Circulating biomarkers of airflow limitation across the life span.

BACKGROUND: Airflow limitation is a hallmark of chronic obstructive pulmonary disease, which can develop through different lung function trajectories across the life span. There is a need for longitudinal studies aimed at identifying circulating biomarkers of airflow limitation across different stages of life. OBJECTIVES: This study sought to identify a signature of serum proteins associated with airflow limitation and evaluate their relation to lung function longitudinally in adults and children. METHODS: This study used data from 3 adult cohorts (TESAOD [Tucson Epidemiological Study of Airway Obstructive Disease], SAPALDIA [Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults], LSC [Lovelace Smoker Cohort]) and 1 birth cohort (TCRS [Tucson Children's Respiratory Study]) (N = 1940). In TESAOD, among 46 circulating proteins, we identified those associated with FEV1/forced vital capacity (FVC) percent (%) predicted levels and generated a score based on the sum of their z-scores. Cross-sectional analyses were used to test the score for association with concomitant lung function. Longitudinal analyses were used to test the score for association with subsequent lung function growth in childhood and decline in adult life. RESULTS: After false discovery rate adjustment, serum levels of 5 proteins (HP, carcinoembryonic antigen, ICAM1, CRP, TIMP1) were associated with percent predicted levels of FEV1/FVC and FEV1 in TESAOD. In cross-sectional multivariate analyses the 5-biomarker score was associated with FEV1 % predicted in all adult cohorts (meta-analyzed FEV1 decrease for 1-SD score increase: -2.9%; 95% CI: -3.9%, -1.9%; P = 2.4 × 10-16). In multivariate longitudinal analyses, the biomarker score at 6 years of age was inversely associated with FEV1 and FEV1/FVC levels attained by young adult life (P = .02 and .005, respectively). In adults, persistently high levels of the biomarker score were associated with subsequent accelerated decline of FEV1 and FEV1/FVC (P = .01 and .001). CONCLUSIONS: A signature of 5 circulating biomarkers of airflow limitation was associated with both impaired lung function growth in childhood and accelerated lung function decline in adult life, indicating that these proteins may be involved in multiple lung function trajectories leading to chronic obstructive pulmonary disease.

Integrating decision-making preferences into ecosystem service conservation area identification: A case study of water-related ecosystem services in the Dawen River watershed, China.

The degradation of ecosystems and their services is threatening human wellbeing, making ecosystem service (ES) conservation an urgent necessity. In ES conservation planning, conservation area identification is crucial for the success of conservation initiatives. However, different decision-making preferences have not been fully considered and integrated in ES conservation area identification. This study takes the Dawen River watershed as the study area and considers three water-related ESs to be conserved. We aim to integrate the decision-making preferences of cost-effectiveness, ES sustainable supply, and ES social benefit into identifying ES conservation areas by using conservation cost, ecosystem health, and ES social importance as spatial constraints, respectively. We identified ES conservation area alternatives under the scenarios set according to different decision-making preferences. Specifically, ES conservation targets, i.e., the expected proportion of each ES in conservation areas, are designed to be met where there is low conservation cost (cost-oriented scenario), high ecosystem health (ES sustainable supply scenario), or high ES social importance (ES social benefit scenario). A balanced scenario considering all three decision-making preferences together is further established. The results show that under each scenario, the identified conservation areas can concurrently meet the conservation targets and decision-making preferences. The consideration of different decision-making preferences can greatly influence the spatial distributions of ES conservation areas. Moreover, a severe trade-off between conservation cost and ES social importance is observed under the ES social benefit scenario, and the balanced scenario can achieve a synergy of decision-making preferences. Our study provides a method to integrate the decision-making preference into ES conservation area identification, which can improve the rationality and practicality of ES conservation planning.

Racial and Ethnic Minorities Have a Lower Prevalence of Airflow Obstruction than Non-Hispanic Whites.

