The critical need for pooled data on coronavirus disease 2019 in African children : an AFREhealth call for action through multicountry research collaboration

Globally, there are prevailing knowledge gaps in the epidemiology, clinical manifestations, and outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among children and adolescents; and these gaps are especially wide in African countries. The availability of robust age-disaggregated data is a critical first step in improving knowledge on disease burden and manifestations of coronavirus disease 2019 (COVID-19) among children. Furthermore, it is essential to improve understanding of SARS-CoV-2 interactions with comorbidities and coinfections such as human immunodeficiency virus (HIV), tuberculosis, malaria, sickle cell disease, and malnutrition, which are highly prevalent among children in sub-Saharan Africa. The African Forum for Research and Education in Health (AFREhealth) COVID-19 Research Collaboration on Children and Adolescents is conducting studies across Western, Central, Eastern, and Southern Africa to address existing knowledge gaps. This consortium is expected to generate key evidence to inform clinical practice and public health policy-making for COVID-19 while concurrently addressing other major diseases affecting children in African countries.The US National Institutes of Health (NIH)/ Fogarty International Centre (FIC) to the African Forum for Research and Education in Health (AFREhealth).https://academic.oup.com/cidam2022Paediatrics and Child Healt

Eur J Med Genet

Oculocutaneous albinism type 2 (OCA2) is a pigmentation disorder characterized by hypopigmentation of the skin, hair and eyes and ocular features. Sickle cell disease (SCD) is caused either by homozygosity of the beta globin gene variant c.20A > T/p.Glu6Val giving rise to severe anemia or by combined abnormal hemoglobins (HbS/βthal) leading to mild SCD. We report a 45 years old female patient from the Democratic Republic of Congo affected with these two disorders. She presented with creamy white skin and numerous pigmented patches called dendritic freckles, nystagmus, foveal hypoplasia grade 2, photophobia and very poor visual acuity. Sequencing of the OCA2 gene identified the common exon 7 deletion and a new pathogenic variant c.1444A > C/p.Thr482Pro. She had mild SCD with a total Hb level of 101 g/l. Hbβ sequencing identified variants c.20A > T giving rise to HbS and c.315 + 1 G > A characteristic of β-thalassemia. A heterozygous 3.7 kb deletion of the α globin gene was also found. The combined Hbβ/α globin genotype explains the mild SCD phenotype. Co-occurrence of OCA2 and SCD raises the question whether the patient's phenotype simply results from the addition of the two diseases' phenotypes or whether interaction between the two diseases modulates the phenotype of each other

Novel genetic loci that influence fetal hemoglobin expression in children with sickle cell anemia

Introduction: Elevated levels of fetal hemoglobin (HbF) are known to ameliorate both the morbidity and mortality of sickle cell anemia (SCA). Sustained post-natal HbF expression is heritable and regulated by multiple quantitative trait loci. Previous genomic studies have identified three major gene loci (BCL11A, HBS1L-MYB, and HBG2) that account for ~40% of HbF variation in SCA, but additional genetic modifiers remain to be discovered. We performed a genome wide association study (GWAS) using DNA collected from multiple cohorts of children with SCA, to identify novel genes and variants involved in HbF expression. Methods: We analyzed genomic DNA from 1009 children with SCA and pre-treatment steady-state HbF levels who enrolled in prospective research trials from the United States (HUSTLE, SWiTCH, TWiTCH), the Caribbean (SACRED) or sub-Saharan Africa (REACH, NOHARM). Whole blood DNA was first genotyped using the H3Africa SNP array (Illumina) that identifies over 2.2 million single nucleotide variants (SNVs) across the genome. Most samples also underwent whole exome sequencing (WES) using NimbleGen VCRome 2.1 capture reagents and the Illumina HiSeq2500 platform analysis, which identifies coding variants in all known exons. Results: From the combined SNP and WES dataset, 8 BCL11A variants passed genome wide significance (p\u3c10-8) in the discovery analysis, and 1,048 additional variants were identified with nominal HbF association (p\u3c0.001). We found that 173 of these novel variants had sustained association in at least one of the replication cohorts (p\u3c0.05). We selected 20 variants with the strongest and most consistent associations with HbF from the discovery and replication analyses for further verification (Table 1). Conclusions: Our large GWAS of HbF with diverse global cohorts of children with SCA from Africa, the United States, and the Caribbean validated the strong associations of HbF with common genetic variants near the BCL11A and HBS1L-MYB gene loci. We also identified two novel gene loci, ITGA1 and RUNX1T1, that have statistical associations with HbF expression. The RUNX1T1 gene is a broad transcriptional corepressor known to impact myeloid differentiation in hematopoiesis, while ITGA1 encodes the integrin alpha subunit of a cell-surface receptor involved in cell-cell adhesion and inflammation

Genetic variants that influence fetal hemoglobin expression from hydroxyurea treatment

