Search

Alpha-1 antitrypsin deficiency (AATD) is a significantly under-diagnosed genetic condition caused by reduced levels and/or functionality of alpha-1 antitrypsin (AAT), predisposing individuals to lung, liver or other systemic diseases. The management of individuals with the PI*MZ genotype, characterized by mild or moderate AAT deficiency, is less clear than of those with the most common severe deficiency genotype (PI*ZZ). Recent genetic data suggest that the PI*MZ genotype may be significantly more prevalent than currently thought. The only specific treatment for lung disease associated with severe AATD is the intravenous infusion of AAT augmentation therapy, which has been shown to slow disease progression in PI*ZZ individuals. There is no specific evidence for the clinical benefit of AAT therapy in PI*MZ individuals, and the risk of emphysema development in this group remains controversial. As such, current guidelines do not support the use of AAT augmentation in PI*MZ individuals. Here, we discuss the limited data on the PI*MZ genotype and offer pro and con perspectives on pursuing an AAT-specific therapeutic strategy in PI*MZ individuals with lung disease. Ultimately, further research to demonstrate the safety, risk/benefit balance and efficacy of AAT therapy in PI*MZ individuals is needed.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Faster lung function impairment occurs earlier in the disease, particularly in mild-to-moderate COPD, highlighting the need for early and effective targeted interventions. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2024 report recommends initial pharmacologic treatment with a long-acting muscarinic antagonist (LAMA) and long-acting β2-agonist (LABA) combination in group B (0 or 1 moderate exacerbation not leading to hospitalization, modified Medical Research Council score of ⩾2, and COPD Assessment Test™ score of ⩾10) and E (⩾2 moderate exacerbations or ⩾1 exacerbation leading to hospitalization and blood eosinophil count <300 cells/µL) patients. In randomized controlled trials (RCTs), LAMA/LABA combination therapy improved lung function, St. George's Respiratory Questionnaire (SGRQ) total score, and Transitional Dyspnea Index (TDI) focal score and reduced the use of rescue medications, exacerbation risk, and risk of first clinically important deterioration (CID), compared with LAMA or LABA monotherapy. However, there is limited evidence regarding the efficacy and safety of LAMA/LABA combination therapy versus LAMA or LABA monotherapy in maintenance therapy–naïve patients. This review discusses the rationale for the early initiation of LAMA/LABA combination therapy in maintenance therapy–naïve patients with COPD. In post hoc analyses of pooled data from RCTs, compared with LAMA or LABA monotherapy, LAMA/LABA combination therapy improved lung function and quality of life and reduced COPD symptoms, risk of first moderate/severe exacerbation, risk of first CID, and use of rescue medication, with no new safety signals. In a real-world study, patients initiating LAMA/LABA had significantly reduced risk of COPD-related inpatient admissions and rate of on-treatment COPD-related inpatient admissions over 12 months than those initiating LAMA. Consequently, LAMA/LABA combination therapy could be considered the treatment of choice in maintenance therapy–naïve patients with COPD, as recommended by the GOLD 2024 report. Plain language summary: Long-acting bronchodilator combination therapy for the treatment of maintenance therapy–naïve patients with chronic obstructive pulmonary disease Chronic obstructive pulmonary disease (COPD) is a common lung disease that makes it hard to breathe and is a leading cause of death and disability worldwide. This disease tends to worsen lung function from an early stage, especially in people who only have mild or moderate symptoms. To help stop the loss of lung function and maintain the quality of life for patients with COPD, two main types of long-lasting inhaler medications are used: one type focuses on relaxing the muscles around the airways, and the other type helps open the airways making it easier to breathe. Some medications combine these two types of action and are approved for long-term management of COPD. However, there is not much information on the effectiveness and safety of these combination medications in patients who have never taken long-lasting COPD medication before. Current health guidelines suggest starting these combination medications in patients who are likely to see their symptoms get worse quickly, and who do not have a high level of a specific type of white blood cell. In this review, we discuss the evidence for starting these combination treatments early in patients who have never used long-lasting COPD medications before. There is no strong evidence yet that shows starting treatment early benefits patients with newly diagnosed COPD. However, about 30% of patients in clinical trials designed to study the effectiveness of these combination medications, had never received any long-lasting treatment before. After-the-fact analyses of these patients showed that these combination medications could reduce symptoms such as breathlessness, improve lung function, enhance quality of life, lessen the need for emergency medications, and decrease the risk of severe symptom flare-ups. Overall, the evidence supports using these combination inhaler medications as the first choice of treatment for patients with moderate COPD symptoms who have not previously been treated with long-lasting inhalers. [ABSTRACT FROM AUTHOR]

Background: Chronic obstructive pulmonary disease (COPD) and asthma can be treated with inhaled corticosteroids (ICS) delivered by low climate impact inhalers (dry powder inhalers) or high climate impact inhalers (pressurized metered-dose inhalers containing potent greenhouse gasses). ICS delivered with greenhouse gasses is prescribed ubiquitously and frequent despite limited evidence of superior effect. Our aim was to examine the beneficial and harmful events of ICS delivered by low and high climate impact inhalers in patients with asthma and COPD. Methods: Nationwide retrospective cohort study of Danish outpatients with asthma and COPD treated with ICS delivered by low and high climate impact inhalers. Patients were propensity score matched by the following variables; age, gender, tobacco exposure, exacerbations, dyspnoea, body mass index, pulmonary function, ICS dose and entry year. The primary outcome was a composite of hospitalisation with exacerbations and all-cause mortality analysed by Cox proportional hazards regression. Results: Of the 10,947 patients with asthma and COPD who collected ICS by low or high climate impact inhalers, 2,535 + 2,535 patients were propensity score matched to form the population for the primary analysis. We found no association between high climate impact inhalers and risk of exacerbations requiring hospitalization and all-cause mortality (HR 1.02, CI 0.92–1.12, p = 0.77), nor on pneumonia, exacerbations requiring hospitalization, all-cause mortality, or all-cause admissions. Delivery with high climate impact inhalers was associated with a slightly increased risk of exacerbations not requiring hospitalization (HR 1.10, CI 1.01–1.21, p = 0.03). Even with low lung function there was no sign of a superior effect of high climate impact inhalers. Conclusion: Low climate impact inhalers were not inferior to high climate impact inhalers for any risk analysed in patients with asthma and COPD. [ABSTRACT FROM AUTHOR]

The article addresses the global impact of chronic obstructive pulmonary disease (COPD), noting its high prevalence and the significant burden of undiagnosed cases. Topics include the limitations of current screening practices and the U.S. Preventive Services Task Force's stance against routine spirometry for asymptomatic individuals, despite evidence suggesting that at-risk populations could benefit from early detection.

