Susceptibility of SARS-CoV2 infection in children

Coronavirus disease 2019 in children presents with distinct phenotype in comparison to adults. Overall, the pediatric infection with a generally milder clinical course of the acute infection compared to adults still faces several unknown aspects. Specifically, the presence of a wide range of inflammatory manifestations, including multisystem inflammatory syndrome in children (MIS-C), myocarditis, and long COVID in the period after infection suggests a particular susceptibility of some children upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Albeit peculiar complications such as long covid are less frequent in children compared to adults, research on the relationship between inflammatory syndromes and SARS-CoV-2 is rapidly evolving. Conclusions: new studies and findings continue to emerge, providing further insights into the underlying mechanisms and potential therapeutic strategies. In the present work, we revised current knowledge of the main factors accounting for such variability upon SARS-CoV-2 infection over the pediatric age group.What is Known:& BULL; COVID19 in children overall showed a milder course compared to adults during the acute phase of the infection.& BULL; Children showed to be susceptible to a wide range of post infectious complications including multisystem inflammatory syndrome in children (MIS-C), myocarditis, neuroinflammation, and long COVID.What is New:& BULL; Mechanisms underlying susceptibility to a severe course of the infection were recently shown to pertain to the host.& BULL; A specific combination of HLA was recently shown to be associated to higher susceptibility to MIS-C in children

Screening for Latent Tuberculosis Infection among Students of Healthcare Professions and Postgraduates of the Faculty of Medicine of the University of Palermo

Introduction and objective: Italy is a country with a low incidence of tuberculosis and in the last fifty years the annual number of TB cases decreased from 12,247 to 4,418, showing a reduction of approximately 64% in the number of cases and 71% in incidence. Despite of this encouraging trend, in the last years the epidemiology of tuberculosis changed and today it is a re-emerging infectious. The aim of this study is to measure the prevalence of positivity to tuberculosis infection (latent TB) in students, without any obvious manifestation of disease, attending degree courses of the health care professions and postgraduate medical courses of the School of Medicine of the University of Palermo, Italy. Materials and methods: A cross-sectional observational study in students of nursing, midwifery, dentistry degree courses and in resident physicians of postgraduate medical schools was carried out from January 2012 to July 2016. Mantoux test was performed and all positive cases were tested with Interferon-Gamma Release Assay (IGRA). Results: Of the 1,351 subjects evaluated, 25 (1.8%) resulted positive to Mantoux test; in 17 students (1.2%) the diagnosis was confirmed with IGRA. Positive cases were significantly more frequent among students attending Postgraduated Medical School Courses (p<0.001) and were older than negative cases (p<0.001). Conclusion: This study suggests that in our geographic area, latent TB shows a relatively low prevalence among students of medical schools. Despite of this evidence, and considering that several students have been found to be positive for TB, this infectious disease has to be considered a re-emerging biohazard that requires preventive strategies for the containment of the risk in exposed workers as well as in the general population

LncRNA NEAT1 in Paraspeckles: A Structural Scaffold for Cellular DNA Damage Response Systems?

Nuclear paraspeckle assembly transcript 1 (NEAT1) is a long non-coding RNA (lncRNA) reported to be frequently deregulated in various types of cancers and neurodegenerative processes. NEAT1 is an indispensable structural component of paraspeckles (PSs), which are dynamic and membraneless nuclear bodies that affect different cellular functions, including stress response. Furthermore, increasing evidence supports the crucial role of NEAT1 and essential structural proteins of PSs (PSPs) in the regulation of the DNA damage repair (DDR) system. This review aims to provide an overview of the current knowledge on the involvement of NEAT1 and PSPs in DDR, which might strengthen the rationale underlying future NEAT1-based therapeutic options in tumor and neurodegenerative diseases

Neural correlates of mentalizing-related computations during strategic interactions in humans

Competing successfully against an intelligent adversary requires the ability to mentalize an opponent's state of mind to anticipate his/her future behavior. Although much is known about what brain regions are activated during mentalizing, the question of how this function is implemented has received little attention to date. Here we formulated a computational model describing the capacity to mentalize in games. We scanned human subjects with functional MRI while they participated in a simple two-player strategy game and correlated our model against the functional MRI data. Different model components captured activity in distinct parts of the mentalizing network. While medial prefrontal cortex tracked an individual's expectations given the degree of model-predicted influence, posterior superior temporal sulcus was found to correspond to an influence update signal, capturing the difference between expected and actual influence exerted. These results suggest dissociable contributions of different parts of the mentalizing network to the computations underlying higher-order strategizing in humans

Treatment of sudden sensorineural hearing loss with transtympanic injection of steroids as single therapy: a randomized clinical study.

