A Single-Cell Atlas of Small Airway Disease in Chronic Obstructive Pulmonary Disease: A Cross-Sectional Study.

Rationale: Emerging data demonstrate that the smallest conducting airways, terminal bronchioles, are the early site of tissue destruction in chronic obstructive pulmonary disease (COPD) and are reduced by as much as 41% by the time someone is diagnosed with mild (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 1) COPD. Objectives: To develop a single-cell atlas that describes the structural, cellular, and extracellular matrix alterations underlying terminal bronchiole loss in COPD. Methods: This cross-sectional study of 262 lung samples derived from 34 ex-smokers with normal lung function (n = 10) or GOLD stage 1 (n = 10), stage 2 (n = 8), or stage 4 (n = 6) COPD was performed to assess the morphology, extracellular matrix, single-cell atlas, and genes associated with terminal bronchiole reduction using stereology, micro-computed tomography, nonlinear optical microscopy, imaging mass spectrometry, and transcriptomics. Measurements and Main Results: The lumen area of terminal bronchioles progressively narrows with COPD severity as a result of the loss of elastin fibers within alveolar attachments, which was observed before microscopic emphysematous tissue destruction in GOLD stage 1 and 2 COPD. The single-cell atlas of terminal bronchioles in COPD demonstrated M1-like macrophages and neutrophils located within alveolar attachments and associated with the pathobiology of elastin fiber loss, whereas adaptive immune cells (naive, CD4, and CD8 T cells, and B cells) are associated with terminal bronchiole wall remodeling. Terminal bronchiole pathology was associated with the upregulation of genes involved in innate and adaptive immune responses, the interferon response, and the degranulation of neutrophils. Conclusions: This comprehensive single-cell atlas highlights terminal bronchiole alveolar attachments as the initial site of tissue destruction in centrilobular emphysema and an attractive target for disease modification.

This Is Your Brain on Autopilot 2.0: The Influence of Practice on Driver Workload and Engagement During On-Road, Partially Automated Driving.

OBJECTIVE: This on-road study employed behavioral and neurophysiological measurement techniques to assess the influence of six weeks of practice driving a Level 2 partially automated vehicle on driver workload and engagement. BACKGROUND: Level 2 partial automation requires a driver to maintain supervisory control of the vehicle to detect "edge cases" that the automation is not equipped to handle. There is mixed evidence regarding whether drivers can do so effectively. There is also an open question regarding how practice and familiarity with automation influence driver cognitive states over time. METHOD: Behavioral and neurophysiological measures of driver workload and visual engagement were recorded from 30 participants at two testing sessions-with a six-week familiarization period in-between. At both testing sessions, participants drove a vehicle with partial automation engaged (Level 2) and not engaged (Level 0) on two interstate highways while reaction times to the detection response task (DRT) and neurophysiological (EEG) metrics of frontal theta and parietal alpha were recorded. RESULTS: DRT results demonstrated that partially automated driving placed more cognitive load on drivers than manual driving and six weeks of practice decreased driver workload-though only when the driving environment was relatively simple. EEG metrics of frontal theta and parietal alpha showed null effects of partial automation. CONCLUSION: Driver workload was influenced by level of automation, specific highway characteristics, and by practice over time, but only on a behavioral level and not on a neural level. APPLICATION: These findings expand our understanding of the influence of practice on driver cognitive states under Level 2 partial automation.

This Is Your Brain on Autopilot: Neural Indices of Driver Workload and Engagement During Partial Vehicle Automation.

OBJECTIVE: This research explores the effect of partial vehicle automation on neural indices of mental workload and visual engagement during on-road driving. BACKGROUND: There is concern that the introduction of automated technology in vehicles may lead to low driver stimulation and subsequent disengagement from the driving environment. Simulator-based studies have examined the effect of automation on a driver's cognitive state, but it is unknown how the conclusions translate to on-road driving. Electroencephalographic (EEG) measures of frontal theta and parietal alpha can provide insight into a driver's mental workload and visual engagement while driving under various conditions. METHOD: EEG was recorded from 71 participants while driving on the roadway. We examined two age cohorts, on two different highway configurations, in four different vehicles, with partial vehicle automation both engaged and disengaged. RESULTS: Analysis of frontal theta and parietal alpha power revealed that there was no change in mental workload or visual engagement when driving manually compared with driving under partial vehicle automation. CONCLUSION: Drivers new to the technology remained engaged with the driving environment when operating under partial vehicle automation. These findings suggest that the concern surrounding driver disengagement under vehicle automation may need to be tempered, at least for drivers new to the experience. APPLICATION: These findings expand our understanding of the effects of partial vehicle automation on drivers' cognitive states.