Introduction: Physical activity (PA) has shown great benefits in patients with chronic obstructive pulmonary disease (COPD); however, their PA is below average. Motivational factors associated with PA in COPD have not been widely studied and could be a target for improving adherence to PA. The objective of our study was to identify and understand the different motivational and confidence factors related to low levels of PA in a COPD cohort. Method: Observational, prospective, multicenter study of COPD patients. Sociodemographic data, respiratory symptoms, comorbidities, spirometry, and exercise capacity were collected. PA was measured using the Dynaport accelerometer and patient motivation and confidence in PA were assessed by a questionnaire previously used in a COPD population in the USA. Results: Eighty six COPD patients were included, 68.6% being male, with a mean (SD) age of 66.6 (8.5) years and a mean forced expiratory volume in the first second (%) of 50.9% (17.3%). The mean walking time was 82.8 (37.8) minutes/day. Questions related to health benefits and enjoying exercise were ranked highest in the motivation questionnaire and statistically significant differences were found in PA measures between patients with low and high motivation. A lack of confidence regarding hot weather and health-related issues significantly influenced PA levels. Advice from third parties, including healthcare providers, was not associated with higher PA levels. Conclusions: Improving the health of COPD patients is their main motivation to perform PA. Lack of confidence when it is hot or when they fear for their health is related to low levels of PA. Advice from third parties, including healthcare professionals, is not associated with higher PA. These results are relevant for developing strategies to increase the adherence of COPD patients to PA programs. [ABSTRACT FROM AUTHOR]

Background: Alpha-1 antitrypsin deficiency (AATD) is an underdiagnosed condition despite being one of the most common inherited disorders in adults that is associated with an increased risk of developing chronic obstructive pulmonary disease (COPD). The aim was to evaluate the frequency of performing AAT levels and associated factors in COPD patients in an audit conducted in 2021–2022, as well as to compare with a previous audit conducted in 2014–2015. Methods: EPOCONSUL 2021 is a cross-sectional audit that evaluated the outpatient care provided to COPD patients in respiratory clinics in Spain based on available data from medical registries. Results: 4225 patients with a diagnosis of COPD from 45 centers were audited in 2021. A total of 1670 (39.5%) patients underwent AAT determination. Being treated at a specialized COPD outpatient clinic (OR 1.88, p = 0.007), age ≤ 55 years old (OR 1.84, p = 0.007) and a FEV1 < 50% (OR 1.86, p < 0.001) were associated with a higher likelihood of being tested for AAT, while Charlson index ≥ 3 (OR 0.63, p < 0.001) and genotyping of AATD availability (OR 0.42, p < 0.001) showed a statistically significant negative association. The analysis of cases included in respiratory units that participated in both audits showed an increase in the proportion of cases with AAT serum level testing available (adjusted OR 2.81, p < 0.001). The percentage of individuals with serum AAT levels < 60 mg/dL (a severe AATD) was 4%. Conclusions: Our analysis identifies significant improvements in adherence to the recommendation to test AAT levels in COPD patients, performed in 4 out of 10 patients, being more likely at younger ages and with higher COPD severity, and with a detection of severe AATD of 4% among those tested, suggesting that clinicians still perform AAT testing in COPD patients selectively. Therefore, efforts are still needed to optimize AATD screening and establish new early detection strategies to reduce morbidity and mortality in these patients. [ABSTRACT FROM AUTHOR]

Inhaled bronchodilator therapy with long-acting muscarinic antagonists (LAMAs) and long-acting β2-agonists (LABAs) in combination is currently the mainstay of treatment for chronic obstructive pulmonary disease (COPD). Treatment guidelines recommend the addition of inhaled corticosteroids (ICS) to LABA/LAMA only in patients with a history of frequent/severe exacerbations and high blood eosinophil counts, or in those with concomitant asthma. Despite this, real-world data suggest that clinicians are not adhering to this guidance and that ICS are frequently overused. This is possibly due to the incorrect assumption that when LABA/LAMA therapy is not sufficient, adding an ICS to the treatment regimen is the logical next step. In this narrative review, we describe global and country-specific guideline recommendations from Germany, Spain, and Japan and compare these with real-world data on LABA/LAMA and ICS use in clinical practice. We also provide a clinical guide to the use of add-on therapies with LABA/LAMA for different patient phenotypes, including (1) patients still symptomatic (but not exacerbating) despite LABA/LAMA treatment; (2) patients still exacerbating despite LABA/LAMA treatment who have high blood eosinophil counts; and (3) patients still exacerbating despite LABA/LAMA treatment who do not have high blood eosinophils or concomitant asthma. Plain language summary: What are the options for patients with COPD when LABA/LAMA is not enough? Treatment guidelines for chronic obstructive pulmonary disease (COPD) recommend dual bronchodilator therapy for the majority of patients, consisting of an inhaled combination of long-acting β2-agonist (LABA) and long-acting muscarinic antagonist (LAMA). Patients whose COPD is not well controlled on LABA/LAMA require further clinical intervention, which may or may not involve treatment with additional drugs. Data from observational studies reflecting routine clinical practice suggest that inhaled corticosteroids (ICS) are often added to LABA/LAMA, even though treatment guidelines recommend only adding ICS in a specific group of patients with a history of exacerbations and high levels of eosinophils (a type of inflammatory cell) in the blood, or in those with current asthma. As long-term ICS use may be associated with an increased risk of side effects such as pneumonia, it is important to avoid overuse of ICS. When a patient's COPD is not well controlled on LABA/LAMA, other treatable conditions should first be ruled out, and factors such as medication adherence, inhaler technique, and co-existing health conditions should also be considered. This review gives advice on what follow-up options physicians should consider when LABA/LAMA is not providing adequate control of a patient's COPD. Specifically, recommendations are given for three different patient profiles: 1. Patients who still have symptoms of COPD (but no acute/sudden worsenings of symptoms, known as exacerbations). 2. Patients who have exacerbations, as well as high levels of eosinophils in the blood. 3. Patients who have exacerbations, but without high levels of eosinophils in the blood or current asthma. [ABSTRACT FROM AUTHOR]

