Rare genetic variants of NLRP12 in Admixed Latino-American Children with SARS-CoV-2-related Multisystem Inflammatory Syndrome.

Multisystem Inflammatory Syndrome in Children (MIS-C) is a rare, potentially fatal complication of SARS-CoV-2 infection. Genetic defects in inflammation-related pathways have been linked to MIS-C, but additional research is needed, especially in diverse ethnic groups. The present study aimed to identify genetic variants underlying MIS-C in Brazilian patients. Whole-exome sequencing was performed, focusing on genes involved in the host immune response to SARS-CoV-2. Functional assays assessed the impact of selected variants on NF-κB signaling. Nine rare, potentially deleterious variants were found in eight of 21 patients, located in IL17RC, IFNA10, or NLRP12 genes. Unlike the wild-type NLRP12 protein, which inhibits NF-κB activation in HEK 293T cells, the mutant NLRP12 proteins have significantly reduced inhibitory properties. In conclusion, our results indicate that rare autosomal variants in immune-related genes may underlie MIS-C, highlighting the potential role of NLRP12 in its predisposition. These findings provide new insights for the appropriate management of MIS-C.

Role of Interleukin-22 in chronic liver injury.

Liver fibrosis is the result of an exacerbated wound-healing response associated with chronic liver injury. Advanced liver fibrosis results in cirrhosis, liver failure, and portal hypertension and frequently requires liver transplantation. The host immune response has an important role driving fibrosis deposition by activating hepatic stellate cells (HSCs). Interleukin-22 (IL-22) is a cytokine that plays a key role in promoting antimicrobial immunity and tissue repair at barrier surfaces. Data from literature suggest that IL-22 has a protective role in the liver by reducing fibrosis in some pathological conditions, however the results are contradictory. This review highlights current knowledge of IL-22' role in chronic liver injury, as well as its therapeutic potential for the treatment of chronic liver injury.

Association of Catalase and Glutathione Peroxidase 1 Polymorphisms with Chronic Hepatitis C Outcome.

The hepatic damage caused by hepatitis C virus (HCV) infection is associated with the host immune response and viral regulatory factors. Catalase (CAT) and glutathione peroxidase 1 (GPX1) are antioxidant enzymes located in the peroxisomes and mitochondria, respectively, and are responsible for the control of intracellular hydrogen peroxide levels. Polymorphisms in CAT (C-262T) and GPX1 (Pro198Leu) are correlated with serum levels and enzyme activity. This study aimed to investigate the association of genetic polymorphisms of CAT C-262T (rs1001179) and GPX1 Pro198Leu (rs1050450) with different stages of liver fibrosis and development of hepatocellular carcinoma (HCC). This study included 445 patients with chronic hepatitis C, of whom 139 patients had mild fibrosis (F0-F1), 200 had moderate/severe fibrosis (F2-F4), and 106 had HCC. Genotyping of SNPs was performed by real-time PCR using TaqMan probes. The Pro/Pro genotype of GPX1 was significantly associated with fibrosis severity, HCC, Child Pugh score, and BCLC staging. Additionally, patients carrying both CT+TT genotypes in the CAT gene and the Pro/Pro genotype in the GPX1 gene had higher risk for developing moderate/severe fibrosis or HCC (p = 0.009, OR 2.40 and p = 0.002, OR 3.56, respectively). CAT and GPX1 polymorphisms may be implicated in the severity of liver fibrosis and HCC caused by HCV.

IL-22 and IL-22 binding protein (IL-22BP) regulate fibrosis and cirrhosis in hepatitis C virus and schistosome infections.

