HLA haplotypes and differential regional mortality caused by COVID-19 in Brazil: an ecological study based on a large bone marrow donor bank dataset.

The coronavirus disease 2019 (COVID-19) mortality rates varied among the states of Brazil during the course of the pandemics. The human leukocyte antigen (HLA) is a critical component of the antigen presentation pathway. Individuals with different HLA genotypes may trigger different immune responses against pathogens, which could culminate in different COVID-19 responses. HLA genotypes are variable, especially in the highly admixed Brazilian population. In this ecological study, we aimed to investigate the correlation between HLA haplotypes and the different regional distribution of COVID-19 mortality in Brazil. HLA data was obtained from 4,148,713 individuals registered in The Brazilian Voluntary Bone Marrow Donors Registry. COVID-19 data was retrieved from epidemiological bulletins issued by State Health Secretariats via Brazil's Ministry of Health from February/2020 to July/2022. We found a positive significant correlation between the HLA-A*01~B*08~DRB1*03 haplotype and COVID-19 mortality rates when we analyzed data from 26 states and the Federal District. This result indicates that the HLA-A*01~B*08~DRB1*03 haplotype may represent an additional risk factor for dying due to COVID-19. This haplotype should be further studied in other populations for a better understanding of the variation in COVID-19 outcomes across the world.

Investigation of the impact of AXL, TLR3, and STAT2 in congenital Zika syndrome through genetic polymorphisms and protein-protein interaction network analyses.

INTRODUCTION: Zika virus (ZIKV) is a human teratogen that causes congenital Zika syndrome (CZS). AXL, TLR3, and STAT2 are proteins involved in the ZIKV's entry into cells (AXL) and host's immune response (TLR3 and STAT2). In this study, we evaluated the role of genetic polymorphisms in these three genes as risk factors to CZS, and highlighted which proteins that interact with them could be important for ZIKV infection and teratogenesis. MATERIALS AND METHODS: We evaluate eighty-eight children exposed to ZIKV during the pregnancy, 40 with CZS and 48 without congenital anomalies. The evaluated polymorphisms in AXL (rs1051008), TLR3 (rs3775291), and STAT2 (rs2066811) were genotyped using TaqMan® Genotyping Assays. A protein-protein interaction network was created in STRING database and analyzed in Cytoscape software. RESULTS: We did not find any statistical significant association among the polymorphisms and the occurrence of CZS. Through the analyses of the network composed by AXL, TLR3, STAT2 and their interactions targets, we found that EGFR and SRC could be important proteins for the ZIKV infection and its teratogenesis. CONCLUSION: In summary, our results demonstrated that the evaluated polymorphisms do not seem to represent risk factors for CZS; however, EGFR and SRC appear to be important proteins that should be investigated in future studies.

A New Strategy for the Old Challenge of Thalidomide: Systems Biology Prioritization of Potential Immunomodulatory Drug (IMiD)-Targeted Transcription Factors.

Several molecular mechanisms of thalidomide embryopathy (TE) have been investigated, from anti-angiogenesis to oxidative stress to cereblon binding. Recently, it was discovered that thalidomide and its analogs, named immunomodulatory drugs (IMiDs), induced the degradation of C2H2 transcription factors (TFs). This mechanism might impact the strict transcriptional regulation of the developing embryo. Hence, this study aims to evaluate the TFs altered by IMiDs, prioritizing the ones associated with embryogenesis through transcriptome and systems biology-allied analyses. This study comprises only the experimental data accessed through bioinformatics databases. First, proteins and genes reported in the literature as altered/affected by the IMiDs were annotated. A protein systems biology network was evaluated. TFs beta-catenin (CTNNB1) and SP1 play more central roles: beta-catenin is an essential protein in the network, while SP1 is a putative C2H2 candidate for IMiD-induced degradation. Separately, the differential expressions of the annotated genes were analyzed through 23 publicly available transcriptomes, presenting 8624 differentially expressed genes (2947 in two or more datasets). Seventeen C2H2 TFs were identified as related to embryonic development but not studied for IMiD exposure; these TFs are potential IMiDs degradation neosubstrates. This is the first study to suggest an integration of IMiD molecular mechanisms through C2H2 TF degradation.

Clusters of rare disorders and congenital anomalies in South America / Conglomerados de trastornos y malformaciones congénitas poco frecuentes en América del Sur / Agrupamentos de doenças raras e anomalias congênitas na América do Sul

ABSTRACT Objective. To map geographic clusters of rare disorders and congenital anomalies reported in South America. Methods. Qualitative systematic review conducted in Medline/PubMed, Lilacs, and Scielo electronic databases to identify studies meeting eligibility criteria. The strategy resulted in 1 672 unique articles, from which 164 were selected for full reading by a pair of reviewers. Results. Fifty-five articles reported at least one cluster of genetic disorders or congenital anomalies in South American territory. From these papers, 122 clusters were identified, of which half (61) were related to autosomal recessive disorders. Sixty-five (53.3%) of the clusters were located in Brazil. Conclusions. The results of the review reinforce that rare diseases and congenital anomalies can occur in a non-random way in space, which is discussed in the perspective of the complex history of formation, social organization, and genetic structure of the South American population. Mapping clusters in population medical genetics can be an important public health tool, given that such places concentrate cases of rare diseases that frequently require multiprofessional, specialized care. Therefore, these results can support important agendas in public health related to rare diseases and congenital anomalies, such as health promotion and surveillance.

