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Abstract The Nav1.7 voltage-gated sodium channel plays a key role in nociception. Three functional variants in the SCN9A gene (encoding M932L, V991L, and D1908G in Nav1.7), have recently been identified as stemming from Neanderthal introgression and to associate with pain symptomatology in UK BioBank data. In 1000 genomes data, these variants are absent in Europeans but common in Latin Americans. Analysing high-density genotype data from 7594 Latin Americans, we characterized Neanderthal introgression in SCN9A. We find that tracts of introgression occur on a Native American genomic background, have an average length of ~123 kb and overlap the M932L, V991L, and D1908G coding positions. Furthermore, we measured experimentally six pain thresholds in 1623 healthy Colombians. We found that Neanderthal ancestry in SCN9A is significantly associated with a lower mechanical pain threshold after sensitization with mustard oil and evidence of additivity of effects across Nav1.7 variants. Our findings support the reported association of Neanderthal Nav1.7 variants with clinical pain, define a specific sensory modality affected by archaic introgression in SCN9A and are consistent with independent effects of the Neanderthal variants on Nav1.7 function.

Abstract We report a genome-wide association study of facial features in >6000 Latin Americans based on automatic landmarking of 2D portraits and testing for association with inter-landmark distances. We detected significant associations (P-value

ABSTRACT This cross-sectional study sought to evaluate motor development in infants exposed to ZIKV born with normal head circumference (HC). Thirty one children, distributed into two groups, participated in the study: 15 whose mothers were infected by ZIKV during pregnancy, born with HC from −1.9 to +2 Z-scores, adjusted for sex and gestational age (exposed group); and 16 randomly selected infants without known prenatal exposure to ZIKV, paired by sex and age (control group). Alberta Infant Motor Scale (AIMS) was used to evaluate gross motor development. We found no significant difference between the exposed and control groups. However, considering that AIMS is a screening test that assesses only the gross motor development and the small size of our sample, infants exposed to ZIKV during pregnancy should be continuously evaluated for different aspects of their development.

Abstract In Brazil, the population in general has little knowledge about genetic risks, as well as regarding the role and importance of the Cancer Genetic Counseling (CGC). The goal of this study was to evaluate cancer-related worry and cancer risk perception during CGC sessions in Brazilian women at-risk for hereditary breast cancer. This study was performed in 264 individuals seeking CGC for hereditary breast cancer. Both cancer-affected and unaffected individuals were included. As results, individuals with and without cancer reported different motivations for seeking CGC and undergoing genetic testing. A correlation was observed between age at the first CGC session and age at which the closest relative was diagnosed with cancer. Multivariate analysis showed that educational level, cancer risk discussion within the family, and number of deaths by cancer among first-degree relatives influenced positively the cancer risk perception. In conclusion, the results of this study indicate that cancer-related worry and cancer risk perception are significant aspects of morbidity in individuals seeking CGC, whether they are cancer-affected or unaffected. CGC has an important role in health education and cancer prevention for its potential of promoting an accurate perception of the risk.

Abstract In 1990, the first Teratogen Information Service in Brazil (SIAT) was implemented in the Medical Genetics Service at Hospital de Clinicas de Porto Alegre. SIAT is a free-to-use information service both to health professionals and the general population, especially to women who are pregnant or planning pregnancy. The main objective of this paper is to present the activities of SIAT in its initial years (1990-2006), compared to those in the last decade (2007-2017). In addition we review the scientific contribution of SIAT in the field of human teratogenesis. Since 1990, SIAT received 10,533 calls. Use of medications were the main reason for concern, accounting for 74% of all questions, followed by other chemical exposures (occupational, cosmetics, environmental), and maternal infectious diseases. Among its main contributions to scientific knowledge was the collaboration for the identification of two new human teratogens: misoprostol in the 1990s and Zika virus in 2015/16. In conclusion, SIAT is still evolving, as is the Medical Genetics Service that hosts it. Through its 27 years of existence more than 300 undergraduate and graduate students have rotated at SIAT. Presently, SIAT is expanding the research to experimental teratogenesis and to investigation of molecular mechanisms of teratogens.

Background KAMUTHE is a video microanalysis system which observes preverbal communication within the music therapy setting. This system is indicated for children with autism spectrum disorder (ASD) or multiple disabilities. The purpose of this study was to translate, adapt to Brazilian Portuguese language and analyze some psychometric properties (reliability and validity evidence) of KAMUTHE administration in Brazil for individuals with ASD. Participants and procedure Translation, back translation, analysis by judges, and pilot application were performed to obtain evidence of content and face validity. The second part of this study was to administer KAMUTHE in 39 consecutive children with ASD. An individual session of improvisational music therapy was applied to assess the different behaviors included in KAMUTHE. The intra-rater reliability, concurrent validity and convergent validity were analyzed. Results Translation and cross-cultural adaptation were followed and some cultural adaptations were needed. Inter-rater reliability was very good (ICCs 0.95-0.99) for the three child’s behaviors analyzed. Criteria validity with a moderate negative association was found (r = –.38, p = .017) comparing the behavior “Gazes at therapist” and the level of ASD along with the Childhood Autism Rating Scale (CARS). Convergent validity was established between the behavior “Gazes at therapist” and the two nonlinguistic communication scales (social interaction and interests) of the Children’s Communication Checklist (CCC) with a moderate correlation (r = –.43, p = .005). Conclusions The administration of the KAMUTHE video microanalysis system showed positive results in children with ASD. Further studies are needed to improve the reliability and validity of the instrument in Brazil.

OBJECTIVE: To characterize a sample of Brazilian patients with maple syrup urine disease (MSUD) diagnosed between 1992 and 2011. METHODS: In this retrospective study, patients were identified through a national reference laboratory for the diagnosis of MSUD and through contact with other medical genetics services across Brazil. Data were collected by means of a chart review. RESULTS: Eighty-three patients from 75 families were enrolled in the study (median age, 3 years; interquartile range [IQR], 0.57-7). Median age at onset of symptoms was 10 days (IQR 5-30), whereas median age at diagnosis was 60 days (IQR 29-240, p = 0.001). Only three (3.6%) patients were diagnosed before the onset of clinical manifestations. A comparison between patients with (n = 12) and without (n = 71) an early diagnosis shows that early diagnosis is associated with the presence of positive family history and decreased prevalence of clinical manifestations at the time of diagnosis, but not with a better outcome. Overall, 98.8% of patients have some psychomotor or neurodevelopmental delay. CONCLUSION: In Brazil, patients with MSUD are usually diagnosed late and exhibit neurological involvement and poor survival even with early diagnosis. We suggest that specific public policies for diagnosis and treatment of MSUD should be developed and implemented in the country.

