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1.  Development of a Modified BODE Index as a Mortality Risk Measure Among Older Adults With and Without Chronic Obstructive Pulmonary Disease 
American Journal of Epidemiology  2013;178(7):1150-1160.
The BODE index was developed as a prognostic mortality risk tool for persons with chronic obstructive pulmonary disease (COPD). It incorporates 4 measures: body mass index, lung obstruction, dyspnea, and exercise capacity. The intent of this study was to examine how well a BODE-like index constructed using a simpler lung function measure, peak expiratory flow, in combination with physical functioning and symptom information more readily found in survey data (a quasi-BODE index), performs in identifying persons at higher risk of mortality and whether it may be extended as an assessment of mortality risk to persons without diagnosed COPD. Using US national survey data from the Health Retirement Study for 2006–2010, each unit increase in the quasi-BODE index score was associated with a multiplicative 50% increase in mortality risk (odds ratio = 1.50, 95% confidence interval: 1.41, 1.59). The quasi-BODE index is a multidimensional health status instrument based on the BODE index, which is a good predictor of mortality. The quasi-BODE index was compiled using simple measures of physical and respiratory function. It is a potentially useful prognostic instrument for older adult populations with or without COPD, including those with severe physical limitations, particularly when combined with demographic factors and comorbid conditions.
PMCID: PMC3857925  PMID: 23928262
chronic disease; dyspnea; frail elderly; health status indicators; lung diseases, obstructive; mortality; respiratory function tests; survival
2.  Predictors for mortality in hospitalized patients with chronic obstructive pulmonary disease 
SpringerPlus  2014;3:359.
Chronic obstructive pulmonary disease (COPD) has been the only leading cause of death associated with a continuously increasing trend in the US over the past 30 years.
The aim of this research was to identify predictors for all-cause in-hospital mortality for COPD patients.
We conducted a cross-sectional study of patients with the discharge diagnosis of COPD, utilizing the 2007 Premier Perspective database. Inpatients aged 40 years and above were selected if they had a discharge with a primary diagnosis of COPD between January 1, 2007 and December 31, 2007. All data analyses were based on individual level. If a patient had multiple discharges, only the last discharge was included for mortality analysis. Predictors for mortality were identified by multiple logistic regressions. Bonferroni correction for multiple logistic regression models was adapted to control for family-wise errors.
The total of 57,224 patients was selected for data analysis in the study. All-cause in-hospital mortality for patients with COPD was 2.4%. Older age, insurance coverage, elective admission, intensive care unit admission, prolonged length of stay, increased Deyo-adapted Charlson Index (DCI) score and Elixhauser comorbidities of renal failure, metastatic cancer, solid tumor without metastasis, and weight loss were identified as independent predictors for all-cause in-hospital mortality. Antibiotics and β-blockers were predictors of lower all-cause in-hospital mortality risk after adjusting for other factors.
The nationwide discharge database provides useful information to identify predictors for all-cause in-hospital mortality of patients with COPD.
Electronic supplementary material
The online version of this article (doi:10.1186/2193-1801-3-359) contains supplementary material, which is available to authorized users.
PMCID: PMC4108717  PMID: 25061552
Chronic obstructive pulmonary disease; Mortality; Predictor
3.  Fracture Risk in Older, Long-term Survivors of Early-Stage Breast Cancer 
Breast cancer survivorship has increased and the association of long-term bone health with breast cancer and its treatment is unclear. This issue is important for older women who face an increased risk of osteoporotic fracture-related morbidity and mortality.
To examine the effect of breast cancer and its treatment on fracture risk in older breast cancer survivors and non-breast cancer comparisons.
A 10-year prospective cohort study beginning 5 years after a diagnosis of breast cancer for survivors and match date for comparison women.
The study was conducted within six integrated health care systems.
Women 65 years and older who were alive and recurrence free 5 years after a diagnosis of early-stage breast cancer and matched on age, study site, and enrollment year to a non-breast cancer comparison cohort.
Cox proportional hazards models were used to estimate the association between fracture risk and survivor-comparison status, adjusting for drugs and risk factors associated with bone health. A subanalysis was conducted to evaluate the association between tamoxifen exposure and fracture risk.
