Association of PHACTR1 with Coronary Artery Calcium Differs by Sex and Cigarette Smoking.

Background: Coronary artery calcium (CAC) is a marker of subclinical atherosclerosis and is a complex heritable trait with both genetic and environmental risk factors, including sex and smoking. Methods: We performed genome-wide association (GWA) analyses for CAC among all participants and stratified by sex in the COPDGene study (n = 6144 participants of European ancestry and n = 2589 participants of African ancestry) with replication in the Diabetes Heart Study (DHS). We adjusted for age, sex, current smoking status, BMI, diabetes, self-reported high blood pressure, self-reported high cholesterol, and genetic ancestry (as summarized by principal components computed within each racial group). For the significant signals from the GWA analyses, we examined the single nucleotide polymorphism (SNP) by sex interactions, stratified by smoking status (current vs. former), and tested for a SNP by smoking status interaction on CAC. Results: We identified genome-wide significant associations for CAC in the chromosome 9p21 region [CDKN2B-AS1] among all COPDGene participants (p = 7.1 × 10-14) and among males (p = 1.0 × 10-9), but the signal was not genome-wide significant among females (p = 6.4 × 10-6). For the sex stratified GWA analyses among females, the chromosome 6p24 region [PHACTR1] had a genome-wide significant association (p = 4.4 × 10-8) with CAC, but this signal was not genome-wide significant among all COPDGene participants (p = 1.7 × 10-7) or males (p = 0.03). There was a significant interaction for the SNP rs9349379 in PHACTR1 with sex (p = 0.02), but the interaction was not significant for the SNP rs10757272 in CDKN2B-AS1 with sex (p = 0.21). In addition, PHACTR1 had a stronger association with CAC among current smokers (p = 6.2 × 10-7) than former smokers (p = 7.5 × 10-3) and the SNP by smoking status interaction was marginally significant (p = 0.03). CDKN2B-AS1 had a strong association with CAC among both former (p = 7.7 × 10-8) and current smokers (p = 1.7 × 10-7) and the SNP by smoking status interaction was not significant (p = 0.40). Conclusions: Among current and former smokers of European ancestry in the COPDGene study, we identified a genome-wide significant association in the chromosome 6p24 region [PHACTR1] with CAC among females, but not among males. This region had a significant SNP by sex and SNP by smoking interaction on CAC.

Race-Specific Spirometry Equations Do Not Improve Models of Dyspnea and Quantitative Chest CT Phenotypes.

BACKGROUND: Race-specific spirometry reference equations are used globally to interpret lung function for clinical, research, and occupational purposes, but inclusion of race is under scrutiny. RESEARCH QUESTION: Does including self-identified race in spirometry reference equation formation improve the ability of predicted FEV1 values to explain quantitative chest CT abnormalities, dyspnea, or Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification? STUDY DESIGN AND METHODS: Using data from healthy adults who have never smoked in both the National Health and Nutrition Survey (2007-2012) and COPDGene study cohorts, race-neutral, race-free, and race-specific prediction equations were generated for FEV1. Using sensitivity/specificity, multivariable logistic regression, and random forest models, these equations were applied in a cross-sectional analysis to populations of individuals who currently smoke and individuals who formerly smoked to determine how they affected GOLD classification and the fit of models predicting quantitative chest CT phenotypes or dyspnea. RESULTS: Race-specific equations showed no advantage relative to race-neutral or race-free equations in models of quantitative chest CT phenotypes or dyspnea. Race-neutral reference equations reclassified up to 19% of Black participants into more severe GOLD classes, while race-neutral/race-free equations may improve model fit for dyspnea symptoms relative to race-specific equations. INTERPRETATION: Race-specific equations offered no advantage over race-neutral/race-free equations in three distinct explanatory models of dyspnea and chest CT scan abnormalities. Race-neutral/race-free reference equations may improve pulmonary disease diagnoses and treatment in populations highly vulnerable to lung disease.

Longitudinal Association Between Muscle Loss and Mortality in Ever Smokers.

