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1.  Chronic Productive Cough is Associated with Death in Smokers with Early COPD 
COPD  2013;11(4):451-458.
Cough and phlegm are common in COPD. Previous studies have shown conflicting evidence regarding their association with mortality and lung function. We sought to better understand how cough and phlegm impact mortality and lung function in COPD. We analyzed data from the Lung Health Study, consisting of 5,887 smokers with mild to moderate airflow obstruction followed longitudinally. We assessed the association between baseline symptoms of cough alone, phlegm alone, and cough and phlegm with 12.5-year mortality and annual lung function decline. Average age at entry was 48.5 years (± 6.8) with 63% males and 4% African Americans. Cough alone was present in 17%, phlegm alone in 12%, while 31% had both. Neither symptom alone was associated with death, but the combination was associated with increased risk of death after adjustment for age, gender, race, smoking status at year 5, pack-years smoked, randomization group, baseline FEV1 percent predicted (HR 1.27, 95% CI 1.02–1.59). Individuals with cough and phlegm together more commonly died of respiratory causes than those without. Cough with phlegm was associated with 48 mL lower baseline FEV1 (95% CI −90, −6), while neither symptom alone was associated with baseline FEV1. No symptom was associated with FEV1 longitudinally. Cough and phlegm together are associated with mortality and lung function decrement in mild-to-moderate COPD, independent of lung function and smoking status. Respiratory causes of death are common among those with cough and phlegm. Such information can help to identify subsets of individuals with COPD having higher risk for adverse outcomes.
PMCID: PMC5120399  PMID: 24127996
Symptoms; subtypes; survival; lung function
2.  COPD Exacerbation Biomarkers Validated Using Multiple Reaction Monitoring Mass Spectrometry 
PLoS ONE  2016;11(8):e0161129.
Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) result in considerable morbidity and mortality. However, there are no objective biomarkers to diagnose AECOPD.
We used multiple reaction monitoring mass spectrometry to quantify 129 distinct proteins in plasma samples from patients with COPD. This analytical approach was first performed in a biomarker cohort of patients hospitalized with AECOPD (Cohort A, n = 72). Proteins differentially expressed between AECOPD and convalescent states were chosen using a false discovery rate <0.01 and fold change >1.2. Protein selection and classifier building were performed using an elastic net logistic regression model. The performance of the biomarker panel was then tested in two independent AECOPD cohorts (Cohort B, n = 37, and Cohort C, n = 109) using leave-pair-out cross-validation methods.
Five proteins were identified distinguishing AECOPD and convalescent states in Cohort A. Biomarker scores derived from this model were significantly higher during AECOPD than in the convalescent state in the discovery cohort (p<0.001). The receiver operating characteristic cross-validation area under the curve (CV-AUC) statistic was 0.73 in Cohort A, while in the replication cohorts the CV-AUC was 0.77 for Cohort B and 0.79 for Cohort C.
A panel of five biomarkers shows promise in distinguishing AECOPD from convalescence and may provide the basis for a clinical blood test to diagnose AECOPD. Further validation in larger cohorts is necessary for future clinical translation.
PMCID: PMC4985129  PMID: 27525416
3.  Individualized prediction of lung-function decline in chronic obstructive pulmonary disease 
The rate of lung-function decline in chronic obstructive pulmonary disease (COPD) varies substantially among individuals. We sought to develop and validate an individualized prediction model for forced expiratory volume at 1 second (FEV1) in current smokers with mild-to-moderate COPD.
Using data from a large long-term clinical trial (the Lung Health Study), we derived mixed-effects regression models to predict future FEV1 values over 11 years according to clinical traits. We modelled heterogeneity by allowing regression coefficients to vary across individuals. Two independent cohorts with COPD were used for validating the equations.
We used data from 5594 patients (mean age 48.4 yr, 63% men, mean baseline FEV1 2.75 L) to create the individualized prediction equations. There was significant between-individual variability in the rate of FEV1 decline, with the interval for the annual rate of decline that contained 95% of individuals being −124 to −15 mL/yr for smokers and −83 to 15 mL/yr for sustained quitters. Clinical variables in the final model explained 88% of variation around follow-up FEV1. The C statistic for predicting severity grades was 0.90. Prediction equations performed robustly in the 2 external data sets.
A substantial part of individual variation in FEV1 decline can be explained by easily measured clinical variables. The model developed in this work can be used for prediction of future lung health in patients with mild-to-moderate COPD.
Trial registration:
Lung Health Study —, no. NCT00000568; Pan-Canadian Early Detection of Lung Cancer Study —, no. NCT00751660
PMCID: PMC5047815  PMID: 27486205
4.  Preserved Insulin Secretory Capacity and Weight Loss Are the Predominant Predictors of Glycemic Control in Patients With Type 2 Diabetes Randomized to Roux-en-Y Gastric Bypass 
Diabetes  2015;64(9):3104-3110.
