Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature

Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as "non-FLHS SRCAP-related NDD.'' All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations.Genetics of disease, diagnosis and treatmen

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant

Comparative multicentre trial of three IUDs inserted immediately following delivery of the placenta

A multinational comparative trial of three IUDs (Copper 7, Lippes loop size D and the Postpartum T) randomly inserted immediately following delivery of the placenta was conducted in six centres. A total of 841 women entered the study. As the predetermined termination indices for expulsions were exceeded at six months the trial was prematurely closed. An excess of expulsions during the first 48 hours following insertion was observed for the Lippes loop compared to the other devices. At six months the expulsion rate for the Lippes loop was significantly higher than that for the Copper 7. In addition, the discontinuation rate for the Lippes loop at 12 months was significantly higher than that for the Copper 7. There were no significant differences in either the expulsion rates or the discontinuation rate at six or twelve months between the postpartum T and the other devices. At 12 months the pregnancy rates with all three devices was high; there were no ectopic pregnancies. Considerable between-centre differences were observed, particularly for expulsion rates. Possible reasons for this are discussed and future research lines are suggested. © 1980.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Mediating the Asian Olympics: The Summer Games – Image Projection and Gaze Reception

Every Olympic Games involves a dual process of attempting to project favourable images of the host city/country/region and seeking to manage the international gaze that is invited as a key rationale for staging the Games in the first place. How each site seeks to be seen varies, though, with historical, political, social, cultural, spatial and technological context. The three Summer Olympic Games that have taken place in East Asia all attempted to demonstrate in different ways that its host had arrived as a global force. A key variable in each case was the communicative apparatus available to hosts, guests and the world watching from afar before, during and after the event itself. This article addresses Tokyo 1964, Seoul 1988 and Beijing 2008, seeking to demonstrate how the balance of power to represent and be represented has changed significantly over the almost half a century spanning the first and the last Games