Pattee, Jack

IMPORTANCE: Accurate and reliable sedation assessment is crucial to improving patient outcomes in the ICU. OBJECTIVE: To evaluate the inter-rater agreement and reliability of Richmond Agitation Sedation Scale (RASS) assessments between bedside nurses and trained investigators in patients receiving mechanical ventilation in the ICU. DESIGN, SETTING, AND PARTICIPANTS: An assessor triad, comprising an ICU nurse providing direct patient care and two trained investigators, simultaneously performed RASS assessments during 79 encounters with 62 unique patients receiving mechanical ventilation at two ICUs at a tertiary care academic hospital in Colorado. A total of 58 nurses participated in the study. MAIN OUTCOMES AND MEASURES: The inter-rater reliability of RASS assessments was evaluated with the intraclass correlation coefficient (ICC) and weighted kappa (κ), and inter-rater agreement was evaluated with percentage agreement and Bland-Altman analysis. RESULTS: Acute respiratory failure (55%) and altered mental status (21%) were the most common reasons for mechanical ventilation. Most patients were receiving one (interquartile range, 0.5–2) continuous sedative during the assessment. The inter-rater reliability of RASS assessments between the nurses and investigators (ICC, 0.728–0.779; weighted κ, 0.62–0.63) was lower than between the two investigators (ICC, 0.891; weighted κ, 0.80). The assessor triad agreed on the same RASS values in only 35% of observations. The average differences in RASS were greater between the investigators and nurses, ranging from –0.658 to –0.544, compared with 0.114 between the two investigators. Compared with the mean of the two investigators, RASS values recorded by nurses were more likely to be higher (52% of observations), indicating a lighter sedation level. In 16% of observations, at least one assessor commented on uncertainty or ambiguity with the RASS. CONCLUSIONS AND RELEVANCE: The inter-rater reliability of RASS assessments was high. However, we observed variations in the degree of agreement by assessor category. Further studies are necessary to explore how factors such as assessor characteristics, ICU environment, and patient conditions influence the inter-rater agreement of the RASS in contemporary ICU practices.

Background: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources. Methods: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations. Results: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis. Conclusions: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.

Background We examined feasibility of a unique approach towards gaining insight into heritable risk for early atherosclerosis: surveying gene expression by endothelial cells from living subjects. Methods and Results Subjects aged <50 years (mean age, 37; range, 22–49) without obstructive coronary artery disease underwent coronary reactivity testing that identified them as having normal or abnormal coronary endothelial function. Cultures of Blood Outgrowth Endothelial Cells (BOEC) from 6 normal and 13 abnormal subjects passed rigorous quality control and were used for microarray assessment of gene expression. Of 9 genes differentially expressed at false discovery rate <0.1%, we here focus upon abnormal subjects having elevated expression of HMGB1 (high mobility group box 1) which we unexpectedly found to be linked to low LAMC1 (laminin gamma 1) expression. This linkage was corroborated by 3 of our past studies and confirmed bio‐functionally. Compared with normal BOEC, abnormal BOEC released 13±3‐fold more HMGB1 in response to lipopolysaccharide; and they deposited one tenth as much LAMC1 into collagen subendothelial matrix during culture. Clinical follow‐up data are provided for 4 normal subjects (followed 13.4±0.1 year) and for 12 abnormal subjects (followed 9.1±4.5 years). Conclusions The known pathogenic effects of high‐ HMGB1 and low‐ LAMC1 predict that the combination would biologically converge upon the focal adhesion complex, to the detriment of endothelial shear responsiveness. This gene expression pattern may comprise a heritable risk state that promotes early coronary atherosclerosis. If so, the testing could be applied even in childhood, enabling early intervention. This approach offers a way to bridge the information gap between genetics and clinical phenotype.

In this work related to familial aggregation of familial venous thromboembolism, the investigators report genomic and transcriptomic association of 16 novel susceptibility loci for venous thromboembolism.