Improvement in type 2 diabetes after Roux-en-Y gastric bypass (RYGB) has been attributed partly to weight loss, but mechanisms beyond weight loss remain unclear. We performed an ancillary study to the Diabetes Surgery Study to assess changes in incretins, insulin sensitivity, and secretion 1 year after randomization to lifestyle modification and intensive medical management (LS/IMM) alone (n = 34) or in conjunction with RYGB (n = 34). The RYGB group lost more weight and had greater improvement in HbA1c. Fasting glucose was lower after RYGB than after LS/IMM, although the glucose area under the curve decreased comparably for both groups. Insulin sensitivity increased in both groups. Insulin secretion was unchanged after LS/IMM but decreased after RYGB, except for a rapid increase during the first 30 min after meal ingestion. Glucagon-like peptide 1 (GLP-1) was substantially increased after RYGB, while gastric inhibitory polypeptide and glucagon decreased. Lower HbA1c was most strongly correlated with the percentage of weight loss for both groups. At baseline, a greater C-peptide index and 90-min postprandial C-peptide level were predictive of lower HbA1c at 1 year after RYGB. β-Cell glucose sensitivity, which improved only after RYGB, and improved disposition index were associated with lower HbA1c in both groups, independent of weight loss. Weight loss and preserved β-cell function both predominantly determine the greatest glycemic benefit after RYGB.
PMCID: PMC4542441  PMID: 25901097
5.  β-Blockers for the prevention of acute exacerbations of chronic obstructive pulmonary disease (βLOCK COPD): a randomised controlled study protocol 
BMJ Open  2016;6(6):e012292.
A substantial majority of chronic obstructive pulmonary disease (COPD)-related morbidity, mortality and healthcare costs are due to acute exacerbations, but existing medications have only a modest effect on reducing their frequency, even when used in combination. Observational studies suggest β-blockers may reduce the risk of COPD exacerbations; thus, we will conduct a randomised, placebo-controlled trial to definitively assess the impact of metoprolol succinate on the rate of COPD exacerbations.
Methods and analyses
This is a multicentre, placebo-controlled, double-blind, prospective randomised trial that will enrol 1028 patients with at least moderately severe COPD over a 3-year period. Participants with at least moderate COPD will be randomised in a 1:1 fashion to receive metoprolol or placebo; the cohort will be enriched for patients at high risk for exacerbations. Patients will be screened and then randomised over a 2-week period and will then undergo a dose titration period for the following 6 weeks. Thereafter, patients will be followed for 42 additional weeks on their target dose of metoprolol or placebo followed by a 4-week washout period. The primary end point is time to first occurrence of an acute exacerbation during the treatment period. Secondary end points include rates and severity of COPD exacerbations; rate of major cardiovascular events; all-cause mortality; lung function (forced expiratory volume in 1 s (FEV1)); dyspnoea; quality of life; exercise capacity; markers of cardiac stretch (pro-NT brain natriuretic peptide) and systemic inflammation (high-sensitivity C reactive protein and fibrinogen). Analyses will be performed on an intent-to-treat basis.
Ethics and dissemination
The study protocol has been approved by the Department of Defense Human Protection Research Office and will be approved by the institutional review board of all participating centres. Study findings will be disseminated through presentations at national and international conferences and publications in peer-reviewed journals.
Trial registration number
NCT02587351; Pre-results.
PMCID: PMC4908863  PMID: 27267111
6.  Roux-en-Y gastric bypass for diabetes (the Diabetes Surgery Study): 2-year outcomes of a 5-year, randomised, controlled trial 
Conventional treatments for patients with type 2 diabetes are often inadequate. We aimed to assess outcomes of diabetes control and treatment risks 2 years after adding Roux-en-Y gastric bypass to intensive lifestyle and medical management.
We report 2-year outcomes of a 5-year randomised trial (the Diabetes Surgery Study) at four teaching hospitals (three in the USA and one in Taiwan). At baseline, eligible participants had to have HbA1c of at least 8·0% (64 mmol/mol), BMI between 30·0 and 39·9 kg/m2, and type 2 diabetes for at least 6 months, and be aged 30–67 years. We randomly assigned participants to receive either intensive lifestyle and medical management alone (lifestyle and medical management), or lifestyle and medical management plus standard Roux-en-Y gastric bypass surgery (gastric bypass). Staff from the clinical centres had access to data from individual patients, but were masked to other patients’ data and aggregated data until the 2-year follow-up. Drugs for hyperglycaemia, hypertension, and dyslipidaemia were prescribed by protocol. The primary endpoint was achievement of the composite treatment goal of HbA1c less than 7·0% (53 mmol/mol), LDL cholesterol less than 2·59 mmol/L, and systolic blood pressure less than 130 mm Hg at 12 months; here we report the composite outcome and other pre-planned secondary outcomes at 24 months. Analyses were done on an intention-to-treat basis, with multiple imputations for missing data. This study is registered with, number NCT00641251, and is still ongoing.
