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1.  Asthma Outcomes: Asthma Symptoms 
Background
Respiratory symptoms are commonly used to assess the impact of patient-centered interventions.
Objective
At the request of National Institutes of Health (NIH) institutes and other federal agencies, an expert group was convened to propose which measurements of asthma symptoms should be used as a standardized measure in future clinical research studies.
Methods
Asthma symptom instruments were classified as daily diaries (prospectively recording symptoms between research visits) or retrospective questionnaires (completed at research visits). We conducted a systematic search in PubMed and a search for articles that cited key studies describing development of instruments. We classified outcome instruments as either core (required in future studies), supplemental (used according to study aims and standardized), or emerging (requiring validation and standardization). This work was discussed at an NIH-organized workshop in March 2010 and finalized in September 2011.
Results
Four instruments (3 daily diaries, 1 for adults and 2 for children; and 1 retrospective questionnaire for adults) were identified. Minimal clinically important differences have not been established for these instruments, and validation studies were only conducted in a limited number of patient populations. Validity of existing instruments may not be generalizable across racial-ethnic or other subgroups.
Conclusions
An evaluation of symptoms should be a core asthma outcome measure in clinical research. However, available instruments have limitations that preclude selection of a core instrument. The working group participants propose validation studies in diverse populations, comparisons of diaries versus retrospective questionnaires, and evaluations of symptom assessment alone versus composite scores of asthma control.
doi:10.1016/j.jaci.2011.12.981
PMCID: PMC4263029  PMID: 22386505
Asthma Symptom Utility Index; Asthma Symptom Diary Scales; Pediatric Asthma Caregiver Diary
2.  Chronic Obstructive Pulmonary Disease Readmissions at Minority-serving Institutions 
About 20% of patients hospitalized for chronic obstructive pulmonary disease (COPD) exacerbations are readmitted within 30 days. High 30-day risk-standardized readmission rates after COPD exacerbations will likely place hospitals at risk for financial penalties from the Centers for Medicare and Medicaid Services starting in fiscal year 2015. Factors contributing to hospital readmissions include healthcare quality, access to care, coordination of care between hospital and ambulatory settings, and factors linked to socioeconomic resources (e.g., social support, stable housing, transportation, and food). These concerns are exacerbated at minority-serving institutions, which provide a disproportionate share of care to patients with low socioeconomic resources. Solutions tailored to the needs of minority-serving institutions are urgently needed. We recommend research that will provide the evidence base for strategies to reduce readmissions at minority-serving institutions. Promising innovative approaches include using a nontraditional healthcare workforce, such as community health workers and peer-coaches, and telemedicine. These strategies have been successfully used in other conditions and need to be studied in patients with COPD.
doi:10.1513/AnnalsATS.201307-223OT
PMCID: PMC3960968  PMID: 24364772
COPD; hospital readmission; minority health
3.  Effect of Vitamin D3 on Asthma Treatment Failures in Adults With Symptomatic Asthma and Lower Vitamin D Levels 
JAMA  2014;311(20):2083-2091.
IMPORTANCE
In asthma and other diseases, vitamin D insufficiency is associated with adverse outcomes. It is not known if supplementing inhaled corticosteroids with oral vitamin D3 improves outcomes in patients with asthma and vitamin D insufficiency.
OBJECTIVE
To evaluate if vitamin D supplementation would improve the clinical efficacy of inhaled corticosteroids in patients with symptomatic asthma and lower vitamin D levels.
DESIGN, SETTING, AND PARTICIPANTS
The VIDA (Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma) randomized, double-blind, parallel, placebo-controlled trial studying adult patients with symptomatic asthma and a serum 25-hydroxyvitamin D level of less than 30 ng/mL was conducted across 9 academic US medical centers in the National Heart, Lung, and Blood Institute’s AsthmaNet network, with enrollment starting in April 2011 and follow-up complete by January 2014. After a run-in period that included treatment with an inhaled corticosteroid, 408 patients were randomized.
INTERVENTIONS
Oral vitamin D3 (100 000 IU once, then 4000 IU/d for 28 weeks; n = 201) or placebo (n = 207) was added to inhaled ciclesonide (320 µg/d). If asthma control was achieved after 12 weeks, ciclesonide was tapered to 160 µg/d for 8 weeks, then to 80 µg/d for 8 weeks if asthma control was maintained.
MAIN OUTCOMES AND MEASURES
The primary outcome was time to first asthma treatment failure (a composite outcome of decline in lung function and increases in use of β-agonists, systemic corticosteroids, and health care).
RESULTS
Treatment with vitamin D3 did not alter the rate of first treatment failure during 28 weeks (28%[95% CI, 21%-34%] with vitamin D3 vs 29% [95% CI, 23%–35%] with placebo; adjusted hazard ratio, 0.9 [95% CI, 0.6–1.3]). Of 14 prespecified secondary outcomes, 9 were analyzed, including asthma exacerbation; of those 9, the only statistically significant outcome was a small difference in the overall dose of ciclesonide required to maintain asthma control (111.3 µg/d [95% CI, 102.2–120.4 µg/d] in the vitamin D3 group vs 126.2 µg/d [95% CI, 117.2–135.3 µg/d] in the placebo group; difference of 14.9 µg/d [95% CI, 2.1–27.7 µg/d]).
