Clinical Features of Genetic Resilience in Chronic Obstructive Pulmonary Disease.

Introduction: In the personalized risk quantification of chronic obstructive pulmonary disease (COPD), genome-wide association studies and polygenic risk scores (PRS) complement traditional risk factors, such as age and cigarette smoking. However, despite being at considerable levels of risk, some individuals do not develop COPD. Research on COPD resilience remains largely unexplored. Methods: We applied the previously published COPD PRS to whole genome sequencing data from non-Hispanic white and African American individuals in the COPDGene study. We defined genetic resilience as individuals unaffected by COPD with a polygenic risk score above the 90 th percentile. We defined risk-matched case individuals as those with COPD (i.e., FEV 1 /FVC < 0.70) and a PRS above the 90 th percentile. We defined low risk individuals without COPD (i.e., FEV 1 /FVC > 0.70) as a polygenic risk score below the 10 th percentile. We compared genetically resilient individuals to risk-matched individuals with COPD and low risk individuals by demographics, lung function, respiratory symptoms, co-morbidities, and chest CT scan measurements. We also performed survival analyses, differential expression analysis, and matching for sensitivity analyses. Results: We identified 211 resilient individuals without COPD, 605 genetic risk-matched individuals with COPD, and 527 low-risk individuals without COPD. Resilient individuals had higher FEV 1 % predicted and lower percent emphysema. In contrast, resilient individuals had higher airway wall thickness compared to low-risk unaffected individuals. While there was no difference in survival between low-risk and resilient individuals, resilient individuals had higher survival compared to risk matched cases. We also identified two genes that were differentially expressed between low-risk unaffected individuals and resilient individuals. Conclusion: Genetically resilient individuals had a reduced burden of COPD disease-related measures compared to risk-matched cases but had subtly increased measures compared to low-risk unaffected individuals. Further genetic studies will be needed to illuminate the underlying pathobiology of our observations.

Impact of Deliberate Practice on Point-of-Care Ultrasound Interpretation of Right Ventricle Pathology.

Background: Point-of-care (POC) ultrasound (POCUS) has become an essential tool in caring for critically ill patients in several specialties. Mastery in POCUS requires competency in image acquisition, image interpretation, and integration into clinical care. Deliberate practice is an effective method for performance improvement in many areas of medical education; however, it is not well described in the literature for POCUS training. Objective: To analyze differences in the effect of deliberate practice in POCUS image interpretation on performance improvement in groups with varying skill levels. Methods: We recruited attending physicians and trainees with varying degrees of expertise in POCUS to complete a 50-item educational instrument on the interpretation of right ventricle size and function. The instrument incorporated deliberate practice for the task of correctly identifying right ventricle size and function as either normal or abnormal. Pulmonary critical care trainees obtained and interpreted POCUS images of patients with diagnosed acute pulmonary embolism, which were compared with gold-standard, two-dimensional echocardiographic scans obtained by an expert technician and interpreted by a cardiologist board-certified in echocardiography. We mapped learners' cumulative accuracy on a learning curve to assess their performance. In addition, we compared groups on the basis of prior experience with using POC echocardiography. Results: Seventy-nine of 81 participants completed the survey and examination and were included in the analysis. Of the participants, 69 (87.3%) were trainees. The overall cumulative accuracy for the group was 72.9%. All groups demonstrated improvement in accuracy with repetitive practice. Conclusion: Deliberate practice in POC echocardiograph interpretation is effective for improving performance in a wide range of learners. Further study is needed to define accuracy cutoffs for competency to help guide learning plans and program requirements and for application into a model for global POC echocardiography competence.

Influence of head-of-bed elevation on the measurement of inferior vena cava diameter and collapsibility.

