Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year

Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Tranexamic Acid

https://scholarlycommons.pacific.edu/phs-facbooks/1047/thumbnail.jp

Insect pollinators: linking research and policy. Workshop report.

EXECUTIVE SUMMARY Pollinators interact with plants to underpin wider biodiversity, ecosystem function, ecosystem services to agricultural crops and ultimately human nutrition. The conservation of pollinators is thus an important goal. Pollinators and pollination represent a tractable example of how biodiversity can be linked to an ecosystem service. This represents a case study for exploring the impacts of various policy instruments aiming to halt/reverse the loss of ecosystem services. There is a need to understand how multiple pressures (e.g. habitat loss, fragmentation and degradation, climate change, pests and diseases, invasive species and environmental chemicals) can combine or interact to affect diversity, abundance and health of different pollinator groups. Decision makers need to balance consideration of the effects of single pressures on pollinators against the suite of other pressures on pollinators. For instance, the threat from pesticide use (with its high public and media profile) also needs to be considered in the context of the other threats facing pollinators and balanced against the need for food security. An independent review of the balance of risks across pollinator groups from pesticide use would help synthesise current knowledge into an accessible form for decision makers. To manage or lessen these threats to pollinators (wild and managed) and pollination requires improved knowledge about their basic ecology. We still need to know where and in what numbers different pollinator species occur, how they use different environments, how they interact with each other through shared plants and diseases and how wild pollinator abundance is changing. Decision makers need clear factual evidence for i) the relative contribution of different managed and wild pollinator groups to wildflower and crop pollination and ii) how this varies across different land-uses, ecosystems and regions. Addressing these basic and applied questions will improve our ability to forecast impacts on pollination service delivery to agricultural crops arising from current and future environmental changes, pesticide use and emerging diseases. The development of a long-term, multi-scale monitoring scheme to monitor trends in pollinator (wild and managed) population size and delivery of pollination services (ideally tied to data collection on land-use, pesticide applications and disease incidence at relevant spatial scales) would provide the evidence base for developing the effectiveness of policy and management interventions over time. Such a monitoring scheme would benefit from including research council organisations (e.g. CEH), governmental departments (e.g. Fera), universities, museums and NGOs (e.g. BBKA,SBA, Bumblebee Conservation Trust etc) Insect Pollinators: linking research and policy Workshop Report | 5 In the context of agricultural intensification and conservation we need to establish what type, quality and quantity of interventions (e.g. agri-environment schemes, protected areas) are needed, where to place them and how they can sustain different pollinator populations and effective pollination services. Current monitoring of the risks from diseases and pesticides requires broadening to consider other insects aside from honey bees, unless we can demonstrate that honey bees are good surrogates for all other pollinators. There is a need to increase confidence in regulatory risk assessments pertaining to pathogens and pesticides by incorporating other pollinator species, investigating chronic exposure to multiple chemicals and using field relevant dosages (specific to regions, not using other data sources as surrogates). At present the effects of spatial, social and temporal scales on the benefits stakeholders receive from pollination services are only beginning to be understood. Economic valuation of pollination services can help optimise the cost-effectiveness of service management measures and offer new opportunities to incentivise action or raise awareness among stakeholders. Novel tools and instruments (e.g. education and training) are needed to translate broad international (e.g. CBD, EU Biodiversity Strategy) and national (e.g. England‟s Biodiversity Strategy) policies into local actor (e.g. beekeeper, farmer, citizen scientist) contributions to meet biodiversity commitments Refocusing some public funding to link basic science to development of practical solutions (e.g. better crop protection products, improved disease resistance or treatment) could help science deliver better-targeted evidence for pollinator protection. Scientists need to make more use of opportunities (e.g. POSTnotes1; practitioner guides) to transfer knowledge to a broad audience in order to better influence decision maker and practitioner behaviours. Improved knowledge exchange between scientists and decision makers is important to combating threats to pollination. Central to this is improved understanding of the respective positions of policy makers and scientists. For instance, policy-makers usually need to be presented with a range of options to balance against other areas of policy. Science does not always arrive at a consensus due to uncertainties in data or models. Policy-makers need to understand that scientists are communicating the “best available knowledge at present” and that consequently it is not always possible to give a definitive answer

Thigh-length compression stockings and DVT after stroke

Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment on survival in patients with this disease

Insect pollinators: linking research and policy

International audienc

The HEALing (Helping to End Addiction Long-term SM) Communities Study: Protocol for a cluster randomized trial at the community level to reduce opioid overdose deaths through implementation of an integrated set of evidence-based practices

•HEALing Communities Study is a parallel-group cluster randomized controlled trial.•Communities That Heal intervention’s goal is to reduce opioid overdose deaths.•Structured consensus decision-making strategy guided study measure development.•More than 80 study measure specifications and a common data model were developed.•The study will provide methodology and longitudinal community data for research. Opioid overdose deaths remain high in the U.S. Despite having effective interventions to prevent overdose deaths, there are numerous barriers that impede their adoption. The primary aim of the HEALing Communities Study (HCS) is to determine the impact of an intervention consisting of community-engaged, data-driven selection, and implementation of an integrated set of evidence-based practices (EBPs) on reducing opioid overdose deaths. The HCS is a four year multi-site, parallel-group, cluster randomized wait-list controlled trial. Communities (n = 67) in Kentucky, Massachusetts, New York and Ohio are randomized to active intervention (Wave 1), which starts the intervention in Year 1 or the wait-list control (Wave 2), which starts the intervention in Year 3. The HCS will test a conceptually driven framework to assist communities in selecting and adopting EBPs with three components: 1) a community engagement strategy with local coalitions to guide and implement the intervention; 2) a compendium of EBPs coupled with technical assistance; and 3) a series of communication campaigns to increase awareness and demand for EBPs and reduce stigma. An implementation science framework guides the intervention and allows for examination of the multilevel contexts that promote or impede adoption and expansion of EBPs. The primary outcome, number of opioid overdose deaths, will be compared between Wave 1 and Wave 2 communities during Year 2 of the intervention for Wave 1. Numerous secondary outcomes will be examined. The HCS is the largest community-based implementation study in the field of addiction with an ambitious goal of significantly reducing fatal opioid overdoses