Racial and ethnic disparities in chronic obstructive pulmonary disease (COPD) are not well-studied. Our objective was to examine differences in limited COPD-related outcomes between three minority groups-African Americans (AAs), Hispanics, and American Indians (AIs) versus non-Hispanic Whites (NHWs), as the referent group, in separate cohorts. Separate cross-sectional evaluations were performed of three US-based cohorts of subjects at risk for COPD: COPDGene Study with 6,884 NHW and 3,416 AA smokers; Lovelace Smokers' Cohort with 1,598 NHW and 378 Hispanic smokers; and Mining Dust Exposure in the United States Cohort with 2,115 NHW, 2,682 Hispanic, and 2,467 AI miners. Prebronchodilator spirometry tests were performed at baseline visits using standard criteria. The primary outcome was the prevalence of airflow obstruction. Secondary outcomes were self-reported physician diagnosis of COPD, chronic bronchitis, and modified Medical Research Council dyspnea score. All minority groups had a lower prevalence of airflow obstruction than NHWs (adjusted ORs varied from 0.29 in AIs to 0.85 in AAs; p < 0.01 for all analyses). AAs had a lower prevalence of chronic bronchitis than NHWs. In our study, all minority groups had a lower prevalence of airflow obstruction but a greater level of self-reported dyspnea than NHWs, and covariates did not explain this association. A better understanding of racial and ethnic differences in smoking-related and occupational airflow obstruction may improve prevention and therapeutic strategies.

An ecological perspective for understanding regional integration based on ecosystem service budgets, bundles, and flows: A case study of the Jinan metropolitan area in China.

Regional integration can contribute to co-occurring benefits of different parts of an urban agglomeration by managing these parts as a whole. However, current regional integration mainly focuses on the socioeconomic rather than the ecological dimension. To interpret regional ecological integration, we firstly selected six typical ecosystem services (ESs) to represent ecological benefits that potentially need to be improved by ecological integration for further analysis. Then we used ES budgets, bundles, and flows to investigate the potential, basic analysis unit, and occurring manners of ecological integration, respectively. Our results show that supply-demand mismatches were observed in all the ES types. Meanwhile, coexisting ES surpluses and deficits on the town scale were found in supporting biodiversity, soil retention, water yield, green space recreation, and crop yield, which indicates that their supply-demand mismatches can be mitigated with ecological integration. Furthermore, all the towns were classified into five spatial clusters with distinct ES budget bundles, which acted as the basic analysis unit of ecological integration. ES flows with three flow characteristic types were observed between different clusters, and all the clusters had ES provider-beneficiary relationships with each other. Based on the ES approach, we provided an ecological perspective for understanding regional integration, which has the potential to promote regional ecological sustainability.

ADAM15 expression is increased in lung CD8+ T cells, macrophages, and bronchial epithelial cells in patients with COPD and is inversely related to airflow obstruction.

BACKGROUND: A disintegrin and metalloproteinase domain-15 (ADAM15) is expressed by activated leukocytes, and fibroblasts in vitro. Whether ADAM15 expression is increased in the lungs of COPD patients is not known. METHODS: ADAM15 gene expression and/or protein levels were measured in whole lung and bronchoalveolar lavage (BAL) macrophage samples obtained from COPD patients, smokers, and non-smokers. Soluble ADAM15 protein levels were measured in BAL fluid (BALF) and plasma samples from COPD patients and controls. Cells expressing ADAM15 in the lungs were identified using immunostaining. Staining for ADAM15 in different cells in the lungs was related to forced expiratory volume in 1 s (FEV1), ratio of FEV1 to forced vital capacity (FEV1/FVC), and pack-years of smoking history. RESULTS: ADAM15 gene expression and/or protein levels were increased in alveolar macrophages and whole lung samples from COPD patients versus smokers and non-smokers. Soluble ADAM15 protein levels were similar in BALF and plasma samples from COPD patients and controls. ADAM15 immunostaining was increased in macrophages, CD8+ T cells, epithelial cells, and airway α-smooth muscle (α-SMA)-positive cells in the lungs of COPD patients. ADAM15 immunostaining in macrophages, CD8+ T cells and bronchial (but not alveolar) epithelial cells was related inversely to FEV1 and FEV1/FVC, but not to pack-years of smoking history. ADAM15 staining levels in airway α-SMA-positive cells was directly related to FEV1/FVC. Over-expressing ADAM15 in THP-1 cells reduced their release of matrix metalloproteinases and CCL2. CONCLUSIONS: These results link increased ADAM15 expression especially in lung leukocytes and bronchial epithelial cells to the pathogenesis of COPD.