RESUMEN Objetivo. Trazar los conglomerados geográficos de los trastornos y las malformaciones congénitas poco frecuentes notificados en América del Sur. Métodos. Se realizó una revisión sistemática cualitativa en las bases de datos electrónicas Medline/PubMed, Lilacs y Scielo para encontrar los estudios que cumplieran con los criterios de selección. Se encontraron 1672 artículos originales, de los que se seleccionaron 164 para su lectura completa por un par de revisores. Resultados. En 55 artículos se informó de al menos un conglomerado de trastornos genéticos o malformaciones congénitas en América del Sur. A partir de estos artículos, se encontraron 122 conglomerados, de los cuales la mitad (61) se asociaron con trastornos autosómicos recesivos. Sesenta y cinco (53,3%) de los conglomerados se ubicaron en Brasil. Conclusiones. Los resultados de la revisión confirman que las enfermedades raras y las malformaciones congénitas pueden presentarse de una forma no aleatoria en el espacio, lo que se comenta desde la perspectiva de la complejidad histórica del proceso de formación, organización social y estructura genética de la población de América del Sur. Definir geográficamente los conglomerados en la genética médica poblacional puede ser una importante herramienta de salud pública, ya que en esos lugares se concentran casos de enfermedades raras que suelen requerir una atención especializada y multidisciplinaria. Por lo tanto, estos resultados pueden servir de apoyo a importantes programas de salud pública relacionados con las enfermedades raras y las malformaciones congénitas como, por ejemplo, la promoción de la salud y la vigilancia.

RESUMO Objetivo. Mapear agrupamentos geográficos de doenças raras e anomalias congênitas relatados na América do Sul. Métodos. Revisão sistemática qualitativa realizada nas bases de dados eletrônicos Medline/PubMed, Lilacs e Scielo para identificar estudos que atendessem aos critérios de elegibilidade. A estratégia resultou em 1.672 artigos únicos, dos quais 164 foram selecionados para leitura completa por uma dupla de revisores. Resultados. Cinquenta e cinco artigos relataram pelo menos um agrupamento de distúrbios genéticos ou anomalias congênitas no território sul-americano. A partir desses artigos, foram identificados 122 agrupamentos, dos quais metade (61) estava relacionada a doenças autossômicas recessivas. Sessenta e cinco (53,3%) dos agrupamentos estavam localizados no Brasil. Conclusões. Os resultados da revisão reforçam a observação de que doenças raras e anomalias congênitas podem ocorrer de forma não aleatória no espaço, o que é discutido na perspectiva da complexa história de formação, organização social e estrutura genética da população sul-americana. O mapeamento de agrupamentos em genética médica populacional pode ser uma importante ferramenta de saúde pública, visto que esses locais concentram casos de doenças raras que frequentemente requerem atendimento multiprofissional especializado. Portanto, esses resultados podem apoiar importantes agendas de saúde pública relacionadas a doenças raras e anomalias congênitas, como a vigilância e a promoção da saúde.

Anomalías congénitas frecuentes en Uruguay entre 2011 y 2014: importancia de un registro para la evaluación de las necesidades de salud / Frequent congenital anomalies in Uruguay in 2011-2014; importance of a medical record for health assessment / Anomalias congênitas frequentes no Uruguai entre 2011-2014, importância de um registro para avaliação das necessidades de saúde

Introducción: las anomalías congénitas (AC) son un problema de salud pública con impacto en la infancia, la mortalidad infantil (MI) y la discapacidad. En Uruguay, así como en otros países desarrollados, las AC y la prematuridad son las principales causas de MI. Objetivos: el objetivo de este trabajo fue analizar las anomalías más frecuentes en el país entre 2011 y 2014, y evaluar los factores de riesgo. Material y método: los datos se obtuvieron del Registro Nacional de Defectos Congénitos y Enfermedades Raras y Estadísticas Vitales del Ministerio de Salud Pública. Resultados: se determinó que prácticamente la mitad de los casos fueron: cardiopatías congénitas, síndrome de Down y defectos del tubo neural (anencefalia, encefalocele y mielomeningocele), representando 0,42% (812/191.820) y 2,85% (38/1334) de los nacidos vivos (NV) y de los óbitos fetales respectivamente. Las prevalencias por 10.000 NV y OF fueron: 38,52 y 149,93 para cardiopatías congénitas; 3,6 y 7,5 para síndrome de Down; 2,1 y 127,4 para defectos del tubo neural. La edad materna avanzada fue el principal factor de riesgo de síndrome de Down. Los factores de riesgo observados en las tres anomalías seleccionadas fueron: prematurez, depresión neonatal y bajo peso al nacer. Conclusiones: las anomalías congénitas en general y las seleccionadas en este trabajo en particular, constituyen una causa relevante de morbimortalidad en el período neonatal e infantil, plausibles de prevención. El diagnóstico temprano es fundamental para planificar servicios de salud especializados. Los resultados aquí presentados se pueden utilizar como línea de base para medir el impacto de las acciones de salud a nivel nacional.

Introduction: congenital anomalies (CA) are a public health problem with an impact on childhood, infant mortality (IM) and disability. In Uruguay, as well as in other developed countries, CA and prematurity are the main causes of IM. Objectives: analyze the most frequent anomalies in the country in 2011-2014 and evaluate risk factors. Material and methods: the data were obtained from the National Record of Congenital Defects and Rare Diseases and health statistics from the Ministry of Public Health. Results: it was determined that practically half of the cases were: congenital heart disease, Down syndrome and Neural Tube Defects (anencephaly, encephalocele and myelomeningocele), accounting for 0.42% (812/191,820) and 2.85% (38/1334) of live births and stillbirths respectively. The prevalence per 10,000 NV and stillbirths were: 38.52 and 149.93 for Congenital Heart Disease; 3.6 and 7.5 for Down Syndrome; 2.1 and 127.4 for neural tube defects. Advanced maternal age was the main risk factor for Down syndrome. The risk factors observed in the three selected anomalies were: prematurity, neonatal depression and low birth weight. Conclusions: congenital anomalies in general, and those selected in this study in particular, are a relevant cause of morbidity and mortality in newborns and infants, likely to be prevented. Early diagnosis is essential for planning specialized health services. The results presented in the present paper can be used as a baseline to measure the impact of health actions at national level.