CONCLUSIONS AND RELEVANCE
Vitamin D3 did not reduce the rate of first treatment failure or exacerbation in adults with persistent asthma and vitamin D insufficiency. These findings do not support a strategy of therapeutic vitamin D3 supplementation in patients with symptomatic asthma.
TRIAL REGISTRATION
clinicaltrials.gov Identifier: NCT01248065
doi:10.1001/jama.2014.5052
PMCID: PMC4217655  PMID: 24838406
4.  Feasibility of Implementing a Comprehensive Warfarin Pharmacogenetics Service 
Pharmacotherapy  2013;33(11):1156-1164.
Objective
To determine the procedural feasibility of a pharmacist-led interdisciplinary service for providing genotype-guided warfarin dosing for hospitalized patients newly starting warfarin.
Design
Prospective observational study
Setting
483-bed hospital affiliated with a large academic institution
Participants
Eighty patients started on warfarin and managed by a newly implemented pharmacogenetics service.
Intervention
Routine warfarin genotyping and clinical pharmacogenetics consultation
Measurements and Main Results
The primary outcomes were percent of genotype-guided dose recommendations available prior to the second warfarin dose and adherence of the medical staff to doses recommended by the pharmacogenetics service. Of 436 genotype orders during the first 6 months of the service, 190 were deemed appropriate. For 80 patients on the service who consented to data collection, 77% of genotypes were available prior to the second warfarin dose. The median (range) time from the genotype order to the genotype result was 26 (7 to 80) hours, and the time to genotype-guided dosing recommendation was 30 (7 to 80) hours. Seventy-three percent of warfarin doses ordered by the medical staff were within 0.5 mg of the dose recommended by the pharmacogenetics consult service.
Conclusions
Providing routine genotype-guided warfarin dosing supported by a pharmacogenetics consult service is feasible from a procedural standpoint, with the majority of genotypes available prior to the second warfarin dose and good adherence to genotype-guided dose recommendations by the medical staff.
doi:10.1002/phar.1329
PMCID: PMC3985126  PMID: 23864527
warfarin; pharmacogenetics; CYP2C9; VKORC1; genotype feasibility; implementation; pharmacogenetics service
5.  Health Monitors for Chronic Disease by Gait Analysis with Mobile Phones 
Telemedicine Journal and e-Health  2014;20(11):1035-1041.
Abstract
We have developed GaitTrack, a phone application to detect health status while the smartphone is carried normally. GaitTrack software monitors walking patterns, using only accelerometers embedded in phones to record spatiotemporal motion, without the need for sensors external to the phone. Our software transforms smartphones into health monitors, using eight parameters of phone motion transformed into body motion by the gait model. GaitTrack is designed to detect health status while the smartphone is carried during normal activities, namely, free-living walking. The current method for assessing free-living walking is medical accelerometers, so we present evidence that mobile phones running our software are more accurate. We then show our gait model is more accurate than medical pedometers for counting steps of patients with chronic disease. Our gait model was evaluated in a pilot study involving 30 patients with chronic lung disease. The six-minute walk test (6MWT) is a major assessment for chronic heart and lung disease, including congestive heart failure and especially chronic obstructive pulmonary disease (COPD), affecting millions of persons. The 6MWT consists of walking back and forth along a measured distance for 6 minutes. The gait model using linear regression performed with 94.13% accuracy in measuring walk distance, compared with the established standard of direct observation. We also evaluated a different statistical model using the same gait parameters to predict health status through lung function. This gait model has high accuracy when applied to demographic cohorts, for example, 89.22% accuracy testing the cohort of 12 female patients with ages 50–64 years.
doi:10.1089/tmj.2014.0025
PMCID: PMC4229704  PMID: 24694291
home health monitoring; chronic obstructive pulmonary disease; mobile phones; gait analysis; health monitors; m-health
6.  Bidirectional Relationship between Cognitive Function and Pneumonia 
Rationale: Relationships between chronic health conditions and acute infections remain poorly understood. Preclinical studies suggest crosstalk between nervous and immune systems.
Objectives: To determine bidirectional relationships between cognition and pneumonia.
Methods: We conducted longitudinal analyses of a population-based cohort over 10 years. We determined whether changes in cognition increase risk of pneumonia hospitalization by trajectory analyses and joint modeling. We then determined whether pneumonia hospitalization increased risk of subsequent dementia using a Cox model with pneumonia as a time-varying covariate.
Measurements and Main Results: Of the 5,888 participants, 639 (10.9%) were hospitalized with pneumonia at least once. Most participants had normal cognition before pneumonia. Three cognition trajectories were identified: no, minimal, and severe rapid decline. A greater proportion of participants hospitalized with pneumonia were on trajectories of minimal or severe decline before occurrence of pneumonia compared with those never hospitalized with pneumonia (proportion with no, minimal, and severe decline were 67.1%, 22.8%, and 10.0% vs. 76.0%, 19.3%, and 4.6% for participants with and without pneumonia, respectively; P < 0.001). Small subclinical changes in cognition increased risk of pneumonia, even in those with normal cognition and physical function before pneumonia (β = −0.02; P < 0.001). Participants with pneumonia were subsequently at an increased risk of dementia (hazard ratio, 2.24 [95% confidence interval, 1.62–3.11]; P = 0.01). Associations were independent of demographics, health behaviors, other chronic conditions, and physical function. Bidirectional relationship did not vary based on severity of disease, and similar associations were noted for those with severe sepsis and other infections.