Objective: To characterize a sample of Brazilian patients with maple syrup urine disease (MSUD) diagnosed between 1992 and 2011. Methods: In this retrospective study, patients were identified through a national reference laboratory for the diagnosis of MSUD and through contact with other medical genetics services across Brazil. Data were collected by means of a chart review. Results: Eighty‐three patients from 75 families were enrolled in the study (median age, 3 years; interquartile range [IQR], 0.57‐7). Median age at onset of symptoms was 10 days (IQR 5‐30), whereas median age at diagnosis was 60 days (IQR 29‐240, p = 0.001). Only three (3.6%) patients were diagnosed before the onset of clinical manifestations. A comparison between patients with (n = 12) and without (n = 71) an early diagnosis shows that early diagnosis is associated with the presence of positive family history and decreased prevalence of clinical manifestations at the time of diagnosis, but not with a better outcome. Overall, 98.8% of patients have some psychomotor or neurodevelopmental delay. Conclusion: In Brazil, patients with MSUD are usually diagnosed late and exhibit neurological involvement and poor survival even with early diagnosis. We suggest that specific public policies for diagnosis and treatment of MSUD should be developed and implemented in the country.

Objective: To characterize a sample of Brazilian patients with maple syrup urine disease (MSUD) diagnosed between 1992 and 2011. Methods: In this retrospective study, patients were identified through a national reference laboratory for the diagnosis of MSUD and through contact with other medical genetics services across Brazil. Data were collected by means of a chart review. Results: Eighty-three patients from 75 families were enrolled in the study (median age, 3 years; interquartile range [IQR], 0.57–7). Median age at onset of symptoms was 10 days (IQR 5–30), whereas median age at diagnosis was 60 days (IQR 29–240, p = 0.001). Only three (3.6%) patients were diagnosed before the onset of clinical manifestations. A comparison between patients with (n = 12) and without (n = 71) an early diagnosis shows that early diagnosis is associated with the presence of positive family history and decreased prevalence of clinical manifestations at the time of diagnosis, but not with a better outcome. Overall, 98.8% of patients have some psychomotor or neurodevelopmental delay. Conclusion: In Brazil, patients with MSUD are usually diagnosed late and exhibit neurological involvement and poor survival even with early diagnosis. We suggest that specific public policies for diagnosis and treatment of MSUD should be developed and implemented in the country. Resumo: Objetivo: Caracterizar uma amostra de pacientes brasileiros com a doença da urina de xarope de bordo (DXB) diagnosticados entre 1992 e 2011. Métodos: Neste estudo retrospectivo, os pacientes foram identificados por meio de um laboratório de referência nacional para o diagnóstico de DXB e por meio do contato com outros serviços de genética médica no Brasil. Os dados foram coletados por meio de uma revisão de prontuários. Resultados: 83 pacientes de 75 famílias foram incluídos no estudo (idade média: 3 anos; intervalo interquartil (IQR): 0,57-7). A idade média no surgimento dos sintomas era de 10 dias (IQR: 5-30), ao passo que a idade média no diagnóstico era de 60 dias (IQR: 29-240; p = 0,001). Somente três (3,6%) pacientes foram diagnosticados antes do surgimento de manifestações clínicas. Uma comparação entre pacientes com (n = 12) e sem (n = 71) um diagnóstico precoce mostra que o diagnóstico precoce está associado à presença de histórico familiar positivo e à redução na prevalência de manifestações clínicas no momento do diagnóstico, porém sem melhor resultado. Em geral, 98,8% dos pacientes têm algum atraso no desenvolvimento psicomotor ou neurológico. Conclusão: No Brasil, os pacientes com DXB normalmente recebem um diagnóstico tardio e exibem um envolvimento neurológico e baixa sobrevivência, mesmo com um diagnóstico precoce. Sugerimos que políticas públicas específicas para o diagnóstico e tratamento da DXB sejam desenvolvidas e implementadas no país. Keywords: Maple syrup urine disease, MSUD, Inborn errors of metabolism, Diagnosis, Palavras-chave: Doença da urina de xarope de bordo, DXB, Erros inatos do metabolismo, Diagnóstico

Campomelic dysplasia (CD) is an autosomal, dominantly inherited, skeletal abnormality belonging to the subgroup of bent bone dysplasias. In addition to bowed lower limbs, CD typically includes the following: disproportionate short stature, flat face, micrognathia, cleft palate, bell-shaped thorax, and club feet. Up to three quarters of 46, XY individuals may be sex-reversed. Radiological signs include scapular and pubic hypoplasia, narrow iliac wings, spaced ischia, and bowed femora and tibiae. Lethal CD is usually due to heterozygous mutations in SOX9, a major regulator of chondrocytic development. We present a detailed clinical and molecular characterization of nine Brazilian CD patients. Infants were either stillborn (n = 2) or died shortly after birth and presented similar phenotypes. Sex-reversal was observed in one of three chromosomally male patients. Sequencing of SOX9 revealed new heterozygous mutations in seven individuals. Six patients had mutations that resulted in premature transcriptional termination, while one infant had a single-nucleotide substitution at the conserved splice-site acceptor of intron 1. No clear genotype-phenotype correlations were observed. This study highlights the diversity of SOX9 mutations leading to lethal CD, and expands the group of known genetic alterations associated with this skeletal dysplasia.

Resumo 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.

Abstract Human reproduction goes through many challenges to its success and in many cases it fails. Cases of pregnancy loss are common outcomes for pregnancies, and implantation failures (IF) are common in assisted reproduction attempts. Although several risk factors have already been linked to adverse outcomes in reproduction, many cases remain without a definitive cause. Genetics of female reproduction is a field that may bring some pieces of this puzzle; however, there are no well-defined genes that might be related to the risk for recurrent pregnancy loss (RPL) and IF. Here, we present a literature review of the studies of genetic association in RPL and IF carried out in the Brazilian population and complemented with a database search to explore genes previously related to RPL and IF, where a search for genes previously involved in these conditions was performed in OMIM, HuGE, and CTD databases. Finally, we present the next steps for reproductive genetics investigation, through genomic sequencing analyses and discuss future plans in the study of RPL genetics. The combined strategy of looking for literature and databases is useful to raise hypotheses and to identify underexplored genes related to RPL and IF.

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.