Introdução: as anomalias congênitas (AC) são um problema de saúde pública com impacto na infância, na mortalidade infantil (MI) e na deficiência. No Uruguai, assim como em outros países desenvolvidos as AC e prematuridade são as principais causas de MI. Objetivos: analisar as anomalias mais frequentes no país, entre 2011-2014 e avaliar os fatores de risco. Material e métodos: os dados foram obtidos do Registro Nacional de Defeitos Congênitos e Doenças Raras e estatísticas vitais do Ministério da Saúde Pública. Resultados: determinou-se que praticamente a metade dos casos eram: cardiopatias congênitas, Síndrome de Down e Defeitos do tubo neural (anencefalia, encefalocele e mielomeningocele), representando 0,42% (812/191.820) e 2,85% (38/1334) de nascidos vivos-NV e natimortos, respectivamente. As prevalências por 10.000 NV e natimortos foram: 38,52 e 149,93 para Cardiopatia Congênita; 3,6 e 7,5 para Síndrome de Down; 2,1 e 127,4 para defeitos do tubo neural. A idade materna avançada foi o principal fator de risco para a síndrome de Down. Os fatores de risco observados nas três anomalias selecionadas foram: prematuridade, depressão neonatal e baixo peso ao nascer. Conclusões: as anomalias congênitas em geral e as selecionadas neste estudo em particular, constituem causa relevante de morbimortalidade no período neonatal e infantil, possível de ser prevenida. O diagnóstico precoce é fundamental para o planejamento de serviços de saúde especializados. Os resultados aqui apresentados podem ser usados como base para medir o impacto das ações de saúde realizadas a nível nacional.

Recent dengue virus infection: epidemiological survey on risk factors associated with infection in a medium-sized city in Mato Grosso

ABSTRACT BACKGROUND: Dengue is considered to be the most important arbovirus worldwide, with important complications that increase its lethality. In Brazil, an endemic country, the disease reaches significant incidence levels, with occurrences of serious cases and high costs of hospitalizations for its treatment. OBJECTIVE: To analyze risk factors among individuals with recent histories of dengue infection in a medium-sized city in Mato Grosso. DESIGN AND SETTING: Descriptive cross-sectional study, of epidemiological-survey type, conducted among the urban population of a city located in mid-northern Mato Grosso. METHODS: A seroepidemiological survey using questionnaires and collection of biological material was conducted among 596 adults aged ≥ 18 years who had been selected through a cluster sampling process. Positive dengue cases were those with positive results from anti-dengue immunoassays (ELISA). Statistical analyses with descriptive and inferential techniques were used, with 95% confidence intervals and a 5% significance level. RESULTS: The seroepidemiological profile of the study participants was predominantly female, with ages between 18 and 39 years, self-declared non-white race/color, not more than eight years of education and not living with a companion. Among the sanitary factors analyzed, the following were risk factors for dengue virus infection: no running water at home; no water supply from the public piped network; no waste from drains or toilets sent to the sewage network; endemic disease combat agents visiting the home; and presence of mosquito breeding sites at home. CONCLUSION: Low schooling levels and previous dengue virus infection were associated with current dengue virus infection.

Revisão: exposição pré-natal e pesticidas / Revisión: exposición prenatal y pesticidas / Review: Prenatal Exposure and Pesticides

Resumo Introdução: Para uma proteção adequada da saúde humana, especialmente em populações de gestantes e crianças vulneráveis, é necessário estimar com precisão os riscos nos efeitos na saúde da exposição ao pesticida. Objetivo: Identificar por meio de artigos selecionados em pesquisa eletrônica nas bases de dados PubMed y Science Direct que relacionaram os efeitos dos pesticidas com problemas na saúde das mulheres gravidas e seus recém-nascidos. Método: Nesta revisão, foram caracterizados estudos epidemiológicos que avaliam os efeitos na saúde pela exposição aos pesticidas, especialmente organofosforados (OPs) e organoclorados (OCs). Também analisasse estudos nos quais são realizadas avaliações de exposição em gestantes que moram em áreas agrícolas, homens com exposição ocupacional, crianças nascidas e residentes nas áreas onde são utilizados agrotóxicos; estudos associados ao uso de agrotóxicos com anormalidades citogenéticas em recém-nascidos, danos ao DNA e efeitos adversos ao nascer pela exposição aos pesticidas. Resultados: Os resultados dos estudos forneceram evidências para sustentar a hipótese de que a exposição a agrotóxicos está negativamente associada aos efeitos na qualidade de vida de crianças cujos pais estão expostos aos agrotóxicos, uma vez que as crianças estão expostas a diferentes níveis de agrotóxicos durante a gravidez, nascimento e crescimento. Conclusão: A validade dos estudos revisados epidemiológicos y científicos é fortemente reforçada pela avaliação da exposição com base na quantificação dos biomarcadores moleculares.