Our analysis included 1,286 survivors and 1,286 comparison women with a mean age of 77.7 years in both groups. Survivor and comparison women were predominantly white and non-Hispanic, 81.6% and 85.2%, respectively. We observed no difference in fracture rates between groups (HR=1.1; 95%CI 0.9, 1.3). The protective effect of tamoxifen was not statistically significant (HR=0.9; 95%CI 0.6, 1.2).
Our findings suggest long-term survivors of early stage breast cancer diagnosed at age 65 and older are not at increased risk of osteoporotic fractures compared to age-matched non-breast cancer women. There appears to be no long-term protection from fractures following tamoxifen use.
PMCID: PMC3686911  PMID: 23647433
Osteoporotic fractures; breast cancer survivors; postmenopausal women; cohort study; pharmacoepidemiology
4.  Increased methylation of lung cancer-associated genes in sputum DNA of former smokers with chronic mucous hypersecretion 
Respiratory Research  2014;15(1):2.
Chronic mucous hypersecretion (CMH) contributes to COPD exacerbations and increased risk for lung cancer. Because methylation of gene promoters in sputum has been shown to be associated with lung cancer risk, we tested whether such methylation was more common in persons with CMH.
Eleven genes commonly silenced by promoter methylation in lung cancer and associated with cancer risk were selected. Methylation specific PCR (MSP) was used to profile the sputum of 900 individuals in the Lovelace Smokers Cohort (LSC). Replication was performed in 490 individuals from the Pittsburgh Lung Screening Study (PLuSS).
CMH was significantly associated with an overall increased number of methylated genes, with SULF2 methylation demonstrating the most consistent association. The association between SULF2 methylation and CMH was significantly increased in males but not in females both in the LSC and PLuSS (OR = 2.72, 95% CI = 1.51-4.91, p = 0.001 and OR = 2.97, 95% CI = 1.48-5.95, p = 0.002, respectively). Further, the association between methylation and CMH was more pronounced among 139 male former smokers with persistent CMH compared to current smokers (SULF2; OR = 3.65, 95% CI = 1.59-8.37, p = 0.002).
These findings demonstrate that especially male former smokers with persistent CMH have markedly increased promoter methylation of lung cancer risk genes and potentially could be at increased risk for lung cancer.
PMCID: PMC3893562  PMID: 24405663
Methylation of gene promoters; Persistent cough and phlegm; Sputum DNA; Former smoker; Lung cancer genes
5.  New Mexican Hispanic Smokers Have Lower Odds of Chronic Obstructive Pulmonary Disease and Less Decline in Lung Function Than Non-Hispanic Whites 
Rationale: The epidemiology of cigarette smoking–related chronic obstructive pulmonary disease (COPD) is not well characterized in Hispanics in the United States. Understanding how ethnicity influences COPD is important for a number of reasons, from informing public health policies to dissecting the genetic and environmental effects that contribute to disease.
Objectives: The present study assessed differences in risk between Hispanics and non-Hispanic whites for longitudinal and cross-sectional COPD phenotypes. Genetic ancestry was used to verify findings based on self-reported ethnicity. Hispanics in New Mexico are primarily differentiated from non-Hispanic whites by their proportion of Native American ancestry.
Methods: The study was performed in a New Mexican cohort of current and former smokers. Self-reported Hispanic and non-Hispanic white ethnicity was validated by defining genetic ancestry proportions at the individual level using 48 single-nucleotide polymorphism markers. Self-reported ethnicity and genetic ancestry were independently used to assess associations with cross-sectional and longitudinal measures of lung function. Multivariable models were adjusted for indicators of smoking behavior.
Measurements and Main Results: Self-reported Hispanic ethnicity was significantly associated with lower odds of COPD (odds ratio, 0.49; 95% confidence interval, 0.35–0.71; P = 0.007), and this protection was validated by the observation that Hispanic smokers have reduced risk of rapid decline in lung function (odds ratio, 0.48; 95% confidence interval, 0.30–0.78; P = 0.003). Similar findings were noted when Native American genetic ancestry proportions were used as predictors instead of self-report of Hispanic ethnicity.
