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1.  The PROactive innovative conceptual framework on physical activity 
The European Respiratory Journal  2014;44(5):1223-1233.
Although physical activity is considered an important therapeutic target in chronic obstructive pulmonary disease (COPD), what “physical activity” means to COPD patients and how their perspective is best measured is poorly understood. We designed a conceptual framework, guiding the development and content validation of two patient reported outcome (PRO) instruments on physical activity (PROactive PRO instruments).
116 patients from four European countries with diverse demographics and COPD phenotypes participated in three consecutive qualitative studies (63% male, age mean±sd 66±9 years, 35% Global Initiative for Chronic Obstructive Lung Disease stage III–IV). 23 interviews and eight focus groups (n = 54) identified the main themes and candidate items of the framework. 39 cognitive debriefings allowed the clarity of the items and instructions to be optimised.
Three themes emerged, i.e. impact of COPD on amount of physical activity, symptoms experienced during physical activity, and adaptations made to facilitate physical activity. The themes were similar irrespective of country, demographic or disease characteristics. Iterative rounds of appraisal and refinement of candidate items resulted in 30 items with a daily recall period and 34 items with a 7-day recall period.
For the first time, our approach provides comprehensive insight on physical activity from the COPD patients’ perspective. The PROactive PRO instruments’ content validity represents the pivotal basis for empirically based item reduction and validation.
Conceptual framework as basis of PROactive PRO instruments to assess physical activity from COPD patient perspective
PMCID: PMC4216453  PMID: 25034563
2.  Outcome Preferences in Patients With Noninfectious Uveitis: Results of a Best–Worst Scaling Study 
To estimate patient preferences regarding potential adverse outcomes of local versus systemic corticosteroid therapies for noninfectious uveitis by using a best–worst scaling (BWS) approach.
Local and systemic therapies are alternatives for noninfectious uveitis that have different potential adverse outcomes. Patients participating in the Multicenter Uveitis Steroid Treatment Trial Follow-up Study (MUST FS) and additional patients with a history of noninfectious uveitis treated at two academic medical centers (Johns Hopkins University and University of Pennsylvania) were surveyed about their preferences regarding six adverse outcomes deemed important to patients. Using “case 1” BWS, patients were asked to repeatedly select the most and least worrying from a list of outcomes (in the survey three outcomes per task).
Eighty-two patients in the MUST FS and 100 patients treated at the academic medical centers completed the survey. According to BWS, patients were more likely to select vision not meeting the requirement for driving (individual BWS score: median = 3, interquartile range, 0–5), development of glaucoma (2, 1–4), and needing eye surgery (1, 0–3) as the most worrying outcomes as compared to needing medicine for high blood pressure/cholesterol (−2, −4 to 0), development of cataracts (−2, −3 to −1), or infection (sinusitis) (−3, −5 to 0). Larger BWS scores indicated the outcomes were more worrying to patients.
Patients with noninfectious uveitis considered impaired vision, development of glaucoma, and need for eye surgery worrying adverse outcomes, which suggests that it is especially desirable to avoid these outcomes if possible. ( number, NCT00132691.)
Using a best-worst scaling approach, we elicited and quantified patient preferences for potential adverse outcomes of local versus systemic corticosteroid therapies for noninfectious uveitis.
PMCID: PMC4627251  PMID: 26501236
patient preferences; uveitis; medical decision making
3.  Personalized Respiratory Medicine: Exploring the Horizon, Addressing the Issues. Summary of a BRN-AJRCCM Workshop Held in Barcelona on June 12, 2014 
This Pulmonary Perspective summarizes the content and main conclusions of an international workshop on personalized respiratory medicine coorganized by the Barcelona Respiratory Network ( and the AJRCCM in June 2014. It discusses (1) its definition and historical, social, legal, and ethical aspects; (2) the view from different disciplines, including basic science, epidemiology, bioinformatics, and network/systems medicine; (3) the bottlenecks and opportunities identified by some currently ongoing projects; and (4) the implications for the individual, the healthcare system and the pharmaceutical industry. The authors hope that, although it is not a systematic review on the subject, this document can be a useful reference for researchers, clinicians, healthcare managers, policy-makers, and industry parties interested in personalized respiratory medicine.
PMCID: PMC4351599  PMID: 25531178
4.  Use of surrogate outcomes in US FDA drug approvals, 2003–2012: a survey 
BMJ Open  2015;5(11):e007960.
To evaluate, across a spectrum of diseases, how often surrogate outcomes are used as a basis for drug approvals by the US Food and Drug Administration (FDA), and whether and how the rationale for using treatment effects on surrogates as predictors of treatment effects on patient-centred outcomes is discussed.
Study design and setting
We used the Drugs@FDA website to identify drug approvals produced from 2003 to 2012 by the FDA. We focused on four diseases (chronic obstructive pulmonary disease (COPD), type 1 or 2 diabetes, glaucoma and osteoporosis) for which surrogates are commonly used in trials. We reviewed the drug labels and medical reviews to provide empirical evidence on how surrogate outcomes are handled by the FDA.
Of 1043 approvals screened, 58 (6%) were for the four diseases of interest. Most drugs for COPD (7/9, 78%), diabetes (26/26, 100%) and glaucoma (9/9, 100%) were approved based on surrogates while for osteoporosis, most drugs (10/14, 71%) were also approved for patient-centred outcomes (fractures). The rationale for using surrogates was discussed in 11 of the 43 (26%) drug approvals based on surrogates. In these drug approvals, we found drug approvals for diabetes are more likely than the other examined conditions to contain a discussion of trial evidence demonstrating that treatment effects on surrogate outcomes predict treatment effects on patient-centred outcomes.
Our results suggest that the FDA did not use a consistent approach to address surrogates in assessing the benefits and harms of drugs for COPD, type 1 or 2 diabetes, glaucoma and osteoporosis. For evaluating new drugs, patient-centred outcomes should be chosen whenever possible. If the use of surrogate outcomes is necessary, then a consistent approach is important to review the evidence for surrogacy and consider surrogate's usage in the treatment and population under study.
PMCID: PMC4663404  PMID: 26614616
5.  The PROactive instruments to measure physical activity in patients with chronic obstructive pulmonary disease 
The European Respiratory Journal  2015;46(4):988-1000.
