Identification of a new locus at 16q12 associated with time-to-asthma onset

International audienceBackground: Asthma is a heterogeneous disease in which age-of-onset plays an important role.Objective: We sought to identify the genetic variants associated with time-to-asthma onset.Methods: We conducted a large-scale meta-analysis of nine genome-wide association studies of time-to-asthma onset (total of 5,462 asthmatics with a broad range of age-of-asthma onset and 8,424 controls of European ancestry) performed using survival analysis techniques.Results: We detected five regions associated with time-to-asthma onset at genome-wide significant level (P<5x10-8). We evidenced a new locus in 16q12 region (near cylindromatosis turban tumor syndrome gene (CYLD)) and confirmed four asthma risk regions: 2q12 (IL1RL1), 6p21 (HLA-DQA1), 9p24 (IL33) and 17q12-q21 (ZPBP2-GSDMA). Conditional analyses identified two distinct signals at 9p24 (both upstream of IL33) and at 17q12-q21 (near ZPBP2 and within GSDMA). These seven distinct loci explained together 6.0% of the variance in time-to-asthma onset. In addition, we showed that genetic variants at 9p24 and 17q12-q21 were strongly associated with an earlier onset of childhood asthma (P≤0.002) whereas 16q12 SNP was associated with a later asthma onset (P=0.04). A high burden of disease risk alleles at these loci was associated with earlier age-of-asthma onset (4 years versus 9-12 years, P=10-4).Conclusion: The new susceptibility region for time-to-asthma onset at 16q12 harbors variants that correlate with the expression of CYLD and NOD2 (nucleotide-binding oligomerization domain 2), two strong candidates for asthma. This study demonstrates that incorporating the variability of age-of-asthma onset in asthma modeling is a helpful approach in the search for disease susceptibility genes

The effectiveness, acceptability and cost-effectiveness of psychosocial interventions for maltreated children and adolescents: an evidence synthesis.

BACKGROUND: Child maltreatment is a substantial social problem that affects large numbers of children and young people in the UK, resulting in a range of significant short- and long-term psychosocial problems. OBJECTIVES: To synthesise evidence of the effectiveness, cost-effectiveness and acceptability of interventions addressing the adverse consequences of child maltreatment. STUDY DESIGN: For effectiveness, we included any controlled study. Other study designs were considered for economic decision modelling. For acceptability, we included any study that asked participants for their views. PARTICIPANTS: Children and young people up to 24 years 11 months, who had experienced maltreatment before the age of 17 years 11 months. INTERVENTIONS: Any psychosocial intervention provided in any setting aiming to address the consequences of maltreatment. MAIN OUTCOME MEASURES: Psychological distress [particularly post-traumatic stress disorder (PTSD), depression and anxiety, and self-harm], behaviour, social functioning, quality of life and acceptability. METHODS: Young Persons and Professional Advisory Groups guided the project, which was conducted in accordance with Cochrane Collaboration and NHS Centre for Reviews and Dissemination guidance. Departures from the published protocol were recorded and explained. Meta-analyses and cost-effectiveness analyses of available data were undertaken where possible. RESULTS: We identified 198 effectiveness studies (including 62 randomised trials); six economic evaluations (five using trial data and one decision-analytic model); and 73 studies investigating treatment acceptability. Pooled data on cognitive-behavioural therapy (CBT) for sexual abuse suggested post-treatment reductions in PTSD [standardised mean difference (SMD) -0.44 (95% CI -4.43 to -1.53)], depression [mean difference -2.83 (95% CI -4.53 to -1.13)] and anxiety [SMD -0.23 (95% CI -0.03 to -0.42)]. No differences were observed for post-treatment sexualised behaviour, externalising behaviour, behaviour management skills of parents, or parental support to the child. Findings from attachment-focused interventions suggested improvements in secure attachment [odds ratio 0.14 (95% CI 0.03 to 0.70)] and reductions in disorganised behaviour [SMD 0.23 (95% CI 0.13 to 0.42)], but no differences in avoidant attachment or externalising behaviour. Few studies addressed the role of caregivers, or the impact of the therapist-child relationship. Economic evaluations suffered methodological limitations and provided conflicting results. As a result, decision-analytic modelling was not possible, but cost-effectiveness analysis using effectiveness data from meta-analyses was undertaken for the most promising intervention: CBT for sexual abuse. Analyses of the cost-effectiveness of CBT were limited by the lack of cost data beyond the cost of CBT itself. CONCLUSIONS: It is not possible to draw firm conclusions about which interventions are effective for children with different maltreatment profiles, which are of no benefit or are harmful, and which factors encourage people to seek therapy, accept the offer of therapy and actively engage with therapy. Little is known about the cost-effectiveness of alternative interventions. LIMITATIONS: Studies were largely conducted outside the UK. The heterogeneity of outcomes and measures seriously impacted on the ability to conduct meta-analyses. FUTURE WORK: Studies are needed that assess the effectiveness of interventions within a UK context, which address the wider effects of maltreatment, as well as specific clinical outcomes. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013003889. FUNDING: The National Institute for Health Research Health Technology Assessment programme