Resumen Introducción: Para una adecuada protección de la salud humana, especialmente en poblaciones de mujeres embarazadas y niños vulnerables, es necesario estimar con precisión los riesgos en los efectos de la exposición de los plaguicidas en la salud. Objetivo: Identificar artículos seleccionados a través de una búsqueda electrónica en las bases de datos PubMed y Science Direct que relacionaban los efectos de los plaguicidas con problemas de salud en las mujeres embarazadas y sus recién nacidos. Métodos: Esta revisión caracterizó estudios epidemiológicos que evalúan los efectos sobre la salud de la exposición a los plaguicidas, especialmente los organofosforados (OP) y los organoclorados (OC). También se analizaron estudios en los que se evaluó la exposición en mujeres embarazadas que viven en zonas agrícolas, hombres con exposición ocupacional, niños nacidos y residentes en zonas donde se utilizan plaguicidas, estudios asociados al uso de plaguicidas con anomalías citogenéticas en los recién nacidos, daños en el ADN y efectos adversos al nacimiento por exposición a plaguicidas. Resultados: Los resultados de los estudios aportaron pruebas que apoyan la hipótesis de que la exposición a los plaguicidas se asocia negativamente con los efectos en la calidad de vida de los niños cuyos padres están expuestos a los plaguicidas, ya que los niños están expuestos a diferentes niveles de plaguicidas durante el embarazo, el embarazo, el nacimiento y el crecimiento. Conclusión: La validez de los estudios epidemiológicos y científicos revisados se ve muy reforzada por la evaluación de la exposición basada en la cuantificación de biomarcadores moleculares.

Evaluation of the influence of genetic variants in Cereblon gene on the response to the treatment of erythema nodosum leprosum with thalidomide

BACKGROUND Erythema nodosum leprosum (ENL) is an acute and systemic inflammatory reaction of leprosy characterised by painful nodules and involvement of various organs. Thalidomide is an immunomodulatory and anti-inflammatory drug currently used to treat this condition. Cereblon (CRBN) protein is the primary target of thalidomide, and it has been pointed out as necessary for the efficacy of this drug in others therapeutics settings. OBJECTIVES In this study, we aimed to evaluate the influence of CRBN gene variants on the dose of thalidomide as well as its adverse effects during treatment of ENL. METHODS A total of 103 ENL patients in treatment with thalidomide were included in this study. DNA samples were obtained from saliva and molecular analysis of CRBN gene were performed to investigate the variants rs1620675, rs1672770 and rs4183. Different genotypes of CRBN variants were evaluated in relation to their influence on the dose of thalidomide and on the occurrence of adverse effects. FINDINGS No association was found between CRBN variants and thalidomide dose variation. However, the genotypes of rs1672770 showed association with gastrointestinal effects (p = 0.040). Moreover, the haplotype DEL/C/T (rs4183/rs1672770/rs1620675) was also associated with gastrointestinal adverse effects (p = 0.015). MAIN CONCLUSIONS Our results show that CRBN variants affect the treatment of ENH with thalidomide, especially on the adverse effects related to the drug.

Functional Polymorphisms in the p53 Pathway Genes on the Genetic Susceptibility to Zika Virus Teratogenesis.

Congenital Zika Syndrome (CZS) occurs in up to 42% of individuals exposed to ZIKV prenatally. Deregulation in gene expression and protein levels of components of the p53 signaling pathway, such as p53 and MDM2, due to ZIKV infection has been reported. Here, we evaluate functional polymorphisms in genes of the p53 signaling pathway as risk factors to CZS. Forty children born with CZS and forty-eight children exposed to ZIKV, but born without congenital anomalies were included in this study. Gestational and sociodemographic information as well as the genotypic and allelic frequencies of functional polymorphisms in TP53, MDM2, MIR605 and LIF genes were compared between the two groups. We found children with CZS exposed predominantly in the first trimester and controls in the third trimester (p<0.001). Moreover, children with CZS were predominantly from families with a lower socioeconomic level (p=0.008). We did not find a statistically significant association between the investigated polymorphisms and development of CZS; however, by comparing individuals with CZS and lissencephaly or without lissencephaly, we found a significative difference in the allelic frequencies of the TP53 rs1042522, which is associated with a more potent p53-induced apoptosis (p=0.007). Our findings suggest that the TP53 rs1042522 polymorphism should be better investigate as a genetic risk factor for the development of lissencephaly in children with CZS.

Sociodemographic and sanitary profile of chikungunya virus infection in medium-sized municipality in Mato Grosso, from January to March 2018, Brasil / Perfil sociodemográfico y sanitario de la infección por el virus de la chikungunya en un municipio de tamaño medio de Mato Grosso, de enero a marzo de 2018, Brasil

Abstract Introduction: The chikungunya virus has already been identified in more than 60 countries in Asia, Africa, Europe and the Americas, and chronicity after the disease impacts the lives of those affected by the virus, as well as society, the economy and public health. The objective was to characterize, through epidemiological survey, the profile of chikungunya infection in a mid-sized municipality in Mato Grosso according to sociodemographic and sanitary factors. Methods: The serum-epidemiological survey was conducted with 596 adults aged ≥ 18 years selected by cluster sampling process, with application of questionnaires and biological material collection. Positive cases of chikungunya fever were those with positive results in the anti-chikungunya virus enzyme immunoassay (ELISA). The statistical analyses used descriptive and inferential techniques with confidence intervals of 95% and a significance level of 5%. Results: The overall prevalence of chikungunya fever found in the community was 8.4%. The profile of infection by chikungunya fever is composed of women (p<0.204), aged between 18 and 39 years (p<0.780), more than 08 years of study (p<0.079), non-white reported race/color p<0.871) and employed in the past 12 months (p<0.927). Not residing with affective companion was statistically significant for infection by chikungunya virus (CHIKV) (p<0.028). Conclusion: The study found that women are the most affected by the infection, as well as being single represented a risk factor, and risk behaviors, such as presence of larvae and breeding of mosquitos at home, reflect a low level of awareness of the disease.