The molecular and cellular mechanisms associated with the destruction of terminal bronchioles in COPD.

RATIONALE: Peripheral airway obstruction is a key feature of chronic obstructive pulmonary disease (COPD), but the mechanisms of airway loss are unknown. This study aims to identify the molecular and cellular mechanisms associated with peripheral airway obstruction in COPD. METHODS: Ten explanted lung specimens donated by patients with very severe COPD treated by lung transplantation and five unused donor control lungs were sampled using systematic uniform random sampling (SURS), resulting in 240 samples. These samples were further examined by micro-computed tomography (CT), quantitative histology and gene expression profiling. RESULTS: Micro-CT analysis showed that the loss of terminal bronchioles in COPD occurs in regions of microscopic emphysematous destruction with an average airspace size of ≥500 and <1000 µm, which we have termed a "hot spot". Based on microarray gene expression profiling, the hot spot was associated with an 11-gene signature, with upregulation of pro-inflammatory genes and downregulation of inhibitory immune checkpoint genes, indicating immune response activation. Results from both quantitative histology and the bioinformatics computational tool CIBERSORT, which predicts the percentage of immune cells in tissues from transcriptomic data, showed that the hot spot regions were associated with increased infiltration of CD4 and CD8 T-cell and B-cell lymphocytes. INTERPRETATION: The reduction in terminal bronchioles observed in lungs from patients with COPD occurs in a hot spot of microscopic emphysema, where there is upregulation of IFNG signalling, co-stimulatory immune checkpoint genes and genes related to the inflammasome pathway, and increased infiltration of immune cells. These could be potential targets for therapeutic interventions in COPD.

Small Airway Reduction and Fibrosis Is an Early Pathologic Feature of Idiopathic Pulmonary Fibrosis.

Rationale: To improve disease outcomes in idiopathic pulmonary fibrosis (IPF), it is essential to understand its early pathophysiology so that it can be targeted therapeutically. Objectives: Perform three-dimensional assessment of the IPF lung microstructure using stereology and multiresolution computed tomography (CT) imaging. Methods: Explanted lungs from patients with IPF (n = 8) and donor control subjects (n = 8) were inflated with air and frozen. CT scans were used to assess large airways. Unbiased, systematic uniform random samples (n = 8/lung) were scanned with microCT for stereological assessment of small airways (count number, and measure airway wall and lumen area) and parenchymal fibrosis (volume fraction of tissue, alveolar surface area, and septal wall thickness). Measurements and Main Results: The total number of airways on clinical CT was greater in IPF lungs than control lungs (P < 0.01), owing to an increase in the wall (P < 0.05) and lumen area (P < 0.05) resulting in more visible airways with a lumen larger than 2 mm. In IPF tissue samples without microscopic fibrosis, assessed by the volume fraction of tissue using microCT, there was a reduction in the number of the terminal (P < 0.01) and transitional (P < 0.001) bronchioles, and an increase in terminal bronchiole wall area (P < 0.001) compared with control lungs. In IPF tissue samples with microscopic parenchymal fibrosis, terminal bronchioles had increased airway wall thickness (P < 0.05) and dilated airway lumens (P < 0.001) leading to honeycomb cyst formations. Conclusions: This study has important implications for the current thinking on how the lung tissue is remodeled in IPF and highlights small airways as a potential target to modify IPF outcomes.

Physicians' and Attorneys' Beliefs and Attitudes Related to the Brain Disease Model of Addiction.

BACKGROUND AND OBJECTIVES: Addiction is increasingly considered a chronic, relapsing brain disease; however, many scholars still disagree with the brain disease model of addiction. We set out to provide evidence of attorneys' and physicians' beliefs regarding the model. First, we asked the following question: do attorneys and physicians affirm the full brain disease model, or its modified form, or do they believe that addiction is driven by deficits in self-control or moral weakness? Second, we evaluated the extent to which such beliefs correspond to attitudes toward individuals with substance use disorders (SUDs). METHODS: A questionnaire was sent to resident physicians (N = 301) and criminal defense attorneys (N = 483) practicing in the United States. It was comprised of (i) an attitudes measure, (ii) a measure regarding conceptions of addiction, and (iii) demographic questions. RESULTS: Attorneys were more likely to believe that individuals with SUDs had "practically no choice" about whether to seek and use, whereas physicians were more likely to believe that such individuals had "genuine choice." For both groups of participants, the rejection of the full brain disease model of addiction was associated with more negative attitudes toward individuals with SUDs. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: These results represent an important advance, as past research has neglected attorneys' attitudes and is inconclusive regarding the manner in which beliefs about the brain disease model of addiction are related to attitudes toward individuals with SUDs. Educating practitioners regarding this relationship would raise awareness regarding when and to what extent stigma is likely to be present, which may in turn provide a foundation from which to address stigma. (Am J Addict 2020;00:00-00).