Plasma metabolomics and clinical predictors of survival differences in COPD patients.

BACKGROUND: Plasma metabolomics profile (PMP) in COPD has been associated with clinical characteristics, but PMP's relationship to survival has not been reported. We determined PMP differences between patients with COPD who died an average of 2 years after enrollment (Non-survivors, NS) compared to those who survived (S) and also with age matched controls (C). METHODS: We studied prospectively 90 patients with severe COPD and 30 controls. NS were divided in discovery and validation cohorts (30 patients each) and the results compared to the PMP of 30 S and C. All participants completed lung function tests, dyspnea scores, quality of life, exercise capacity, BODE index, and plasma metabolomics by liquid and gas chromatography / mass spectometry (LC/MS, LC/MS2, GC/MS). Statistically, we used Random Forest Analysis (RFA) and Support Vector Machine (SVM) to determine metabolites that differentiated the 3 groups and compared the ability of metabolites vs. clinical characteristics to classify patients into survivors and non-survivors. RESULTS: There were 79 metabolites statistically different between S and NS [p < 0.05 and false discovery rate (q value) < 0.1]. RFA and SVM classification of COPD survivors and non-survivors had a predicted accuracy of 74 and 85% respectively. Elevation of tricyclic acid cycle intermediates branched amino acids depletion and increase in lactate, fructose and xylonate showed the most relevant differences between S vs. NS suggesting alteration in mitochondrial oxidative energy generation. PMP had similar predictive power for risk of death as information provided by clinical characteristics. CONCLUSIONS: A plasma metabolomic profile characterized by an oxidative energy production difference between survivors and non-survivors was observed in COPD patients 2 years before death.

Outcomes of human adenovirus infection and disease in a retrospective cohort of pediatric solid organ transplant recipients.

Information about HAdV infection in SOT recipients is limited. We aimed to describe HAdV infection epidemiology and outcomes in a single-center retrospective cohort during the era of PCR availability. SOT recipients transplanted at the CHOP 2004-2013 were followed up for 180 days post-transplant. HAdV infection was defined as a positive HAdV PCR from a clinical specimen. HAdV disease was defined by organ-specific radiologic and/or laboratory abnormalities. No HAdV surveillance protocols were employed during the study period; testing was solely per clinician discretion. Progression of HAdV infection was defined as HAdV disease or ≥1-log viral load increase since a corresponding site's first positive specimen. Of the assembled 425 SOT recipients, 227 (52.6%) had ≥1 HAdV PCR. Twenty-four (10.6%) had ≥1 HAdV-positive PCR. HAdV-positive subjects were younger than uninfected subjects (2.0 years vs 6.5, P = 0.001). Infection incidence rates were highest in liver recipients (15.3%), followed by heart (8.6%), kidney (8.3%), and lung (4.2%). Four subjects (16.7%) met HAdV disease criteria at virus detection. Five subjects (20.8%) had progression of HAdV infection. All-cause mortality rates in positive and negative subjects were 0% and 3.9%, respectively. HAdV infection was infrequently detected in SOT recipients. Over one-third of HAdV-positive patients met disease criteria at detection or had infection progression, but none died. This low all-cause mortality raises questions about benefits of HAdV surveillance. Larger multicenter studies are needed to assess incidence variance by center and comparative effectiveness of therapeutic interventions.

A Disintegrin and Metalloproteinase Domain-8: A Novel Protective Proteinase in Chronic Obstructive Pulmonary Disease.

