A genome-wide association study of bronchodilator response in participants of European and African ancestry from six independent cohorts

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<5×10−8). Performing fine mapping and using a threshold of p<5×10−6 to identify suggestive variants of interest, we identified three SNPs with possible biological relevance: rs35870000 (within FREM1), which may be involved in IgE- and IL5-induced changes in airway smooth muscle cell responsiveness; rs10426116 (within ZNF284), a zinc finger protein, which has been implicated in asthma and BDR previously; and rs4782614 (near ATP2C2), involved in calcium transmembrane transport. Validation in paediatric cohorts yielded no significant SNPs, possibly due to age–genotype interaction effects. Conclusion Ancestry-stratified and ancestry-combined GWAS meta-analyses of over 14 000 participants did not identify genetic variants associated with BDR at the genome-wide significance threshold, although a less stringent threshold identified three variants showing suggestive evidence of association. A common definition and protocol for measuring BDR in research may improve future efforts to identify variants associated with BDR.publishedVersio

Efeito inibitório em metaloproteinase de matriz

Dissertação para obtenção do grau de Mestre no Instituto Superior de Ciências da Saúde Egas MonizAs metaloproteinases de matriz (MMPs) são um grupo de endopeptidases que contêm um ião de Zinco (Zn2+) no seu centro activo. Estas enzimas estão envolvidas em vários processos biológicos do organismo humano como por exemplo na embriogénese, na remodelação dos tecidos, na cicatrização e na angiogénese. A sua principal função é a degradação de proteínas da matriz extracelular controlando desta forma a extensão da remodelação da mesma. A actividade das MMPs é controlada por inibidores endógenos como a α2-macroglobulina e os inibidores tecidulares das metaloproteinases de matriz (TIMPs). Em condições normais existe um equilíbrio entre a actividade das MMPs e a actividade dos seus inibidores endógenos, no entanto, quando existe um desequilíbrio, o organismo deixa de ter a capacidade regular as MMPs e estas expressam em excesso a sua actividade o que pode provocar alguns processos patológicos, sendo os mais graves o cancro, a artrite e as doenças vasculares. O envolvimento destas enzimas nas referidas doenças serviu de impulsionador para despertar o interesse da comunidade científica, que nas últimas décadas tem tentado incessantemente desenvolver inibidores para poder controlar a actividade das MMPs e assim encontrar uma terapêutica para estas patologias. Apesar de terem sido desenvolvidos inibidores que comprovaram a efectividade da sua acção, estes acarretavam uma grande toxicidade que se traduzia numa serie de reacções adversas derivadas da sua instabilidade e falta de selectividade. Devido a tudo isto, nos últimos anos, aprofundou-se o estudo da estrutura química das MMPs e surgiu uma revolução no design de novos inibidores das metaloproteinases de matriz (MMPi) com o objectivo de sintetizar compostos que apresentem uma inibição mais potente aliada a especificidade necessária para que estes possam ser utilizados como terapêutica para algumas das mais graves doenças dos dias de hoje

Distribution of Hyperpolarized Xenon in the Brain Following Sensory Stimulation: Preliminary MRI Findings

In hyperpolarized xenon magnetic resonance imaging (HP 129Xe MRI), the inhaled spin-1/2 isotope of xenon gas is used to generate the MR signal. Because hyperpolarized xenon is an MR signal source with properties very different from those generated from water-protons, HP 129Xe MRI may yield structural and functional information not detectable by conventional proton-based MRI methods. Here we demonstrate the differential distribution of HP 129Xe in the cerebral cortex of the rat following a pain stimulus evoked in the animal's forepaw. Areas of higher HP 129Xe signal corresponded to those areas previously demonstrated by conventional functional MRI (fMRI) methods as being activated by a forepaw pain stimulus. The percent increase in HP 129Xe signal over baseline was 13–28%, and was detectable with a single set of pre and post stimulus images. Recent innovations in the production of highly polarized 129Xe should make feasible the emergence of HP 129Xe MRI as a viable adjunct method to conventional MRI for the study of brain function and disease