There is limited evidence about the use of medications among pregnant women with COVID-19, as well as risk factors for hospitalization due to COVID-19 in pregnancy. We aimed to describe the use of medications among SARS-CoV-2-positive pregnant women at the time around infection and identify predictors for hospitalization due to COVID-19 in two hospitals in Brazil. This is a hospital record-based study among pregnant women with positive SARS-CoV-2 tests between March 2020 and August 2022 from two Brazilian hospitals. Characteristics of sociodemographic, obstetrical, and COVID-19 symptoms were extracted retrospectively. The prevalence use of medications was based on self-reported use, and this was administered at the hospital. Logistic regression was used to estimate predictors of hospitalization due to COVID-19. There were 278 pregnant women included in the study, of which 41 (14.7%) required hospitalization due to COVID-19. The remaining 237 (85.3%) had mild symptoms or were asymptomatic. Most of the women had the infection in the third trimester (n=149; 53.6%). The most prevalent medications used across all trimesters were analgesics (2.4% to 20.0%), antibacterials (15.0% to 23.1%), and corticosteroids (7.2% to 10.4%). Pre- or gestational hypertensive disorder (odds ratio (OR) 4.94, 95% confidence interval (CI) 1.65, 14.87) and having at least one dose of vaccine against SARS-CoV-2 (OR 0.13, 95% CI 0.04, 0.39) were associated with hospitalization due to COVID-19. Analgesics, antibacterials, and corticosteroids were the most frequently used medications among pregnant women with COVID-19. Women with hypertensive disorders have almost a five-fold increased risk of hospitalization due to COVID-19. Vaccination was the strongest protective factor for severe COVID-19. The COVID-19 vaccination among pregnant women should be promoted, and pregnant women diagnosed with COVID-19 who have hypertensive disorders should be closely monitored.

Abstract Northeast Brazil was the first region to detect a significant increase in babies born with microcephaly associated with prenatal zika virus infection in 2015. Rio Grande do Sul (RS) state was less impacted due to the temperate climate preventing the spread of the vector. This study investigated the prevalence and etiology of congenital microcephaly in RS in two different periods. This cross-sectional descriptive study included all live births with congenital microcephaly in RS from 2015 to 2022. Cases were divided into two groups: P1 “outbreak” (2015-16); and P2 “endemic” (2017-22). There were 58 cases of microcephaly (3.8/10,000) in P1 and 148 (1.97/10,000) in P2. Congenital Zika Virus infection was the etiology in 5.2% (n=3) in P1 and 6.7% (n=10) in P2. In conclusion, although the ZIKV outbreak in Brazil has receded, RS remains an area of concern, with a possible slight increase of live births with microcephaly secondary to ZIKV prenatal infection relative to the number of cases due to congenital infections. The broader distribution of the vector Aedes aegypti with warmer temperatures in our state might be linked to the increase in recent years. This study can be an alert to other regions of temperate or subtropical climates.

Abstract Evidence indicates that oral microbiota plays a crucial role in human health and disease. For instance, diseases with multifactorial etiology, such as periodontitis and caries, which cause a detrimental impact on human well-being and health, can be caused by alterations in the host-microbiota interactions, where non-pathogenic bacteria give way to pathogenic orange/red-complex bacterial species (a change from a eubiotic to dysbiotic state). In this scenario, where thousands of oral microorganisms, including fungi, archaea, and phage species, and their host are co-evolving, a set of phenomena, such as the arms race and Red or Black Queen dynamics, are expected to operate. We review concepts on the subject and revisit the nature of bacterial complexes linked to oral health and diseases, as well as the problem of the bacterial resistome in the face of the use of antibiotics and what is the impact of this on the evolutionary trajectory of the members of this symbiotic ecosystem. We constructed a 16SrRNA tree to show that adaptive consortia of oral bacterial complexes do not necessarily rescue phylogenetic relationships. Finally, we remember that oral health is not exempt from health disparity trends in some populations, such as Native Americans, when compared with non-Indigenous people.

Abstract Oculocutaneous albinism (OCA) is a heterogeneous group of genetic disorders involving deficiencies in melanin biosynthesis, with consequent skin, hair, and eye hypopigmentation. The world prevalence is estimated at 1/17,000, but there is high variability among populations. The affected individuals, besides clinical complications, can suffer from discrimination. The Brazilian population is highly admixed, with isolated and inbred communities. Previous reports indicated the presence of diverse isolated communities with a high prevalence of OCA in Brazil. The present work sought to review and characterize clusters of albinism in this country based on scientific literature search, newspapers, and websites. We identified and characterized 18 clusters, 13 confirmed by scientific studies. Seven clusters are in the Northeast region, with predominant African ancestry, and seven others in indigenous communities, particularly among the Kaingaing in South Brazil. Isolation and inbreeding associated with founder effects seem to be the most plausible explanation. Molecular studies and clinical classification are still limited. Their localization in deprived regions with poor infrastructure makes them particularly vulnerable to the social and clinical consequences of lacking melanin. We reinforce the need for a tailored approach to these communities, including appropriate medical care, social support, and genetic counselling.

Zika virus (ZIKV) cause Congenital Zika Syndrome (CZS) in individuals exposed during pregnancy. Studies have shown that ZIKV infection positively regulates the miR-124 expression in neural cells, which leads to a decrease of TFRC, a gene targeted of this miRNA. Both miR-124 and TFRC exhibit a pivotal role in nervous system development. Therefore, in this study we aimed to investigate whether genetic variants that affect the expression of these genes could act together with ZIKV to increase the risk of individuals developing CZS. TFRC rs406271 and MIR-124-1 rs531564 polymorphisms were genotyped, using TaqMan® Genotyping Assays, in a sample of children who were exposed to ZIKV during pregnancy, of whom 40 were born with CZS and 48 without congenital anomalies. We identified that individuals with CZS presented a higher frequency of CG genotype of rs531564 polymorphism in MIR-124-1 (p=0.048), which is associated with increased expression of miR-124. Since ZIKV also upregulates the expression of this miRNA, the presence of CG genotype in individuals exposed to the virus could lead to a scenario of overexpression of miR-124 in the brain. Since teratogenesis is a multifactorial event, this genetic finding could partly explain why such individuals are more susceptible to CZS, considering both the downregulation of important neurodevelopment genes, as well as deregulation of the neurogenesis process. Thus, we provide preliminary evidence about a possible genetic risk factor to CZS and highlight the importance of analyzing functional polymorphisms related to epigenetic modulators of neurodevelopment genes in the context of ZIKV teratogenesis.

Abstract 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.

Abstract Objective This study aims to describe clinical findings and determine the medium-term survival of congenital zika syndrome (CZS) suspected cases. Methods A retrospective cohort study using routine register-based linked data. It included all suspected cases of CZS born in Brazil from January 1, 2015, to December 31, 2018, and followed up from birth until death, 36 months, or December 31, 2018, whichever came first. Latent class analysis was used to cluster unconfirmed cases into classes with similar combinations of anthropometry at birth, imaging findings, maternally reported rash, region, and year of birth. Kaplan–Meier curves were plotted, and Cox proportional hazards models were fitted to determine mortality up to 36 months. Results We followed 11,850 suspected cases of CZS, of which 28.3% were confirmed, 9.3% inconclusive and 62.4% unconfirmed. Confirmed cases had almost two times higher mortality when compared with unconfirmed cases. Among unconfirmed cases, we identified three distinct clusters with different mortality trajectories. The highest mortality risk was observed in those with abnormal imaging findings compatible with congenital infections (HR = 12.6; IC95%8.8–18.0) and other abnormalities (HR = 11.6; IC95%8.6–15.6) compared with those with normal imaging findings. The risk was high in those with severe microcephaly (HR = 8.2; IC95%6.4–10.6) and macrocephaly (HR = 6.6; IC95%4.5–9.7) compared with normal head size. Conclusion Abnormal imaging and head circumference appear to be the main drivers of the increased mortality among suspected cases of CZS. We suggest identifying children who are more likely to die and have a greater need to optimise interventions and resource allocation regardless of the final diagnoses.