UNLABELLED: Interleukin (IL)-22 acts on epithelia, hepatocytes, and pancreatic cells and stimulates innate immunity, tissue protection, and repair. IL-22 may also cause inflammation and abnormal cell proliferation. The binding of IL-22 to its receptor is competed by IL-22 binding protein (IL-22BP), which may limit the deleterious effects of IL-22. The role of IL-22 and IL-22BP in chronic liver diseases is unknown. We addressed this question in individuals chronically infected with schistosomes or hepatitis C virus (HCV). We first demonstrate that schistosome eggs stimulate production of IL-22 transcripts and inhibit accumulation of IL22-BP transcripts in schistosome-infected mice, and that schistosome eggs selectively stimulate production of IL-22 in cultures of blood leukocytes from individuals chronically infected with Schistosoma japonicum. High IL-22 levels in cultures correlated with protection against hepatic fibrosis and portal hypertension. To test further the implication of IL-22/IL-22BP in hepatic disease, we analyzed common genetic variants of IL22RA2, which encodes IL-22BP, and found that the genotypes, AA, GG of rs6570136 (P = 0.003; odds ratio [OR] = 2), and CC, TT of rs2064501 (P = 0.01; OR = 2), were associated with severe fibrosis in Chinese infected with S. japonicum. We confirmed this result in Sudanese (rs6570136 GG [P = 0.0007; OR = 8.2], rs2064501 TT [P = 0.02; OR = 3.1]), and Brazilians (rs6570136 GG [P = 0.003; OR = 26], rs2064501 TC, TT (P = 0.03; OR = 11]) infected with S. mansoni. The aggravating genotypes were associated with high IL22RA2 transcripts levels. Furthermore, these same variants were also associated with HCV-induced fibrosis and cirrhosis (rs6570136 GG, GA [P = 0.007; OR = 1.7], rs2064501 TT, TC (P = 0.004; OR = 2.4]). CONCLUSIONS: These results provide strong evidence that IL-22 protects against and IL-22BP aggravates liver fibrosis and cirrhosis in humans with chronic liver infections. Thus, pharmacological modulation of IL-22 BP may be an effective strategy to limit cirrhosis.

Temporal and spatial trends in human visceral leishmaniasis in an endemic area in Northeast Brazil and their association with social vulnerability.

BACKGROUND: Visceral leishmaniasis is a neglected tropical disease of great importance to public health due to its wide distribution and close relationship with social and economic conditions. This study aimed to analyse the spatiotemporal dynamics of human visceral leishmaniasis (HVL) in an endemic state in the Northeast Region of Brazil and its spatial correlation with the Social Vulnerability Index (SVI) and the Municipal Human Development Index (MHDI). METHODS: The study included all confirmed cases of HVL in Bahia from 2010 to 2017. A joinpoint regression model was used for trend analysis. Incidence rates were smoothed by a local empirical Bayesian model. Global and local Moran indices and space-time scan statistics were used for identification of spatial clusters. Bivariate and multivariate analyses were carried out to investigate the relationship between HVL incidence and the SVI and MHDI. RESULTS: Cases of HVL demonstrated stationary behaviour during the period analysed. A significant association was observed between the HVL incidence rate and social vulnerability, with high-risk clusters concentrated in the central region of the state. CONCLUSIONS: HVL has a strong correlation with social vulnerability in the state of Bahia. This study may provide assistance in planning actions and organizing health services to combat HVL.

Methylene tetrahydrofolate reductase (MTHFR) and vascular endothelial growth factor (VEGF) polymorphisms in Brazilian patients with Hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC).

OBJECTIVE: The folate pathway is involved in hepatic carcinogenesis and angiogenesis. Polymorphisms in genes related to such processes, including methylene tetrahydrofolate reductase (MTHFR) and vascular endothelial growth factor (VEGF)] may play an important role in the development of hepatocellular carcinoma (HCC). The objective of this study was to evaluate MTHFR and VEGF polymorphisms in Brazilian patients with hepatitis C virus (HCV)-related HCC. METHODS: A total of 119 patients diagnosed with confirmed HCC and HCV were included in the study. SNP genotyping assays were performed using real-time PCR. VEGFA (rs2010963, rs3025039, and rs833061) and MTHFRC677T (rs1801133, rs1801131) polymorphisms were evaluated. RESULTS: The C alleles of MTHFR (rs1801131) and VEGF (rs2010963) were associated with protection against the development of multinodular HCC, while the T allele of MTHFR (rs1801133) was associated with a higher risk of multinodular presentation [p=0.04 OR 1.835 CI (1.022-3.297)]. Multivariate analysis revealed that the GG/GC genotypes of VEGF rs2010963 were independently associated with multinodular tumors at diagnosis (p=0.013; OR 4.78 CI (1.38-16.67)]. CONCLUSION: Our results suggest that these polymorphisms may increase the risk of rapid tumor progression in patients with HCV infection. This subgroup of patients with HCC and who present polymorphism is more likely to be diagnosed with multinodular disease and not be amenable to receiving curative treatments. These data must be validated in larger cohorts, and the screening intervals can be customized based on genetic history.

Analysis of spatial clustering, time trend, social vulnerability and risk of human visceral leishmaniasis in an endemic area in Brazil: an ecological study.

