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Prior work has shown substantial between-hospital variation in do-not-resuscitate orders, but stability of do-not-resuscitate preferences between hospitalizations and the institutional influence on do-not-resuscitate reversals are unclear. We determined the extent of do-not-resuscitate reversals between hospitalizations and the association of the readmission hospital with do-not-resuscitate reversal.Retrospective cohort study.California Patient Discharge Database, 2016-2018.Nonsurgical patients admitted to an acute care hospital with an early do-not-resuscitate order (within 24 hr of admission).None.We identified nonsurgical adult patients who survived an initial hospitalization with an early-do-not-resuscitate order and were readmitted within 30 days. The primary outcome was the association of do-not-resuscitate reversal with readmission to the same or different hospital from the initial hospital. Secondary outcomes included association of readmission to a low versus high do-not-resuscitate-rate hospital with do-not-resuscitate reversal. Among 49,336 patients readmitted within 30 days following a first do-not-resuscitate hospitalization, 22,251 (45.1%) experienced do-not-resuscitate reversal upon readmission. Patients readmitted to a different hospital versus the same hospital were at higher risk of do-not-resuscitate reversal (59.5% vs 38.5%; p0.001; adjusted odds ratio = 2.4; 95% CI, 2.3-2.5). Patients readmitted to low versus high do-not-resuscitate-rate hospitals were more likely to have do-not-resuscitate reversals (do-not-resuscitate-rate quartile 1 77.0% vs quartile 4 27.2%; p0.001; adjusted odds ratio = 11.9; 95% CI, 10.7-13.2). When readmitted to a different versus the same hospital, patients with do-not-resuscitate reversal had higher rates of mechanical ventilation (adjusted odds ratio = 1.9; 95% CI, 1.6-2.1) and hospital death (adjusted odds ratio = 1.2; 95% CI, 1.1-1.3).Do-not-resuscitate reversals at the time of readmission are more common than previously reported. Although changes in patient preferences may partially explain between-hospital differences, we observed a strong hospital effect contributing to high do-not-resuscitate-reversal rates with significant implications for patient outcomes and resource.

Background Neurovascular insult, nonunion, and iatrogenic rotator cuff injury are concerns when using an intramedullary nail (IMN) for proximal humerus fracture. The purpose of this study was to identify a reproducible starting point and intraoperative imaging for nail insertion optimizing nail depth, tuberosity screw position, and protecting the axillary nerve and rotator cuff insertion. Our hypothesis was that a more medialized starting point would protect soft tissue structures and improve locking screw positioning. Methods Ten fresh-frozen cadavers underwent antegrade IMN with Grashey and modified lateral “precipice” view imaging. A guidewire was positioned medial to the coracoacromial ligament (CAL) in 5 cadavers and lateral to the CAL in 5. Distances from the nail entry point to anatomic landmarks were measured. Anatomic and histologic evaluations were performed, characterizing the nail perforation zone. Radiographs were compared between groups. Results The medial CAL group had a greater distance of screw fixation to the axillary nerve, a shorter distance of greater tuberosity (GT) screw fixation at the rotator cuff insertion on the infraspinatus and teres minor tubercles, and greater screw spread with improved lesser tuberosity capture. Two laterally placed implants violated the rotator cuff tendon. Imaging demonstrated that the ideal starting pin position was medial to the articular margin at a distance equal to the width of the rotator cuff insertion footprint. Conclusions Medial placement optimized fixation of the GT, avoided violation of the rotator cuff tendon and footprint, and was associated with an increased distance of proximal locking screw to the axillary nerve.

Rationale: Interstitial macrophages (IMs) and airspace macrophages (AMs) play critical roles in lung homeostasis and host defense, and are central to the pathogenesis of a number of lung diseases. ...

Tracheostomy utilization has dramatically increased recently. Large gaps exist between expected and actual outcomes resulting in significant decisional conflict and regret. We determined 1-year patient outcomes and healthcare utilization following tracheostomy to aid in decision-making and resource allocation.Retrospective cohort study.All California hospital discharges from 2012 to 2013 with follow-up through 2014.Nonsurgical patients who received a tracheostomy for acute respiratory failure.None.Our primary outcome was 30-day, 90-day, and 1-year mortality. We also determined hospitals readmissions rates and healthcare utilization in the first year following tracheostomy. We identified 8,343 tracheostomies during the study period. One-year mortality following tracheostomy was high, 46.5%. Older adults (≥ 65 yr) had significantly higher mortality compared with younger patients (65 yr) (54.7% vs 36.5%; p0.0001). Median survival for older adults was 175 days (95% CI, 150-202 d) compared with greater than 1 year for younger adults (adjusted hazard ratio, 1.25; 95% CI, 1.14-1.36). Within 1 year of tracheostomy, 60.3% of patients required hospital readmission. Older adults were more likely to be readmitted in the first year after tracheostomy compared with younger adults (66.1% vs 55.2%; adjusted hazard ratio, 1.19; 95% CI, 1.09-1.29). Total short-term acute care hospital costs (index and readmissions) in the first year after tracheostomy were high (mean, $215,369; SD, $160,874).Long-term outcomes following tracheostomy are extremely poor with high mortality, morbidity, and healthcare resource utilization especially among older patients. Some subsets of younger patients may have better outcomes compared with the general tracheostomy population. Short-term acute care costs were extremely high in the first year following tracheostomy. If extended to the entire U.S. population, total short-term acute care hospital costs approach $11 billion dollars per year for tracheostomy-related to acute respiratory failure. These findings may aid families and surrogates in the decision-making process.

