A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Broncoespasmo induzido pelo exercício em adolescentes asmáticos obesos e não-obesos Exercise-induced bronchospasm in obese and non-obese asthmatic adolescents

OBJETIVO: Avaliar e comparar a frequência e intensidade do broncoespasmo induzido pelo exercício (BIE) em adolescentes asmáticos obesos e não-obesos. MÉTODOS: Estudo transversal e descritivo realizado com 39 adolescentes de ambos os sexos, com idade entre dez e 16 anos, divididos em dois grupos conforme o histórico clínico de asma e/ou rinite alérgica e o índice de massa corporal: asmáticos obesos (n=18); asmáticos não-obesos (n=21). Utilizou-se o teste de broncoprovocação com exercício para a avaliação do BIE, considerando-se positiva uma diminuição do volume expiratório forçado no primeiro segundo (VEF1) >15% do valor pré-exercício. Para avaliar a intensidade e a recuperação do BIE, foram calculadas a queda percentual máxima do VEF1 (QM%VEF1) e a área acima da curva (AAC0-30). A análise estatística utilizou o teste exato de Fischer para comparar a frequência de BIE e o teste de Mann-Whitney para a intensidade e recuperação. Rejeitou-se a hipótese de nulidade se p<0,05. RESULTADOS: Não houve diferença significativa na frequência de BIE entre os grupos de asmáticos obesos (50%) e não-obesos (38%). Entretanto, a queda máxima do VEF1 e a AAC0-30 foram maiores nos asmáticos obesos em comparação aos não-obesos (respectivamente 37,7% e 455 versus 24,5% e 214, p<0,03). CONCLUSÕES: A obesidade não contribuiu para o aumento da frequência do BIE em asmáticos e não-asmáticos, entretanto, a obesidade contribuiu para o aumento da intensidade e do tempo de recuperação da crise de BIE em asmáticos<br>OBJECTIVE: To assess and compare the frequency and severity of exercise-induced bronchospasm (EIB) in obese and non-obese asthmatic adolescents. METHODS: Cross-sectional and descriptive study with 39 subjects aged ten to 16 years of both genders divided into two groups according to clinical history of asthma and/or allergic rhinitis and body mass index, as follows: asthmatic obese (n=18) and asthmatic non-obese (n=21). An exercise bronchoprovocation test was applied to diagnose EIB and was considered positive if the forced expiratory volume in one second (FEV1) decreased >15% in relation to pre-exercise FEV1. Maximum percent of fall in FEV1 (MF%FEV1) and the area above the curve (AAC0-30) were calculated to evaluate the intensity and recovery of EIB. Fisher exact test was used to compare the frequency of EIB and Mann-Whitney test to compare the severity and recovery of EIB. Null hypothesis was rejected when p<0.05. RESULTS: No significant difference was found in the frequency of EIB between the asthmatic obese (50%) and non-obese (38%) adolescents. However, the MF%FEV1 and AAC0-30 were significantly higher in the asthmatic obese as compared to the asthmatic non-obese patients (respectively, 37.7% and 455 versus 24.5% e 214, p<0.03). CONCLUSIONS: Obesity did not contribute to the increase of the frequency of EIB in asthmatic and non-asthmatic patients. However, obesity contributed to the increase of severity and recovery time of EIB in asthmatic

Ferrovias, doenças e medicina tropical no Brasil da Primeira República Railroads, disease, and tropical medicine in Brazil under the First Republic

Aborda o impacto da malária no âmbito da modernização republicana, basicamente nas ferrovias, que asssumiram então o papel de integrar o território e operar a expansão simbólica e material da nação brasileira. Os cientistas destacados para debelar os surtos epidêmicos não se limitaram a realizar as campanhas. Fizeram observações sobre aspectos da doença, inclusive suas relações com hospedeiros e ambientes, contribuindo com novos conhecimentos e com a institucionalização, no Brasil, de novo campo que então se estabelecia nas potências coloniais européias: a medicina tropical. O artigo articula essas inovações - especialmente a teoria da infecção domiciliária - com as campanhas em prol de ferrovias e com estágio subseqüente no enfrentamento da malária no Brasil, nos anos 1920.<br>The article explores the impact of malaria on infrastructure works - above all, railroads - under the republican drive towards modernization. Railways helped tie the territory together and foster the symbolic and material expansion of the Brazilian nation. The scientists entrusted with vanquishing such epidemic outbreaks did not just conduct campaigns; they also undertook painstaking observations of aspects of the disease, including its relations to hosts and the environment, thus contributing to the production of new knowledge of malaria and to the institutionalization of a new field in Brazil, then taking root in Europe's colonies: "tropical medicine." The article shows the ties between these innovations (especially the theory of domiciliary infection) and the sanitary campaigns that helped the railways, which in the 1920s were followed by a new phase in Brazil's anti-malaria efforts