SummaryBackgroundRisk markers for later autism identified in the first year of life present plausible intervention targets during early development. We aimed to assess the effect of a parent-mediated intervention for infants at high risk of autism on these markers.MethodsWe did a two-site, two-arm assessor-blinded randomised controlled trial of families with an infant at familial high risk of autism aged 7–10 months, testing the adapted Video Interaction to Promote Positive Parenting (iBASIS-VIPP) versus no intervention. Families were randomly assigned to intervention or no intervention groups using a permuted block approach stratified by centre. Assessors, but not families or therapists, were masked to group assignment. The primary outcome was infant attentiveness to parent. Regression analysis was done on an intention-to-treat basis. This trial is registered with ISCRTN Registry, number ISRCTN87373263.FindingsWe randomly assigned 54 families between April 11, 2011, and Dec 4, 2012 (28 to intervention, 26 to no intervention). Although CIs sometimes include the null, point estimates suggest that the intervention increased the primary outcome of infant attentiveness to parent (effect size 0·29, 95% CI −0·26 to 0·86, thus including possibilities ranging from a small negative treatment effect to a strongly positive treatment effect). For secondary outcomes, the intervention reduced autism-risk behaviours (0·50, CI −0·15 to 1·08), increased parental non-directiveness (0·81, 0·28 to 1·52), improved attention disengagement (0·48, −0·01 to 1·02), and improved parent-rated infant adaptive function (χ2[2] 15·39, p=0·0005). There was a possibility of nil or negative effect in language and responsivity to vowel change (P1: ES–0·62, CI −2·42 to 0·31; P2: −0·29, −1·55 to 0·71).InterpretationWith the exception of the response to vowel change, our study showed positive estimates across a wide range of behavioural and brain function risk-markers and developmental outcomes that are consistent with a moderate intervention effect to reduce the risk for later autism. However, the estimates have wide CIs that include possible nil or small negative effects. The results are encouraging for development and prevention science, but need larger-scale replication to improve precision.FundingAutistica, Waterloo Foundation, Autism Speaks, and the UK Medical Research Council.

Restricted and repetitive behaviors (RRBs) are characteristic of autism spectrum disorders (ASD). However, compared to social and communicative impairments, less is known about their development, trajectory and etiology. This study explored RRBs in young children with ASD matched to typically developing (TD) children on non-verbal development. RRBs were coded from direct observation at three time points within 13 months of development. Children with ASD displayed higher frequency and greater diversity of RRBs at all time points, however RRBs were not unique to ASD and evident in the TD control group albeit at a reduced frequency. RRBs did not correlate with social and communicative impairments in the ASD group, suggesting dissociation between these domains.

Although reduced social attention and increased nonsocial attention have been reported in individuals with autism spectrum disorder (ASD), the studies have relied on predominantly male samples and have been underpowered to examine sex differences. These processes may differ for females with ASD, who have been shown to be dissimilar to males in social motivation and nonsocial features, including circumscribed interests (CI). The goal of this study was to compare social and nonsocial visual attention between males and females with ASD on a validated eye-tracking paradigm. Eighty-five school-aged (6-10 years) males and females with and without ASD completed a paired preference task of face and object stimuli (half of which related to common CI). After covarying for chronological and mental age, the presence of concurrently presented CI images reduced prioritization and attention to faces for males more than females, replicating previous findings. ASD females maintained comparable attention patterns to typically developing females, suggesting that previous findings of reduced social attention and increased attention to CI-related objects in autism may be specific to males. These findings are also inconsistent with the "extreme male brain" theory of autism. The more normative orienting and attention to social stimuli for females with ASD may indicate distinct phenotypic characteristics relative to males and possibly serve as a protective effect.Lay Summary: As autism is more commonly diagnosed in males, less is known about females with autism. Two areas of interest include the interests held by individuals with autism and how socially motivated they are. We used eye tracking as a way to understand these two areas. Our data reveal that elementary school-aged females (6-10 years) with autism attended to faces comparatively to females without autism, suggesting that (1) they were more socially motivated than males with autism and (2) the images of common interests were less motivating to them.

Background: The male bias in autism spectrum disorder (ASD) diagnoses is well documented. As a result, less is known about the female ASD phenotype. Recent research suggests that conclusions drawn from predominantly male samples may not accurately capture female behavior. In this study, we explore potential sex differences in attention to social stimuli, which is generally reported to be diminished in ASD. Population-based sex differences in attention to faces have been reported, such that typically developing (TD) females attend more to social stimuli (including faces) from infancy through adulthood than TD males. It is yet unknown whether population-based sex differences in the face domain are preserved in ASD. Methods: A dynamic, naturalistic infrared eye-tracking paradigm measured attention to social stimuli (faces) in 74 school-aged males and females with ASD (male N = 23; female N = 19) and without ASD (male N = 16; female N = 16). Two kinds of video stimuli were presented that varied in social content: rich social scenes (dyadic play between two children) and lean social scenes (parallel play by two children). Results: Results revealed a significant 3-way interaction between sex, diagnosis, and condition after controlling for chronological and mental age. ASD females attended more to faces than ASD males in the socially lean condition. This effect was not found in the typically developing (TD) group. ASD males attended less to faces regardless of social context; however, ASD females only attended significantly less to faces compared to TD females in the socially rich condition. TD males and ASD females did not differ in their attention to faces in either condition. Conclusions: This study has implications for how the field understands core social deficits in children with ASD, which should ideally be benchmarked against same-sex peers (male and female). Social attention in ASD females fell on a continuum-greater than their ASD male peers, but not as great as TD females. Overall, their social attention mirrored that of TD males. Improved understanding of the female social phenotype in ASD will enhance early screening and diagnostic efforts and will guide the development of sex-sensitive experimental paradigms and social interventions.

While sex differences in play have been extensively observed in typical development, only a handful of studies have explored this phenomenon in depth with children with autism spectrum disorders. This study explored sex differences in play complexity and toy engagement within caregiver-child interaction samples for preschool-aged children (2-5 years 11 months) with an autism spectrum disorder who were matched to typically developing children on sex and non-verbal development. Overall we found that girls and boys with autism spectrum disorder were largely equivalent in their play complexity. Despite similar play, girls and boys with autism spectrum disorder differed in a number of ways in their toy engagement, replicating traditional gender differences-girls played more with dolls and domestic items (though at lower rates than typically developing girls) and boys played more with the garage and cars (though at lower rates than typically developing boys). Our findings support the importance and utility of examining sex differences in autism spectrum disorder in light of those observed within typical development.

Recent studies suggest that circumscribed interests (CI) in females with Autism Spectrum Disorder (ASD) may align more closely with interests reported in typical female development than those typically reported for ASD males. We used eye-tracking to quantify attention to arrays containing combinations of male, female and neutral images in elementary-aged males and females with and without ASD. A number of condition × sex effects emerged, with both groups attending to images that corresponded with interests typically associated with their biological sex. Diagnostic effects reported in similar studies were not replicated in our modified design. Our findings of more typical attention patterns to gender-typical images in ASD females is consistent with evidence of sex differences in CI and inconsistent with the "Extreme Male Brain" theory of ASD.

Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

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