Supplemental Digital Content is available in the text., Purpose: The purpose of this study was to define the optimal scoring method for identifying benign intrapulmonary lymph nodes. Materials and Methods: Subjects for this study were selected from the COPDGene study, a large multicenter longitudinal observational cohort study. A retrospective case-control analysis was performed using identified nodules on a subset of 377 patients who demonstrated 765 pulmonary nodules on their baseline computed tomography (CT) study. Nodule characteristics of 636 benign nodules (which resolved or showed

Objectives Prior studies investigating hospital mechanical ventilation volume-outcome associations have had conflicting findings. Volume-outcome relationships within contemporary mechanical ventilation practices are unclear. We sought to determine associations between hospital mechanical ventilation volume and patient outcomes. Design Retrospective cohort study. Setting The California Patient Discharge Database 2016. Patients Adult nonsurgical patients receiving mechanical ventilation. Interventions The primary outcome was hospital death with secondary outcomes of tracheostomy and 30-day readmission. We used multivariable generalized estimating equations to determine the association between patient outcomes and hospital mechanical ventilation volume quartile. Measurements and main results We identified 51,689 patients across 274 hospitals who required mechanical ventilation in California in 2016. 38.2% of patients died in the hospital with 4.4% receiving a tracheostomy. Among survivors, 29.5% required readmission within 30 days of discharge. Patients admitted to high versus low volume hospitals had higher odds of death (quartile 4 vs quartile 1 adjusted odds ratio, 1.40; 95% CI, 1.17-1.68) and tracheostomy (quartile 4 vs quartile 1 adjusted odds ratio, 1.58; 95% CI, 1.21-2.06). However, odds of 30-day readmission among survivors was lower at high versus low volume hospitals (quartile 4 vs quartile 1 adjusted odds ratio, 0.77; 95% CI, 0.67-0.89). Higher hospital mechanical ventilation volume was weakly correlated with higher hospital risk-adjusted mortality rates (ρ = 0.16; p = 0.008). These moderately strong observations were supported by multiple sensitivity analyses. Conclusions Contrary to previous studies, we observed worse patient outcomes at higher mechanical ventilation volume hospitals. In the setting of increasing use of mechanical ventilation and changes in mechanical ventilation practices, multiple mechanisms of worse outcomes including resource strain are possible. Future studies investigating differences in processes of care between high and low volume hospitals are necessary.

Author(s): Regan, Elizabeth A; Lowe, Katherine E; Make, Barry J; Lynch, David A; Kinney, Gregory L; Budoff, Matthew J; Mao, Song Shou; Dyer, Debra; Curtis, Jeffrey L; Bowler, Russell P; Han, MeiLan K; Beaty, Terri H; Hokanson, John E; Kern, Elizabeth; Humphries, Stephen; Curran-Everett, Douglas; van Beek, Edwin JR; Silverman, Edwin K; Crapo, James D; Finigan, James H; COPDGene® Investigators | Abstract: BackgroundLung cancer screening (LCS) via chest computed tomography (CT) scans can save lives by identifying early-stage tumors. However, most smokers die of comorbid smoking-related diseases. LCS scans contain information about smoking-related conditions that is not currently systematically assessed. Identifying these common comorbid diseases on CT could increase the value of screening with minimal impact on LCS programs. We determined the prevalence of 3 comorbid diseases from LCS eligible scans and quantified related adverse outcomes.MethodsWe studied COPD Genetic Epidemiology study (COPDGene®) participants (n=4078) who met criteria for LCS screening at enrollment (age g 55 years, and l 80 years, g 30 pack years smoking, current smoker or former smoker within 15 years of smoking cessation). CT scans were assessed for coronary artery calcification (CAC), emphysema, and vertebral bone density. We tracked the following clinically significant events: myocardial infarctions (MIs), strokes, pneumonia, respiratory exacerbations, and hip and vertebral fractures.ResultsOverall, 77% of eligible CT scans had one or more of these diagnoses identified. CAC (g 100 mg) was identified in 51% of scans, emphysema in 44%, and osteoporosis in 54%. Adverse events related to the underlying smoking-related diseases were common, with 50% of participants reporting at least one. New diagnoses of cardiovascular disease, emphysema and osteoporosis were made in 25%, 7% and 46%, of participants respectively. New diagnosis of disease was associated with significantly more adverse events than in participants who did not have CT diagnoses for both osteoporosis and cardiovascular risk.ConclusionsExpanded analysis of LCS CT scans identified individuals with evidence of previously undiagnosed cardiovascular disease, emphysema or osteoporosis that corresponded with adverse events. LCS CT scans can potentially facilitate diagnoses of these smoking-related diseases and provide an opportunity for treatment or prevention.

Rationale: Asthma in children generally starts as being mild but may progress to being severe and may stay severe for unknown reasons. Objectives: To identify factors in childhood that predict the persistence of severe asthma in late adolescence and early adulthood. Methods: The CAMP (Childhood Asthma Management Program) is, to our knowledge, the largest and longest asthma trial to date; it includes 1,041 children aged 5–12 years with mild to moderate asthma. We evaluated 682 program participants with analyzable data in late adolescence (age, 17–19 yr) and early adulthood (age, 21–23 yr). Measurements and Main Results: To best capture the cases of severe asthma, a status of severe asthma was defined by using criteria from the American Thoracic Society and the National Asthma Education and Prevention Program. Logistic regression with stepwise elimination was used to analyze the clinical features, biomarkers, and lung function that are predictive of the persistence of severe asthma. In late adolescence and early adulthood, 12% and 19% of the participants had severe asthma, respectively; only 6% at both time points had severe cases. For every 5% decrease in the postbronchodilator FEV(1)/FVC ratio in childhood, the odds of the persistence of severe asthma increased by 2.36-fold (95% confidence interval [CI], 1.70–3.28; P