No current patient-centred instrument captures all dimensions of physical activity in chronic obstructive pulmonary disease (COPD). Our objective was item reduction and initial validation of two instruments to measure physical activity in COPD.
Physical activity was assessed in a 6-week, randomised, two-way cross-over, multicentre study using PROactive draft questionnaires (daily and clinical visit versions) and two activity monitors. Item reduction followed an iterative process including classical and Rasch model analyses, and input from patients and clinical experts.
236 COPD patients from five European centres were included. Results indicated the concept of physical activity in COPD had two domains, labelled “amount” and “difficulty”. After item reduction, the daily PROactive instrument comprised nine items and the clinical visit contained 14. Both demonstrated good model fit (person separation index >0.7). Confirmatory factor analysis supported the bidimensional structure. Both instruments had good internal consistency (Cronbach's α>0.8), test–retest reliability (intraclass correlation coefficient ≥0.9) and exhibited moderate-to-high correlations (r>0.6) with related constructs and very low correlations (r<0.3) with unrelated constructs, providing evidence for construct validity.
Daily and clinical visit “PROactive physical activity in COPD” instruments are hybrid tools combining a short patient-reported outcome questionnaire and two activity monitor variables which provide simple, valid and reliable measures of physical activity in COPD patients.
Both PROactive hybrid tools are simple, valid, and reliable measures of physical activity in COPD patients
PMCID: PMC4589432  PMID: 26022965
6.  Benefit-harm analysis and charts for individualized and preference-sensitive prevention: example of low dose aspirin for primary prevention of cardiovascular disease and cancer 
BMC Medicine  2015;13:250.
Clinical practice guidelines provide separate recommendations for different diseases that may be prevented or treated by the same intervention. Also, they commonly provide recommendations for entire populations but not for individuals. To address these two limitations, our aim was to conduct benefit-harm analyses for a wide range of individuals using the example of low dose aspirin for primary prevention of cardiovascular disease and cancer and to develop Benefit-Harm Charts that show the overall benefit-harm balance for individuals.
We used quantitative benefit-harm modeling that included 16 outcomes to estimate the probability that low dose aspirin provides more benefits than harms for a wide range of men and women between 45 and 84 years of age and without a previous myocardial infarction, severe ischemic stroke, or cancer. We repeated the quantitative benefit-harm modeling for different combinations of age, sex, and outcome risks for severe ischemic and hemorrhagic stroke, myocardial infarction, cancers, and severe gastrointestinal bleeds. The analyses considered weights for the outcomes, statistical uncertainty of the effects of aspirin, and death as a competing risk. We constructed Benefit-Harm Charts that show the benefit-harm balance for different combinations of outcome risks.
The Benefit-Harm Charts ( we have created show that the benefit-harm balance differs largely across a primary prevention population. Low dose aspirin is likely to provide more benefits than harms in men, elderly people, and in those at low risk for severe gastrointestinal bleeds. Individual preferences have a major impact on the benefit-harm balance. If, for example, it is a high priority for individuals to prevent stroke and severe cancers while severe gastrointestinal bleeds are deemed to be of little importance, the benefit-harm balance is likely to favor low dose aspirin for most individuals. Instead, if severe gastrointestinal bleeds are judged to be similarly important compared to the benefit outcomes, low dose aspirin is unlikely to provide more benefits than harms.
Benefit-Harm Charts support individualized benefit-harm assessments and decision making. Similarly, individualized benefit-harm assessments may allow guideline developers to issue more finely granulated recommendations that reduce the risk of over- and underuse of interventions. The example of low dose aspirin for primary prevention of cardiovascular disease and cancer shows that it may be time for guideline developers to provide combined recommendations for different diseases that may be prevented or treated by the same intervention.
PMCID: PMC4589917  PMID: 26423305
Prevention; Personalized; Cardiovascular; Cancer; Benefit-risk; Aspirin; Harm; Randomized trials; Guidelines
7.  Aspirin for Primary Prevention of Cardiovascular Disease and Cancer. A Benefit and Harm Analysis 
PLoS ONE  2015;10(7):e0127194.
Aspirin is widely used for prevention of cardiovascular disease. In recent years randomized trials also suggested a preventive effect for various types of cancer. We aimed to assess, in a quantitative way, benefits and harms of aspirin for primary prevention of both cardiovascular disease and cancer for a general US population between 40 and 85 years of age.
We used the Gail/National Cancer Institute approach for assessing benefits and harms. This approach provides a probability that a treatment is more beneficial than harmful and incorporates multiple outcomes, the importance of these outcomes, considers different outcome risks and treats mortality as a competing risk. Our main outcomes were the risks of seven types of cancer, myocardial infarction, ischemic and hemorrhagic stroke and gastrointestinal bleeding. We obtained effect estimates from recent meta-analyses of randomized trials and used baseline risks from the Centers for Disease Control. We conducted four sensitivity analyses to assess the influence of different assumptions about outcome risks and preferences and considered the sampling variation of the effect estimates for aspirin.
The main analysis as well as the sensitivity analyses showed that aspirin has more benefits than harms. In the main analysis, the index (positive if number of prevented events > excess number of harm events over 10 years per 1,000 persons) ranged from 2 (95% CI 0.0 to 11.8; in women age 45 to 54 years) to 8 (95% CI -0.1 to 83.7; in men age 65 to 74 years). In the sensitivity analyses, the index was also positive for all age categories suggesting more benefits than harms.
This study suggests an overall benefit of aspirin for primary prevention of cardiovascular disease and cancer based on population-based data. For individual preventive counseling, additional benefit harm analyses should explore which individuals should or should not take aspirin based on their risk profile for cardiovascular, cancer and gastrointestinal outcomes and based on their outcome preferences. Thereby, risk-stratified and preference-sensitive prevention could become a reality.
PMCID: PMC4494891  PMID: 26151751
8.  Quantitative benefit–harm assessment for setting research priorities: the example of roflumilast for patients with COPD 
BMC Medicine  2015;13:157.
When faced with uncertainties about the effects of medical interventions regulatory agencies, guideline developers, clinicians, and researchers commonly ask for more research, and in particular for more randomized trials. The conduct of additional randomized trials is, however, sometimes not the most efficient way to reduce uncertainty. Instead, approaches such as value of information analysis or other approaches should be used to prioritize research that will most likely reduce uncertainty and inform decisions.