RATIONALE: ADAM8 (a disintegrin and metalloproteinase domain-8) is expressed by leukocytes and epithelial cells in health, but its contribution to the pathogenesis of chronic obstructive pulmonary disease (COPD) is unknown. OBJECTIVES: To determine whether the expression of ADAM8 is increased in the lungs of patients with COPD and cigarette smoke (CS)-exposed mice, and whether ADAM8 promotes the development of COPD. METHODS: ADAM8 levels were measured in lung, sputum, plasma, and/or BAL fluid samples from patients with COPD, smokers, and nonsmokers, and wild-type (WT) mice exposed to CS versus air. COPD-like lung pathologies were compared in CS-exposed WT versus Adam8-/- mice. MEASUREMENTS AND MAIN RESULTS: ADAM8 immunostaining was reduced in macrophages, and alveolar and bronchial epithelial cells in the lungs of patients with COPD versus control subjects, and CS- versus air-exposed WT mice. ADAM8 levels were similar in plasma, sputum, and BAL fluid samples from patients with COPD and control subjects. CS-exposed Adam8-/- mice had greater airspace enlargement and airway mucus cell metaplasia than WT mice, but similar small airway fibrosis. CS-exposed Adam8-/- mice had higher lung macrophage counts, oxidative stress levels, and alveolar septal cell death rates, but lower alveolar septal cell proliferation rates and soluble epidermal growth factor receptor BAL fluid levels than WT mice. Adam8 deficiency increased lung inflammation by reducing CS-induced activation of the intrinsic apoptosis pathway in macrophages. Human ADAM8 proteolytically shed the epidermal growth factor receptor from bronchial epithelial cells to reduce mucin expression in vitro. Adam8 bone marrow chimera studies revealed that Adam8 deficiency in leukocytes and lung parenchymal cells contributed to the exaggerated COPD-like disease in Adam8-/- mice. CONCLUSIONS: Adam8 deficiency increases CS-induced lung inflammation, emphysema, and airway mucus cell metaplasia. Strategies that increase or prolong ADAM8's expression in the lung may have therapeutic efficacy in COPD.

Early Endotyping: A Chance for Intervention in Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is a syndrome that comprises several lung pathologies, but subphenotyping the various disease subtypes has been difficult. One reason may be that current efforts focused on studying COPD once it has occurred do not allow tracing back to the different origins of disease. This perspective proposes that emphysema originates when susceptible airway, endothelial, and/or hematopoietic cells are exposed to environmental toxins such as cigarette smoke, biomass fuel, or traffic emissions. These susceptible cell types may initiate distinct pathobiological mechanisms ("COPD endotypes") that ultimately manifest the emphysematous destruction of the lung. On the basis of evidence from the "airway" endotype, we suggest that grading these endotypes by severity may allow better diagnosis of disease at early stages when intervention can be designed on the basis of the mechanisms involved. Therefore, genomic, proteomic, and metabolomic studies on at-risk patients will be important in the identification of biomarkers that help designate each endotype. Together with understanding of the involved molecular pathways that lead to disease manifestation, these efforts may lead to development of intervention strategies.

Lung-Function Trajectories Leading to Chronic Obstructive Pulmonary Disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is thought to result from an accelerated decline in forced expiratory volume in 1 second (FEV1) over time. Yet it is possible that a normal decline in FEV1 could also lead to COPD in persons whose maximally attained FEV1 is less than population norms. METHODS: We stratified participants in three independent cohorts (the Framingham Offspring Cohort, the Copenhagen City Heart Study, and the Lovelace Smokers Cohort) according to lung function (FEV1 ≥80% or <80% of the predicted value) at cohort inception (mean age of patients, approximately 40 years) and the presence or absence of COPD at the last study visit. We then determined the rate of decline in FEV1 over time among the participants according to their FEV1 at cohort inception and COPD status at study end. RESULTS: Among 657 persons who had an FEV1 of less than 80% of the predicted value before 40 years of age, 174 (26%) had COPD after 22 years of observation, whereas among 2207 persons who had a baseline FEV1 of at least 80% of the predicted value before 40 years of age, 158 (7%) had COPD after 22 years of observation (P<0.001). Approximately half the 332 persons with COPD at the end of the observation period had had a normal FEV1 before 40 years of age and had a rapid decline in FEV1 thereafter, with a mean (±SD) decline of 53±21 ml per year. The remaining half had had a low FEV1 in early adulthood and a subsequent mean decline in FEV1 of 27±18 ml per year (P<0.001), despite similar smoking exposure. CONCLUSIONS: Our study suggests that low FEV1 in early adulthood is important in the genesis of COPD and that accelerated decline in FEV1 is not an obligate feature of COPD. (Funded by an unrestricted grant from GlaxoSmithKline and others.).