Idiopathic pulmonary fibrosis (IPF) is a progressive, fibrotic interstitial lung disease characterized by (myo)fibroblast accumulation and collagen deposition. Resistance to Fas-induced apoptosis is thought to facilitate (myo)fibroblast persistence in fibrotic lung tissues by poorly understood mechanisms.To test the hypothesis that PTPN13 (protein tyrosine phosphatase-N13) is expressed by IPF lung (myo)fibroblasts, promotes their resistance to Fas-induced apoptosis, and contributes to the development of pulmonary fibrosis.PTPN13 was localized in lung tissues from patients with IPF and control subjects by immunohistochemical staining. Inhibition of PTPN13 function in primary IPF and normal lung (myo)fibroblasts was accomplished by: 1) downregulation with TNF-α (tumor necrosis factor-α)/IFN-γ, 2) siRNA knockdown, or 3) a cell-permeable Fas/PTPN13 interaction inhibitory peptide. The role of PTPN13 in the development of pulmonary fibrosis was assessed in mice with genetic deficiency of PTP-BL, the murine ortholog of PTPN13.PTPN13 was constitutively expressed by (myo)fibroblasts in the fibroblastic foci of patients with IPF. Human lung (myo)fibroblasts, which are resistant to Fas-induced apoptosis, basally expressed PTPN13 in vitro. TNF-α/IFN-γ or siRNA-mediated PTPN13 downregulation and peptide-mediated inhibition of the Fas/PTPN13 interaction in human lung (myo)fibroblasts promoted Fas-induced apoptosis. Bleomycin-challenged PTP-BLThese findings suggest that PTPN13 mediates the resistance of human lung (myo)fibroblasts to Fas-induced apoptosis and promotes pulmonary fibrosis in mice. Our results suggest that strategies aimed at interfering with PTPN13 expression or function may represent a novel strategy to reduce fibrosis in IPF.

Purpose To determine whether visually assessed patterns of emphysema at CT might provide a simple assessment of mortality risk among cigarette smokers. Materials and Methods Of the first 4000 cigarette smokers consecutively enrolled between 2007 and 2011 in this COPDGene study, 3171 had data available for both visual emphysema CT scores and survival. Each CT scan was retrospectively visually scored by two analysts using the Fleischner Society classification system. Severity of emphysema was also evaluated quantitatively by using percentage lung volume occupied by low-attenuation areas (voxels with attenuation of −950 HU or less) (LAA-950). Median duration of follow-up was 7.4 years. Regression analysis for the relationship between imaging patterns and survival was based on the Cox proportional hazards model, with adjustment for age, race, sex, height, weight, pack-years of cigarette smoking, current smoking status, educational level, LAA-950, and (in a second model) forced expiratory volume in 1 second (FEV1). Results Observer agreement in visual scoring was good (weighted κ values, 0.71–0.80). There were 519 deaths in the study cohort. Compared with subjects who did not have visible emphysema, mortality was greater in those with any grade of emphysema beyond trace (adjusted hazard ratios, 1.7, 2.5, 5.0, and 4.1, respectively, for mild centrilobular emphysema, moderate centrilobular emphysema, confluent emphysema, and advanced destructive emphysema, P < .001). This increased mortality generally persisted after adjusting for LAA-950. Conclusion The visual presence and severity of emphysema is associated with significantly increased mortality risk, independent of the quantitative severity of emphysema. Online supplemental material is available for this article.

Discipline-based education research (DBER) is an emergent, interdisciplinary field of scholarship aimed at understanding and improving discipline-specific teaching and learning. The number of DBER faculty members in science, technology, engineering, and mathematics (STEM) departments has grown rapidly in recent years. Because the interdisciplinary nature of DBER involves social science, senior STEM faculty members may find it challenging to evaluate the quality or impact of DBER scholarship. This essay aims to address this issue by providing guidance on evaluating the scholarly accomplishments of DBER faculty members in a way that is useful to departmental colleagues and administrators during the tenure and promotion evaluation process.

Statistics is essential to the process of scientific discovery. An inescapable tenet of statistics, however, is the notion of uncertainty which has reared its head within the arena of reproducibility of research. The Journal of Applied Physiology’s recent initiative, “Cores of Reproducibility in Physiology,” is designed to improve the reproducibility of research: each article is designed to elucidate the principles and nuances of using some piece of scientific equipment or some experimental technique so that other researchers can obtain reproducible results. But other researchers can use some piece of equipment or some technique with expert skill and still fail to replicate an experimental result if they neglect to consider the fundamental concepts of statistics of hypothesis testing and estimation and their inescapable connection to the reproducibility of research. If we want to improve the reproducibility of our research, then we want to minimize the chance that we get a false positive and—at the same time—we want to minimize the chance that we get a false negative. In this review I outline strategies to accomplish each of these things. These strategies are related intimately to fundamental concepts of statistics and the inherent uncertainty embedded in them.