Visual and Cognitive Demands of CarPlay, Android Auto, and Five Native Infotainment Systems.

OBJECTIVE: The present research compared and contrasted the workload associated with using in-vehicle information systems commonly available in five different automotive original equipment manufacturers (OEMs) with that of CarPlay and Android Auto when used in the same vehicles. BACKGROUND: A growing trend is to provide access to portable smartphone-based systems (e.g., CarPlay and Android Auto) that support an expansion of various in-vehicle infotainment system features and functions. METHOD/RESULTS: The study involved on-road testing of 24 participants in each configuration of five vehicles crossed with the three different infotainment systems: the embedded portion of the native OEM systems, CarPlay, and Android Auto. Our analysis found that workload was significantly greater for the embedded portion of the native OEM systems than for CarPlay and Android Auto. The strengths and weaknesses of each CarPlay and Android Auto traded off in such a way that the overall demand associated with using the two systems did not differ. CONCLUSION: CarPlay and Android Auto provided more functionality and resulted in lower levels of workload than the embedded portion of the native OEM infotainment systems. APPLICATION: Potential applications of this research include refinements to CarPlay and Android Auto to address variations in workload as a function of task type, the modality of interaction, and OEM implementation of the system.

Attitudes toward defendants with substance-related charges: An analysis of a national sample of criminal defense attorneys.

BACKGROUND AND OBJECTIVES: While a large percentage of criminal offenders suffer from substance use disorders (SUDs), virtually nothing is known about the attitudes criminal defense attorneys possess toward their clients who are facing substance-related charges. This is a serious concern, as the burden of steering individuals with SUDs into treatment often falls to criminal defense attorneys. The goal of this study was to examine the attitudes of criminal defense attorneys toward individuals who have been accused of drug crimes. METHODS: A questionnaire was sent to criminal defense attorneys (N = 1,933) from all 50 U.S. states and the District of Columbia. It was comprised of (i) demographic information and (ii) a version of the 11-item Medical Condition Regard Scale (MCRS). RESULTS: Criminal defense attorneys held generally positive attitudes toward clients with substance-related charges, but there was a significant divergence in attitudes between private and public attorneys, with the latter showing both greater familiarity with and better attitudes toward this same group of clients. These differences were impactful: worse attitudes toward clients strongly correlated with greater predictions that the clients would reoffend. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: Given the magnitude of the incarcerated population with SUDs and the centrality of defense attorneys in the treatment process, especially its initiation, the divergence in attitudes between private and public criminal defense attorneys is concerning. There is a clear need for increased collaboration between physicians and attorneys, with an aim of increasing the number of individuals with SUDs receiving proper treatment (Am J Addict 2018;XX:1-7).

Micro-Computed Tomography Comparison of Preterminal Bronchioles in Centrilobular and Panlobular Emphysema.

RATIONALE: Very little is known about airways that are too small to be visible on thoracic multidetector computed tomography but larger than the terminal bronchioles. OBJECTIVES: To examine the structure of preterminal bronchioles located one generation proximal to terminal bronchioles in centrilobular and panlobular emphysema. METHODS: Preterminal bronchioles were identified by backtracking from the terminal bronchioles, and their centerlines were established along the entire length of their lumens. Multiple cross-sectional images perpendicular to the centerline were reconstructed to evaluate the bronchiolar wall and lumen, and the alveolar attachments to the outer airway walls in relation to emphysematous destruction in 28 lung samples from six patients with centrilobular emphysema, 20 lung samples from seven patients with panlobular emphysema associated with alpha-1 antitrypsin deficiency, and 47 samples from seven control (donor) lungs. MEASUREMENTS AND MAIN RESULTS: The preterminal bronchiolar length, wall volume, total volume (wall + lumen), lumen circularity, and number of alveolar attachments were reduced in both centrilobular and panlobular emphysema compared with control lungs. In contrast, thickening of the wall and narrowing of the lumen were more severe and heterogeneous in centrilobular than in panlobular emphysema. The bronchiolar lumen was narrower in the middle than at both ends, and the decreased number of alveolar attachments was associated with increased wall thickness in centrilobular emphysema. CONCLUSIONS: These results provide new information about small airways pathology in centrilobular and panlobular emphysema and show that these changes affect airways that are not visible with thoracic multidetector computed tomography scans but located proximal to the terminal bronchioles in chronic obstructive pulmonary disease.