Resumen Introducción: el virus chikunugnya ya se ha identificado en más de 60 países de Asia, África, Europa y América, y la cronicidad después de la enfermedad afecta la vida de los afectados por el virus, así como la sociedad, la economía y la salud pública. El objetivo fue caracterizar, mediante encuestas epidemiológicas, el perfil de la infección por chikungunya en un municipio de tamaño medio en Mato Grosso de acuerdo con factores sociodemográficos y sanitarios. Métodos: La encuesta epidemiológica en suero se realizó con 596 adultos de ≥ 18 años seleccionados mediante un proceso de muestreo por conglomerados, con aplicación de cuestionarios y recolección de material biológico. Los casos positivos de fiebre chikungunya fueron aquellos con resultados positivos en el inmunoensayo enzimático del virus anti-chikungunya (ELISA). Los análisis estadísticos utilizaron técnicas descriptivas e inferenciales con intervalos de confianza del 95% y un nivel de significación del 5%. Resultados: La prevalencia general de fiebre chikungunya encontrada en la comunidad fue de 8.4%. El perfil de infección por fiebre chikungunya está compuesto por mujeres (p <0.204), con edades comprendidas entre 18 y 39 años (p <0.780), más de 08 años de estudio (p <0.079), raza/color no blanco (p <0.871) y empleado en los últimos 12 meses (p <0.927). No residir con compañero afectivo fue estadísticamente significativo para la infección por el virus chikungunya (CHIKV) (p <0.028). Conclusión: El estudio encontró que las mujeres son las más afectadas por la infección, además de ser solteras representaban un factor de riesgo, y los comportamientos de riesgo, como la presencia de larvas y la cría de mosquitos en el hogar, reflejan un bajo nivel de conciencia de la enfermedad.

A importância da Odontologia na assistência a indivíduos com defeitos congênitos / The importance of Dentistry in assisting individuals with birth defects

Introdução: Defeitos congênitos são alterações estruturais ou funcionais que acontecem durante a vida intrauterina. O cirurgião-dentista deve reconhecer os defeitos craniofaciais para complementar a caracterização fenotípica e manejá-los junto a uma equipe multiprofissional. A presente revisão tem como objetivo auxiliar o cirurgião-dentista para o diagnóstico desses achados e apresentar quadros sindrômicos tipicamente associados a malformações craniofaciais. Revisão de Literatura: Manifestações craniofaciais de defeitos congênitos são condições que devem ser reconhecidas pelos cirurgiões--dentistas, pois frequentemente estão presentes em sua prática diária, podendo ser este profissional o primeiro a identificar tais achados. Os principais quadros sindrômicos tipicamente associados a micrognatia, fendas orais e displasias esqueléticas com manifestação craniofacial são apresentados, assinalando suas características clínicas e genéticas. Discussão: O cirurgião-dentista deve realizar uma anamnese detalhada incluindo a história familiar, bem como reconhecer as dismorfias tanto clínica quanto radiograficamente, observando o paciente de forma sistêmica. Conclusão: Os profissionais da odontologia devem receber treinamento teórico-prático para o diagnóstico, tratamento e vigilância de indivíduos com defeitos congênitos, seja na avaliação individual ou como parte de uma equipe multiprofissional.

Introduction: Birth defects are structural or functional changes that occur during intrauterine life. The dentist must recognize the craniofacial defects, complement the phenotypic characterization and manage them within a multidisciplinary team. The present review aims to assist the dentist to diagnose these findings and present syndromic conditions typically associated with cranio-facial malformations. Literature Review: Craniofacial manifestations of birth defects are conditions that must be recognized by dentists, as they are frequently present in their daily practices, and this professional may be the first to identify such findings. The main syndromic clinical pictures typically associated with micrognathia, oral clefts and skeletal dysplasias with craniofacial man-ifestation are presented, pointing out their clinical and genetic features. Discussion: The dentist must perform a detailed anamnesis including family history, as well as should recognize both clinical and radiographically the dysmorphisms, observing the patient systemically. Conclusion: Dentistry professionals should receive the-oretical-practical training for the diagnosis, treatment and surveillance of individuals with congenital defects, either in individual assessment or as part of a multipro-fessional team.

Association between Genetic Variants in NOS2 and TNF Genes with Congenital Zika Syndrome and Severe Microcephaly.

Zika virus (ZIKV) causes Congenital Zika Syndrome (CZS) in individuals exposed prenatally. Here, we investigated polymorphisms in VEGFA, PTGS2, NOS3, TNF, and NOS2 genes as risk factors to CZS. Forty children with CZS and forty-eight children who were in utero exposed to ZIKV infection, but born without congenital anomalies, were evaluated. Children with CZS were predominantly infected by ZIKV in the first trimester (p < 0.001) and had mothers with lower educational level (p < 0.001) and family income (p < 0.001). We found higher risk of CZS due the allele rs2297518[A] of NOS2 (OR = 2.28, CI 95% 1.17-4.50, p = 0.015). T allele and TT/CT genotypes of the TNF rs1799724 and haplotypes associated with higher expression of TNF were more prevalent in children with CZS and severe microcephaly (p = 0.029, p = 0.041 and p = 0.030, respectively). Our findings showed higher risk of CZS due ZIKV infection in the first trimester and suggested that polymorphisms in NOS2 and TNF genes affect the risk of CZS and severe microcephaly.

