Lead Exposure during Early Human Development and DNA Methylation of Imprinted Gene Regulatory Elements in Adulthood

BACKGROUND: Lead exposure during early development causes neurodevelopmental disorders by unknown mechanisms. Epidemiologic studies have focused recently on determining associations between lead exposure and global DNA methylation; however, such approaches preclude the identification of loci that may alter human disease risk. OBJECTIVES: The objective of this study was to determine whether maternal, postnatal, and early childhood lead exposure can alter the differentially methylated regions (DMRs) that control the monoallelic expression of imprinted genes involved in metabolism, growth, and development. METHODS: Questionnaire data and serial blood lead levels were obtained from 105 participants (64 females, 41 males) of the Cincinnati Lead Study from birth to 78 months. When participants were adults, we used Sequenom EpiTYPER assays to test peripheral blood DNA to quantify CpG methylation in peripheral blood leukocytes at DMRs of 22 human imprinted genes. Statistical analyses were conducted using linear regression. RESULTS: Mean blood lead concentration from birth to 78 months was associated with a significant decrease in PEG3 DMR methylation (β = -0.0014; 95% CI: -0.0023, -0.0005, p = 0.002), stronger in males (β = -0.0024; 95% CI: -0.0038, -0.0009, p = 0.003) than in females (β = -0.0009; 95% CI: -0.0020, 0.0003, p = 0.1). Elevated mean childhood blood lead concentration was also associated with a significant decrease in IGF2/H19 (β = -0.0013; 95% CI: -0.0023, -0.0003, p = 0.01) DMR methylation, but primarily in females, (β = -0.0017; 95% CI: -0.0029, -0.0006, p = 0.005) rather than in males, (β = -0.0004; 95% CI: -0.0023, 0.0015, p = 0.7). Elevated blood lead concentration during the neonatal period was associated with higher PLAGL1/HYMAI DMR methylation regardless of sex (β = 0.0075; 95% CI: 0.0018, 0.0132, p = 0.01). The magnitude of associations between cumulative lead exposure and CpG methylation remained unaltered from 30 to 78 months. CONCLUSIONS: Our findings provide evidence that early childhood lead exposure results in sex-dependent and gene-specific DNA methylation differences in the DMRs of PEG3, IGF2/H19, and PLAGL1/HYMAI in adulthood. CITATION: Li Y, Xie C, Murphy SK, Skaar D, Nye M, Vidal AC, Cecil KM, Dietrich KN, Puga A, Jirtle RL, Hoyo C. 2016. Lead exposure during early human development and DNA methylation of imprinted gene regulatory elements in adulthood. Environ Health Perspect 124:666-673; http://dx.doi.org/10.1289/ehp.1408577

Intervenção com ivermectina para COVID-19 (SARS-Cov 2): sinopse baseada em evidências

