Monitoring the ageing of the cardiovascular system

This research developed a way of measuring blood flow through the capillaries and thereby monitoring the health of the endothelium, the inner lining of the blood vessels

An efficient direct solver for a class of mixed finite element problems

In this paper we present an efficient, accurate and parallelizable direct method for the solution of the (indefinite) linear algebraic systems that arise in the solution of fourth-order partial differential equations (PDEs) using mixed finite element approximations. The method is intended particularly for use when multiple right-hand sides occur, and when high accuracy is required in these solutions. The algorithm is described in some detail and its performance is illustrated through the numerical solution of a biharmonic eigenvalue problem where the smallest eigenpair is approximated using inverse iteration after discretization via the Ciarlet–Raviart mixed finite element method

Using kinematic analyses to explore sensorimotor control impairments in children with 22q11.2 deletion syndrome

Background: The 22q11.2 deletion is associated with psychiatric and behavioural disorders, intellectual disability and multiple physical abnormalities. Recent research also indicates impaired coordination skills may be part of the clinical phenotype. This study aimed to characterise sensorimotor control abilities in children with 22q11.2 deletion syndrome (22q11.2DS) and investigate their relationships with co-occurring IQ impairments and psychopathology. Methods: Fifty-four children with 22q11.2DS and 24 unaffected sibling controls, comparable in age and gender, underwent kinematic analysis of their hand movements, whilst performing a battery of three visuo-manual coordination tasks that measured their tracking, aiming and steering abilities. Additionally, standardised assessments of full-scale IQ (FSIQ), attention deficit hyperactivity disorder, indicative autism spectrum disorder (ASD) and anxiety disorder symptomatology were conducted. Results: Children with 22q11.2DS showed deficits on seven of eight kinematic descriptors of movement quality across the three coordination tasks, compared to controls. Within 22q11.2DS cases, the extent of impairment on only three kinematic descriptors was significantly related to FSIQ after correction for multiple testing. Moreover, only error whilst visuo-manually tracking was nominally associated with ADHD symptom counts. Conclusions: Impairments in sensorimotor control are seen on a range of visuo-manual tasks in children with 22q11.2DS but the extent of these impairments are largely unrelated to the severity of other psychopathological and intellectual impairments commonly found in children with 22q11.2DS.</p

Neuropsychiatric risk in children with intellectual disability of genetic origin:IMAGINE, a UK national cohort study

Background: Children with intellectual disability frequently have multiple co-morbid neuropsychiatric conditions and poor physical health. Genomic testing is increasingly recommended as a first-line investigation for these children. We aim to determine the effect of genomics, inheritance, and socioeconomic deprivation on neuropsychiatric risk in children with intellectual disability of genetic origin as compared with the general population. Methods: IMAGINE is a prospective cohort study using online mental health and medical assessments in a cohort of 3407 UK participants with intellectual disability and pathogenic genomic variants as identified by the UK's National Health Service (NHS). Our study is on a subset of these participants, including all children aged 4–19 years. We collected diagnostic genomic reports from NHS records and asked primary caregivers to provide an assessment of their child using the Development and Well-Being Assessment (DAWBA), the Strengths and Difficulties Questionnaire (SDQ), the Adaptive Behaviour Assessment System 3 (ABAS-3), and a medical history questionnaire. Each child was assigned a rank based on their postcode using the index of multiple deprivation (IMD). We compared the IMAGINE cohort with the 2017 National Survey of Children's Mental Health in England. The main outcomes of interest were mental health and neurodevelopment according to the DAWBA and SDQ. Findings: We recruited 2770 children from the IMAGINE study between Oct 1, 2014 and June 30, 2019, of whom 2397 (86·5%) had a basic assessment of their mental health completed by their families and 1277 (46·1%) completed a medical history questionnaire. The mean age of participants was 9·2 years (SD 3·9); 1339 (55·9%) were boys and 1058 (44·1%) were girls. 355 (27·8%) of 1277 reported a seizure disorder and 814 (63·7%) reported movement or co-ordination problems. 1771 (73·9%) of 2397 participants had a pathogenic copy number variant (CNV) and 626 (26·1%) had a pathogenic single nucleotide variant (SNV). Participants were representative of the socioeconomic spectrum of the UK general population. The relative risk (RR) of co-occurring neuropsychiatric diagnoses, compared with the English national population, was high: autism spectrum disorder RR 29·2 (95% CI 23·9–36·5), ADHD RR 13·5 (95% CI 11·1–16·3). In children with a CNV, those with a familial variant tended to live in more socioeconomically deprived areas than those with a de novo variant. Both inheritance and socioeconomic deprivation contributed to neuropsychiatric risk in those with a CNV.Interpretation: Children with genomic variants and intellectual disability are at an increased risk of neuropsychiatric difficulties. CNV variant inheritance and socioeconomic deprivation also contribute to the risk. Early genomic investigations of children with intellectual disability could facilitate the identification of the most vulnerable children. Additionally, harnessing parental expertise using online DAWBA assessments could rapidly identify children with exceptional needs to child mental health services. Funding: UK Medical Research Council and Medical Research Foundation.</p

