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Introduction Good quality parenting in early childhood is reliably associated with positive mental and physical health over the lifespan. Objectives The hypothesis that early parenting quality has significant long-term financial benefits has not been previously tested. Methods Design: Longitudinal study with follow-up from 2012 to 2016; UK multicentre study cohort. Participants: 174 young people drawn from 2 samples, one at moderate risk of poor outcomes and one at high risk, assessed aged 4–6 years then followed up in early adolescence (mean age 12.1 years). Measures : The primary outcome was total costs: health, social care, extra school support, out-of-home placements and family-born expenditure, determined through semistructured economic interviews. Early parenting quality was independently assessed through direct observation of parent–child interaction. Results Costs were lower for youths exposed to more sensitive parenting (most sensitive quartile mean £1,619, least sensitive quartile mean £21,763; p < .001). Costs were spread across personal family expenditure and education, health, social and justice services. The cost difference remained significant after controlling for several potential confounders. These included demographic variables (family poverty, parental education); exposure to child abuse; and child/young person variables including level of antisocial behaviour in both childhood and adolescence, IQ and attachment security. Conclusions This study is the first showing that more sensitive early parental care predicts lower costs to society many years later, independent of poverty, child and youth antisocial behaviour levels and IQ. The findings provide novel evidence for the public health impact of early caregiving quality and likely financial benefits of improving it. Disclosure No significant relationships.

This study evaluated the impact of training two practitioners to create and implement video-based intervention (VBI) to teach vocational skills to three autistic young adults in authentic workplace settings, via a multiple-probe single-case research design. A behavioral skills training (BST) package was used to train the practitioners to create and implement VBI. Practitioners' fidelity of VBI creation and implementation was also evaluated via pretest-posttest. There was a functional relation between the practitioner-created and -implemented VBI and the autistic young adults' vocational skill acquisition, with all three reaching 100% independent accuracy and demonstrating maintenance of the learned vocational skills. The practitioners also showed large increases in their fidelity of VBI creation and implementation from pretest to posttest, although their VBI creation performance decreased slightly at follow-up. All participants reported positive experiences with the VBI and rated it as socially valid.

Abstract This report presents results of parent-implemented behavioral treatments for a child with cortical visual impairment (CVI), intellectual disability (ID), epilepsy, and autism spectrum disorder (ASD) associated with a pathogenic variant in the SCN2A gene (i.e., SCN2A-Related Disorder). Treatment evaluations were informed by combined results of functional behavior assessment (FBA) and functional vision assessment (FVA) which yielded CVI-related accommodations. The treatment of escape-maintained challenging behavior involved the evaluation of behavioral prompting strategies in accordance with CVI-related accommodations, extinction (EXT), and differential reinforcement modifications. The treatment for behavior problems maintained by access to food (tangible-edible) included functional communication training (FCT), EXT, and schedule thinning with schedule-correlated visual signals. Overall, integrating child-specific CVI-related accommodations was essential for developing effective behavioral interventions for this child. FVAs are accessible and practical for uptake by behavior analysts in vision-informed assessment and treatment of challenging behavior.

Objective: Understanding compliance with COVID-19 mitigation recommendations is critical for informing efforts to contain future infectious disease outbreaks. This study tested the hypothesis that higher levels of worry about COVID-19 illness among household caregivers would predict lower (a) levels of overall and discretionary social exposure activities and (b) rates of household SARS-CoV-2 infections. Methods: Data were drawn from a surveillance study of households with children (N = 1913) recruited from 12 U.S. cities during the initial year of the pandemic and followed for 28 weeks (data collection: 1-May-2020 through 22-Feb-2021). Caregivers rated how much they worried about family members getting COVID-19 and subsequently reported household levels of outside-the-home social activities that could increase risk for SARS-CoV-2 transmission at 14 follow-ups. Caregivers collected household nasal swabs on a fortnightly basis and peripheral blood samples at study conclusion to monitor for SARS-CoV-2 infections by polymerase chain reaction and serology. Primary analyses used generalized linear and generalized mixed-effects modelling. Results: Caregivers with high enrollment levels of worry about COVID-19 illness were more likely to reduce direct social contact outside the household, particularly during the U.S.'s most deadly pandemic wave. Households of caregivers with lower COVID-19 worry had higher odds of (a) reporting discretionary outside-the-home social interaction and (b) SARS-CoV-2 infection. Conclusions: This was, to our knowledge, the first study showing that caregiver COVID-19 illness worry was predictive of both COVID-19 mitigation compliance and laboratory-determined household infection. Findings should inform studies weighing the adaptive value of worrying about infectious disease outbreaks against established detrimental health effects.

