RESUMO
ImportanceAdults with Down syndrome (DS) are at higher risk for severe outcomes of coronavirus disease 2019 (COVID-19), but further evidence is required to determine the exact risks for children with DS. The clinical features and epidemiological characteristics of COVID-19 in children with DS, and risk factors for severe outcomes, must be established to inform COVID-19 shielding advice and vaccination priority. ObjectiveTo determine risk factors for a severe course of COVID-19 in pediatric DS patients and to compare the prevalence of severe COVID-19 between pediatric patients with and without DS. DesignThis retrospective cohort study included pediatric cases (aged <18 years) with DS from the Trisomy 21 Research Society international survey and pediatric cases from the general population published by the US Centers for Disease Control and Prevention (COVID-NET) collected during the first wave of the COVID-19 pandemic (controls). SettingCohorts included 328 children with DS (127 hospitalized, 39%) and 224 children without DS (all hospitalized) with COVID-19. Of the pediatric DS patients, 64.1% were from low-to-middle-income countries (LMICs), and 35.9% from high-income countries (HICs). ParticipantsClinicians, family members, or caregivers completed the survey on behalf of children with DS affected by COVID-19. ResultsAmong the 328 COVID-19 patients with DS; older age, obesity, and epilepsy were significant risk factors for hospitalization; and age and thyroid disorder were significant risk factors for acute respiratory distress syndrome. The 127 hospitalized COVID-19 patients with DS had a higher incidence of cough, fever, nasal signs and shortness of breath than controls. Compared with controls, hospitalized children with DS (especially those from LMICs) had a higher prevalence of COVID-19-related medical complications (pneumonia, ARDS, acute renal failure). Conclusions and relevanceChildren with DS are at higher risk for severe COVID-19 than the general pediatric population. Efforts should be made to monitor the health of children and young people with DS during the ongoing pandemic and to report any COVID-19 signs and symptoms in a timely manner, especially for those who have comorbidities which are risk factors for severe COVID-19. When vaccination rollout for pediatric populations begins, children with DS should be prioritised. Key PointsO_ST_ABSQuestionC_ST_ABSWhat are the epidemiological and clinical characteristics of coronavirus disease 2019 (COVID-19) in paediatric patients with Down syndrome (DS)? FindingsHospitalised COVID-19 patients <18 years of age with DS from a range of countries had a higher incidence of respiratory symptoms, fever, and several medical complications from COVID-19 than patients without DS <18 years from the United States (US). Older age, obesity, and epilepsy were significant risk factors for hospitalisation among paediatric COVID-19 patients with DS; and age and thyroid disorder were significant risk factors for acute respiratory distress syndrome. Mortality rates were low in all paediatric COVID-19 patients (with and without DS), in contrast to previous findings in adults with DS (who exhibit higher mortality than those without DS). SignificanceChildren with DS are at increased risk for more severe presentations of COVID-19. Efforts should be made to ensure comprehensive and early detection of COVID-19 in this population, and to identify children with DS who present comorbidities that pose a risk for a severe course of COVID-19. Children with DS should be prioritised for COVID-19 vaccination as part of childrens vaccination programmes.
RESUMO
<p><b>AIM</b>To analyze the functional interactions of Cyclin with p53 and Atm in spermatogenesis and DNA double-strand break repair.</p><p><b>METHODS</b>Two lines of double knockout mice were generated. Spermatogenesis and double strand break repair mechanisms were analyzed in Cyclin A1 (Ccna1); p53- and Ccna1; Atm-double knockout mice.</p><p><b>RESULTS</b>The block in spermatogenesis observed in Cyclin A1-/- (Ccna1-/-) testes at the mid-diplotene stage is associated with polynucleated giant cells. We found that Ccna1-deficient testes and especially the giant cells accumulate unrepaired DNA double-strand breaks, as detected by immunohistochemistry for phosphorylated H2AX. In addition, the giant cells escape from apoptosis. The development of giant cells occurred in meiotic prophase I, because testes lacking ATM, which are known to develop spermatogenic arrest earlier than prophase I, do not develop giant cells in the absence of cyclin A1. Cyclin A1 interacted with p53 and phosphorylated p53 in complex with CDK2. Interestingly, p53-deficiency significantly increased the number of giant cells in Ccna1-deficient testes. Gene expression analyses of a panel of DNA repair genes in the mutant testes revealed that none of the genes examined were consistently misregulated in the absence of cyclin A1.</p><p><b>CONCLUSION</b>Ccna1-deficiency in spermatogenesis is associated with defects in DNA double-strand break repair, which is enhanced by loss of p53.</p>