Background: Previous attempts to explore the heterogeneity of chronic obstructive pulmonary disease (COPD) clustered individual patients using clinical, demographic, and disease features. We developed continuous multidimensional disease axes based on radiographic and spirometric variables that split into an airway-predominant axis and an emphysema-predominant axis. Methods: The COPD Genetic Epidemiology study (COPDGene(®)) is a cohort of current and former smokers, > 45 years, with at least 10 pack years of smoking history. Spirometry measures, blood pressure and body mass were directly measured. Mortality was assessed through continuing longitudinal follow-up and cause of death was adjudicated. Among 8157 COPDGene(®) participants with complete spirometry and computed tomography (CT) measures, the top 2 deciles of the airway-predominant and emphysema-predominant axes previously identified were used to categorize individuals into 3 groups having the highest risk for mortality using Cox proportional hazard ratios. These groups were also assessed for causal mortality. Biomarkers of COPD (fibrinogen, soluble receptor for advanced glycation end products [sRAGE], C-reactive protein [CRP], clara cell secretory protein [CC16], surfactant-D [SP-D]) were compared by group. Findings: High-risk subtype classification was defined for 2638 COPDGene(®) participants who were in the highest 2 deciles of either the airway-predominant and/or emphysema-predominant axis (32% of the cohort). These high-risk participants fell into 3 groups: airway-predominant disease only (APD-only), emphysema-predominant disease only (EPD-only) and combined APD-EPD. There was 26% mortality for the APD-only group, 21% mortality for the EPD-only group, and 54% mortality for the combined APD-EPD group. The APD-only group (n=1007) was younger, had a lower forced expiratory volume in 1 second (FEV(1)) percent (%) predicted and a strong association with the preserved ratio-impaired spirometry (PRISm) quadrant. The EPD-only group (n=1006) showed a relatively higher FEV(1) % predicted and included largely GOLD stage 0, 1 and 2 partipants. Individuals in each of the 3 high-risk groups were at greater risk for respiratory mortality, while those in the APD-only group were additionally at greater risk for cardiovascular mortality. Biomarker analysis demonstrated a significant association of the APD-only group with CRP, and sRAGE demonstrated greatest significance with both the EPD-only and the combined APD-EPD groups. Interpretation: Among current and former smokers, individuals in the highest 2 deciles for mortality risk on the airway-predominant axis and the emphysema-predominant axis have unique associations to spirometric patterns, different imaging characteristics, biomarkers and causal mortality.

Background: Chronic obstructive pulmonary disease (COPD) remains a major cause of morbidity and mortality. Present-day diagnostic criteria are largely based solely on spirometric criteria. Accumulating evidence has identified a substantial number of individuals without spirometric evidence of COPD who suffer from respiratory symptoms and/or increased morbidity and mortality. There is a clear need for an expanded definition of COPD that is linked to physiologic, structural (computed tomography [CT]) and clinical evidence of disease. Using data from the COPD Genetic Epidemiology study (COPDGene(®)), we hypothesized that an integrated approach that includes environmental exposure, clinical symptoms, chest CT imaging and spirometry better defines disease and captures the likelihood of progression of respiratory obstruction and mortality. Methods: Four key disease characteristics – environmental exposure (cigarette smoking), clinical symptoms (dyspnea and/or chronic bronchitis), chest CT imaging abnormalities (emphysema, gas trapping and/or airway wall thickening), and abnormal spirometry – were evaluated in a group of 8784 current and former smokers who were participants in COPDGene(®) Phase 1. Using these 4 disease characteristics, 8 categories of participants were identified and evaluated for odds of spirometric disease progression (FEV(1) > 350 ml loss over 5 years), and the hazard ratio for all-cause mortality was examined. Results: Using smokers without symptoms, CT imaging abnormalities or airflow obstruction as the reference population, individuals were classified as Possible COPD, Probable COPD and Definite COPD. Current Global initiative for obstructive Lung Disease (GOLD) criteria would diagnose 4062 (46%) of the 8784 study participants with COPD. The proposed COPDGene(®) 2019 diagnostic criteria would add an additional 3144 participants. Under the new criteria, 82% of the 8784 study participants would be diagnosed with Possible, Probable or Definite COPD. These COPD groups showed increased risk of disease progression and mortality. Mortality increased in patients as the number of their COPD characteristics increased, with a maximum hazard ratio for all cause-mortality of 5.18 (95% confidence interval [CI]: 4.15–6.48) in those with all 4 disease characteristics. Conclusions: A substantial portion of smokers with respiratory symptoms and imaging abnormalities do not manifest spirometric obstruction as defined by population normals. These individuals are at significant risk of death and spirometric disease progression. We propose to redefine the diagnosis of COPD through an integrated approach using environmental exposure, clinical symptoms, CT imaging and spirometric criteria. These expanded criteria offer the potential to stimulate both current and future interventions that could slow or halt disease progression in patients before disability or irreversible lung structural changes develop.

Good presentation skills are important. Why? When you improve your presentation skills, you improve your ability to engage your audience and communicate whatever science you happen to do. In graduate school you learn how to do research, and you sometimes learn how to teach, but how often do you actually learn how to give an effective, engaging presentation? In this personal view I recount some of my early experiences as a presenter and some of the techniques I use to (hopefully) engage my audiences.

In this issue of Temperature, Caldwell and Cheuvront summarize what they consider to be basic statistical considerations for occupational and environmental physiology [1]. In their Comprehensive Re...

Epithelial-fibroblast interactions are thought to be very important in the adult lung in response to injury, but the specifics of these interactions are not well defined. We developed coculture systems to define the interactions of adult human alveolar epithelial cells with lung fibroblasts. Alveolar type II cells cultured on floating collagen gels reduced the expression of type 1 collagen (COL1A1) and α-smooth muscle actin (ACTA2) in fibroblasts. They also reduced fibroblast expression of hepatocyte growth factor (HGF), fibroblast growth factor 7 (FGF7, KGF), and FGF10. When type II cells were cultured at an air-liquid interface to maintain high levels of surfactant protein expression, this inhibitory activity was lost. When type II cells were cultured on collagen-coated tissue culture wells to reduce surfactant protein expression further and increase the expression of some type I cell markers, the epithelial cells suppressed transforming growth factor-β (TGF-β)-stimulated ACTA2 and connective tissue growth factor (CTGF) expression in lung fibroblasts. Our results suggest that transitional alveolar type II cells and likely type I cells but not fully differentiated type II cells inhibit matrix and growth factor expression in fibroblasts. These cells express markers of both type II cells and type I cells. This is probably a normal homeostatic mechanism to inhibit the fibrotic response in the resolution phase of wound healing. Defining how transitional type II cells convert activated fibroblasts into a quiescent state and inhibit the effects of TGF-β may provide another approach to limiting the development of fibrosis after alveolar injury.