Abstract Background As omics measurements profiled on different molecular layers are interconnected, integrative approaches that incorporate the regulatory effect from multi-level omics data are needed. When the multi-level omics data are from the same individuals, gene expression (GE) clusters can be identified using information from regulators like genetic variants and DNA methylation. When the multi-level omics data are from different individuals, the choice of integration approaches is limited. Methods We developed an approach to improve GE clustering from microarray data by integrating regulatory data from different but partially overlapping sets of individuals. We achieve this through (1) decomposing gene expression into the regulated component and the other component that is not regulated by measured factors, (2) optimizing the clustering goodness-of-fit objective function. We do not require the availability of different omics measurements on all individuals. A certain amount of individual overlap between GE data and the regulatory data is adequate for modeling the regulation, thus improving GE clustering. Results A simulation study shows that the performance of the proposed approach depends on the strength of the GE-regulator relationship, degree of missingness, data dimensionality, sample size, and the number of clusters. Across the various simulation settings, the proposed method shows competitive performance in terms of accuracy compared to the alternative K-means clustering method, especially when the clustering structure is due mostly to the regulated component, rather than the unregulated component. We further validate the approach with an application to 8,902 Framingham Heart Study participants with data on up to 17,873 genes and regulation information of DNA methylation and genotype from different but partially overlapping sets of participants. We identify clustering structures of genes associated with pulmonary function while incorporating the predicted regulation effect from the measured regulators. We further investigate the over-representation of these GE clusters in pathways of other diseases that may be related to lung function and respiratory health. Conclusion We propose a novel approach for clustering GE with the assistance of regulatory data that allowed for different but partially overlapping sets of individuals to be included in different omics data.

IgG4-related disease (IgG4-RD) is a new clinical entity characterized by lymphoplasmacytic lesions rich in IgG4-positive plasma cells. Myocardial involvement is extremely rare and not a typical cardiovascular manifestation of IgG4-RD. We report a rare case of IgG4-RD–associated myocardial mass causing severe aortic incompetence, successfully treated with surgery and corticosteroids. (Level of Difficulty: Intermediate.)

Summary: Background: Identifying novel epigenetic signatures associated with serum immunoglobulin E (IgE) may improve our understanding of molecular mechanisms underlying asthma and IgE-mediated diseases. Methods: We performed an epigenome-wide association study using whole blood from Framingham Heart Study (FHS; n = 3,471, 46% females) participants and validated results using the Childhood Asthma Management Program (CAMP; n = 674, 39% females) and the Genetic Epidemiology of Asthma in Costa Rica Study (CRA; n = 787, 41% females). Using the closest gene to each IgE-associated CpG, we highlighted biologically plausible pathways underlying IgE regulation and analyzed the transcription patterns linked to IgE-associated CpGs (expression quantitative trait methylation loci; eQTMs). Using prior UK Biobank summary data from genome-wide association studies of asthma and allergy, we performed Mendelian randomization (MR) for causal inference testing using the IgE-associated CpGs from FHS with methylation quantitative trait loci (mQTLs) as instrumental variables. Findings: We identified 490 statistically significant differentially methylated CpGs associated with IgE in FHS, of which 193 (39.3%) replicated in CAMP and CRA (FDR < 0.05). Gene ontology analysis revealed enrichment in pathways related to transcription factor binding, asthma, and other immunological processes. eQTM analysis identified 124 cis-eQTMs for 106 expressed genes (FDR < 0.05). MR in combination with drug-target analysis revealed CTSB and USP20 as putatively causal regulators of IgE levels (Bonferroni adjusted P