Conclusions: Hispanic ethnicity is inversely associated with cross-sectional and longitudinal spirometric COPD phenotypes even after adjustment for smoking. Native American genetic ancestry may account for this “Hispanic protection.”
PMCID: PMC3262041  PMID: 21908412
6.  Severity of COPD at initial spirometry-confirmed diagnosis: data from medical charts and administrative claims 
This study was conducted to determine COPD severity at the time of diagnosis as confirmed by spirometry in patients treated in a US managed care setting.
Patients and methods
All patients with one or more inpatient stays, one or more emergency department visits, or two or more outpatient visits with diagnosis codes for COPD during 1994–2006 were identified from the Lovelace Patient Database. From this group, a subset of continuously enrolled patients with evidence in claims of a first available pulmonary function test or pulmonary clinic visit and a confirmatory claim for a COPD diagnosis was selected. Medical chart abstraction was undertaken for this subset to gather information for diagnosis and severity staging of each patient based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria for COPD.
Of the 12,491 patients with a primary or secondary COPD diagnosis between 1994 and 2006, there were 1520 continuously enrolled patients who comprised the study cohort. Among the 648 eligible records from patients with evidence of a pulmonary function test, 366 were identified by spirometry as having COPD of GOLD stage I or higher (average percentage of predicted forced expiratory volume in 1 second: 60%): 19% were diagnosed at the stage of mild disease (GOLD stage I); 50% at moderate disease (GOLD stage II); and 31% at severe or very severe disease (GOLD stage III or IV, respectively). The majority of patients in these groups were not receiving maintenance treatment.
The results demonstrate a very low incidence of early-stage diagnosis, confirmed by a pulmonary function test, of COPD in a large US sample and support calls for increased screening for COPD and treatment upon diagnosis.
PMCID: PMC3224652  PMID: 22135490
lung function; Global Initiative for Chronic Obstructive Lung Disease (GOLD); detection; early treatment
7.  Wood Smoke Exposure and Gene Promoter Methylation Are Associated with Increased Risk for COPD in Smokers 
Rationale: Wood smoke–associated chronic obstructive pulmonary disease (COPD) is common in women in developing countries but has not been adequately described in developed countries.
Objectives: Our objective was to determine whether wood smoke exposure was a risk factor for COPD in a population of smokers in the United States and whether aberrant gene promoter methylation in sputum may modify this association.
Methods: For this cross-sectional study, 1,827 subjects were drawn from the Lovelace Smokers' Cohort, a predominantly female cohort of smokers. Wood smoke exposure was self-reported. Postbronchodilator spirometry was obtained, and COPD outcomes studied included percent predicted FEV1, airflow obstruction, and chronic bronchitis. Effect modification of wood smoke exposure with current cigarette smoke, ethnicity, sex, and promoter methylation of lung cancer-related genes in sputum on COPD outcomes were separately explored. Multivariable logistic and poisson regression models were used for binary and rate-based outcomes, respectively.
Measurements and Main Results: Self-reported wood smoke exposure was independently associated with a lower percent predicted FEV1 (point estimate [± SE] −0.03 ± 0.01) and a higher prevalence of airflow obstruction and chronic bronchitis (odds ratio, 1.96; 95% confidence interval, 1.52–2.52 and 1.64 (95% confidence interval, 1.31–2.06, respectively). These associations were stronger among current cigarette smokers, non-Hispanic whites, and men. Wood smoke exposure interacted in a multiplicative manner with aberrant promoter methylation of the p16 or GATA4 genes on lower percent predicted FEV1.
Conclusions: These studies identify a novel link between wood smoke exposure and gene promoter methylation that synergistically increases the risk for reduced lung function in cigarette smokers.
PMCID: PMC3001253  PMID: 20595226
wood smoke; cigarette smokers; airflow obstruction; gene promoter methylation in sputum DNA
8.  Economic burden of chronic bronchitis in the United States: a retrospective case-control study 
Chronic bronchitis (CB) is often misdiagnosed or diagnosed at a later stage of chronic obstructive pulmonary disease (COPD). We examined how this later diagnosis may impact health care costs and utilization during the 12 months prior to and 24 months post initial CB diagnosis.