Gene panel for the diagnosis of epidermolysis bullosa: proposal for a viable and efficient approach

Abstract Background: Epidermolysis bullosa is characterized by cutaneous fragility and blistering. Historically, diagnosis is achieved by immunofluorescence mapping or transmission electron microscopy, both involving biopsy procedures. Genetic analysis, especially through next-generation sequencing, is an important tool for the diagnosis of this disease. In Brazil, access to diagnostic methods is limited, and consequently, most patients do not have an accurate diagnosis. Diagnosis allows the indication of prognosis and genetic counselling of the patient. Objectives: To evaluate the cost-effectiveness of a gene panel compared to immunofluorescence mapping and transmission electron microscopy by analyzing its benefits, limitations, and economic aspects. Methods: The gene panel included the 11 main genes associated with epidermolysis bullosa. The techniques were compared, assessing the average cost, advantages, and limitations, through a price survey and literature review. Results: Both immunofluorescence mapping and transmission electron microscopy require skin biopsy, are dependent on the investigator's expertise, and are subject to frequent inconclusive results. The gene panel is effective for the conclusive diagnosis of epidermolysis bullosa, presents high efficiency and accuracy, is economically feasible, and excludes the need for biopsy. The gene panel allows for prognosis, prenatal genetic diagnosis, and genetic counseling. Study limitations: It was not possible to find laboratories that perform transmission electron microscopy for epidermolysis bullosa diagnosis in Brazil. Conclusion: This study supports the gene panel as the first-choice method for epidermolysis bullosa diagnosis.

Gene panel for the diagnosis of epidermolysis bullosa: proposal for a viable and efficient approach.

BACKGROUND: Epidermolysis bullosa is characterized by cutaneous fragility and blistering. Historically, diagnosis is achieved by immunofluorescence mapping or transmission electron microscopy, both involving biopsy procedures. Genetic analysis, especially through next-generation sequencing, is an important tool for the diagnosis of this disease. In Brazil, access to diagnostic methods is limited, and consequently, most patients do not have an accurate diagnosis. Diagnosis allows the indication of prognosis and genetic counselling of the patient. OBJECTIVES: To evaluate the cost-effectiveness of a gene panel compared to immunofluorescence mapping and transmission electron microscopy by analyzing its benefits, limitations, and economic aspects. METHODS: The gene panel included the 11 main genes associated with epidermolysis bullosa. The techniques were compared, assessing the average cost, advantages, and limitations, through a price survey and literature review. RESULTS: Both immunofluorescence mapping and transmission electron microscopy require skin biopsy, are dependent on the investigator's expertise, and are subject to frequent inconclusive results. The gene panel is effective for the conclusive diagnosis of epidermolysis bullosa, presents high efficiency and accuracy, is economically feasible, and excludes the need for biopsy. The gene panel allows for prognosis, prenatal genetic diagnosis, and genetic counseling. STUDY LIMITATIONS: It was not possible to find laboratories that perform transmission electron microscopy for epidermolysis bullosa diagnosis in Brazil. CONCLUSION: This study supports the gene panel as the first-choice method for epidermolysis bullosa diagnosis.

Genotype-phenotype correlations on epidermolysis bullosa with congenital absence of skin: A comprehensive review.

Congenital absence of skin (CAS) is a clinical sign associated with the main types of epidermolysis bullosa (EB). Very few studies have investigated the genetic background that may influence the occurrence of this condition. Our objective was to investigate genotype-phenotype correlations on EB with CAS through a literature revision on the pathogenic variants previously reported. A total of 171 cases (49 EB simplex, EBS; 23 junctional EB, JEB; and 99 dystrophic EB, DEB), associated with 132 pathogenic variants in eight genes, were included in the genotype-phenotype analysis. In EBS, CAS showed to be a recurrent clinical sign in EBS with pyloric atresia (PA) and EBS associated with kelch-like protein 24; CAS was also described in patients with keratins 5/14 alterations, particularly involving severe phenotypes. In JEB, this is a common clinical sign in JEB with PA associated with premature termination codon variants and/or amino acid substitutions located in the extracellular domain of integrin α6ß4 genes. In DEB with CAS, missense variants occurring close to non-collagenous interruptions of the triple-helix domain of collagen VII appear to influence this condition. This study is the largest review of patients with EB and CAS and expands the spectrum of known variants on this phenomenon.

Prevalence of congenital anomalies at birth among live births in the state of Maranhão from 2001 to 2016: temporal and spatial analysis / Prevalências ao nascimento de anomalias congênitas entre nascidos vivos no estado do Maranhão de 2001 a 2016: análise temporal e espacial

ABSTRACT: Objectives: To analyze the prevalence at birth and the spatial and temporal distribution of congenital anomalies (CAs) among live births in the state of Maranhão in 2001 to 2016. To describe demographic, gestational and neonatal variables of interest. Methods: Ecological, population-based study, using secondary data from the Live Birth Information System (SINASC). Annual prevalence of total and per-group CAs was calculated. Spatial analyzes were based on the Local Indicators of Spatial Association (LISA) and the Moran I Index, and interactive maps were generated. Demographic, gestational and neonatal variables of interest available from SINASC were described in the group of newborns with CAs. Results: 1,831,830 live births, 6,110 with CAs (33.4/10,000) were included. Higher frequencies occurred in more recent years. Spatial clusters have been observed in specific years. The prevalence of newborns with CAs was different between categories of variables considered as risk factors for this outcome. Conclusion: The prevalence at birth of total CAs was lower than expected for major human defects (3%). The temporal peak of records in 2015/2016 is probably related to the increase in CAs caused by gestational infection by the Zika virus. The spatial clusters were probably due to variations at random due to the small number of births as they are not repeated in other years. Studies like this are the basis for the establishment of CA surveillance programs.