Abstract Background Asthma is the most common chronic disease in children, occurring at higher frequencies and with more severe disease in children with African ancestry. Methods We tested for association with haplotypes at the most replicated and significant childhood-onset asthma locus at 17q12-q21 and asthma in European American and African American children. Following this, we used whole-genome sequencing data from 1060 African American and 100 European American individuals to identify novel variants on a high-risk African American–specific haplotype. We characterized these variants in silico using gene expression and ATAC-seq data from airway epithelial cells, functional annotations from ENCODE, and promoter capture (pc)Hi-C maps in airway epithelial cells. Candidate causal variants were then assessed for correlation with asthma-associated phenotypes in African American children and adults. Results Our studies revealed nine novel African-specific common variants, enriched on a high-risk asthma haplotype, which regulated the expression of GSDMA in airway epithelial cells and were associated with features of severe asthma. Using ENCODE annotations, ATAC-seq, and pcHi-C, we narrowed the associations to two candidate causal variants that are associated with features of T2 low severe asthma. Conclusions Previously unknown genetic variation at the 17q12-21 childhood-onset asthma locus contributes to asthma severity in individuals with African ancestries. We suggest that many other population-specific variants that have not been discovered in GWAS contribute to the genetic risk for asthma and other common diseases.

ABSTRACT. It has been shown that the partial molar excess Gibbs energy (G̅ex) can be used as an indicator of hydrophobicity and hence contributes to explaining the behaviour of collectors in the recovery of minerals by flotation. This is because hydrophobicity of a mineral particle on which a collector is adsorbed is related to the fact that the alkyl chain associated with the collector behaves in the same way as any hydrocarbon would in a non-ideal mixture with water. Such mixtures are quantified thermodynamically by determining the activity coefficient of the hydrocarbon moiety of the collector and hence its G̅ex in the mixture. The present paper is aimed at extending the above concepts in two different ways. Firstly, an investigation is made of the relationship between G̅ex and contact angle and/or recovery for systems such as ionic liquids and aminothiophenols. Secondly, on the basis of the observation that increases in G̅ex are indicative of increases in the hydrophobicity of the mineral particle-collector aggregate, a study was undertaken to examine, respectively, the effects of the presence of electrolytes or alcohols in the system, of pH and changing concentrations of the collector, on G̅ex of the collector alkyl group and hence its hydrophobicity. In the first instance, the relationship between G̅ex and contact angle and recovery is sustained. With respect to the latter, the absence of any correlation between G̅ex and recoveries supported the proposition that the major effect of electrolytes and added alcohols is rather on particle – bubble attachment. Similarly, it is also indicated that since the change in G̅ex is minimal when collector concentration or pulp temperature is increased these changes do not significantly affect the hydrophobicity of the collector-mineral particle and hence also the recovery in a microflotation.

Impaired lung function in early life is associated with the subsequent development of chronic respiratory disease. Most genetic associations with lung function have been identified in adults of European descent and therefore may not represent those most relevant to pediatric populations and populations of different ancestries. In this study, we performed genome-wide association analyses of lung function in a multiethnic cohort of children (n = 1,035) living in low-income urban neighborhoods. We identified one novel locus at the TDRD9 gene in chromosome 14q32.33 associated with percent predicted forced expiratory volume in one second (FEV1) (p = 2.4x10-9; βz = -0.31, 95% CI = -0.41- -0.21). Mendelian randomization and mediation analyses revealed that this genetic effect on FEV1 was partially mediated by DNA methylation levels at this locus in airway epithelial cells, which were also associated with environmental tobacco smoke exposure (p = 0.015). Promoter-enhancer interactions in airway epithelial cells revealed chromatin interaction loops between FEV1-associated variants in TDRD9 and the promoter region of the PPP1R13B gene, a stimulator of p53-mediated apoptosis. Expression of PPP1R13B in airway epithelial cells was significantly associated the FEV1 risk alleles (p = 1.3x10-5; β = 0.12, 95% CI = 0.06-0.17). These combined results highlight a potential novel mechanism for reduced lung function in urban youth resulting from both genetics and smoking exposure.

