Explore the vast range of titles available.

In December 2019, an initial cluster of interstitial bilateral pneumonia emerged in Wuhan, China. A human-to-human transmission was assumed and a previously unrecognized entity, termed coronavirus disease-19 (COVID-19) due to a novel coronavirus (SARS-CoV-2) was described. The infection has rapidly spread out all over the world and Italy has been the first European country experiencing the endemic wave with unexpected clinical severity in comparison with Asian countries. It has been shown that SARS-CoV-2 utilizes angiotensin converting enzyme 2 (ACE2) as host receptor and host proteases for cell surface binding and internalization. Thus, a predisposing genetic background can give reason for interindividual disease susceptibility and/or severity. Taking advantage of the Network of Italian Genomes (NIG), here we mined whole-exome sequencing data of 6930 Italian control individuals from five different centers looking for ACE2 variants. A number of variants with a potential impact on protein stability were identified. Among these, three more common missense changes, p.(Asn720Asp), p.(Lys26Arg), and p.(Gly211Arg) were predicted to interfere with protein structure and stabilization. Rare variants likely interfering with the internalization process, namely p.(Leu351Val) and p.(Pro389His), predicted to interfere with SARS-CoV-2 spike protein binding, were also observed. Comparison of ACE2 WES data between a cohort of 131 patients and 258 controls allowed identifying a statistically significant (P value < 0.029) higher allelic variability in controls compared with patients. These findings suggest that a predisposing genetic background may contribute to the observed interindividual clinical variability associated with COVID-19, allowing an evidence-based risk assessment leading to personalized preventive measures and therapeutic options.

Recently, loss-of-function variants in TLR7 were identified in two families in which COVID-19 segregates like an X-linked recessive disorder environmentally conditioned by SARS-CoV-2. We investigated whether the two families represent the tip of the iceberg of a subset of COVID-19 male patients. This is a nested case-control study in which we compared male participants with extreme phenotype selected from the Italian GEN-COVID cohort of SARS-CoV-2-infected participants (<60 y, 79 severe cases versus 77 control cases). We applied the LASSO Logistic Regression analysis, considering only rare variants on young male subsets with extreme phenotype, picking up TLR7 as the most important susceptibility gene. Overall, we found TLR7 deleterious variants in 2.1% of severely affected males and in none of the asymptomatic participants. The functional gene expression profile analysis demonstrated a reduction in TLR7-related gene expression in patients compared with controls demonstrating an impairment in type I and II IFN responses. Young males with TLR7 loss-of-function variants and severe COVID-19 represent a subset of male patients contributing to disease susceptibility in up to 2% of severe COVID-19. Funded by private donors for the Host Genetics Research Project, the Intesa San Paolo for 2020 charity fund, and the Host Genetics Initiative. NCT04549831.

Toll-like receptors (TLR) are crucial components in the initiation of innate immune responses to a variety of pathogens, triggering the production of pro-inflammatory cytokines and type I and II interferons, which are responsible for innate antiviral responses. Among the different TLRs, TLR7 recognizes several single-stranded RNA viruses including SARS-CoV-2. We and others identified rare loss-of-function variants in X-chromosomal TLR7 in young men with severe COVID-19 and with no prior history of major chronic diseases, that were associated with impaired TLR7 signaling as well as type I and II IFN responses. Here, we performed RNA sequencing to investigate transcriptome variations following imiquimod stimulation of peripheral blood mononuclear cells isolated from patients carrying previously identified hypomorphic, hypofunctional, and loss-of-function TLR7 variants. Our investigation revealed a profound impairment of the TLR7 pathway in patients carrying loss-of-function variants. Of note, a failure in IFNγ upregulation following stimulation was also observed in cells harboring the hypofunctional and hypomorphic variants. We also identified new TLR7 variants in severely affected male patients for which a functional characterization of the TLR7 pathway was performed demonstrating a decrease in mRNA levels in the IFNα, IFNγ, RSAD2, ACOD1, IFIT2, and CXCL10 genes.

Within the GEN-COVID Multicenter Study, biospecimens from more than 1000 SARS-CoV-2 positive individuals have thus far been collected in the GEN-COVID Biobank (GCB). Sample types include whole blood, plasma, serum, leukocytes, and DNA. The GCB links samples to detailed clinical data available in the GEN-COVID Patient Registry (GCPR). It includes hospitalized patients (74.25%), broken down into intubated, treated by CPAP-biPAP, treated with O2 supplementation, and without respiratory support (9.5%, 18.4%, 31.55% and 14.8, respectively); and non-hospitalized subjects (25.75%), either pauci- or asymptomatic. More than 150 clinical patient-level data fields have been collected and binarized for further statistics according to the organs/systems primarily affected by COVID-19: heart, liver, pancreas, kidney, chemosensors, innate or adaptive immunity, and clotting system. Hierarchical clustering analysis identified five main clinical categories: (1) severe multisystemic failure with either thromboembolic or pancreatic variant; (2) cytokine storm type, either severe with liver involvement or moderate; (3) moderate heart type, either with or without liver damage; (4) moderate multisystemic involvement, either with or without liver damage; (5) mild, either with or without hyposmia. GCB and GCPR are further linked to the GCGDR, which includes data from whole-exome sequencing and high-density SNP genotyping. The data are available for sharing through the Network for Italian Genomes, found within the COVID-19 dedicated section. The study objective is to systematize this comprehensive data collection and begin identifying multi-organ involvement in COVID-19, defining genetic parameters for infection susceptibility within the population, and mapping genetically COVID-19 severity and clinical complexity among patients.