Morphometric Analysis of Explant Lungs in Cystic Fibrosis.

RATIONALE: After repeated cycles of lung infection and inflammation, patients with cystic fibrosis (CF) evolve to respiratory insufficiency. Although histology and imaging have provided descriptive information, a thorough morphometric analysis of end-stage CF lung disease is lacking. OBJECTIVES: To quantify the involvement of small and large airways in end-stage CF. METHODS: Multidetector computed tomography (MDCT) and micro-CT were applied to 11 air-inflated CF explanted lungs and 7 control lungs to measure, count, and describe the airway and parenchymal abnormalities in end-stage CF lungs. Selected abnormalities were further investigated with thin section histology. MEASUREMENTS AND MAIN RESULTS: On MDCT, CF explanted lungs showed an increased median (interquartile range) number (631 [511-710] vs. 344 [277-349]; P = 0.003) and size of visible airways (cumulative airway diameter 217 cm [209-250] vs. 91 cm [80-105]; P < 0.001) compared with controls. Airway obstruction was seen, starting from generation 6 and increasing to 40 to 50% of airways from generation 9 onward. Micro-CT showed that the total number of terminal bronchioles was decreased (2.9/ml [2.6-4.4] vs. 5.3/ml [4.8-5.7]; P < 0.001); 49% were obstructed, and the cross-sectional area of the open terminal bronchioles was reduced (0.093 mm(2) [0.084-0.123] vs. 0.179 mm(2) [0.140-0.196]; P < 0.001). On micro-CT, 41% of the obstructed airways reopened more distally. This remodeling was confirmed on histological analysis. Parenchymal changes were also seen, mostly in a patchy and peribronchiolar distribution. CONCLUSIONS: Extensive changes of dilatation and obstruction in nearly all airway generations were observed in end-stage CF lung disease.

Host Response to the Lung Microbiome in Chronic Obstructive Pulmonary Disease.

RATIONALE: The relatively sparse but diverse microbiome in human lungs may become less diverse in chronic obstructive pulmonary disease (COPD). This article examines the relationship of this microbiome to emphysematous tissue destruction, number of terminal bronchioles, infiltrating inflammatory cells, and host gene expression. METHODS: Culture-independent pyrosequencing microbiome analysis was used to examine the V3-V5 regions of bacterial 16S ribosomal DNA in 40 samples of lung from 5 patients with COPD (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 4) and 28 samples from 4 donors (controls). A second protocol based on the V1-V3 regions was used to verify the bacterial microbiome results. Within lung tissue samples the microbiome was compared with results of micro-computed tomography, infiltrating inflammatory cells measured by quantitative histology, and host gene expression. MEASUREMENTS AND MAIN RESULTS: Ten operational taxonomic units (OTUs) was found sufficient to discriminate between control and GOLD stage 4 lung tissue, which included known pathogens such as Haemophilus influenzae. We also observed a decline in microbial diversity that was associated with emphysematous destruction, remodeling of the bronchiolar and alveolar tissue, and the infiltration of the tissue by CD4(+) T cells. Specific OTUs were also associated with neutrophils, eosinophils, and B-cell infiltration (P < 0.05). The expression profiles of 859 genes and 235 genes were associated with either enrichment or reductions of Firmicutes and Proteobacteria, respectively, at a false discovery rate cutoff of less than 0.1. CONCLUSIONS: These results support the hypothesis that there is a host immune response to microorganisms within the lung microbiome that appears to contribute to the pathogenesis of COPD.

Linking clinical phenotypes of chronic lung allograft dysfunction to changes in lung structure.