Between April 21, 2008, and Nov 21, 2011, we randomly assigned 120 eligible patients to either lifestyle and medical management alone (n=60) or with the addition of gastric bypass (n=60). One patient in the lifestyle and medical management group died (from pancreatic cancer), thus 119 were included in the primary analysis. Significantly more participants in the gastric bypass group achieved the composite triple endpoint at 24 months than in the lifestyle and medical management group (26 [43%] vs eight [14%]; odds ratio 5·1 [95% CI 2·0–12·6], p=0·0004), mainly through improved glycaemic control (HbA1c <7·0% [53 mmol/mol] in 45 [75%] vs 4 [24%]; treatment difference −1·9% (−2·5 to −1·4); p=0·0001). 46 clinically important adverse events occurred in the gastric bypass group and 25 in the lifestyle and medical management group (mainly infections in both groups [four in the lifestyle and medical management group, eight in the gastric bypass group]). With a negative binomial model adjusted for site, the event rate for the gastric bypass group was non-significantly higher than the lifestyle and medical management group by a factor of 1·67 (95% CI 0·98–2·87, p=0·06). Across both years of the study, the gastric bypass group had seven serious falls with five fractures, compared with three serious falls and one fracture in the lifestyle and medical management group. All fractures happened in women. Many more nutritional deficiencies occurred in the gastric bypass group (mainly deficiencies in iron, albumin, calcium, and vitamin D), despite protocol use of nutritional supplements.
The addition of gastric bypass to lifestyle and medical management in patients with type 2 diabetes improved diabetes control, but adverse events and nutritional deficiencies were more frequent. Larger and longer studies are needed to investigate whether the benefits and risk of gastric bypass for type 2 diabetes can be balanced.
Covidien, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases Nutrition Obesity Research Centers, and the National Center for Advancing Translational Sciences.
PMCID: PMC4477840  PMID: 25979364
7.  Pulmonary function in an international sample of HIV-positive, treatment-naïve adults with CD4 counts >500 cells/μL: a substudy of the INSIGHT Strategic Timing of AntiRetroviral Treatment trial 
HIV medicine  2015;16(0 0):119-128.
To describe the prevalence and correlates of chronic obstructive pulmonary disease (COPD) in a multicentre international cohort of persons living with HIV (PLWH).
We performed a cross-sectional analysis of adult PLWH, naïve to HIV treatment, with baseline CD4 cell count >500 cells/μL enrolled in the Pulmonary Substudy of the Strategic Timing of AntiRetroviral Treatment trial. We collected standardised, quality-controlled spirometry. COPD was defined as forced expiratory volume in one second/forced vital capacity (FEV1/FVC) ratio less than the lower limit of normal.
Among 1026 participants from 80 sites and 20 countries, median (IQR) age was 36 (30, 44) years, 29% were female, and time since HIV diagnosis was 1.2 (0.4, 3.5) years. Baseline CD4 cell count was 648 (583, 767) cells/μL, viral load was 4.2 (3.5, 4.7) log10 copies/mL, and 10% had viral load ≤400 copies/mL despite lack of HIV treatment. Current/former/never smokers comprised 28%/11%/61% of the cohort, respectively. COPD was present in 6.8% of participants, and varied by age, smoking status, and region. 48% of those with COPD reported lifelong nonsmoking. In multivariable regression, age and pack-years of smoking had the strongest associations with FEV1/FVC ratio (p<0.0001). There were significant differences between the effect of region on FEV1/FVC ratio (p=0.010).
Our data suggest that among PLWH, naïve to HIV treatment and with CD4 cell count >500 cells/μL, smoking and age are important factors related to COPD. Smoking cessation should remain a high global priority for clinical care and research in PLWH.
PMCID: PMC4341938  PMID: 25711330
HIV; pulmonary disease; spirometry; smoking; START trial
8.  Measuring Central Airway Obstruction. What Do Bronchoscopists Do? 
Rationale: All bronchoscopists will encounter, at some point, central airway obstruction (CAO) and will face the problem of documenting its severity. Axial imaging is suggested as the gold standard for assessing CAO, but anecdotal evidence indicates that many bronchoscopists use visual estimation. The prevalence and reliability of this method have not been extensively studied.
Objectives: This study aimed to determine bronchoscopists’ opinions about assessing CAO and to assess the variability of visual estimation.
Methods: All 438 members of the American Association of Bronchology and Interventional Pulmonology were invited to participate in an online questionnaire. In addition to reporting opinions and practice in measuring CAO, participants estimated degree of obstruction for 10 bronchoscopic photos of abnormal central airway lesions using a sliding scale from 0 to 100%.
Measurements and Main Results: Responses were obtained from 118 individuals with varied interventional bronchoscopy experience. Most participants reported using visual estimation of CAO (91%) and largely by numeric estimates (87%). A total of 55 participants volunteered additional methods they employed, and their comments reflected discontent with the dependability of those. When shown the same 10 bronchoscopic photos, estimates varied considerably, with very large ranges of responses for all images. Most (86%) agreed that measurement of airway narrowing should be standardized.
Conclusions: Although limited by sample size and static photos of abnormal airways, this study supports the tenet that most bronchoscopists use a subjective and variable method of estimating CAO, which is anecdotally pervasive in the absence of a clinically practical alternative.
PMCID: PMC4342806  PMID: 25514623
tracheal stenosis; lung transplant; tracheal neoplasm; Wegener’s granulomatosis; bronchial stenosis
9.  Does levodopa improve vision in albinism? Results of a randomized, controlled clinical trial 
Dopamine is an intermediate product in the biosynthesis of melanin pigment, which is absent or reduced in albinism. Animal research has shown that supplying a precursor to dopamine, levodopa, may improve visual acuity in albinism by enhancing neural networks. This study examines the safety and effectiveness of levodopa on best-corrected visual acuity in human subjects with albinism.