Poor sleep quality is frequent among COPD patients and it has been related to worse outcomes. The objective of this study was to compare the COPD and Asthma Sleep Impact Scale (CASIS) and the generic Pittsburgh Sleep Quality Index (PSQI) questionnaires as reliable tools for evaluating sleep quality and its relationship with COPD characteristics and survival. Stable COPD patients were prospectively evaluated. Anthropometric, sociodemographic, comorbidity, lung function and treatment data were collected. All patients completed CASIS and PSQI, mMRC dyspnea severity scale, COPD Assessment Test (CAT), sleep apnoea STOP-Bang and Hospital Anxiety and Depression Scale (HADS) questionnaires. Body mass index, airflow Obstruction, Dyspnea and Exacerbations (BODEx) index was calculated. Life status was determined after a mean follow-up of 3.7 (SD 1) years. We included 200 patients, 69.5% male, mean age 65.8 (9) years. Poor sleep was detected in 100 (50%) and 84 patients (42%) according to PSQI and CASIS questionnaires, respectively, with an agreement of 63%. Poor sleep was related to female gender, more severe dyspnea and worse BODEx, HADS and CAT scores according to both questionnaires. PSQI was associated to chronic pain or inferior urinary tract symptoms and CASIS to exacerbations, shorter walked distance in the 6-min walking test and treatment with oral corticosteroids or chronic oxygen. Thirty nine (19.5%) patients died during follow-up. Mortality was not associated to PSQI nor CASIS results. Unlike PSQI, CASIS is more related to COPD severity and its results are not influenced by comorbidities with known impact on sleep quality. In our sample, poor sleep quality was not associated with increased mortality. [ABSTRACT FROM AUTHOR]

Background: In 2008, a dedicated American Thoracic Society/European Respiratory Society task force published a paper on the possible use and limitations of clinical outcomes and biomarkers to evaluate the impact of pharmacological therapy in patients with chronic obstructive pulmonary disease. Since then, our scientific understanding of chronic obstructive pulmonary disease has increased considerably; there has been a progressive shift from a one-size-fits-all diagnostic and therapeutic approach to a personalized approach; and many new treatments currently in development will require new endpoints to evaluate their efficacy adequately. Objectives: The emergence of several new relevant outcome measures motivated the authors to review advances in the field and highlight the need to update the content of the original report. Methods: The authors separately created search strategies for the literature, primarily based on their opinions and assessments supported by carefully chosen references. No centralized examination of the literature or uniform criteria for including or excluding evidence were used. Measurements and Main Results: Endpoints, outcomes, and biomarkers have been revisited. The limitations of some of those reported in the American Thoracic Society/European Respiratory Society task force document have been highlighted. In addition, new tools that may be useful, especially in evaluating personalized therapy, have been described. Conclusions: Because the "label-free" treatable traits approach is becoming an important step toward precision medicine, future clinical trials should focus on highly prevalent treatable traits, and this will influence the choice of outcomes and markers to be considered. The use of the new tools, particularly combination endpoints, could help better identify the right patients to be treated with the new drugs. [ABSTRACT FROM AUTHOR]

Background: The objective of this analysis is to evaluate tobacco use and the level of chronic obstructive pulmonary disease (COPD) knowledge among the general adult population in Spain and to compare these results to those obtained in the 2011 survey. Methods: A cross-sectional, observational, epidemiological study was conducted by telephone interviews and stratified by sex, age, and setting. The study design was identical to that of the study conducted in 2011. Results: Of a total of 89,601 phone contacts, there were 6534 respondents. The average age was 61.5 years. With respect to smoking, 30.9% reported being former smokers and 14.7% were current smokers, 63.6% of whom reported having attempted to quit. Among the current smokers, 19.7% claimed to use electronic cigarettes, although 88% believe these pose a health risk. No significant differences were found in smoking prevalence or frequency of attempts to quit according to residential setting (rural/urban). The highest prevalence of current smoking in men was recorded in the 55–64 years age range (31.6%), while in women it was from 45 to 54 years (34.6%). Smoking has decreased with respect to 2011, from 21.1% to 16.1% in men and from 17.9% to 13.2% in women, with a clear variability according to region. Of the population surveyed, 32.5% had spontaneous knowledge about COPD, with significant geographic variability. The most frequent sources of information about the disease were social media and the Internet (39.6%), followed by the media (35.2%). Conclusions: The prevalence of tobacco use in adults has considerably decreased and there is greater knowledge about COPD in Spain, although there is significant variability according to region, which could explain the geographic variability in the prevalence of COPD. Strategies are needed to increase COPD education and awareness and to reinforce smoking prevention measures among women. [ABSTRACT FROM AUTHOR]

Background: Persistent airflow limitation and dyspnoea may reduce chronic obstructive pulmonary disease (COPD) patients exercise capacity and physical activity, undermining their physical status and quality of life. Long-acting muscarinic antagonists and long-acting beta-2 agonists (LAMA/LABA) combinations are amongst moderate-to-severe COPD recommended treatments. This article analyses LAMA/LABA combinations effect on COPD patients exercise capacity and physical activity outcomes. Methods: A systematic review and meta-analysis of double-blind randomized controlled trials comparing LAMA/LABA combinations against monotherapy or placebo was conducted. Results: Seventeen articles were identified (N = 4041 patients). In endurance shuttle walk test and constant work rate cycle ergometry, LAMA/LABA combinations obtained better results than placebo, but not monotherapy, whereas in 6-min walking test, results favoured LAMA/LABA over monotherapy (four studies), but not over placebo (one study). Moreover, LAMA/LABA combinations obtained better results than placebo in number of steps per day, reduction in percentage of inactive patients and daily activity-related energy expenditure, and better than monotherapy when measuring time spent on ≥ 1.0–1.5, ≥ 2.0 and ≥ 3.0 metabolic equivalents of task activities. Conclusions: LAMA/LABA combinations in COPD patients provided better results than monotherapy or placebo in most exercise capacity and physical activity outcomes. [ABSTRACT FROM AUTHOR]