BACKGROUND: Body composition measures, specifically low weight or reduced muscle mass, are associated with mortality in COPD, but the effect of longitudinal body composition changes is undefined. RESEARCH QUESTION: Is the longitudinal loss of fat-free mass (FFM) associated with increased mortality, including in those with initially normal or elevated body composition metrics? STUDY DESIGN AND METHODS: Participants with complete data for at least one visit in the COPDGene study (n = 9,268) and the ECLIPSE study (n = 1,760) were included and monitored for 12 and 8 years, respectively. Pectoralis muscle area (PMA) was derived from thoracic CT scans and used as a proxy for FFM. A longitudinal mixed submodel for PMA and a Cox proportional hazards submodel for survival were fitted on a joint distribution, using a shared random intercept parameter and Markov chain Monte Carlo parameter estimation. RESULTS: Both cohorts demonstrated a left-shifted distribution of baseline FFM, not reflected in BMI, and an increase in all-cause mortality risk associated with longitudinal loss of PMA. For each 1-cm2 PMA loss, mortality increased 3.1% (95% CI, 2.4%-3.7%; P < .001) in COPDGene, and 2.4% (95% CI, 0.9%-4.0%; P < .001) in ECLIPSE. Increased mortality risk was independent of enrollment values for BMI and disease severity [BODE (body mass, airflow obstruction, dyspnea, and exercise capacity) index quartiles] and was significant even in participants with initially greater than average PMA. INTERPRETATION: Longitudinal loss of PMA is associated with increased all-cause mortality, regardless of BMI or initial muscle mass. Consideration of novel screening tests and further research into mechanisms contributing to muscle decline may improve risk stratification and identify novel therapeutic targets in ever smokers.

Inadvertent Burst Suppression During Total Intravenous Anesthesia in 112 Consecutive Patients Undergoing Spinal Instrumentation Surgery: A Retrospective Observational Quality Improvement Project.

INTRODUCTION: The incidence and quantification of inadvertent electroencephalographic burst suppression during total intravenous anesthesia (TIVA) for spine instrumentation surgery has not previously been reported. METHODS: The primary aim of this retrospective observational quality improvement project was to establish the prevalence of burst suppression during spine instrumentation surgery with TIVA. The secondary outcome was the incidence of postoperative delirium. RESULTS: One hundred twelve consecutive patients, aged between 20 and 88 years, underwent spinal instrumentation surgery. Seventy-eight (69.6%) patients experienced inadvertent burst suppression; the maximal degree of burst suppression ratio was 20% to 100%. Median (interquartile range [IQR]) time spent in burst suppression was 44 (77) minutes, and burst suppression was present for 22% (range: 2% to 93%) of the monitoring period. Average (±SD) propofol dose was lower in patients with burst suppression (87±19 vs. 93±15 µg/kg/min, P=0.04). Ten (8.9%) patients experienced postoperative delirium. Intraoperative burst suppression was more prevalent in those that experienced delirium (100% vs. 66.7%, P=0.03, relative risk: 1.5, 95% confidence interval: 1.3-1.7). The proportion of the monitoring period spent in maximal burst suppression (15.3 [25.9]% vs.11.7 [21.7]%) was similar between those that did, and did not, experience delirium. CONCLUSIONS: High rates and prolonged periods of inadvertent burst suppression may be prevalent during spine instrumentation surgery with TIVA. Our findings suggest that usage of electroencephalography alone is incomplete without prompt interpretation and intervention, mandating close communication between neuromonitoring and anesthesia teams. The dose-response relationship between burst suppression, total time spent in maximal burst suppression, and their association with delirium warrants further evaluation.

Metformin: Experimental and Clinical Evidence for a Potential Role in Emphysema Treatment.

Rationale: Cigarette smoke (CS) inhalation triggers oxidative stress and inflammation, leading to accelerated lung aging, apoptosis, and emphysema, as well as systemic pathologies. Metformin is beneficial for protecting against aging-related diseases. Objectives: We sought to investigate whether metformin may ameliorate CS-induced pathologies of emphysematous chronic obstructive pulmonary disease (COPD). Methods: Mice were exposed chronically to CS and fed metformin-enriched chow for the second half of exposure. Lung, kidney, and muscle pathologies, lung proteostasis, endoplasmic reticulum (ER) stress, mitochondrial function, and mediators of metformin effects in vivo and/or in vitro were studied. We evaluated the association of metformin use with indices of emphysema progression over 5 years of follow-up among the COPDGene (Genetic Epidemiology of COPD) study participants. The association of metformin use with the percentage of emphysema and adjusted lung density was estimated by using a linear mixed model. Measurements and Main Results: Metformin protected against CS-induced pulmonary inflammation and airspace enlargement; small airway remodeling, glomerular shrinkage, oxidative stress, apoptosis, telomere damage, aging, dysmetabolism in vivo and in vitro; and ER stress. The AMPK (AMP-activated protein kinase) pathway was central to metformin's protective action. Within COPDGene, participants receiving metformin compared with those not receiving it had a slower progression of emphysema (-0.92%; 95% confidence interval [CI], -1.7% to -0.14%; P = 0.02) and a slower adjusted lung density decrease (2.2 g/L; 95% CI, 0.43 to 4.0 g/L; P = 0.01). Conclusions: Metformin protected against CS-induced lung, renal, and muscle injury; mitochondrial dysfunction; and unfolded protein responses and ER stress in mice. In humans, metformin use was associated with lesser emphysema progression over time. Our results provide a rationale for clinical trials testing the efficacy of metformin in limiting emphysema progression and its systemic consequences.