Background: Chronic obstructive pulmonary disease (COPD) remains a major cause of morbidity and mortality. Present-day diagnostic criteria are largely based solely on spirometric criteria. Accumulating evidence has identified a substantial number of individuals without spirometric evidence of COPD who suffer from respiratory symptoms and/or increased morbidity and mortality. There is a clear need for an expanded definition of COPD that is linked to physiologic, structural (computed tomography [CT]) and clinical evidence of disease. Using data from the COPD Genetic Epidemiology study (COPDGene®), we hypothesized that an integrated approach that includes environmental exposure, clinical symptoms, chest CT imaging and spirometry better defines disease and captures the likelihood of progression of respiratory obstruction and mortality. Methods: Four key disease characteristics – environmental exposure (cigarette smoking), clinical symptoms (dyspnea and/or chronic bronchitis), chest CT imaging abnormalities (emphysema, gas trapping and/or airway wall thickening), and abnormal spirometry – were evaluated in a group of 8784 current and former smokers who were participants in COPDGene® Phase 1. Using these 4 disease characteristics, 8 categories of participants were identified and evaluated for odds of spirometric disease progression (FEV1 > 350 ml loss over 5 years), and the hazard ratio for all-cause mortality was examined. Results: Using smokers without symptoms, CT imaging abnormalities or airflow obstruction as the reference population, individuals were classified as Possible COPD, Probable COPD and Definite COPD. Current Global initiative for obstructive Lung Disease (GOLD) criteria would diagnose 4062 (46%) of the 8784 study participants with COPD. The proposed COPDGene® 2019 diagnostic criteria would add an additional 3144 participants. Under the new criteria, 82% of the 8784 study participants would be diagnosed with Possible, Probable or Definite COPD. These COPD groups showed increased risk of disease progression and mortality. Mortality increased in patients as the number of their COPD characteristics increased, with a maximum hazard ratio for all cause-mortality of 5.18 (95% confidence interval [CI]: 4.15–6.48) in those with all 4 disease characteristics. Conclusions: A substantial portion of smokers with respiratory symptoms and imaging abnormalities do not manifest spirometric obstruction as defined by population normals. These individuals are at significant risk of death and spirometric disease progression. We propose to redefine the diagnosis of COPD through an integrated approach using environmental exposure, clinical symptoms, CT imaging and spirometric criteria. These expanded criteria offer the potential to stimulate both current and future interventions that could slow or halt disease progression in patients before disability or irreversible lung structural changes develop.

Chronic obstructive pulmonary disease (COPD) is a progressive disease with both environmental and genetic risk factors. Genome-wide association studies (GWAS) have identified multiple genomic regions influencing risk of COPD. To thoroughly investigate the genetic etiology of COPD, however, it is also important to explore the role of copy number variants (CNVs) because the presence of structural variants can alter gene expression and can be causal for some diseases. Here, we investigated effects of polymorphic CNVs on quantitative measures of pulmonary function and chest computed tomography (CT) phenotypes among subjects enrolled in COPDGene, a multisite study. COPDGene subjects consist of roughly one-third African American (AA) and two-thirds non-Hispanic white adult smokers (with or without COPD). We estimated CNVs using PennCNV on 9,076 COPDGene subjects using Illumina's Omni-Express genome-wide marker array. We tested for association between polymorphic CNV components (defined as disjoint intervals of copy number regions) for several quantitative phenotypes associated with COPD within each racial group. Among the AAs, we identified a polymorphic CNV on chromosome 5q35.2 located between two genes (FAM153B and SIMK1, but also harboring several pseudo-genes) giving genome-wide significance in tests of association with total lung capacity (TLCCT ) as measured by chest CT scans. This is the first study of genome-wide association tests of polymorphic CNVs and TLCCT . Although the ARIC cohort did not have the phenotype of TLCCT , we found similar counts of CNV deletions and amplifications among AA and European subjects in this second cohort.

Current clinical chest CT reporting includes limited qualitative assessment of emphysema with rare mention of lung volumes and limited reporting of emphysema, based upon retrospective review of CT reports. Quantitative CT analysis performed in COPDGene and other research cohorts utilize semiautomated segmentation procedures and well-established research method (Thirona). We compared this reference QCT data with fully automated QCT analysis that can be obtained at the time of CT scan and sent to PACS along with standard chest CT images. 164 COPDGene(®) cohort study subjects enrolled at Brigham and Women’s Hospital had baseline and 5-year follow-up CT scans. Subjects included 17 nonsmoking controls, 92 smokers with normal spirometry, 15 preserved ratio impaired spirometry (PRISm) patients, 12 GOLD 1, 20 GOLD 2, and 8 GOLD 3–4. 97% ([Formula: see text]) of clinical reports did not mention lung volumes, and 14% ([Formula: see text]) made no mention of emphysema. Total lung volumes determined by the fully automated algorithm were consistently 47 milliliters (ml) less than the Thirona reference value for all subjects (95% confidence interval [Formula: see text] to [Formula: see text]). Percent emphysema values were equivalent to the Thirona reference values. Well-established research reference data can be used to evaluate and validate automated QCT software. Validation can be repeated as software is updated.

The problem of inadequate statistical reporting is long standing and widespread in the biomedical literature, including in cardiovascular physiology. Although guidelines for reporting statistics have been available in clinical medicine for some time, there are currently no guidelines specific to cardiovascular physiology. To assess the need for guidelines, we determined the type and frequency of statistical tests and procedures currently used in the American Journal of Physiology-Heart and Circulatory Physiology. A PubMed search for articles published in the American Journal of Physiology-Heart and Circulatory Physiology between January 1, 2017, and October 6, 2017, provided a final sample of 146 articles evaluated for methods used and 38 articles for indepth analysis. The t-test and ANOVA accounted for 71% (212 of 300 articles) of the statistical tests performed. Of six categories of post hoc tests, Bonferroni and Tukey tests were used in 63% (62 of 98 articles). There was an overall lack in details provided by authors publishing in the American Journal of Physiology-Heart and Circulatory Physiology, and we compiled a list of recommended minimum reporting guidelines to aid authors in preparing manuscripts. Following these guidelines could substantially improve the quality of statistical reports and enhance data rigor and reproducibility. Listen to this article’s corresponding podcast at https://ajpheart.podbean.com/e/statistical-considerations-in-reporting-cardiovascular-research/ .