Inhaled bronchodilators (alone or in combination) are the cornerstone of treatment for symptomatic patients with COPD, either as initial/first-line treatment or for second-line/treatment escalation in patients who experience persistent symptoms or exacerbations on monotherapy. The Global Initiative for Chronic Obstructive Lung Disease 2022 report recommends initial pharmacological treatment with a long-acting muscarinic antagonist (LAMA) or a long-acting β2-agonist (LABA) as monotherapy for most patients, or dual bronchodilator therapy (LABA/LAMA) in patients with more severe symptoms, regardless of exacerbation history. The recommendations for LABA/LAMA are broader in the American Thoracic Society treatment guidelines, which strongly recommend LABA/LAMA combination therapy over LAMA or LABA monotherapy in patients with COPD and dyspnea or exercise intolerance. However, despite consistent guideline recommendations, real-world prescribing data indicate that LAMA and/or LABA without an inhaled corticosteroid are not the most widely prescribed therapies in COPD. This article reviews global and regional/national guideline recommendations for the use of LABA/LAMA in COPD, examines the evidence for the effectiveness and safety of LABA/LAMA versus other therapies and offers a practical guide for clinicians to help ensure appropriate use of LABA/LAMA therapy. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases are common in patients with chronic obstructive pulmonary disease (COPD). Clot formation and resolution secondary to systemic inflammation may be a part of the explanation. The aim was to determine whether biomarkers of clot formation (products of von Willebrand Factor formation and activation) and clot resolution (product of fibrin degeneration) during COPD exacerbation predicted major cardiovascular events (MACE). The cohort was based on clinical data and biobank plasma samples from a trial including patients admitted with an acute exacerbation of COPD (CORTICO-COP). Neo-epitope biomarkers of formation and the activation of von Willebrand factor (VWF-N and V-WFA, respectively) and cross-linked fibrin degradation (X-FIB) were assessed using ELISAs in EDTA plasma at the time of acute admission, and analyzed for time-to-first MACE within 36 months, using multivariable Cox proportional hazards models. In total, 299/318 participants had samples available for analysis. The risk of MACE for patients in the upper quartile of each biomarker versus the lower quartile was: X-FIB: HR 0.98 (95% CI 0.65–1.48), VWF-N: HR 1.56 (95% CI 1.07–2.27), and VWF-A: HR 0.78 (95% CI 0.52–1.16). Thus, in COPD patients with an acute exacerbation, VWF-N was associated with future MACE and warrants further studies in a larger population. [ABSTRACT FROM AUTHOR]

Factors such as seeking medical attention for respiratory symptoms and health professionals ordering spirometry come into play in the underdiagnosis of chronic obstructive pulmonary disease (COPD). The objective of this study was to analyze seeking medical attention and the use of spirometry in individuals with chronic respiratory symptoms and to compare these results with those obtained in the 2005 and 2011 surveys. Material and Methods: A cross-sectional, observational, epidemiological study was conducted via phone interview in December 2020 in Spain, with a representative sample from 17 autonomous communities. The study design was identical to that of the studies carried out in 2005 and 2011 to evaluate the changes that have occurred in seeking medical attention and performing spirometry in Spain, as well as the variability between autonomous communities. Results: From 89,601 phone contacts, a total of 6534 respondents were obtained. A total of 24.8% reported having some chronic respiratory symptom, and 17.9% reported a respiratory disease. Only 51.6% of those who had some chronic respiratory symptom had seen their doctor, which was less likely among current smokers (OR: 0.599, 95% CI: 0.467–0.769, p < 0.001) and those living in a rural setting (OR: 0.797, 95% CI: 0.651–0.975, p = 0.027). A total of 68.7% of the individuals who saw a doctor reported having undergone spirometry, most frequently males (OR: 1.535, 95% CI: 2.074–1.136, p < 0.005), former smokers (OR: 1.696, 95% CI: 2.407–1.195, p < 0.003), and those seen by a pulmonologist (OR: 6.151, 95% CI: 8.869–4.265, p < 0.001). With respect to the 2005 survey, more frequent use of spirometry has been observed (42.6 vs. 68.7%), without any change in seeking medical attention for respiratory symptoms. There is a clear variability according to the autonomous community (p < 0.05). Conclusions: Many individuals with chronic respiratory symptoms do not seek medical attention and although the use of spirometry has increased in the past 15 years, it is still an important area that needs improving in the primary care setting, especially among women. Both of these factors can be determinants in the underdiagnosis of COPD and its variability between autonomous communities. [ABSTRACT FROM AUTHOR]

We aimed to examine the prevalence of suicidal ideation in patients with chronic obstructive pulmonary disease (COPD) and the association between demographic and clinical variables and the occurrence of suicidal thoughts. This was a cross-sectional study. Sociodemographic and clinical data were recorded, and questionnaires were used to assess depressive symptoms (Beck Depression Inventory), comorbidities (Charlson Index), cognitive performance (Mini Mental State Examination), and quality of life (EuroQoL-5 dimensions and CAT). Specific questions about suicide-related behavior were included. Multivariate logistic regression analysis identified the significant factors associated with previous suicidal ideation and suicide attempts. The analysis included 1190 subjects. The prevalence of suicidal ideation and suicide attempts were 12.1% and 2.5%, respectively. Severely depressed patients had the highest prevalence of suicide-related behavior. The adjusted logistic model identified factors significantly associated with suicidal ideation: sex (odds ratio (OR) for women vs. men = 2.722 (95% confidence interval (CI) = 1.771–4.183)), depression score (OR = 1.163 (95% IC = 1.127–1.200)), and Charlson Index (OR 1.228 (95% IC 1.082–1.394)). Suicidal ideation is common in COPD patients, especially in women. While addressing suicidal ideation and suicide prevention, clinicians should first consider the management of depressive symptomatology and the improvement of coping strategies. [ABSTRACT FROM AUTHOR]

