170 research outputs found
Reliability and validity of a life course passive smoke exposure questionnaire in an australian cohort from childhood to adulthood
Objectives:Life course exposure to passive smoke may predict health, but there are few validated measures. We tested the reliability and validity of a retrospective life course passive smoking questionnaire. Methods:Participants from the third follow-up of the Childhood Determinants of Adult Health study (2014-2019, ages 36-49 years) retrospectively reported mother/father/other household member smoking when living at home during childhood, including duration (years) and smoking location (never/sometimes/always inside house). The severity of exposure index (SEI; sum of mother/father/other years smoked multiplied by smoking location), cumulative years of exposure (CYE; sum of mother/father/other years), and total household smokers (THS) were derived. The reliability of retrospective passive smoking reports was examined with intraclass correlation coefficients (ICCs) using household smoking reported 34 years earlier in 1985 by participants when aged 7-15 years. Construct validity was examined by correlating retrospective passive smoking with participants’ smoking in adulthood and lung function in childhood and adulthood. Results:Among 2082 participants (mean±standard deviation [SD], 45.0±2.5 years; 55.2% females), THS ranged from 0 to 5 (mean± SD, 0.9±1.0), CYE ranged from 0 to 106 (mean±SD, 10.5±13.9), and SEI ranged from 0 to 318 (mean±SD, 24.4±36.0). Retrospective measures showed moderate agreement with total household smokers reported in childhood (ICC, 0.58 to 0.62). The retrospective measures were weakly but significantly (pConclusions:The retrospective passive smoking questionnaire showed reasonable reliability and validity. This measure may be useful for epidemiological studies.</p
Using digital tools in the recruitment and retention in randomised controlled trials:Survey of UK Clinical Trial Units and a qualitative study
The influence of anti-TNF therapy upon incidence of keratinocyte skin cancer in patients with rheumatoid arthritis: longitudinal results from the British Society for Rheumatology Biologics Register
Determining the contribution of IL33 and IL1RL1 polymorphisms to clinical and immunological features of asthma
Rationale: IL33 (9p24.1) and the IL33 receptor (IL1RL, 2q12) have been reproducibly identified as asthma susceptibility genes. However, the variants driving genetic associations are not yet fully defined. Using a population based birth cohort of 1059 children (Manchester Asthma and Allergy Study-(MAAS)) and 2536 adults with asthma (Genetics of Asthma Severity and Phenotypes- (GASP)) cohort we aimed to define genetic variants associated with clinical and immunological features of asthma.
Methods: MAAS samples were genotyped using the Illumina 610 Quad array and imputed using 1000G reference panel. GASP samples were genotyped using two custom designed Affymetrix arrays (UK BiLEVE/UK Biobank array). Datasets were quality controlled for gender mismatches, outliers and relatedness. Data was generated for the IL33/IL1RL1 regions consisting of the genes and surrounding regions (chr9:5715785−6757983 & chr2:102427961−103468497) on the following traits: asthma diagnosis (MAAS), atopy, FEV1 (GASP) and FEV1/FVC (MAAS and GASP) as well as total blood eosinophil counts and serum total IgE levels (GASP). Variables for blood eosinophils and total IgE were log10 transformed. Analysis was carried out in PLINK using linear or logistic regression modelling including appropriate covariates for each trait.
Results: In the MAAS cohort, we replicated the association of the IL33 locus with asthma diagnosis, identifying potentially two independent novel signals in that locus (rs10975398; P=1.70E-05; B= -1.519; MAF=0.32 and rs2890697; P=1.10E-04; B= -1.573; MAF=0.43). This association survived a Bonferroni correction for multiple testing. Although not surviving correction, an association was also identified for atopy in the IL1RL1 locus for MAAS (P=1.08E-04; MAF=0.48). In GASP we identified modest associations not in known LD with published loci (P-value range: 5.00E-02 – 7.60E-04) for FEV1, FEV1/FVC, atopy, blood eosinophils and total IgE in both the IL33 and IL1RL1 loci. Multiple SNPs presented nominal association (P<0.01) with more than one trait such as atopy & total IgE, providing supporting evidence for association.