Context: COVID-19 is a viral disease that has recently emerged and is associated with severe respiratory distress syndrome (SARS). Its potential for severity and impact on the health of the population and the global economy is a prime object in the search for effective therapy and ivermectin has been recommended for prevention and treatment. Objective: To evaluate the evidence in the literature regarding the use of ivermectin for the prevention and treatment of cases of COVID-19. Study design: This is a synopsis of evidence. Methods: We searched the electronic databases PubMed (1966-2021), EMBASE (1974-2021) and Clinical Trials (2021) and two evidence megabusers: Turning Research Into Practice (TRIP) database (2021) and Epstemonikos (2021). There was no geographic or language restriction, using DeCS descriptors and terms (Health Sciences Descriptors). The synthesis method involved the combination of similar studies in a narrative review. Results: 527 citations were identified and 5 studies were included. There are few completed clinical trials, all of which have a small sample size. Discussion: Most of the studies available in the literature are based on in vitro therapeutic responses and the recommendation for use in humans has been based on the findings of these studies. The question cannot be answered with current studies, and quality clinical trials are recommended. Conclusions: There is currently no support in the literature for the use of ivermectin in the prevention or treatment of COVID-19.Contexto: A COVID-19 é uma doença viral que surgiu recentemente e associada à síndrome da angústia respiratória severa (SARS). Seu potencial de gravidade e impacto na saúde da população e economia global é objeto primordial na busca por uma terapêutica eficaz ea ivermectina tem sido recomendada para prevenção e tratamento da COVID-19. Objetivo: avaliar como evidências na literatura relativa ao uso de ivermectina para prevenção e tratamento de casos de COVID-19. Desenho de estudo: Trata-se de sinopse de evidências. Métodos:Procedeu-se à busca de bases eletrônicas de dados PubMed (1966-2021), EMBASE (1974-2021) e Clinical Trials (2021) e em dois megabuscadores de evidências: Turning Research Into Practice (TRIP) database (2021) e Epstemonikos ( 2021). Não houve restrição geográfica e de idioma, sendo utilizados descritores e termos do DeCS (Descritores em Ciências da Saúde). O método de síntese envolveu uma combinação de estudos semelhantes em uma revisão narrativa. Resultados: Foram identificados 527 citações e 5 estudos foram incluídos. Há poucos ensaios clínicos concluídos todos apresentam pequena. Discussão: A maioria dos estudos disponíveis na literatura respalda-se em respostas terapêuticas in vitroea recomendação para uso em humanos tem-se baseado nos achados desses estudos. A questão não pode ser respondida com os estudos atuais, sendo recomendada a realização de ensaios de qualidade. Conclusões: Não há suporte atualmente na literatura para uso da ivermectina na prevenção ou tratamento COVID-19

Estatinas para a progressão da estenose da valva aórtica e a melhor evidência para tomar decisões em saúde

In the Western world, calcified aortic valve stenosis is the most common form of valvular heart disease, affecting up to 3% of adults over the age of 75 years. It is a gradually progressive disease, characterized by a long asymptomatic phase that may last for several decades, followed by a short symptomatic phase associated with severe restriction of the valve orifice. Investigations on treatments for aortic valve stenosis are still in progress. Thus, it is believed that calcification of aortic valve stenosis is similar to the process of atherosclerosis that occurs in coronary artery disease. Recent studies have suggested that cholesterol lowering through the use of station may have a salutary effect on the progression of aortic valve stenosis.Fac Med Marilia Famema, Sao Paulo, BrazilUniv Fed Sao Paulo Escola Paulista Med Unifesp EP, Hosp Sao Paulo, Dept Emergency Serv, Sao Paulo, BrazilUniv Fed Sao Paulo Escola Paulista Med Unifesp EP, Hosp Sao Paulo, Emergency Intens Care Unit, Sao Paulo, BrazilBrazilian Cochrane Ctr, Sao Paulo, BrazilUniv Fed Sao Paulo Escola Paulista Med Unifesp EP, Hosp Sao Paulo, Dept Emergency Serv, Sao Paulo, BrazilUniv Fed Sao Paulo Escola Paulista Med Unifesp EP, Hosp Sao Paulo, Emergency Intens Care Unit, Sao Paulo, BrazilWeb of Scienc

Pharmacological interventions for COVID-19: Protocol for a Rapid Living Systematic Review with network meta-analysis

CONTEXT AND OBJECTIVE: Coronavirus disease 2019 (COVID-19) has emerged in China in December 2019 and rapidly spread. Although extraordinary efforts have been made on research regarding pharmacological interventions, none have proven effective. This is the protocol for a rapid living systematic review that aims to compare the effectiveness and safety of different pharmacological interventions for the treatment of COVID-19. METHODS: rapid living systematic review methodology with Network Meta-Analysis following the recommendations of Cochrane Handbook. We will include randomized controlled trials (RCT) and quasi-RCTs that evaluate single and/or combined pharmacological interventions at any dose for the treatment of COVID-19. We will search Medline via PubMed, Embase via Elsevier, Cochrane Library - Cochrane Central Register of Controlled Trials (CENTRAL), Portal Regional BVS - LILACS, Scopus and WebofScience to identify potentially eligible studies. No language restrictions will be used in the selection. We will perform the critical appraisal of included studies with the Risk of Bias tool and the certainty of evidence will be evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE)

Telehealth interventions in the context of the COVID-19 pandemic: Protocol for a scoping review