Abstract. Objective:. Prenatal infection with the Zika virus (ZIKV) can lead to congenital Zika syndrome (CZS), characterized by microcephaly and brain injury. However, there are questions regarding the prevalence of microcephaly/CZS after the ZIKV outbreak in defined geographic areas. This study aimed to identify adverse outcomes in live births of fetuses exposed in utero to the ZIKV, compared to unexposed births, as well as maternal sociodemographic, delivery, and birth characteristics. Methods:. Here, we conducted a cross-sectional observational study to investigate the characteristics of all live births in the city of Tangará da Serra, Mato Grosso, Brazil, in 2016, after the outbreak of ZIKV infection in late 2015. All live births of children to women residing in the municipality of Tangará da Serra between January 1 and December 31, 2016, were evaluated, and head circumference was measured at birth and after 24 hours. Children born with microcephaly or a maternal history of confirmed or suspected prenatal ZIKV infection were evaluated by a multidisciplinary team. The outcomes of the exposed and non-exposed children were compared. Prevalence ratios and their respective 95% confidence intervals were calculated for sociodemographic, delivery, and live birth characteristics. Results:. Of 1,441 live births, 106 (7.3%) were from mothers with confirmed or highly probable exposure to ZIKV. The prevalence of severe congenital microcephaly (41.7/10,000) in Tangará da Serra in 2016 was ten-fold higher than that in Latin America before 2015. Conclusion:. This study may serve as a model to investigate possible outbreaks of infections in a defined geographical space in the future.

BackgroundChildren with congenital Zika syndrome (CZS) have severe damage to the peripheral and central nervous system (CNS), greatly increasing the risk of death. However, there is no information on the sequence of the underlying, intermediate, immediate, and contributing causes of deaths among these children. The aims of this study are describe the sequence of events leading to death of children with CZS up to 36 months of age and their probability of dying from a given cause, 2015 to 2018.Methods and findingsIn a population-based study, we linked administrative data on live births, deaths, and cases of children with CZS from the SINASC (Live Birth Information System), the SIM (Mortality Information System), and the RESP (Public Health Event Records), respectively. Confirmed and probable cases of CZS were those that met the criteria established by the Brazilian Ministry of Health. The information on causes of death was collected from death certificates (DCs) using the World Health Organization (WHO) DC template. We estimated proportional mortality (PM%) among children with CZS and among children with non-Zika CNS congenital anomalies (CA) by 36 months of age and proportional mortality ratio by cause (PMRc). A total of 403 children with confirmed and probable CZS who died up to 36 months of age were included in the study; 81.9% were younger than 12 months of age. Multiple congenital malformations not classified elsewhere, and septicemia unspecified, with 18 (PM = 4.5%) and 17 (PM = 4.2%) deaths, respectively, were the most attested underlying causes of death. Unspecified septicemia (29 deaths and PM = 11.2%) and newborn respiratory failure (40 deaths and PM = 12.1%) were, respectively, the predominant intermediate and immediate causes of death. Fetuses and newborns affected by the mother's infectious and parasitic diseases, unspecified cerebral palsy, and unspecified severe protein-caloric malnutrition were the underlying causes with the greatest probability of death in children with CZS (PMRc from 10.0 to 17.0) when compared to the group born with non-Zika CNS anomalies. Among the intermediate and immediate causes of death, pneumonitis due to food or vomiting and unspecified seizures (PMRc = 9.5, each) and unspecified bronchopneumonia (PMRc = 5.0) were notable. As contributing causes, fetus and newborn affected by the mother's infectious and parasitic diseases (PMRc = 7.3), unspecified cerebral palsy, and newborn seizures (PMRc = 4.5, each) were more likely to lead to death in children with CZS than in the comparison group. The main limitations of this study were the use of a secondary database without additional clinical information and potential misclassification of cases and controls.ConclusionThe sequence of causes and circumstances involved in the deaths of the children with CZS highlights the greater vulnerability of these children to infectious and respiratory conditions compared to children with abnormalities of the CNS not related to Zika.

Background Children with congenital Zika syndrome (CZS) have severe damage to the peripheral and central nervous system (CNS), greatly increasing the risk of death. However, there is no information on the sequence of the underlying, intermediate, immediate, and contributing causes of deaths among these children. The aims of this study are describe the sequence of events leading to death of children with CZS up to 36 months of age and their probability of dying from a given cause, 2015 to 2018. Methods and findings In a population-based study, we linked administrative data on live births, deaths, and cases of children with CZS from the SINASC (Live Birth Information System), the SIM (Mortality Information System), and the RESP (Public Health Event Records), respectively. Confirmed and probable cases of CZS were those that met the criteria established by the Brazilian Ministry of Health. The information on causes of death was collected from death certificates (DCs) using the World Health Organization (WHO) DC template. We estimated proportional mortality (PM%) among children with CZS and among children with non-Zika CNS congenital anomalies (CA) by 36 months of age and proportional mortality ratio by cause (PMRc). A total of 403 children with confirmed and probable CZS who died up to 36 months of age were included in the study; 81.9% were younger than 12 months of age. Multiple congenital malformations not classified elsewhere, and septicemia unspecified, with 18 (PM = 4.5%) and 17 (PM = 4.2%) deaths, respectively, were the most attested underlying causes of death. Unspecified septicemia (29 deaths and PM = 11.2%) and newborn respiratory failure (40 deaths and PM = 12.1%) were, respectively, the predominant intermediate and immediate causes of death. Fetuses and newborns affected by the mother’s infectious and parasitic diseases, unspecified cerebral palsy, and unspecified severe protein-caloric malnutrition were the underlying causes with the greatest probability of death in children with CZS (PMRc from 10.0 to 17.0) when compared to the group born with non-Zika CNS anomalies. Among the intermediate and immediate causes of death, pneumonitis due to food or vomiting and unspecified seizures (PMRc = 9.5, each) and unspecified bronchopneumonia (PMRc = 5.0) were notable. As contributing causes, fetus and newborn affected by the mother’s infectious and parasitic diseases (PMRc = 7.3), unspecified cerebral palsy, and newborn seizures (PMRc = 4.5, each) were more likely to lead to death in children with CZS than in the comparison group. The main limitations of this study were the use of a secondary database without additional clinical information and potential misclassification of cases and controls. Conclusion The sequence of causes and circumstances involved in the deaths of the children with CZS highlights the greater vulnerability of these children to infectious and respiratory conditions compared to children with abnormalities of the CNS not related to Zika. Maria da Conceição Costa and colleagues investigate the sequence of events leading to death of children with Congenital Zika syndrome up to 36 months of age. Author summary Why was this study done? Children with congenital Zika syndrome (CZS) have a broad spectrum of clinical manifestations due to sequelae of central and peripheral nervous system damage that can impair important vital functions and greatly increase the risk of death in affected children. Little is known about the circumstances involved in the death of children affected by this syndrome. Analysis of the sequences of causes attested on the death certificate (DC) can contribute to this understanding and thus support the implementation of health programs and specific postnatal protocols to meet the needs of these children. Brazil was the country with the highest number of live births with CZS. What did the researchers do and find? We linked administrative data of all reporting live births, deaths, and notification of probable and confirmed CZS cases in Brazil in the period from January 1, 2015 to December 31, 2018. We analyzed the proportional mortality of the main underlying, intermediate, immediate, and contributing causes of death of 403 children with CZS up to 36 months age and compared with the same causes of death of 734 children with non-Zika–related CNS congenital anomalies (CA) who died by 36 months of age from the proportional mortality ratio. The leading underlying causes of death for children with CZS were multiple congenital malformations not classified elsewhere and unspecified septicemia. What do these findings mean? The sequence of causes and circumstances involved in the deaths of the CZS children by 36 months age, in Brazil, highlighted the greater vulnerability of these children to infectious and respiratory conditions. It is necessary to develop evidence-based health protocols and raising awareness of conditions associated with high mortality in children affected by congenital Zika virus infection to guide health professionals responsible for caring for these children.