In situations where additional research for specific interventions needs to be prioritized, we propose the use of quantitative benefit–harm assessments that illustrate how the benefit–harm balance may change as a consequence of additional research. The example of roflumilast for patients with chronic obstructive pulmonary disease shows that additional research on patient preferences (e.g., how important are exacerbations relative to psychiatric harms?) or outcome risks (e.g., what is the incidence of psychiatric outcomes in patients with chronic obstructive pulmonary disease without treatment?) is sometimes more valuable than additional randomized trials.
We propose that quantitative benefit–harm assessments have the potential to explore the impact of additional research and to identify research priorities Our approach may be seen as another type of value of information analysis and as a useful approach to stimulate specific new research that has the potential to change current estimates of the benefit–harm balance and decision making.
PMCID: PMC4490602  PMID: 26137986
Benefit–harm assessment; Chronic obstructive pulmonary disease; Randomized trials; Research priorities
9.  Impact of co-morbidities on self-rated health in self-reported COPD: An analysis of NHANES 2001–2008 
COPD  2013;10(3):324-332.
Chronic Obstructive Pulmonary Disease (COPD) coexists with co-morbidities. While co-morbidity has been associated with poorer health status, it is unclear which conditions have the greatest impact on self-rated health. We sought to determine which, and how much, specific co-morbid conditions impact on self-rated health in current and former smokers with self-reported COPD. Using the 2001–2008 National Health and Nutrition Examination Survey we characterized the association between thirteen co-morbidities and health status among individuals self-reporting COPD. Adjusted odds ratios (ORs) were generated using ordinal logistic regression. Additionally we evaluated the impact of increasing number of co-morbidities with self-rated health. Eight illnesses had significant associations with worse self-rated health, however after mutually adjusting for these conditions, congestive heart failure (OR 3.07, 95% CI 1.69–5.58), arthritis (OR 1.69, 95% CI 1.13–2.52), diabetes (OR 1.63, 95% CI 1.01–2.64), and incontinence/prostate disease (OR 1.63, 95% CI 1.01–2.62) remained independent predictors of self-rated health. Each increase in co-morbidities was associated with a 43% higher chance of worse self-rated health (95% CI 1.27–1.62). Individuals with COPD have a substantial burden of co-morbidity, which is associated with worse self-rated health. CHF, arthritis, diabetes and incontinence/prostate disease have the most impact on self-rated health. Targeting these co-morbidities in COPD may result in improved self-rated health.
PMCID: PMC4459792  PMID: 23713595
multi-morbidity; quality of life; national survey; patient-reported outcomes
10.  Benefits and harms of roflumilast in moderate to severe COPD 
Thorax  2013;69(7):616-622.
Roflumilast, a phosphodiesterase 4 inhibitor, was approved for the prevention of COPD exacerbations. It is unclear in which patients roflumilast will have a favorable benefit-harm balance. Our aim was to quantitatively assess the benefits and harms of roflumilast (500 mcg per day) compared to placebo.
Methods and Findings
We used trial data released by the US Food and Drug Administration to estimate the treatment effects of roflumilast. We used data from observational studies when available to estimate the baseline risks for COPD exacerbations and gastrointestinal, neurological and psychiatric harms associated with roflumilast. Using simulation, we calculated the probability that roflumilast provides net benefit. We examined the impacts of different baseline risks for exacerbations and the severity of exacerbations. We varied weights (i.e., relative importance) for outcomes and treated death as a competing risk in the analyses. The probability that roflumilast provides net benefit approximates 0% across different age categories of men and women with varying baseline risks for exacerbations. Using different weights for outcomes did not change the probability that roflumilast provides net benefit. Only in the sensitivity analysis restricted to the prevention of severe exacerbations there was a probability of >50% that roflumilast provides net benefit if the baseline risk of having at least one severe exacerbation per year exceeds 22%.
Our results suggest roflumilast only provides net benefit to patients at a high risk of severe exacerbations. Guideline developers should consider different recommendations for COPD patients at different baseline risks for exacerbations.
PMCID: PMC4455881  PMID: 24347460
Pulmonary Disease, Chronic Obstructive; Phosphodiesterase 4 Inhibitors; Risk Assessment
11.  Medication incidents in primary care medicine: protocol of a study by the Swiss Federal Sentinel Reporting System 
BMJ Open  2015;5(4):e007773.
Patient safety is a major concern in healthcare systems worldwide. Although most safety research has been conducted in the inpatient setting, evidence indicates that medical errors and adverse events are a threat to patients in the primary care setting as well. Since information about the frequency and outcomes of safety incidents in primary care is required, the goals of this study are to describe the type, frequency, seasonal and regional distribution of medication incidents in primary care in Switzerland and to elucidate possible risk factors for medication incidents.
Methods and analysis
Study design and setting: We will conduct a prospective surveillance study to identify cases of medication incidents among primary care patients in Switzerland over the course of the year 2015. Participants: Patients undergoing drug treatment by 167 general practitioners or paediatricians reporting to the Swiss Federal Sentinel Reporting System. Inclusion criteria: Any erroneous event, as defined by the physician, related to the medication process and interfering with normal treatment course. Exclusion criteria: Lack of treatment effect, adverse drug reactions or drug–drug or drug–disease interactions without detectable treatment error. Primary outcome: Medication incidents. Risk factors: Age, gender, polymedication, morbidity, care dependency, hospitalisation. Statistical Analysis: Descriptive statistics to assess type, frequency, seasonal and regional distribution of medication incidents and logistic regression to assess their association with potential risk factors. Estimated sample size: 500 medication incidents. Limitations: We will take into account under-reporting and selective reporting among others as potential sources of bias or imprecision when interpreting the results.
Ethics and dissemination
No formal request was necessary because of fully anonymised data. The results will be published in a peer-reviewed journal.