Abstract Genome-wide association studies have identified numerous common genetic variants associated with spirometric measures of pulmonary function, including forced expiratory volume in one second (FEV1), forced vital capacity, and their ratio. However, variants with lower minor allele frequencies are less explored. We conducted a large-scale gene-smoking interaction meta-analysis on exonic rare and low-frequency variants involving 44,429 individuals of European ancestry in the discovery stage and sought replication in the UK BiLEVE study with 45,133 European ancestry samples and UK Biobank study with 59,478 samples. We leveraged data on cigarette smoking, the major environmental risk factor for reduced lung function, by testing gene-by-smoking interaction effects only and simultaneously testing the genetic main effects and interaction effects. The most statistically significant signal that replicated was a previously reported low-frequency signal in GPR126, distinct from common variant associations in this gene. Although only nominal replication was obtained for a top rare variant signal rs142935352 in one of the two studies, interaction and joint tests for current smoking and PDE3B were significantly associated with FEV1. This study investigates the utility of assessing gene-by-smoking interactions and underscores their effects on potential pulmonary function.

Epigenetic architecture is influenced by genetic and environmental factors, but little is known about their relative contributions or longitudinal dynamics. Here, we studied DNA methylation (DNAm) at over 750,000 CpG sites in mononuclear blood cells collected at birth and age 7 from 196 children of primarily self-reported Black and Hispanic ethnicities to study race-associated DNAm patterns. We developed a novel Bayesian method for high-dimensional longitudinal data and showed that race-associated DNAm patterns at birth and age 7 are nearly identical. Additionally, we estimated that up to 51% of all self-reported race-associated CpGs had race-dependent DNAm levels that were mediated through local genotype and, quite surprisingly, found that genetic factors explained an overwhelming majority of the variation in DNAm levels at other, previously identified, environmentally-associated CpGs. These results indicate that race-associated blood DNAm patterns in particular, and blood DNAm levels in general, are primarily driven by genetic factors, and are not as sensitive to environmental exposures as previously suggested, at least during the first 7 years of life.

Summary: This protocol describes the preparation of Drosophila melanogaster pupae for laser ablation and live imaging of the notum (dorsal thorax). Because the pupa is stationary, it can be continuously live imaged for multiple days if desired, making it ideal for studying wound signaling and repair, from before laser ablation through wound closure. In this protocol, we demonstrate the processes of staging, partially dissecting, mounting, wounding, and live imaging the pupal notum, with the wounding occurring during the live imaging process.For complete details on the use and execution of this protocol, please refer to O’Connor et al. (2021b). : Publisher's note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Introduction Bronchodilator response (BDR) is a measurement of acute bronchodilation in response to short-acting β2-agonists, with a heritability between 10 and 40%. Identifying genetic variants associated with BDR may lead to a better understanding of its complex pathophysiology. Methods We performed a genome-wide association study (GWAS) of BDR in six adult cohorts with participants of European ancestry (EA) and African ancestry (AA) including community cohorts and cohorts ascertained on the basis of obstructive pulmonary disease. Validation analysis was carried out in two paediatric asthma cohorts. Results A total of 10 623 EA and 3597 AA participants were included in the analyses. No single nucleotide polymorphism (SNP) was associated with BDR at the conventional genome-wide significance threshold (p

Chronic obstructive pulmonary disease is a leading cause of morbidity and mortality. Here, the authors analyse whole genome sequence data and find new loci associated with lung function and COPD.

RationaleIt has been speculated that shared mechanisms underlie respiratory and cardiovascular diseases (CVD) including systemic inflammation or mutual risk factors. In this context, we sought to examine the associations of CVD-related plasma proteins with lung function as measured by spirometry in a large community-based cohort of adults.MethodsThe study included 5777 Framingham Heart Study participants who had spirometry and measurement of 71 CVD-related plasma proteins. The association of plasma proteins with lung function was assessed cross-sectionally and longitudinally using models accounting for familial correlations. Linear mixed models were used for the following measurements: FEV1%predicted, FVC%predicted, and FEV1/FVC ratio with secondary analyses examining obstructive and restrictive physiology at baseline and their new onset during follow up.Measurements and main resultsAmong the 71 CVD-related plasma proteins, 13 proteins were associated in cross-sectional analyses with FEV1%predicted, 17 proteins were associated with FVC%predicted, and 1 protein was associated with FEV1/FVC. The proteins with the greatest inverse relations to FEV1%predicted and FVC%predicted included leptin, adrenomedullin, and plasminogen activator inhibitor-1; in contrast there were three proteins with positive relations to FEV1%predicted and FVC%predicted including insulin growth factor binding protein 2, tetranectin, and soluble receptor for advanced glycation end products. In longitudinal analyses, three proteins were associated with longitudinal change in FEV1 (ΔFEV1) and four with ΔFVC; no proteins were associated with ΔFEV1/FVC.ConclusionOur findings highlight CVD-related plasma proteins that are associated with lung function including markers of inflammation, adiposity, and fibrosis, representing proteins that may contribute both to respiratory and CVD risk.