Clinical and molecular characterization by Whole Exome Sequencing (WES) is reported in 35 COVID-19 patients attending the University Hospital in Siena, Italy, from April 7 to May 7, 2020. Eighty percent of patients required respiratory assistance, half of them being on mechanical ventilation. Fiftyone percent had hepatic involvement and hyposmia was ascertained in 3 patients. Searching for common genes by collapsing methods against 150 WES of controls of the Italian population failed to give straightforward statistically significant results with the exception of two genes. This result is not unexpected since we are facing the most challenging common disorder triggered by environmental factors with a strong underlying heritability (50%). The lesson learned from Autism-Spectrum-Disorders prompted us to re-analyse the cohort treating each patient as an independent case, following a Mendelian-like model. We identified for each patient an average of 2.5 pathogenic mutations involved in virus infection susceptibility and pinpointing to one or more rare disorder(s). To our knowledge, this is the first report on WES and COVID-19. Our results suggest a combined model for COVID-19 susceptibility with a number of common susceptibility genes which represent the favorite background in which additional host private mutations may determine disease progression.

The class of diamino-naphthalene exhibits antioxidant properties, which are partly related to the relative positions of the two amino groups. This study demonstrates how the reactivity of one of these compounds, 1,5-diamino-naphthalene (DAN), can be adjusted by introducing a single amide bond through a simple thermal coupling with l-pyroglutamic acid (PyroGlu). The solventless thermal reaction between PyroGlu and DAN at 160 °C yielded a new mono-pyroglutanilide compound (PyroDAN) that was characterized using various analytical techniques, including a thermal and infrared analysis, HRMS (ESI), and one- (1D) and two-dimensional (2D) NMR. The optical properties were investigated using UV-Vis and fluorescence spectroscopy. Additionally, two chemical standard assays were used to measure both the antioxidant and pro-oxidant properties of PyroDAN. The molecule has shown nearly negligible pro-oxidant activity, while a mild antioxidant activity is still retained. These findings indicate that the transformation of DAN into a mono-pyroglutanilide derivative breaks the original molecular symmetry and effectively modifies the electronic distribution of the aromatic system, suppressing the oxidant properties while keeping a mild antioxidant activity. Furthermore, the tuneable fluorescent properties of PyroDAN—the mild antioxidant activity and the inhibition of the cytologically harmful pro-oxidant properties—suggest promising applications in bioimaging and other biological fields.

The role of prophylactic central lymph node dissection (pCLND) in the treatment of differentiated thyroid cancer (DTC) is controversial and still a matter of debate. The primary outcome of our study was to assess whether pCLND is effective in reducing the incidence of recurrent disease, and the secondary goal was to estimate the incidence of postoperative complications in patients who underwent pCLND and to evaluate the prognostic value of occult node metastases. In this retrospective study, we included patients with preoperative diagnosis of DTC and clinically uninvolved lymph nodes (cN0). The patients were divided into two groups, depending on the surgical approach: total thyroidectomy alone (TT group) or total thyroidectomy and pCLND (pCLND group). Three hundred and ninety-nine patients were included in this study, 320 (80.2%) in the TT group and 79 (19.8%) in the pCLND group. There were no significant differences in morbidity among the two groups. Histopathological evaluation demonstrated a similar distribution of aggressive features, especially regarding multicentricity, extrathyroidal extension, and angioinvasivity between the two groups. Occult lymph node metastases were found in 20 (25.3%) patients in the pCLND group. Prophylactic CLND was effective in improving disease-free survival in patients with intermediate and high risk of disease recurrence (p = 0.0392); occult lymph node metastases resulted as a significant negative prognostic factor (p < 0.001).

The emergence of SARS-CoV-2 variants requires close monitoring to prevent the reoccurrence of a new pandemic in the near future. The Omicron variant, in particular, is one of the fastest-spreading viruses, showing a high ability to infect people and evade neutralization by antibodies elicited upon infection or vaccination. Therefore, the search for broad-spectrum antivirals that can inhibit the infectious capacity of SARS-CoV-2 is still the focus of intense research. In the present work, hyperbranched poly-L-lysine nanopolymers, which have shown an excellent ability to block the original strain of SARS-CoV-2 infection, were modified with L-arginine. A thermal reaction at 240 °C catalyzed by boric acid yielded Lys-Arg hyperbranched nanopolymers. The ability of these nanopolymers to inhibit viral replication were assessed for the original, Delta, and Omicron strains of SARS-CoV-2 together with their cytotoxicity. A reliable indication of the safety profile and effectiveness of the various polymeric compositions in inhibiting or suppressing viral infection was obtained by the evaluation of the therapeutic index in an in vitro prevention model. The hyperbranched L-arginine-modified nanopolymers exhibited a twelve-fold greater therapeutic index when tested with the original strain. The nanopolymers could also effectively limit the replication of the Omicron strain in a cell culture.

The outbreak of the SARS-COVID-2 pandemic (COVID-19) had a significant effect on the organisation of healthcare systems. Surgical units saw a significant reduction in the volume of surgical procedures performed, with lengthening waiting lists as a consequence. We assessed the surgical activity in relation to breast cancer that took place at the University Hospital of Cagliari, Italy, from February 2018 to March 2022. Two phases were identified based on the epidemiological circumstances: Phase 1—February 2018 to February 2020; Phase 2—March 2020 to March 2022. The surgery performed in the two phases was then compared. All the patients in our sample underwent a breast surgical procedure involving a lymph node biopsy using OSNA associated with the ACOSOG Z0011 criteria. In the study period overall at our facility, there were 4214 procedures, 417 of which involved breast surgery. In Phase 2, 91 procedures were performed using the OSNA method and ACOSOG Z0011 criteria, enabling the intraoperative staging of axillary nodes. Axillary treatment in breast cancer using this approach resulted in a significant reduction in the number of reoperations for the radicalisation of metastatic sentinel lymph nodes.