Summary: Background: Knowledge regarding the risks associated with Zika virus (ZIKV) infections in pregnancy has relied on individual studies with relatively small sample sizes and variable risk estimates of adverse outcomes, or on surveillance or routinely collected data. Using data from the Zika Brazilian Cohorts Consortium, this study aims, to estimate the risk of adverse outcomes among offspring of women with RT-PCR-confirmed ZIKV infection during pregnancy and to explore heterogeneity between studies. Methods: We performed an individual participant data meta-analysis of the offspring of 1548 pregnant women from 13 studies, using one and two-stage meta-analyses to estimate the absolute risks. Findings: Of the 1548 ZIKV-exposed pregnancies, the risk of miscarriage was 0.9%, while the risk of stillbirth was 0.3%. Among the pregnancies with liveborn children, the risk of prematurity was 10,5%, the risk of low birth weight was 7.7, and the risk of small for gestational age (SGA) was 16.2%. For other abnormalities, the absolute risks were: 2.6% for microcephaly at birth or first evaluation, 4.0% for microcephaly at any time during follow-up, 7.9% for neuroimaging abnormalities, 18.7% for functional neurological abnormalities, 4.0% for ophthalmic abnormalities, 6.4% for auditory abnormalities, 0.6% for arthrogryposis, and 1.5% for dysphagia. This risk was similar in all sites studied and in different socioeconomic conditions, indicating that there are not likely to be other factors modifying this association. Interpretation: This study based on prospectively collected data generates the most robust evidence to date on the risks of congenital ZIKV infections over the early life course. Overall, approximately one-third of liveborn children with prenatal ZIKV exposure presented with at least one abnormality compatible with congenital infection, while the risk to present with at least two abnormalities in combination was less than 1.0%. Funding: National Council for Scientific and Technological Development - Brazil (Conselho Nacional de Desenvolvimento Científico e Tecnológico – CNPq); Wellcome Trust and the United Kingdom's Department for International Development; European Union's Horizon 2020 research and innovation program; Medical Research Council on behalf of the Newton Fund and Wellcome Trust; National Institutes of Health/National Institute of Allergy and Infectious Diseases; Foundation Christophe et Rodolphe Mérieux; Coordination for the improvement of Higher Education Personnel (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Capes); Ministry of Health of Brazil; Brazilian Department of Science and Technology; Foundation of Research Support of the State of São Paulo (Fundação de Amparo à Pesquisa do Estado de São Paulo – FAPESP); Foundation of Research Support of the State of Rio de Janeiro (Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro – FAPERJ); Foundation of Support for Research and Scientific and Technological Development of Maranhão; Evandro Chagas Institute/Brazilian Ministry of Health (Instituto Evandro Chagas/Ministério da Saúde); Foundation of Research Support of the State of Goiás (Fundação de Amparo à Pesquisa do Estado de Goiás – FAPEG); Foundation of Research Support of the State of Rio Grande do Sul (Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul – FAPERGS); Foundation to Support Teaching, Research and Assistance at Hospital das Clínicas, Faculty of Medicine of Ribeirão Preto (Fundação de Apoio ao Ensino, Pesquisa e Assistência do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto); São Paulo State Department of Health (Secretaria de Saúde do Estado de São Paulo); Support Foundation of Pernambuco Science and Technology (Fundação de Amparo à Ciência e Tecnologia de Pernambuco – FACEPE).

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.

Introdução: Os defeitos congênitos são alterações estruturais ou funcionais que acontecem durante a vida intra-uterina. 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.

Abstract Pregnant women may be at higher risk of severe complications associated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which may lead to obstetrical complications. We performed a case control study comparing pregnant women with severe coronavirus disease 19 (cases) to pregnant women with a milder form (controls) enrolled in the COVI-Preg international registry cohort between March 24 and July 26, 2020. Risk factors for severity, obstetrical and immediate neonatal outcomes were assessed. A total of 926 pregnant women with a positive test for SARS-CoV-2 were included, among which 92 (9.9%) presented with severe COVID-19 disease. Risk factors for severe maternal outcomes were pulmonary comorbidities [aOR 4.3, 95% CI 1.9–9.5], hypertensive disorders [aOR 2.7, 95% CI 1.0–7.0] and diabetes [aOR2.2, 95% CI 1.1–4.5]. Pregnant women with severe maternal outcomes were at higher risk of caesarean section [70.7% (n = 53/75)], preterm delivery [62.7% (n = 32/51)] and newborns requiring admission to the neonatal intensive care unit [41.3% (n = 31/75)]. In this study, several risk factors for developing severe complications of SARS-CoV-2 infection among pregnant women were identified including pulmonary comorbidities, hypertensive disorders and diabetes. Obstetrical and neonatal outcomes appear to be influenced by the severity of maternal disease.