Outpatient Complex Case Management: Health System-Tailored Risk Stratification Taxonomy to Identify High-Cost, High-Need Patients.

BACKGROUND: U.S. health systems, incentivized by financial penalties, are designing programs such as case management to reduce service utilization among high-cost, high-need populations. The major challenge is identifying patients for whom targeted programs are most effective for achieving desired outcomes. OBJECTIVE: To evaluate a health system's outpatient complex case management (OPCM) for Medicare beneficiaries for patients overall and for high-risk patients using system-tailored taxonomy, and examine whether OPCM lowers service utilization and healthcare costs. DESIGN: Retrospective case-control study using Medicare data collected between 2012 and 2016 for Ochsner Health System. PARTICIPANTS: Super-utilizers defined as Medicare patients with at least two hospital/ED encounters within 180 days of the index date including the index event. INTERVENTION: Outpatient complex case management. MAIN MEASURES: Propensity score-adjusted multivariable logistic regression analysis was conducted for primary outcomes (90-day hospital readmission; 90-day ED re-visit). A difference-in-difference analysis was conducted to examine changes in per membership per month (PMPM) costs based on OPCM exposure. KEY RESULTS: Among 18,882 patients, 1197 (6.3%) were identified as "high-risk" and 470 (2.5%) were OPCM participants with median enrollment of 49 days. High-risk OPCM cases compared to high-risk controls had lower odds of 90-day hospital readmissions (0.81 [0.40-1.61], non-significant) and lower odds of 90-day ED re-visits (0.50 [0.32-0.79]). Non-high-risk OPCM cases compared to non-high-risk controls had lower odds of 90-day hospital readmissions (0.20 [0.11-0.36]) and 90-day ED re-visits (0.66 [0.47-0.94]). Among OPCM cases, high-risk patients compared to non-high-risk patients had greater odds of 90-day hospital readmissions (4.44 [1.87-10.54]); however, there was no difference in 90-day ED re-visits (0.99 [0.58-1.68]). Overall, OPCM cases had lower total cost of care compared to controls (PMPM mean [SD]: - $1037.71 [188.18]). CONCLUSIONS: Use of risk stratification taxonomy for super-utilizers can identify patients most likely to benefit from case management. Future studies must further examine which OPCM components drive improvements in select outcome for specific populations.

Intensive versus conventional blood pressure monitoring in a general practice population. The Blood Pressure Reduction in Danish General Practice trial: a randomized controlled parallel group trial.

Objective: To compare the effect of a conventional to an intensive blood pressure monitoring regimen on blood pressure in hypertensive patients in the general practice setting. Design: Randomized controlled parallel group trial with 12-month follow-up. Setting: One hundred and ten general practices in all regions of Denmark. Participants: One thousand forty-eight patients with essential hypertension. Intervention: Conventional blood pressure monitoring ('usual group') continued usual ad hoc blood pressure monitoring by office blood pressure measurements, while intensive blood pressure monitoring ('intensive group') supplemented this with frequent home blood pressure monitoring and 24-hour ambulatory blood pressure monitoring. Primary outcome measures: Mean day- and night-time systolic and diastolic 24-hour ambulatory blood pressure. Secondary outcome measures: Change in systolic and diastolic office blood pressure and change in cardiovascular risk profile. Results: Of the patients, 515 (49%) were allocated to the usual group, and 533 (51%) to the intensive group. The reductions in day- and night-time 24-hour ambulatory blood pressure were similar (usual group: 4.6 ± 13.5/2.8 ± 82 mmHg; intensive group: 5.6 ± 13.0/3.5 ± 8.2 mmHg; P = 0.27/P = 0.20). Cardiovascular risk scores were reduced in both groups at follow-up, but more so in the intensive than in the usual group (P = 0.02). Conclusion: An intensive blood pressure monitoring strategy led to a similar blood pressure reduction to conventional monitoring. However, the intensive strategy appeared to improve patients' cardiovascular risk profile through other effects than a reduction of blood pressure. Trial registration: Clinical Trials NCT00244660.