Trial registration number
PMCID: PMC4410132  PMID: 25908679
12.  Multimorbidity and Evidence Generation 
Most people with a chronic disease actually have more than one, a condition known as multimorbidity. Despite this, the evidence base to prevent adverse disease outcomes has taken a disease-specific approach. Drawing on a conference, Improving Guidelines for Multimorbid Patients, the goal of this paper is to identify challenges to the generation of evidence to support the care of people with multimorbidity and to make recommendations for improvement. We identified three broad categories of challenges: 1) challenges to defining and measuring multimorbidity; 2) challenges related to the effects of multimorbidity on study design, implementation and analysis; and 3) challenges inherent in studying heterogeneity of treatment effects in patients with differing comorbid conditions. We propose a set of recommendations for consideration by investigators and others (reviewers, editors, funding agencies, policymaking organizations) involved in the creation of evidence for this common type of person that address each of these challenges. The recommendations reflect a general approach that emphasizes broader inclusion (recruitment and retention) of patients with multimorbidity, coupled with more rigorous efforts to measure comorbidity and comorbidity burden and the influence of multimorbidity on outcomes and the effects of therapy. More rigorous examination of heterogeneity of treatment effects requires careful attention to prioritizing the most important comorbid-related questions, and also requires studies that provide greater statistical power than conventional trials have provided. Relatively modest changes in the orientation of current research along these lines can be helpful in pointing to and partially addressing selected knowledge gaps. However, producing a robust evidence base to support patient-centered decision making in complex individuals with multimorbidity, exposed to many different combinations of potentially interacting factors that can modify the risks and benefits of therapies, is likely to require a clinical research enterprise fundamentally restructured to be more fully integrated with routine clinical practice.
PMCID: PMC3965759  PMID: 24442333
evidence-based medicine; chronic disease; guidelines; comorbidity; clinical trials
13.  A Simplified Score to Quantify Comorbidity in COPD 
PLoS ONE  2014;9(12):e114438.
Comorbidities are common in COPD, but quantifying their burden is difficult. Currently there is a COPD-specific comorbidity index to predict mortality and another to predict general quality of life. We sought to develop and validate a COPD-specific comorbidity score that reflects comorbidity burden on patient-centered outcomes.
Materials and Methods
Using the COPDGene study (GOLD II-IV COPD), we developed comorbidity scores to describe patient-centered outcomes employing three techniques: 1) simple count, 2) weighted score, and 3) weighted score based upon statistical selection procedure. We tested associations, area under the Curve (AUC) and calibration statistics to validate scores internally with outcomes of respiratory disease-specific quality of life (St. George's Respiratory Questionnaire, SGRQ), six minute walk distance (6MWD), modified Medical Research Council (mMRC) dyspnea score and exacerbation risk, ultimately choosing one score for external validation in SPIROMICS.
Associations between comorbidities and all outcomes were comparable across the three scores. All scores added predictive ability to models including age, gender, race, current smoking status, pack-years smoked and FEV1 (p<0.001 for all comparisons). Area under the curve (AUC) was similar between all three scores across outcomes: SGRQ (range 0·7624–0·7676), MMRC (0·7590–0·7644), 6MWD (0·7531–0·7560) and exacerbation risk (0·6831–0·6919). Because of similar performance, the comorbidity count was used for external validation. In the SPIROMICS cohort, the comorbidity count performed well to predict SGRQ (AUC 0·7891), MMRC (AUC 0·7611), 6MWD (AUC 0·7086), and exacerbation risk (AUC 0·7341).
Quantifying comorbidity provides a more thorough understanding of the risk for patient-centered outcomes in COPD. A comorbidity count performs well to quantify comorbidity in a diverse population with COPD.
PMCID: PMC4267736  PMID: 25514500
14.  Validation of prediction models based on lasso regression with multiply imputed data 
In prognostic studies, the lasso technique is attractive since it improves the quality of predictions by shrinking regression coefficients, compared to predictions based on a model fitted via unpenalized maximum likelihood. Since some coefficients are set to zero, parsimony is achieved as well. It is unclear whether the performance of a model fitted using the lasso still shows some optimism. Bootstrap methods have been advocated to quantify optimism and generalize model performance to new subjects. It is unclear how resampling should be performed in the presence of multiply imputed data.
The data were based on a cohort of Chronic Obstructive Pulmonary Disease patients. We constructed models to predict Chronic Respiratory Questionnaire dyspnea 6 months ahead. Optimism of the lasso model was investigated by comparing 4 approaches of handling multiply imputed data in the bootstrap procedure, using the study data and simulated data sets. In the first 3 approaches, data sets that had been completed via multiple imputation (MI) were resampled, while the fourth approach resampled the incomplete data set and then performed MI.
The discriminative model performance of the lasso was optimistic. There was suboptimal calibration due to over-shrinkage. The estimate of optimism was sensitive to the choice of handling imputed data in the bootstrap resampling procedure. Resampling the completed data sets underestimates optimism, especially if, within a bootstrap step, selected individuals differ over the imputed data sets. Incorporating the MI procedure in the validation yields estimates of optimism that are closer to the true value, albeit slightly too larger.
Performance of prognostic models constructed using the lasso technique can be optimistic as well. Results of the internal validation are sensitive to how bootstrap resampling is performed.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2288-14-116) contains supplementary material, which is available to authorized users.
PMCID: PMC4209042  PMID: 25323009
Clinical prediction models; Model validation; Multiple imputation; Quality of life; Shrinkage
15.  Prediction of COPD-specific health-related quality of life in primary care COPD patients: a prospective cohort study 
Health-related quality of life (HRQL) is an important patient-reported outcome for chronic obstructive pulmonary disease (COPD).
We developed models predicting chronic respiratory questionnaire (CRQ) dyspnoea, fatigue, emotional function, mastery and overall HRQL at 6 and 24 months using predictors easily available in primary care.
We used the “least absolute shrinkage and selection operator” (lasso) method to build the models and assessed their predictive performance. Results were displayed using nomograms.
For each domain-specific CRQ outcome, the corresponding score at baseline was the best predictor. Depending on the domain, these predictions could be improved by adding one to six other predictors, such as the other domain-specific CRQ scores, health status and depression score. To predict overall HRQL, fatigue and dyspnoea scores were the best predictors. Predicted and observed values were on average the same, indicating good calibration. Explained variance ranged from 0.23 to 0.58, indicating good discrimination.
To predict COPD-specific HRQL in primary care COPD patients, previous HRQL was the best predictor in our models. Asking patients explicitly about dyspnoea, fatigue, depression and how they cope with COPD provides additional important information about future HRQL whereas FEV1 or other commonly used predictors add little to the prediction of HRQL.