Conclusions: A bidirectional relationship exists between pneumonia and cognition and may explain how a single episode of infection in well-appearing older individuals accelerates decline in chronic health conditions and loss of functional independence.
doi:10.1164/rccm.201212-2154OC
PMCID: PMC3827700  PMID: 23848267
pneumonia; dementia; cognitive function
7.  A National Strategy to Develop Pragmatic Clinical Trials Infrastructure 
An important challenge in comparative effectiveness research is the lack of infrastructure to support pragmatic clinical trials, which compare interventions in usual practice settings and subjects. These trials present challenges that differ from those of classical efficacy trials, which are conducted under ideal circumstances, in patients selected for their suitability, and with highly controlled protocols.
In 2012, we launched a one-year learning network to identify high priority pragmatic clinical trials and to deploy research infrastructure through the NIH Clinical and Translational Science Awards Consortium that could be used to launch and sustain them. The network and infrastructure were initiated as a learning ground and shared resource for investigators and communities interested in developing pragmatic clinical trials.
We followed a three-stage process of developing the network, prioritizing proposed trials, and implementing learning exercises that culminated in a one-day network meeting at the end of the year. The year-long project resulted in five recommendations related to developing the network, enhancing community engagement, addressing regulatory challenges, advancing information technology, and developing research methods. The recommendations can be implemented within 24 months and are designed to lead toward a sustained national infrastructure for pragmatic trials.
doi:10.1111/cts.12143
PMCID: PMC4126802  PMID: 24472114
trials; translational research; ethics; methodology
8.  Measuring health-related quality of life in chronic obstructive pulmonary disease: properties of the EQ-5D-5L and PROMIS-43 short form 
Background
The Patient Reported Outcomes Measurement Information System 43-item short form (PROMIS-43) and the five-level EQ-5D (EQ-5D-5L) are recently developed measures of health-related quality of life (HRQL) that have potentially broad application in evaluating treatments and capturing burden of respiratory-related diseases. The aims of this study were: (1) to examine their psychometric properties in patients with chronic obstructive pulmonary disease (COPD), and (2) to identify dimensions of HRQL that differ and do not differ by lung function.
Methods
We conducted a multi-center, cross-sectional study (“COPD Outcomes-based Network for Clinical Effectiveness & Research Translation” [CONCERT]). We analyzed patients who met spirometric criteria for COPD, and completed EQ-5D-5L and PROMIS questionnaires. Disease severity was graded based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification. Pulmonary function test, PROMIS-43, EQ-5D (index score and EQ-Visual Analog Scale [EQ-VAS]), six minute walk test (6MWT), and three dyspnea scales (mMRC, Borg, FACIT-Dyspnea) were administered. Validity and reliability of EQ-5D-5L and PROMIS-43 were examined, and differences in HRQL by GOLD grade were assessed.
Results
Data from 670 patients with COPD were analyzed (mean age 68.5 years; 58% male). More severe COPD was associated with more problems with mobility, self-care and usual activities (all p-values <0.01) according to EQ-5D-5L. Related domains on EQ-5D-5L, PROMIS and clinical measures were moderately (r = 0.30-0.49) to strongly (r ≥ 0.50) correlated. A statistically significant trend of decreasing HRQL with more severe lung functions was observed for EQ-5D-5L index scores, EQ-VAS scores, and PROMIS physical function and social roles.
Conclusions
Results supported the validity of EQ-5D-5L and PROMIS-43 in COPD patients, and indicate that physical function and social activities decrease with level of lung function by GOLD grade, but not pain, mental health, sleep or fatigue as reported by patients.
doi:10.1186/1471-2288-14-78
PMCID: PMC4072614  PMID: 24934150
COPD; EQ-5D-5L; PROMIS; Psychometric properties
9.  CAPriCORN: Chicago Area Patient-Centered Outcomes Research Network 
The Chicago Area Patient-Centered Outcomes Research Network (CAPriCORN) represents an unprecedented collaboration across diverse healthcare institutions including private, county, and state hospitals and health systems, a consortium of Federally Qualified Health Centers, and two Department of Veterans Affairs hospitals. CAPriCORN builds on the strengths of our institutions to develop a cross-cutting infrastructure for sustainable and patient-centered comparative effectiveness research in Chicago. Unique aspects include collaboration with the University HealthSystem Consortium to aggregate data across sites, a centralized communication center to integrate patient recruitment with the data infrastructure, and a centralized institutional review board to ensure a strong and efficient human subject protection program. With coordination by the Chicago Community Trust and the Illinois Medical District Commission, CAPriCORN will model how healthcare institutions can overcome barriers of data integration, marketplace competition, and care fragmentation to develop, test, and implement strategies to improve care for diverse populations and reduce health disparities.
doi:10.1136/amiajnl-2014-002827
PMCID: PMC4078298  PMID: 24821736
Patient Centered; Clinical Data Network; Outcomes Research
10.  Obesity Is Associated With a Lower Resting Oxygen Saturation in the Ambulatory Elderly: Results From the Cardiovascular Health Study 
Respiratory care  2013;58(5):10.4187/respcare.02008.
BACKGROUND
The contribution of obesity to hypoxemia has not been reported in a community-based study. Our hypothesis was that increasing obesity would be independently associated with lower SpO2 in an ambulatory elderly population.