Prospective, randomized, placebo-controlled, double-masked randomized clinical trial conducted at the University of Minnesota
45 subjects with albinism
Subjects with albinism were randomly assigned to one of three treatment arms: levodopa 0.76 mg/kg with 25% carbidopa, levodopa 0.51 mg/kg with 25% carbidopa, or placebo and followed for 20 weeks, with best-corrected visual acuity measured at enrollment, and at weeks 5, 10, 15, and 20 after enrollment. Side effects were recorded with a symptom survey. Blood was drawn for genotyping.
Main Outcome Measures
Side effects and best-corrected visual acuity 20 weeks after enrollment.
All subjects had at least one mutation found in a gene known to cause albinism. Mean age was 14.5 years (range: 3.5 to 57.8 years). Follow-up was 100% and compliance was good. Minor side effects were reported; there were no serious adverse events. There was no statistically significant improvement in best-corrected visual acuity after 20 weeks with either dose of levodopa.
Levodopa, in the doses used in this trial and for the time course of administration, did not improve visual acuity in subjects with albinism.
PMCID: PMC4169362  PMID: 24641678
albinism; levodopa; visual acuity; randomized controlled trial
10.  Dating Violence, Childhood Maltreatment, and BMI From Adolescence to Young Adulthood 
Pediatrics  2014;134(4):678-685.
This study tested whether dating violence (DV) victimization is associated with increases in BMI across the transition from adolescence to young adulthood and whether gender and previous exposure to child maltreatment modify such increases.
Data were from participants (N = 9295; 49.9% female) in the National Longitudinal Study of Adolescent Health. BMI was calculated from measured height and weight at waves 2, 3, and 4 of the study. DV victimization was measured at waves 2, 3, and 4 by using items from the revised Conflict Tactics Scales. Linear regression by using generalized estimating equations with robust SEs was used to test the association. Models were stratified according to gender and history of child maltreatment.
From baseline to wave 4, BMI increased on average 6.5 units (95% confidence interval [CI]: 6.2–6.7) and 6.8 units (95% CI: 6.5–7.1) among men and women, respectively, and nearly one-half (45.5% of men; 43.9% of women) reported DV at some point. In stratified models, DV victimization (β: 0.3 [95% CI: 0.0–0.6]) independently predicted BMI increase over time in women. Exposure to childhood sexual abuse magnified the increase in BMI associated with DV victimization (β: 1.3 [95% CI: 0.3–2.3]). No other types of childhood maltreatment were significant modifiers of the DV–BMI association. Violence victimization was not associated with BMI among men.
Screening and support for DV victims, especially women who have also experienced childhood maltreatment, may be warranted to reduce the likelihood of health consequences associated with victimization.
PMCID: PMC4179102  PMID: 25201793
adolescents; child neglect; domestic violence; sexual abuse
11.  Associations of interleukin-1 gene cluster polymorphisms with C-reactive protein concentration and lung function decline in smoking-induced chronic obstructive pulmonary disease 
Objective: We reported association of haplotypes formed by IL-1b (IL1B)-511C/T (rs16944) and a variable number of tandem repeats (rs2234663) in intron 3 of IL-1 receptor antagonist (IL1RN) with rate of lung function decline in smoking-induced COPD. The aim of current study was to further investigate this association. Methods: We genotyped an additional 19 polymorphisms in IL1 cluster (including IL1A, IL1B and IL1RN) in non-Hispanic whites who had the fastest (n = 268) and the slowest (n = 292) decline of FEV1% predicted in the same study. We also analyzed the association of all 21 polymorphisms with serum CRP levels. Results: None of 21 polymorphisms showed significant association with rate of decline of lung function or CRP levels after adjusting for multiple comparisons. Before adjusting for multiple comparisons, only IL1RN_19327 (rs315949) showed significant association with lung function decline (P = 0.03, additive model). The frequencies of genotypes containing the IL1RN_19327A allele were 71.9% and 62.2%, respectively in the fast and slow decline groups (P = 0.02, odds ratio = 1.6, 95% confidence interval = 1.1-2.3); the IL1B_5200 (rs1143633) and rs2234663 in IL1RN were associated with serum CRP levels (P=0.04 and 0.03, respectively). Conclusions: No single marker was significantly associated with either rate of lung function decline or serum CRP levels.
PMCID: PMC4680456  PMID: 26722511
Chronic obstructive pulmonary disease (COPD); forced expiratory volume in one second (FEV1); genetic polymorphism; IL1 gene cluster; lung function decline; C-reactive protein
12.  Self-reported alcohol intake and risk of acute exacerbations of chronic obstructive pulmonary disease: a prospective cohort study 
To evaluate the relationship between alcohol consumption and the risk of acute exacerbation of COPD (AECOPD).
Methods and measurements
We conducted a secondary analysis of data previously collected in a large, multicenter trial of daily azithromycin in COPD. To analyze the relationship between amount of baseline self-reported alcohol consumption in the past 12 months and subsequent AECOPD, we categorized the subjects as minimal (<1 drink/month), light-to-moderate (1–60 drinks/month), or heavy alcohol users (>60 drinks/month). The primary outcome was time to first AECOPD and the secondary outcome was AECOPD rate during the 1-year study period.