RESUMO: Objetivos: Analisar as prevalências ao nascimento e a distribuição espacial e temporal das anomalias congênitas (ACs) entre nascidos vivos no estado do Maranhão nos anos de 2001 a 2016; descrever variáves de interesse demográficas, gestacionais e neonatais. Métodos: Estudo ecológico, de base populacional, a partir de dados secundários do Sistema de Informações sobre Nascidos Vivos (SINASC). Foram calculadas prevalências ao nascimento anuais de ACs totais e por grupos. Análises espaciais utilizaram o cálculo de Indicadores Locais de Associação Espacial (LISA) e o Índice Global de Moran I, e mapas interativos foram gerados. Variáveis de interesse demográficos, gestacionais e neonatais disponíveis no SINASC foram descritas no grupo dos recém-nascidos com ACs. Resultados: Neste estudo, foram incluídos 1.831.830 nascidos vivos, 6.110 com ACs (33,4/10 mil). Maiores frequências ocorreram nos anos mais recentes. Aglomerados espaciais foram observados em anos específicos. As prevalências de nascidos vivos com anomalias foram diferentes entre categorias de variáveis consideradas como fatores de risco para esse desfecho. Conclusão: A prevalência ao nascimento de nascidos com ACs foi inferior ao esperado para defeitos maiores na espécie humana (3%). O pico temporal de registros em 2015/2016 está provavelmente relacionado ao aumento de microcefalia causada pela infecção gestacional por vírus Zika. Os aglomerados espaciais provavelmente se deveram a variações ao acaso pelo número pequeno de nascimentos, pois não se repetem em outros anos. Estudos como este são base para o estabelecimento de programas de vigilância de defeitos congênitos.

Prevalence of fetal and neonatal mortality due to congenital anomalies in the state of Maranhão, Brazil, from 2001-2016

Introduction: The infant mortality rate (IMR) is an important health indicator directly associated with living conditions, prenatal care coverage, social development conditions, and parental education, among others. Worldwide, the infant mortality rate was 29/1000 live births in 2017. Therefore, this study aimed to evaluate the fetal and infant mortality rates due to congenital anomalies (CA) in Maranhão from 2001 to 2016. Methods: Data were obtained from the SINASC, and SIM databases. We used simple linear regression, Poisson distribution, and ANOVA (Bonferroni's post hoc test). We analyzed the public data (2001­2016) of 1934858 births and determined the fetal, neonatal, perinatal, and post-neonatal mortality rates associated with CA by mesoregions. Results: The IMR in Maranhão was 17.01/1000 live births (95%CI, 13.30-20.72) and CA was the cause of death in 13.3% of these deaths. Mortality due to CA (per 1000 live births) was 0.76 (95%CI, 0.74­0.85) for fetal mortality rate and 2.27 (95%CI, 1.45-3.10) for infant mortality rate. Geographic and temporal variations were observed with a slight increase in recent years for deaths attributable to CA, and in the northern part of Maranhão. Conclusions: Mortality rates due to CA in Maranhão increased over the period 2001­2016 possibly as a result of improved maternal-infant health conditions eliminating other causes of death. Therefore, efforts to improve early diagnosis and better treatment of congenital anomalies should be considered to reduce its impact on child mortality. (AU)

Lista de anomalias congênitas prioritárias para vigilância no âmbito do Sistema de Informações sobre Nascidos Vivos do Brasil / Lista de anomalías congénitas prioritarias para la vigilancia bajo el Sistema de Información sobre Nacidos Vivos en Brasil / List of priority congenital anomalies for surveillance under the Brazilian Live Birth Information System

Objetivo: Definir a lista de anomalias congênitas prioritárias para o aprimoramento do registro no Sistema de Informações sobre Nascidos Vivos (Sinasc). Métodos: A partir da Décima Revisão da Classificação Estatística Internacional de Doenças e Problemas Relacionados à Saúde (CID-10), protocolos internacionais e reuniões com especialistas, a lista de anomalias prioritárias foi construída considerando-se dois critérios principais: ser diagnosticável ao nascimento; e possuir intervenção disponível em diferentes níveis. A lista foi submetida a apreciação da Sociedade Brasileira de Genética Médica e Genômica. Resultados: Compuseram a lista oito grupos de anomalias congênitas distribuídos de acordo com o tipo de anomalia relacionada, bem como a parte do corpo afetada e sua correspondência ao código do capítulo XVII da CID-10. Conclusão: A lista de anomalias congênitas prioritárias para notificação fornece subsídios para o aprimoramento do registro no Sinasc.

Objetivo: Definir la lista de anomalías congénitas prioritarias para perfeccionar el registro en el Sistema de Información de Nacidos Vivos (Sinasc). Métodos: Con base en la Clasificación Internacional de Enfermedades, Décima Revisión (CIE-10), protocolos internacionales y reuniones con especialistas, la lista de anomalías prioritarias se construyó considerando dos criterios principales: ser diagnosticables al nacer y tener intervención disponible en diferentes niveles. La lista fue sometida a la consideración de la Sociedad Brasileña de Genética y Genómica Médica. Resultados: La lista comprendía ocho grupos de anomalías congénitas distribuidos según el tipo de anomalía relacionada, así como la parte del cuerpo afectada, todos ellos relacionados con algún código del capítulo XVII de la CIE-10. Conclusión: La lista de anomalías congénitas prioritarias para notificación proporciona subsidios para mejorar el registro en Sinasc.