This retrospective case-control analysis used claims data from a large US database from July 1, 2003 through June 30, 2007. Patients with CB aged 40 years and older were propensity matched (N = 11,674) to patients without evidence of COPD or asthma by demographics, CB diagnosis quarter/year, and comorbidities. Group differences were assessed using Student’s t-test and Pearson chi-square test statistics.
Six months prediagnosis, CB patients had higher frequencies of any hospitalization (9.6%, 6.7%; P < 0.05), emergency department/urgent care visits (13.3%, 6.7%; P < 0.05), and prescriptions (97.3%, 94.1%; P < 0.05). Six months postdiagnosis, CB patients had 5.6 times more hospitalizations (P < 0.05) and 3.1 times more emergency department/urgent care visits (P < 0.05) compared with controls. Mean total costs (US$) for CB patients 12 months prediagnosis were significantly higher than controls (months 12–7: $4212, $3826; P < 0.05; months 6–1: $5289, $4285; P < 0.05). CB patients had higher mean total costs ($8919; P < 0.05) 6 months postdiagnosis. Costs remained $2429 higher for CB patients 19–24 months postdiagnosis (P < 0.05).
Health care costs and utilization among CB patients are increased both prior to diagnosis and during the 2 years postdiagnosis. This study suggests that not accurately diagnosing CB early has a substantial impact on health care costs, and that the economic burden for CB patients remains elevated even after adjustment for comorbidities associated with COPD.
PMCID: PMC3034282  PMID: 21311695
chronic bronchitis; burden; economic; chronic obstructive pulmonary disease
9.  Comparative cost-effectiveness of a fluticasone-propionate/salmeterol combination versus anticholinergics as initial maintenance therapy for chronic obstructive pulmonary disease 
Relative costs and utilization-related outcomes of a fluticasone propionate 250 μg + salmeterol 50 μg combination (FSC), tiotropium bromide, and ipratropium as initial maintenance therapy in COPD have not been compared in a commercially-insured population.
This retrospective, observational cohort study used health care claims data from January 2004 to June 2009 from a large administrative database for patients aged ≥40 years with COPD. Time-to-first COPD-related health care event beginning 30 days following therapy initiation with FSC (n = 16,684), ipratropium alone or in fixed dose combination with albuterol (n = 14,449), or tiotropium (n = 12,659) was estimated using Cox proportional hazard models that controlled for differences in patient demographic characteristics, health care utilization, and comorbidities at baseline. Mean adjusted costs and numbers of COPD-related health care encounters and prescription medication fills were compared among patients with 12 months of follow-up (FSC, n = 12,595; ipratropium, n = 10,617; tiotropium, n = 9126).
With FSC as the reference, risk for a COPD-related hospitalization and/or emergency department visit was significantly higher for ipratropium (hazard ratio [HR] 1.64, 95% confidence interval [CI] 1.50–1.79) and tiotropium (HR 1.29, CI 1.17–1.41). Mean adjusted 12-month COPD-related total health care costs were lower for FSC ($2068, standard deviation [SD] $1190) than for ipratropium ($2841, SD $1858) and tiotropium ($2408, SD $1511, both P <0.05). Mean number of COPD-related hospitalizations, emergency department visits, and outpatient visits associated with an oral corticosteroid or antibiotic were also lower for FSC than for ipratropium and tiotropium (all P <0.05).
In this retrospective “real-world” observational sample of COPD patients, initiating treatment with FSC was associated with significantly better clinical and economic outcomes compared with short- and long-acting anticholinergic therapy. Consistent with the goal of preventing and reducing exacerbations advocated by global guidelines, the findings suggest that initiation of maintenance treatment with FSC may afford clinical benefits at a lower cost than anticholinergic treatment.
PMCID: PMC3034283  PMID: 21311689
chronic obstructive pulmonary disease; Advair®; tiotropium; ipratropium; utilization; costs
10.  Cost-effectiveness of combination fluticasone propionate–salmeterol 250/50 μg versus salmeterol in severe COPD patients 
To estimate the cost-effectiveness of fluticasone propionate–salmeterol combination (FSC) compared to salmeterol for maintenance therapy in severe chronic obstructive pulmonary disease (COPD).