Neuropsychiatric risk in children with intellectual disability of genetic origin:IMAGINE, a UK national cohort study

Background: Children with intellectual disability frequently have multiple co-morbid neuropsychiatric conditions and poor physical health. Genomic testing is increasingly recommended as a first-line investigation for these children. We aim to determine the effect of genomics, inheritance, and socioeconomic deprivation on neuropsychiatric risk in children with intellectual disability of genetic origin as compared with the general population. Methods: IMAGINE is a prospective cohort study using online mental health and medical assessments in a cohort of 3407 UK participants with intellectual disability and pathogenic genomic variants as identified by the UK's National Health Service (NHS). Our study is on a subset of these participants, including all children aged 4–19 years. We collected diagnostic genomic reports from NHS records and asked primary caregivers to provide an assessment of their child using the Development and Well-Being Assessment (DAWBA), the Strengths and Difficulties Questionnaire (SDQ), the Adaptive Behaviour Assessment System 3 (ABAS-3), and a medical history questionnaire. Each child was assigned a rank based on their postcode using the index of multiple deprivation (IMD). We compared the IMAGINE cohort with the 2017 National Survey of Children's Mental Health in England. The main outcomes of interest were mental health and neurodevelopment according to the DAWBA and SDQ. Findings: We recruited 2770 children from the IMAGINE study between Oct 1, 2014 and June 30, 2019, of whom 2397 (86·5%) had a basic assessment of their mental health completed by their families and 1277 (46·1%) completed a medical history questionnaire. The mean age of participants was 9·2 years (SD 3·9); 1339 (55·9%) were boys and 1058 (44·1%) were girls. 355 (27·8%) of 1277 reported a seizure disorder and 814 (63·7%) reported movement or co-ordination problems. 1771 (73·9%) of 2397 participants had a pathogenic copy number variant (CNV) and 626 (26·1%) had a pathogenic single nucleotide variant (SNV). Participants were representative of the socioeconomic spectrum of the UK general population. The relative risk (RR) of co-occurring neuropsychiatric diagnoses, compared with the English national population, was high: autism spectrum disorder RR 29·2 (95% CI 23·9–36·5), ADHD RR 13·5 (95% CI 11·1–16·3). In children with a CNV, those with a familial variant tended to live in more socioeconomically deprived areas than those with a de novo variant. Both inheritance and socioeconomic deprivation contributed to neuropsychiatric risk in those with a CNV.Interpretation: Children with genomic variants and intellectual disability are at an increased risk of neuropsychiatric difficulties. CNV variant inheritance and socioeconomic deprivation also contribute to the risk. Early genomic investigations of children with intellectual disability could facilitate the identification of the most vulnerable children. Additionally, harnessing parental expertise using online DAWBA assessments could rapidly identify children with exceptional needs to child mental health services. Funding: UK Medical Research Council and Medical Research Foundation.</p

Multimessenger astronomy with the Einstein Telescope

Gravitational waves (GWs) are expected to play a crucial role in the development of multimessenger astrophysics. The combination of GW observations with other astrophysical triggers, such as from gamma-ray and X-ray satellites, optical/radio telescopes, and neutrino detectors allows us to decipher science that would otherwise be inaccessible. In this paper, we provide a broad review from the multimessenger perspective of the science reach offered by the third generation interferometric GW detectors and by the Einstein Telescope (ET) in particular. We focus on cosmic transients, and base our estimates on the results obtained by ET's predecessors GEO, LIGO, and Virgo.Comment: 26 pages. 3 figures. Special issue of GRG on the Einstein Telescope. Minor corrections include

Early-Life Determinants of Total and HDL Cholesterol Concentrations in 8-Year-Old Children; The PIAMA Birth Cohort Study

BACKGROUND: Adult cholesterol concentrations might be influenced by early-life factors, such as breastfeeding and birth weight, referred to as "early programming". How such early factors exert their influence over the life course is still poorly understood. Evidence from studies in children and adolescents is scarce and conflicting. We investigated the influence of 6 different perinatal risk factors on childhood total and HDL cholesterol concentrations and total-to-HDL cholesterol ratio measured at 8 years of age, and additionally we studied the role of the child's current Body Mass Index (BMI). METHODS: Anthropometric measures and blood plasma samples were collected during a medical examination in 751 8-year-old children participating in the prospective Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort study. Linear and logistic regression were performed to estimate associations of total and HDL cholesterol concentrations with breastfeeding, birth weight, infant weight gain, maternal overweight before pregnancy, gestational diabetes and maternal smoking during pregnancy, taking into account the child's current BMI. RESULTS: Linear regressions showed an association between total-to-HDL cholesterol ratio and maternal pre-pregnancy overweight (β = 0.15, Confidence Interval 95% (CI): 0.02, 0.28), rapid infant weight gain (β = 0.13, 95%CI: 0.01, 0.26), and maternal smoking during pregnancy (β = 0.14, 95%CI: 0.00, 0.29). These associations were partly mediated by the child's BMI. CONCLUSION: Total-to-HDL cholesterol ratio in 8-year-old children was positively associated with maternal pre-pregnancy overweight, maternal smoking during pregnancy and rapid infant weight gain