Chronic lung allograft dysfunction (CLAD) remains the major barrier to long-term success after lung transplantation. This report compares gross and microscopic features of lungs removed from patients receiving a redo-transplant as treatment for CLAD. Lungs donated by patients with either the bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS) phenotype of CLAD and appropriate control lungs (eight per group) were air-inflated, frozen solid and kept frozen while a multi-detector computed tomography (MDCT) was obtained. The lung was then cut into 2-cm thick transverse slices and sampled for micro-CT and histopathology. The MDCT showed reduced lung volume with increased lung weight and density in RAS versus BOS and control (p<0.05). Although pre-terminal bronchioles were obstructed in both phenotypes, RAS lungs showed a reduction of pre-terminal bronchioles (p<0.01). Micro-CT and matched histopathology showed that RAS was associated with reduced numbers of terminal bronchioles/lung compared to BOS and controls (p<0.01), with expansion of the interstitial compartment and obliteration of the alveolar airspaces by fibrous connective tissue. RAS is associated with greater destruction of both pre-terminal and terminal bronchioles. Additionally, the interstitial compartments are expanded and alveolar airspaces are obliterated by accumulation of fibrous connective tissue.

Similar failure and patency rates when comparing one- and two-stage basilic vein transposition.

OBJECTIVE: Basilic vein transposition is recommended in patients who are not candidates for a radial or brachial artery to cephalic vein fistula for dialysis access. Both one-stage and two-stage procedures have their advantages and disadvantages. Which procedure results in improved outcomes remains unclear. METHODS: A systematic review was conducted of the MEDLINE and EMBASE databases for studies that compared one-stage and two-stage brachial-basilic vein transpositions. Abstracts and full-text studies were screened independently by two reviewers with data abstraction done in duplicate. Random-effects meta-analysis was used to identify differences in primary failure rates and 1-year primary and secondary patency rates. Study quality was assessed by a previously described tool designed for observational studies reporting on dialysis access outcomes. RESULTS: Of 1662 abstracts screened, 97 were selected for full-text review. Of these, eight studies (one randomized trial, seven observational studies) involving 882 patients met the inclusion criteria. The pooled odds ratio estimate for primary failure was 1.21 (95% confidence interval [CI], 0.73-1.98; P = .46), suggesting no difference in failure rate between one-stage and two-stage transpositions. Similarly, the estimated odds ratio for 1-year primary patency rate of 1.39 (95% CI, 0.71-2.72; P = .33) and 1-year secondary patency rate of 1.02 (95% CI, 0.36-2.87; P = .98) indicated no difference between the two groups. Study quality was limited by unclear outcome definitions, minimal control for confounding, and variable selection criteria. The decision to pursue a one-stage vs a two-stage procedure was often based on size of the basilic vein, with a two-stage procedure reserved for patients with smaller veins. CONCLUSIONS: Meta-analysis of the existing literature comparing one-stage and two-stage basilic vein transposition suggests no difference in failure and patency rates, despite the two-stage procedure's being used in patients with smaller basilic veins. These findings are limited by the small size, observational design, and inconsistent quality of included studies. Reserving a two-stage procedure for patients with smaller basilic veins appears justified, although the strength of the evidence is limited.

The site and nature of airway obstruction after lung transplantation.

RATIONALE: The chronic rejection of lung allografts is attributable to progressive small airway obstruction. OBJECTIVES: To determine precisely the site and nature of this type of airway obstruction. METHODS: Lungs from patients with rejected lung allografts treated by a second transplant (n = 7) were compared with unused donor (control) lungs (n = 7) using multidetector computed tomography (MDCT) to determine the percentage of visible airways obstructed in each airway generation, micro-computed tomography (microCT) to visualize the site of obstruction, and histology to determine the nature of this obstruction. MEASUREMENTS AND MAIN RESULTS: The number of airways visible with MDCT was not different between rejected and control lungs. However, 10 ± 7% of observed airways greater than 2 mm in diameter, 50 ± 22% of airways between 1 and 2 mm in diameter, and 73 ± 10% of airways less than 1 mm in diameter were obstructed in the rejected lungs. MicroCT confirmed that the mean lumen diameter of obstructed airways was 647 ± 317 µm but showed no difference in either total number and cross-sectional area of the terminal bronchioles or in alveolar dimensions (mean linear intercept) between groups (P > 0.05). In addition, microCT demonstrated that only segments of the airways are obstructed. Histology confirmed a constrictive form of bronchiolitis caused by expansion of microvascular-rich granulation tissue in some locations and collagen-rich scar tissue in others. CONCLUSIONS: Chronic lung allograft rejection is associated with a progressive form of constrictive bronchiolitis that targets conducting airways while sparing larger airways as well as terminal bronchioles and the alveolar surface.

Canadian vascular surgery residents' perceptions regarding future job opportunities.

