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ObjectivesTo analyse how previous comorbidities, ethnicity, regionality and socioeconomic development are associated with COVID-19 mortality in hospitalised children and adolescents.DesignCross-sectional observational study using publicly available data from the Brazilian Ministry of Health.SettingNationwide.Participants5857 patients younger than 20 years old, all of them hospitalised with laboratory-confirmed COVID-19, from 1 January 2020 to 7 December 2020.Main outcome measureWe used multilevel mixed-effects generalised linear models to study in-hospital mortality, stratifying the analysis by age, region of the country, presence of non-communicable diseases, ethnicity and socioeconomic development.ResultsIndividually, most of the included comorbidities were risk factors for mortality. Notably, asthma was a protective factor (OR 0.4, 95% CI 0.24 to 0.67). Having more than one comorbidity increased almost tenfold the odds of death (OR 9.67, 95% CI 6.89 to 13.57). Compared with white children, Indigenous, Pardo (mixed) and East Asian had significantly higher odds of mortality (OR 5.83, 95% CI 2.43 to 14.02; OR 1.93, 95% CI 1.48 to 2.51; OR 2.98, 95% CI 1.02 to 8.71, respectively). We also found a regional influence (higher mortality in the North—OR 3.4, 95% CI 2.48 to 4.65) and a socioeconomic association (lower mortality among children from more socioeconomically developed municipalities—OR 0.26, 95% CI 0.17 to 0.38)ConclusionsBesides the association with comorbidities, we found ethnic, regional and socioeconomic factors shaping the mortality of children hospitalised with COVID-19 in Brazil. Our findings identify risk groups among children that should be prioritised for public health measures, such as vaccination.

Background Although many studies identify the presence of comorbidities and socioeconomic vulnerabilities as risk factors for worse COVID-19 outcomes, few have addressed this issue in children. We aimed to study how these factors have impacted COVID-19 mortality in Brazilian children and adolescents. Methods This is an observational study using publicly available data from the Brazilian Ministry of Health. We studied 5,857 patients younger than 20 years old, all of them hospitalized with laboratory-confirmed COVID-19. We used multilevel mixed-effects generalized linear models to study mortality, stratifying the analysis by age, region of the country, presence of noncommunicable diseases, ethnicity, and socioeconomic development. Findings Individually, most of the comorbidities included were risk factors. Having more than one comorbidity increased almost tenfold the risk of death (OR 9.67 95%CI 6.89-13.57). Compared to White children, Indigenous, Pardo (mixed), and East Asian had a significantly higher risk of mortality. We also found a regional effect (higher mortality in the North), and a socioeconomic effect (higher mortality among children from less socioeconomically developed municipalities). Interpretation Besides the impact of comorbidities, we identified ethnic, regional, and socioeconomic effects shaping the mortality of children hospitalized with COVID-19 in Brazil. Putting these findings together, we propose that there is a syndemic among COVID-19 and noncommunicable diseases, driven and fostered by large-scale sociodemographic inequalities. Facing COVID-19 in Brazil must also include addressing these structural issues. Our findings also identify risk groups among children that should be prioritized for public health measures, such as vaccination.

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Background: Small for gestational age (SGA) children are defined as the one with birth weight and/or length 2 or more standard deviations below the population mean for gestational age. The underlying causes of pre and postnatal growth failure are diverse 1 . SGA boys present a high frequency of hypospadias (15 to 30%) of unknown etiology 2 . Objective: To analyze the prevalence of SGA individuals with hypospadias in a large cohort of 46, XY disorders of sex development (DSD) patients (n=272) followed in a tertiary center and to search for a molecular etiology associated with this phenotype. Patients and methods: We evaluated 30 SGA children with medium or proximal hypospadias, four of them presented syndromic characteristics associated. DNA samples of 24 patients were studied by target massively parallel sequencing (TPMS) using an amplicon-based capture panel of 63 genes related to DSD, and one by whole exome sequencing (WES). TPMS and WES were performed in the Illumina MiSEQ/HiSEQ platforms, respectively. Paired-end reads were aligned to the hg19 assembly of the human genome with BWA-MEM. Variants were called and annotated with Platypus and ANNOVAR. Results: The prevalence of SGA individuals with hypospadias in the 46, XY DSD cohort was 11%. Two children had clinical features of Silver-Russell syndrome and their diagnosis was confirmed (11p15 LOM) by MLPA. The two other syndromic patients were suspected with three M syndrome and Mulibrey Nanism. The TPMS study identified three likely pathogenic variants in these patients: p.Trp1538* and p.Gln813fs variants in compound heterozygosis in CUL7 gene and the homozygous p.Gly340fs variant in TRIM37 . Seven heterozygous variants with uncertain significance in 5 DSD related genes were identified: two in the DHX37 , p.V717I and p.A737T, associated with GATA4 p.P407R variant and with WWOX p.Y85D, respectively; the WT1 p.C350R variant, the IGF1R p.R1337C variant, and the BMP8B p. Arg116Cys variant. The frequency of likely pathogenic variants in SGA children with hypospadias was 10%. Conclusion: The low frequency of pathogenic allelic variants identified in SGA children with hypospadias indicates that other mechanisms, as epigenetic changes, may be involved in the etiology of this condition. 1 CLAYTON, P. E. et al. Management of the Child Born Small for Gestational Age through to Adulthood: A Consensus Statement of the International Societies of Pediatric Endocrinology and the Growth Hormone Research Society. The Journal Of Clinical Endocrinology & Metabolism, [s.l.], v. 92, n. 3, p.804-810, mar. 2007. The Endocrine Society. http://dx.doi.org/10.1210/jc.2006-2017. 2 MOREL, Y et al. Aetiological diagnosis of male sex ambiguity: a collaborative study. ...

Dedico este trabalho à minha família, pelo amor e apoio incondicionais, em especial, a meu pai (in memoriam), exemplo maior de que a realização de todo grande sonho começa com um sonhador. Dedico também às milhares de famílias que perderam entes queridos nesta pandemia. AGRADECIMENTOSA meus pais e minhas irmãs, pelo apoio incondicional, pelo suporte diário, e por uma formação pessoal centrada no amor.A minha esposa Natália, pelo amor e pela parceria de todos os dias, e pela compreensão nos momentos de ausência dedicados à elaboração deste trabalho.Aos meus familiares, pelo convívio fraterno e suporte.Aos meus amigos e às minhas amigas, fontes de inspiração, conforto e carinho.Ao Prof. Alexandre, grande amigo, mentor científico e mestre, cuja orientação extrapolou o campo da produção científica, transbordando para um intercâmbio de ideias e experiências que me tornaram uma pessoa melhor.Aos meus mestres que, durante a graduação e formação pediátrica, foram inestimáveis fontes de conhecimento que me moldaram enquanto pessoa e pediatra.À professora Berenice Bilharinho de Mendonça, exemplo pessoal e profissional, que acendeu precocemente em mim a chama da pesquisa científica. Aos professores Heloísa Marques, Antônio Augusto Silva e NelsonGouveia, membros da banca de qualificação, que contribuíram de maneira ímpar com relevantes sugestões para o aprimoramento desta tese.

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