Background: Blood eosinophils are considered a biomarker for the treatment of chronic obstructive pulmonary disease (COPD). Population-based studies are needed to better understand the determinants of the blood eosinophil count (BEC) in individuals with and without COPD.Methods: EPISCAN II is a multicentre, cross-sectional, population-based epidemiological study aimed at investigating the prevalence and determinants of COPD in Spain. Study subjects were randomly selected from the general population, and COPD was defined by a post-bronchodilator FEV1/FVC < 0.7. For the pre-specified outcomes related to BEC, the first 35 COPD and 35 non-COPD subjects were consecutively recruited in 12 of the participating centres with the objective of analysing 400 individuals in each group. Baseline BEC and its association with demographic, clinical and functional variables were analysed.Results: A total of 326 COPD and 399 non-COPD subjects were included in the analysis. The mean age (standard deviation [SD]) was 63.2 years (11.0), 46.3% were male, and 27.6% were active smokers. BEC was significantly higher in individuals with COPD [192 cells/μL (SD: 125) vs. 160 cells/μL (SD: 114); p = 0.0003]. In a stepwise multivariate model, being male, active smoker and having a previous diagnosis of asthma were independently associated with having a higher BEC.Conclusions: This population-based study estimated the distribution of eosinophils in the healthy adult population and concluded that COPD patients have a significantly higher BEC. Male sex, active smoking and concomitant asthma were significantly associated with a higher BEC. [ABSTRACT FROM AUTHOR]

Objective: To assess the frequency and severity of 24-hour respiratory symptoms according to COPD GOLD-ABCD classification (2017-version), the distribution of the patients with COPD into GOLD categories using mMRC (=2) or CAT (=10) scores, and agreement between these cut-off points. Methods: In this cross-sectional study (LASSYC study), 24-hour day respiratory symptoms were assessed by the Evaluating Respiratory Symptoms in COPD (E-RS) questionnaire, Nighttime Symptoms of COPD Instrument (NiSCI), Early Morning Symptoms of COPD Instrument (EMSCI), CAT and mMRC scores. Results: Among the 734 patients with COPD, 61% were male, age 69.6±8.7 years, FEV1% post-BD 49.1±17.5%, mMRC 1.8±1.0 and CAT 15.3±.8.1. By mMRC 33.7% were group-A, 29.2% group-B, 10.2% group-C and 26.9% group-D. By CAT 22.3% were group-A, 41% group-B, 4.8% group-C and 31.9% group-D. Using the mMRC the severity of E-RS, NiSCI and EMSCI scores increased from group A to D. Using the CAT, the groups B and D had the higher scores. Agreement between mMRC and CAT was 89.5% (Kappa statistics=75.7%). For mMRC score of 2, CAT score of =11 showed the maximum Youden's index (1.34). For mMRC score of 1, CAT score of =9 and =10 showed the maximum Youden's index (1.48). Conclusion: GOLD COPD classification by CAT seems to better discriminate 24-hour symptoms. Results do not support the equivalent use of CAT=10 and mMRC=2 for assessing symptoms. [ABSTRACT FROM AUTHOR]

Introduction: Since chronic obstructive pulmonary disease (COPD) is a heterogeneous condition, a composite endpoint of clinically important deterioration (CID) may provide a more holistic assessment of treatment efficacy. We compared long-acting muscarinic antagonist/long-acting β2-agonist combination therapy with tiotropium/olodaterol versus tiotropium alone using a composite endpoint for CID. CID was evaluated overall and in patients with low exacerbation history (at most one moderate exacerbation in the past year [not leading to hospitalisation]), Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2 patients and maintenance-naïve patients with COPD. We assessed whether early treatment optimisation is more effective with tiotropium/olodaterol versus tiotropium in delaying and reducing the risk of CID.Methods: Data were analysed from 2055 patients treated with either tiotropium/olodaterol 5/5 μg or tiotropium 5 μg (delivered via Respimat®) in two replicate, 52-week, parallel-group, double-blind studies (TONADO® 1/2). CID was defined as a decline of at least 0.1 L from baseline in trough forced expiratory volume in 1 s, increase from baseline of at least 4 units in St. George's Respiratory Questionnaire score, or moderate/severe exacerbation. Time to first occurrence of one of these events was recorded as time to first CID.Results: Overall, treatment with tiotropium/olodaterol significantly increased the time to, and reduced the risk of, CID versus tiotropium (median time to CID 226 versus 169 days; hazard ratio [HR] 0.76 [95% confidence interval 0.68, 0.85]; P < 0.0001). Significant reductions were also observed in patients with low exacerbation history (241 versus 170; HR 0.73 [0.64, 0.83]; P < 0.0001), GOLD 2 patients (241 versus 169; 0.72 [0.61, 0.84]; P < 0.0001) and maintenance-naïve patients (233 versus 171; 0.75 [0.62, 0.91]; P = 0.0030).Conclusion: In patients with COPD, including patients with low exacerbation history, GOLD 2 patients and maintenance-naïve patients, tiotropium/olodaterol reduced the risk of CID versus tiotropium. These results demonstrate the advantages of treatment optimisation with tiotropium/olodaterol over tiotropium monotherapy.Trial Registration: ClinicalTrials.gov identifier: TONADO® 1 and 2 (NCT01431274 and NCT01431287, registered 8 September 2011). [ABSTRACT FROM AUTHOR]