African-specific alleles modify risk for asthma at the 17q12-q21 locus in African Americans

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

Pediatric Residents\u27 Knowledge and Comfort With Oral Health Bright Futures Concepts: A CORNET Study

OBJECTIVE: Training residents in oral health helps eliminate disparities and improves access. The American Academy of Pediatrics Bright Futures Guidelines curriculum is used as a training guide. We assessed knowledge, confidence, and perceived barriers to incorporating Bright Futures oral health concepts into well-child care for children below 3 years in a national sample of pediatric residents. METHODS: A sample of postgraduate year 1 and 2 residents from CORNET sites completed demographic, Bright Futures oral health concepts confidence and knowledge cross-sectional surveys before any intervention. Measures were tested for reliability using Cronbach\u27s alpha coefficient. RESULTS: One hundred sixty-three residents from 28 CORNET sites completed the surveys. One third reported no prior training in oral health. Time (42%) and knowledge (33%) led the perceived barriers to addressing these concepts in well visits. Although 63% rated their confidence as excellent in identifying tooth decay risk factors, a significant percentage rated their oral health risk assessment skills as poor or neutral (64%) and identifying caries at examination (53%). Only 49% conveyed oral health messages during encounters and 80% correctly scored 75% or higher on knowledge questions. CONCLUSIONS: This cross-sectional study shows that residents from a wide geographic range have high self-reported oral health knowledge but low perceived skills and competency in clinical implementation. Lack of time and knowledge in identifying caries led the perceived barriers. Barriers are addressed by implementing oral health curricula that promote competence and skill-development. This study helps programs effectively implement Bright Futures concepts to train graduates to incorporate oral health in well visits

A systematic review of the primary squamous cell carcinoma of the external auditory canal: survival outcome based on T-staging and proposal of a new classification.

This study aimed to provide a systematic review on survival outcome based on Pittsburgh T-staging for patients with primary external auditory canal squamous cell carcinoma. This study was a systematic review in compliance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines performed until January 2018; pertinent studies were screened. Quality of evidence was assessed using the grading of recommendation, assessment, development and evaluation working group system. Eight articles were chosen that reported on 437 patients with external auditory carcinoma. The 5-year overall survival rate was 53.0 per cent. The pooled proportion of survivors at 5 years for T1 tumours was 88.4 per cent and for T2 tumours was 88.6 per cent. For the combined population of T1 and T2 cancer patients, it was 84.5 per cent. For T3 and T4 tumours, it was 53.3 per cent and 26.8 per cent, respectively, whereas for T3 and T4 tumours combined, it was 40.4 per cent. Individual analysis of 61 patients with presence of cervical nodes showed a poor survival rate. From this review, there was not any significant difference found in the survival outcome between T1 and T2 tumours. A practical classification incorporating nodal status that accurately stratifies patients was proposed

Retarding Ion Migration for Stable Blade-Coated Inverted Perovskite Solar Cells

\ua9 2023 Wiley-VCH GmbH.The fabrication of perovskite solar cells (PSCs) through blade coating is seen as one of the most viable paths toward commercialization. However, relative to the less scalable spin coating method, the blade coating process often results in more defective perovskite films with lower grain uniformity. Ion migration, facilitated by those elevated defect levels, is one of the main triggers of phase segregation and device instability. Here, a bifunctional molecule, p-aminobenzoic acid (PABA), which enhances the barrier to ion migration, induces grain growth along the (100) facet, and promotes the formation of homogeneous perovskite films with fewer defects, is reported. As a result, PSCs with PABA achieved impressive power conversion efficiencies (PCEs) of 23.32% and 22.23% for devices with active areas of 0.1 cm2 and 1 cm2, respectively. Furthermore, these devices maintain 93.8% of their initial efficiencies after 1 000 h under 1-sun illumination, 75 \ub0C, and 10% relative humidity conditions