CONTEXT AND OBJECTIVE: The current health crisis due to COVID-19 is forcing us to profoundly rethink our social organizations and practices in health. While there is no effective treatment for the virus, staying home and social isolation are the control measures recommended by health authorities. The aim of this study is to perform a scoping review in order to summarize the current evidence in telehealth for COVID-19. METHODS: This study is a protocol to describe the rationale, hypothesis and planned methods of our scoping review. We will include randomized controlled trials (RCTs), observational cohort studies, case-control studies, cross-sectional studies, qualitative studies, and/or case series that describe telehealth interventions applied or developed to respond to COVID-19. We will search Medline via PubMed, Embase via Elsevier, Cochrane Library - Cochrane Central Register of Controlled Trials (CENTRAL), Portal Regional BVS - LILACS, and Scopus. We will include studies performed since December 2019 with no language restrictions. We will use the Risk of Bias tool and the Newcastle-Ottawa Scale to perform the critical appraisal of included studies. We will assess the certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE)

PROGNOSTIC FACTORS FOR CLINICAL COURSE OF PATIENTS WITH COVID-19: PROTOCOL FOR A RAPID LIVING SYSTEMATIC REVIEW

CONTEXT AND OBJECTIVE: Determining prognostic factors in a context of health crises such as the COVID-19 scenario may provide the best possible care for patients and optimize the management and the resource utilization of the health system. Thus, we aim to systematically review the prognostic factors for different outcomes of patients with COVID-19. DESIGN AND SETTING: Protocol for a rapid living systematic review methodology following the recommendations proposed by the Cochrane Handbook. METHODS: We will include cohorts and case‐control studies. We will search Medline via PubMed, Embase via Elsevier, Cochrane Library - Cochrane Central Register of Controlled Trials (CENTRAL), Portal Regional BVS- LILACS, Scopus and WebofScience to identify studies. No language restrictions will be applied. We will perform the critical appraisal of included studies with the Quality in Prognosis Studies (QUIPS) tool and the certainty of evidence will be evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE)

COVID-19 AND PATIENTS UNDERGOING PHARMACOLOGICAL TREATMENTS FOR IMMUNE-MEDIATED INFLAMMATORY DISEASES: PROTOCOL FOR A RAPID LIVING SYSTEMATIC REVIEW

CONTEXT AND OBJECTIVE: We propose to systematically review the available evidence to evaluate if patients with immune mediated or inflammatory diseases under pharmacological treatment with immunosuppressants, immunobiologics, DMARDs or targeted synthetic DMARDs have better or worse outcomes when infected by SARS-CoV-2. This study is a protocol for our rapid living systematic review. METHODS: Protocol for a rapid living systematic review methodology following the preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) guidance. To conduct the rapid systematic review, we will employ abbreviated systematic review methods, including: not performing independent screens of abstracts and not searching grey literature. As this will be a living review, it will be continuously updated

Heme oxygenase-1 induction by NRF2 requires inactivation of the transcriptional repressor BACH1

Oxidative stress activates the transcription factor NRF2, which in turn binds cis-acting antioxidant response element (ARE) enhancers and induces expression of protective antioxidant genes. In contrast, the transcriptional repressor BACH1 binds ARE-like enhancers in cells naïve to oxidative stress and antagonizes NRF2 binding until it becomes inactivated by pro-oxidants. Here, we describe the dynamic roles of BACH1 and NRF2 in the transcription of the heme oxygenase-1 (HMOX1) gene. HMOX1 induction, elicited by arsenite-mediated oxidative stress, follows inactivation of BACH1 and precedes activation of NRF2. BACH1 repression is dominant over NRF2-mediated HMOX1 transcription and inactivation of BACH1 is a prerequisite for HMOX1 induction. In contrast, thioredoxin reductase 1 (TXNRD1) is regulated by NRF2 but not by BACH1. By comparing the expression levels of HMOX1 with TXNRD1, we show that nuclear accumulation of NRF2 is not necessary for HMOX1 induction; rather, BACH1 inactivation permits NRF2 already present in the nucleus at low basal levels to bind the HMOX1 promoter and elicit HMOX1 induction. Thus, BACH1 confers an additional level of regulation to ARE-dependent genes that reveals a new dimension to the oxidative stress response