METHODS
The Cardiovascular Health Study ascertained resting SpO2 in 2,252 subjects over age 64. We used multiple linear regression to estimate the association of body mass index (BMI) with SpO2 and to adjust for potentially confounding factors. Covariates including age, sex, race, smoking, airway obstruction (based on spirometry), self reported diagnosis of emphysema, asthma, heart failure, and left ventricular function (by echocardiography) were evaluated.
RESULTS
Among 2,252 subjects the mean and median SpO2 were 97.6% and 98.0% respectively; 5% of subjects had SpO2 values below 95%. BMI was negatively correlated with SpO2 (Spearman R = −0.27, P < .001). The mean difference in SpO2 between the lowest and highest BMI categories (< 25 kg/m2 and ≥ 35 kg/m2) was 1.33% (95% CI 0.89–1.78%). In multivariable linear regression analysis, SpO2 was significantly inversely associated with BMI (1.4% per 10 units of BMI, 95% CI 1.2–1.6, for whites/others, and 0.87% per 10 units of BMI, 95% CI 0.47–1.27, for African Americans).
CONCLUSIONS
We found a narrow distribution of SpO2 values in a community-based sample of ambulatory elderly. Obesity was a strong independent contributor to a low SpO2, with effects comparable to or greater than other factors clinically associated with lower SpO2.
doi:10.4187/respcare.02008
PMCID: PMC3885157  PMID: 23107018
pulse oximetry; oxygen; obesity; body mass index; waist circumference; hypoxemia; pulmonary function test
11.  Stakeholder Priorities for Comparative Effectiveness Research in Chronic Obstructive Pulmonary Disease 
Comparative effectiveness research (CER) is intended to address the expressed needs of patients, clinicians, and other stakeholders. Representatives of 54 stakeholder groups with an interest in chronic obstructive pulmonary disease (COPD) participated in workshops convened by the COPD Outcomes-based Network for Clinical Effectiveness and Research Translation (CONCERT) over a 2-year period. Year 1 focused on chronic care and care coordination. Year 2 focused on acute care and transitions in care between healthcare settings. Discussions and provisional voting were conducted via teleconferences and e-mail exchanges before the workshop. Final prioritization votes occurred after in-person discussions at the workshop. We used a modified Delphi approach to facilitate discussions and consensus building. To more easily quantify preferences and to evaluate the internal consistency of rankings, the Analytic Hierarchy Process was incorporated in Year 2. Results of preworkshop and final workshop voting often differed, suggesting that prioritization efforts relying solely on requests for topics from stakeholder groups without in-person discussion may provide different research priorities. Research priorities varied across stakeholder groups, but generally focused on studies to evaluate different approaches to healthcare delivery (e.g., spirometry for diagnosis and treatment, integrated healthcare strategies during transitions in care) rather than head-to-head comparisons of medications. This research agenda may help to inform groups intending to respond to CER funding opportunities in COPD. The methodologies used, detailed in the online supplement, may also help to inform prioritization efforts for CER in other health conditions.
doi:10.1164/rccm.201206-0994WS
PMCID: PMC3603554  PMID: 23155144
health services research; research priorities; care coordination; stakeholders
12.  Effects of respiratory and non-respiratory factors on disability among older adults with airway obstruction: The Cardiovascular Health Study 
COPD  2013;10(5):588-596.
Background:
High rates of disability associated with chronic airway obstruction may be caused by impaired pulmonary function, pulmonary symptoms, other chronic diseases, or systemic inflammation.
Methods:
We analyzed data from the Cardiovascular Health Study, a longitudinal cohort of 5888 older adults. Categories of lung function (normal; restricted; borderline, mild-moderate, and severe obstruction) were delineated by baseline spirometry (without bronchodilator). Disability-free years were calculated as total years alive and without self-report of difficulty performing ≥1 Instrumental Activities of Daily Living over 6 years of follow-up. Using linear regression, we compared disability-free years by lung disease category, adjusting for demographic factors, body mass index, smoking, cognition, and other chronic comorbidities. Among participants with airflow obstruction, we examined the association of respiratory factors (FEV1 and dyspnea) and non-respiratory factors (ischemic heart disease, congestive heart failure, diabetes, muscle weakness, osteoporosis, depression and cognitive impairment) on disability-free years.
Results:
The average disability free years were 4.0 out of a possible 6 years. Severe obstruction was associated with 1 fewer disability-free year compared to normal spirometry in the adjusted model. For the 1,048 participants with airway obstruction, both respiratory factors (FEV1 and dyspnea) and non-respiratory factors (heart disease, coronary artery disease, diabetes, depression, osteoporosis, cognitive function, and weakness) were associated with decreased disability-free years.
Conclusions:
Severe obstruction is associated with greater disability compared to patients with normal spirometery. Both respiratory and non-respiratory factors contribute to disability in older adults with abnormal spirometry.
doi:10.3109/15412555.2013.781148
PMCID: PMC3903127  PMID: 23819728
Chronic airflow obstruction; instrumental activities of daily living; disability; disablement process
13.  Safety and Feasibility of Bronchial Thermoplasty in Asthma Patients with Very Severe Fixed Airflow Obstruction: A Case Series 
Objective
Bronchial thermoplasty (BT) can provide relief for patients with severe, uncontrolled asthma despite maximal medical therapy. However, it is unclear whether BT is safe in patients with very severe airflow obstruction.