This original research article provides a case study that describes how Métis indigenous knowledge was incorporated into the design of a community-based monitoring (CBM) program in the South Athabasca Oil Sands Area of Alberta, Canada. Athabasca Landing Métis Community (ALMC) members have traditional knowledge of local wildlife and climatic conditions in a region that has seen intense oil and gas-related industrial activity over the last 50 years. Informed by a multiple evidence-based approach to CBM, ALMC’s program design combined traditional hunting, fishing, trapping, and plant gathering activities with photomapping methods. By taking geo-referenced photos of their environmental observations, which they shared with other project participants during regular monitoring meetings, Métis knowledge holders connected changes in local conditions such as resource scarcity or species abundance to broader ecological processes including climate change. Further, the monitoring program had an innovative cultural camp component that brought elders, heads of family, and youth together to deliberately interact and pass on Indigenous and local knowledge. The information drawn from photomapping, cultural camps, and traditional knowledge shared during meetings was gathered into a database. The database serves as a repository of traditional knowledge and land use data that will support ALMC’s ongoing efforts to identify territory to promote self-governance and assert rights to lands and resources. We discuss how the ALMC’s adoption of a multiple evidence-based approach to monitoring asserts control over data collection methods, storage, and dissemination, supports local capacity for self-determination, and amplifies the voices of Métis harvesters in the resource management sector.

Abstract Background Characterization of allergic responses to cockroach (CR), a common aeroallergen associated with asthma, has focused mainly on IgE reactivity, but little is known about T cell responses, particularly in children. We conducted a functional evaluation of CR allergen‐specific T cell reactivity in a cohort of CR allergic children with asthma. Methods Peripheral blood mononuclear cells (PBMCs) were obtained from 71 children, with mild‐to‐moderate asthma who were enrolled in a CR immunotherapy (IT) clinical trial, prior to treatment initiation. PBMC were stimulated with peptide pools derived from 11 CR allergens, and CD4+ T cell responses assessed by intracellular cytokine staining. Results Highly heterogeneous responses in T cell reactivity were observed among participants, both in terms of the magnitude of cytokine response and allergen immunodominance. Reactivity against Bla g 9 and Bla g 5 was most frequent. The phenotype of the T cell response was dominated by IL‐4 production and a Th2 polarized profile in 54.9% of participants, but IFNγ production and Th1 polarization was observed in 25.3% of the participants. The numbers of regulatory CD4+ T cells were also highly variable and the magnitude of effector responses and Th2 polarization were positively correlated with serum IgE levels specific to a clinical CR extract. Conclusions Our results demonstrate that in children with mild‐to‐moderate asthma, CR‐specific T cell responses display a wide range of magnitude, allergen dominance, and polarization. These results will enable examination of whether any of the variables measured are affected by IT and/or are predictive of clinical outcomes.

Abstract Background Research indicates that low omega-3 polyunsaturated fatty acid (n-3 PUFA) may be associated with decreased cognitive function. This study examined the association between n-3 PUFA status and cognitive function in young Australian women. Methods This was a secondary outcome analysis of a cross-sectional study that recruited 300 healthy women (18–35 y) of normal weight (NW: BMI 18.5–24.9 kg/m2) or obese weight (OB: BMI ≥30.0 kg/m2). Participants completed a computer-based cognition testing battery (IntegNeuro™) evaluating the domains of impulsivity, attention, information processing, memory and executive function. The Omega-3 Index (O3I) was used to determine n-3 PUFA status (percentage of EPA (20:5n-3) plus DHA (22:6n3) in the red cell membrane) and the participants were divided into O3I tertile groups: T1 6.75%. Potential confounding factors of BMI, inflammatory status (C-reactive Protein), physical activity (total MET-min/wk), alpha1-acid glycoprotein, serum ferritin and hemoglobin, were assessed. Data reported as z-scores (mean ± SD), analyses via ANOVA and ANCOVA. Results Two hundred ninety-nine women (26.9 ± 5.4 y) completed the study (O3I data, n = 288). The ANOVA showed no overall group differences but a significant group × cognition domain interaction (p