Of the 1,142 enrolled participants, 1,082 completed baseline alcohol questionnaires and were included in this analysis. Six hundred and forty-five participants reported minimal alcohol intake, 363 reported light-to-moderate intake, and 74 reported heavy intake. There were no statistically significant differences in median time to first AECOPD among minimal (195 days), light-to-moderate (241 days), and heavy drinkers (288 days) (P=0.11). The mean crude rate of AECOPD did not significantly differ between minimal (1.62 events per year) and light-to-moderate (1.44 events per year) (P=0.095), or heavy drinkers (1.68 events per year) (P=0.796). There were no significant differences in hazard ratios for AECOPD after adjustment for multiple covariates.
Among persons with COPD at high risk of exacerbation, we found no significant relationship between self-reported baseline alcohol intake and subsequent exacerbations. The number of patients reporting heavy alcohol intake was small and further study is needed to determine the effect of heavy alcohol intake on AECOPD risk.
PMCID: PMC4516185  PMID: 26229455
pulmonary disease; chronic obstructive; ethanol; alcohol; alcoholism
13.  Motivational Interviewing to Enhance Nicotine Patch Treatment for Smoking Cessation among Homeless Smokers: A Randomized Controlled Trial 
Addiction (Abingdon, England)  2013;108(6):1136-1144.
To assess the effects of adding motivational interviewing (MI) counseling to nicotine patch for smoking cessation among homeless smokers.
Two-group randomized controlled trial with 26-week follow-up.
430 homeless smokers from emergency shelters and transitional housing units in Minneapolis/St. Paul, Minnesota, USA.
All participants received 8-week treatment of 21mg nicotine patch. In addition, participants in the intervention group received six individual sessions of MI counseling which aimed to increase adherence to nicotine patch and to motivate cessation. Participants in the Standard Care control group received one session of brief advice to quit smoking. Primary outcome was seven-day abstinence from cigarette smoking at 26 weeks as validated by exhaled carbon monoxide and salivary cotinine.
Using intention-to-treat analysis, verified seven-day abstinence rate at week 26 for the intervention group was non-significantly higher than for the control group (9.3% vs. 5.6%, p=0.15). Among participants that did not quit smoking, reduction in number of cigarettes from baseline to week 26 was equally high in both study groups (−13.7 ±11.9 for MI vs. −13.5 ±16.2 for Standard Care).
Adding motivational interviewing counseling to nicotine patch did not significantly increase smoking rate at 26-week follow-up for homeless smokers.
PMCID: PMC3651796  PMID: 23510102
14.  Self-reported sleep quality and acute exacerbations of chronic obstructive pulmonary disease 
Many patients with chronic obstructive pulmonary disease (COPD) suffer from poor sleep quality. We hypothesized that poor sleep quality in otherwise stable patients predicted exacerbations in these patients.
This is a secondary analysis of the results of a previously published randomized trial of azithromycin in 1,117 patients with moderate to severe COPD who were clinically stable on enrollment. Sleep quality was measured using the Pittsburgh Sleep Quality Index. Other quality of life indices included the Medical Outcome Study 36-item Short Form Health Survey and the St Georges Respiratory Questionnaire. Outcomes included time to first exacerbation and exacerbation rate.
Sleep quality was “poor” (Pittsburgh Sleep Quality Index >5) in 53% of participants but was not related to age or severity of airflow obstruction. Quality of life scores were worse in “poor” sleepers than in “good” sleepers. Major classes of comorbid conditions, including psychiatric, neurologic, and musculoskeletal disease, were more prevalent in the “poor” sleepers. Unadjusted time to first exacerbation was shorter (190 versus 239 days) and exacerbation rate (1.7 versus 1.37 per year) was greater in the poor sleepers, but no differences were observed after adjusting for medications and comorbid conditions associated with poor sleep.
Poor sleepers had greater exacerbation rates than did good sleepers. This appeared to be due largely to them having more, or more severe, concomitant medical conditions and taking more medications.
PMCID: PMC4345936  PMID: 25759571
Pittsburgh Sleep Quality Index; SF-36; St George’s Respiratory Questionnaire
16.  Club Cell Protein 16 and Disease Progression in Chronic Obstructive Pulmonary Disease 
Rationale: Club (Clara) cell protein 16 (CC-16) is a protein that is synthesized predominantly in the lungs and is detectable in serum. Its expression decreases with lung injury and smoking, and is thus a marker of bronchial cell dysfunction.
Objectives: To evaluate the possibility of using serum CC-16 as a biomarker for disease progression in chronic obstructive pulmonary disease (COPD).
Methods: We measured serum CC-16 levels from 4,724 subjects with mild-to-moderate airflow limitation in the Lung Health Study. Using a linear regression model, we determined the relationship of serum CC-16 concentrations to decline in lung function over 9 years. In addition, to determine whether CC-16 plays a major role in the pathogenesis of mild COPD, we exposed CC-16–deficient (−/−) mice to 6 months of cigarette smoke.