A exposição humana a contaminantes ambientais é onipresente. Uma grande preocupação em relação à população que vive perto de fontes poluentes é o risco potencial de efeitos adversos para as gestações, especialmente defeitos congênitos. Excetuando-se o mercúrio, o chumbo e os bifenis pliclorinados (PCBs), não há uma evidência clara de teratogenicidade causada por outros contaminantes ambientais, possivelmente devido a dificuldades metodológicas. Contrariamente ao que ocorre em experimentos com animais de laboratório, as pessoas são raramente expostas a um único contaminante potencialmente perigoso. Porém, a maioria das informações que documentam efeitos adversos secundários à contaminação ambiental na saúde reprodutiva são oriundas de exposição a somente um agente e há pouca informação disponível sobre de que maneira dois ou mais contaminantes ambientais podem afetar a gestação. Este artigo revisará as abordagens metodológicas utilizadas para se dispor de um acesso aos resultados adversos decorrentes da exposição aos poluentes e seus principais resultados.

O Sistema Nacional de Informações sobre Agentes Teratogênicos (SIAT) foi implantado em Porto Alegre, Rio Grande do Sul, em 1990, com a proposta de fornecer a médicos e à população em geral informações rápidas e atualizadas sobre os riscos reprodutivos relacionados à exposição a agentes teratogênicos. O SIAT, que foi o primeiro serviço deste tipo a operar na América Latina também é uma importante fonte de dados para investigações prospectivas sobre teratogenicidade em humanos. Neste artigo nós relatamos a experiência deste serviço nos seus primeiros 11 anos de funcionamento e suas possíveis contribuições. A introdução em anos posteriores de outros três serviços similares em outras três capitais brasileiras (Rio de Janeiro, São Paulo e Salvador), faz com que a integração destes quatro serviços dentro de uma rede nacional coordenada aumente o potencial do SIAT tanto no que diz respeito a cuidados de saúde como à pesquisa.

Abstract Background Due to the diversity of studies in animal models reporting that molecular mechanisms are involved in the teratogenic effect of the Zika virus (ZIKV), the objective of the present study is to evaluate the methodological quality of these studies, as well as to demonstrate which genes and which molecular pathways are affected by ZIKV in different animal models. Methods This search will be performed in four databases: PubMed/MEDLINE, EMBASE, Web of Science, and Scopus, as well as in the grey literature. The studies selection process will be reported through the PRISMA Statement diagram model. All studies describing the molecular mechanisms possibly involved in the development of malformations caused by embryonic/fetal ZIKV exposure in animal models with an appropriate control group and methodology will be included (including, for instance, randomized and non-randomized studies). All animals used as experimental models for ZIKV teratogenesis may be included as long as exposure to the virus occurred during the embryonic/fetal period. From the selected studies, data will be extracted using a previously prepared standard form. Bias risk evaluation will be conducted following the SYRCLE’s Risk of Bias tool. All data obtained will be tabulated and organized by outcomes (morphological and molecular). Discussion With the proposed systematic review, we expect to present results about the methodological quality of the published studies with animal models that investigated the molecular mechanisms involved in the teratogenic effect of ZIKV, as well as to show the studies with greater reliability. Systematic review registration PROSPERO CRD42019157316

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.

Abstract Zika virus was responsible for the microcephaly epidemic in Brazil which began in October 2015 and brought great challenges to the scientific community and health professionals in terms of diagnosis and classification. Due to the difficulties in correctly identifying Zika cases, it is necessary to develop an automatic procedure to classify the probability of a CZS case from the clinical data. This work presents a machine learning algorithm capable of achieving this from structured and unstructured available data. The proposed algorithm reached 83% accuracy with textual information in medical records and image reports and 76% accuracy in classifying data without textual information. Therefore, the proposed algorithm has the potential to classify CZS cases in order to clarify the real effects of this epidemic, as well as to contribute to health surveillance in monitoring possible future epidemics.

Five years after the identification of Zika virus as a human teratogen, we reviewed the early clinical manifestations, collectively called congenital Zika syndrome (CZS). Children with CZS have a very poor prognosis with extremely low performance in motor, cognitive, and language development domains, and practically all feature severe forms of cerebral palsy. However, these manifestations are the tip of the iceberg, with some children presenting milder forms of deficits. Additionally, neurodevelopment can be in the normal range in the majority of the non-microcephalic children born without brain or eye abnormalities. Vertical transmission and the resulting disruption in development of the brain are much less frequent when maternal infection occurs in the second half of the pregnancy. Experimental studies have alerted to the possibility of other behavioral outcomes both in prenatally infected children and in postnatal and adult infections. Cofactors play a vital role in the development of CZS and involve genetic, environmental, nutritional, and social determinants leading to the asymmetric distribution of cases. Some of these social variables also limit access to multidisciplinary professional treatment.

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.

Erythema nodosum leprosum (ENL) is an inflammatory complication caused by a dysregulated immune response to Mycobacterium leprae. Some Toll-like receptors (TLRs) have been identified as capable of recognizing antigens from M. leprae, triggering a wide antimicrobial and inflammatory response. Genetic polymorphisms in these receptors could influence in the appearance of ENL as well as in its treatment. Thus, the objective of this work was to evaluate the association of genetic variants of TLRs genes with the response to treatment of ENL with thalidomide and prednisone. A total of 162 ENL patients were recruited from different regions of Brazil and clinical information was collected from their medical records. Genomic DNA was isolated from blood and saliva samples and genetic variants in TLR1 (rs4833095), TLR2 (rs3804099), TLR4 (rs1927914), and TLR6 (rs5743810) genes were genotyped by TaqMan real-time PCR system. In order to evaluate the variants' association with the dose of the medications used during the treatment, we applied the Generalized Estimating Equations (GEE) analysis. In the present sample, 123 (75.9%) patients were men and 86 (53.1%) were in treatment for leprosy during the ENL episode. We found an association between polymorphisms in TLR1/rs4833095, TLR2/rs3804099, TLR4/rs1927914, and TLR6/rs5783810 with the dose variation of thalidomide in a time-dependent manner, i.e., the association with the genetic variant and the dose of the drug was different depending on the moment of the treatment evaluated. In addition, we identified that the association of polymorphisms in TLR1/rs4833095, TLR2/rs3804099, and TLR6/rs5783810 with the dose variation of prednisone also were time-dependent. Despite these associations, in all the interactions found, the influence of genetic variants on dose variation was not clinically relevant for therapeutic changes. The results obtained in this study show that TLRs polymorphism might play a role in the response to ENL treatment, however, in this context, they could not be considered as useful biomarkers in the clinical setting due small differences in medication doses. A larger sample size with patients with a more genetic profile is fundamental in order to estimate the association of genetic variants with the treatment of ENL and their clinical significance.

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 (2001–2016) 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, 0.74–0.85) 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 2001–2016 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.