Sleep EEG in young people with 22q11.2 deletion syndrome: A cross-sectional study of slow-waves, spindles and correlations with memory and neurodevelopmental symptoms

Background:: Young people living with 22q11.2 Deletion Syndrome (22q11.2DS) are at increased risk of schizophrenia, intellectual disability, attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). In common with these conditions, 22q11.2DS is also associated with sleep problems. We investigated whether abnormal sleep or sleep-dependent network activity in 22q11.2DS reflects convergent, early signatures of neural circuit disruption also evident in associated neurodevelopmental conditions. Methods:: In a cross-sectional design, we recorded high-density sleep EEG in young people (6–20 years) with 22q11.2DS (n=28) and their unaffected siblings (n=17), quantifying associations between sleep architecture, EEG oscillations (spindles and slow waves) and psychiatric symptoms. We also measured performance on a memory task before and after sleep. Results:: 22q11.2DS was associated with significant alterations in sleep architecture, including a greater proportion of N3 sleep and lower proportions of N1 and REM sleep than in siblings. During sleep, deletion carriers showed broadband increases in EEG power with increased slow-wave and spindle amplitudes, increased spindle frequency and density, and stronger coupling between spindles and slow-waves. Spindle and slow-wave amplitudes correlated positively with overnight memory in controls, but negatively in 22q11.2DS. Mediation analyses indicated that genotype effects on anxiety, ADHD and ASD were partially mediated by sleep EEG measures. Conclusions:: This study provides a detailed description of sleep neurophysiology in 22q11.2DS, highlighting alterations in EEG signatures of sleep which have been previously linked to neurodevelopment, some of which were associated with psychiatric symptoms. Sleep EEG features may therefore reflect delayed or compromised neurodevelopmental processes in 22q11.2DS, which could inform our understanding of the neurobiology of this condition and be biomarkers for neuropsychiatric disorders. Funding:: This research was funded by a Lilly Innovation Fellowship Award (UB), the National Institute of Mental Health (NIMH 5UO1MH101724; MvdB), a Wellcome Trust Institutional Strategic Support Fund (ISSF) award (MvdB), the Waterloo Foundation (918-1234; MvdB), the Baily Thomas Charitable Fund (2315/1; MvdB), MRC grant Intellectual Disability and Mental Health: Assessing Genomic Impact on Neurodevelopment (IMAGINE) (MR/L011166/1; JH, MvdB and MO), MRC grant Intellectual Disability and Mental Health: Assessing Genomic Impact on Neurodevelopment 2 (IMAGINE-2) (MR/T033045/1; MvdB, JH and MO); Wellcome Trust Strategic Award ‘Defining Endophenotypes From Integrated Neurosciences’ Wellcome Trust (100202/Z/12/Z MO, JH). NAD was supported by a National Institute for Health Research Academic Clinical Fellowship in Mental Health and MWJ by a Wellcome Trust Senior Research Fellowship in Basic Biomedical Science (202810/Z/16/Z). CE and HAM were supported by Medical Research Council Doctoral Training Grants (C.B.E. 1644194, H.A.M MR/K501347/1). HMM and UB were employed by Eli Lilly & Co during the study; HMM is currently an employee of Boehringer Ingelheim Pharma GmbH & Co KG. The views and opinions expressed are those of the author(s), and not necessarily those of the NHS, the NIHR or the Department of Health funders

Active Galactic Nuclei at the Crossroads of Astrophysics

Over the last five decades, AGN studies have produced a number of spectacular examples of synergies and multifaceted approaches in astrophysics. The field of AGN research now spans the entire spectral range and covers more than twelve orders of magnitude in the spatial and temporal domains. The next generation of astrophysical facilities will open up new possibilities for AGN studies, especially in the areas of high-resolution and high-fidelity imaging and spectroscopy of nuclear regions in the X-ray, optical, and radio bands. These studies will address in detail a number of critical issues in AGN research such as processes in the immediate vicinity of supermassive black holes, physical conditions of broad-line and narrow-line regions, formation and evolution of accretion disks and relativistic outflows, and the connection between nuclear activity and galaxy evolution.Comment: 16 pages, 5 figures; review contribution; "Exploring the Cosmic Frontier: Astrophysical Instruments for the 21st Century", ESO Astrophysical Symposia Serie

Magnetic Field Amplification in Galaxy Clusters and its Simulation

We review the present theoretical and numerical understanding of magnetic field amplification in cosmic large-scale structure, on length scales of galaxy clusters and beyond. Structure formation drives compression and turbulence, which amplify tiny magnetic seed fields to the microGauss values that are observed in the intracluster medium. This process is intimately connected to the properties of turbulence and the microphysics of the intra-cluster medium. Additional roles are played by merger induced shocks that sweep through the intra-cluster medium and motions induced by sloshing cool cores. The accurate simulation of magnetic field amplification in clusters still poses a serious challenge for simulations of cosmological structure formation. We review the current literature on cosmological simulations that include magnetic fields and outline theoretical as well as numerical challenges.Comment: 60 pages, 19 Figure