Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD

Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p 10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10−392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms. Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group

Development of the Functional Flow Block Diagram for the J-2X Rocket Engine System

The J-2X program calls for the upgrade of the Apollo-era Rocketdyne J-2 engine to higher power levels, using new materials and manufacturing techniques, and with more restrictive safety and reliability requirements than prior human-rated engines in NASA history. Such requirements demand a comprehensive systems engineering effort to ensure success. Pratt & Whitney Rocketdyne system engineers performed a functional analysis of the engine to establish the functional architecture. J-2X functions were captured in six major operational blocks. Each block was divided into sub-blocks or states. In each sub-block, functions necessary to perform each state were determined. A functional engine schematic consistent with the fidelity of the system model was defined for this analysis. The blocks, sub-blocks, and functions were sequentially numbered to differentiate the states in which the function were performed and to indicate the sequence of events. The Engine System was functionally partitioned, to provide separate and unique functional operators. Establishing unique functional operators as work output of the System Architecture process is novel in Liquid Propulsion Engine design. Each functional operator was described such that its unique functionality was identified. The decomposed functions were then allocated to the functional operators both of which were the inputs to the subsystem or component performance specifications. PWR also used a novel approach to identify and map the engine functional requirements to customer-specified functions. The final result was a comprehensive Functional Flow Block Diagram (FFBD) for the J-2X Engine System, decomposed to the component level and mapped to all functional requirements. This FFBD greatly facilitates component specification development, providing a well-defined trade space for functional trades at the subsystem and component level. It also provides a framework for function-based failure modes and effects analysis (FMEA), and a rigorous baseline for the functional architecture

Évaluation de l’efficacité du programme d’intervention Check and Connect à l’école primaire

La présente étude a pour but d’évaluer l’efficacité de l’adaptation québécoise du programme d’intervention Check and Connect tel qu’implanté sur une période de deux ans dans des conditions réelles auprès d’élèves ciblés du primaire (n = 216). À partir d’un devis expérimental randomisé, les élèves ciblés par le programme (n = 107) ont été comparés avant et après l’intervention aux élèves d’un groupe de contrôle (n = 109). Cet examen a permis d’évaluer les effets du programme chez les élèves y participant, sous l’angle 1) de leur adaptation scolaire, 2) des relations qu’ils entretiennent avec leurs parents et leurs enseignants, 3) de leur inadaptation psychosociale et 4) de leur assiduité et de leur réussite scolaire. Nos résultats indiquent que le programme Check and Connect a certains effets positifs sur l’adaptation scolaire et psychosociale des élèves à risque du primaire ainsi que sur le soutien et les relations que les élèves entretiennent avec leurs parents et leurs enseignants. Par contre, les effets du programme sont plus mitigés quant au retard en classe et au rendement dans les matières de base. Ces derniers résultats méritent cependant d’être mieux compris à la lumière des données d’implantation.The present study aimed to evaluate the effectiveness of the Check and Connect program adapted in Quebec (Canada) schools. The program was implemented over a two-year period among a sample of elementary school students (n = 216). Students who participated in the intervention (n = 107) were selected using a randomized experimental design and compared pre- and post-intervention to a control group (n = 109). Different aspects of students’ academic and psychosocial experiences were assessed: 1) school adjustment, 2) relationships with parents and teachers, 3) psychosocial adjustment, and 4) school attendance and achievement. Results indicate that participation to the Check and Connect program is associated with positive school and psychosocial adjustment and better relationships with parents and teachers. However, the program effects were more mitigated in terms of classroom attendance and academic achievement. These last results deserve to be better understood in light of our implementation data