Background: Genome-wide association studies (GWAS) have accelerated our understanding of the genetic underpinnings of chronic obstructive pulmonary disease (COPD); however, GWAS populations have typically consisted of European descent, with ∼1% of Latin American ancestry. Objective: To overcome this limitation, we conducted a GWAS in a rural Chilean population with increased COPD risk to investigate genetic variation of COPD risk in this understudied minority population. Method: We carried out a case-control study of 214 COPD patients (defined by the GOLD criteria) and 193 healthy controls in Talca, Chile. DNA was extracted from venous blood and genotyped on the Illumina Global Screening Array (n = 754,159 markers). After exclusion based on Hardy-Weinberg equilibrium (p ≤ 0.001), call rates (<95%), and minor allele frequencies (<0.5%) in controls, 455,564 markers were available for logistic regression. Results:PRDM15 rs1054761 C allele (p = 2.22 × 10–7) was associated with decreased COPD risk. Three PRDM15 SNPs located on chromosome 21 were significantly associated with COPD risk (p < 10–6). Two of these SNPs, rs1054761 and rs4075967, were located on a noncoding transcript variant region of the gene. Conclusion: PRDM15 overexpression may play a role in the B-cell dysregulation in COPD pathogenesis. To the best of our knowledge, the association between PRDM15 and COPD risk was not previously found in GWAS studies in largely European populations, highlighting the importance of investigating novel variants associated with COPD risk among ethnically diverse populations. [ABSTRACT FROM AUTHOR]

Copyright of Revista Española de Quimioterapia is the property of Sociedad Espanola de Quimioterapia and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Archivos de Bronconeumología (English Edition) is the property of Sociedad Espanola de Neumologia y Cirugia Toracica (SEPAR) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Archivos de Bronconeumología (English Edition) is the property of Sociedad Espanola de Neumologia y Cirugia Toracica (SEPAR) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

An exacerbation of chronic obstructive pulmonary disease (COPD) is an acute worsening of respiratory symptoms accompanied by a variable degree of physiological deterioration. The traditional assessment of an exacerbation consists of the reporting of symptoms by the patient to a clinician and subsequent clinical assessment. It would be valuable to also gather symptom reports directly from patients, and thus patient-reported outcome (PRO) tools should be ideally suited to the evaluation of COPD exacerbations. However, most pharmaceutical industry- and large academy-sponsored studies have used a healthcare resource use definition alone, which is based on sustained worsening of a patient's condition from the stable state that requires a change in regular medication. This Review explores the use of PROs for the detection, quantification, and evaluation of COPD exacerbations. It examines symptom diary cards as exacerbation detection tools and their evolution into electronic diaries used in pharmaceutical trials. This paper also describes the development of specifically designed PROs that have been used in exacerbation settings, focusing on the Exacerbations and Symptoms in COPD e-Diary, Exacerbations of Chronic Obstructive Pulmonary Disease Tool, COPD Assessment Test, and Chronic Respiratory Disease Questionnaire, highlighting the strengths and weaknesses of these instruments. We describe the effectiveness of these tools to enhance exacerbation reporting; quantify exacerbation characteristics, including the frequency, duration, and severity of events; and evaluate the outcome. We also explore the potential use of PROs in future studies to discriminate the effect of therapies on different exacerbation phenotypes and thus enhance personalized therapeutic approaches. [ABSTRACT FROM AUTHOR]

Surveys estimating chronic obstructive pulmonary disease (COPD) prevalence are unevenly distributed in the Americas, which make it difficult to estimate accurately its geographical distribution. The geographic information system inverse distance weighted (IDW) interpolation technique has proved to be an effective tool in spatial distribution estimation of epidemiological variables, even when real data are few or widely spread. We aimed to represent cartographically the COPD prevalence in the Americas by means of a blue to red scale representation of the prevalence data, where different values are represented as different colours, and a population density filtered IDW interpolation mapping, where areas with a population density <0.1 inhabitants/km2 are hidden. We systematically searched for prevalence rates from population surveys of individuals 40 years and older, and a COPD diagnosis confirmed by spirometry. Interpolation maps were obtained for the whole Americas, even from extensive areas lacking real data. Maps showed high prevalence values in the Southeast and Southwest regions of Canada bordering the United States; in several states of the Great Lakes region, and in the lower Missouri, Ohio and Mississippi basins of the United States; in the coastal regions of south-eastern and southern Brazil; Uruguay, and the Argentine Pampas. In general, most of the remaining American regions showed intermediate values of COPD prevalence. IDW interpolation seems to be a suitable tool to visually display estimates of COPD prevalence, and it may be a valuable help to draw attention about the worrying prevalence of this preventable and treatable disease. [ABSTRACT FROM AUTHOR]

Background: Alpha-1 antitrypsin deficiency (AATD) is the most common hereditary disorder in adults, but is under-recognized. In Spain, the number of patients diagnosed with AATD is much lower than expected according to epidemiologic studies. The objectives of this study were to assess the frequency and determinants of testing serum α1-antitrypsin (AAT) levels in COPD patients, and to describe factors associated with testing. Methods: EPOCONSUL is a cross-sectional clinical audit, recruiting consecutive COPD cases over one year. The study evaluated serum AAT level determination in COPD patients and associations between individual, disease-related, and hospital characteristics. Results: A total of 4,405 clinical records for COPD patients from 57 Spanish hospitals were evaluated. Only 995 (22.5%) patients had serum AAT tested on some occasion. A number of patient characteristics (being male [OR 0.5, p < 0.001], ≤55 years old [OR 2.38, p<0.001], BMI≤21 kg/m2 [OR 1.71, p<0.001], FEV1(%)<50% [OR 1.35, p<0.001], chronic bronchitis [OR 0.79, p < 0.001], Charlson index ≥ 3 [OR 0.66, p < 0.001], or history or symptoms of asthma [OR 1.32, p<0.001]), and management at a specialized COPD outpatient clinic [OR 2.73,p<0.001] were identified as factors independently associated with ever testing COPD patients for AATD. Overall, 114 COPD patients (11.5% of those tested) had AATD. Of them, 26 (22.8%) patients had severe deficiency. Patients with AATD were younger, with a low pack-year index, and were more likely to have emphysema (p<0.05). Conclusion: Testing of AAT blood levels in COPD patients treated at outpatient respiratory clinics in Spain is infrequent. However, when tested, AATD (based on the serum AAT levels ≤100 mg/dL) is detected in one in five COPD patients. Efforts to optimize AATD case detection in COPD are needed. [ABSTRACT FROM AUTHOR]