Conclusion: We replicated the association of IL33 region SNPs with asthma diagnosis in MAAS, highlighting the role of this locus in childhood asthma. Although trait association signals did not survive correction for multiple testing, nominal association across multiple phenotypes in GASP provides suggestive evidence of the role of the IL33/IL1RL1 genetic polymorphisms in determining clinical and immunological features of asthma
Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial
Background
Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy
A genome wide association study of moderate-severe asthma in subjects from the United Kingdom
Rationale: Genome wide association studies (GWAS) in asthma have been successful in identifying disease susceptibility genes, however to date these have focused on mild disease. The genetic risk factors for moderate-severe asthma remain unclear.
Aim: To identify common genetic variants affecting susceptibility to develop moderate-severe asthma.
Methods: We identified asthma cases and controls from UK Biobank and additional cases from the Genetics of Asthma Severity & Phenotypes (GASP) cohort. A genome-wide association study was undertaken in 5,135 European ancestry individuals with moderate-severe asthma based on British Thoracic Society criteria 3 or above and 25,675 controls free from lung disease, allergic rhinitis and atopic dermatitis. After imputation (UK10K + 1000 genomes Phase 3) and standard quality control measures, the association of 33,771,858 single nucleotide polymorphisms (SNPs) were tested. A logistic model of association of asthma status with imputed genotype dose was fitted using SNPTEST adjusted for ancestry principal components.
Results: We identified 22 loci showing association (P < 5 × 10(-8)) including novel signals in or near D2HGDH, STAT6, HLA-B, CD247, GATA3, PDCD1LG2, ZNF652, RPAP3, MUC5AC and BACH2. Previously described asthma loci where replicated including signals in or near HLA-DQB1, TSLP, IL1RL1/IL18R1, CLEC16A, GATA3, IL33, SMAD3, SLC22A5/IL13, C11orf30, ZBTB10, IKZF3-ORMDL3 and IKZF4.
Conclusion: The largest genome-wide association study of moderate-severe asthma to date was carried out and multiple novel loci where identified. These findings may provide new insight into the molecular mechanisms underlying this difficult to treat population
De novo mutations in GRIN1 cause extensive bilateral polymicrogyria
Polymicrogyria is a malformation of cortical development. The aetiology of polymicrogyria remains poorly understood. Using whole-exome sequencing we found de novo heterozygous missense GRIN1 mutations in 2 of 57 parent-offspring trios with polymicrogyria. We found nine further de novo missense GRIN1 mutations in additional cortical malformation patients. Shared features in the patients were extensive bilateral polymicrogyria associated with severe developmental delay, postnatal microcephaly, cortical visual impairment and intractable epilepsy. GRIN1 encodes GluN1, the essential subunit of the N-methyl-d-aspartate receptor. The polymicrogyria-associated GRIN1 mutations tended to cluster in the S2 region (part of the ligand-binding domain of GluN1) or the adjacent M3 helix. These regions are rarely mutated in the normal population or in GRIN1 patients without polymicrogyria. Using two-electrode and whole-cell voltage-clamp analysis, we showed that the polymicrogyria-associated GRIN1 mutations significantly alter the in vitro activity of the receptor. Three of the mutations increased agonist potency while one reduced proton inhibition of the receptor. These results are striking because previous GRIN1 mutations have generally caused loss of function, and because N-methyl-d-aspartate receptor agonists have been used for many years to generate animal models of polymicrogyria. Overall, our results expand the phenotypic spectrum associated with GRIN1 mutations and highlight the important role of N-methyl-d-aspartate receptor signalling in the pathogenesis of polymicrogyria
Training future generations to deliver evidence-based conservation and ecosystem management
1. To be effective, the next generation of conservation practitioners and managers need to be critical thinkers with a deep understanding of how to make evidence-based decisions and of the value of evidence synthesis. 2. If, as educators, we do not make these priorities a core part of what we teach, we are failing to prepare our students to make an effective contribution to conservation practice. 3. To help overcome this problem we have created open access online teaching materials in multiple languages that are stored in Applied Ecology Resources. So far, 117 educators from 23 countries have acknowledged the importance of this and are already teaching or about to teach skills in appraising or using evidence in conservation decision-making. This includes 145 undergraduate, postgraduate or professional development courses. 4. We call for wider teaching of the tools and skills that facilitate evidence-based conservation and also suggest that providing online teaching materials in multiple languages could be beneficial for improving global understanding of other subject areas.Peer reviewe
New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism.
Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism
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