Learning about statistics is a lot like learning about science: the learning is more meaningful if you can actively explore. This thirteenth installment of Explorations in Statistics explores the log transformation, an established technique that rescales the actual observations from an experiment so that the assumptions of some statistical analysis are better met. A general assumption in statistics is that the variability of some response Y is homogeneous across groups or across some predictor variable X. If the variability—the standard deviation—varies in rough proportion to the mean value of Y, a log transformation can equalize the standard deviations. Moreover, if the actual observations from an experiment conform to a skewed distribution, then a log transformation can make the theoretical distribution of the sample mean more consistent with a normal distribution. This is important: the results of a one-sample t test are meaningful only if the theoretical distribution of the sample mean is roughly normal. If we log-transform our observations, then we want to confirm the transformation was useful. We can do this if we use the Box-Cox method, if we bootstrap the sample mean and the statistic t itself, and if we assess the residual plots from the statistical model of the actual and transformed sample observations.

Although skin-prick testing (SPT) is commonly used by allergists in the evaluation of allergy, in-vitro testing for specific IgE (sIgE) is an attractive alternate because it can be performed remotely and is of utility when SPT is contraindicated, as in patients on anti-histamines, or with dermatitis or severe eczema. It is, however, necessary to determine the extent of correlation between the in-vitro and in-vivo methods. In this study, we examined the qualitative concordance between SPT and sIgE as measured on the HYTEC™288 platform for 10 commonly encountered inhalant allergens in 232 subjects, and analysed the performance characteristics for the HYTEC™288. Overall concordance between SPT and sIgE was >70% for all allergens tested. Sensitivity ranged from 25% to 95%, depending on the allergen, while specificity was significantly higher for all allergens (78-97%). NPV was >85% for all allergens tested, while PPV was more variable, ranging from 22% to 88%. These results are similar to findings in other studies comparing SPT with sIgE. Lack of concordance in a percentage of samples might be partly attributed to differences in allergen preparations for SPT and HYTEC™ 288. Follow-up studies utilizing identical allergen preparations for both in-vivo and in-vitro testing may address these discrepancies.

To identify a predictive value for the exacerbation status of chronic obstructive pulmonary disease (COPD) subjects, we evaluated the relationship between pulmonary vascular measurements on chest CT and severe COPD exacerbation. Six hundred three subjects enrolled in the COPDGene population were included and divided into nonexacerbator (n = 313) and severe exacerbator (n = 290) groups, based on whether they had an emergency room visit and/or hospitalization for COPD exacerbation. We measured the diameter of the main pulmonary artery (MPA) and ascending aorta (AA) at 2 different sites of the MPA (the tubular midportion and bifurcation) on both axial images and multiplanar reconstructions. Using multiple logistic regression analyses, we evaluated the relationship between each CT-measured pulmonary vasculature and exacerbation status. Axial and multiplanar MPA to AA diameter ratios (PA:AA ratios) at the tubular midportion and the axial PA:AA ratios at the bifurcation indicated significant association with severe exacerbation. The strongest association was found with the axial PA:mean AA ratio at the bifurcation (adjusted odds ratio [OR] = 12.53, 95% confidence interval [CI] = 2.35–66.74, P = .003) and the axial PA:major AA ratio at the tubular midportion (adjusted OR = 10.72, 95% CI = 1.99–57.86, P = .006). No differences were observed in the MPA diameter. Receiver operating characteristic analysis of these variables indicates that they may serve as a good predictive value for severe exacerbation (area under the curve, 0.77–0.78). The range of cut-off value for PA:AA ratio was 0.8 to 0.87. CT-measured PA:AA ratios at either the bifurcation or the tubular site, measured either on axial or multiplanar images, are useful for identification of the risk of severe exacerbation, and consequently can be helpful in guiding the management of COPD. Although CT measurement was used at the level of pulmonary bifurcation in previous studies, we suggest that future studies should monitor the tubular site of the MPA for maximum diagnostic value of CT in pulmonary hypertension or severe COPD exacerbation, as the tubular site of the MPA remains relatively constant on CT images.

Percutaneous patent foramen ovale (PFO) occluder placement improves dyspnea and oxygen requirement in hypoxic patients with PFO-mediated right-to-left shunt (RTLS). Although saline contrast echocardiography (SCE) in the resting state can identify PFO RTLS, SCE performed with exercise stress testing may provide incremental diagnostic yield compared to rest SCE. We evaluated the ability of exercise SCE to predict PFO presence and size using intracardiac echocardiography (ICE) as a gold standard in a hypoxic cohort. Thirty-three hypoxic patients with suspected PFO RTLS who underwent rest, Valsalva, and exercise stress SCE prior to ICE were evaluated retrospectively. PFO RTLS was defined by ICE findings including PFO anatomy, RTLS by saline contrast and color Doppler, and probe patency. SCE shunt severity was compared to the presence of ICE-defined PFO RTLS and PFO size. Exercise SCE for the detection of PFO RTLS performed with an area under the curve of 0.77, sensitivity of 73 %, and specificity of 86 %. Among 26 patients with PFO RTLS, exercise SCE identified four additional patients with PFO that had negative rest SCE and two patients with negative Valsalva SCE. Exercise SCE had a stronger correlation with PFO size than resting or Valsalva SCE. Exercise SCE detects PFO RTLS and predicts PFO size in a hypoxic cohort. In addition, exercise SCE can identify PFO RTLS that is otherwise undetected with rest or Valsalva SCE. Exercise SCE may be appropriate when a clinical suspicion for PFO RTLS persists despite negative rest and Valsalva SCE.

