Background: The association of haplotype combinations of polymorphisms at positions 16 and 27 of the β2-adrenergic receptor (ADRB2) gene and the risk of asthma exacerbations among users of long-acting β2-agonists (LABA) is still unclear. Aim: We investigated the association between these haplotypes of the ADRB2 gene and asthma exacerbations in asthmatic patients using LABA and inhaled corticosteroids (ICS) from the multi-ethnic Pharmacogenomics in Childhood Asthma (PiCA) consortium. Methods: We conducted a meta-analysis of 880 children and young adults aged (4-21) with asthma treated with LABA and ICS. We extracted two polymorphisms; rs1042713 (16Arg>Gly) and rs1042714 (27Gln>Glu) in the ADRB2 gene. Asthma exacerbations were defined as prescribed courses of oral corticosteroids and/or asthma-related hospitalizations/emergency room visits in the past 6 or 12 months prior to the study visit. The association between the haplotypes and asthma exacerbations was performed by using the Haplo-Stats package adjusted for age and sex. A meta-analysis was performed using an inverse variance–weighted method assuming a random-effect. Results: Three haplotypes were determined; Gly16Glu27, Arg16Gln27 and Gly16Gln27. Compared to the Gly16Glu27 haplotype, the Arg16Gln27 haplotype was significantly associated with an increased risk of asthma exacerbations (OR:1.37, 95%CI;1.03-1.81, P=0.028, I2=0.0%). Conclusion: We found that the Arg haplotype (Arg16Gln27) in the ADRB2 gene increased the risk of exacerbations among users of LABA and ICS. Whether or not this argues against use of LABA in patients with this haplotype needs further research.
Summary Background The clinical response to inhaled corticosteroids ( ICS ) is associated with single nucleotide polymorphisms ( SNP s) in various genes. This study aimed to relate variations in genes in the steroid pathway and asthma susceptibility genes to exacerbations in children and young adults treated with ICS . Methods We performed a meta‐analysis of three cohort studies: Pharmacogenetics of Asthma Medication in Children: Medication with Anti‐Inflammatory effects ( n = 357, age: 4–12 years, the Netherlands), BREATHE ( n = 820, age: 3–22 years, UK ) and Paediatric Asthma Gene Environment Study ( n = 391, age: 2–16 years, UK ). Seventeen genes were selected based on a role in the glucocorticoid signalling pathway or a reported association with asthma. Two outcome parameters were used to reflect exacerbations: hospital visits and oral corticosteroid ( OCS ) use in the previous year. The most significant associations were tested in three independent validation cohorts; the Childhood Asthma Management Programme (clinical trial, n = 172, age: 5–12 years, USA ), the Genes‐ environment and Mixture in Latino Americans II‐ study ( n = 745, age: 8–21, USA ) and the Pharmacogenetics of adrenal suppression cohort ( n = 391, age: 5–18, UK ) to test the robustness of the findings. Finally, all results were meta‐analysed. Results Two SNP s in ST 13 (rs138335 and rs138337), but not in the other genes, were associated at a nominal level with an increased risk of exacerbations in asthmatics using ICS in the three cohorts studied. In a meta‐analysis of all six studies, ST 13 rs138335 remained associated with an increased risk of asthma‐related hospital visits and OCS use in the previous year; OR = 1.22 ( P = 0.013) and OR = 1.22 ( P = 0.0017), respectively. Conclusion and clinical relevance A novel susceptibility gene, ST 13 , coding for a cochaperone of the glucocorticoid receptor, is associated with exacerbations in asthmatic children and young adults despite their ICS use. Genetic variation in the glucocorticoid signalling pathway may contribute to the interindividual variability in clinical response to ICS treatment in children and young adults.
Current tests for diagnosing liver disease in dogs are sub-optimal. MicroRNA-122 (miR-122) is a sensitive and specific biomarker of liver injury in humans and rodents. Circulating miR-122 could have utility in identifying dogs with liver disease.Establish the reference interval for miR-122 in healthy dogs and determine performance in a range of dog breeds with liver disease and control animals with non-liver disease.Stored serum from 120 healthy dogs, 100 dogs with non-liver diseases, and 30 dogs with histologically confirmed liver disease was analyzed.Retrospective study. Medical records of dogs with liver disease, non-liver disease and healthy dogs were reviewed. Serum miR-122 concentrations were measured by PCR and compared with the characteristics of the dogs and their conventional clinical measurements.In healthy dogs the 2.5th, 50th, and 97.5th quartiles of miR-122 were 110 (90% CI 80-114), 594 (505-682), and 3312 (2925-5144) copies/μL, respectively. There was no difference between healthy dogs and dogs with non-liver disease (median ± IQR: healthy dogs 609 [327-1014] copies/μL; non-liver disease 607 [300-1351] copies/μL). miR-122 was higher in dogs with liver disease (11 332 [4418-20 520] copies/μL, P < .001 compared to healthy dogs). miR-122 identified dogs with liver disease with high accuracy (receiver operating characteristic area under curve for comparison with healthy dogs: 0.93 [95% CI 0.86-0.99]). The upper limit of normal for healthy dogs (3312 copies/μL) had a sensitivity of 77% and specificity of 97% for identifying liver disease.Liver disease can be sensitively and specifically diagnosed in dogs by measurement of miR-122.
Niobium-zirconium (Nb-Zr) alloy is an old superconductor that is a promising new candidate for superconducting radio-frequency (SRF) cavity applications. Using density-functional and Eliashberg theories, we show that addition of Zr to a Nb surface in small concentrations increases the critical temperature $T_c$ and improves other superconducting properties. Furthermore, we calculate $T_c$ for Nb-Zr alloys across a broad range of Zr concentrations, showing good agreement with the literature for disordered alloys as well as the potential for significantly higher $T_c$ in ordered alloys near 75%Nb/25%Zr composition. We provide experimental verification on Nb-Zr alloy samples and SRF sample test cavities prepared with either physical vapor or our novel electrochemical deposition recipes. These samples have the highest measured $T_c$ of any Nb-Zr superconductor to date and indicate a reduction in BCS resistance compared to the conventional Nb reference sample; they represent the first steps along a new pathway to greatly enhanced SRF performance. Finally, we use Ginzburg-Landau theory to show that the addition of Zr to a Nb surface increases the superheating field $B_{sh}$, a key figure of merit for SRF which determines the maximum accelerating gradient at which cavities can operate.
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