PURPOSE: Inferior vena cava (IVC) diameter and variation are commonly measured in the supine position to estimate intravascular volume status of critically ill patients. Many scientific societies describe the measurement of IVC diameter in the supine position. However, critically ill patients are rarely placed supine due to concerns for aspiration risk, worsened respiratory mechanics, increases in intracranial pressure, and the time it takes to change patient position. We assessed the influence of head-of-bed (HOB) elevation on IVC measurements. METHODS: We conducted a prospective observational study of critically ill patients undergoing critical care ultrasound. With HOB at 0°, IVC maximum (IVCmax0°) and minimum (IVCmin0°) diameters were measured. Measurements were then repeated with HOB elevated to 30° and 45°. Collapsibility index (CI), defined as (IVCmax - IVCmin)/IVCmax, was calculated for each HOB elevation. Mean differences were then compared. RESULTS: A convenience sample of 95 patients was studied, of whom 45% were on vasopressors and 44% were spontaneously breathing. The CI did not significantly differ between the three positions. We found a significant difference (P ≤ .0001) between IVCmax at 45° (2.09 cm) and 0° (1.96 cm), IVCmin at 45° (1.75 cm) and 0° (1.59 cm), IVCmax at 45° (2.09 cm) and 30° (1.97 cm), and IVCmin at 45° (1.75 cm) and 30° (1.61 cm). CONCLUSIONS: In a population of critically ill patients undergoing goal-directed ultrasound examinations, elevating HOB to 30° did not significantly alter IVC measurements or CI. At 45°, however, IVCmax and IVCmin diameters increased significantly, albeit with no significant change in CI. Performing ultrasound measurements of the IVC with HOB elevated to 30° is unlikely to produce clinically meaningful changes.

BRCA Share: A Collection of Clinical BRCA Gene Variants.

As next-generation sequencing increases access to human genetic variation, the challenge of determining clinical significance of variants becomes ever more acute. Germline variants in the BRCA1 and BRCA2 genes can confer substantial lifetime risk of breast and ovarian cancer. Assessment of variant pathogenicity is a vital part of clinical genetic testing for these genes. A database of clinical observations of BRCA variants is a critical resource in that process. This article describes BRCA Share™, a database created by a unique international alliance of academic centers and commercial testing laboratories. By integrating the content of the Universal Mutation Database generated by the French Unicancer Genetic Group with the testing results of two large commercial laboratories, Quest Diagnostics and Laboratory Corporation of America (LabCorp), BRCA Share™ has assembled one of the largest publicly accessible collections of BRCA variants currently available. Although access is available to academic researchers without charge, commercial participants in the project are required to pay a support fee and contribute their data. The fees fund the ongoing curation effort, as well as planned experiments to functionally characterize variants of uncertain significance. BRCA Share™ databases can therefore be considered as models of successful data sharing between private companies and the academic world.

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

We developed a rules-based scoring system to classify DNA variants into five categories including pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, and benign. Over 16,500 pathogenicity assessments on 11,894 variants from 338 genes were analyzed for pathogenicity based on prediction tools, population frequency, co-occurrence, segregation, and functional studies collected from internal and external sources. Scores were calculated by trained scientists using a quantitative framework that assigned differential weighting to these five types of data. We performed descriptive and comparative statistics on the dataset and tested interobserver concordance among the trained scientists. Private variants defined as variants found within single families (n = 5,182), were either VUS (80.5%; n = 4,169) or likely pathogenic (19.5%; n = 1,013). The remaining variants (n = 6,712) were VUS (38.4%; n = 2,577) or likely benign/benign (34.7%; n = 2,327) or likely pathogenic/pathogenic (26.9%, n = 1,808). Exact agreement between the trained scientists on the final variant score was 98.5% [95% confidence interval (CI) (98.0, 98.9)] with an interobserver consistency of 97% [95% CI (91.5, 99.4)]. Variant scores were stable and showed increasing odds of being in agreement with new data when re-evaluated periodically. This carefully curated, standardized variant pathogenicity scoring system provides reliable pathogenicity scores for DNA variants encountered in a clinical laboratory setting.

"It's a hurricane! it's a hurricane!": can music facilitate social constructive and sociodramatic play in a preschool classroom?

Sustaining attention and successfully engaging with others in collaborative play are important accomplishments focused on in preschool classrooms and childcare centers. In addition, music is frequently used in early childhood classrooms, and even recommended as an environmental feature to motivate and regulate children's behavior. Although pretend play provides appealing opportunities for developing these social abilities, no studies to date have explored the use of music as a tool to motivate and sustain constructive and social pretend play. Results from the current study indicate that within 1 preschool classroom, more sustained play (with fewer interruptions) occurred when music played as compared to when no music played in the background. In addition, significantly more dyadic play occurred when slower music played in the background, than when no music played.