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Human genome sequencing has transformed our understanding of genomic variation and its relevance to health and disease, and is now starting to enter clinical practice for the diagnosis of rare diseases. The question of whether and how some categories of genomic findings should be shared with individual research participants is currently a topic of international debate, and development of robust analytical workflows to identify and communicate clinically relevant variants is paramount. The Deciphering Developmental Disorders (DDD) study has developed a UK-wide patient recruitment network involving over 180 clinicians across all 24 regional genetics services, and has performed genome-wide microarray and whole exome sequencing on children with undiagnosed developmental disorders and their parents. After data analysis, pertinent genomic variants were returned to individual research participants via their local clinical genetics team. Around 80 000 genomic variants were identified from exome sequencing and microarray analysis in each individual, of which on average 400 were rare and predicted to be protein altering. By focusing only on de novo and segregating variants in known developmental disorder genes, we achieved a diagnostic yield of 27% among 1133 previously investigated yet undiagnosed children with developmental disorders, whilst minimising incidental findings. In families with developmentally normal parents, whole exome sequencing of the child and both parents resulted in a 10-fold reduction in the number of potential causal variants that needed clinical evaluation compared to sequencing only the child. Most diagnostic variants identified in known genes were novel and not present in current databases of known disease variation. Implementation of a robust translational genomics workflow is achievable within a large-scale rare disease research study to allow feedback of potentially diagnostic findings to clinicians and research participants. Systematic recording of relevant clinical data, curation of a gene–phenotype knowledge base, and development of clinical decision support software are needed in addition to automated exclusion of almost all variants, which is crucial for scalable prioritisation and review of possible diagnostic variants. However, the resource requirements of development and maintenance of a clinical reporting system within a research setting are substantial. Health Innovation Challenge Fund, a parallel funding partnership between the Wellcome Trust and the UK Department of Health.

Background Local health protection systems play a crucial role in infectious disease prevention and control and were critical to COVID-19 pandemic responses. Despite this vital function, few studies have explored the lived experience of health protection responders managing COVID-19. We provide new insights by examining how COVID-19 shaped infectious disease prevention and control in local health protection systems in England. Methods Semi-structured interviews were conducted with twenty local health protection responders from three contrasting local authority areas, and Public Health England (PHE) health protection teams, in England between June 2021 - March 2022. Participants were from: PHE health protection teams ( n =6); local authority public health teams ( n =5); local authority Public Protection Services ( n =7); and local authority commissioned Infection Prevention and Control Teams ( n =2). Data were analysed using reflexive thematic analysis. Results First, participants acknowledged the pandemic caused an unprecedented workload and disruption to local health protection service delivery. There was not enough capacity within existing local health protection systems to manage the increased workload. PHE health protection teams therefore transferred some COVID-19 related health protection tasks to other staff, mainly those employed by local authorities. Second, health protection responders highlighted how COVID-19 drew attention to the weaknesses in local health protection systems already stressed by reduced funding in the years leading up to the pandemic. Injecting money into the COVID-19 response did not completely overcome former losses in specialist health protection workforce. Third, health protection responders described how pandemic management raised the profile of public health, especially infectious disease prevention and control. Managing COVID-19 strengthened collaborative working, resulting in enhanced capacity of local health protection systems at the time. Conclusion The COVID-19 pandemic challenged the public health preparedness of all countries. Health protection responders in this study also expressed many challenges. There was insufficient resilience in these local health protection systems and an inability to scale up the specialist health protection workforce, as required in a pandemic situation. The UK needs to learn from the pandemic experience by acknowledging and addressing the challenges faced by local health protection responders so that it can more effectively respond to future threats.

\"Batman leaves the team and the JLA is at each other's throats! As Vixen tries to affirm her role as team leader and fill the vacuum, the villain Prometheus arrives in Happy Harbor to prove to the world that the Justice League must be destroyed and lay waste to the heroes once and for all. And he's brought a friend. Steve Orlando (Midnighter, Supergirl) and artist Andy MacDonald (Teen Titans: Earth One Vol. 2) bring together Batman, Black Canary, the Ray, the Atom, Vixen, Killer Frost and Lobo in what is one of the most offbeat and compelling lineups the Justice League of America has ever seen.\"-- Provided by publisher.

The broadening utilisation of ancient DNA to address archaeological, palaeontological, and biological questions is resulting in a rising diversity in the size of laboratories and scale of analyses being performed. In the context of this heterogeneous landscape, we present an advanced, and entirely redesigned and extended version of the EAGER pipeline for the analysis of ancient genomic data. This Nextflow pipeline aims to address three main themes: accessibility and adaptability to different computing configurations, reproducibility to ensure robust analytical standards, and updating the pipeline to the latest routine ancient genomic practices. The new version of EAGER has been developed within the nf-core initiative to ensure high-quality software development and maintenance support; contributing to a long-term life-cycle for the pipeline. nf-core/eager will assist in ensuring that a wider range of ancient DNA analyses can be applied by a diverse range of research groups and fields.