The reliability and reproducibility of science are under scrutiny. However, a major cause of this lack of repeatability is not being considered: the wide sample-to-sample variability in the P value. We explain why P is fickle to discourage the ill-informed practice of interpreting analyses based predominantly on this statistic.

Learning about statistics is a lot like learning about science: the learning is more meaningful if you can actively explore. This twelfth installment of Explorations in Statistics explores the assumption of normality, an assumption essential to the meaningful interpretation of a t test. Although the data themselves can be consistent with a normal distribution, they need not be. Instead, it is the theoretical distribution of the sample mean or the theoretical distribution of the difference between sample means that must be roughly normal. The most versatile approach to assess normality is to bootstrap the sample mean, the difference between sample means, or t itself. We can then assess whether the distributions of these bootstrap statistics are consistent with a normal distribution by studying their normal quantile plots. If we suspect that an inference we make from a t test may not be justified—if we suspect that the theoretical distribution of the sample mean or the theoretical distribution of the difference between sample means is not normal—then we can use a permutation method to analyze our data.

Alpha-1 antitrypsin deficiency, caused primarily by homozygosity for the Z allele of the SERPINA1 gene, is a well-established genetic cause of chronic obstructive pulmonary disease (COPD). Whether the heterozygous PiMZ genotype for alpha-1 antitrypsin confers increased risk for COPD has been debated.We analyzed 8,271 subjects in the Genetic Epidemiology of COPD (COPDGene) Study, hypothesizing that PiMZ would independently associate with COPD and COPD-related phenotypes.The COPDGene Study comprises a multiethnic, cross-sectional, observational cohort of non-Hispanic white and African American current and former smokers with at least 10 pack-years of smoking who were enrolled for detailed clinical and genetic studies of COPD and COPD-related traits. We performed multivariate logistic regression analysis for moderate to severe COPD and assessed Pi genotype with other relevant covariates in models stratified by race. We analyzed quantitative characteristics on the basis of volumetric computed tomography with generalized linear models controlling for genotype, scanner type, and similar covariates.White PiMZ COPDGene subjects had significantly lower lung function, FEVIn the COPDGene Study, we demonstrate that PiMZ heterozygous individuals who smoke are at increased risk for COPD and obstructive lung function impairment compared with Z-allele noncarriers, regardless of race. Although severe alpha-1 antitrypsin deficiency is uncommon in African Americans, our study adds further support for initial targeted detection of all subjects with COPD for alpha-1 antitrypsin deficiency, including African Americans. Clinical trial registered with www.clinicaltrials.gov (NCT00608784).

in 2004 dale benos and i published guidelines for reporting statistics in journals published by the American Physiological Society ([6][1]). In so doing, we had hoped the guidelines would help improve the caliber of statistical information reported in those journals. By 2007, an admittedly short

Changes made in the 8th edition of the Guide for the Care and Use of Laboratory Animals included new recommendations for the amount of space for breeding female mice. Adopting the new recommendations required, in essence, the elimination of trio breeding practices for all institutions. Both public opinion and published data did not readily support the new recommendations. In response, the National Jewish Health Institutional Animal Care and Use Committee established a program to directly compare the effects of breeding format on mouse pup survival and growth. Our study showed an overall parity between trio and pairwise breeding formats on the survival and growth of the litters, suggesting that the housing recommendations for breeding female mice as stated in the current Guide for the Care and Use of Laboratory Animals should be reconsidered.

BACKGROUND In ARDS, the extent of fibroproliferative activity on chest high-resolution CT (HRCT) scan has been reported to correlate with poorer short-term outcomes and pulmonary-associated quality of life. However, clinical factors associated with HRCT scan fibroproliferation are incompletely characterized. We questioned if lung compliance assessed at the bedside would be associated with fibroproliferation on HRCT scans obtained during the resolution phase of ARDS. METHODS We used data from a published randomized, controlled clinical trial in ARDS. All patients were cared for using a low tidal volume strategy. Demographic data and ventilator parameters were examined in association with radiologic scores from chest HRCT scans obtained 14 days after diagnosis. RESULTS Data from 82 patients with ARDS were analyzed. Average static respiratory compliance over the first 14 days after diagnosis was inversely associated with chest HRCT scan reticulation (ρ = −0.46); this relationship persisted in multivariable analysis including APACHE (Acute Physiology and Chronic Health Evaluation) II scores, initial Pa o 2 /F io 2 , pneumonia diagnosis, and ventilator days. Average static respiratory compliance was also lower among patients with bronchiectasis at day 14 ( P = .007). Initial static respiratory compliance obtained within the first day after ARDS diagnosis was correlated inversely with the presence of HRCT scan reticulation (ρ = −0.38) and was lower among patients who demonstrated bronchiectasis on the day 14 HRCT scan ( P = .008). CONCLUSIONS In patients with ARDS, diminished lung compliance measured bedside was associated with radiologic fibroproliferation 14 days post diagnosis. Establishing factors that predispose to development of excessive fibroproliferation with subsequent confirmation by chest HRCT scan represents a promising strategy to identify patients with ARDS at risk for poorer clinical outcomes.

