The effect of smoking on exacerbation risk in eosinophilic patients with chronic obstructive pulmonary disease

Support statement: Funded by the Respiratory Effectiveness Group. Funding information for this article has been deposited with the Crossref Funder Registry.Peer reviewedPostprin

Persistence of eosinophilic asthma endotype and clinical outcomes : A real-world observational study

Acknowledgments Writing and editing support, including preparation of the draft manuscript under the direction and guidance of the authors, incorporating author feedback, and manuscript submission, was provided by Crystal Murcia, PhD (CiTRUS Healthcare Communications Group). This support was funded by AstraZeneca (Gaithersburg, Maryland). Funding This work was supported by AstraZeneca. A named author is an employee of AstraZeneca; therefore, AstraZeneca was involved in the study design; collection, analysis, and interpretation of data; and the development and review of the manuscript. The decision to submit the manuscript for publication was made by the authors.Peer reviewedPublisher PD

Healthcare resource use and costs of severe, uncontrolled eosinophilic asthma in the UK general population

Acknowledgments The authors thank Derek Skinner (Cambridge Research Support Ltd, Oakington, Cambridge, UK) for assistance with data extraction.Peer reviewedPublisher PD

Adverse outcomes from initiation of systemic corticosteroids for asthma : long-term observational study

This study was funded by AstraZeneca. We thank Aruni Seneviratna and Shreyasee Pradhan for their contributions to the project management for this study and Derek Skinner for his contributions to the data acquisition and handling. Writing and editorial support was provided by Elizabeth V. Hillyer, DVM, supported by the Observational and Pragmatic Research Institute Pte. Ltd (OPRI).Peer reviewedPublisher PD

BMI and Waist Circumference; Cross-Sectional and Prospective Associations with Blood Pressure and Cholesterol in 12-Year-Olds

Objective: Childhood and adolescent overweight, defined by body mass index (BMI) are associated with an increased risk of cardiovascular disease in later life. Abdominal adiposity may be more important in associations with cardiovascular diseases but waist circumference (WC) has been rarely studied in children. We studied associations between BMI and WC and blood pressure (BP) and cholesterol in 12-year-old children and prospectively changes in BMI or WC status between age 8 and 12 years and BP and cholesterol at age 12. Study Design: Weight, height, WC, BP and cholesterol concentrations were measured in 1432 children at age 12 years. Linear regression was used to study the associations between high BMI and large WC (>90th percentile) and BP and cholesterol. Results: Systolic BP was 4.9 mmHg higher (95% (CI 2.5, 7.2) in girls and 4.2 mmHg (95%CI 1.9, 6.5) in boys with a high BMI. Large WC was also associated with higher systolic BP in girls (3.7 mmHg (95%CI 1.3, 6.1)) and boys (3.5 mmHg (95%CI 1.2, 5.8)). Diastolic BP and cholesterol concentrations were significantly positively (HDL cholesterol negatively) associated with high BMI and large WC, too. Normal weight children with a history of overweight did not have higher blood pressure levels or adverse cholesterol concentrations than children that were normal weight at both ages. Conclusion: A high BMI and large WC were associated with higher BP levels and adverse cholesterol concentrations. WC should be taken into account when examining cardiovascular risk factors in children

Healthcare resource utilization and costs associated with incremental systemic corticosteroid exposure in asthma

Editorial support was provided by Mike Jaqua, PhD, and AlanSaltzman, PhD, of JK Associates, Inc., and Michael A. Nissen, ELS, ofAstraZeneca. This support was funded by AstraZeneca.Peer reviewedPublisher PD

Association of Interacting Genes in the Toll-Like Receptor Signaling Pathway and the Antibody Response to Pertussis Vaccination

BACKGROUND: Activation of the Toll-like receptor (TLR) signaling pathway through TLR4 may be important in the induction of protective immunity against Bordetella pertussis with TLR4-mediated activation of dendritic and B cells, induction of cytokine expression, and reversal of tolerance as crucial steps. We examined whether single nucleotide polymorphisms (SNPs) in genes of the TLR4 pathway and their interaction are associated with the response to whole-cell vaccine (WCV) pertussis vaccination in 490 one-year-old children. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed associations of 75 haplotype-tagging SNPs in genes in the TLR4 signaling pathway with pertussis toxin (PT)-IgG titers. We found significant associations between the PT-IgG titer and SNPs in CD14, TLR4, TOLLIP, TIRAP, IRAK3, IRAK4, TICAM1, and TNFRSF4 in one or more of the analyses. The strongest evidence for association was found for two SNPs (rs5744034 and rs5743894) in TOLLIP that were almost completely in linkage disequilibrium, provided statistically significant associations in all tests with the lowest p-values, and displayed a dominant mode of inheritance. However, none of these single gene associations would withstand correction for multiple testing. In addition, Multifactor Dimensionality Reduction Analysis, an approach that does not need correction for multiple testing, showed significant and strong two and three locus interactions between SNPs in TOLLIP (rs4963060), TLR4 (rs6478317) and IRAK1 (rs1059703). CONCLUSIONS/SIGNIFICANCE: We have identified significant interactions between genes in the TLR pathway in the induction of vaccine-induced immunity. These interactions underline that these genes are functionally related and together form a true biological relationship in a protein-protein interaction network. Practically all our findings may be explained by genetic variation in directly or indirectly interacting proteins at the extra- and intracytoplasmic sites of the cell membrane of antigen-presenting cells, B cells, or both. Fine tuning of interacting proteins in the TLR pathway appears important for the induction of an optimal vaccine response