Inhaled Medication Use in Smokers With Normal Spirometry.

BACKGROUND: The objective of our study was to identify variables associated with inhaled medication use in smokers with normal spirometry (GOLD-0) and to examine the association of inhaled medication use with development of exacerbations and obstructive spirometry in the future. METHODS: We performed a retrospective multivariable analysis of GOLD-0 subjects identified in data from the COPDGene study to examine factors associated with medication use. Five categories were identified: (1) no medications, (2) short-acting bronchodilator, (3) long-acting bronchodilator; long-acting muscarinic antagonists and/or long-acting ß agonist, (4) inhaled corticosteroids (ICS) with or without long-acting bronchodilator, and (5) dual bronchodilator with ICS. Sensitivity analysis was performed excluding subjects with history of asthma. We also evaluated whether long-acting inhaled medication use was associated with exacerbations and obstructive spirometry at the follow-up visit 5 y after enrollment. RESULTS: Of 4,303 GOLD-0 subjects within the analysis, 541 of them (12.6%) received inhaled medications. Of these, 259 (6%) were using long-acting inhaled medications and 282 (6.6%) were taking short-acting bronchodilator. Female sex (odds ratio [OR] 1.47, P = .003), numerous medical comorbidities, radiographic emphysema (OR 2.22, P = .02), chronic bronchitis (OR 1.77, P < .001), dyspnea (OR 2.24, P < .001), asthma history (OR 15.56, P < .001), prior exacerbation (OR 8.45, P < .001), and 6-min walk distance (OR 0.9, P < .001) were associated with medication use. Minimal changes were noted in a sensitivity analysis. Additionally, inhaled medications were associated with increased total (incidence rate ratio 2.83, P < .001) and severe respiratory exacerbations (incidence rate ratio 3.64, P < .001) and presence of obstructive spirometry (OR 2.83, P = .002) at follow-up. CONCLUSIONS: Respiratory symptoms, history of asthma, and radiographic emphysema were associated with inhaled medication use in smokers with normal spirometry. These individuals were more likely to develop obstructive spirometry, which suggests that health care providers may be able to identify obstructive lung disease prior to meeting the current criteria for COPD.

Respiratory exacerbations are associated with muscle loss in current and former smokers.

OBJECTIVES: Muscle wasting is a recognised extra-pulmonary complication in chronic obstructive pulmonary disease and has been associated with increased risk of death. Acute respiratory exacerbations are associated with reduction of muscle function, but there is a paucity of data on their long-term effect. This study explores the relationship between acute respiratory exacerbations and long-term muscle loss using serial measurements of CT derived pectoralis muscle area (PMA). DESIGN AND SETTING: Participants were included from two prospective, longitudinal, observational, multicentre cohorts of ever-smokers with at least 10 pack-year history. PARTICIPANTS: The primary analysis included 1332 (of 2501) participants from Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) and 4384 (of 10 198) participants from Genetic Epidemiology of COPD (COPDGene) who had complete data from their baseline and follow-up visits. INTERVENTIONS: PMA was measured on chest CT scans at two timepoints. Self-reported exacerbation data were collected from participants in both studies through the use of periodic longitudinal surveys. MAIN OUTCOME MEASURES: Age-related and excess muscle loss over time. RESULTS: Age, sex, race and body mass index were associated with baseline PMA. Participants experienced age-related decline at the upper end of reported normal ranges. In ECLIPSE, the exacerbation rate over time was associated with an excess muscle area loss of 1.3% (95% CI 0.6 to 1.9, p<0.001) over 3 years and in COPDGene with an excess muscle area loss of 2.1% (95% CI 1.2 to 2.8, p<0.001) over 5 years. Excess muscle area decline was absent in 273 individuals who participated in pulmonary rehabilitation. CONCLUSIONS: Exacerbations are associated with accelerated skeletal muscle loss. Each annual exacerbation was associated with the equivalent of 6 months of age-expected decline in muscle mass. Ameliorating exacerbation-associated muscle loss represents an important therapeutic target.