Measurements and Main Results: Reduced serum concentrations of CC-16 were associated with accelerated decline in FEV1 over 9 years (P < 0.0001), and this association persisted after adjustments for age, sex, race, smoking status, airway reactivity, body mass index, and baseline FEV1 (P = 0.0002). However, CC-16−/− mice did not demonstrate an enhanced risk of emphysema or small airway remodeling in response to cigarette smoke.
Conclusions: Serum CC-16 is associated with disease progression, and may assist in the identification of “rapid progressors.” However, the absence of CC-16 does not appear to modify the risk of cigarette-related COPD in mice.
PMCID: PMC3917377  PMID: 24245748
biomarker; chronic obstructive pulmonary disease; disease progression; smoking
17.  Statistical Approaches to Assess the Effects of Disease on Neurocognitive Function Over Time 
Assessment of the effects of disease on neurocognitive outcomes in children over time presents several challenges. These challenges are particularly pronounced when conducting studies in low-income countries, where standardization and validation is required for tests developed originally in high-income countries. We present a statistical methodology to assess multiple neurocognitive outcomes over time. We address the standardization and adjustment for age in neurocognitive testing, present a statistical methodology for development of a global neurocognitive score, and assess changes in individual and global neurocognitive scores over time in a cohort of children with cerebral malaria.
Ugandan children with cerebral malaria (CM, N = 44), uncomplicated malaria (UM, N = 54) and community controls (N = 89) were assessed by cognitive tests of working memory, executive attention and tactile learning at 0, 3, 6 and 24 months after recruitment. Tests were previously developed and validated for the local area. Test scores were adjusted for age, and a global score was developed based on the controls that combined the assessments of impairment in each neurocognitive domain. Global normalized Z-scores were computed for each of the three study groups. Model-based tests compare the Z-scores between groups.
We found that continuous Z-scores gave more powerful conclusions than previous analyses of the dataset. For example, at all four time points, children with CM had significantly lower global Z-scores than controls and children with UM. Our methods also provide more detailed descriptions of longitudinal trends. For example, the Z-scores of children with CM improved from initial testing to 3 months, but remained at approximately the same level below those of controls or children with UM from 3 to 24 months. Our methods for combining scores are more powerful than tests of individual cognitive domains, as testing of the individual domains revealed differences at only some but not all time points.
PMCID: PMC4221235  PMID: 25383237
Neurocognitive; Development; Malaria; Normalization; Longitudinal data analysis; Cumulative; Global score
18.  Roux-en-Y Gastric Bypass versus Intensive Medical Management for the Control of Type 2 Diabetes, Hypertension and Hyperlipidemia: An International, Multicenter, Randomized Trial 
Guideline directed care for diabetes calls for control of glycemia, blood pressure and cholesterol (composite goal). Most patients treated medically do not reach this goal.
Determine the efficacy and safety of Roux-en-Y gastric bypass (RYGB) added to lifestyle modification and intensive medical management (LS/IMM) to achieve control of all 3 endpoints.
Two-arm unblinded randomized clinical trial with 120 participants. The primary endpoint of the composite outcome was assessed at 12 months. The study began in April 2008 and completed one year follow-up in all participants in December 2012.
Four academic teaching hospitals in the U.S. and Taiwan, involving five operating surgeons.
Inclusion criteria for the Diabetes Surgery Study (DSS) included HbA1c ≥ 8.0%, BMI 30.0-39.9 kg/m2, diagnosis and treatment of type 2 diabetes for at least six months, and stimulated C peptide > 1.0 ng/ml.
All patients received lifestyle intervention modeled after the Look AHEAD study. Medications for hyperglycemia, hypertension, and dyslipidemia were prescribed according to protocol. RYGB techniques were standardized.
Main Outcome Measure
Attainment of a composite goal: HbA1c < 7.0%, LDL-C < 100 mg/dl, and SBP < 130 mmHg.
One hundred and twenty participants were randomized with equal probability into LS/IMM or RYGB (60 in each group). Baseline characteristics were similar between groups. Mean BMI was 34.6 kg/m2 (95% CI 29.2 to 40.8 kg/m2) with 71 (59%; 95% CI 50% to 68%) participants having BMI < 35 kg/m2, and mean HbA1c was 9.6% (95% CI 9.4% to 9.8%). At 12 months the followup rate was 95%, and 11 (19%) in the LS/IMM group and 28 (49%) in the RYGB group achieved the primary endpoint (OR = 4.8, 95% CI 1.9 to 11.6). RYGB participants required 3.1 fewer medications than LS/IMM (4.8 versus 1.7, 95% CI -3.6 to -2.3). Weight loss was 7.9% LS/IMM vs. 26.1% RYGB (difference 18.2% 95% CI 14.2% to 20.7%). Regression analyses indicate that achieving the composite endpoint was primarily attributable to weight loss. There were 22 serious adverse events in the RYGB group, including one cardiovascular event, and 15 in the LS/IMM group. There were 4 peri-operative complications and 6 late postoperative complications in the RYGB group. Nutritional deficiency of iron, vitamin B12 and albumin were observed more frequently with RYGB.
In mild to moderately obese patients with type 2 diabetes addition of RYGB to LS/IMM resulted in greater likelihood of achieving the composite treatment goal. RYGB participants required fewer medications but had more complications.
