The 5S rDNA family evolves through concerted and birth-and-death evolution in fish genomes: an example from freshwater stingrays

Background: Ribosomal 5S genes are well known for the critical role they play in ribosome folding and functionality. These genes are thought to evolve in a concerted fashion, with high rates of homogenization of gene copies. However, the majority of previous analyses regarding the evolutionary process of rDNA repeats were conducted in invertebrates and plants. Studies have also been conducted on vertebrates, but these analyses were usually restricted to the 18S, 5.8S and 28S rRNA genes. The recent identification of divergent 5S rRNA gene paralogs in the genomes of elasmobranches and teleost fishes indicate that the eukaryotic 5S rRNA gene family has a more complex genomic organization than previously thought. The availability of new sequence data from lower vertebrates such as teleosts and elasmobranches enables an enhanced evolutionary characterization of 5S rDNA among vertebrates.Results: We identified two variant classes of 5S rDNA sequences in the genomes of Potamotrygonidae stingrays, similar to the genomes of other vertebrates. One class of 5S rRNA genes was shared only by elasmobranches. A broad comparative survey among 100 vertebrate species suggests that the 5S rRNA gene variants in fishes originated from rounds of genome duplication. These variants were then maintained or eliminated by birth-and-death mechanisms, under intense purifying selection. Clustered multiple copies of 5S rDNA variants could have arisen due to unequal crossing over mechanisms. Simultaneously, the distinct genome clusters were independently homogenized, resulting in the maintenance of clusters of highly similar repeats through concerted evolution.Conclusions: We believe that 5S rDNA molecular evolution in fish genomes is driven by a mixed mechanism that integrates birth-and-death and concerted evolution

Time to Switch to Second-line Antiretroviral Therapy in Children With Human Immunodeficiency Virus in Europe and Thailand.

Background: Data on durability of first-line antiretroviral therapy (ART) in children with human immunodeficiency virus (HIV) are limited. We assessed time to switch to second-line therapy in 16 European countries and Thailand. Methods: Children aged <18 years initiating combination ART (≥2 nucleoside reverse transcriptase inhibitors [NRTIs] plus nonnucleoside reverse transcriptase inhibitor [NNRTI] or boosted protease inhibitor [PI]) were included. Switch to second-line was defined as (i) change across drug class (PI to NNRTI or vice versa) or within PI class plus change of ≥1 NRTI; (ii) change from single to dual PI; or (iii) addition of a new drug class. Cumulative incidence of switch was calculated with death and loss to follow-up as competing risks. Results: Of 3668 children included, median age at ART initiation was 6.1 (interquartile range (IQR), 1.7-10.5) years. Initial regimens were 32% PI based, 34% nevirapine (NVP) based, and 33% efavirenz based. Median duration of follow-up was 5.4 (IQR, 2.9-8.3) years. Cumulative incidence of switch at 5 years was 21% (95% confidence interval, 20%-23%), with significant regional variations. Median time to switch was 30 (IQR, 16-58) months; two-thirds of switches were related to treatment failure. In multivariable analysis, older age, severe immunosuppression and higher viral load (VL) at ART start, and NVP-based initial regimens were associated with increased risk of switch. Conclusions: One in 5 children switched to a second-line regimen by 5 years of ART, with two-thirds failure related. Advanced HIV, older age, and NVP-based regimens were associated with increased risk of switch

Coinfection with HIV and hepatitis C virus in 229 children and young adults living in Europe

[Objective] To characterize children, adolescents and young adults infected with HIV/hepatitis C virus (HCV) vertically or before age of 18 years and living in Europe regarding mode of acquisition, HCV genotype, clinical status and treatment.[Design] Retrospective, cross-sectional study using pooled data from 11 European paediatric HIV cohorts.[Methods] Patients aged more than 18 months and less than 25 years, with HIV/HCV acquired vertically or in childhood, were included. Anonymized individual patient data were collected using a standard protocol and modified HIV Cohorts Data Exchange Protocol.[Results] Of 229 patients included, 142 (62%) had vertically acquired infection. Median age at last follow-up was 16.2 years. Most children had HCV genotype 1 (101/184, 55%) or 3 (57/184, 31%). One-fifth (46/214) had a previous AIDS diagnosis (data missing on prior AIDS diagnoses for 15). At their last clinic visit, 70% (145/208) had no/mild immunosuppression (Centers for Disease Control and Prevention stage 1), and 131 of 179 on antiretroviral therapy had undetectable HIV RNA (assay thresholds varied from <20 to <150 copies/ml). Overall, 42% (86/204) had hepatomegaly in the previous year, and 55% (116/213) had alanine aminotransferase more than 40 IU/l at their last test. Of 97 patients with transient elastography, 12 had results more than 9 kPa; this was associated with duration of HCV infection (P = 0.033), but not with CD4+ cell count, antiretroviral therapy use or sex in univariable analysis. Of 17 patients with liver biopsies, six had bridging fibrosis and one had cirrhosis. Twenty-five (11%) had been treated successfully for HCV.[Conclusion] The high proportion of patients with progressive liver disease underscores the need for close monitoring and earlier and more effective HCV treatment.This work was supported by funding from the EU Seventh Framework Programme (FP7/2007–2013) under EuroCoord grant agreement [no. 260694] and additional funding from Janssen.Peer reviewe