PMCID: PMC4373411  PMID: 25164146
16.  Determinants and outcomes of physical activity in patients with COPD: a systematic review 
Thorax  2014;69(8):731-739.
The relationship between physical activity, disease severity, health status and prognosis in patients with COPD has not been systematically assessed. Our aim was to identify and summarise studies assessing associations between physical activity and its determinants and/or outcomes in patients with COPD and to develop a conceptual model for physical activity in COPD.
We conducted a systematic search of four databases (Medline, Embase, CINAHL and Psychinfo) prior to November 2012. Teams of two reviewers independently selected articles, extracted data and used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) to assess quality of evidence.
86 studies were included: 59 were focused on determinants, 23 on outcomes and 4 on both. Hyperinflation, exercise capacity, dyspnoea, previous exacerbations, gas exchange, systemic inflammation, quality of life and self-efficacy were consistently related to physical activity, but often based on cross-sectional studies and low-quality evidence. Results from studies of pharmacological and non-pharmacological treatments were inconsistent and the quality of evidence was low to very low. As outcomes, COPD exacerbations and mortality were consistently associated with low levels of physical activity based on moderate quality evidence. Physical activity was associated with other outcomes such as dyspnoea, health-related quality of life, exercise capacity and FEV1 but based on cross-sectional studies and low to very low quality evidence.
Physical activity level in COPD is consistently associated with mortality and exacerbations, but there is poor evidence about determinants of physical activity, including the impact of treatment.
PMCID: PMC4112490  PMID: 24558112
COPD epidemiology; Exercise; COPD Exacerbations
17.  Nonsurgical Strategies in Patients With NET Liver Metastases: A Protocol of Four Systematic Reviews 
JMIR Research Protocols  2014;3(1):e9.
Patients diagnosed with neuroendocrine tumors (NETs) with hepatic metastases generally have a worse prognosis as compared with patients with nonmetastasized NETs. Due to tumor location and distant metastases, a surgical approach is often not possible and nonsurgical therapeutic strategies may apply.
The aim of these systematic reviews is to evaluate the role of nonsurgical therapy options for patients with nonresectable liver metastases of NETs.
An objective group of librarians will provide an electronic search strategy to examine the MEDLINE, EMBASE, and The Cochrane Library (Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Cochrane Central Register of Controlled Trials [CENTRAL]) databases. There will be no restriction concerning language and publication date. The qualitative and quantitative synthesis of the systematic review will be conducted with randomized controlled trials (RCT), prospective, and retrospective comparative cohort, and case-control studies. Case series will be collected in a separate database and only used for descriptive purposes.
This study is ongoing and presents a protocol of four systematic reviews to assess the role of nonsurgical treatment options in patients with neuroendocrine liver metastases.
These systematic reviews, performed according to this protocol, will assess the value of noninvasive therapy options for patients with nonresectable liver metastases of NETs in combination with invasive techniques, such as percutaneous liver-directed techniques and local ablation techniques.
Trial Registration
International Prospective Register of Systematic Reviews (PROSPERO): CRD42012002657; (Archived by WebCite at; CRD42012002658; (Archived by WebCite at; CRD42012002659; (Arichived by Webcite at; and CRD42012002660; (Archived by WebCite at
PMCID: PMC3961806  PMID: 24610518
neuroendocrine tumor; NET; liver resection; adjuvant; neoadjuvant; liver transplantation; primary NET; systematic review
18.  Diagnosis and Prediction of Neuroendocrine Liver Metastases: A Protocol of Six Systematic Reviews 
JMIR Research Protocols  2013;2(2):e60.
Patients with hepatic metastases from neuroendocrine tumors (NETs) benefit from an early diagnosis, which is crucial for the optimal therapy and management. Diagnostic procedures include morphological and functional imaging, identification of biomarkers, and biopsy.
The aim of six systematic reviews discussed in this study is to assess the predictive value of Ki67 index and other biomarkers, to compare the diagnostic accuracy of morphological and functional imaging, and to define the role of biopsy in the diagnosis and prediction of neuroendocrine tumor liver metastases.
An objective group of librarians will provide an electronic search strategy to examine the following databases: MEDLINE, EMBASE and The Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects). There will be no restriction concerning language and publication date. The qualitative and quantitative synthesis of the systematic review will be conducted with randomized controlled trials (RCT), prospective and retrospective comparative cohort studies, and case-control studies. Case series will be collected in a separate database and only used for descriptive purposes.
This study is ongoing and presents a protocol of six systematic reviews to elucidate the role of histopathological and biochemical markers, biopsies of the primary tumor and the metastases as well as morphological and functional imaging modalities for the diagnosis and prediction of neuroendocrine liver metastases.
These systematic reviews will assess the value and accuracy of several diagnostic modalities in patients with NET liver metastases, and will provide a basis for the development of clinical practice guidelines.
Trial Registration
The systematic reviews have been prospectively registered with the International Prospective Register of Systematic Reviews (PROSPERO): CRD42012002644; (Archived by WebCite at, CRD42012002647; (Archived by WebCite at, CRD42012002648; (Archived by WebCite at, CRD42012002649; (Archived by WebCite at, CRD42012002650; (Archived by WebCite at, CRD42012002651; (Archived by WebCite at
PMCID: PMC3875889  PMID: 24366180
neuroendocrine tumors (NET); liver metastases; Ki67; mitotic count; genetic signatures; tumor cells; biochemical markers; morphological imaging; functional imaging; systematic review
19.  Transplantation and Surgical Strategies in Patients With Neuroendocrine Liver Metastases: Protocol of Four Systematic Reviews 
JMIR Research Protocols  2013;2(2):e58.
Hepatic metastases of neuroendocrine tumors (NETs) are considered a major prognostic factor associated with significantly reduced survival compared to patients without liver metastases. Several surgical and nonsurgical strategies are present to treat resectable and nonresectable liver metastases, some of which have the potential to cure liver mestatases.
The aims of the four systematic reviews presented in the paper are to determine the effectiveness of liver resection versus nonsurgical treatment of patients with NET liver metastases, to investigate the impact of neoadjuvant and adjuvant treatment options on the tumor-free survival, to assess the role of liver transplantation in patients presenting with unresectable bilateral hepatic metastases, and to evaluate the role of primary tumor resection in presence of unresectable liver metastases.