BACKGROUND: More than 95% of visceral leishmaniasis (VL) cases in Latin America occur in Brazil, most of them in the northeast. The objective of this study was to identify spatial clusters with the highest risks of VL and to analyse the temporal behaviour of the incidence and the effects of social vulnerability on the disease transmission dynamic in northeastern Brazil. METHODS: All confirmed cases registered as residents in the state of Pernambuco during the period from 2007 to 2017 were analysed. The local empirical Bayesian method was applied and the association -between the VL incidence rate and municipal social vulnerability was tested via classic multivariate regression. RESULTS: A total of 1186 new cases were registered during the study period. Spatial analysis showed heterogeneous distribution, with the highest rates observed in the São Francisco and Sertão mesoregions. Moreover, the main factors associated with VL were urban infrastructure, income and work. CONCLUSIONS: It was observed that spatial and temporal techniques are important tools for defining risk areas for VL, in conjunction with the evaluation of indexes of social vulnerability, which was shown to be an important factor for comprehending associations with VL in the state of Pernambuco.

Spatiotemporal clustering, social vulnerability and risk of congenital syphilis in northeast Brazil: an ecological study.

BACKGROUND: To investigate the spatial distribution of congenital syphilis (CS) and its association to social vulnerability indexes in northeast Brazil. METHODS: This was an ecological study referring to all cases of CS and CS deaths recorded in the northeast region of Brazil from 2008 to 2015. Data were obtained from three Brazilian information systems. We examined statistical correlations between CS indicators by state and municipality and their socioeconomic and social vulnerability characteristics. We used Bayesian empirical local models to identify fluctuations of the indicators. Spatial statistical tests were used to identify spatial clusters and the municipalities at high risk of CS. RESULTS: The incidence of CS ranged from 2.1 cases/1000 live births (LB) in 2008 to 6.9/1000 LB in 2015, with an annual increase of 19.9% (p < 0.001). The mortality coefficient of CS ranged from 2.9/1000 LB in 2008 to 6.5/1000 LB in 2015, resulting in an annual increase of 15.1% (p < 0.001). Nine spatial clusters were identified. Cases of congenital syphilis occurred in well-defined spatiotemporal clusters and in areas with high levels of social vulnerability. CONCLUSIONS: CS incidence is associated with social vulnerability. CS control programmes should target spatial clusters and populations with high levels of social vulnerability.

Case Report: Severe Visceral Leishmaniasis in a Patient with HIV Coinfection Undergoing Treatment for Erythema Nodosum Leprosum.

We report a case of visceral leishmaniasis (VL)/HIV coinfection in a patient undergoing regular antiretroviral therapy and treatment with thalidomide for erythema nodosum leprosum. He presented at a health service with high fever, chills, asthenia, pale skin, lower limb edema, hepatomegaly, and splenomegaly. Visceral leishmaniasis was confirmed by direct examination, and serological and molecular tests. Serum levels of Th1/Th2 cytokines were measured. The patient began treatment with liposomal amphotericin B, with good clinical response; however, VL recurred 6 months later. Treatment was reinitiated, maintaining secondary prophylaxis with liposomal amphotericin B. The patient showed clinical improvement with important recovery of CD4+ T-lymphocyte count.

Clinical manifestations and factors associated with mortality from COVID-19 in older adults: Retrospective population-based study with 9807 older Brazilian COVID-19 patients.

AIM: Older adults are the main risk group for coronavirus disease 2019 (COVID-19). This study aimed to describe the clinical manifestations and factors associated with mortality from COVID-19 among older adults in Brazil. METHODS: A cross-sectional observational study was carried out with data from 9807 cases of COVID-19 among older adults in the state of Alagoas, Brazil. We determined the case fatality rate between age groups and clinical factors associated with mortality. RESULTS: A total of 52.5% (n = 5145) were women, and with an average age of 70.21 ± 8.37 years. The fatality rate was 11.9%, with a higher rate in men (14.4%) compared with women (9.8%). The fatality rate increased with age. The most common manifestations were fever (n = 4926; 50.2%), cough (n = 5737; 58.5%), headache (n = 1980; 20.2%) and fatigue (n = 2022; 20.6%). The most prevalent comorbidities were diabetes (n = 1528; 5.6%), cardiovascular disease (n = 1528; 15.6%) and systemic arterial hypertension (n = 597; 6.1%). The factors associated with mortality were male sex (OR 1.54), age ≥75 years (OR 2.40), dyspnea (OR 2.92), diabetes (OR 2.33), hypertension (OR 1.53) and chronic kidney disease (OR 2.02). CONCLUSIONS: The profile and the risk factors evidenced show the need to adopt mechanisms to protect the elderly population.

