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)

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Application of the Fuller-Thompson equation in sinter blend design to increase sinter plant productivity

TATA Steel Europe are the second largest steel producers in Europe (2015) with operations focused in the UK and Netherlands. The sintering process is an upstream process in the iron and steelmaking chain to create part of the blast furnace burden. A blend of raw materials composing of iron ore, flux, coke breeze and revert materials are sintered on a moving strand to produce an iron rich, strong and porous agglomerate known as sinter. Before sintering, the blend is processed through a mixer and granulator to create granules, which enhances sinter bed permeability. Sinter bed permeability is the driving factor behind sinter strand productivity. Differing compositions of sinter blends are known to impact the sintering process. More specifically concerned in this study is blend particle size distribution (PSD). A new application of the Fuller-Thompson (FT) equation is proposed, which was originally developed for designing the aggregates in concrete and shown to improve properties like strength. The FT equation determines the PSD to create the maximum particle packing density. The FT equation is applied to sinter blend design through the granulation process. During granulation, finer particles are layered around coarser nuclei particles to produce granules. Designing the finer or layering proportion of sinter blends to the FT equation is proposed to create granules with denser and stronger layers. Thus, enabling greater bed permeability during the process and increased sinter strand productivity. The first phase of the Author’s study determined the parameters of the FT equation that gave the optimum granule beds in terms of ‘cold’ bed permeability and efficiency in maintaining ‘cold’ permeability under an applied motion. These were established to be a maximum layering particle size (D) of 0.5mm and a FT exponent (Y) of 0.5. Bimodal sinter blends were used to study the impact of layering PSD spread (n), which is a relative measure for the uniformity of sizes in the distribution on bed permeability and sintering time. Widening the spread of layering particle sizes increased ‘cold’ bed permeability due to the narrowing in granule size distribution spread and increasing mean granule diameter. With the blends investigated the layering PSD spread of the FT blend gave the greatest ‘hot’ permeability and shortest sintering times, as it maintained more permeability than expected based on the trend with mean granule diameter. Industrial base blends were compared with blends designed to the FT equation. At equal layering particle proportions the FT blends increased ‘cold’ permeability by up to 20% and reduced sintering times by up to 9.5%. The FT blends could also incorporate 4wt% more layering particles and still exhibit the same ‘cold’ permeability and sintering times as the base blends. No changes in sinter quality were observed. Full-scale plant trials with FT blend design at Tata Steel Europe showed positive impacts on ignition permeability, flame front speed and net production rate compared to typically used blends. No changes in sinter quality were identified. The methodology is currently being implemented into sinter blend design practice at Tata Steel Europe

Application of the Fuller-Thompson equation in sinter blend design to increase sinter productivity

Sintering is an important phase of the iron-making chain, as it allows the usage of finer iron ore particles in the blast furnace whilst still maintaining furnace performance. An on-going challenge for sinter plants is to obtain higher productivity from their sinter blends, or maintain sinter productivity whilst using more financially attractive iron ores. One of the most effective means to reduced blend cost is to use a higher proportion of concentrated iron ores in the blend. The key characteristic of concentrated ores is that they have a finer particle size distribution (PSD) than traditional sinter feeds and are widely known to negatively impact sinter bed permeability and sinter productivity. In this study, various iron ore blends were used to demonstrate the effect that the PSD of the sinter blend has on granulation and subsequent sintering process parameters during laboratory-scale sintering. Particular focus was applied to the impact of the PSD of the layering material in blend (−0.5 mm). Cold bed superficial gas velocity (SGV) was correlated to the spread of the PSD within the layers around granule nuclei. Widening the PSD spread within the layer increased cold SGV due to a narrowing in the spread of the granule size distribution (GSD) and increase in mean granule diameter. The Fuller–Thompson (FT) blend exhibited increased SGV during sintering (hot SGV) which led to shorter sintering times. This was a result of an enhanced ‘hot SGV efficiency’ (a measure for the ratio of hot SGV to cold SGV) over what was anticipated based on the trend with mean granule diameter. Complete industrial blends were compared with blends designed to the FT equation at varying proportions of layering particles in the blends (−0.5 mm). At equal proportions of layering particles in the blends, the FT blends exhibited increased cold and hot SGV by up to 20% and 25%, respectively, and led to a maximum 10% decrease in sintering time. Further, blends designed to the FT equation enabled the incorporation of 4 wt-% more layering particles and still exhibited similar cold SGV, hot SGV and sintering times to the industrial blends

vrSensory: Designing Inclusive Virtual Games with Neurodiverse Children

We explore virtual environments and accompanying interaction styles to enable inclusive play. In designing games for three neurodiverse children, we explore how designing for sensory diversity can be understood through a formal game design framework. Our process reveals that by using sensory processing needs as requirements we can make sensory and social accessible play spaces. We contribute empirical findings for accommodating sensory differences for neurodiverse children in a way that supports inclusive play. Specifically, we detail the sensory driven design choices that not only support the enjoyability of the leisure activities, but that also support the social inclusion of sensory-diverse participants. The participants displayed behaviors in the multi-user version consistent with their behaviors in the single user version with the addition of social behavior. We tie these techniques to game design mechanics to iterate on our efforts to support inclusive game development. Preliminary results are discussed

Synthesis and Characterization of [Zn(Acetate)\u3csub\u3e2\u3c/sub\u3e(Amine)\u3csub\u3ex\u3c/sub\u3e] Compounds (x= 1 or 2) and Their Use as Precursors to ZnO

As an obvious candidate for a p-type dopant in ZnO, nitrogen remains elusive in this role. Nitrogen containing precursors are a potential means to incorporate nitrogen during MOCVD growth. One class of nitrogen-containing precursors are zinc acetate amines, yet, they have received little attention. The synthesis and single crystal X-ray structure of [Zn(acetate)2(en)], and the synthesis of [Zn(acetate)2(en)2], [Zn(acetate)2(benzylamine)2], [Zn(acetate)2(butylamine)2], [Zn(acetate)2(NH3)2], and [Zn(acetate)2(tris)2], where en = ethylenediamine and tris = (tris[hydroxymethyl]aminomethane) are reported. The compounds were characterized by thermogravimetric analysis and pyrolyzed in air and inert gas to yield ZnO. These compounds are useful single source precursors to ZnO bulk powders by alkali precipitation and ZnO thin films by spray pyrolysis. The amine bound to the zinc influences the ZnO crystal size and shape and acts as a nitrogen donor for preparing nitrogen-doped ZnO during alkali precipitation. Thin films of ZnO prepared by spray pyrolysis using the precursors had a (100) preferred orientation and measured n-type to intrinsic conductivity