian people with multiple sclerosis.

INTRODUCTION: Vaccine hesitancy promotes the spread of infectious diseases including COVID-19 virus, limiting the herd immunity. Complications caused by COVID-19 in people with multiple sclerosis forced governments to ensure them prior access to vaccinations. Their propensity to be vaccinated needs to be assessed to promote adhesion to vaccination programs. The aim of this study was to explore the COVID-19 vaccine hesitancy rate in pwMS. METHODS: We conducted an observational study recruiting patients affected by multiple sclerosis followed at MS Clinical and Research Unit of Tor Vergata University, Rome. We invited them to fill in an online survey about their intent to get COVID-19 vaccination. Fisher's exact test and Kruskal-Wallis test were performed to explore differences in sociodemographic, clinical, and emotional variables relative to the opinions about vaccinations. An exploratory factor analysis (EFA) was performed to assess the factorial structure of the questionnaire; Pearson's correlations between the factors and Big Five personality dimensions were also calculated. RESULTS: Of 276 respondents, 90% was willing to get vaccinated, while only 1.4% was sure to refuse the vaccination. Education level, opinions on safety and efficacy of vaccines, and emotional status were found to be associated to the propensity of getting the COVID-19 vaccination (respectively: p = 0.012, p < 0.001, and p = 0.0001). Moreover, general opinions on healthcare system were related to the intention to get vaccinated. CONCLUSION: Our results reinforce the importance of a good relationship between doctor and patient and the need to adapt doctors' communication strategy to patients' personalities and beliefs.

Taming Keteniminium Reactivity by Steering Reaction Pathways: Computational Predictions and Experimental Validations.

Keteniminium ions, the nitrogen analogues of ketenes, exhibit high reactivity toward olefins and π-systems. Previous results from the Maulide group demonstrated an unexpected propensity for an alternative intramolecular Bellus-Claisen-type rearrangement rather than an expected intramolecular (2 + 2) cycloaddition. We have conducted a cooperative density functional theory/experimental investigation of this process, seeking insights into the competition between the observed Claisen-type reaction and the historically expected (2 + 2) cyclization. Our calculations revealed a surprisingly small difference in the free energy barrier between these two intramolecular reactions. Further theoretical and experimental investigations probe the electronics of the substrate, rationalize a competing deallylation side reaction, and demonstrate the proof-of-concept for an enantioselective (2 + 2) variant.

Chemoselective Alpha-Deuteration of Amides via Retro-ene Reaction.

A synthetically convenient approach for the direct α-deuteration of amides is reported. This mechanistically unusual process relies on a retro-ene-type process, triggered by the addition of deuterated dimethyl sulfoxide to a keteniminium intermediate, generated through electrophilic amide activation. The transformation displays broad functional-group tolerance and high deuterium incorporation.

An α-Cyclopropanation of Carbonyl Derivatives by Oxidative Umpolung.

The reactivity of iodine(III) reagents towards nucleophiles is often associated with umpolung and cationic mechanisms. Herein, we report a general process converting a range of ketone derivatives into α-cyclopropanated ketones by oxidative umpolung. Mechanistic investigation and careful characterization of side products revealed that the reaction follows an unexpected pathway and suggests the intermediacy of non-classical carbocations.

A Domino 10-Step Total Synthesis of FR252921 and Its Analogues, Complex Macrocyclic Immunosuppressants.

FR252921, FR252922, and FR256523 are a family of potent macrocyclic polyene immunosuppressive agents with a novel mode of action. However, the lack of an efficient and flexible synthesis has hindered further biological studies, mostly due to the fact that the natural products appear to be kinetic isomers regarding the triene moiety. Herein, we report the development and application of an unprecedented, unique domino Suzuki-Miyaura/4π-electrocyclic ring-opening macrocyclization, resulting in a concise, unified, and stereoselective synthetic route to these complex targets in only 10 steps. This in turn enables ready access to a range of unnatural analogues, among which several compounds showed inhibition of T-lymphocyte proliferation at levels equal or superior to those of the natural products themselves.

α-Arylation of Carbonyl Compounds through Oxidative C-C Bond Activation.

A synthetically useful approach for the direct α-arylation of carbonyl compounds through a novel oxidative C-C bond activation is reported. This mechanistically unusual process relies on a 1,2-aryl shift and results in all-carbon quaternary centers. The transformation displays broad functional-group tolerance and can in principle also be applied as an asymmetric variant.

Hydrative Aminoxylation of Ynamides: One Reaction, Two Mechanisms.

Organic synthesis boasts a wide array of reactions involving either radical species or ionic intermediates. The combination of radical and polar species, however, has not been explored to a comparable extent. Herein we present the hydrative aminoxylation of ynamides, a reaction which can proceed by either a polar-radical crossover mechanism or through a rare cationic activation. Common to both processes is the versatility of the persistent radical TEMPO and its oxidised oxoammonium derivative TEMPO+ . The unique mechanisms of these processes are elucidated experimentally and by in-depth DFT-calculations.

Effectiveness of Highly Purified Cannabidiol in Refractory and Super-Refractory Status Epilepticus: A Case Series.

INTRODUCTION: Refractory and super-refractory status epilepticus are medical emergencies that must be promptly treated in consideration of their high mortality and morbidity rate. Nevertheless, the available evidence of effective treatment of these conditions is scarce. Among novel antiseizure medications (ASMs), highly purified cannabidiol (hpCBD) has shown noteworthy efficacy in reducing seizures in Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and Tuberous Sclerosis Complex (TSC). CASE PRESENTATION: Here, we present two cases of effective use of hpCBD in both refractory and super- refractory status epilepticus. The administration of the nasogastric tube permitted the resolution of status epilepticus without adverse events. At 6-month follow-up, both patients were on hpCBD treatment, which continued to be efficacious for treating seizures. CONCLUSION: According to our experience, hpCBD should be taken into consideration as an add-on therapy of RSE and SRSE while also considering the possibility of maintaining this treatment during the follow-up of patients. However, more studies and real-world experiences are needed to better understand its effectiveness in this setting and the interaction with other ASMs.

Inverse hydride shuttle catalysis enables the stereoselective one-step synthesis of complex frameworks.

The rapid assembly of complex scaffolds in a single step from simple precursors identifies as an ideal reaction in terms of efficiency and sustainability. Indeed, the direct single-step synthesis of complex alkaloid frameworks remains an unresolved problem at the heart of organic chemistry in spite of the tremendous progress of the discipline. Herein, we present a broad strategy in which dynamically assembled ternary complexes are converted into valuable azabicyclic scaffolds based on the concept of inverse hydride shuttle catalysis. The ternary complexes are readily constructed in situ from three simple precursors and enable a highly modular installation of various substitution patterns. Upon subjection to a unique dual-catalytic system, the transient intermediates undergo an unusual hydride shuttle process that is initiated by a hydride donation event. Furthermore, we show that, in combination with asymmetric organocatalysis, the product alkaloid frameworks are obtained in excellent optical purity.

Anti-HBs titers are not decreased after treatment with oral Cladribine in patients with Multiple Sclerosis vaccinated against Hepatitis B virus.

BACKGROUND: Oral cladribine is a novel treatment for Multiple Sclerosis (MS). It is a purine nucleoside antimetabolite analogue that is incorporated into the DNA, resulting in single-strand breaks in DNA and apoptosis of replicating lymphocytes. Specifically, Cladribine induces limited depletion of CD4 and CD8 T cell subsets and more marked depletion of memory B cell subsets. Therefore, natural and acquired humoral responses against pathogens may be potentially reduced. The aim of this study was to assess longitudinal variation of antiHBs titers in patients with MS treated with Cladribine. METHODS: Patients with MS treated with 1 cycle of Cladribine (3,5 mg/kg) and previously vaccinated against Hepatitis B virus (HBV) were enrolled. Anti-HBs titers were compared before and after 12 months from Cladribine treatment. Total lymphocyte count was also analysed. RESULTS: Among the 13 RMS patients (10 F, 3 M, mean age 33,8, SD 5,9) enrolled, all had anti-HBs titers >10 mg/dl at baseline. Anti-HBs titer dropped below the reference value at 12 months after Cladribine only in 1 case. Pre-post Cladribine mean anti-HBs values were not significantly different considering the whole cohort (Wilcoxon-Mann-Whitney Test p = 0,762). Four patients had grade 1 and 1 patient grade 2 lymphocytopenia at 12 months. CONCLUSIONS: Cladribine does not seem to reduce humoral immune responses in subjects previously vaccinated against HBV, even in case of lymphocytopenia. These results, if confirmed in larger populations, appear reassuring also for other vaccinations (i.e. COVID19). The low impact of Cladribine on plasma cells may explain such findings.