Facial Nerve Branching Patterns Vary With Vascular Anomalies.

OBJECTIVES: At our institution, in vivo facial nerve mapping (FNM) is used during vascular anomaly (VAN) surgeries involving the facial nerve (FN) to create an FN map and prevent injury. During mapping, FN anatomy seemed to vary with VAN type. This study aimed to characterize FN branching patterns compared to published FN anatomy and VAN type. STUDY DESIGN: Retrospective study of surgically relevant facial nerve anatomy. METHODS: VAN patients (n = 67) with FN mapping between 2005 and 2018 were identified. Results included VAN type, FN relationship to VAN, FNM image with branch pattern, and surgical approach. A Fisher exact test compared FN relationships and surgical approach between VAN pathology, and FN branching types to published anatomical studies. MATLAB quantified FN branching with Euclidean distances and angles. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) analyzed quantitative FN patterns amongst VAN types. RESULTS: VANs included were hemangioma, venous malformation, lymphatic malformation, and arteriovenous malformation (n = 17, 13, 25, and 3, respectively). VAN FN patterns differed from described FN anatomy (P < .001). PCA and HCA in MATLAB-quantified FN branching demonstrated no patterns associated with VAN pathology (P = .80 and P = .91, one-way analysis of variance for principle component 1 (PC1) and priniciple component 2 (PC2), respectively). FN branches were usually adherent to hemangioma or venous malformation as compared to coursing through lymphatic malformation (both P = .01, Fisher exact). CONCLUSIONS: FN branching patterns identified through electrical stimulation differ from cadaveric dissection determined FN anatomy. This reflects the high sensitivity of neurophysiologic testing in detecting small distal FN branches. Elongated FN branches traveling through lymphatic malformation may be related to abnormal nerve patterning in these malformations. LEVEL OF EVIDENCE: NA Laryngoscope, 130:2708-2713, 2020.

Extensive Soot Compaction by Cloud Processing from Laboratory and Field Observations.

Soot particles form during combustion of carbonaceous materials and impact climate and air quality. When freshly emitted, they are typically fractal-like aggregates. After atmospheric aging, they can act as cloud condensation nuclei, and water condensation or evaporation restructure them to more compact aggregates, affecting their optical, aerodynamic, and surface properties. Here we survey the morphology of ambient soot particles from various locations and different environmental and aging conditions. We used electron microscopy and show extensive soot compaction after cloud processing. We further performed laboratory experiments to simulate atmospheric cloud processing under controlled conditions. We find that soot particles sampled after evaporating the cloud droplets, are significantly more compact than freshly emitted and interstitial soot, confirming that cloud processing, not just exposure to high humidity, compacts soot. Our findings have implications for how the radiative, surface, and aerodynamic properties, and the fate of soot particles are represented in numerical models.

Common and Rare Variants Genetic Association Analysis of Cigarettes per Day Among Ever-Smokers in Chronic Obstructive Pulmonary Disease Cases and Controls.