The aim of this study was to verify the efficacy and the safety of transtympanic dexamethasone to treat sudden sensorineural hearing loss as first and single drug method. Considering ethical implication of performing a mininvasive procedure on middle ear, we matched such proposed treatment with systemic prednisone administration that represents the widest adopted protocol. Randomized prospective study was conducted. The inclusion criterion was a sudden sensorineural hearing loss of at least 30 dB across three contiguous frequencies over a period of 24 h. Group A received transtympanic steroid injections; Group B received oral administration of steroids. 25 patients were treated with transtympanic therapy whereas 21 underwent systemic treatment. The mean of initial PTA was 59 dB for the whole series: 65 dB for group A and 51 dB for group B. The recovery better than 10 dB was obtained in 80% of patients of group A and in 17 81% of patients of group B, with a total of 80.5%. The mean relative gain in PTA was 41.16% in the group A and 44.7% in the group B. In the frequencies tested (0.5, 1, 2, and 4 kHz) PTA improvements after transtympanic treatment were higher than after systemic treatment, but these differences were not statistically significant (P = 0.61). Both transtympanic and systemic treatment had similar clinical recovery times. This prospective randomized clinical study showed good result in terms of hearing recovery, better than the expected results of the simple observation without treatment. We can consider transtympanic administration as a first line treatment, because of the statistical analysis confirmed similar results with systemic therapy, reducing possible side effects of systemic drug administration. The delay of treatment does not influence the outcome, allowing treating patients within 10 days of onset

Mechanisms of immune escape and resistance to checkpoint inhibitor therapies in mismatch repair deficient metastatic colorectal cancers

SIMPLE SUMMARY: A subset of colorectal cancers (CRCs) is characterized by a mismatch repair deficiency that is frequently associated with microsatellite instability (MSI). The compromised DNA repair machinery leads to the accumulation of tumor neoantigens affecting the sensitivity of MSI metastatic CRC to immune checkpoint inhibitors (CPIs), both upfront and in later lines of treatment. However, up to 30% of MSI CRCs exhibit primary resistance to frontline immune based therapy, and an additional subset develops acquired resistance. Here, we first discuss the clinical and molecular features of MSI CRCs and then we review how the loss of antigenicity, immunogenicity, and a hostile tumor microenvironment could influence primary and acquired resistance to CPIs. Finally, we describe strategies to improve the outcome of MSI CRC patients upon CPI treatment. ABSTRACT: Immune checkpoint inhibitors (CPIs) represent an effective therapeutic strategy for several different types of solid tumors and are remarkably effective in mismatch repair deficient (MMRd) tumors, including colorectal cancer (CRC). The prevalent view is that the elevated and dynamic neoantigen burden associated with the mutator phenotype of MMRd fosters enhanced immune surveillance of these cancers. In addition, recent findings suggest that MMRd tumors have increased cytosolic DNA, which triggers the cGAS STING pathway, leading to interferon-mediated immune response. Unfortunately, approximately 30% of MMRd CRC exhibit primary resistance to CPIs, while a substantial fraction of tumors acquires resistance after an initial benefit. Profiling of clinical samples and preclinical studies suggests that alterations in the Wnt and the JAK-STAT signaling pathways are associated with refractoriness to CPIs. Intriguingly, mutations in the antigen presentation machinery, such as loss of MHC or Beta-2 microglobulin (B2M), are implicated in initial immune evasion but do not impair response to CPIs. In this review, we outline how understanding the mechanistic basis of immune evasion and CPI resistance in MMRd CRC provides the rationale for innovative strategies to increase the subset of patients benefiting from CPIs

Silica-magnesium-titanium Ziegler-Natta catalysts. Part 1: Structure of the pre-catalyst at a molecular level

In this paper, which is the first part of a more extended work, we elucidate the molecular level structure of a highly active SiO2-supported Ziegler-Natta precatalyst obtained by reacting a dehydroxylated silica and a solution of an organomagnesium compound with TiCl4. The synergetic combination of Ti K-edge and Ti L3-edge X-ray Absorption spectroscopy (XAS) and diffuse reflectance UV–Vis spectroscopies, complemented by Density Functional Theory (DFT) simulations, indicate that small TiCl3 clusters similar to β-TiCl3 coexist with isolated monomeric Ti(IV) species. Ti K-edge Extended X-ray Absorption Fine Structure (EXAFS) Spectroscopy allows the quantification of these two phases and demonstrates that the Ti(IV) sites are 6-fold coordinated (either by six chlorine ligands or by five chlorine and one oxygen ligands), but highly distorted, similar to what is modelled for TiCl4-capped MgCl2 nanoplatelets. Finally, IR spectroscopy suggests that the MgCl2 phase has a molecular character (Far-IR) and that the only accessible Mg2+ sites are uncoordinated cations acting as Lewis acid sites (IR of CO adsorbed at 100 K). Based on these experimental findings, we propose the co-existence in the precatalyst of small TiCl3 clusters and of mixed oxo-chloride magnesium-titanium structures deposited at the silica surface. The evolution of the precatalyst in the presence of the activator and of the monomer is discussed in the second part of this work