Maternal Exposure to Nitrogen Dioxide, Intake of Methyl Nutrients, and Congenital Heart Defects in Offspring

Nutrients that regulate methylation processes may modify susceptibility to the effects of air pollutants. Data from the National Birth Defects Prevention Study (United States, 1997-2006) were used to estimate associations between maternal exposure to nitrogen dioxide (NO2), dietary intake of methyl nutrients, and the odds of congenital heart defects in offspring. NO2 concentrations, a marker of traffic-related air pollution, averaged across postconception weeks 2-8, were assigned to 6,160 nondiabetic mothers of cases and controls using inverse distance-squared weighting of air monitors within 50 km of maternal residences. Intakes of choline, folate, methionine, and vitamins B6 and B12 were assessed using a food frequency questionnaire. Hierarchical regression models, which accounted for similarities across defects, were constructed, and relative excess risks due to interaction were calculated. Relative to women with the lowest NO2 exposure and high methionine intake, women with the highest NO2 exposure and lowest methionine intake had the greatest odds of offspring with a perimembranous ventricular septal defect (odds ratio = 3.23, 95% confidence interval: 1.74, 6.01; relative excess risk due to interaction = 2.15, 95% confidence interval: 0.39, 3.92). Considerable departure from additivity was not observed for other defects. These results provide modest evidence of interaction between nutrition and NO2 exposure during pregnancy

Cardiovascular Outcomes and the Physical and Chemical Properties of Metal Ions Found in Particulate Matter Air Pollution: a QICAR Study

Background: This paper presents an application of quantitative ion character–activity relationships (QICAR) to estimate associations of human cardiovascular (CV) diseases (CVDs) with a set of metal ion properties commonly observed in ambient air pollutants. QICAR has previously been used to predict ecotoxicity of inorganic metal ions based on ion properties

A Portable Wireless Particulate Sensor System for Continuous Real-Time Environmental Monitoring

Airborne particulate matter has been shown to be associated with morbidity and mortality, and may interfere with certain sensitive experiment. Understanding the levels and movements of particulate matter in an enclosed space can lead to a reduction in the impact of this material on health and experimental results. A system of environmental sensors including particulate matter, selected gasses, humidity, temperature, and pressure can be used to assist in tracking air movement, providing real-time mapping of potential contaminants as they move through a space. In this paper we present a system that is capable of sensing these environmental factors, collecting data from multiple dispersed nodes and presenting the aggregated information in real-time. The highly modular system is based on a flexible and scalable framework developed for use in aircraft cabin environments. Use of this framework enables the deployment of a custom suite of sensors with minimal development effort. Individual nodes communicate using a self-organizing mesh network and can be powered from a variety of sources, bringing a high level of flexibility in the arrangement and distribution of the sensor array. Sensor data is transmitted to a coordinator node, which then passes the time-correlated information to a server-hosted database through a choice of wired or wireless networks. Presentation software is used to either monitor the real-time data stream, or to extract records of interest from the database. A reference implementation has been created for the National Institutes of Health consisting of a custom optical particle counter and off-the-shelf sensors for CO2, CO, temperature, humidity, pressure, and acoustic noise. The total environmental sensing system provides continuous, real-time data in a readable format that can be used to analyze ambient air for events of interest

A Dimer of the Toll-Like Receptor 4 Cytoplasmic Domain Provides a Specific Scaffold for the Recruitment of Signalling Adaptor Proteins

The Toll-like receptor 4 (TLR4) is a class I transmembrane receptor expressed on the surface of immune system cells. TLR4 is activated by exposure to lipopolysaccharides derived from the outer membrane of Gram negative bacteria and forms part of the innate immune response in mammals. Like other class 1 receptors, TLR4 is activated by ligand induced dimerization, and recent studies suggest that this causes concerted conformational changes in the receptor leading to self association of the cytoplasmic Toll/Interleukin 1 receptor (TIR) signalling domain. This homodimerization event is proposed to provide a new scaffold that is able to bind downstream signalling adaptor proteins. TLR4 uses two different sets of adaptors; TRAM and TRIF, and Mal and MyD88. These adaptor pairs couple two distinct signalling pathways leading to the activation of interferon response factor 3 (IRF-3) and nuclear factor κB (NFκB) respectively. In this paper we have generated a structural model of the TLR4 TIR dimer and used molecular docking to probe for potential sites of interaction between the receptor homodimer and the adaptor molecules. Remarkably, both the Mal and TRAM adaptors are strongly predicted to bind at two symmetry-related sites at the homodimer interface. This model of TLR4 activation is supported by extensive functional studies involving site directed mutagenesis, inhibition by cell permeable peptides and stable protein phosphorylation of receptor and adaptor TIR domains. Our results also suggest a molecular mechanism for two recent findings, the caspase 1 dependence of Mal signalling and the protective effects conferred by the Mal polymorphism Ser180Leu

Psychological morbidity and health related quality of life after injury: multicentre cohort study

Purpose: To demonstrate the impact of psychological morbidity 1 month post-injury on subsequent post-injury quality of life (HRQoL) in a general injury population in the UK to inform development of trauma care and rehabilitation services. Methods: Multicentre cohort study of 16–70-year-olds admitted to 4 UK hospitals following injury. Psychological morbidity and HRQoL (EQ-5D-3L) were measured at recruitment and 1, 2, 4 and 12 months post-injury. A reduction in EQ-5D compared to retrospectively assessed pre-injury levels of at least 0.074 was taken as the minimal important difference (MID). Multilevel logistic regression explored relationships between psychological morbidity 1 month post-injury and MID in HRQoL over the 12 months after injury. Results: A total of 668 adults participated. Follow-up rates were 77% (1 month) and 63% (12 months). Substantial reductions in HRQoL were seen; 93% eported a MID at 1 month and 58% at 12 months. Problems with pain, mobility and usual activities were commonly reported at each time point. Depression and anxiety scores month post-injury were independently associated with subsequent MID in HRQoL. The relationship between depression and HRQoL was partly explained by anxiety and to a lesser extent by pain and social functioning. The relationship between anxiety and HRQoL was not explained by factors measured in our study. Conclusions: Hospitalised injuries result in substantial reductions in HRQoL up to 12 months later. Depression and anxiety early in the recovery period are independently associated with lower HRQoL. Identifying and managing these problems, ensuring adequate pain control and facilitating social functioning are key elements in improving HRQoL post-injury

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types