Methods
We performed BT in eight patients with severe asthma as defined by Expert Panel Report 3 (EPR-3) guidelines who were poorly controlled despite step 5 therapy. Data were available on each subject for 1 year prior to and 15–72 weeks following BT.
Results
The mean (±SEM) pre-bronchodilator forced expiratory volume in one second (FEV1) prior to BT was 51.8 ± 8.6% of predicted, and the mean (±SEM) number of hospitalizations for asthma in the year prior to BT was 2.9 ± 1.2. No subject had an unexpected severe adverse event due to BT. Among the eight patients with follow-up of at least 15 weeks, there was no significant decline in FEV1 (p = .4).
Conclusion
We suggest that BT may be safe for asthma patients with severe airflow obstruction and higher hospitalization rates than previously reported.
doi:10.3109/02770903.2012.751997
PMCID: PMC3842587  PMID: 23252954
airway smooth muscle; persistent airflow obstruction; poorly controlled asthma; radiofrequency ablation; refractory asthma
14.  Teaching the Use of Respiratory Inhalers to Hospitalized Patients with Asthma or COPD: a Randomized Trial 
Journal of General Internal Medicine  2012;27(10):1317-1325.
ABSTRACT
BACKGROUND
Hospitalized patients frequently misuse their respiratory inhalers, yet it is unclear what the most effective hospital-based educational intervention is for this population.
OBJECTIVE
To compare two strategies for teaching inhaler use to hospitalized patients with asthma or chronic obstructive pulmonary disease (COPD).
DESIGN
A Phase-II randomized controlled clinical trial enrolled hospitalized adults with physician diagnosed asthma or COPD.
PARTICIPANTS
Hospitalized adults (age 18 years or older) with asthma or COPD.
INTERVENTIONS
Participants were randomized to brief intervention [BI]: single-set of verbal and written step-by-step instructions, or, teach-to-goal [TTG]: BI plus repeated demonstrations of inhaler use and participant comprehension assessments (teach-back).
MAIN MEASURES
The primary outcome was metered-dose inhaler (MDI) misuse post-intervention (<75% steps correct). Secondary outcomes included Diskus® misuse, self-reported inhaler technique confidence and prevalence of 30-day health-related events.
KEY RESULTS
Of 80 eligible participants, fifty (63%) were enrolled (BI n = 26, TTG n = 24). While the majority of participants reported being confident with their inhaler technique (MDI 70%, Diskus® 94%), most misused their inhalers pre-intervention (MDI 62%, Diskus® 78%). Post-intervention MDI misuse was significantly lower after TTG vs. BI (12.5 vs. 46%, p = 0.01). The results for Diskus® were similar and approached significance (25 vs. 80%, p = 0.05). Participants with 30-day acute health-related events were less common in the group receiving TTG vs. BI (1 vs. 8, p = 0.02).
CONCLUSIONS
TTG appears to be more effective compared with BI. Patients over-estimate their inhaler technique, emphasizing the need for hospital-based interventions to correct inhaler misuse. Although TTG was associated with fewer post-hospitalization health-related events, larger, multi-centered studies are needed to evaluate the durability and clinical outcomes associated with this hospital-based education.
doi:10.1007/s11606-012-2090-9
PMCID: PMC3445679  PMID: 22592354
respiratory inhalers; teach-to-goal; hospitalized patients; health literacy; asthma; COPD
15.  Maternal asthma and microRNA regulation of soluble HLA-G in the airway. 
Background
We previously reported an interaction between maternal asthma and the child’s HLA-G genotype on the child’s subsequent risk for asthma. The implicated SNP at +3142 disrupted a target site for the microRNA (miR)-152 family. We hypothesized that the interaction effect may be mediated by these miRs
Objective
The objective of this study was to test this hypothesis in adults with asthma who are a subset of the same subjects who participated in our earlier family-based studies.
Methods
We measured soluble (s)HLA-G concentrations in bronchial alveolar lavage (BAL) fluid (N=36) and plasma (N=57) from adult asthmatics with and without a mother with asthma, and HLA-G and miR-152 family (miR-148a, -148b, and -152) transcript levels in airway epithelial cells from the same individuals.
Results
miR-148b levels were significantly elevated in airway epithelial cells from asthmatics with an asthmatic mother compared to asthmatics without an asthmatic mother, and +3142 genotypes were associated with sHLA-G concentrations in BAL fluid among asthmatic individuals with an asthmatic mother but not among those with a non-asthmatic mother. Neither effect was observed in the plasma (sHLA-G) or white blood cells (miRNA).
Conclusion
These combined results are consistent with +3142 allele-specific targeting of HLA-G by the miR-152 family, and support our hypothesis that miRNA regulation of sHLA-G in the airway is influenced by both the asthma status of the subject’s mother and the subject’s genotype. Moreover, we demonstrate that the effects of maternal asthma on the gene regulatory landscape in the airways of her children persist into adulthood.
doi:10.1016/j.jaci.2013.01.037
PMCID: PMC3779062  PMID: 23534973
Asthma; maternal asthma; microRNA; Human Leukocyte Antigen
16.  Patient factors associated with hospital discharge to care facility following critical illness 
Background
Many critically ill (CI) patients are transferred to other care facilities instead of to home at hospital discharge.