Study design:
Pooled economic analysis.
We performed an economic analysis of pooled data from two randomized clinical trials (combined N = 1554) that evaluated the effect of maintenance therapy with FSC (250/50 μg twice daily) or salmeterol (50 μg twice daily) on exacerbation rates in patients with severe COPD. We calculated exacerbation rates and applied standardized costs to exacerbation-related health care utilization reported in the trials (office, urgent care, and emergency department visits; hospitalizations; and oral corticosteroids and antibiotics) to determine cost differences between FSC and salmeterol treatment outcomes.
Annual rates of any exacerbation and moderate/severe exacerbation were lower in the FSC group than the salmeterol group (4.91 vs 5.78 and 1.32 vs 2.00 respectively, both P < 0.05). Total adjusted annual COPD related exacerbation and therapeutic costs were $4,842 (95% CI; $4,731–$4,952) in the FSC group and $5,066 (95% CI; $4,937–$5,195) in the salmeterol group.
FSC combination therapy is associated with reduced risk of any exacerbation and moderate/severe exacerbation, and incurs lower annual COPD-related health care costs compared to treatment with salmeterol. This analysis demonstrates that FSC therapy may be advantageous from both a clinical and cost-benefit standpoint for patients with severe COPD.
PMCID: PMC2921685  PMID: 20714371
COPD; cost-effectiveness analysis; economic; maintenance therapy
11.  Hitting bacteria at the heart of the central dogma: sequence-specific inhibition 
An important objective in developing new drugs is the achievement of high specificity to maximize curing effect and minimize side-effects, and high specificity is an integral part of the antisense approach. The antisense techniques have been extensively developed from the application of simple long, regular antisense RNA (asRNA) molecules to highly modified versions conferring resistance to nucleases, stability of hybrid formation and other beneficial characteristics, though still preserving the specificity of the original nucleic acids. These new and improved second- and third-generation antisense molecules have shown promising results. The first antisense drug has been approved and more are in clinical trials. However, these antisense drugs are mainly designed for the treatment of different human cancers and other human diseases. Applying antisense gene silencing and exploiting RNA interference (RNAi) are highly developed approaches in many eukaryotic systems. But in bacteria RNAi is absent, and gene silencing by antisense compounds is not nearly as well developed, despite its great potential and the intriguing possibility of applying antisense molecules in the fight against multiresistant bacteria. Recent breakthrough and current status on the development of antisense gene silencing in bacteria including especially phosphorothioate oligonucleotides (PS-ODNs), peptide nucleic acids (PNAs) and phosphorodiamidate morpholino oligomers (PMOs) will be presented in this review.
PMCID: PMC1995221  PMID: 17692125
12.  Initiation of Protein Synthesis in Bacteria 
Valuable information on translation initiation is available from biochemical data and recently solved structures. We present a detailed description of current knowledge about the structure, function, and interactions of the individual components involved in bacterial translation initiation. The first section describes the ribosomal features relevant to the initiation process. Subsequent sections describe the structure, function, and interactions of the mRNA, the initiator tRNA, and the initiation factors IF1, IF2, and IF3. Finally, we provide an overview of mechanisms of regulation of the translation initiation event. Translation occurs on ribonucleoprotein complexes called ribosomes. The ribosome is composed of a large subunit and a small subunit that hold the activities of peptidyltransfer and decode the triplet code of the mRNA, respectively. Translation initiation is promoted by IF1, IF2, and IF3, which mediate base pairing of the initiator tRNA anticodon to the mRNA initiation codon located in the ribosomal P-site. The mechanism of translation initiation differs for canonical and leaderless mRNAs, since the latter is dependent on the relative level of the initiation factors. Regulation of translation occurs primarily in the initiation phase. Secondary structures at the mRNA ribosomal binding site (RBS) inhibit translation initiation. The accessibility of the RBS is regulated by temperature and binding of small metabolites, proteins, or antisense RNAs. The future challenge is to obtain atomic-resolution structures of complete initiation complexes in order to understand the mechanism of translation initiation in molecular detail.
PMCID: PMC1082788  PMID: 15755955

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