Introduction: Although Asthma-COPD Overlap (ACO) has been described among populations of subjects with COPD or asthma, ACO has never been described among a population of subjects with occupational asthma (OA). Objectives: The aims of this study were to: 1. identify ACO in a population of subjects with OA; and 2. compare the clinical characteristics between ACO and OA. Methods: This retrospective study included all subjects diagnosed with OA between 2000 and 2017 in an OA referral center. Occupational Asthma-COPD Overlap (OACO) was defined as post-bronchodilator FEV1/FVC < 70% and smoking history ≥ 10 pack-years, along with a diagnosis of OA. Results: Three hundred and four subjects were included, 262 (86.2%) were classified as OA and 42 (13.8%) as OACO. OA subjects presented higher sputum eosinophil counts after a specific-inhalation challenge than subjects with OACO (median [IQR]: 6.5 [17.0] vs 2.3 [3.5]). After adjusting for confounding factors, subjects with OACO were older (OR: 1.10 [1.05; 1.14]) and were taking higher doses of inhaled corticosteroids than OA subjects (OR, 5.20 [1.77; 16.48]). Subjects with OACO were less often atopic than OA subjects (OR, 0.19 [0.07; 0.62]). Conclusions: Subjects with OACO constitute a distinct clinical and inflammatory phenotype from subjects with OA. [ABSTRACT FROM AUTHOR]

Clinical practice guidelines are ubiquitous and are developed to provide recommendations for the management of many diseases, including chronic obstructive pulmonary disease. The development of these guidelines is burdensome, demanding a significant investment of time and money. In Europe, the majority of countries develop their own national guidelines, despite the potential for overlap or duplication of effort. A concerted effort and consolidation of resources between countries may alleviate the resource-intensity of maintaining individual national guidelines. Despite significant resource investment into the development and maintenance of clinical practice guidelines, their implementation is suboptimal. Effective strategies of guideline dissemination must be given more consideration, to ensure adequate implementation and improved patient care management in the future. [ABSTRACT FROM AUTHOR]

Nutritional abnormalities and physical inactivity are highly prevalent in patients with chronic obstructive pulmonary disease (COPD). The aim of this study was to determine the association between nutritional status/body composition and physical performance in patients with COPD. A cross-sectional observational study was conducted in outpatients with clinically stable, moderate to very severe COPD. In the assessment of nutritional status, we used dual energy X-ray absorptiometry, anthropometry, serum biomarkers, and the Mini-Nutritional Assessment (MNA) questionnaire. Physical performance was measured by the 6-minute walk distance (6MWD), 4-metre gait speed (4MGS), and physical activity. Univariate and multivariate analyses were performed. In 111 patients (mean age 68 years, 69% men), the mean 6MWD was 376 ± 119 m, 4MGS 0.9 ± 0.2 m/s, and the average daily step count 8,059 ± 4,757. Patients with low exercise capacity (6MWD ≤ 350 m) had a significantly lower lean mass index (LMI)(p< 0.01), fat-free mass index (FFMI) (p< 0.01), bone mineral content (p< 0.01), bone mineral density (p< 0.01),T-score (p< 0.05), MNA score (p< 0.01), and serum albumin and prealbumin levels (p< 0.05). Patients with low physical activity (daily step count ≤ median) had lower LMI, FFMI, MNA score, serum prealbumin (for all comparisonsp< 0.05) and vitamin D levels (p< 0.01). However, none of the nutritional variables showed an independent association with low physical performance in the multivariate models. In conclusion, patients with low physical performance have deficient nutritional status, but we could not demonstrate an independent relationship between nutritional parameters and physical performance. [ABSTRACT FROM AUTHOR]

According to the current clinical practice guidelines for chronic obstructive pulmonary disease (COPD), the addition of inhaled corticosteroids (ICS) to long-acting β2 agonist therapy is recommended in patients with moderate-to-severe disease and an increased risk of exacerbations. However, ICS are largely overprescribed in clinical practice, and most patients are unlikely to benefit from long-term ICS therapy.Evidence from recent randomized-controlled trials supports the hypothesis that ICS can be safely and effectively discontinued in patients with stable COPD and in whom ICS therapy may not be indicated, without detrimental effects on lung function, health status, or risk of exacerbations. This article summarizes the evidence supporting the discontinuation of ICS therapy, and proposes an algorithm for the implementation of ICS withdrawal in patients with COPD in clinical practice.Given the increased risk of potentially serious adverse effects and complications with ICS therapy (including pneumonia), the use of ICS should be limited to the minority of patients in whom the treatment effects outweigh the risks. [ABSTRACT FROM AUTHOR]

Background: This study assessed the adherence profiles to inhaled therapies and the agreement between two patient self-report adherence methods in stable COPD lpatients from seven Latin American countries. Methods: This observational, cross-sectional, multinational, multicenter study involved 795 COPD patients (post-bronchodilator forced expiratory volume in 1 second/forced vital capacity [FEV1/FVC] <0.70). Adherence to inhaled therapy was assessed using the specific Test of Adherence to Inhalers (10-item TAI) and the generic 8-item Morisky Medication Adherence Scale (MMAS-8) questionnaires. The percentage agreement and the kappa index were used to compare findings. Results: 59.6% of patients were male (69.5±8.7 years); post-bronchodilator FEV1 percent predicted was 50.0±18.6%. Mean values for 10-item TAI and MMAS-8 questionnaires were 47.4±4.9 and 6.8±1.6, respectively. Based on the TAI questionnaire, 54.1% of patients had good, 26.5% intermediate, and 19.4% poor adherence. Using the MMAS-8 questionnaire, 51% had high, 29.1% medium, and 19.9% low adherence. According to both questionnaires, patients with poor adherence had lower smoking history, schooling but higher COPD Assessment Test score, exacerbations in the past-year and post-bronchodilator FEV1. The agreement between 10-item TAI and MMAS-8 questionnaires was moderate (Kappa index: 0.42; agreement: 64.7%). Conclusion: Suboptimal adherence to medication was frequent in COPD patients from Latin America. Low adherence was associated with worse health status impairment and more exacerbations. There was inadequate agreement between the two questionnaires. Greater effort should be made to improve COPD patients’ adherence to treatment, and assessment of adherence with more specific instruments, such as the TAI questionnaire, would be more convenient in these patients. Clinical Trial Registration: [ABSTRACT FROM AUTHOR]