Literature search was performed on Medical Literature Analysis and Retrieval System Online, Excerpta Medica Database, and the Cochrane Library (Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, and Cochrane Central Register of Controlled Trials). No language restrictions were applied. Randomized controlled trials, prospective and retrospective comparative cohort studies, and case-control studies will be used for the qualitative and quantitative synthesis of the systematic reviews. Case series will be only included in a separate database for descriptive purposes.
This study is ongoing and presents a protocol system of four systematic reviews that will assist in determining the effectiveness of liver resection versus nonsurgical treatment of patients with NET liver metastases. This study is also assumed to investigate the impact of neoadjuvant and adjuvant treatment options on the tumor-free survival, the role of liver transplantation, and the relevance of primary tumor resection in presence of unresectable liver metastasis.
The systematic reviews will show the current evidence based on the effectiveness of surgical strategies in patients with NET liver metastases and serve as basis for clinical practice guidelines.
Trial Registration
The systematic reviews have been prospectively registered with the International Prospective Register of Systematic Reviews: liver resection (CRD42012002652); (Archived by WebCite at,). neoadjuvant and adjuvant treatment strategies (CRD42012002656); (Archived by WebCite at liver transplantation (CRD42012002655); (Archived by WebCite at,). resection of the locoregional primary NET (CRD42012002654); (Archived by WebCite at
PMCID: PMC3875902  PMID: 24366112
neuroendocrine tumors; NET; liver resection; adjuvant neoadjuvant; liver transplantation; primary NET; systematic review
20.  Early fluid resuscitation with hydroxyethyl starch 130/0.4 (6%) in severe burn injury: a randomized, controlled, double-blind clinical trial 
Critical Care  2013;17(6):R299.
There are limited data on the efficacy of early fluid resuscitation with third-generation hydroxyethyl starch (HES 130) in burn injury. Adverse effects of HES on survival and organ function have been reported.
In this randomized, controlled, double-blind trial, 48 patients with severe burn injury were assigned to receive either lactated Ringer’s solution plus 6% HES 130/0.4 in a ratio of 2:1 or lactated Ringer’s solution with no colloid supplement for the first 72 hours. Primary outcome parameter was the group difference of administered total fluid from intensive care unit (ICU) admission up to day 3. Secondary outcomes included kidney and lung injury and failure, length of stay, and mortality.
Three-day totals of administered resuscitation fluid (medians) were 21,190 mL in the lactated Ringer’s group and 19,535 mL in the HES group (HES: −1,213 mL; P = 0.39). Creatinine levels from day 1 to 3 (HES: +0.4 μmol/L; 95% confidence interval (CI) −18.7 to 19.5; P = 0.97) and urinary outputs from day 1 to 3 (HES: −58 mL; 95% CI −400 to 283; P = 0.90) were not different. Six patients in each group developed acute respiratory distress syndrome (ARDS) (risk ratio 0.96; 95% CI 0.35 to 2.64; P = 0.95). Length of ICU stay (HES vs. lactated Ringer’s: 28 vs. 24 days; P = 0.80) and length of hospital stay (31 vs. 29 days; P = 0.57) were similar. Twenty-eight-day mortality was 4 patients in each group (risk ratio 0.96; 95% CI 0.27 to 4.45; P = 0.95), and in-hospital mortality was 8 in the HES group vs. 5 patients in the lactated Ringer’s group (hazard ratio 1.86; 95% CI 0.56 to 6.19; P = 0.31).
There was no evidence that early fluid resuscitation with balanced HES 130/0.4 (6%) in addition to lactated Ringer’s solution would lead to a volume-sparing effect in severe burn injury. Together with the findings that early renal function, incidence of ARDS, length of stay, and mortality were not negatively influenced by HES in this setting, balanced HES 130/0.4 (6%) plus lactated Ringer’s solution could not be considered superior to lactated Ringer’s solution alone.
Trial registration NCT01012648
PMCID: PMC4057504  PMID: 24365167
21.  All That Glitters Isn't Gold: A Survey on Acknowledgment of Limitations in Biomedical Studies 
PLoS ONE  2013;8(11):e73623.
Acknowledgment of all serious limitations to research evidence is important for patient care and scientific progress. Formal research on how biomedical authors acknowledge limitations is scarce.
To assess the extent to which limitations are acknowledged in biomedical publications explicitly, and implicitly by investigating the use of phrases that express uncertainty, so-called hedges; to assess the association between industry support and the extent of hedging.
We analyzed reporting of limitations and use of hedges in 300 biomedical publications published in 30 high and medium -ranked journals in 2007. Hedges were assessed using linguistic software that assigned weights between 1 and 5 to each expression of uncertainty.
Twenty-seven percent of publications (81/300) did not mention any limitations, while 73% acknowledged a median of 3 (range 1–8) limitations. Five percent mentioned a limitation in the abstract. After controlling for confounders, publications on industry-supported studies used significantly fewer hedges than publications not so supported (p = 0.028).
Detection and classification of limitations was – to some extent – subjective. The weighting scheme used by the hedging detection software has subjective elements.
Reporting of limitations in biomedical publications is probably very incomplete. Transparent reporting of limitations may protect clinicians and guideline committees against overly confident beliefs and decisions and support scientific progress through better design, conduct or analysis of new studies.
PMCID: PMC3854521  PMID: 24324540
22.  Serotype-Specific Changes in Invasive Pneumococcal Disease after Pneumococcal Conjugate Vaccine Introduction: A Pooled Analysis of Multiple Surveillance Sites 
PLoS Medicine  2013;10(9):e1001517.
In a pooled analysis of data collected from invasive pneumococcal disease surveillance databases, Daniel Feikin and colleagues examine serotype replacement after the introduction of 7-valent pneumococcal conjugate vaccine (PCV7) into national immunization programs.
Please see later in the article for the Editors' Summary
Vaccine-serotype (VT) invasive pneumococcal disease (IPD) rates declined substantially following introduction of 7-valent pneumococcal conjugate vaccine (PCV7) into national immunization programs. Increases in non-vaccine-serotype (NVT) IPD rates occurred in some sites, presumably representing serotype replacement. We used a standardized approach to describe serotype-specific IPD changes among multiple sites after PCV7 introduction.
Methods and Findings
Of 32 IPD surveillance datasets received, we identified 21 eligible databases with rate data ≥2 years before and ≥1 year after PCV7 introduction. Expected annual rates of IPD absent PCV7 introduction were estimated by extrapolation using either Poisson regression modeling of pre-PCV7 rates or averaging pre-PCV7 rates. To estimate whether changes in rates had occurred following PCV7 introduction, we calculated site specific rate ratios by dividing observed by expected IPD rates for each post-PCV7 year. We calculated summary rate ratios (RRs) using random effects meta-analysis. For children <5 years old, overall IPD decreased by year 1 post-PCV7 (RR 0·55, 95% CI 0·46–0·65) and remained relatively stable through year 7 (RR 0·49, 95% CI 0·35–0·68). Point estimates for VT IPD decreased annually through year 7 (RR 0·03, 95% CI 0·01–0·10), while NVT IPD increased (year 7 RR 2·81, 95% CI 2·12–3·71). Among adults, decreases in overall IPD also occurred but were smaller and more variable by site than among children. At year 7 after introduction, significant reductions were observed (18–49 year-olds [RR 0·52, 95% CI 0·29–0·91], 50–64 year-olds [RR 0·84, 95% CI 0·77–0·93], and ≥65 year-olds [RR 0·74, 95% CI 0·58–0·95]).
Consistent and significant decreases in both overall and VT IPD in children occurred quickly and were sustained for 7 years after PCV7 introduction, supporting use of PCVs. Increases in NVT IPD occurred in most sites, with variable magnitude. These findings may not represent the experience in low-income countries or the effects after introduction of higher valency PCVs. High-quality, population-based surveillance of serotype-specific IPD rates is needed to monitor vaccine impact as more countries, including low-income countries, introduce PCVs and as higher valency PCVs are used.
Please see later in the article for the Editors' Summary
Editors’ Summary
Pneumococcal disease–a major cause of illness and death in children and adults worldwide–is caused by Streptococcus pneumoniae, a bacterium that often colonizes the nose and throat harmlessly. Unfortunately, S. pneumoniae occasionally spreads into the lungs, bloodstream, or covering of the brain, where it causes pneumonia, septicemia, and meningitis, respectively. These invasive pneumococcal diseases (IPDs) can usually be successfully treated with antibiotics but can be fatal. Consequently, it is better to avoid infection through vaccination. Vaccination primes the immune system to recognize and attack disease-causing organisms (pathogens) rapidly and effectively by exposing it to weakened or dead pathogens or to pathogen molecules that it recognizes as foreign (antigens). Because there are more than 90 S. pneumoniae variants or “serotypes,” each characterized by a different antigenic polysaccharide (complex sugar) coat, vaccines that protect against S. pneumoniae have to include multiple serotypes. Thus, the pneumococcal conjugate vaccine PCV7, which was introduced into the US infant immunization regimen in 2000, contains polysaccharides from the seven S. pneumoniae serotypes mainly responsible for IPD in the US at that time.
Why Was This Study Done?
Vaccination with PCV7 was subsequently introduced in several other high- and middle-income countries, and IPD caused by the serotypes included in the vaccine declined substantially in children and in adults (because of reduced bacterial transmission and herd protection) in the US and virtually all these countries. However, increases in IPD caused by non-vaccine serotypes occurred in some settings, presumably because of “serotype replacement.” PCV7 prevents both IPD caused by the serotypes it contains and carriage of these serotypes. Consequently, after vaccination, previously less common, non-vaccine serotypes can colonize the nose and throat, some of which can cause IPD. In July 2010, a World Health Organization expert consultation on serotype replacement called for a comprehensive analysis of the magnitude and variability of pneumococcal serotype replacement following PCV7 use to help guide the introduction of PCVs in low-income countries, where most pneumococcal deaths occur. In this pooled analysis of data from multiple surveillance sites, the researchers investigate serotype-specific changes in IPD after PCV7 introduction using a standardized approach.
What Did the Researchers Do and Find?
The researchers identified 21 databases that had data about the rate of IPD for at least 2 years before and 1 year after PCV7 introduction. They estimated whether changes in IPD rates had occurred after PCV7 introduction by calculating site-specific rate ratios–the observed IPD rate for each post-PCV7 year divided by the expected IPD rate in the absence of PCV7 extrapolated from the pre-PCV7 rate. Finally, they used a statistical approach (random effects meta-analysis) to estimate summary (pooled) rate ratios. For children under 5 years old, the overall number of observed cases of IPD in the first year after the introduction of PCV7 was about half the expected number; this reduction in IPD continued through year 7 after PCV7 introduction. Notably, the rate of IPD caused by the S. pneumonia serotypes in PCV7 decreased every year, but the rate of IPD caused by non-vaccine serotypes increased annually. By year 7, the number of cases of IPD caused by non-vaccine serotypes was 3-fold higher than expected, but was still smaller than the decrease in vaccine serotypes, thereby leading to the decrease in overall IPD. Finally, smaller decreases in overall IPD also occurred among adults but occurred later than in children 2 years or more after PCV7 introduction.
What Do These Findings Mean?
These findings show that consistent, rapid, and sustained decreases in overall IPD and in IPD caused by serotypes included in PCV7 occurred in children and thus support the use of PCVs. The small increases in IPD caused by non-vaccine serotypes that these findings reveal are likely to be the result of serotype replacement, but changes in antibiotic use and other factors may also be involved. These findings have several important limitations, however. For example, PCV7 is no longer made and extrapolation of these results to newer PCV10 and PCV13 formulations should be done cautiously. On the other hand, many of the serotypes causing serotype replacement after PCV7 are included in these higher valency vaccines. Moreover, because the data analyzed in this study mainly came from high-income countries, these findings may not be generalizable to low-income countries. Nevertheless, based on their analysis, the researchers make recommendations for the collection and analysis of IPD surveillance data that should allow valid interpretations of the effect of PCVs on IPD to be made, an important requisite for making sound policy decisions about vaccination against pneumococcal disease.