Abstract Background Single birth cohort studies have been the basis for many discoveries about early life risk factors for childhood asthma but are limited in scope by sample size and characteristics of the local environment and population. The Children’s Respiratory and Environmental Workgroup (CREW) was established to integrate multiple established asthma birth cohorts and to investigate asthma phenotypes and associated causal pathways (endotypes), focusing on how they are influenced by interactions between genetics, lifestyle, and environmental exposures during the prenatal period and early childhood. Methods and results CREW is funded by the NIH Environmental influences on Child Health Outcomes (ECHO) program, and consists of 12 individual cohorts and three additional scientific centers. The CREW study population is diverse in terms of race, ethnicity, geographical distribution, and year of recruitment. We hypothesize that there are phenotypes in childhood asthma that differ based on clinical characteristics and underlying molecular mechanisms. Furthermore, we propose that asthma endotypes and their defining biomarkers can be identified based on personal and early life environmental risk factors. CREW has three phases: 1) to pool and harmonize existing data from each cohort, 2) to collect new data using standardized procedures, and 3) to enroll new families during the prenatal period to supplement and enrich extant data and enable unified systems approaches for identifying asthma phenotypes and endotypes. Conclusions The overall goal of CREW program is to develop a better understanding of how early life environmental exposures and host factors interact to promote the development of specific asthma endotypes.

Background Epigenetics may play an important role in the pathogenesis of lung diseases. However, little is known about the epigenetic factors that influence impaired gas exchange at the lung. Aim To identify the epigenetic signatures of the diffusing capacity of the lung measured by carbon monoxide uptake (the diffusing capacity of the lung for carbon monoxide (DLCO)). Methods An epigenome-wide association study (EWAS) was performed on diffusing capacity, measured by carbon monoxide uptake (DLCO) and per alveolar volume (VA) (as DLCO/VA), using the single-breath technique in 2674 individuals from two population-based cohort studies. These were the Rotterdam Study (RS, the “discovery panel”) and the Framingham Heart Study (FHS, the “replication panel”). We assessed the clinical relevance of our findings by investigating the identified sites in whole blood and by lung tissue specific gene expression. Results We identified and replicated two CpG sites (cg05575921 and cg05951221) that were significantly associated with DLCO/VA and one (cg05575921) suggestively associated with DLCO. Furthermore, we found a positive association between aryl hydrocarbon receptor repressor (AHRR) gene (cg05575921) hypomethylation and gene expression of exocyst complex component 3 (EXOC3) in whole blood. We confirmed that the expression of EXOC3 in lung tissue is positively associated with DLCO/VA and DLCO. Conclusions We report on epigenome-wide associations with diffusing capacity in the general population. Our results suggest EXOC3 to be an excellent candidate, through which smoking-induced hypomethylation of AHRR might affect pulmonary gas exchange.

Heart rate variability (HRV) describes the individual variation in cardiac cycle duration and is a measure of vagal control of heart rate. Here, the authors identify seventeen single-nucleotide polymorphisms associated with HRV, lending new insight into the vagal regulation of heart rhythm.

Abstract Background We conducted a genome-wide association study (GWAS) of subclinical interstitial lung disease (ILD), defined as high attenuation areas (HAA) on CT, in the population-based Multi-Ethnic Study of Atherosclerosis Study. Methods We measured the percentage of high attenuation areas (HAA) in the lung fields on cardiac CT scan defined as voxels with CT attenuation values between -600 and -250 HU. Genetic analyses were performed in MESA combined across race/ethnic groups: non-Hispanic White (n = 2,434), African American (n = 2,470), Hispanic (n = 2,065) and Chinese (n = 702), as well as stratified by race/ethnicity. Results Among 7,671 participants, regions at genome-wide significance were identified for basilar peel-core ratio of HAA in FLJ35282 downstream of ANRIL (rs7852363, P = 2.1x10−9) and within introns of SNAI3-AS1 (rs140142658, P = 9.6x10−9) and D21S2088E (rs3079677, P = 2.3x10−8). Within race/ethnic groups, 18 additional loci were identified at genome-wide significance, including genes related to development (FOXP4), cell adhesion (ALCAM) and glycosylation (GNPDA2, GYPC, GFPT1 and FUT10). Among these loci, SNP rs6844387 near GNPDA2 demonstrated nominal evidence of replication in analysis of n = 1,959 participants from the Framingham Heart Study (P = 0.029). FOXP4 region SNP rs2894439 demonstrated evidence of validation in analysis of n = 228 White ILD cases from the Columbia ILD Study compared to race/ethnicity-matched controls from MESA (one-sided P = 0.007). In lung tissue from 15 adults with idiopathic pulmonary fibrosis compared to 15 adults without lung disease. ANRIL (P = 0.001), ALCAM (P = 0.03) and FOXP4 (P = 0.046) were differentially expressed. Conclusions Our results suggest novel roles for protein glycosylation and cell cycle disinhibition by long non-coding RNA in the pathogenesis of ILD.

