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Host-mediated lung inflammation is present 1 , and drives mortality 2 , in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development 3 . Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P  = 1.65 × 10 −8 ) in a gene cluster that encodes antiviral restriction enzyme activators ( OAS1 , OAS2 and OAS3 ); on chromosome 19p13.2 (rs74956615, P  = 2.3 × 10 −8 ) near the gene that encodes tyrosine kinase 2 ( TYK2 ); on chromosome 19p13.3 (rs2109069, P  = 3.98 ×  10 −12 ) within the gene that encodes dipeptidyl peptidase 9 ( DPP9 ); and on chromosome 21q22.1 (rs2236757, P  = 4.99 × 10 −8 ) in the interferon receptor gene IFNAR2 . We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2 , or high expression of TYK2 , are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte–macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice. A genome-wide association study of critically ill patients with COVID-19 identifies genetic signals that relate to important host antiviral defence mechanisms and mediators of inflammatory organ damage that may be targeted by repurposing drug treatments.

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management.

It is not known whether early intervention can improve long-term autism symptom outcomes. We aimed to follow-up the Preschool Autism Communication Trial (PACT), to investigate whether the PACT intervention had a long-term effect on autism symptoms and continued effects on parent and child social interaction. PACT was a randomised controlled trial of a parent-mediated social communication intervention for children aged 2–4 years with core autism. Follow-up ascertainment was done at three specialised clinical services centres in the UK (London, Manchester, and Newcastle) at a median of 5·75 years (IQR 5·42–5·92) from the original trial endpoint. The main blinded outcomes were the comparative severity score (CSS) from the Autism Diagnostic Observation Schedule (ADOS), the Dyadic Communication Assessment Measure (DCMA) of the proportion of child initiatiations when interacting with the parent, and an expressive-receptive language composite. All analyses followed the intention-to-treat principle. PACT is registered with the ISRCTN registry, number ISRCTN58133827. 121 (80%) of the 152 trial participants (59 [77%] of 77 assigned to PACT intervention vs 62 [83%] of 75 assigned to treatment as usual) were traced and consented to be assessed between July, 2013, and September, 2014. Mean age at follow-up was 10·5 years (SD 0·8). Group difference in favour of the PACT intervention based on ADOS CSS of log-odds effect size (ES) was 0·64 (95% CI 0·07 to 1·20) at treatment endpoint and ES 0·70 (95% CI −0·05 to 1·47) at follow-up, giving an overall reduction in symptom severity over the course of the whole trial and follow-up period (ES 0·55, 95% CI 0·14 to 0·91, p=0·004). Group difference in DCMA child initiations at follow-up showed a Cohen's d ES of 0·29 (95% CI −0.02 to 0.57) and was significant over the course of the study (ES 0·33, 95% CI 0·11 to 0·57, p=0·004). There were no group differences in the language composite at follow-up (ES 0·15, 95% CI −0·23 to 0·53). The results are the first to show long-term symptom reduction after a randomised controlled trial of early intervention in autism spectrum disorder. They support the clinical value of the PACT intervention and have implications for developmental theory. Medical Research Council.

Results of small trials suggest that early interventions for social communication are effective for the treatment of autism in children. We therefore investigated the efficacy of such an intervention in a larger trial. Children with core autism (aged 2 years to 4 years and 11 months) were randomly assigned in a one-to-one ratio to a parent-mediated communication-focused (Preschool Autism Communication Trial [PACT]) intervention or treatment as usual at three specialist centres in the UK. Those assigned to PACT were also given treatment as usual. Randomisation was by use of minimisation of probability in the marginal distribution of treatment centre, age (≤42 months or >42 months), and autism severity (Autism Diagnostic Observation Schedule-Generic [ADOS-G] algorithm score 12–17 or 18–24). Primary outcome was severity of autism symptoms (a total score of social communication algorithm items from ADOS-G, higher score indicating greater severity) at 13 months. Complementary secondary outcomes were measures of parent-child interaction, child language, and adaptive functioning in school. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN58133827. 152 children were recruited. 77 were assigned to PACT (London [n=26], Manchester [n=26], and Newcastle [n=25]); and 75 to treatment as usual (London [n=26], Manchester [n=26], and Newcastle [n=23]). At the 13-month endpoint, the severity of symptoms was reduced by 3·9 points (SD 4·7) on the ADOS-G algorithm in the group assigned to PACT, and 2·9 (3·9) in the group assigned to treatment as usual, representing a between-group effect size of −0·24 (95% CI −0·59 to 0·11), after adjustment for centre, sex, socioeconomic status, age, and verbal and non-verbal abilities. Treatment effect was positive for parental synchronous response to child (1·22, 0·85 to 1·59), child initiations with parent (0·41, 0·08 to 0·74), and for parent-child shared attention (0·33, −0·02 to 0·68). Effects on directly assessed language and adaptive functioning in school were small. On the basis of our findings, we cannot recommend the addition of the PACT intervention to treatment as usual for the reduction of autism symptoms; however, a clear benefit was noted for parent-child dyadic social communication. UK Medical Research Council, and UK Department for Children, Schools and Families.

Curbing demand for wild fish in aquafeeds is critical China is the world's largest producer, consumer, processor, and exporter of finfish and shellfish (defined here as “fish”), and its fish imports are steadily rising ( 1 – 3 ). China produces more than one-third of the global fish supply, largely from its ever-expanding aquaculture sector, as most of its domestic fisheries are overexploited ( 3 – 6 ). Aquaculture accounts for ∼72% of its reported domestic fish production, and China alone contributes >60% of global aquaculture volume and roughly half of global aquaculture value ( 1 , 3 ).

The northwest basins of the Atlantic and Pacific oceans are regions of intense western boundary currents (WBCs): the Gulf Stream and the Kuroshio. The variability of these poleward currents and their extensions in the open ocean is of major importance to the climate system. It is largely dominated by in-phase meridional shifts downstream of the points at which they separate from the coast. Tide gauges on the adjacent coastlines have measured the inshore sea level for many decades and provide a unique window on the past of the oceanic circulation. The relationship between coastal sea level and the variability of the western boundary currents has been previously studied in each basin separately, but comparison between the two basins is missing. Here we show for each basin that the inshore sea level upstream of the separation points is in sustained agreement with the meridional shifts of the western boundary current extension over the period studied, i.e. the past 7 (5) decades in the Atlantic (Pacific). Decomposition of the coastal sea level into principal components allows us to discriminate this variability in the upstream sea level from other sources of variability such as the influence of large meanders in the Pacific. Our result extends previous findings limited to the altimetry era and suggests that prediction of inshore sea-level changes could be improved by the inclusion of meridional shifts of the western boundary current extensions as predictors. Long-duration tide gauges, such as Key West, Fernandina Beach or Hosojima, could be used as proxies for the past meridional shifts of the western boundary current extensions.

China’s 13th Five-Year Plan, launched in March 2016, provides a sound policy platform for the protection of marine ecosystems and the restoration of capture fisheries within China’s exclusive economic zone. What distinguishes China among many other countries striving for marine fisheries reform is its size—accounting for almost one-fifth of global catch volume—and the unique cultural context of its economic and resource management. In this paper, we trace the history of Chinese government priorities, policies, and outcomes related to marine fisheries since the 1978 Economic Reform, and examine how the current leadership’s agenda for “ecological civilization” could successfully transform marine resource management in the coming years. We show how China, like many other countries, has experienced a decline in the average trophic level of its capture fisheries during the past few decades, and how its policy design, implementation, and enforcement have influenced the status of its wild fish stocks. To reverse the trend in declining fish stocks, the government is introducing a series of new programs for sustainable fisheries and aquaculture, with greater traceability and accountability in marine resource management and area controls on coastal development. As impressive as these new plans are on paper, we conclude that serious institutional reforms will be needed to achieve a true paradigm shift in marine fisheries management in China. In particular, we recommend new institutions for science-based fisheries management, secure fishing access, policy consistency across provinces, educational programs for fisheries managers, and increasing public access to scientific data.

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.

Syndromic autism has been described in children adopted after orphanage rearing. We investigated whether the same existed in children adopted after family breakdown. Families of 54/60 adopted children aged 6–11 years (mean 102 months; SD 20; 45 % male) returned screening questionnaires for autism spectrum disorder (ASD); 21/54 (39 %) screened positive. Detailed in-person phenotyping of screen positive cases showed ASD in 6/54 (11 %), Broad ASD (sub threshold traits) in 10/54 (18.5 %); 5/54 (9 %) screened false positive. The ASD group showed impairments across both social communication and restrictive repetitive behaviour domains, Broad ASD was more mixed. These rates, much higher than population prevalence, are comparable with institutionalised samples. There are implications for developmental science, and assessment, treatment and policy for adopted children.

Background Autism Spectrum Disorder (ASD) is a neurodevelopmental disability affecting at least 5 million children in South Asia. Majority of these children are without access to evidence-based care. The UK Pre-school Autism Communication Therapy (PACT) is the only intervention to have shown sustained impact on autism symptoms. It was systematically adapted for non-specialist community delivery in South Asia, as the ‘Parent-mediated Autism Social Communication Intervention for non-Specialists (PASS)’ and extended ‘PASS Plus’ interventions. RCTs of both showed feasibility, acceptability and positive effect on parent and child dyadic outcomes. Methods The Communication-centred Parent-mediated treatment for Autism Spectrum Disorder in South Asia (COMPASS) trial is now a scale-up two-centre, two-arm single (rater) blinded random allocation parallel group study of the PASS Plus intervention in addition to treatment as usual (TAU) compared to TAU alone, plus health economic evaluation embedded in the India health system. Two hundred forty children (approximately 120 intervention/120 TAU) with ASD aged 2–9 years will be recruited from two tertiary care government hospitals in New Delhi, India. Accredited Social Health Activists will be one of the intervention delivery agents. Families will undertake up to 12 communication sessions over 8 months and will be offered the Plus modules which address coexisting problems. The trial’s primary endpoint is at 9 months from randomisation, with follow-up at 15 months. The primary outcome is autism symptom severity; secondary outcomes include parent–child communication, child adaptation, quality of life and parental wellbeing. Primary analysis will follow intention-to-treat principles using linear mixed model regressions with group allocation and repeated measures as random effects. The cost-effectiveness analysis will use a societal perspective over the 15-month period of intervention and follow-up. Discussion If clinically and cost-effective, this programme will fill an important gap of scalable interventions delivered by non-specialist health workers within the current care pathways for autistic children and their families in low-resource contexts. The programme has been implemented through the COVID-19 pandemic when restrictions were in place; intervention delivery and evaluation processes have been adapted to address these conditions. Trial registration ISRCTN; ISRCTN21454676 ; Registered 22 June 2018.