Background Patients with cystic fibrosis (CF) exhibit a wide range of disease severity, and can be broadly stratified into high-risk and low-risk groups based on cystic fibrosis transmembrane conductance regulator (CFTR) mutation class. Patients with a low-risk genotype are often diagnosed as adults, with milder disease and lower sweat chloride values. The aim of the current study was to better understand radiographic and clinical characteristics of sinus disease in adult CF patients within this risk category. Methods Adult CF patients were retrospectively compared to a control group of patients with chronic rhinosinusitis. CF diagnostic testing and pulmonary characteristics were compared between high-risk and low-risk CF groups, and sinus CT findings were compared among all 3 groups. Results When comparing CF cohorts (n = 25 and 30, respectively), earlier age at diagnosis (p < 0.001), higher sweat chloride values (p < 0.001), lower forced expiratory volume in 1 second (FEV1) values (p < 0.001), and a higher prevalence of pulmonary infection with Pseudomonas aeruginosa (p = 0.001) were found in the high-risk genotype group. A significantly increased incidence of sinus hypoplasia/aplasia and bony sclerosis was seen when comparing both CF groups to the control cohort (n = 30), as well as when comparing the high-risk and low-risk CF genotype cohorts. Conclusion The current study describes clinicopathologic findings of sinus disease in adult CF patients in the context of genotype severity. Our data demonstrate that while patients within a low-risk genotype cohort have generally milder lung disease, they retain classic radiographic findings of CF sinus disease that can help raise the index of suspicion for undiagnosed CF.

The first aim of this investigation was to quantify the distribution of trapezius muscle activity with different scapular postures while seated. The second aim of this investigation was to examine the association between changes in cervical and scapular posture when attempting to recruit different subdivisions of the trapezius muscle. Cervical posture, scapular posture, and trapezius muscle activity were recorded from 20 healthy participants during three directed shoulder postures. Planar angles formed by reflective markers placed on the acromion process, C7, and tragus were used to quantify cervical and scapular posture. Distribution of trapezius muscle activity was recorded using two high-density surface electromyography (HDsEMG) electrodes positioned over the upper, middle, and lower trapezius. Results validated the assumption that directed scapular postures preferentially activate different subdivisions of the trapezius muscle. In particular, scapular depression was associated with a more inferior location of trapezius muscle activity (r = 0.53). Scapular elevation was coupled with scapular abduction (r = 0.52). Scapular adduction was coupled with cervical extension (r = 0.35); all other changes in cervical posture were independent of changes in scapular posture. This investigation provides empirical support for reductions in static loading of the upper trapezius and improvements in neck posture through verbal cueing of scapular posture.

Background Previous studies have identified asthma phenotypes based on small numbers of clinical, physiologic, or inflammatory characteristics. However, no studies have used a wide range of variables using machine learning approaches. Objectives We sought to identify subphenotypes of asthma by using blood, bronchoscopic, exhaled nitric oxide, and clinical data from the Severe Asthma Research Program with unsupervised clustering and then characterize them by using supervised learning approaches. Methods Unsupervised clustering approaches were applied to 112 clinical, physiologic, and inflammatory variables from 378 subjects. Variable selection and supervised learning techniques were used to select relevant and nonredundant variables and address their predictive values, as well as the predictive value of the full variable set. Results Ten variable clusters and 6 subject clusters were identified, which differed and overlapped with previous clusters. Patients with traditionally defined severe asthma were distributed through subject clusters 3 to 6. Cluster 4 identified patients with early-onset allergic asthma with low lung function and eosinophilic inflammation. Patients with later-onset, mostly severe asthma with nasal polyps and eosinophilia characterized cluster 5. Cluster 6 asthmatic patients manifested persistent inflammation in blood and bronchoalveolar lavage fluid and exacerbations despite high systemic corticosteroid use and side effects. Age of asthma onset, quality of life, symptoms, medications, and health care use were some of the 51 nonredundant variables distinguishing subject clusters. These 51 variables classified test cases with 88% accuracy compared with 93% accuracy with all 112 variables. Conclusion The unsupervised machine learning approaches used here provide unique insights into disease, confirming other approaches while revealing novel additional phenotypes.

Background Patients with refractory asthma frequently have elements of laryngopharyngeal reflux (LPR) with potential aspiration contributing to their poor control. We previously reported on a supraglottic index (SGI) scoring system that helps in the evaluation of LPR with potential aspiration. However, to further the usefulness of this SGI scoring system for bronchoscopists, a teaching system was developed that included both interobserver and intraobserver reproducibility. Methods Five pulmonologists with expertise in fiber-optic bronchoscopy but novice to the SGI participated. A training system was developed that could be used via Internet interaction to make this learning technique widely available. Results By the final testing, there was excellent interreader agreement (κ of at least 0.81), thus documenting reproducibility in scoring the SGI. For the measure of intrareader consistency, one reader was arbitrarily selected to rescore the final test 4 weeks later and had a κ value of 0.93, with a 95% CI of 0.79 to 1.00. Conclusions In this study, we demonstrate that with an organized educational approach, bronchoscopists can develop skills to have highly reproducible assessment and scoring of supraglottic abnormalities. The SGI can be used to determine which patients need additional intervention to determine causes of LPR and gastroesophageal reflux. Identification of this problem in patients with refractory asthma allows for personal, individual directed therapy to improve asthma control.

OBJECTIVE: Psychosocial stress has been associated with a variety of chronic pain disorders although the mechanisms responsible for this relationship are unknown. The purpose of this study was to compare the excitability of intracortical and corticospinal pathways to the trapezius muscle in individuals with and without chronic neck pain during exposure to low and high levels of psychosocial stress. METHODS: Single and paired-pulse transcranial magnetic stimulation was used to assess motor evoked potentials (MEPs) and short-interval intracortical inhibition (SICI) during mental math performed in the presence and absence of social evaluative threat. RESULTS: All participants demonstrated higher amplitude MEPs in the high stress compared to the low stress condition (p

The editors of Advances in Physiology Education and the leadership of the American Physiological Society (APS) History of Physiology Group would like to express their profound appreciation to Charles M. Tipton, PhD, for his extraordinary service to both the journal and to the History of Physiology