Summary: Large-scale collections of induced pluripotent stem cells (iPSCs) could serve as powerful model systems for examining how genetic variation affects biology and disease. Here we describe the iPSCORE resource: a collection of systematically derived and characterized iPSC lines from 222 ethnically diverse individuals that allows for both familial and association-based genetic studies. iPSCORE lines are pluripotent with high genomic integrity (no or low numbers of somatic copy-number variants) as determined using high-throughput RNA-sequencing and genotyping arrays, respectively. Using iPSCs from a family of individuals, we show that iPSC-derived cardiomyocytes demonstrate gene expression patterns that cluster by genetic background, and can be used to examine variants associated with physiological and disease phenotypes. The iPSCORE collection contains representative individuals for risk and non-risk alleles for 95% of SNPs associated with human phenotypes through genome-wide association studies. Our study demonstrates the utility of iPSCORE for examining how genetic variants influence molecular and physiological traits in iPSCs and derived cell lines. : Working as part of the NHLBI NextGen consortium, Panopoulos and colleagues report the derivation and characterization of 222 publicly available iPSCs from ethnically diverse individuals with corresponding genomic data including SNP arrays, RNA-seq, and whole-genome sequencing. This collection provides a powerful resource to investigate the function of genetic variants. Keywords: iPSCORE, iPSC, GWAS, molecular traits, physiological traits, cardiac disease, NHLBI Next Gen, LQT2, KCNH2, iPSC-derived cardiomyocytes

The Framingham Heart Study (FHS) is one of the largest and established longitudinal populational cohorts. CT cohorts of the FHS since 2002 provided a unique opportunity to assess non-cardiac thoracic imaging findings. This review deals with image-based phenotyping studies from recent major publications regarding interstitial lung abnormalities (ILAs), pulmonary cysts, emphysema, pulmonary nodules, pleural plaques, normal spectrum of the thymus, and anterior mediastinal masses, concluding with the discussion of future directions of FHS CT cohorts studies in the era of radiomics and artificial intelligence.

Repetitive hypoxia is a key feature of obstructive sleep apnoea (OSA), a condition characterized by intermittent airways obstruction. Patients with OSA present with persistent increases in sympathetic activity and commonly develop hypertension. The objectives of this study were to determine if the persistent increases in sympathetic nerve activity, known to be induced by acute intermittent hypoxia (AIH), are mediated through activation of the pituitary adenylate cyclase activating polypeptide (PACAP) signaling system. Here, we show that the excitatory neuropeptide PACAP, acting in the spinal cord, is important for generating the sympathetic response seen following AIH. Using PACAP receptor knockout mice, and pharmacological agents in Sprague Dawley rats, we measured blood pressure, heart rate, pH, PaCO2, and splanchnic sympathetic nerve activity, under anaesthesia, to demonstrate that the sympathetic response to AIH is mediated via the PAC1 receptor, in a cAMP-dependent manner. We also report that both intermittent microinjection of glutamate into the rostroventrolateral medulla (RVLM) and intermittent infusion of a sub-threshold dose of PACAP into the subarachnoid space can mimic the sympathetic response to AIH. All the sympathetic responses are independent of blood pressure, pH or PaCO2 changes. Our results show that in AIH, PACAP signaling in the spinal cord helps drive persistent increases in sympathetic nerve activity. This mechanism may be a precursor to the development of hypertension in conditions of chronic intermittent hypoxia, such as OSA.