Objective
To identify patient factors associated with hospital discharge to care facility following CI, and to estimate the magnitude of risk associated with each factor.
Methods
Retrospective cohort study conducted in a medical intensive care unit. We studied 548 survivors of CI. Multivariable logistic regression was employed to identify independent risk factors for discharge to care facility. Only the first 72 hours of intensive care were analyzed.
Results
Approximately one-quarter of the survivors of CI were discharged to a care facility instead of to home (143/548, 26.1%). This event occurred more commonly in older patients, even after adjustment for severity of illness and comorbidities (odds ratio [OR] 1.8 for patients ≥ 65 years of age versus patients < 65 years; 95% confidence interval [CI] 1.1–3.1, p=0.02). The risk was greatest for patients who received mechanical ventilation (OR 3.4; 95% CI 2.0–5.8; p<0.001) or had hospitalizations characterized by severe cognitive dysfunction (OR 8.1; 95% CI 1.3–50.6; p=0.02) or poor strength and/or mobility (OR 31.7; 95% CI 6.4–157.3; p<0.001). The model showed good discrimination (area under the curve 0.82; 95% CI 0.77–0.86).
Conclusion
Our model, which did not include baseline function or social variables, provided good discrimination between patients discharged to care facility following CI and patients discharged to home. These results suggest that future research should focus on the debilitating effects of respiratory failure and on conditions with cognitive and neuromuscular sequelae.
doi:10.4037/ajcc2011827
PMCID: PMC3735167  PMID: 21885459
critical illness; critical care nursing; chronic disease; long term care; nursing homes
17.  Outcomes of Noninvasive Ventilation for Acute Exacerbations of Chronic Obstructive Pulmonary Disease in the United States, 1998–2008 
Rationale: The patterns and outcomes of noninvasive, positive-pressure ventilation (NIPPV) use in patients hospitalized for acute exacerbations of chronic obstructive pulmonary disease (COPD) nationwide are unknown.
Objectives: To determine the prevalence and trends of noninvasive ventilation for acute COPD.
Methods: We used data from the Healthcare Cost and Utilization Project's Nationwide Inpatient Sample to assess the pattern and outcomes of NIPPV use for acute exacerbations of COPD from 1998 to 2008.
Measurements and Main Results: An estimated 7,511,267 admissions for acute exacerbations occurred from 1998 to 2008. There was a 462% increase in NIPPV use (from 1.0 to 4.5% of all admissions) and a 42% decline in invasive mechanical ventilation (IMV) use (from 6.0 to 3.5% of all admissions) during these years. This was accompanied by an increase in the size of a small cohort of patients requiring transition from NIPPV to IMV. In-hospital mortality in this group appeared to be worsening over time. By 2008, these patients had a high mortality rate (29.3%), which represented 61% higher odds of death compared with patients directly placed on IMV (95% confidence interval, 24–109%) and 677% greater odds of death compared with patients treated with NIPPV alone (95% confidence interval, 475–948%). With the exception of patients transitioned from NIPPV to IMV, in-hospital outcomes were favorable and improved steadily year by year.
Conclusions: The use of NIPPV has increased significantly over time among patients hospitalized for acute exacerbations of COPD, whereas the need for intubation and in-hospital mortality has declined. However, the rising mortality rate in a small but expanding group of patients requiring invasive mechanical ventilation after treatment with noninvasive ventilation needs further investigation.
doi:10.1164/rccm.201106-1094OC
PMCID: PMC3297087  PMID: 22016446
COPD; positive-pressure ventilation; artificial respiration; epidemiology
18.  Adherence to inhaled corticosteroids: An ancillary study of the Childhood Asthma Management Program clinical trial 
Background
Information comparing subjective and objective measurements of adherence to study medications and the effects of adherence on treatment-related differences in asthma clinical trials are limited.
Objective
We sought to compare subjective and objective measurements of children’s adherence to inhaled corticosteroids or placebo and to determine whether adherence to study medications modified treatment-related differences in outcomes.
Methods
In an ancillary study conducted in 3 of 8 Childhood Asthma Management Program Clinical Centers, adherence was assessed by using self-reported and objective data in 5- to 12-year-old children with mild or moderate asthma who were randomly assigned to 200 μg of inhaled budesonide twice per day (n = 84) or placebo (n = 56) for 4 years. The κ statistic was used to evaluate agreement between self-reported adherence (daily diary cards) and objectively measured adherence (number of doses left in study inhalers). Multivariable analyses were used to determine whether adherence to study treatment modified treatment-related differences in outcomes.
Results
Adherence of less than 80% was seen in 75% of 140 children when adherence was measured objectively but only in 6% of children when measured by means of self-report. There was poor agreement between objective and subjective measurements of adherence of at least 80% (κ = 0.00; 95% CI, −0.05 to 0.04); self-reported adherence over the 4-year period generally overestimated objectively measured adherence (93.6% vs 60.8%, P < .0001). There was little evidence to indicate that adherence modified treatment-related differences in outcomes.