Mannose-binding lectin gene (MBL2) polymorphisms related to the mannose-binding lectin low levels are associated to dengue disease severity.

Dengue is the main arbovirosis in the tropical and subtropical areas of the world. The majority of infected individuals present an asymptomatic outcome while others progress to dengue fever (DF) or dengue haemorrhagic fever (DHF). Dengue infection evolution to severe outcomes is in part, related to innate immunity response. The MBL2 gene encodes for a pathogen recognition pattern molecule, the mannose-binding lectin (MBL). Variant alleles at promoter and structural regions of the MBL2 are related to serum MBL levels and function. Due to the important inflammatory modulation role of MBL, MBL2 polymorphisms could influence dengue progression. Therefore, this study investigated associations of MBL2 polymorphisms and serum MBL levels in patients with dengue. Genotyping of promoter and structural regions of MBL2 was performed by real-time PCR using Taqman® probes in 161 patients presenting DF or DHF outcome. For the serum MBL determination a commercial ELISA kit was used. The variant OO genotype and O allele were associated with DHF (p=0.008 and p=0.009 respectively). Haplotypes correlated to MBL low levels were associated with DHF (p=0.04). Our results support the hypothesis that patients carrying genotypes or haplotypes of low production of MBL would be more susceptible to DHF.

Methylene tetrahydrofolate reductase (MTHFR) and vascular endothelial growth factor (VEGF) polymorphisms in Brazilian patients with Hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC)

OBJECTIVE: The folate pathway is involved in hepatic carcinogenesis and angiogenesis. Polymorphisms in genes related to such processes, including methylene tetrahydrofolate reductase (MTHFR) and vascular endothelial growth factor (VEGF)] may play an important role in the development of hepatocellular carcinoma (HCC). The objective of this study was to evaluate MTHFR and VEGF polymorphisms in Brazilian patients with hepatitis C virus (HCV)-related HCC. METHODS: A total of 119 patients diagnosed with confirmed HCC and HCV were included in the study. SNP genotyping assays were performed using real-time PCR. VEGFA (rs2010963, rs3025039, and rs833061) and MTHFRC677T (rs1801133, rs1801131) polymorphisms were evaluated. RESULTS: The C alleles of MTHFR (rs1801131) and VEGF (rs2010963) were associated with protection against the development of multinodular HCC, while the T allele of MTHFR (rs1801133) was associated with a higher risk of multinodular presentation [p=0.04 OR 1.835 CI (1.022-3.297)]. Multivariate analysis revealed that the GG/GC genotypes of VEGF rs2010963 were independently associated with multinodular tumors at diagnosis (p=0.013; OR 4.78 CI (1.38-16.67)]. CONCLUSION: Our results suggest that these polymorphisms may increase the risk of rapid tumor progression in patients with HCV infection. This subgroup of patients with HCC and who present polymorphism is more likely to be diagnosed with multinodular disease and not be amenable to receiving curative treatments. These data must be validated in larger cohorts, and the screening intervals can be customized based on genetic history.

High frequency of variant alleles of the mannose-binding lectin 2 (MBL2) gene are associated with patients infected by hepatitis B virus.

Patients with hepatitis B virus (HBV) infection may develop severe chronic liver disease. Carriers of HBV have an increased risk of developing cirrhosis, hepatic decompensation, and hepatocellular carcinoma. Worldwide an estimated 350 million people are infected with HBV, and 15-40% will develop serious sequelae in their lifetime. In our study we investigated the association of single nucleotide polymorphisms (SNPs) in the first exon and promoter region of the mannose-binding lectin gene 2 (MBL2) situated on chromosome 10, with susceptibility to HBV infection. One-hundred and two patients infected with HBV were included in this study, and 232 uninfected individuals were used as healthy controls. Genotyping of the first exon (alleles A/O) was performed using a melting temperature assay. Genotyping of the promoter region (-550 H/L; -221 Y/X) was performed using the Taqman PCR technique. In the HBV-infected group we found a significantly increased frequency of haplotypes associated with low serum MBL. Our findings may indicate that MBL has a protective role against HBV infection in the studied population.