Stomatal responses of Eucalyptus species to elevated CO2 concentration and drought stress

Five species of Eucalyptus (E. grandis, E. urophylla, E. camaldulensis, E. torelliana, and E. phaeotrica), among the ten species most commonly used in large scale plantations, were selected for studies on the effects of elevated CO2 concentration [CO2] and drought stress on stomatal responses of 2.5-month old seedlings. The first three species belong to the subgenus Smphyomyrtus, whereas the fourth species belongs to the subgenus Corymbia and E. phaeotrica is from the subgenus Monocalyptus. Seedlings were grown in four pairs of open-top chambers, arranged to have 2 plants of each species in each chamber, with four replications in each of two CO2 concentrations: 350 &plusmn; 30 mumol mol-1 and 700 &plusmn; 30 mumol mol-1. After 100 days in the chambers, a series of gas exchange measurements were made. Half the plants in each chamber, one plant per species per chamber, were drought-stressed by withholding irrigation, while the remaining plants continued to be watered daily. Drought stress decreased stomatal conductance, photosynthesis and transpiration rates in all the species. The effect of drought stress on stomatal closure was similar in both [CO2]. The positive effects of elevated [CO2] on photosynthesis and water use efficiency were maintained longer during the stress period than under well-watered conditions. The photosynthetic rate of E. phaeotrica was higher even in the fourth day of the drought stress. Drought stress increased photoinhibition of photosynthesis, as measured by chlorophyll fluorescence, which varied among the species, as well as in relation to [CO2]. The results are in agreement with observed differences in stomatal responses between some eucalyptus species of the subgenera Symphyomyrtus and Monocalyptus

Enhancing epidemiological surveillance of the emergence of the SARS-CoV-2 Omicron variant using spike gene target failure data, England, 15 November to 31 December 2021

When SARS-CoV-2 Omicron emerged in 2021, S gene target failure enabled differentiation between Omicron and the dominant Delta variant. In England, where S gene target surveillance (SGTS) was already established, this led to rapid identification (within ca 3 days of sample collection) of possible Omicron cases, alongside real-time surveillance and modelling of Omicron growth. SGTS was key to public health action (including case identification and incident management), and we share applied insights on how and when to use SGTS

Association of Forced Vital Capacity with the Developmental Gene <i>NCOR2</i>

Background Forced Vital Capacity (FVC) is an important predictor of all-cause mortality in the absence of chronic respiratory conditions. Epidemiological evidence highlights the role of early life factors on adult FVC, pointing to environmental exposures and genes affecting lung development as risk factors for low FVC later in life. Although highly heritable, a small number of genes have been found associated with FVC, and we aimed at identifying further genetic variants by focusing on lung development genes. Methods Per-allele effects of 24,728 SNPs in 403 genes involved in lung development were tested in 7,749 adults from three studies (NFBC1966, ECRHS, EGEA). The most significant SNP for the top 25 genes was followed-up in 46,103 adults (CHARGE and SpiroMeta consortia) and 5,062 chi

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

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p&lt;0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p&lt;0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p&lt;0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP &gt;5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification