Briefing Two: Justice for All and the Economic Crisis

The world faces its biggest economic crisis in almost 100 years. COVID-19's economic impacts are sure to last longer than the public health emergency and will trigger a massive increase in justice problems. Unemployment is rising, people are increasingly threatened by eviction, many companies are fighting to stave off bankruptcy. In our briefing on Justice for All and the Economic Crisis we present strategies for how justice systems can help, not hinder economic recovery, and how justice leaders can take action to reshape justice systems and support more inclusive, sustainable, and resilient patterns of growth.This report was commisioned by Pathfinders for Peaceful, Just and Inclusive Societie

Developing drone experimentation facility: progress, challenges and cUAS consideration

The operation of Unmanned Aerial Systems (UAS) is widely recognised to be limited globally by challenges associated with gaining regulatory approval for flight Beyond Visual Line of Sight (BVLOS) from the UAS Remote Pilot. This challenge extends from unmanned aircraft flights having to follow the same ‘see and avoid’ regulatory principles with respect to collision avoidance as for manned aircraft. Due to the technical challenges of UAS and Remote Pilots being adequately informed of potential traffic threats, this requirement effectively prohibits BVLOS UAS flight in uncontrolled airspace, unless a specific UAS operational airspace is segregated from manned aviation traffic, often achieved by use of a Temporary Danger Area (TDA) or other spatial arrangements. The UK Civilian Aviation Authority (CAA) has defined a Detect and Avoid (DAA) framework for operators of UAS to follow in order to demonstrate effective collision avoidance capability, and hence the ability to satisfy the ‘see and avoid’ requirement. The National BVLOS Experimentation Corridor (NBEC) is an initiative to create a drone experimentation facility that incorporates a range of surveillance and navigation information sources, including radars, data fusion, and operational procedures in order to demonstrate a capable DAA System. The NBEC is part located within an active Airodrome Traffic Zone (ATZ) at Cranfield Airport, which further creates the opportunity to develop and test systems and procedures together with an operational Air Traffic Control (ATC) unit. This allows for manned and unmanned traffic to be integrated from both systems and procedural perspectives inside segregated airspace in a first stage, and then subsequently transiting to/from non-segregated airspace. The NBEC provides the environment in which a number of challenges can be addressed. This paper discusses the lack of target performance parameters, the methodology for gaining regulatory approval for non-segregated BVLOS flights and for defining peformance parameters for counter UAS (cUAS)

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)

Right iliac fossa pain other than appendicitis: A pictorial review

Right iliac fossa pain is a common presentation. Although appendicitis is the most common surgical emergency, many other pathologies can have similar presentations and should be considered. This review describes the findings and shows examples of conditions other than appendicitis that should be examined for in a patient who presents with right iliac fossa pain, particularly if the appendix is not seen or seen to be normal

Late Holocene geoarchaeological investigation of the Middle Thames floodplain at Dorney, Buckinghamshire, UK: An evaluation of the Bronze Age, Iron Age, Roman and Saxon landscapes

Large-scale floodplain excavations at Dorney in the Middle Thames valley have revealed organic-rich Holocene palaeochannels as well as a rich archaeological record. High-resolution (decadal) palaeobotanical and sedimentological analyses from a Late Holocene palaeochannel have enabled detailed reconstruction of the landscape spanning from ca. 2850 C-14 yr BP (Late Bronze Age), through the Iron Age, Roman and Saxon periods and into the Medieval period (ca. 450 C14 yr BP). The application of sedimentological, palaeovegetation and mineral magnetic analyses coupled with the use of simultaneous R- and Q-mode factor analysis helps to underpin phases of active channel flow, phases of channel 'ponding', and alluviation. These phases developed in response to human activity and land use within the region that resulted from deforestation, changes from pastoral to arable practice, burning and the associated destabilisation and inwash of soils into the channel.A series of wooden bridges and timber structures were constructed across this channel between the Middle Bronze Age and Late Iron Age which influenced local sedimentation patterns, fluvial energy and competency within the channel. A number of erosive events coupled with inwashing from the clearance of the last vestiges of woodland for agriculture into an active channel were identified.During the Roman period, flow along the Thames channel ceased, resulting in a pond-like feature in which peaty silts rapidly accumulated. This phase of ponding was punctuated by renewed channel activity in which inorganic carbonate sediments rich in ferrimagnetic minerals were deposited. This coincides with a major peak in cereal cultivation and related catchment disturbance of soils because of ploughing with associated runoff and inwash of soils associated with flooding. (C) 2008 Elsevier B.V. All rights reserved.</p