A Pilot Study Linking Endothelial Injury in Lungs and Kidneys in Chronic Obstructive Pulmonary Disease.

RATIONALE: Patients with chronic obstructive pulmonary disease (COPD) frequently have albuminuria (indicative of renal endothelial cell injury) associated with hypoxemia. OBJECTIVES: To determine whether (1) cigarette smoke (CS)-induced pulmonary and renal endothelial cell injury explains the association between albuminuria and COPD, (2) CS-induced albuminuria is linked to increases in the oxidative stress-advanced glycation end products (AGEs) receptor for AGEs (RAGE) pathway, and (3) enalapril (which has antioxidant properties) limits the progression of pulmonary and renal injury by reducing activation of the AGEs-RAGE pathway in endothelial cells in both organs. METHODS: In 26 patients with COPD, 24 ever-smokers without COPD, 32 nonsmokers who underwent a renal biopsy or nephrectomy, and in CS-exposed mice, we assessed pathologic and ultrastructural renal lesions, and measured urinary albumin/creatinine ratios, tissue oxidative stress levels, and AGEs and RAGE levels in pulmonary and renal endothelial cells. The efficacy of enalapril on pulmonary and renal lesions was assessed in CS-exposed mice. MEASUREMENTS AND MAIN RESULTS: Patients with COPD and/or CS-exposed mice had chronic renal injury, increased urinary albumin/creatinine ratios, and increased tissue oxidative stress and AGEs-RAGE levels in pulmonary and renal endothelial cells. Treating mice with enalapril attenuated CS-induced increases in urinary albumin/creatinine ratios, tissue oxidative stress levels, endothelial cell AGEs and RAGE levels, pulmonary and renal cell apoptosis, and the progression of chronic renal and pulmonary lesions. CONCLUSIONS: Patients with COPD and/or CS-exposed mice have pulmonary and renal endothelial cell injury linked to increased endothelial cell AGEs and RAGE levels. Albuminuria could identify patients with COPD in whom angiotensin-converting enzyme inhibitor therapy improves renal and lung function by reducing endothelial injury.

Grading Severity of Productive Cough Based on Symptoms and Airflow Obstruction.

The binary approach to the diagnosis of Chronic Bronchitis (CB) is a major barrier to the study of the disease. We investigated whether severity of productive cough can be graded using symptoms and presence of fixed airflow obstruction (FAO), and whether the severity correlates with health status, exposures injurious to the lung, biomarkers of inflammation, and measures of airway wall thickening. Findings from a cross-sectional sample of 1,422 participants from the Lovelace Smokers Cohort (LSC) were validated in 4,488 participants from the COPDGene cohort (COPDGene). Health status was based on the St. George's Respiratory Questionnaire, and Medical Outcomes Study 36-Item Short Form Health Survey. Circulating CC16 levels were quantified by ELISA (LSC), and airway wall thickening was measured using computed tomography (COPDGene). FAO was defined as postbronchodilator FEV1/FVC <0.7. The presence and duration of productive cough and presence of FAO or wheeze were graded into Healthy Smokers, Productive Cough (PC), Chronic PC, PC with Signs of Airflow Obstruction, and Chronic PC with Signs of Airflow Obstruction. In both cohorts, higher grade of severity correlated with lower health status, greater frequency of injurious exposures, greater airway wall thickening, and lower circulating CC16 levels. Further, longitudinal follow-up suggested that disease resolution can occur at every grade of severity but is more common in groups of lower severity and least common once airway remodeling develops. Therefore, severity of productive cough can be graded based on symptoms and FAO and early intervention may benefit patients by changing the natural history of disease.

Do COPD subtypes really exist? COPD heterogeneity and clustering in 10 independent cohorts.