Objective: To define the list of priority congenital anomalies for improving their recording on the Brazilian Live Birth Information System (Sinasc). Methods: Based on the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10), international protocols and meetings with specialists, the list of priority anomalies was built considering two main criteria: being diagnosable at birth and having intervention available at different levels. The list was submitted for consideration by the Brazilian Medical Genetics and Genomics Society. Results: The list comprised eight groups of congenital anomalies distributed according to the type of related anomaly, as well as the affected part of the body and its corresponding code in ICD-10 Chapter XVII. Conclusion: The list of priority congenital anomalies for notification provides a basis for improving case recording on Sinasc.

Mapeamento dinâmico da probabilidade de infestação por vetores urbanos de arbovírus nos municípios do Rio Grande do Sul, 2016-2017 / Mapeo dinámico de la probabilidad de infestación por vectores urbanos de arbovirus en los municipios de Rio Grande do Sul, Brasil, 2016-2017 / Dynamic mapping of the probability of infestation by urban arbovirus vectors in the municipalities of Rio Grande do Sul state, Brazil, 2016-2017

Objetivo: Comparar o mapeamento oficial com um mapeamento probabilístico da infestação por Aedes spp. nos municípios do Rio Grande do Sul, Brasil. Métodos: Estudo ecológico com dados de amostras de criadouros em 2016-2017; obteve-se a classificação oficial em boletins epidemiológicos e estimou-se a probabilidade de infestação por município e semana, ajustando-se um modelo dinâmico de ocupação de sítios aos dados da vigilância epidemiológica municipal. Resultados: 187.245 amostras coletadas em 473 municípios originaram 10.648 detecções de Aedes aegypti e 8.414 de Aedes albopictus; o mapeamento oficial concorda com o probabilístico em municípios da região noroeste e oeste do RS; os mapeamentos discordam nas regiões leste, centro, nordeste e sul, revelando municípios oficialmente não infestados com alta probabilidade de infestação e notificação de arboviroses. Conclusão: A classificação oficial identificou infestação nos municípios infestados do noroeste e oeste, e não identificou infestação em municípios com possíveis falsos zeros e onde ela varia temporalmente.

Objetivo: Comparar el mapeo oficial con un mapeo probabilístico de infestación por Aedes spp. en los municipios de Rio Grande do Sul, Brasil. Métodos: Estudio ecológico analizando muestras colectadas en criaderos en 2016-2017; se obtuvo la clasificación oficial en boletines epidemiológicos, y la probabilidad de infestación por municipio y semana ajustando un modelo dinámico de ocupación de sitios a los datos de la vigilancia epidemiológica municipal. Resultados: 187.245 muestras de 473 municipios generaron 10.648 detecciones de Aedes aegypti y 8.414 detecciones de Aedes albopictus. El mapeo oficial está de acuerdo con el probabilístico en municipios del noroeste y oeste de RS; los mapeos no concuerdan en el este, centro, nordeste y sur, revelando municipios oficialmente no infestados con alta probabilidad de infestación y notificación de arbovirus. Conclusión: Mientras la clasificación oficial identifica municipios del noroeste y oeste infestados críticamente, no identifica infestación en municipios con posiblemente falsos ceros y en donde la infestación varía temporalmente.

Objective: To compare official mapping with probabilistic mapping of infestation by Aedes spp. in the municipalities of Rio Grande do Sul state, Brazil. Methods: This was an ecological study using data from samples of mosquito breeding sites collected in 2016-2017; official classification was obtained from epidemiological reports, and infestation per municipality and week was estimated by fitting a dynamic site-occupancy model to data from municipal epidemiological surveillance. Results: 187,245 samples collected in 473 municipalities returned 10,648 detections of Aedes aegypti, and 8,414 detections of Aedes albopictus; official mapping agrees with probabilistic mapping in municipalities in the northwestern and western regions of the state. The mappings are not in agreement in the eastern, central, northeastern and southern regions, revealing municipalities officially not infested but with high probability of infestation and notification of arbovirus infection. Conclusion: While official classification identified critically infested municipalities in the state's northwestern and western regions, it did not identify infestation in municipalities with possible false zero errors and where infestation varies over time.

Inherited epidermolysis bullosa: update on the clinical and genetic aspects

Abstract Inherited epidermolysis bullosa is a group of genetic diseases characterized by skin fragility and blistering on the skin and mucous membranes in response to minimal trauma. Epidermolysis bullosa is clinically and genetically very heterogeneous, being classified into four main types according to the layer of skin in which blistering occurs: epidermolysis bullosa simplex (intraepidermal), junctional epidermolysis bullosa (within the lamina lucida of the basement membrane), dystrophic epidermolysis bullosa (below the basement membrane), and Kindler epidermolysis bullosa (mixed skin cleavage pattern). Furthermore, epidermolysis bullosa is stratified into several subtypes, which consider the clinical characteristics, the distribution of the blisters, and the severity of cutaneous and extracutaneous signs. Pathogenic variants in at least 16 genes that encode proteins essential for the integrity and adhesion of skin layers have already been associated with different subtypes of epidermolysis bullosa. The marked heterogeneity of the disease, which includes phenotypes with a broad spectrum of severity and many causal genes, hinders its classification and diagnosis. For this reason, dermatologists and geneticists regularly review and update the classification criteria. This review aimed to update the state of the art on inherited epidermolysis bullosa, with a special focus on the associated clinical and genetic aspects, presenting data from the most recent reclassification consensus, published in 2020.