INTRODUCTION: Cigarette smoking is a major environmental risk factor for many diseases, including chronic obstructive pulmonary disease (COPD). There are shared genetic influences on cigarette smoking and COPD. Genetic risk factors for cigarette smoking in cohorts enriched for COPD are largely unknown. METHODS: We performed genome-wide association analyses for average cigarettes per day (CPD) across the Genetic Epidemiology of COPD (COPDGene) non-Hispanic white (NHW) (n = 6659) and African American (AA) (n = 3260), GenKOLS (the Genetics of Chronic Obstructive Lung Disease) (n = 1671), and ECLIPSE (the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) (n = 1942) cohorts. In addition, we performed exome array association analyses across the COPDGene NHW and AA cohorts. We considered analyses across the entire cohort and stratified by COPD case-control status. RESULTS: We identified genome-wide significant associations for CPD on chromosome 15q25 across all cohorts (lowest p = 1.78 × 10-15), except in the COPDGene AA cohort alone. Previously reported associations on chromosome 19 had suggestive and directionally consistent associations (RAB4, p = 1.95 × 10-6; CYP2A7, p = 7.50 × 10-5; CYP2B6, p = 4.04 × 10-4). When we stratified by COPD case-control status, single nucleotide polymorphisms on chromosome 15q25 were nominally associated with both NHW COPD cases (ß = 0.11, p = 5.58 × 10-4) and controls (ß = 0.12, p = 3.86 × 10-5) For the gene-based exome array association analysis of rare variants, there were no exome-wide significant associations. For these previously replicated associations, the most significant results were among COPDGene NHW subjects for CYP2A7 (p = 5.2 × 10-4). CONCLUSIONS: In a large genome-wide association study of both common variants and a gene-based association of rare coding variants in ever-smokers, we found genome-wide significant associations on chromosome 15q25 with CPD for common variants, but not for rare coding variants. These results were directionally consistent among COPD cases and controls. IMPLICATIONS: We examined both common and rare coding variants associated with CPD in a large population of heavy smokers with and without COPD of NHW and AA descent. We replicated genome-wide significant associations on chromosome 15q25 with CPD for common variants among NHW subjects, but not for rare variants. We demonstrated for the first time that common variants on chromosome 15q25 associated with CPD are similar among COPD cases and controls. Previously reported associations on chromosome 19 showed suggestive and directionally consistent associations among common variants (RAB4, CYP2A7, and CYP2B6) and for rare variants (CYP2A7) among COPDGene NHW subjects. Although the genetic effect sizes for these single nucleotide polymorphisms on chromosome 15q25 are modest, we show that this creates a substantial smoking burden over the lifetime of a smoker.

Automated quantitative 3D analysis of aorta size, morphology, and mural calcification distributions.

PURPOSE: The purpose of this work is to develop a fully automated pipeline to compute aorta morphology and calcification measures in large cohorts of CT scans that can be used to investigate the potential of these measures as imaging biomarkers of cardiovascular disease. METHODS: The first step of the automated pipeline is aorta segmentation. The algorithm the authors propose first detects an initial aorta boundary by exploiting cross-sectional circularity of aorta in axial slices and aortic arch in reformatted oblique slices. This boundary is then refined by a 3D level-set segmentation that evolves the boundary to the location of nearby edges. The authors then detect the aortic calcifications with thresholding and filter out the false positive regions due to nearby high intensity structures based on their anatomical location. The authors extract the centerline and oblique cross sections of the segmented aortas and compute the aorta morphology and calcification measures of the first 2500 subjects from COPDGene study. These measures include volume and number of calcified plaques and measures of vessel morphology such as average cross-sectional area, tortuosity, and arch width. RESULTS: The authors computed the agreement between the algorithm and expert segmentations on 45 CT scans and obtained a closest point mean error of 0.62 ± 0.09 mm and a Dice coefficient of 0.92 ± 0.01. The calcification detection algorithm resulted in an improved true positive detection rate of 0.96 compared to previous work. The measurements of aorta size agreed with the measurements reported in previous work. The initial results showed associations of aorta morphology with calcification and with aging. These results may indicate aorta stiffening and unwrapping with calcification and aging. CONCLUSIONS: The authors have developed an objective tool to assess aorta morphology and aortic calcium plaques on CT scans that may be used to provide information about the presence of cardiovascular disease and its clinical impact in smokers.

Dexmedetomidine Does Not Affect Evoked Potentials During Spine Surgery.

BACKGROUND: The effect of dexmedetomidine on evoked potentials (EPs) has not been elucidated. We aimed to investigate the effect of dexmedetomidine on somatosensory, motor, and visual EPs. METHODS: After IRB approval, 40 adult patients scheduled for elective spine surgery using total IV anesthesia with propofol and remifentanil were randomly assigned to receive either dexmedetomidine (n = 20) or placebo (n = 20) in a double-blind, placebo-controlled trial. After obtaining informed consent, positioning, and baseline EPs recording, patients were randomly assigned to either IV dexmedetomidine 0.6 µg/kg infused over 10 minutes, followed by 0.6 µg/kg/h, or a corresponding volume of IV normal saline (placebo). EP measures at 60 ± 30 minutes after initiation of study drug were defined as T1 and at 150 ± 30 minutes were defined as T2. Changes from baseline to T1 (primary end point) and from baseline to T2 (secondary end point) in EP latencies (milliseconds) and amplitudes (microvolts) were compared between groups. Data presented as mean ± SD (95% confidence interval). RESULTS: Data from 40 patients (dexmedetomidine: n = 20; age, 54 ± 3 years; 10 males; placebo: n = 20; age, 52 ± 2 years; 5 males) were analyzed. There was no difference between dexmedetomidine versus placebo groups in primary end points: change of somatosensory EPs at T1, latency: 0.01 ± 1.3 (-0.64, 0.65) vs 0.01 ± 1.3 (-0.64, 0.65), P = 0.43 (-1.24, 0.45); amplitude: 0.03 ± 0.14 (-0.06, 0.02) vs -0.01 ± 0.13 (-0.07, 0.05), P = 0.76 (-0.074, 0.1); motor EPs amplitude at T1: 65.1 ± 194.8 (-35, 165; n = 18) vs 109.2 ± 241.4 (-24, 243; n = 16), P = 0.57 (-113.5, 241.57); visual EPs at T1 (right eye), amplitude: 2.3 ± 3.6 (-0.4, 5.1; n = 11) vs 0.3 ± 6.0 (-3.3, 3.9; n = 16), P = 0.38 (-6.7, 2.6); latency N1: 2.3 ± 3.6 (-0.4, 5.1) vs 0.3 ± 6.0 (-3.3, 3.9), P = 0.38 (-6.7, 2.6); latency P1: -1.6 ± 13.4 (-11.9, 8.7) vs -1.4 ± 8.1 (-6.3, 3.5), P = 0.97 (-9.3, 9.7) or secondary end points. There were no differences between right and left visual EPs either at T1 or at T2. CONCLUSIONS: In clinically relevant doses, dexmedetomidine as an adjunct to total IV anesthesia does not seem to alter EPs and therefore can be safely used during surgeries requiring monitoring of EPs.

Quantitative computed tomography measures of pectoralis muscle area and disease severity in chronic obstructive pulmonary disease. A cross-sectional study.

RATIONALE: Muscle wasting in chronic obstructive pulmonary disease (COPD) is associated with a poor prognosis and is not readily assessed by measures of body mass index (BMI). BMI does not discriminate between relative proportions of adipose tissue and lean muscle and may be insensitive to early pathologic changes in body composition. Computed tomography (CT)-based assessments of the pectoralis muscles may provide insight into the clinical significance of skeletal muscles in smokers. OBJECTIVES: We hypothesized that objective assessment of the pectoralis muscle area on chest CT scans provides information that is clinically relevant and independent of BMI. METHODS: Data from the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) Study (n = 73) were used to assess the relationship between pectoralis muscle area and fat-free mass. We then used data in a subset (n = 966) of a larger cohort, the COPDGene (COPD Genetic Epidemiology) Study, to explore the relationship between pectoralis muscle area and COPD-related traits. MEASUREMENTS AND MAIN RESULTS: We first investigated the correlation between pectoralis muscle area and fat-free mass, using data from a subset of participants in the ECLIPSE Study. We then further investigated pectoralis muscle area in COPDGene Study participants and found that higher pectoralis muscle area values were associated with greater height, male sex, and younger age. On subsequent clinical correlation, compared with BMI, pectoralis muscle area was more significantly associated with COPD-related traits, including spirometric measures, dyspnea, and 6-minute-walk distance (6MWD). For example, on average, each 10-cm(2) increase in pectoralis muscle area was associated with a 0.8-unit decrease in the BODE (Body mass index, Obstruction, Dyspnea, Exercise) index (95% confidence interval, -1.0 to -0.6; P < 0.001). Furthermore, statistically significant associations between pectoralis muscle area and COPD-related traits remained even after adjustment for BMI. CONCLUSIONS: CT-derived pectoralis muscle area provides relevant indices of COPD morbidity that may be more predictive of important COPD-related traits than BMI. However, the relationship with clinically relevant outcomes such as hospitalization and death requires additional investigation. Pectoralis muscle area is a convenient measure that can be collected in the clinical setting in addition to BMI.

Cluster analysis in the COPDGene study identifies subtypes of smokers with distinct patterns of airway disease and emphysema.

BACKGROUND: There is notable heterogeneity in the clinical presentation of patients with COPD. To characterise this heterogeneity, we sought to identify subgroups of smokers by applying cluster analysis to data from the COPDGene study. METHODS: We applied a clustering method, k-means, to data from 10 192 smokers in the COPDGene study. After splitting the sample into a training and validation set, we evaluated three sets of input features across a range of k (user-specified number of clusters). Stable solutions were tested for association with four COPD-related measures and five genetic variants previously associated with COPD at genome-wide significance. The results were confirmed in the validation set. FINDINGS: We identified four clusters that can be characterised as (1) relatively resistant smokers (ie, no/mild obstruction and minimal emphysema despite heavy smoking), (2) mild upper zone emphysema-predominant, (3) airway disease-predominant and (4) severe emphysema. All clusters are strongly associated with COPD-related clinical characteristics, including exacerbations and dyspnoea (p<0.001). We found strong genetic associations between the mild upper zone emphysema group and rs1980057 near HHIP, and between the severe emphysema group and rs8034191 in the chromosome 15q region (p<0.001). All significant associations were replicated at p<0.05 in the validation sample (12/12 associations with clinical measures and 2/2 genetic associations). INTERPRETATION: Cluster analysis identifies four subgroups of smokers that show robust associations with clinical characteristics of COPD and known COPD-associated genetic variants.

Facial nerve mapping and monitoring in lymphatic malformation surgery.

OBJECTIVE: Establish the efficacy of preoperative facial nerve mapping and continuous intraoperative EMG monitoring in protecting the facial nerve during resection of cervicofacial lymphatic malformations. METHODS: Retrospective study in which patients were clinically followed for at least 6 months postoperatively, and long-term outcome was evaluated. Patient demographics, lesion characteristics (i.e., size, stage, location) were recorded. Operative notes revealed surgical techniques, findings, and complications. Preoperative, short-/long-term postoperative facial nerve function was standardized using the House-Brackmann Classification. Mapping was done prior to incision by percutaneously stimulating the facial nerve and its branches and recording the motor responses. Intraoperative monitoring and mapping were accomplished using a four-channel, free-running EMG. Neurophysiologists continuously monitored EMG responses and blindly analyzed intraoperative findings and final EMG interpretations for abnormalities. RESULTS: Seven patients collectively underwent 8 lymphatic malformation surgeries. Median age was 30 months (2-105 months). Lymphatic malformation diagnosis was recorded in 6/8 surgeries. Facial nerve function was House-Brackmann grade I in 8/8 cases preoperatively. Facial nerve was abnormally elongated in 1/8 cases. EMG monitoring recorded abnormal activity in 4/8 cases--two suggesting facial nerve irritation, and two with possible facial nerve damage. Transient or long-term facial nerve paresis occurred in 1/8 cases (House-Brackmann grade II). CONCLUSIONS: Preoperative facial nerve mapping combined with continuous intraoperative EMG and mapping is a successful method of identifying the facial nerve course and protecting it from injury during resection of cervicofacial lymphatic malformations involving the facial nerve.

Lifestyle risk factors for atherosclerosis in adults with type 1 diabetes.

The objective of this study was to compare the amount of self-reported physical activity, alcohol and tobacco use in a large sample of adults with type 1 diabetes and non-diabetic subjects. A second aim is to test the hypothesis that these lifestyle risk factors are associated cross-sectionally with coronary artery calcification. In 2000-2002, the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study applied validated questionnaires for smoking, alcohol and physical activity to 582 type 1 diabetes subjects and 724 non-diabetic subjects. More type 1 diabetes subjects reported current smoking than non-diabetic subjects (12.3% versus 8.6%, p=0.027). Overall, reported physical activity did not differ by diabetes status (p=0.79). More type 1 diabetes subjects reported never having consumed alcohol (10% versus 4%, p<0.0001) and those who drank consumed less alcohol (p=0.0015) than non-diabetic subjects. Physical activity and smoking were significantly associated with the presence of coronary artery calcification (adjusted OR=0.9, 95% CI: 0.8-0.996, p=0.045, and OR=1.7, CI: 1.1-2.6, p=0.03, respectively). Type 1 diabetes was independently associated with increased odds of coronary artery calcification (OR=3.5, 95% CI: 2.5-5.0, p<0.0001). Differences exist in lifestyle-related cardiovascular risk factors in men and women with type 1 diabetes compared with non-diabetic subjects in the CACTI study.