PMCID: PMC3954742  PMID: 23736733
19.  Effect of Partner Violence in Adolescence and Young Adulthood on Blood Pressure and Incident Hypertension 
PLoS ONE  2014;9(3):e92204.
Intimate partner violence has adverse health consequences, but little is known about its association with hypertension. This study investigates sex differences in the relationship between intimate partner violence and blood pressure outcomes. Data included 9,699 participants from waves 3 (2001–02) and 4 (2008–09) of the National Longitudinal Study of Adolescent Health (51% female). Systolic (SBP) and diastolic (DBP) blood pressure and incident hypertension (SBP≥140 mmHg, DBP≥90 mmHg, or taking antihypertensive medication) were ascertained at wave 4. Intimate partner violence was measured at wave 3 with 8 items from the revised Conflict Tactics Scales. Separate victimization and perpetration scores were calculated. Sex-specific indicators of severe victimization and perpetration were created using the 66th percentile among those exposed as a cut point. Sex-specific, linear and logistic regression models were developed adjusting for age, race, financial stress, and education. Thirty-three percent of men and 47% of women reported any intimate partner violence exposure; participants were categorized as having: no exposure, moderate victimization and / or perpetration only, severe victimization, severe perpetration, and severe victimization and perpetration. Men experiencing severe perpetration and victimization had a 2.66 mmHg (95% CI: 0.05, 5.28) higher SBP and a 59% increased odds (OR: 1.59, 95% CI: 1.07, 2.37) of incident hypertension compared to men not exposed to intimate partner violence. No other category of violence was associated with blood pressure outcomes in men. Intimate partner violence was not associated with blood pressure outcomes in women. Intimate partner violence may have long-term consequences for men's hemodynamic health. Screening men for victimization and perpetration may assist clinicians to identify individuals at increased risk of hypertension.
PMCID: PMC3962399  PMID: 24658452
20.  Fibrotic extracellular matrix activates a profibrotic positive feedback loop 
The Journal of Clinical Investigation  2014;124(4):1622-1635.
Pathological remodeling of the extracellular matrix (ECM) by fibroblasts leads to organ failure. Development of idiopathic pulmonary fibrosis (IPF) is characterized by a progressive fibrotic scarring in the lung that ultimately leads to asphyxiation; however, the cascade of events that promote IPF are not well defined. Here, we examined how the interplay between the ECM and fibroblasts affects both the transcriptome and translatome by culturing primary fibroblasts generated from IPF patient lung tissue or nonfibrotic lung tissue on decellularized lung ECM from either IPF or control patients. Surprisingly, the origin of the ECM had a greater impact on gene expression than did cell origin, and differences in translational control were more prominent than alterations in transcriptional regulation. Strikingly, genes that were translationally activated by IPF-derived ECM were enriched for those encoding ECM proteins detected in IPF tissue. We determined that genes encoding IPF-associated ECM proteins are targets for miR-29, which was downregulated in fibroblasts grown on IPF-derived ECM, and baseline expression of ECM targets could be restored by overexpression of miR-29. Our data support a model in which fibroblasts are activated to pathologically remodel the ECM in IPF via a positive feedback loop between fibroblasts and aberrant ECM. Interrupting this loop may be a strategy for IPF treatment.
PMCID: PMC3971953  PMID: 24590289
22.  Smoking Characteristics and Comorbidities in the Power To Quit Randomized Clinical Trial for Homeless Smokers 
Nicotine & Tobacco Research  2012;15(1):22-28.
Smoking prevalence in homeless populations is strikingly high (∼70%); yet, little is known about effective smoking cessation interventions for this population. We conducted a community-based clinical trial, Power To Quit (PTQ), to assess the effects of motivational interviewing (MI) and nicotine patch (nicotine replacement therapy [NRT]) on smoking cessation among homeless smokers. This paper describes the smoking characteristics and comorbidities of smokers in the study.
Four hundred and thirty homeless adult smokers were randomized to either the intervention arm (NRT + MI) or the control arm (NRT + Brief Advice). Baseline assessment included demographic information, shelter status, smoking history, motivation to quit smoking, alcohol/other substance abuse, and psychiatric comorbidities.
Of the 849 individuals who completed the eligibility survey, 578 (68.1%) were eligible and 430 (74.4% of eligibles) were enrolled. Participants were predominantly Black, male, and had mean age of 44.4 years (S D = 9.9), and the majority were unemployed (90.5%). Most participants reported sleeping in emergency shelters; nearly half had been homeless for more than a year. Nearly all the participants were daily smokers who smoked an average of 20 cigarettes/day. Nearly 40% had patient health questionnaire-9 depression scores in the moderate or worse range, and more than 80% screened positive for lifetime history of drug abuse or dependence.
This study demonstrates the feasibility of enrolling a diverse sample of homeless smokers into a smoking cessation clinical trial. The uniqueness of the study sample enables investigators to examine the influence of nicotine dependence as well as psychiatric and substance abuse comorbidities on smoking cessation outcomes.
PMCID: PMC3611988  PMID: 22589422
23.  Randomized Trial of Zileuton for Treatment of COPD Exacerbations Requiring Hospitalization 
COPD  2011;8(1):21-29.