Poor sleep and attention deficits are common in COPD. To assess the relationship between self-reported poor sleep and attention deficits in COPD. We also studied the association between self-reported sleep and the attention tests with the objective characteristics of sleep. Fifty-nine COPD patients were prospectively studied. Self-reported sleep quality was assessed using the Pittsburgh sleep quality index (PSQI). Objective characteristics of sleep were assessed by actigraphy and polysomnography. Attention was evaluated with the Oxford sleep resistance test (OSLER) and the Psychomotor vigilance test (PVT). 28 (47 %) patients referred poor sleep (PSQI >5). In the OSLER test they showed earlier sleep onset than patients with good sleep, median (Interquartil range): 31.2 min (25.4–40) vs 40 min (28.5–40), p: 0.048. They also spent more time making errors: 4.5 % (0.6–7.6) of total test time vs 0.7 % (0.2–5.3), p: 0.048. In PVT, patients with poor sleep presented a greater dispersion of the reaction time values with a higher value in the slowest 10 % of the reactions, 828 (609–1667) msec. vs 708 (601–993) msec, p: 0.028. No association was found between self-reported poor sleep and objective sleep variables. We found no correlation between OSLER and PVT results and polysomnographic variables except between sleep efficiency and PVT response speed (β: 0.309, p: 0.018). Self-reported poor sleep in COPD is associated with attention deficits. Sleep quality should be included in future studies of this facet of cognition in COPD, as well as to assess its potential usefulness as a therapeutic target. • Poor sleep quality is frequent in COPD patients. • Self-reported poor sleep is associated with attention deficits in COPD patients. • COPD patients with reported poor sleep make more errors and have slower reactions. • Pittsburgh questionnaire and polysomnographic variables are not related in COPD. [ABSTRACT FROM AUTHOR]

Copyright of Archivos de Bronconeumología (English Edition) is the property of Sociedad Espanola de Neumologia y Cirugia Toracica (SEPAR) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Archivos de Bronconeumología (English Edition) is the property of Sociedad Espanola de Neumologia y Cirugia Toracica (SEPAR) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Alpha-1 antitrypsin deficiency (AATD) is a common hereditary disorder caused by mutations in the SERPINA1 gene, which encodes alpha-1 antitrypsin (AAT; also known as alpha 1-proteinase inhibitor, A1-PI). An important function of A1-PI in the lung is to inhibit neutrophil elastase, one of various proteolytic enzymes released by activated neutrophils during inflammation. Absence or deficiency of A1-PI leads to an imbalance between elastase and anti-elastase activity, which results in progressive, irreversible destruction of lung tissue, and ultimately the development of chronic obstructive pulmonary disease with early-onset emphysema. AATD is under-diagnosed, patients can experience long delays before obtaining an accurate diagnosis, and the consequences of delayed diagnosis or misdiagnosis can be severe. Currently, A1-PI therapy is the only available treatment that addresses disease etiology in patients with AATD; however, demonstrating clinical efficacy of A1-PI therapy is challenging. In order to show therapeutic efficacy with traditional endpoints such as forced expiratory volume in one second and mortality, large sample sizes and longer duration trials are required. However, AATD is a rare, slow progressive disease, which can take decades to manifest clinically and recruiting sufficient numbers of patients into prolonged placebo-controlled trials remains a significant obstacle. Despite this, the Randomized, placebo-controlled trial of augmentation therapy in Alpha 1-Proteinase Inhibitor Deficiency (RAPID) and RAPID Extension trial, the largest clinical program completed to date, utilized quantitative chest computed tomography as a sensitive and specific measure of the extent of emphysema. Findings from the RAPID/RAPID Extension program definitively confirmed the benefits of A1-PI therapy in slowing disease progression and provided evidence of a disease-modifying effect of A1-PI therapy in patients with AATD. These findings suggest that the early introduction of treatment in patients with severe emphysema-related AATD may delay the time to death, lung transplantation or crippling respiratory complaints. In addition, there is now limited evidence that A1-PI therapy provides a gain of more than five life-years, supporting previous observations based on registry data. With the clinical efficacy of A1-PI therapy now demonstrated, further studies are required to assess long-term outcomes. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) imposes a substantial burden on individuals with the disease, which can include a range of symptoms (breathlessness, cough, sputum production, wheeze, chest tightness) of varying severities. We present an overview of the biomedical literature describing reported relationships between COPD symptoms and disease burden in terms of quality of life, health status, daily activities, physical activity, sleep, comorbid anxiety, and depression, as well as risk of exacerbations and disease prognosis. In addition, the substantial variability of COPD symptoms encountered (morning, daytime, and nighttime) is addressed and their implications for disease burden considered. The findings from this narrative review, which mainly focuses on real-world and observational studies, demonstrate the impact of COPD symptoms on the burden of disease and that improved recognition and understanding of their impact is central to alleviating this burden. [ABSTRACT FROM AUTHOR]

Copyright of Archivos de Bronconeumología (English Edition) is the property of Sociedad Espanola de Neumologia y Cirugia Toracica (SEPAR) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Chronic obstructive pulmonary disease (COPD) represents one of the main causes of death worldwide. It affects hundreds of millions of people and is likely to spread further in the coming years. Despite the chronic nature of the disease and the proven efficacy of current therapies, treatment nonadherence is unfortunately common and too often related to treatment failure, disease exacerbations, hospitalizations, and high healthcare costs. At present, studies aimed to assess and improve patients' adherence in chronic respiratory diseases—and especially in COPD—are limited, but a review of the few data available makes it clear that there is a need for an innovative approach that leverages health technology to encourage patients to adhere to prescribed chronic treatments. [ABSTRACT FROM PUBLISHER]

Copyright of Archivos de Bronconeumología (English Edition) is the property of Sociedad Espanola de Neumologia y Cirugia Toracica (SEPAR) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)