First thermostable CLIP-tag by rational design applied to an archaeal O6 -alkyl-guanine-DNA-alkyl-transferase.

Self-labelling protein tags (SLPs) are resourceful tools that revolutionized sensor imaging, having the versatile ability of being genetically fused with any protein of interest and undergoing activation with alternative probes specifically designed for each variant (namely, SNAP-tag, CLIP-tag and Halo-tag). Commercially available SLPs are highly useful in studying molecular aspects of mesophilic organisms, while they fail in characterizing model organisms that thrive in harsh conditions. By applying an integrated computational and structural approach, we designed a engineered variant of the alkylguanine-DNA-alkyl-transferase (OGT) from the hyper-thermophilic archaeon Saccharolobus solfataricus (SsOGT), with no DNA-binding activity, able to covalently react with O6 -benzyl-cytosine (BC-) derivatives, obtaining the first thermostable CLIP-tag, named SsOGT-MC8 . The presented construct is able to recognize and to covalently bind BC- substrates with a marked specificity, displaying a very low activity on orthogonal benzyl-guanine (BG-) substrate and showing a remarkable thermal stability that broadens the applicability of SLPs. The rational mutagenesis that, starting from SsOGT, led to the production of SsOGT-MC8 was first evaluated by structural predictions to precisely design the chimeric construct, by mutating specific residues involved in protein stability and substrate recognition. The final construct was further validated by biochemical characterization and X-ray crystallography, allowing us to present here the first structural model of a CLIP-tag establishing the molecular determinants of its activity, as well as proposing a general approach for the rational engineering of any O6 -alkylguanine-DNA-alkyl-transferase turning it into a SNAP- and a CLIP-tag variant.

Complex Rearrangement of the Entire Retinal Posterior Pole in Patients with Relapsing Remitting Multiple Sclerosis.

There are consolidated data about multiple sclerosis (MS)-dependent retinal neurodegeneration occurring in the optic disk and the macula, although it is unclear whether other retinal regions are affected. Our objective is to evaluate, for the first time, the involvement of the entire retinal posterior pole in patients diagnosed with relapsing remitting multiple sclerosis (RRMS) unaffected by optic neuritis using Spectral Domain-Optical Coherence Tomography (SD-OCT). The study protocol was approved by Tor Vergata Hospital Institutional Ethics Committee (Approval number 107/16), and conforms to the tenets of the Declaration of Helsinki. After a comprehensive neurological and ophthalmological examination, 53 untreated RRMS patients (aged 37.4 ± 10) and 53 matched controls (aged 36.11 ± 12.94) were enrolled. In addition, each patient underwent an examination of the posterior pole using the SD-OCT built-in Spectralis posterior pole scanning protocol. After segmentation, the mean thickness, as well as the thickness of the 64 single regions of interest, were calculated for each retinal layer. No statistically significant difference in terms of average retinal thickness was found between the groups. However, MS patients showed both a significantly thinner ganglion cell layer (p < 0.001), and, although not statistically significant, a thinner inner nuclear layer (p = 0.072) and retinal nerve fiber layer (p = 0.074). In contrast, the retinal pigment epithelium (p = 0.014) and photoreceptor layers p < 0.001) resulted significantly thicker in these patients. Interestingly, the analysis of the region of interest showed that neurodegeneration was non-homogeneously distributed across each layer. This is the first report that suggests a complex rearrangement that affects, layer by layer, the entire retinal posterior pole of RRMS retinas in response to the underlying neurotoxic insult.

Mechanistic Pathways in Amide Activation: Flexible Synthesis of Oxazoles and Imidazoles.

The preparation of substituted aminooxazoles and aminoimidazoles from α-arylamides and α-aminoamides through triflic anhydride-mediated amide activation is reported. These reactions proceed via the intermediacy of nitrilium adducts and feature N-oxide-promoted umpolung of the α-position of amides as well as a mechanistically intriguing sequence that results in sulfonyl migration from nitrogen to carbon. Quantum-chemical mechanistic analysis sheds light on the intricacies of the process.