ABSTRACT Infections caused by arboviruses that have mostly impacted the Brazilian morbidity and mortality are caused by the same vector, Aedes aegypti. Preventive actions related to the vector are the most effective strategies in the prevention and control of these diseases. This study aimed to associate the knowledge on the vector that transmits dengue, Zika and chikungunya with the sociodemographic and behavioral preventive practices towards Aedes aegypti in the municipality of Tangara da Serra, Mato Grosso State, in the Brazilian Legal Amazon. A probabilistic urban population sampling was obtained by clusters: census sectors and households. The sample size calculation considered 10% of loss and a 1.5 design effect. This is a cross-sectional research carried out through a household survey in February and March 2018. There were 583 participants. The study variables were knowledge on the vector, sociodemographic characteristics and preventive practices related to the vector. The statistical analysis was based on a bivariate analysis and Poisson multiple regressions. Inadequate or insufficient knowledge on the vector Aedes aegypti remained associated with education in the categories illiterate (p

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

The identification of thalidomide–Cereblon-induced SALL4 degradation has brought new understanding for thalidomide embryopathy (TE) differences across species. Some questions, however, regarding species variability, still remain. The aim of this study was to detect sequence divergences between species, affected or not by TE, and to evaluate the regulated gene co-expression in a murine model. Here, we performed a comparative analysis of proteins experimentally established as affected by thalidomide exposure, evaluating 14 species. The comparative analysis, regarding synteny, neighborhood, and protein conservation, was performed in 42 selected genes. Differential co-expression analysis was performed, using a publicly available assay, GSE61306, which evaluated mouse embryonic stem cells (mESC) exposed to thalidomide. The comparative analyses evidenced 20 genes in the upstream neighborhood of NOS3, which are different between the species who develop, or not, the classic TE phenotype. Considering protein sequence alignments, RECQL4, SALL4, CDH5, KDR, and NOS2 proteins had the biggest number of variants reported in unaffected species. In co-expression analysis, Crbn was a gene identified as a driver of the co-expression of other genes implicated in genetic, non-teratogenic, limb reduction defects (LRD), such as Tbx5, Esco2, Recql4, and Sall4; Crbn and Sall4 were shown to have a moderate co-expression correlation, which is affected after thalidomide exposure. Hence, even though the classic TE phenotype is not identified in mice, a deregulatory Crbn-induced mechanism is suggested in this animal. Functional studies are necessary, especially evaluating the genes responsible for LRD syndromes and their interaction with thalidomide–Cereblon.

Objective: The aim of this study was to identify the causes of congenital microcephaly in Rio Grande do Sul, a state in southern Brazil, where no ZIKV outbreak was detected, from December 2015 to December 2016, which was the period when ZIKV infection was at its peak in northeast Brazil. Methods: This was a cross‐sectional study where all notifications of congenital microcephaly in the state of Rio Grande do Sul were included for analysis. Evaluation of cases followed the guidelines of the Brazilian Ministry of Health. Dysmorphological and neurological evaluations were performed by a specialized team, and genetic tests and neuroimaging were performed when clinically indicated. STORCH infections were diagnosed using standard tests. ZIKV infection was diagnosed through maternal serum RT‐PCR and/or neuroimaging associated with clinical/epidemiological criteria. Results: From 153 744 registered live births in the study period, 148 cases were notified, but 90 (60.8%) of those were later excluded as “non‐confirmed” microcephaly. In the 58 confirmed cases of microcephaly (prevalence = 3.8/10 000 live births), congenital infections (syphilis, toxoplasmosis, cytomegalovirus, and ZIKV) constituted the predominant etiology (50.0%), followed by isolated CNS (15.5%), and genetic syndromes (10.3%). Congenital ZIKV syndrome (CZS) with typical phenotype was diagnosed in three cases (5.2% of all confirmed microcephaly cases or 10.4% of all congenital infections). Conclusion: In Rio Grande do Sul, where no outbreak of ZIKV infection was recorded, congenital infections were the leading cause of congenital microcephaly, and the attributable risk for CZS in the etiology of microcephaly was 5.2%. Resumo: Objetivo: Identificar as causas da microcefalia congênita no Rio Grande do Sul, Região Sul do Brasil, onde não foi detectado surto de ZIKV, de dezembro de 2015 a dezembro de 2016. Esse foi o período em que a infecção por ZIKV estava em seu auge no Nordeste do Brasil. Métodos: Este é um estudo transversal no qual todas as notificações de microcefalia congênita no estado do Rio Grande do Sul foram incluídas para análise. A avaliação dos casos seguiu as orientações do Ministério da Saúde. A avaliação dismorfológica e neurológica foi feita por uma equipe especializada e os testes genéticos e as neuroimagens foram feitos quando indicado clinicamente. As infecções STORCH (Sífilis, Toxoplasmose, Rubéola, Citomegalovírus e Herpes simples) foram diagnosticadas utilizando testes padrão. A infecção por ZIKV foi diagnosticada por meio da transcriptase reversa seguida de reação em cadeia da polimerase (RT‐PCR) no soro materno e/ou neuroimagem associada a critérios clínicos/epidemiológicos. Resultados: De 153.744 nascidos vivos registrados no período do estudo, 148 bebês foram casos notificados, porém 90 (60,8%) casos foram excluídos posteriormente como microcefalia “não confirmada”. Nos 58 casos confirmados de microcefalia (prevalência = 3,8/10.000 nascidos vivos), as infecções congênitas (sífilis, toxoplasmose, citomegalovírus e ZIKV) constituíram a etiologia predominante (50,0%), seguidas de doenças ligadas ao SNC isolado (15,5%) e síndromes genéticas (10,3%). A síndrome congênita do ZIKV (SCZ) com fenótipo típico foi diagnosticada em três casos (5,2% de todos os casos confirmados de microcefalia ou 10,4% de todas as infecções congênitas). Conclusão: No Rio Grande do Sul, Brasil, onde não foi registrado surto de infecção por ZIKV, a principal causa de microcefalia congênita foram infecções congênitas e o risco atribuível para SCZ na etiologia de microcefalia foi de 5,2%. Keywords: Microcephaly, ZIKV, Congenital infection, Palavras‐chave: Microcefalia, ZIKV, Infecção congênita