Additional Information
Please access these websites via the online version of this summary at
The US Centers for Disease Control and Prevention provides information for patients and health professionals on all aspects of pneumococcal disease and pneumococcal vaccination, including personal stories
Public Health England provides information on pneumococcal disease and on pneumococcal vaccines
The World Health Organization also provides information on pneumococcal vaccines
The not-for-profit Immunization Action Coalition has information on pneumococcal disease, including personal stories
MedlinePlus has links to further information about pneumococcal infections (in English and Spanish)
The International Vaccine Access Center at Johns Hopkins Bloomberg School of Public Health has more information on introduction of pneumococcal conjugate vaccines in low-income countries
PMCID: PMC3782411  PMID: 24086113
23.  The Minimal Important Difference in the 6-Minute Walk Test for Patients with Pulmonary Arterial Hypertension 
Rationale: Although commonly used as the primary outcome measure of clinical trials in pulmonary arterial hypertension (PAH), the minimal important difference (MID) of the 6-minute walk test (6MWT) has not been well defined for this population of patients.
Objectives: To estimate the MID in the 6MWT in patients with PAH.
Methods: Study subjects from the clinical trial of tadalafil in PAH, a 16-week, parallel-group, randomized clinical trial of patients who were treatment naive or on background therapy with an endothelin receptor antagonist, were eligible. 6MWT was performed using a standardized protocol. Distributional and anchor-based methods were used to estimate the MID; the latter method used the Physical Component Summary Score (PCS) of the Medical Outcomes Study 36-item short form (SF-36).
Measurements and Main Results: Four hundred five subjects were analyzed. Domains of the SF-36 were weakly to modestly associated with 6MWT. Change in the PCS of the SF-36 was most strongly associated with change in 6MWT (r = 0.40, P < 0.001) and thus was selected as the anchor for subsequent anchor-based analyses. Distributional analyses yielded estimates of the MID ranging from 25.1 to 38.5 m, whereas anchor-based analyses yielded an estimate of 38.6 m.
Conclusions: Using both distributional and anchor-based methods, the estimated consensus MID in the 6MWT for PAH is approximately 33 m. These results have important implications for (1) assessing treatment responses from clinical trials and metaanalyses of specific PAH therapy, and (2) sample size calculations for future study design.
PMCID: PMC3443803  PMID: 22723290
pulmonary hypertension; outcome measures; 6-minute walk test; minimal important difference
24.  Comparative Effectiveness and Safety of Medications for Type 2 Diabetes: An Update Including New Drugs and 2-Drug Combinations 
Annals of internal medicine  2011;154(9):602-613.
Given the increase in medications for type 2 diabetes mellitus, clinicians and patients need information about their effectiveness and safety to make informed choices.
To summarize the benefits and harms of metformin, second-generation sulfonylureas, thiazolidinediones, meglitinides, dipeptidyl peptidase-4 (DPP-4) inhibitors, and glucagon-like peptide-1 receptor agonists, as monotherapy and in combination, to treat adults with type 2 diabetes.
Data Sources
MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from inception through April 2010 for English-language observational studies and trials. The MEDLINE search was updated to December 2010 for long-term clinical outcomes.
Study Selection
Two reviewers independently screened reports and identified 140 trials and 26 observational studies of head-to-head comparisons of monotherapy or combination therapy that reported intermediate or long-term clinical outcomes or harms.
Data Extraction
Two reviewers following standardized protocols serially extracted data, assessed applicability, and independently evaluated study quality.
Data Synthesis
Evidence on long-term clinical outcomes (all-cause mortality, cardiovascular disease, nephropathy, and neuropathy) was of low strength or insufficient. Most medications decreased the hemoglobin A1c level by about 1 percentage point and most 2-drug combinations produced similar reductions. Metformin was more efficacious than the DPP-4 inhibitors, and compared with thiazolidinediones or sulfonylureas, the mean differences in body weight were about −2.5 kg. Metformin decreased low-density lipoprotein cholesterol levels compared with pioglitazone, sulfonylureas, and DPP-4 inhibitors. Sulfonylureas had a 4-fold higher risk for mild or moderate hypoglycemia than metformin alone and, in combination with metformin, had more than a 5-fold increased risk compared with metformin plus thiazolidinediones. Thiazolidinediones increased risk for congestive heart failure compared with sulfonylureas and increased risk for bone fractures compared with metformin. Diarrhea occurred more often with metformin than with thiazolidinediones.
Only English-language publications were reviewed. Some studies may have selectively reported outcomes. Many studies were small, were of short duration, and had limited ability to assess clinically important harms and benefits.
Evidence supports metformin as a first-line agent to treat type 2 diabetes. Most 2-drug combinations similarly reduce hemoglobin A1c levels, but some increased risk for hypoglycemia and other adverse events.
Primary Funding Source
Agency for Healthcare Research and Quality.
PMCID: PMC3733115  PMID: 21403054
25.  Population Specific and Up to Date Cardiovascular Risk Charts Can Be Efficiently Obtained with Record Linkage of Routine and Observational Data 
PLoS ONE  2013;8(2):e56149.
Only few countries have cohorts enabling specific and up-to-date cardiovascular disease (CVD) risk estimation. Individual risk assessment based on study samples that differ too much from the target population could jeopardize the benefit of risk charts in general practice. Our aim was to provide up-to-date and valid CVD risk estimation for a Swiss population using a novel record linkage approach.
Anonymous record linkage was used to follow-up (for mortality, until 2008) 9,853 men and women aged 25–74 years who participated in the Swiss MONICA (MONItoring of trends and determinants in CVD) study of 1983–92. The linkage success was 97.8%, loss to follow-up 1990–2000 was 4.7%. Based on the ESC SCORE methodology (Weibull regression), we used age, sex, blood pressure, smoking, and cholesterol to generate three models. We compared the 1) original SCORE model with a 2) recalibrated and a 3) new model using the Brier score (BS) and cross-validation.
Based on the cross-validated BS, the new model (BS = 14107×10−6) was somewhat more appropriate for risk estimation than the original (BS = 14190×10−6) and the recalibrated (BS = 14172×10−6) model. Particularly at younger age, derived absolute risks were consistently lower than those from the original and the recalibrated model which was mainly due to a smaller impact of total cholesterol.
Using record linkage of observational and routine data is an efficient procedure to obtain valid and up-to-date CVD risk estimates for a specific population.
PMCID: PMC3573036  PMID: 23457516

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