Matthew Hurles, David FitzPatrick and colleagues report the discovery of four novel Mendelian disorders based on their analysis of exome sequence data from 4,125 families with diverse rare developmental disorders. They present their analytical pipeline as a general strategy for the discovery of genetic causes of autosomal recessive disorders. Discovery of most autosomal recessive disease-associated genes has involved analysis of large, often consanguineous multiplex families or small cohorts of unrelated individuals with a well-defined clinical condition. Discovery of new dominant causes of rare, genetically heterogeneous developmental disorders has been revolutionized by exome analysis of large cohorts of phenotypically diverse parent-offspring trios 1 , 2 . Here we analyzed 4,125 families with diverse, rare and genetically heterogeneous developmental disorders and identified four new autosomal recessive disorders. These four disorders were identified by integrating Mendelian filtering (selecting probands with rare, biallelic and putatively damaging variants in the same gene) with statistical assessments of (i) the likelihood of sampling the observed genotypes from the general population and (ii) the phenotypic similarity of patients with recessive variants in the same candidate gene. This new paradigm promises to catalyze the discovery of novel recessive disorders, especially those with less consistent or nonspecific clinical presentations and those caused predominantly by compound heterozygous genotypes.

Objective The aim of the present study was to assess the effect of probiotic/synbiotic supplementation on anthropometric measures in adults with diabetes, independent of body weight. Methods PubMed, Scopus, Web of Sciences and the Cochrane Library were searched for randomized controlled trials (RCTs) up until December 14, 2022. The effect sizes were pooled using an inverse-variance random-effects model. The methodological quality of studies as well as the quality of evidence was assessed using standard tools. Results Thirty-two RCTs met the established inclusion criteria. Overall, compared with the respective control groups, probiotic/synbiotic supplementation resulted in a significant reduction in body weight (weighted mean difference [WMD]: -0.50 kg; 95% CI: -0.83, -0.17; I 2  = 79.8%, n = 27 studies]), body mass index (WMD: -0.24 kg/m 2 ; 95% CI: -0.39, -0.09; I 2  = 85.7%, n = 30 studies), and waist circumference (WMD: -0.90 cm; 95% CI: -1.13, -0.52; I 2  = 0%, n = 11 studies). However, hip circumference and waist to hip ratio were not significantly improved. Conclusions Our analysis revealed that probiotic/synbiotic supplementation may assist with weight management in patients with diabetes, especially when consumed at higher doses, in younger adults, and in participants with obesity. However, more studies are needed to elucidate the anti-obesity effects of specific strains of probiotics/synbiotics.

Down syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and presents a complex phenotype that arises from abnormal dosage of genes on this chromosome. However, the individual dosage-sensitive genes underlying each phenotype remain largely unknown. To help dissect genotype--phenotype correlations in this complex syndrome, the first fully transchromosomic mouse model, the Tc1 mouse, which carries a copy of human chromosome 21 was produced in 2005. The Tc1 strain is trisomic for the majority of genes that cause phenotypes associated with DS, and this freely available mouse strain has become used widely to study DS, the effects of gene dosage abnormalities, and the effect on the basic biology of cells when a mouse carries a freely segregating human chromosome. Tc1 mice were created by a process that included irradiation microcell-mediated chromosome transfer of Hsa21 into recipient mouse embryonic stem cells. Here, the combination of next generation sequencing, array-CGH and fluorescence in situ hybridization technologies has enabled us to identify unsuspected rearrangements of Hsa21 in this mouse model; revealing one deletion, six duplications and more than 25 de novo structural rearrangements. Our study is not only essential for informing functional studies of the Tc1 mouse but also (1) presents for the first time a detailed sequence analysis of the effects of gamma radiation on an entire human chromosome, which gives some mechanistic insight into the effects of radiation damage on DNA, and (2) overcomes specific technical difficulties of assaying a human chromosome on a mouse background where highly conserved sequences may confound the analysis. Sequence data generated in this study is deposited in the ENA database, Study Accession number: ERP000439.

Background Employment rates of long-term ill and disabled people in the UK are low and 2.63 million are on disability-related state benefits. Since the mid-1990 s, UK governments have experimented with a range of active labour market policies aimed to move disabled people off benefits and into work to reduce the risk of poverty and social exclusion. This systematic review asks what employment impact have these interventions had and how might they work better? Methods A systematic review of observational and qualitative empirical studies and systematic reviews published between 2002 and mid-2008 reporting employment effects and/or process evaluations of national UK government interventions focused on helping long-term sick or disabled people (aged 16-64) into the open labour market. This built on our previous systematic review which covered the years 1970 to 2001. Results Searches identified 42 studies, 31 of which evaluated initiatives with an individual focus (improving an individual's employability or providing financial support in returning to work) while 11 evaluated initiatives with an environmental focus (directed at the employment environment or changing the behaviour of employers). This paper synthesises evidence from the 31 studies with an individual focus. The use of personal advisors and individual case management in these schemes helped some participants back to work. Qualitative studies, however, revealed that time pressures and job outcome targets influenced advisors to select 'easier-to-place' claimants into programmes and also inhibited the development of mutual trust, which was needed for individual case management to work effectively. Financial incentives can help with lasting transitions into work, but the incentives were often set too low or were too short-term to have an effect. Many of the studies suffered from selection bias into these programmes of more work-ready claimants. Even though these were national programmes, they had very low awareness and take-up rates, making it unlikely that a population-level impact would be achieved even if effective for participants. Conclusions The evidence reveals barriers and facilitators for the effective implementation of these types of interventions that could inform the continuing welfare reforms. The evidence points towards the need for more long-term, sustained and staged support for those furthest from the labour market.