Rare genetic variants involved in multisystem inflammatory syndrome in children: a multicenter Brazilian cohort study

IntroductionDespite the existing data on the Multisystem Inflammatory Syndrome in Children (MIS-C), the factors that determine these patients evolution remain elusive. Answers may lie, at least in part, in genetics. It is currently under investigation that MIS-C patients may have an underlying innate error of immunity (IEI), whether of monogenic, digenic, or even oligogenic origin.MethodsTo further investigate this hypothesis, 30 patients with MIS-C were submitted to whole exome sequencing. ResultsAnalyses of genes associated with MIS-C, MIS-A, severe covid-19, and Kawasaki disease identified twenty-nine patients with rare potentially damaging variants (50 variants were identified in 38 different genes), including those previously described in IFNA21 and IFIH1 genes, new variants in genes previously described in MIS-C patients (KMT2D, CFB, and PRF1), and variants in genes newly associated to MIS-C such as APOL1, TNFRSF13B, and G6PD. In addition, gene ontology enrichment pointed to the involvement of thirteen major pathways, including complement system, hematopoiesis, immune system development, and type II interferon signaling, that were not yet reported in MIS-C.DiscussionThese data strongly indicate that different gene families may favor MIS- C development. Larger cohort studies with healthy controls and other omics approaches, such as proteomics and RNAseq, will be precious to better understanding the disease dynamics

The C-Terminal Acidic Tail Modulates the Anticancer Properties of HMGB1

Energy metabolism reprogramming was recently listed as a hallmark of cancer. In this process, the switch from pyruvate kinase isoenzyme type M1 to pyruvate kinase isoenzyme type M2 (PKM2) is believed to play a crucial role. Interestingly, the activity of the active form of PKM2 can efficiently be inhibited by the high-mobility group box 1 (HMGB1) protein, leading to a rapid blockage of glucose-dependent aerobic respiration and cancer cell death. HMGB1 is a member of the HMG protein family. It contains two DNA-binding HMG-box domains and an acidic C-terminal tail capable of positively or negatively modulating its biological properties. In this work, we report that the deletion of the C-terminal tail of HMGB1 increases its activity towards a large panel of cancer cells without affecting the viability of normal immortalized fibroblasts. Moreover, in silico analysis suggests that the truncated form of HMGB1 retains the capacity of the full-length protein to interact with PKM2. However, based on the capacity of the cells to circumvent oxidative phosphorylation inhibition, we were able to identify either a cytotoxic or cytostatic effect of the proteins. Together, our study provides new insights in the characterization of the anticancer activity of HMGB1

Mitigation of Socio-Economical Inequalities on the Profile of Healthcare Workers Infected with SARS-CoV-2 upon Vaccination: The Experience of a Brazilian Public Healthcare Institution during the Omicron Wave

Background: COVID-19 increased health inequalities worldwide. Even among healthcare workers, social-economical features enhanced the risk of infection (having positive serology) during the first outbreak. The Omicron variant changed the pandemic course and differs from previous variants in many aspects (molecular, clinical, and epidemiological). Herein, we investigated if the profile of our hospital SARS-CoV-2-positive workers during the Omicron outbreak was the same as the first COVID-19 wave. Methods: Socio-demographics, previous infection, and vaccine status of 351 healthcare workers from our institution during the Omicron outbreak were compared between SARS-CoV-2-negative and -positive workers, using chi-square tests. These data were confronted with the profile observed at the beginning of the pandemic. Results: Compared to the original COVID-19 wave, higher odds of SARS-CoV-2 positivity in highly exposed workers in our hospital and a loss of impact of public transportation and other socio-demographic features in SARS-CoV-2 transmission were observed. Conclusions: Our data suggest the current phase of the pandemic is associated with a reduction of social inequalities among healthcare workers in Rio de Janeiro, possibly due to vaccine-associated protection. Therefore, a worldwide effort to advance vaccination coverage, especially for healthcare workers in developing countries, should be reinforced

Mitigation of Socio-Economical Inequalities on the Profile of Healthcare Workers Infected with SARS-CoV-2 upon Vaccination: The Experience of a Brazilian Public Healthcare Institution during the Omicron Wave

Background: COVID-19 increased health inequalities worldwide. Even among healthcare workers, social-economical features enhanced the risk of infection (having positive serology) during the first outbreak. The Omicron variant changed the pandemic course and differs from previous variants in many aspects (molecular, clinical, and epidemiological). Herein, we investigated if the profile of our hospital SARS-CoV-2-positive workers during the Omicron outbreak was the same as the first COVID-19 wave. Methods: Socio-demographics, previous infection, and vaccine status of 351 healthcare workers from our institution during the Omicron outbreak were compared between SARS-CoV-2-negative and -positive workers, using chi-square tests. These data were confronted with the profile observed at the beginning of the pandemic. Results: Compared to the original COVID-19 wave, higher odds of SARS-CoV-2 positivity in highly exposed workers in our hospital and a loss of impact of public transportation and other socio-demographic features in SARS-CoV-2 transmission were observed. Conclusions: Our data suggest the current phase of the pandemic is associated with a reduction of social inequalities among healthcare workers in Rio de Janeiro, possibly due to vaccine-associated protection. Therefore, a worldwide effort to advance vaccination coverage, especially for healthcare workers in developing countries, should be reinforced