The objective was to determine the employment environment for graduates of Canadian vascular surgery training programs. A cross-sectional survey of residents and graduates (2011-2012) was used. Thirty-seven residents were invited with a response rate of 57%, and 14 graduates with a response rate of 71%; 70% of graduates felt the job market played an important role in their decision to pursue vascular surgery as a career compared to 43% of trainees. The top three concerns were the lack of surgeons retiring, the overproduction of trainees, and saturation of the job market. The majority (62%) of trainees see themselves extending their training due to lack of employment. All of the graduates obtained employment, with 50% during their second year (of two years) of training and 30% after training was completed. Graduates spent an average of 12 ± 10.6 months seeking a position and applied to 3.3 ± 1.5 positions, with a mean of 1.9 ± 1.3 interviews and 2 ± 1.2 offers. There was a discrepancy between the favorable employment climate experienced by graduates and the pessimistic outlook of trainees. We must be progressive in balancing the employment opportunities with the number of graduates. Number and timing of job offers is a possible future metric of the optimal number of residents.

Driven to Distraction.

We address several themes that emerged in the commentaries related to our target article. First, we consider the relationship between cognitive distraction and crash risk. Second, we discuss the development of our cognitive distraction scale. Third, we weigh issues of self-regulation, appropriate baselines, and satisficing. Finally, we identify several areas where additional research is needed to refine our understanding of driver distraction and crash risk.

Assessing Cognitive Distraction in the Automobile.

OBJECTIVE: The objective was to establish a systematic framework for measuring and understanding cognitive distraction in the automobile. BACKGROUND: Driver distraction from secondary in-vehicle activities is increasingly recognized as a significant source of injuries and fatalities on the roadway. METHOD: Across three studies, participants completed eight in-vehicle tasks commonly performed by the driver of an automobile. Primary, secondary, subjective, and physiological measures were collected and integrated into a cognitive distraction scale. RESULTS: In-vehicle activities, such as listening to the radio or an audio book, were associated with a low level of cognitive workload; the conversation activities of talking to a passenger in the vehicle or conversing with a friend on a handheld or hands-free cell phone were associated with a moderate level of cognitive workload; and using a speech-to-text interfaced e-mail system involved a high level of cognitive workload. CONCLUSION: The research established that there are significant impairments to driving that stem from the diversion of attention from the task of operating a motor vehicle and that the impairments to driving are directly related to the cognitive workload of these in-vehicle activities. Moreover, the adoption of voice-based systems in the vehicle may have unintended consequences that adversely affect traffic safety. APPLICATION: These findings can be used to help inform scientifically based policies on driver distraction, particularly as they relate to cognitive distraction stemming from the diversion of attention to other concurrent activities in the vehicle.

Small-airway obstruction and emphysema in chronic obstructive pulmonary disease.

BACKGROUND: The major sites of obstruction in chronic obstructive pulmonary disease (COPD) are small airways (<2 mm in diameter). We wanted to determine whether there was a relationship between small-airway obstruction and emphysematous destruction in COPD. METHODS: We used multidetector computed tomography (CT) to compare the number of airways measuring 2.0 to 2.5 mm in 78 patients who had various stages of COPD, as judged by scoring on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) scale, in isolated lungs removed from patients with COPD who underwent lung transplantation, and in donor (control) lungs. MicroCT was used to measure the extent of emphysema (mean linear intercept), the number of terminal bronchioles per milliliter of lung volume, and the minimum diameters and cross-sectional areas of terminal bronchioles. RESULTS: On multidetector CT, in samples from patients with COPD, as compared with control samples, the number of airways measuring 2.0 to 2.5 mm in diameter was reduced in patients with GOLD stage 1 disease (P=0.001), GOLD stage 2 disease (P=0.02), and GOLD stage 3 or 4 disease (P<0.001). MicroCT of isolated samples of lungs removed from patients with GOLD stage 4 disease showed a reduction of 81 to 99.7% in the total cross-sectional area of terminal bronchioles and a reduction of 72 to 89% in the number of terminal bronchioles (P<0.001). A comparison of the number of terminal bronchioles and dimensions at different levels of emphysematous destruction (i.e., an increasing value for the mean linear intercept) showed that the narrowing and loss of terminal bronchioles preceded emphysematous destruction in COPD (P<0.001). CONCLUSIONS: These results show that narrowing and disappearance of small conducting airways before the onset of emphysematous destruction can explain the increased peripheral airway resistance reported in COPD. (Funded by the National Heart, Lung, and Blood Institute and others.).