Conclusion
Researchers should use objective rather than self-reported adherence data to identify clinical trial participants with low levels of adherence to study treatment.
doi:10.1016/j.jaci.2011.10.030
PMCID: PMC3350797  PMID: 22104610
Asthma; adherence; compliance; children; lung growth; inhaled corticosteroids; budesonide; clinical trial
19.  Confirmatory spirometry for adults hospitalized with a diagnosis of asthma or chronic obstructive pulmonary disease exacerbation 
Background
Objective measurement of airflow obstruction by spirometry is an essential part of the diagnosis of asthma or COPD. During exacerbations, the feasibility and utility of spirometry to confirm the diagnosis of asthma or chronic obstructive pulmonary disease (COPD) are unclear. Addressing these gaps in knowledge may help define the need for confirmatory testing in clinical care and quality improvement efforts. This study was designed to determine the feasibility of spirometry and to determine its utility to confirm the diagnosis in patients hospitalized with a physician diagnosis of asthma or COPD exacerbation.
Methods
Multi-center study of four academic healthcare institutions. Spirometry was performed in 113 adults admitted to general medicine wards with a physician diagnosis of asthma or COPD exacerbation. Two board-certified pulmonologists evaluated the spirometry tracings to determine the proportion of patients able to produce adequate quality spirometry data. Findings were interpreted to evaluate the utility of spirometry to confirm the presence of obstructive lung disease, according to the 2005 European Respiratory Society/American Thoracic Society recommendations.
Results
There was an almost perfect agreement for acceptability (κ = 0.92) and reproducibility (κ =0.93) of spirometry tracings. Three-quarters (73%) of the tests were interpreted by both pulmonologists as being of adequate quality. Of these adequate quality tests, 22% did not present objective evidence of obstructive lung disease. Obese patients (BMI ≥30 kg/m2) were more likely to produce spirometry tracings with no evidence of obstructive lung disease, compared to non-obese patients (33% vs. 8%, p = 0.007).
Conclusions
Adequate quality spirometry can be obtained in most hospitalized adults with a physician diagnosis of asthma or COPD exacerbation. Confirmatory spirometry could be a useful tool to help reduce overdiagnosis of obstructive lung disease, especially among obese patients.
doi:10.1186/1471-2466-12-73
PMCID: PMC3538708  PMID: 23217023
Asthma; COPD; Exacerbation; Hospitalization; Spirometry; Quality improvement
20.  Comparative effectiveness research in chronic obstructive pulmonary disease 
Chronic obstructive pulmonary disease affects millions worldwide. It is America’s third leading cause of death, and results in significant morbidity and cost. Although many therapies exist and are being developed to alleviate symptoms and decrease morbidity and mortality in chronic obstructive pulmonary disease, most have only been studied in placebo-controlled efficacy studies in highly selected populations. Comparative effectiveness and translational research in chronic obstructive pulmonary disease will require the development of infrastructures to support collaboration between researchers and the stakeholders who generate, disseminate and use new knowledge. Methodologies need to evolve to both prioritize research questions and to conduct collaborative comparative effectiveness research studies. Given the impracticality of testing every clinical intervention in comparative pragmatic trials for comparative effectiveness research in chronic obstructive pulmonary disease, we advocate expanding methodology that includes the use of observational databases with serially performed effectiveness analyses and quasi-experimental designs that include following healthcare changes longitudinally over time to assess benefit, harm, subgroups and cost.
doi:10.2217/cer.11.10
PMCID: PMC3479302  PMID: 23105965
chronic obstructive pulmonary disease; comparative effectiveness research; data warehouse; emphysema; health services research; outcome research; quasi-experimental design; registry; translational research
21.  Comparative Effectiveness Research in Lung Diseases and Sleep Disorders 
The Division of Lung Diseases of the National Heart, Lung, and Blood Institute (NHLBI) held a workshop to develop recommendations on topics, methodologies, and resources for comparative effectiveness research (CER) that will guide clinical decision making about available treatment options for lung diseases and sleep disorders. A multidisciplinary group of experts with experience in efficacy, effectiveness, implementation, and economic research identified (a) what types of studies the domain of CER in lung diseases and sleep disorders should include, (b) the criteria and process for setting priorities, and (c) current resources for and barriers to CER in lung diseases. Key recommendations were to (1) increase efforts to engage stakeholders in developing CER questions and study designs; (2) invest in further development of databases and other infrastructure, including efficient methods for data sharing; (3) make full use of a broad range of study designs; (4) increase the appropriate use of observational designs and the support of methodologic research; (5) ensure that committees that review CER grant applications include persons with appropriate perspective and expertise; and (6) further develop the workforce for CER by supporting training opportunities that focus on the methodologic and practical skills needed.
doi:10.1164/rccm.201104-0634WS
PMCID: PMC3265273  PMID: 21965016
randomized controlled trials; observational studies; implementation; study designs; methodology
22.  The prevalence of clinically-relevant comorbid conditions in patients with physician-diagnosed COPD: a cross-sectional study using data from NHANES 1999–2008 
Background
Treatment of chronic diseases such as chronic obstructive pulmonary disease (COPD) is complicated by the presence of comorbidities. The objective of this analysis was to estimate the prevalence of comorbidity in COPD using nationally-representative data.
Methods
This study draws from a multi-year analytic sample of 14,828 subjects aged 45+, including 995 with COPD, from the National Health and Nutrition Examination Survey (NHANES), 1999–2008. COPD was defined by self-reported physician diagnosis of chronic bronchitis or emphysema; patients who reported a diagnosis of asthma were excluded. Using population weights, we estimated the age-and-gender-stratified prevalence of 22 comorbid conditions that may influence COPD and its treatment.