BACKGROUND: COPD is a heterogeneous disease, but there is little consensus on specific definitions for COPD subtypes. Unsupervised clustering offers the promise of 'unbiased' data-driven assessment of COPD heterogeneity. Multiple groups have identified COPD subtypes using cluster analysis, but there has been no systematic assessment of the reproducibility of these subtypes. OBJECTIVE: We performed clustering analyses across 10 cohorts in North America and Europe in order to assess the reproducibility of (1) correlation patterns of key COPD-related clinical characteristics and (2) clustering results. METHODS: We studied 17 146 individuals with COPD using identical methods and common COPD-related characteristics across cohorts (FEV1, FEV1/FVC, FVC, body mass index, Modified Medical Research Council score, asthma and cardiovascular comorbid disease). Correlation patterns between these clinical characteristics were assessed by principal components analysis (PCA). Cluster analysis was performed using k-medoids and hierarchical clustering, and concordance of clustering solutions was quantified with normalised mutual information (NMI), a metric that ranges from 0 to 1 with higher values indicating greater concordance. RESULTS: The reproducibility of COPD clustering subtypes across studies was modest (median NMI range 0.17-0.43). For methods that excluded individuals that did not clearly belong to any cluster, agreement was better but still suboptimal (median NMI range 0.32-0.60). Continuous representations of COPD clinical characteristics derived from PCA were much more consistent across studies. CONCLUSIONS: Identical clustering analyses across multiple COPD cohorts showed modest reproducibility. COPD heterogeneity is better characterised by continuous disease traits coexisting in varying degrees within the same individual, rather than by mutually exclusive COPD subtypes.

Enantioseparation of citalopram analogues with sulfated ß-cyclodextrin by capillary electrophoresis.

Capillary electrophoresis methods were developed for the enantiomeric separation of 27 citalopram analogues. Sulfated ß-cyclodextrin was the most broadly selective and useful chiral selector. The separations of most of the citalopram analogue compounds reported in this work have not been reported previously. Excellent enantiomeric separations were obtained for 26 out of 27 compounds, and most of the separations were achieved within 10 min. The effects of chemical parameters such as chiral selector types, buffer types, chiral selector and buffer concentrations, buffer pH and organic modifiers on the separation were investigated. The influence of analyte structure on separation also was examined and discussed.

Spirometric variability in smokers: transitions in COPD diagnosis in a five-year longitudinal study.

BACKGROUND: Spirometrically-defined chronic obstructive pulmonary disease (COPD) is considered progressive but its natural history is inadequately studied. We hypothesized that spirometrically-defined COPD states could undergo beneficial transitions. METHODS: Participants in the Lovelace Smokers' Cohort (n = 1553), primarily women, were longitudinally studied over 5 years. Spirometric states included normal postbronchodilator spirometry, COPD Stage I, Unclassified state, and COPD Stage II+, as defined by GOLD guidelines. Beneficial transitions included either a decrease in disease severity, including resolution of spirometric abnormality, or maintenance of non-diseased state. 'All smokers' (n = 1553) and subgroups with normal and abnormal spirometry at baseline (n = 956 and 597 respectively) were separately analyzed. Markov-like model of transition probabilities over an average follow-up period of 5 years were calculated. RESULTS: Among 'all smokers', COPD Stage I, Unclassified, and COPD Stage II+ states were associated with probabilities of 16, 39, and 22 % respectively for beneficial transitions, and of 16, 35, and 4 % respectively for resolution. Beneficial transitions were more common for new-onset disease than for pre-existing disease (p < 0.001). Beneficial transitions were less common among older smokers, men, or those with bronchial hyperresponsiveness but more common among Hispanics and smokers with excess weight. CONCLUSIONS: This observational study of ever smokers, shows that spirometrically-defined COPD states, may not be uniformly progressive and can improve or resolve over time. The implication of these findings is that the spirometric diagnosis of COPD can be unstable. Furthermore, COPD may have a pre-disease state when interventions might help reverse or change its natural history. TRIAL REGISTRATION: NA.

Protective role for club cell secretory protein-16 (CC16) in the development of COPD.