Leukotrienes have been implicated in the pathogenesis of acute exacerbations of COPD, but leukotriene modifiers have not been studied as a possible therapy for exacerbations.
We sought to test the safety and efficacy of adding oral zileuton (a 5-lipoxygenase inhibitor) to usual treatment for acute exacerbations of COPD requiring hospitalization.
Randomized double-blind, placebo-controlled, parallel group study of zileuton 600 mg orally, 4 times daily versus placebo for 14 days starting within 12 hours of hospital admission for COPD exacerbation. Primary outcome measure was hospital length of stay; secondary outcomes included treatment failure and biomarkers of leukotriene production.
Main Findings
Sixty subjects were randomized to zileuton and 59 to placebo (the study was stopped short of enrollment goals because of slow recruitment). There was no difference in hospital length of stay (3.75±2.19 vs. 3.86±3.06 days for zileuton vs. placebo, p=0.39) or treatment failure (23% vs. 27% for zileuton vs. placebo, p=0.63) despite a decline in urinary LTE4 levels in the zileuton-treated group as compared to placebo at 24 hours (change in natural log-transformed ng/mg creatinine −1.38± 1.19 vs. 0.14±1.51, p<0.0001) and 72 hours (−1.32±2.08 vs. 0.26±1.93, p<0.006). Adverse events were similar in both groups.
Principal Conclusions
While oral zileuton during COPD exacerbations that require hospital admission is safe and reduces urinary LTE4 levels, we found no evidence suggesting that this intervention shortened hospital stay, with the limitation that our sample size may have been insufficient to detect a modest but potentially meaningful clinical improvement.
PMCID: PMC3775706  PMID: 21299475
Chronic Obstructive Pulmonary Disease (COPD); Acute exacerbation of COPD (AECOPD); Leukotrienes; Zileuton; Clinical trial
24.  Does nicotine replacement therapy cause cancer? Evidence from the Lung Health Study 
Nicotine & Tobacco Research  2009;11(9):1076-1082.
Recent genetic evidence has implicated nicotine as a possible cause of cancer, suggesting the need to examine the potential contributions of nicotine itself to cancer versus the confounding effects of addiction and thus exposures to known carcinogens. The objective of this study was to examine the relationship between nicotine replacement therapy, smoking, and cancer outcomes.
The Lung Health Study enrolled 5,887 participants in a randomized trial to prevent chronic obstructive pulmonary disease. The present study used surveillance data on 3,320 intervention participants who enrolled in the Lung Health Study for 5 years and who were then followed by the Lung Cancer Substudy for 7.5 years. Nicotine replacement therapy use and smoking exposure were recorded during the 5-year Lung Health Study trial. Surveillance for lung cancer, gastrointestinal cancer (including oral cancers), and all cancers began following the Lung Health Study.
Adjusted Cox proportional hazards regressions assessed the hazards of nicotine replacement therapy and smoking for each diagnosis group. In the adjusted models for lung cancer, nicotine replacement therapy alone was not a significant predictor (p = .57), while smoking during the Lung Health Study was a significant predictor (p = .03). When nicotine replacement therapy and smoking were entered in the same model, nicotine replacement therapy remained not significant (p = .25) and smoking was clearly significant (p = .02). Nicotine replacement therapy and smoking were not significant predictors of cancer in the models for gastrointestinal cancer or all cancers.
Although the surveillance time was short, smoking predicted cancer in this analysis and nicotine replacement therapy did not.
PMCID: PMC2725009  PMID: 19571249
25.  The Relation of Serum Myeloperoxidase to Disease Progression and Mortality in Patients with Chronic Obstructive Pulmonary Disease (COPD) 
PLoS ONE  2013;8(4):e61315.
Myeloperoxidase is a strong oxidant stored in primary granules of neutrophils with potent antibacterial and proatherogenic properties. Myeloperoxidase has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, the relationship of myeloperoxidase to health outcomes in COPD is not well known. We measured serum myeloperoxidase levels from 4,677 subjects with mild to moderate airflow limitation in the Lung Health Study. Using a Cox proportional hazards model, we determined the relationship of serum myeloperoxidase concentration to the risk of all-cause and disease specific causes of mortality. We found that serum myeloperoxidase concentrations were significantly related to accelerated decline in forced expiratory volume in 1 second (FEV1) over 11 years of follow-up (p<0.0001), and this association persisted after adjustments for age, sex, race, baseline FEV1, and smoking status (p = 0.048). Serum myeloperoxidase concentrations were also associated with increased risk of cardiovascular mortality (p = 0.036). Individuals in the highest quintile of myeloperoxidase had a hazard ratio of cardiovascular mortality of 1.90 (95% confidence interval 1.00–3.58; p = 0.049) compared with those in the lowest quintile, which was particularly notable in patients who continued to smoke (adjusted p-value of 0.0396). However, serum myeloperoxidase concentration was not related to total mortality, respiratory mortality, or deaths from malignancies. In conclusion, increased serum myeloperoxidase levels are associated with rapid lung function decline and poor cardiovascular outcomes in COPD patients, which support the emerging role of myeloperoxidase in the pathogenesis of COPD progression and cardiovascular disease.
PMCID: PMC3630209  PMID: 23637811

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