Introduction: Hydroxyurea is a potent therapeutic agent for sickle cell anemia (SCA), and treatment at maximum tolerated dose (MTD) is becoming the standard of care. Hydroxyurea exerts its disease-modifying effects primarily through induction of fetal hemoglobin (HbF), although the cellular and molecular mechanisms by which hydroxyurea increases HbF expression remain unclear. Children with SCA treated with hydroxyurea at MTD have substantial phenotypic variation, however, as some have higher HbF responses than others. We hypothesized that unknown quantitative trait loci modulate the pharmacological induction of HbF, so we performed a large genome wide association study (GWAS) of hydroxyurea-associated HbF responses for children with SCA treated prospectively with dose escalation to MTD. Methods: We analyzed genomic DNA from 831 children with SCA enrolled in pediatric research trials from the US (HUSTLE, SWiTCH, TWiTCH), the Caribbean (EXTEND, SACRED) and sub-Saharan Africa (REACH, NOHARM); all of these trials reported robust treatment responses with average HbF \u3e20%. Study participants received hydroxyurea with dose escalation to MTD based on mild myelosuppression. Whole blood DNA was genotyped using the H3Africa SNP array (Illumina) with whole exome sequencing (WES) using NimbleGen VCRome 2.1 capture reagents and the Illumina HiSeq2500 platform. A transformed z-score for each study cohort gave a standardized measure of HbF induction relative to their steady-state level and their treatment HbF level at MTD. Results: In the discovery GWAS step, no variant passed genome wide significance (p\u3c10-8) for the MTD HbF phenotype, including no significant associations with known genetic modifiers of endogenous HbF (BCL11A, HBS1L-MYB, HBG2). A total of 2057 low frequency and common SNVs had at least nominal association (p\u3c0.001) with the hydroxyurea treatment responses, of which 44 were also significant (p\u3c0.05) and with the same direction of association with HbF induction in the replication cohort. In the final verification step, these 44 significant variants were then tested in additional independent SCA cohorts with at least three demonstrating a strong effect. Conclusions: This large GWAS using global cohorts of children with SCA and robust prospective HbF phenotype data has identified genetic predictors of HbF hydroxyurea treatment responses. Three novel genetic loci, PTPRD, RPH3AL, and ELL2 have SNVs associated with lower HbF responses. PTPRD is a protein tyrosine phosphatase receptor involved in cellular processes such as cell growth and differentiation, while RPH3AL, a rabphilin 3A like protein, is known to be involved in calcium-ion-dependent exocytosis. ELL2 is an elongation factor for RNA polymerase II and could modify RNA processing under the cytostatic effects of hydroxyurea

Evaluation of the global lung initiative 2012 reference values for spirometry in African children

Abstract Rationale: Despite the high burden of respiratory disease, no spirometry reference values for African children are available. Objectives:Investigatewhether the Global Lung Initiative (GLI-2012) reference values for spirometry are appropriate for children in subSaharan Africa and assess the impact of malnutrition on lung function. Methods:Anthropometry and spirometry were obtained in children aged 6 to 12 years from urban and semiurban schools in three African countries. Spirometry z-scores were derived using the GLI-2012 prediction equations for African Americans. Thinness (body mass index z-score , 22) was a surrogate for malnutrition. Spirometry outcomes were compared with those of African American children from the third National Health and Nutrition Survey. Measurements and Main Results: Spirometry data were analyzed from 1,082 schoolchildren (51% boys) aged 6.0 to 12.8 years in Angola (n = 306), Democratic Republic of the Congo (n = 377), and Madagascar (n = 399). GLI-2012 provided a good fit with mean (SD) z-scores of 20.11 (0.83) for FEV1, 20.08 (0.86) for FVC, and 20.07 (0.83) for FEV1/FVC. Because of low scatter, the fifth centile corresponded to 21.3 z-scores in boys and 21.5 z-scores in girls. Malnourished African children had a normal FEV1/FVC ratio but significant reductions of z0.5 z-scores (z5%) in FEV1 and FVC compared with African American peers from the third National Health and Nutrition Survey. Children in Angola had the lowest, and those in Madagascar had the highest, zFEV1 and zFVC. Conclusions: The results of this study support the use of GLI-2012 reference values for schoolchildren in sub-Saharan Africa. Malnutrition affects body growth, leading to a proportionately smaller FEV1 and FVC without respiratory impairment, as shown by the normal FEV1/FVC rati

Artemisia Spp. derivatives for COVID-19 treatment : anecdotal use, political hype, treatment potential, challenges, and road map to randomized clinical trials

CITATION: Kapepula, P. M. et al. 2020. Artemisia Spp. derivatives for COVID-19 treatment : anecdotal use, political hype, treatment potential, challenges, and road map to randomized clinical trials. American Journal of Tropical Medicine and Hygiene, doi:10.4269/ajtmh.20-0820.The original publication is available at https://www.ajtmh.orgThe world is currently facing a novel COVID-19 pandemic caused by SARS-CoV-2 that, as of July 12, 2020, has caused a reported 12,322,395 cases and 556,335 deaths. To date, only two treatments, remdesivir and dexamethasone, have demonstrated clinical efficacy through randomized controlled trials (RCTs) in seriously ill patients. The search for new or repurposed drugs for treatment of COVID-19 continues. We have witnessed anecdotal use of herbal medicines, including Artemisia spp. extracts, in low-income countries, and exaggerated claims of their efficacies that are not evidence based, with subsequent political controversy. These events highlight the urgent need for further research on herbal compounds to evaluate efficacy through RCTs, and, when efficacious compounds are identified, to establish the active ingredients, develop formulations and dosing, and define pharmacokinetics, toxicology, and safety to enable drug development. Derivatives from the herb Artemisia annua have been used as traditional medicine over centuries for the treatment of fevers, malaria, and respiratory tract infections. We review the bioactive compounds, pharmacological and immunological effects, and traditional uses for Artemisia spp. derivatives, and discuss the challenges and controversies surrounding current efforts and the scientific road map to advance them to prevent or treat COVID-19.https://www.ajtmh.org/content/journals/10.4269/ajtmh.20-0820Publisher's versio