Results
Subjects 45+ with physician-diagnosed COPD were more likely than subjects without physician-diagnosed COPD to have coexisting arthritis (54.6% vs. 36.9%), depression (20.6% vs. 12.5%), osteoporosis (16.9% vs. 8.5%), cancer (16.5% vs. 9.9%), coronary heart disease (12.7% vs. 6.1%), congestive heart failure (12.1% vs. 3.9%), and stroke (8.9% vs. 4.6%). Subjects with COPD were also more likely to report mobility difficulty (55.6% vs. 32.5%), use of >4 prescription medications (51.8% vs. 32.1), dizziness/balance problems (41.1% vs. 23.8%), urinary incontinence (34.9% vs. 27.3%), memory problems (18.5% vs. 8.8%), low glomerular filtration rate (16.2% vs. 10.5%), and visual impairment (14.0% vs. 9.6%). All reported comparisons have p < 0.05.
Conclusions
Our study indicates that COPD management may need to take into account a complex spectrum of comorbidities. This work identifies which conditions are most common in a nationally-representative set of COPD patients (physician-diagnosed), a necessary step for setting research priorities and developing clinical practice guidelines that address COPD within the context of comorbidity.
doi:10.1186/1471-2466-12-26
PMCID: PMC3461433  PMID: 22695054
23.  Misuse of Respiratory Inhalers in Hospitalized Patients with Asthma or COPD 
ABSTRACT
BACKGROUND
Patients are asked to assume greater responsibility for care, including use of medications, during transitions from hospital to home. Unfortunately, medications dispensed via respiratory inhalers to patients with asthma or chronic obstructive pulmonary disease (COPD) can be difficult to use.
OBJECTIVES
To examine rates of inhaler misuse and to determine if patients with asthma or COPD differed in their ability to learn how to use inhalers correctly.
DESIGN
A cross-sectional and pre/post intervention study at two urban academic hospitals.
PARTICIPANTS
Hospitalized patients with asthma or COPD.
INTERVENTION
A subset of participants received instruction about the correct use of respiratory inhalers.
MAIN MEASURES
Use of metered dose inhaler (MDI) and Diskus® devices was assessed using checklists. Misuse and mastery of each device were defined as <75% and 100% of steps correct, respectively. Insufficient vision was defined as worse than 20/50 in both eyes. Less-than adequate health literacy was defined as a score of <23/36 on The Short Test of Functional Health Literacy in Adults (S-TOFHLA).
KEY RESULTS
One-hundred participants were enrolled (COPD n = 40; asthma n = 60). Overall, misuse was common (86% MDI, 71% Diskus®), and rates of inhaler misuse for participants with COPD versus asthma were similar. Participants with COPD versus asthma were twice as likely to have insufficient vision (43% vs. 20%, p = 0.02) and three-times as likely to have less-than- adequate health literacy (61% vs. 19%, p = 0.001). Participants with insufficient vision were more likely to misuse Diskus® devices (95% vs. 61%, p = 0.004). All participants (100%) were able to achieve mastery for both MDI and Diskus® devices.
CONCLUSIONS
Inhaler misuse is common, but correctable in hospitalized patients with COPD or asthma. Hospitals should implement a program to assess and teach appropriate inhaler technique that can overcome barriers to patient self-management, including insufficient vision, during transitions from hospital to home.
doi:10.1007/s11606-010-1624-2
PMCID: PMC3101982  PMID: 21249463
asthma; pulmonary disease; chronic disease; hospital medicine; health literacy
25.  Effect of a Community-Wide Asthma Intervention on Appropriate Use of Inhaled Corticosteroids 
Individuals with asthma living in the inner city experience increased asthma morbidity and mortality compared to the US average. The Controlling Asthma in America’s Cities Project’s Chicago site used a multifaceted approach to improve asthma care. The diverse scope of this project’s interventions necessitated the use of novel methods to assess the effect of these interventions on the entire study area. Asthma-related medication-dispensing data were obtained from a large pharmacy chain for prescriptions filled in calendar years 2004–2006 for all individuals aged 5–17 years living in Chicago who filled at least four asthma-related medications within a 12-month period. Inhaled corticosteroid (ICS) use was considered inadequate if an individual had four or more dispensings of a short-acting beta-agonist without at least four dispensings of an ICS agent. Logistic regression was used to compare adequate ICS use in individuals within the intervention area with ICS use in the remainder of the city, after controlling for gender, insurance status, race, and poverty. A significant difference in adequate ICS use was found in years 2 (2005) and 3 (2006) of the project for individuals aged 5–9 in the intervention area (odds ratios for adequate ICS use—year 2, 1.26; CI, 1.04–1.53, p = 0.04; year 3, 1.30; CI, 1.08–1.55, p = 0.008) compared to individuals aged 5–9 in the remainder of the city. There was no similar significant difference in the 10–17 age group. These findings suggest an effect of a large multifaceted asthma intervention in improving medication use in the targeted age group. This methodology might also prove useful in the future for assessing the effect of similar interventions.
doi:10.1007/s11524-010-9476-y
PMCID: PMC3042072  PMID: 21337060
Asthma outcomes; Pharmicoepidemiology; Asthma intervention

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