Club cell secretory protein-16 (CC16) is the major secreted product of airway club cells, but its role in the pathogenesis of chronic obstructive pulmonary disease (COPD) is unclear. We measured CC16 airway expression in humans with and without COPD and CC16 function in a cigarette smoke (CS)-induced COPD murine model. Airway CC16 expression was measured in COPD patients, smokers without COPD and non-smokers. We exposed wildtype (WT) and CC16(-/-)mice to CS or air for up to 6 months, and measured airway CC16 expression, pulmonary inflammation, alveolar septal cell apoptosis, airspace enlargement, airway mucin 5AC (MUC5AC) expression, small airway remodelling and pulmonary function. Smokers and COPD patients had reduced airway CC16 immunostaining that decreased with increasing COPD severity. Exposing mice to CS reduced airway CC16 expression. CC16(-/-) mice had greater CS-induced emphysema, airway remodelling, pulmonary inflammation, alveolar cell apoptosis, airway MUC5AC expression, and more compliant lungs than WT mice. These changes were associated with increased nuclear factor-κB (NF-κB) activation in CC16(-/-) lungs. CS-induced acute pulmonary changes were reversed by adenoviral-mediated over-expression of CC16. CC16 protects lungs from CS-induced injury by reducing lung NF-κB activation. CS-induced airway CC16 deficiency increases CS-induced pulmonary inflammation and injury and likely contributes to the pathogenesis of COPD.

Spirometry and health status worsen with weight gain in obese smokers but improve in normal-weight smokers.

RATIONALE: The literature on the effect of obesity and weight gain on respiratory outcomes in smokers is contradictory. OBJECTIVE: To examine the cross-sectional effect of body mass index (BMI) and the longitudinal effect of change in BMI upon spirometry and health status among smokers at risk for and with milder chronic obstructive pulmonary disease (COPD). METHODS: Participants from the Lovelace Smokers' Cohort were followed for a median period of 6 years, 75% of whom were at risk and 25% of whom had COPD at baseline examination. BMI and gain in BMI were examined as continuous independent variables overall and after stratification into three categories (normal-weight, overweight, and obese) determined on the basis of baseline weight. Spirometry and health status (as assessed by St. George Respiratory Questionnaire total and subscale scores) were dependent variables. Covariates included age, sex, ethnicity, pack-years of smoking, and current smoking status. Cross-sectional analysis used linear and logistic regression; longitudinal analysis used a mixed model approach. MEASUREMENTS AND MAIN RESULTS: In cross-sectional analyses, higher BMI was associated with worse health status among obese smokers but with better health status among normal-weight smokers. In longitudinal analyses, weight gain was associated with a decrease in FEV1 and health status among obese smokers and with an increase in these outcomes among normal-weight smokers. CONCLUSIONS: Weight gain affects respiratory outcomes differently between obese and normal-weight smokers. Whereas FEV1 and health status decrease with weight gain among obese smokers, they improve among normal-weight smokers. The nonlinear relationship between weight gain and respiratory outcomes suggests that this effect of excess weight is unlikely to be mechanical alone.

Incident comorbidities and all-cause mortality among 5-year survivors of Stage I and II breast cancer diagnosed at age 65 or older: a prospective-matched cohort study.

Five-year breast cancer survivors, diagnosed after 65 years of age, may develop more incident comorbidities than similar populations free of cancer. We investigated whether older breast cancer survivors have a similar comorbidity burden 6-15 years after cancer diagnosis to matched women free of breast cancer at start of follow-up and whether incident comorbidities are associated with all-cause mortality. In this prospective cohort study, 1,361 older 5-year early-stage breast cancer survivors diagnosed between 1990 and 1994 and 1,361 age- and health system-matched women were followed for 10 years. Adjudicated medical record review captured prevalent and incident comorbidities during follow-up or until death as collected from the National Death Index. Older 5-year breast cancer survivors did not acquire incident comorbidities more often than matched women free of breast cancer in the subsequent 10 years [hazard ratio (HR) 1.0, 95 % confidence interval (95 % CI) 0.93, 1.1]. Adjusted for cohort membership, women with incident comorbidities had a higher mortality rate than those without incident comorbidities (HR 4.8, 95 % CI 4.1, 5.6). A breast cancer history continued to be a hazard for mortality 6-15 years after diagnosis (HR 1.3, 95 % CI 1.1, 1.4). We found that older breast cancer survivors who developed comorbidities had an increased all-cause mortality rate even after adjusting for age and prevalent comorbidity burden. Additionally, survivors acquire comorbidities at a rate similar to older women free of breast cancer. These results highlight the association between comorbidity burden and long-term mortality risk among older breast cancer survivors and their need for appropriate oncology and primary care follow-up.