Objective: The aim of this study was to identify the causes of congenital microcephaly in Rio Grande do Sul, a state in southern Brazil, where no ZIKV outbreak was detected, from December 2015 to December 2016, which was the period when ZIKV infection was at its peak in northeast Brazil. Methods: This was a cross-sectional study where all notifications of congenital microcephaly in the state of Rio Grande do Sul were included for analysis. Evaluation of cases followed the guidelines of the Brazilian Ministry of Health. Dysmorphological and neurological evaluations were performed by a specialized team, and genetic tests and neuroimaging were performed when clinically indicated. STORCH infections were diagnosed using standard tests. ZIKV infection was diagnosed through maternal serum RT-PCR and/or neuroimaging associated with clinical/epidemiological criteria. Results: From 153 744 registered live births in the study period, 148 cases were notified, but 90 (60.8%) of those were later excluded as “non-confirmed” microcephaly. In the 58 confirmed cases of microcephaly (prevalence = 3.8/10 000 live births), congenital infections (syphilis, toxoplasmosis, cytomegalovirus, and ZIKV) constituted the predominant etiology (50.0%), followed by isolated CNS (15.5%), and genetic syndromes (10.3%). Congenital ZIKV syndrome (CZS) with typical phenotype was diagnosed in three cases (5.2% of all confirmed microcephaly cases or 10.4% of all congenital infections). Conclusion: In Rio Grande do Sul, where no outbreak of ZIKV infection was recorded, congenital infections were the leading cause of congenital microcephaly, and the attributable risk for CZS in the etiology of microcephaly was 5.2%. Resumo: Objetivo: Identificar as causas da microcefalia congênita no Rio Grande do Sul, Região Sul do Brasil, onde não foi detectado surto de ZIKV, de dezembro de 2015 a dezembro de 2016. Esse foi o período em que a infecção por ZIKV estava em seu auge no Nordeste do Brasil. Métodos: Este é um estudo transversal no qual todas as notificações de microcefalia congênita no estado do Rio Grande do Sul foram incluídas para análise. A avaliação dos casos seguiu as orientações do Ministério da Saúde. A avaliação dismorfológica e neurológica foi feita por uma equipe especializada e os testes genéticos e as neuroimagens foram feitos quando indicado clinicamente. As infecções STORCH (Sífilis, Toxoplasmose, Rubéola, Citomegalovírus e Herpes simples) foram diagnosticadas utilizando testes padrão. A infecção por ZIKV foi diagnosticada por meio da transcriptase reversa seguida de reação em cadeia da polimerase (RT-PCR) no soro materno e/ou neuroimagem associada a critérios clínicos/epidemiológicos. Resultados: De 153.744 nascidos vivos registrados no período do estudo, 148 bebês foram casos notificados, porém 90 (60,8%) casos foram excluídos posteriormente como microcefalia “não confirmada”. Nos 58 casos confirmados de microcefalia (prevalência = 3,8/10.000 nascidos vivos), as infecções congênitas (sífilis, toxoplasmose, citomegalovírus e ZIKV) constituíram a etiologia predominante (50,0%), seguidas de doenças ligadas ao SNC isolado (15,5%) e síndromes genéticas (10,3%). A síndrome congênita do ZIKV (SCZ) com fenótipo típico foi diagnosticada em três casos (5,2% de todos os casos confirmados de microcefalia ou 10,4% de todas as infecções congênitas). Conclusão: No Rio Grande do Sul, Brasil, onde não foi registrado surto de infecção por ZIKV, a principal causa de microcefalia congênita foram infecções congênitas e o risco atribuível para SCZ na etiologia de microcefalia foi de 5,2%. Keywords: Microcephaly, ZIKV, Congenital infection, Palavras-Chave: Microcefalia, ZIKV, Infecção congênita

Abstract Thalidomide is widely used for several diseases; however, it causes malformations in embryos exposed during pregnancy. The complete understanding of the mechanisms by which thalidomide affects the embryo development has not yet been obtained. The phenotypic similarity makes TE a phenocopy of syndromes caused by mutations in ESCO2, SALL4 and TBX5 genes. Recently, SALL4 and TBX5 were demonstrated to be thalidomide targets. To understand if these genes act in the TE development, we sequenced them in 27 individuals with TE; we verified how thalidomide affect them in human pluripotent stem cells (hPSCs) through a differential gene expression (DGE) analysis from GSE63935; and we evaluated how these genes are functionally related through an interaction network analysis. We identified 8 variants in ESCO2, 15 in SALL4 and 15 in TBX5. We compared allelic frequencies with data from ExAC, 1000 Genomes and ABraOM databases; eight variants were significantly different (p

Pigmentation variation in humans is influenced by complex genetic architecture in different populations. Here, the authors perform a genome-wide association analysis involving > 6,000 Latin Americans for pigmentation of skin and eyes, and identify known and novel genetic associations.

Latin Americans trace their ancestry to the admixture of Native Americans, Europeans and Sub-Saharan Africans. Here, the authors develop a novel haplotype-based approach and analyse over 6,500 Latin Americans to infer the geographically-detailed genetic structure of this population.

Since the 1960s, drugs have been known to cause teratogenic effects in humans. Such teratogenicity has been postulated to be influenced by genetics. The aim of this review was to provide an overview of the current knowledge on genetic susceptibility to drug teratogenicity in humans and reflect on future directions within the field of genetic teratology. We focused on 12 drugs and drug classes with evidence of teratogenic action, as well as 29 drugs and drug classes with conflicting evidence of fetal safety in humans. An extensive literature search was performed in the PubMed and EMBASE databases using terms related to the drugs of interest, congenital anomalies and fetal development abnormalities, and genetic variation and susceptibility. A total of 29 studies were included in the final data extraction. The eligible studies were published between 1999 and 2020 in 10 different countries, and comprised 28 candidate gene and 1 whole-exome sequencing studies. The sample sizes ranged from 20 to 9,774 individuals. Several drugs were investigated, including antidepressants (nine studies), thalidomide (seven studies), antiepileptic drugs (five studies), glucocorticoids (four studies), acetaminophen (two studies), and sex hormones (estrogens, one study; 17-alpha hydroxyprogesterone caproate, one study). The main neonatal phenotypic outcomes included perinatal complications, cardiovascular congenital anomalies, and neurodevelopmental outcomes. The review demonstrated that studies on genetic teratology are generally small, heterogeneous, and exhibit inconsistent results. The most convincing findings were genetic variants in SLC6A4, MTHFR, and NR3C1, which were associated with drug teratogenicity by antidepressants, antiepileptics, and glucocorticoids, respectively. Notably, this review demonstrated the large knowledge gap regarding genetic susceptibility to drug teratogenicity, emphasizing the need for further efforts in the field. Future studies may be improved by increasing the sample size and applying genome-wide approaches to promote the interpretation of results. Such studies could support the clinical implementation of genetic screening to provide safer drug use in pregnant women in need of drugs.

Resumo 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.

Abstract SARS-CoV-2 virus was first identified in the beginning of 2020 and has spread all over the world, causing the Coronavirus Disease 2019 (COVID-19) pandemic. The virus is a member of the Coronavirus family, which includes viruses that cause common cold, Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS). MERS and SARS are known by causing adverse events in pregnancy. Considering that SARS-CoV-2 is a new infection agent, little is known about the risk of its infection to human embryo/fetal development. However, SARS and MERS were associated with negative outcomes, such as miscarriage, preterm birth, intrauterine growth restriction and perinatal death. Here, we raise concerns and possibilities related the harmful potential of SARS-CoV-2 and COVID-19 to pregnancy, discussing symptoms, immunological changes during pregnancy, SARS-CoV-2 mutation rate (and the risks related to it). Finally, we point out recommendations to be performed by the scientific community and health care workers in order to identify and to manage potential risks to pregnant women and their babies.

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